Section 2: Disorders of Immune-Mediated Injury

The term atopy implies a tendency to manifest asthma, rhinitis, urticaria, and atopic dermatitis alone or in combination, in association with the presence of allergen-specific IgE. However, individuals without an atopic background may also develop hypersensitivity reactions, particularly urticaria and anaphylaxis, associated with the presence of IgE. Since mast cells are key effector cells in allergic rhinitis and asthma, and the dominant effector in urticaria, anaphylaxis, and systemic mastocytosis, its developmental biology, activation pathway, product profile, and target tissues will be considered in the introduction to these clinical disorders. Dysregulation of mast cell development seen in mastocytosis will be covered in a separate chapter.

The binding of IgE to human mast cells and basophils, a process termed sensitization, prepares these cells for subsequent antigen-specific activation. The high-affinity Fc receptor for IgE, designated FcεRI, is composed of one α, one β, and two disulfide-linked γ chains, which together cross the plasma membrane seven times. The α chain is responsible for IgE binding, and the β and γ chains provide for signal transduction that follows the aggregation of the sensitized tetrameric receptors by polymeric antigen. The binding of IgE stabilizes the α chain at the plasma membrane, thus increasing the density of FcεRI receptors at the cell surface while sensitizing the cell for effector responses. This accounts for the correlation between serum IgE levels and the numbers of FcεRI receptors detected on circulating basophils. Signal transduction is initiated through the action of a Src family–related tyrosine kinase termed Lyn that is constitutively associated with the β chain. Lyn transphosphorylates the canonical immunoreceptor tyrosine-based activation motifs (ITAMs) of the β and γ chains of the receptor, resulting in recruitment of more active Lyn to the β chain and of Syk tyrosine kinase. The phosphorylated tyrosines in the ITAMs function as binding sites for the tandem src homology two (SH2) domains within Syk. Syk activates not only phospholipase Cγ, which associates with the linker of activated T cells at the plasma membrane, but also phosphatidylinositol 3-kinase to provide phosphatidylinositol-3,4,5-trisphosphate, which allows membrane targeting of the Tec family kinase Btk and its activation by Lyn. In addition, the Src family tyrosine kinase Fyn becomes activated after aggregation of IgE receptors and phosphorylates the adapter protein Gab2 that enhances activation of phosphatidylinositol 3-kinase. Indeed, this additional input is essential for mast cell activation, but it can be partially inhibited by Lyn, indicating that the extent of mast cell activation is in part regulated by the interplay between these Src family kinases. Activated phospholipase Cγ cleaves phospholipid membrane substrates to provide inositol-1,4,5-trisphosphate (IP₃) and 1,2-diacylglycerols (1,2-DAGs) so as to mobilize intracellular calcium and activate protein kinase C, respectively. The subsequent opening of calcium-regulated activated channels provides the sustained elevations of intracellular calcium required to recruit the mitogen-activated protein kinases, ERK, JNK, and p38 (serine/threonine kinases), which provide cascades to augment arachidonic acid release and to mediate nuclear translocation of transcription factors for various cytokines. The calcium ion–dependent activation of phospholipases cleaves membrane phospholipids to generate lysophospholipids, which, like 1,2-DAG, may facilitate the fusion of the secretory granule perigranular membrane with the cell membrane, a step that releases the membrane-free granules containing the preformed mast cell mediators.

The secretory granule of the human mast cell has a crystalline structure, unlike mast cells of lower species. IgE-dependent cell activation results in solubilization and swelling of the granule contents within the first minute of receptor perturbation; this reaction is followed by the ordering of intermediate filaments about the swollen granule, movement of the granule toward the cell surface, and fusion of the perigranular membrane with that of other granules and with the plasmalemma to form extracellular channels for mediator release while maintaining cell viability.

In addition to exocytosis, aggregation of FcεRI initiates two other pathways for generation of bioactive products, namely, lipid mediators and cytokines. The biochemical steps involved in expression of such cytokines as tumor necrosis factor α (TNF-α), interleukin (IL) 1, IL-6, IL-4, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), and others, including an array of chemokines, have not been specifically defined for mast cells. Inhibition studies of cytokine production (IL-1β, TNF-α, and IL-6) in mouse mast cells with cyclosporine or FK506 reveal binding to the ligand-specific immunophilin and attenuation of the calcium ion- and calmodulin-dependent serine/threonine phosphatase, calcineurin.

Lipid mediator generation (Fig. 345-1) involves translocation of calcium ion–dependent cytosolic phospholipase A₂ to the outer nuclear membrane, with subsequent release of arachidonic acid for metabolic processing by the distinct prostanoid and leukotriene pathways. The constitutive prostaglandin endoperoxide synthase-1 (PGHS-1/cyclooxygenase-1) and the de novo inducible PGHS-2 (cyclooxygenase-2) convert released arachidonic acid to the sequential intermediates, prostaglandins G₂ and H₂. The glutathione-dependent hematopoietic prostaglandin D₂ (PGD₂) synthase then converts PGH₂ to PGD₂, the predominant mast cell prostanoid. The PGD₂ receptor DP₁ is expressed by platelets, natural killer cells, dendritic cells, and epithelial cells, whereas DP₂ is expressed by T_H2 lymphocytes, innate lymphoid type 2 cells, eosinophils, and basophils. Mast cells also generate thromboxane A₂ (TXA₂), a short lived but powerful mediator that induces bronchoconstriction and platelet activation through the T prostanoid (TP) receptor.

For leukotriene biosynthesis, the released arachidonic acid is metabolized by 5-lipoxygenase (5-LO) in the presence of an integral nuclear membrane protein, 5-LO activating protein (FLAP). The calcium ion–dependent translocation of 5-LO to the nuclear membrane converts the arachidonic acid to the sequential intermediates, 5-hydroperoxyeicosatetraenoic acid (5-HPETE) and leukotriene (LT) A₄. LTA₄ is conjugated with reduced glutathione by LTC₄ synthase, an integral nuclear membrane protein homologous to FLAP. Intracellular LTC₄ is released by a carrier-specific export step for extracellular metabolism to the additional cysteinyl leukotrienes, LTD₄ and LTE₄, by the sequential removal of glutamic acid and glycine. Alternatively, cytosolic LTA₄ hydrolase converts some LTA₄ to the dihydroxy leukotriene LTB₄, which also undergoes specific export. Two receptors for LTB₄, BLT₁ and BLT₂, mediate chemotaxis of human neutrophils. Two receptors for the cysteinyl leukotrienes, CysLT₁ and CysLT₂, are present on smooth muscle of the airways and the microvasculature and on hematopoietic cells such as macrophages, eosinophils, and mast cells. Whereas the CysLT₁ receptor has a preference for LTD₄ and is blocked by the receptor antagonists in clinical use, the CysLT₂ receptor is equally responsive to LTD₄ and LTC₄, is unaffected by these antagonists, and is a negative regulator of the function of the CysLT₁ receptor. LTD₄, acting at CysLT₁ receptors, is the most potent known bronchoconstrictor, whereas LTE₄ induces a vascular leak and mediates the recruitment of eosinophils to the bronchial mucosa. Recently, GPR99, CysLT3 receptor, was identified as an LTE4 receptor. The lysophospholipid formed during the release of arachidonic acid from 1-O-alkyl-2-acyl-sn-glyceryl-3-phosphorylcholine can be acetylated in the second position to form platelet-activating factor (PAF). Serum levels of PAF correlated positively with the severity of anaphylaxis to peanut in a recent study, whereas the levels of PAF acetyl hydrolase (a PAF-degrading enzyme) were inversely related to the same outcome.

Unlike most other cells of bone marrow origin, mast cells circulate as committed progenitors lacking their characteristic secretory granules. These committed progenitors express c-kit, the receptor for stem cell factor (SCF). Unlike most other lineages, they retain and increase c-kit expression with maturation. The SCF interaction with c-kit is an absolute requirement for the development of constitutive tissue mast cells residing in skin and connective tissue sites and for the accumulation of mast cells at mucosal surfaces during T_H2-type immune responses. Several T cell-derived cytokines (IL-3, IL-4, IL-5, and IL-9) can potentiate SCF-dependent mast cell proliferation and/or survival in vitro in mice and humans. Indeed, mast cells are absent from the intestinal mucosa in clinical T cell deficiencies, but are present in the submucosa. Based on the immunodetection of secretory granule neutral proteases, mast cells in the lung parenchyma and intestinal mucosa selectively express tryptase, and those in the intestinal and airway submucosa, perivascular spaces, skin, lymph nodes, and breast parenchyma express tryptase, chymase, and carboxypeptidase A (CPA). In the mucosal epithelium of severe asthmatics, mast cells can express tryptase and CPA without chymase. The secretory granules of mast cells selectively positive for tryptase exhibit closed scrolls with a periodicity suggestive of a crystalline structure by electron microscopy, whereas the secretory granules of mast cells with multiple proteases are scroll-poor, with an amorphous or lattice-like appearance.

Mast cells are distributed at cutaneous and mucosal surfaces and in submucosal tissues about venules and could influence the entry of foreign substances by their rapid response capability (Fig. 345-2). Upon stimulus-specific activation and secretory granule exocytosis, histamine and acid hydrolases are solubilized, whereas the neutral proteases, which are cationic, remain largely bound to the anionic proteoglycans, heparin and chondroitin sulfate E, with which they function as a complex. Histamine and the various lipid mediators (PGD₂, LTC₄/D₄/E₄, PAF) alter venular permeability, thereby allowing influx of plasma proteins such as complement and immunoglobulins, whereas LTB₄ mediates leukocyte–endothelial cell adhesion and subsequent directed migration (chemotaxis). The accumulation of leukocytes and plasma opsonins facilitates defense of the microenvironment. The inflammatory response can also be detrimental, as in asthma, where the smooth-muscle constrictor activity of the cysteinyl leukotrienes is evident and much more potent than that of histamine.

The cellular component of the mast cell–mediated inflammatory response is augmented and sustained by cytokines and chemokines. IgE-dependent activation of human skin mast cells in situ elicits TNF-α production and release, which in turn induces endothelial cell responses favoring leukocyte adhesion. Similarly, activation of purified human lung mast cells or cord blood–derived cultured mast cells in vitro results in substantial production of proinflammatory (TNF-α) and immunomodulatory cytokines (IL-4, IL-5, IL-13) and chemokines. Bronchial biopsy specimens from patients with asthma reveal that mast cells are immunohistochemically positive for IL-4 and IL-5, but that the predominant localization of IL-4, IL-5, and GM-CSF is to T cells, defined as T_H2 by this profile. IL-4 modulates the T cell phenotype to the T_H2 subtype, determines the isotype switch to IgE (as does IL-13), and upregulates FcεRI-mediated expression of cytokines by mast cells based on in vitro studies.

An immediate and late cellular phase of allergic inflammation can be induced in the skin, nose, or lung of some allergic humans with local allergen challenge. The immediate phase in the nose involves pruritus and watery discharge; in the lung, it involves bronchospasm and mucus secretion; and in the skin, it involves a wheal-and-flare response with pruritus. The reduced nasal patency, reduced pulmonary function, or erythema with swelling at the skin site in a late-phase response at 6–8 h is associated with biopsy findings of infiltrating and activated T_H2 cells, eosinophils, basophils, and some neutrophils. The progression from early mast cell activation to late cellular infiltration has been used as an experimental surrogate of rhinitis or asthma. However, in asthma, there is an intrinsic hyperreactivity of the airways independent of the associated inflammation. Moreover, early- and late-phase responses (at least in the lung) are far more sensitive to blockade of IgE-dependent mast cell activation (or actions of histamine and cysteinyl leukotrienes) than are spontaneous or virally induced asthma exacerbations.

Consideration of the mechanism of immediate-type hypersensitivity diseases in the human has focused largely on the IgE-dependent recognition of otherwise innocuous substances. A region of chromosome 5 (5q23-31) contains genes implicated in the control of IgE levels including IL-4 and IL-13, as well as IL-3 and IL-9, which are involved in mucosal mast cell hyperplasia, and IL-5 and GM-CSF, which are central to eosinophil development and their enhanced tissue viability. Genes with linkage to the specific IgE response to particular allergens include those encoding the major histocompatibility complex (MHC) and certain chains of the T cell receptor (TCR-αδ). The complexity of atopy and the associated diseases includes susceptibility, severity, and therapeutic responses, each of which is among the separate variables modulated by both innate and adaptive immune stimuli.

The induction of allergic disease requires sensitization of a predisposed individual to a specific allergen. The greatest propensity for the development of atopic allergy occurs in childhood and early adolescence. The allergen is processed by antigen-presenting cells of the monocytic lineage (particularly dendritic cells) located throughout the body at surfaces that contact the outside environment, such as the nose, lungs, eyes, skin, and intestine. These antigen-presenting cells present the epitope-bearing peptides via their MHC to T helper cells and their subsets. The T cell response depends both on cognate recognition and on the cytokine microenvironment provided by the antigen-presenting dendritic cells, with IL-4 directing a T_H2 subset, interferon (IFN) γ a T_H1 profile, and IL-6 with transforming growth factor β (TGF-β) a T_H17 subset. Allergens not only present antigenic epitopes via dendritic cells but also contain pattern recognition ligands that facilitate the immune response by direct initiation of cytokine generation from innate cell types such as basophils, mast cells, eosinophils, and others. The T_H2 response is associated with activation of specific B cells that can also present allergens or that transform into plasma cells for antibody production. Synthesis and release into the plasma of allergen-specific IgE results in sensitization of FcεR1-bearing cells such as mast cells and basophils, which become activated on exposure to the specific allergen. In certain diseases, including those associated with atopy, the monocyte and eosinophil populations can express a trimeric FcεR1, which lacks the β chain, and yet respond to its aggregation. An additional recently recognized class of c-kit-expressing innate cells (termed group 2 innate lymphoid cells of ILC2) can generate large quantities of IL-5 and IL-13 during antihelminth responses, are prominent in nasal polyps from humans, and contribute to inflammation in allergic diseases.

DEFINITION OF URTICARIA AND ANGIOEDEMA

Urticaria and angioedema represent the same pathophysiologic process occurring at different levels of the skin. Urticaria involves dilation of vascular structures in the superficial dermis, while angioedema originates from the deeper dermis and subcutaneous tissues. Not surprisingly they often appear together, with roughly 40% of patients reporting both, and affect >20% of the population at sometime during their lifespan. Urticaria can occur on any area of the body as well-circumscribed wheals with erythematous raised serpiginous borders and blanched centers that may coalesce to become giant wheals. Urticarial lesions last for <24 h, frequently migrate around the body, leave no bruising or scarring and are intensely pruritic. Angioedema is marked by dramatic swelling with more pain than pruritus and minimal erythema, which may develop with a pruritic prodrome and takes hours to days to resolve. Acute urticaria and/or angioedema are episodes that occur for <6 weeks’ duration, whereas attacks persisting >6 weeks are designated chronic.

Predisposing Factors and Etiology of Urticaria and Angioedema

Acute or chronic urticaria and/or angioedema can occur at any point in the lifespan with the third to fifth decade the most common for chronic. Women are affected more often than men with a slight predominance for those with a history of atopy. Acute urticaria is most often the result of exposure to a food, environmental or drug allergen or viral infection while chronic urticaria is often idiopathic.

The classification of urticaria-angioedema presented in Table 345-1 focuses on the different mechanisms for eliciting clinical disease and can be useful for differential diagnosis.

Additional etiologies include physical stimuli such as cold, heat, solar rays, exercise, and mechanical irritation. The physical urticarias can be distinguished by the precipitating event and other aspects of the clinical presentation. Dermographism, which occurs in 1–4% of the population, is defined by the appearance of a linear wheal with surrounding erythema at the site of a brisk stroke with a firm object (Fig. 345-3). Dermographism has a prevalence that peaks in the second to third decades. It is not influenced by atopy and has a duration generally of <5 years. Pressure urticaria, which often accompanies chronic idiopathic urticaria, presents in response to a sustained stimulus such as a shoulder strap or belt, running (feet), or manual labor (hands). Cholinergic urticaria is distinctive in that the pruritic wheals are of small size (1–2 mm) and are surrounded by a large area of erythema; attacks are precipitated by fever, a hot bath or shower, or exercise and are presumptively attributed to a rise in core body temperature. Exercise-induced anaphylaxis can be precipitated by exertion alone or can be dependent on prior food ingestion. There is an association with the presence of IgE specific for α-5 gliadin, a component of wheat. The clinical presentation can be limited to flushing, erythema, and pruritic urticaria but may progress to angioedema of the face, oropharynx, larynx, or intestine or to vascular collapse; it is distinguished from cholinergic urticaria by presenting with wheals of conventional size and by not occurring with fever or a hot bath. Cold urticaria is local at body areas exposed to low ambient temperature or cold objects but can progress to vascular collapse with immersion in cold water (swimming). Solar urticaria is subdivided into six groups by the response to specific portions of the light spectrum. Vibratory angioedema may occur after years of occupational exposure or can be idiopathic; it may be accompanied by cholinergic urticaria. Other rare forms of physical allergy, always defined by stimulus-specific elicitation, include local heat urticaria, aquagenic urticaria from contact with water of any temperature (sometimes associated with polycythemia vera), and contact urticaria from direct interaction with some chemical substance (such as latex).

Isolated Angioedema

Angioedema without urticaria can be idiopathic or due to the generation of bradykinin in the setting of C1 inhibitor (C1INH) deficiency that may be inborn as an autosomal dominant characteristic or may be acquired through the appearance of an autoantibody in the setting of malignancy. The angiotensin-converting enzyme (ACE) inhibitors can provoke a similar clinical presentation in 0.2–0.7% of exposed patients due to delayed degradation of bradykinin. Black race, organ transplant, female gender, smoking, and increasing age are known risk factors for ACE-inhibitor related angioedema.

CLINICAL PRESENTATION AND EPIDEMIOLOGY OF URTICARIA AND ANGIOEDEMA

Urticarial eruptions are distinctly pruritic, may involve any area of the body from the scalp to the soles of the feet, and appear in crops of 12- to 36-h duration, with old lesions fading as new ones appear. Most of the physical urticarias (cold, cholinergic, dermatographism) are an exception, with individual lesions lasting <2 h. Neither urticaria nor angioedema lesions are symmetric or dependent in distribution. The most common sites for angioedema are often periorbital and perioral. Angioedema of the upper respiratory tract may be life-threatening due to transient laryngeal obstruction, whereas gastrointestinal involvement may present with abdominal colic, with or without nausea and vomiting, and can result in unnecessary surgical intervention. No residual scaring occurs with either urticaria or angioedema unless there is an underlying vasculitic process.

The pathology is characterized by edema of the superficial dermis in urticaria and of the subcutaneous tissue and deep dermis in angioedema. Collagen bundles in affected areas are widely separated, and the venules are sometimes dilated. Any perivenular infiltrate consists of lymphocytes, monocytes, eosinophils, and neutrophils that are present in varying combination and numbers.

The best evidence for IgE- and mast cell–involvement in urticaria and angioedema is cold urticaria. Cryoglobulins or cold agglutinins are present in up to 5% of these patients. Immersion of an extremity in an ice bath precipitates angioedema of the distal portion with urticaria at the air interface within minutes of the challenge. Histologic studies reveal marked mast cell degranulation with associated edema of the dermis and subcutaneous tissues. Elevated levels of histamine have been found in the plasma of venous effluent and in the fluid of suction blisters at experimentally induced lesional sites in patients with cold urticaria, dermographism, pressure urticaria, vibratory angioedema, light urticaria, and heat urticaria. By ultrastructural analysis, the pattern of mast cell degranulation in cold urticaria resembles an IgE-mediated response with solubilization of granule contents, fusion of the perigranular and cell membranes, and discharge of granule contents, whereas in a dermatographic lesion, there is additional superimposed zonal (piecemeal) degranulation. Elevations of plasma histamine levels with biopsy-proven mast cell degranulation have also been demonstrated with generalized attacks of cholinergic urticaria.

Up to 45% of patients with chronic urticaria have an autoimmune cause for their disease including autoantibodies to IgE or to the α chain of FcεRI. In some patients, autologous serum injected into their own skin can induce a wheal-and-flare reaction involving mast cell activation. The presence of these antibodies can also be recognized by their capacity to release histamine or induce activation markers such as CD63 or CD203 on basophils. An association with antibodies to microsomal peroxidase and/or thyroglobulin has been observed with both clinically significant Hashimoto’s thyroiditis as well as a euthyroid state. In vitro studies reveal that these autoantibodies can mediate basophil degranulation with enhancement by serum as a source of the anaphylatoxic fragment, C5a.

The urticaria and angioedema associated with classic serum sickness or with hypocomplementemic cutaneous necrotizing angiitis (urticarial vasculitis) are believed to be immune-complex diseases. Reactions to mast cell granule–releasing agents (opioids, contrast media) and to non-steroidal anti-inflammatory drugs are most often limited to urticaria and/or angioedema, but may be systemic.

Hereditary angioedema (HAE) is a fully penetrant, autosomal dominant disease due to a mutation in the SERPING1 gene leading to a deficiency of C1INH (type 1) in about 85% of patients or to a dysfunctional protein (type 2) in the remainder affecting 1:30,000–80,000 in the general population. A third less common type of HAE has been described in which C1INH function is normal, and the causal lesion is a mutant form of factor XII, which leads to generation of excessive bradykinin. C1INH deficiency can also develop in a sporadic acquired form as a result of excessive consumption of C1INH due either to formation of immune complexes or to the generation of an autoantibody directed to C1INH in the setting of lymphoproliferative disease. C1INH blocks the catalytic function of activated factor XII (Hageman factor) and of kallikrein, as well as the C1r/C1s components of C1, with the common result of degrading bradykinin. During clinical attacks of angioedema, C1INH function or levels fall, patients develop elevated plasma levels of bradykinin leading to angioedema and excessive activation of C1 results in a decline in C4 and C2 levels.

The use of ACE inhibitors results in impaired bradykinin degradation and explains the angioedema that occurs idiosyncratically in ACE inhibitor-exposed patients with a normal C1INH. Bradykinin-mediated angioedema, whether caused by ACE inhibitors or by C1INH deficiency, is noteworthy for the conspicuous absence of concomitant urticaria or pruritus, the frequent involvement of the gastrointestinal tract, and the duration of symptoms >24 h.

DIAGNOSIS OF URTICARIA AND ANGIOEDEMA

The classification of urticarial and angioedematous states as presented in Table 345-1 in terms of duration can facilitate identification of possible mechanisms. History alone of self-limited urticarial and/or angioedema episodes can be sufficient to make a diagnosis in the setting of acute disease triggered by drug, environmental or food allergen with history-directed confirmatory skin testing or assay for serum allergen-specific IgE. Direct reproduction of the lesion in physical urticarias is particularly valuable because it so often establishes the cause of the lesion. Even with chronic urticaria/angioedema, initial diagnostic testing should be limited and expanded testing guided by history. Complete blood count with assessment for eosinophilia, erythrocyte sedimentation rate and thyroid stimulation hormone level are recommended by consensus guidelines even though the vast majority of chronic urticaria is associated with no laboratory abnormality. Urticarial lesions that last longer than 36 h result in scarring and are reported as painful and not pruritic warrant biopsy to evaluate for cellular infiltration, nuclear debris, and fibrinoid necrosis of the venules consistent with urticarial vasculitis. Chronic angioedema without urticaria warrants assessment of complement levels. Concomitant flushing and hyperpigmented papules that urticate with stroking in the absence of angioedema raise the question of mastocytosis. An appropriate travel history should trigger an evaluation for parasites.

The diagnosis of HAE is suggested not only by family history but also by the lack of pruritus and of urticarial lesions, the prominence of recurrent gastrointestinal attacks of colic, and episodes of laryngeal edema. Laboratory diagnosis depends on demonstrating a deficiency of C1INH antigen (type 1) or a nonfunctional protein (type 2) by a catalytic inhibition assay. While levels of C1 are normal, its substrates, C4 and C2, are chronically depleted and fall further during attacks due to the activation of additional C1. Patients with the acquired forms of C1INH deficiency have the same clinical manifestations but differ in the lack of a familial element. Furthermore, their sera exhibit a reduction of C1 function and C1q protein as well as C1INH, C4, and C2. Inborn C1INH deficiency and ACE inhibitor–elicited angioedema are associated with elevated levels of bradykinin. Lastly, type 3 HAE is associated with normal levels of complement proteins and a factor XII gene mutation.

TREATMENT OF URTICARIA AND ANGIOEDEMA

DEFINITION OF ALLERGIC RHINITIS

Rhinitis is characterized by sneezing; rhinorrhea; obstruction of the nasal passages; conjunctival, nasal, and pharyngeal itching; and lacrimation and can be classified as allergic or non-allergic. A clinical history of rhinitis symptoms occurring in a temporal relationship to allergen exposure and documentation of sensitization to an environmental allergen are required for a diagnosis of allergic rhinitis. Although commonly seasonal due to elicitation by airborne pollens, it can be perennial in an environment of chronic exposure to house dust mites, animal danders, or insect (cockroach) products. The overall prevalence in North America has increased in the past 20 years and is 10–30%, with the peak prevalence of >30% occurring in the fifth decade.

PREDISPOSING FACTORS AND ETIOLOGY OF ALLERGIC RHINITIS

Allergic rhinitis generally occurs in atopic individuals, often in association with atopic dermatitis, food allergy, urticaria, and/or asthma (Chap. 281). Up to 50% of patients with allergic rhinitis manifest asthma, whereas 70–80% of individuals with asthma and 80% of individuals with chronic bilateral sinusitis experience allergic rhinitis. Female sex, particulate air pollution exposure, and maternal tobacco smoking increase the risk of developing allergic rhinitis over the life span.

Trees, grasses, and weeds that depend on wind rather than insects for pollination produce sufficient quantities of pollen suitable for wide distribution by air currents to elicit seasonal allergic rhinitis. The dates of pollination of these species historically varied little from year to year in a particular locale, but may be quite different in another climate. In the temperate areas of North America, trees typically pollinate from March through May, grasses in June and early July, and ragweed from mid-August to early October. Molds, which are widespread in nature because they occur in soil or decaying organic matter, propagate spores in a pattern that depends on climatic conditions. Climate change is impacting these patterns with early tree pollination and prolonged ragweed season with the delay of the first frost. Perennial allergic rhinitis occurs in response to allergens that are present throughout the year, including animal dander, cockroach-derived proteins, mold spores, or dust mites such as Dermatophagoides farinae and Dermatophagoides pteronyssinus. Dust mites are scavengers of human skin and excrete cysteine protease allergens in their feces. In up to 40% of patients with perennial rhinitis, no clear-cut allergen can be demonstrated as causative.

PATHOPHYSIOLOGY AND MANIFESTATIONS OF ALLERGIC RHINITIS

Episodic rhinorrhea, sneezing, obstruction of the nasal passages with lacrimation, and pruritus of the conjunctiva, nasal mucosa, and oropharynx are the hallmarks of allergic rhinitis. The nasal mucosa is pale and boggy, the conjunctiva congested and edematous, and the pharynx generally unremarkable. Swelling of the turbinates and mucous membranes with obstruction of the sinus ostia and eustachian tubes precipitates secondary infections of the sinuses and middle ear, respectively. A growing number of patients with seasonal allergic rhinitis demonstrate pollen-associated food allergen syndrome characterized by oropharyngeal pruritus and/or mild swelling following the ingestion of raw plant-based foods which contain cross-reacting pollen-related allergens.

Nasal polyps, representing mucosal protrusions containing edema fluid with variable numbers of eosinophils and degranulated mast cells, can increase obstructive symptoms with anosmia as a defining feature and can concurrently arise within the nasopharynx or sinuses. Atopy is not a risk factor for nasal polyps, which instead may occur in the setting of cystic fibrosis, aspirin-exacerbated respiratory disease characterized by the triad of asthma, rhinosinusitis, and respiratory reactions to all cyclooxygenase-1 inhibitors, and in patients with chronic staphylococcal colonization, which produces superantigens leading to an intense T_H2 inflammatory response.

The nose presents a large mucosal surface area through the folds of the turbinates and serves to adjust the temperature and moisture content of inhaled air and to filter out particulate materials >10 μm in size by impingement in a mucous blanket; ciliary action moves the entrapped particles toward the pharynx. Entrapment of pollen and digestion of the outer coat by mucosal enzymes such as lysozymes release protein allergens. The initial interaction occurs between the allergen and intraepithelial mast cells and then proceeds to involve deeper perivenular mast cells, both of which are sensitized with specific IgE. During the symptomatic season when the mucosae are already swollen and hyperemic, there is enhanced adverse reactivity to the seasonal pollen as well as irritants such as tobacco smoke and fragrances. Biopsy specimens of nasal mucosa during seasonal rhinitis show submucosal edema with infiltration by eosinophils, along with some basophils and neutrophils.

The mucosal surface fluid contains IgA that is present because of its secretory piece and also IgE, which apparently arrives by diffusion from plasma cells in proximity to mucosal surfaces. IgE fixes to mucosal and submucosal mast cells, and the intensity of the clinical response to inhaled allergens is quantitatively related to the naturally occurring pollen dose. In sensitive individuals, the introduction of allergen into the nose is associated with sneezing, nasal obstruction, and discharge, and the fluid contains histamine, PGD₂, and leukotrienes. Thus the mast cells of the nasal mucosa and submucosa generate and release mediators through IgE-dependent reactions that are capable of producing tissue edema and eosinophilic infiltration.

DIAGNOSIS OF ALLERGIC RHINITIS

The diagnosis of seasonal allergic rhinitis depends largely on an accurate history of occurrence coincident with the pollination of the offending weeds, grasses, or trees. The continuous character of perennial allergic rhinitis due to contamination of the home or place of work makes historic analysis difficult, but there may be variability in symptoms that can be related to exposure to animal dander, dust mite and/or cockroach allergens, fungal spores, or work-related allergens such as latex. Patients with perennial rhinitis commonly develop the problem in adult life, and manifest nasal congestion and a postnasal discharge, often associated with thickening of the sinus membranes demonstrated by radiography. Perennial nonallergic rhinitis with eosinophilia syndrome (NARES) occurs in the middle decades of life and is characterized by nasal obstruction, anosmia, chronic sinusitis, and prominent eosinophilic nasal discharge in the absence of allergen sensitization. The term vasomotor rhinitis or perennial nonallergic rhinitis designates a condition of enhanced reactivity of the nasopharynx in which a symptom complex resembling perennial allergic rhinitis occurs with nonspecific stimuli, including chemical odors, temperature and humidity variations, and position changes but occurs without tissue eosinophilia or an allergic etiology. Other entities to be excluded are structural abnormalities of the nasopharynx; exposure to irritants; gustatory rhinitis associated with cholinergic activation that occurs while eating or ingesting alcohol; hypothyroidism; upper respiratory tract infection; pregnancy with prominent nasal mucosal edema; prolonged topical use of α-adrenergic agents in the form of nasal sprays (rhinitis medicamentosa); and the use of certain systemic agents such as β-adrenergic antagonists, ACE inhibitors, direct vasodilators (hydralazine), α1-adrenergic receptor antagonists, estrogens, progesterone, NSAIDS, gabapentin, phosphodiesterase-5 inhibitors, and psychotropics (Risperidone, chlorpromazine, amitriptyline).

The nasal secretions of allergic patients are rich in eosinophils, and a modest peripheral eosinophilia can be observed. Local or systemic neutrophilia implies infection. Total serum IgE is frequently elevated, but the demonstration of immunologic specificity for IgE is critical to an etiologic diagnosis. A skin test by the intracutaneous route (puncture or prick) with the allergens of interest provides a rapid and reliable approach to identifying allergen-specific IgE that has sensitized cutaneous mast cells. A positive intracutaneous skin test with 1:10–1:20 weight/volume of extract has a high predictive value for the presence of allergy. An intradermal test with a 1:500–1:1000 dilution of 0.05 mL may follow if indicated by history when the intracutaneous test is negative, but while more sensitive, it is less reliable due to the reactivity of some asymptomatic individuals at the test dose.

Newer methodology for detecting total IgE, including the development of enzyme-linked immunosorbent assays (ELISA) employing anti-IgE bound to either a solid-phase or a liquid-phase particle, provides rapid and cost-effective determinations. Measurements of specific anti-IgE in serum are obtained by its binding to an allergen and quantitation by subsequent uptake of labeled anti-IgE. As compared to the skin test, the assay of specific IgE in serum is less sensitive but has high specificity.

TREATMENT OF ALLERGIC RHINITIS

DEFINITION

Anaphylaxis is a potentially life-threatening systemic allergic reaction involving one or more organ systems that typically occurs within seconds to minutes of exposure to the anaphylactic trigger, most often a drug, food, or hymenoptera sting. Other triggers of anaphylaxis include radiocontrast administration or latex exposure. The term “anaphylaxis” was first described in 1902 by Charles Richet and Paul Portier who attempted to immunize dogs against sea anemone toxin in the same way Pasteur was able to vaccinate individuals against the smallpox virus. To their surprise, repeated administration of small, sub-lethal doses of sea anemone toxin reliably induced acute-onset death when re-administered 2–3 weeks after initial “vaccination” to the toxin. The phenomenon was termed ana (anti)-phylaxis (“protection or guarding”) because vaccination with anemone toxin resulted in the opposite intended immune effect. Charles Richet was awarded the Nobel Prize in Physiology or Medicine in 1913 for this work which led to further insights into hypersensitivity and mast cell biology.

Clinical Manifestations

While 80–90% of anaphylactic episodes are uniphasic, about 10–20% of cases are biphasic in which anaphylactic symptoms return about an hour or longer after resolution of initial symptoms. Anaphylactic reactions are particularly dangerous when hypotension or hypoxia occurs, leading potentially to cardiovascular collapse or respiratory failure, respectively. There may be upper or lower airway obstruction or both. Laryngeal edema may be experienced as a “lump” in the throat, hoarseness, or stridor, whereas bronchial obstruction is associated with a feeling of tightness in the chest and/or audible wheezing. Patients with underlying asthma are predisposed to severe involvement of the lower airways and increased mortality associated with anaphylaxis. In fatal cases with clinical bronchial obstruction, the lungs show marked hyperinflation on gross and microscopic examination. The microscopic findings in the bronchi, however, are limited to luminal secretions, peribronchial congestion, submucosal edema, and eosinophilic infiltration, and the acute emphysema is attributed to intractable bronchospasm that subsides with death. Angioedema resulting in death by mechanical obstruction occurs in the epiglottis and larynx; however, the process also is evident in the hypopharynx and to some extent in the trachea. On microscopic examination, there is wide separation of the collagen fibers and the glandular elements; vascular congestion and eosinophilic infiltration also are present. Patients dying of vascular collapse without antecedent hypoxia from respiratory insufficiency have visceral congestion with a presumptive loss of intravascular fluid volume. The associated electrocardiographic abnormalities, with or without infarction, in some patients may reflect a primary cardiac event mediated by mast cells (which are prominent near the coronary vessels) or may be secondary to a critical reduction in blood volume.

Gastrointestinal manifestations represent another severe presentation of anaphylaxis, and include nausea, vomiting, crampy abdominal pain, and/or fecal incontinence. Angioedema of the bowel wall may also cause sufficient intravascular volume depletion to precipitate cardiovascular collapse.

Cutaneous manifestations are among the most common presentations of anaphylaxis (>90% of cases). Symptoms include urticarial eruptions, flushing with diffuse erythema, and/or a feeling of generalized warmth. Urticarial eruptions are intensely pruritic and may be localized or disseminated. They may coalesce to form giant hives but seldom persist beyond 48 h.

PREDISPOSING FACTORS AND ETIOLOGY

Because the most dangerous manifestations of anaphylaxis involve the cardiovascular and/or respiratory systems, preexisting asthma and underlying cardiovascular disease could lead to more rapid decompensation from anaphylaxis. Atopy is not generally thought to be a risk factor for anaphylaxis from drug reactions or hymenoptera stings, but is associated with radiocontrast sensitivity, exercise-induced anaphylaxis, idiopathic anaphylaxis, and allergy to foods or latex. Severe hymenoptera-induced anaphylaxis (generally with prominent hypotension) can be a presenting feature of underlying systemic mastocytosis. Hymenoptera allergy is also more likely in patients whose occupations (i.e., beekeepers, trash haulers, and landscape workers) place them in regular proximity to stinging insects. Most commonly, allergen-induced cross-linking of IgE-bound FcεRI receptors on mast cells and basophils initiates the signal transduction events leading to hypersensitivity syndromes including anaphylaxis. The generation of allergen-specific IgE is the end result of sensitization via the adaptive immune system. The mechanisms underlying sensitization are beyond the scope of this topic; however, environmental factors, innate immune responses, and cytokines are among the many variables leading to antigen-specific IgE production by B cells and plasma cells. IgE-mediated drug allergies are most common with antibiotics and certain chemotherapy drugs, though theoretically, they can occur with almost any medication. As is the case with environmental allergies, repeated exposure to the allergy-causing antigen is an important risk factor to keep in mind when evaluating patients with anaphylaxis. In the case of allergy to carboplatin, the incidence of hypersensitivity is 27% in patients who have had ≥7 lifetime infusions and as high as 46% in patients who have had ≥15 lifetime infusions. Similarly, patients with cystic fibrosis have a relatively high incidence of allergic reactions to IV antibiotics that they receive periodically to treat exacerbations of bronchiectasis. Drugs can also function as haptens that form immunogenic conjugates with host proteins. The conjugating hapten may be the parent compound, a nonenzymatically derived storage product, or a metabolite formed in the host. Recombinant biologics can also induce the formation of IgE against the proteins or against glycosylated structures that serve as immunogens. More recently, outbreaks of anaphylaxis to the EGFR antibody, cetuximab, were reported in association with elevated titers of serum IgE to alpha-1,3-galactose (alpha-gal), an oligosaccharide found in non-primate mammals. Cetuximab is derived from a mouse cell line expressing a transferase that tags the Fab’ portion of the cetuximab heavy chain with alpha-gal. Interestingly, patients with a history of multiple bites from Amblyomma americanum ticks commonly found in the Carolinas, Arkansas, and Tennessee are more likely to have anti-alpha-gal IgE as compared to control patients living outside those states. Such individuals who become sensitized to alpha-gal can develop episodes of delayed anaphylaxis to beef, lamb, and pork.

PATHOPHYSIOLOGY

Many of the important early mediators of anaphylaxis are derived from mast cells, basophils, and eosinophils. Mast cells and basophils contain preformed granules comprised of histamine, proteases (tryptase, chymase), proteoglycans (heparin, chondroitin sulfate), and TNF-α, which are rapidly released into surrounding tissue upon cell activation, a process known as degranulation. Mast cells, basophils, and eosinophils are also sources of arachidonic acid-derived products which include cysteinyl leukotrienes, prostaglandins, and platelet activating factor (PAF). Histamine release results in flushing, urticaria, pruritus, and, in high concentrations, hypotension and tachycardia. Cysteinyl leukotrienes and prostaglandin D₂ cause bronchoconstriction and increased microvascular permeability. Prostaglandin D₂ causes cutaneous flushing, and attracts eosinophils and basophils to the site of mast cell activation. Serum PAF levels correlate with anaphylaxis severity and are inversely proportional to the constitutive level of PAF acetylhydrolase, which is necessary for PAF inactivation. Tryptase and chymase can activate complement and coagulation pathways. Activation of these pathways results in production of the anaphylotoxins, C3a and C5a, and activation of the kallikrein-kinin system which regulates blood pressure and vascular permeability. The actions of these anaphylactic mediators are likely additive or synergistic at the target tissues.

Non-IgE-mediated reactions to certain drugs (which may occur upon the first exposure) can mimic the pathophysiology of IgE-dependent anaphylaxis due to a similar profile of mediators. For example, paclitaxel is a chemotherapy agent derived from yew tree bark and needles that requires polyethoxylated castor oil (Cremophor) to be solubilized into aqueous solution. Cremophor directly activates the complement cascade, resulting in complement-dependent induced histamine release from mast cells and basophils. A version of paclitaxel that is solubilized by being bound to albumin nanoparticles, Abraxane, has a far lower rate of hypersensitivity, especially for patients who have had infusion reactions to Cremophor-solubilized paclitaxel. Reactions to radiocontrast and vancomycin are other examples of non-IgE-mediated hypersensitivity. Opiates and NSAIDs are other drug categories that can have similar adverse reactions.

DIAGNOSIS

The diagnosis of an anaphylactic reaction depends primarily on a history revealing the onset of symptoms and signs within seconds to minutes after the putative trigger is encountered. An exception is delayed anaphylaxis to meats in alpha-gal sensitized patients. Every attempt to identify the specific cause or causes should be made so as to minimize the risk of recurrent anaphylaxis. If a particular drug or food is suspected, skin or serum specific IgE testing is useful to confirm clinical suspicions. If a specific trigger cannot be identified, a workup of underlying atopic diatheses may be useful to identify risk factors that could play a potential contributory role. In the acute setting, laboratory biomarkers of mast cell degranulation may be useful to document the severity of an anaphylactic episode. The most obvious serum biomarker to assay, histamine, has an extremely short half-life with a measurable time-window that expires <1 h from the onset of anaphylaxis. A more practical and useful biomarker is serum tryptase which peaks 60–90 min after the onset of anaphylaxis and can be measured as long as 5 h after the onset of anaphylaxis. It may be useful to follow-up an elevated tryptase measurement in the acute setting with another measurement when the patient is clinically stable to establish a baseline reference. An elevated baseline tryptase level may warrant further workup for mastocytosis, especially if the presenting reaction occurred in the setting of hymenoptera sting.

TREATMENT

Early recognition of an anaphylactic reaction is mandatory since severe, even fatal, complications, can occur within minutes after symptoms first appear. The treatment of first choice is intramuscular administration of 0.3–0.5 mL of 1:1000 (1 mg/mL) epinephrine, with repeated doses at 5–20 min intervals as needed for a severe reaction. The failure to use epinephrine within the first 20 min of symptoms is a risk factor for poor clinical outcomes in various studies of anaphylaxis. Another important variable that may affect anaphylaxis survival is body posture, as an upright or sitting posture may lead to the “empty heart syndrome” in which there is insufficient venous return to the heart from sudden onset hypotension secondary to intravascular volume depletion. Epinephrine can further accelerate empty heart syndrome due to its chronotropic effects. For this reason, it is recommended that patients who suffer from anaphylaxis be placed in the supine position before receiving epinephrine. IV fluids and vasopressor agents may be administered in the acute medical setting if intractable hypotension occurs. Epinephrine provides both α- and β-adrenergic effects, resulting in vasoconstriction, bronchial smooth-muscle relaxation, and attenuation of enhanced venular permeability. Beta blockers may attenuate this response; therefore, an alternative anti-hypertensive may be considered in patients at high risk of needing emergency epinephrine. Oxygen alone via a nasal catheter or with nebulized albuterol may be helpful; however, either endotracheal intubation or a tracheostomy is mandatory for oxygen delivery if progressive hypoxia develops. Ancillary agents such as antihistamines, glucocorticoids, and bronchodilators are also useful therapeutics to treat urticaria/angioedema and bronchospasm once the patient is hemodynamically stable.

PREVENTION

Avoidance

The simplest, most straightforward approach to the long-term management of a patient with a history of anaphylaxis is strict avoidance of known anaphylactic triggers and education on acute management, that is, instructing the patient on the proper use and indications for use of self-administered epinephrine. Lifelong avoidance is not easy if the trigger is an occupational exposure, hymenoptera sting, a common food (i.e., peanut), or a drug representing the sole or best therapeutic option for the patient. Special management options may exist for these patients.

Specific Immunotherapy

Patients with large local reactions to hymenoptera stings are unlikely to have anaphylaxis with subsequent stings; however, patients of any age who have had documented anaphylaxis should be formally evaluated and started on venom immunotherapy (VIT) if skin or serologic IgE testing confirms the history. Immunotherapy is a means of “tolerizing” patients to allergen by means of serial subcutaneous administration of escalating doses of extract containing relevant allergen until a target maintenance dose is achieved. As in the case of Richet’s unfortunate dogs, anaphylaxis can sometimes occur during the course of administering immunotherapy extracts, so formulating extracts and administering them is typically done under the care of a specialist familiar with this type of treatment. In the case of hymenoptera allergy, patients receive VIT extracts containing actual hymenoptera venom with a maintenance dose equivalent to 2–5 stings. The recommended duration of treatment is 3–5 years; however, patients who have experienced severe respiratory of cardiovascular anaphylaxis are often on lifelong therapy.

Tolerance Induction

IgE sensitization to foods occurs most frequently in infants and young children, especially those with atopic dermatitis, and is a risk factor for anaphylaxis (although detection of specific IgE through skin or serum testing has relatively poor predictive value). While most allergy to egg, milk, soy, and/or wheat resolves spontaneously during childhood, ~80% of children with peanut allergy remain sensitive for life. A sharp rise in the prevalence of peanut allergy was also observed in the late 1990s–early 2000s especially in countries with Western diets where the average age of peanut introduction was age ≥3 years. Curiously, in cultures where peanut was introduced much earlier into children’s diets, the prevalence of peanut allergy remained low. The landmark “Learning Early About Peanut Allergy” (LEAP) study demonstrated that early introduction of peanut protein to the diet of high risk infants (4–11 months of age with atopic dermatitis and/or egg allergy) can prevent the development of most (80% or more) peanut allergy compared with children who did not consume peanuts (avoidance group), even when IgE sensitization (based on positive skin test) had already developed at the time of study entry. While the induction of tolerance at an early age seems to be key to preventing clinical reactivity later in life, it is not yet clear if this principle holds true for other foods commonly associated with hypersensitivity reactions.

Desensitization

For patients who have suffered anaphylaxis from drug allergy and whose treatment regimen requires the administration of the offending drug, desensitization may be a short-term treatment option to prevent reactions. Desensitization elicits a temporary state of tolerance to the drug in sensitized, clinically reactive patients. While it has been a proven technique for penicillin-allergic patients for decades, desensitization has more recently been proven to be effective for certain chemotherapy agents, especially platin-based chemotherapy agents which can induce IgE-mediated sensitization with repeated exposures. The exact mechanisms underlying desensitization are not fully understood; however, temporary tolerance can be achieved through the serial administration of gradually escalating doses of drug, starting from extremely low doses, over the course of hours. So long as the patient continues to receive the drug in question at regular intervals based on drug half-life, a “desensitized” state can also be maintained until the drug is no longer needed. Drug desensitization works best for IgE-mediated reactions; however, it has been performed in cases of non-IgE-mediated anaphylaxis from Cremophor-solubilized paclitaxel as described earlier in this chapter. Other non-IgE-mediated anaphylactic reactions can often be prevented with premedication regimens. A typical premedication regimen for radiocontrast, for example, will have the patient receive prednisone 0.5 mg/kg at 13, 6, and 1 h prior to contrast administration. Diphenhydramine 25 mg is also given 1 h prior to contrast. Flushing reactions from vancomycin can often be alleviated with antihistamine premedication and down titrating the infusion rate.

FURTHER READING

DEFINITION

Mastocytosis is defined by accumulation of clonally expanded mast cells in tissues such as skin, bone marrow, liver, spleen, and gut. The mast cell expansion is generally recognized in skin and/or bone marrow. Mastocytosis occurs at any age and has a slight preponderance in males. Mastocytosis is a rare disorder and its exact prevalence is not known; however, it is estimated to occur in ~1 in 20,000 people. Familial occurrence is rare, and atopy is not increased compared to the general population.

CLASSIFICATION AND PATHOPHYSIOLOGY

A consensus classification for mastocytosis recognizes cutaneous mastocytosis with variants, five systemic forms, and rare mast cell sarcoma (Table 347-1).

Cutaneous mastocytosis is the most common diagnosis of mastocytosis in children and indicates disease limited to skin with absence of pathologic infiltrates in internal organs. It is usually diagnosed within the first year of life with demonstration of fixed, maculopapular, and hyperpigmented lesions (maculopapular cutaneous mastocytosis [MPCM], formerly known as urticaria pigmentosa), mastocytoma(s) or diffuse cutaneous mastocytosis. Systemic mastocytosis (SM) refers to involvement of a non-cutaneous site (usually bone marrow). There are five distinct variants of SM; the form designated as indolent systemic mastocytosis (ISM) accounts for the majority of adult patients. ISM is diagnosed when there is no evidence of an associated hematologic disorder, mast cell leukemia or tissue dysfunction due to mast cell infiltration and is not known to alter life expectancy. Systemic smoldering mastocytosis (formerly considered a subvariant of ISM) is characterized by high mast cell burden as evidenced by a bone marrow infiltration of >30% and a baseline serum tryptase >200 ng/ml (B-findings), but absence of SM-AHNMD or ASM (Table 347-2). In systemic mastocytosis associated with clonal hematologic non–mast cell lineage disease (SM-AHNMD, or SM-AHN for short), the prognosis is determined by the nature of the associated disorder, which can range from dysmyelopoiesis to leukemias usually of myeloid origin. In aggressive systemic mastocytosis (ASM), mast cell infiltration/proliferation in multiple organs such as liver, spleen, gut, bone, and bone marrow resulting in 1 or more C findings and a poor prognosis (Table 347-2). Mast cell leukemia (MCL) is the rarest form of SM and is invariably fatal at present; the peripheral blood contains circulating, metachromatically staining, and atypical mast cells. An aleukemic form of MCL is recognized without circulating mast cells when the percentage of high-grade immature mast cells in bone marrow smears exceeds 20% in a nonspicular area. Mast cell sarcoma is a rare solid mast cell tumor with malignant invasive features.

A point mutation of A to T at codon 816 of KIT that causes an aspartic acid to valine substitution, resulting in a somatic gain-of-function mutation, is found in mast cells and sometimes in multiple other cell lineages in patients with mastocytosis. This substitution, as well as other rare mutations of KIT, is characteristic of patients with all forms of SM, but is also present in some children with cutaneous mastocytosis in lesional skin, as might be anticipated because mast cells are of bone marrow lineage. Additional mutations in genes such as TET2, SRSF2, ASLX1, and RUNX1 known to be associated with other hematologic neoplastic disorders can be detected in patients usually with advanced (non-ISM) forms of SM. The prognosis for patients with cutaneous mastocytosis and for almost all patients with ISM is a normal life expectancy, whereas that for patients with SM-AHNMD is determined by the non–mast cell component. ASM and MCL carry a poorer prognosis, while patients with SSM carry an intermediate prognosis. Progression from ISM to a more advanced form is rare (approximately 3% overall); however, patients should be monitored for emergence of hematologic disease and end organ manifestations of ASM. In infants and children with cutaneous manifestations, namely, maculopapular cutaneous mastocytosis, mastocytoma(s), or bullous lesions, visceral involvement is usually lacking, and spontaneous resolution is common prior to adolescence. Progression from CM to ISM may occur in ~10% of children, especially in those with high mast cell burden (diffuse cutaneous mastocytosis), hematologic abnormalities and those who present with smaller uniform lesions with diameters measuring <2 cm.

CLINICAL MANIFESTATIONS

The clinical manifestations of SM, distinct from a leukemic complication, are due to the release of bioactive substances acting at both local and distal sites, tissue occupancy by the mast cell mass, and the tissue response to that mass. The pharmacologically induced manifestations are intermittent flushing, tachycardia and vascular collapse, gastric distress, lower abdominal crampy pain, and diarrhea. The increase in local cell burden is evidenced by the lesions of MPCM (urticaria pigmentosa) at skin sites and internal organ biopsies such as bone marrow and gastrointestinal tract and may be a direct local cause of bone pain and/or malabsorption. Mast cell–mediated fibrotic changes may occur in liver, spleen, and bone marrow but not in gastrointestinal tissue or skin. Immunofluorescent analysis of bone marrow and skin lesions in ISM and of spleen, lymph node, and skin in ASM has revealed only one mast cell phenotype, namely, scroll-poor cells expressing tryptase, chymase, and CPA.

The cutaneous lesions of MPCM (formerly known as urticaria pigmentosa) are reddish-brown macules, papules, or plaques that respond to trauma with urtication and erythema (Darier’s sign). Children with CM may present with MPCM, mastocytomas, or diffuse cutaneous mastocytosis (DCM). Mastocytomas are generally solitary elevated lesions that are yellow, brown, or red in color. Their size may vary from a few millimeters to several centimeters. Rubbing or irritation of the mastocytoma lesion may lead to systemic symptoms such as flushing and urticaria. Children with DCM present without distinct lesions, but rather a generalized thickening of skin (pachydermia) due to diffuse mast cell infiltration. DCM may be associated with bullae formation and more severe systemic symptoms including upper GI irritation and vascular collapse in the first few years of life. Maculopapular skin lesions of mastocytosis may be present in patients with adult-onset systemic disease. The apparent incidence of cutaneous lesions is ≥80% in patients with ISM and <50% in those with SM-AHNMD or ASM. In the upper gastrointestinal tract, gastritis and peptic ulcer are significant problems. In the lower intestinal tract, the occurrence of diarrhea and abdominal pain is attributed to increased motility due to mast cell mediators; this problem can be aggravated by malabsorption, which can also cause secondary nutritional insufficiency and osteomalacia. The periportal fibrosis associated with mast cell infiltration and a prominence of eosinophils may lead to portal hypertension and ascites. In some patients, anaphylaxis with rapid and life threatening vascular collapse can be induced by hymenoptera stings. These patients often have evidence of venom specific IgE. The neuropsychiatric disturbances are clinically most evident as impaired recent memory, decreased attention span, and “migraine-like” headaches. Patients may experience exacerbation of a specific clinical sign or symptom variably with alcohol ingestion, temperature changes, stress, use of mast cell–interactive opioids, or ingestion of NSAIDs.

DIAGNOSIS

Cutaneous mastocytosis is diagnosed by observing the characteristic lesions of MPCM or mastocytoma(s). A skin biopsy can be obtained to confirm these subvariants of CM, whereas patients with suspected DCM and bullous mastocytosis usually require a skin biopsy to confirm the diagnosis. Although the diagnosis of SM is generally suspected on the basis of the clinical history and physical findings, and can be supported by laboratory procedures, it can be established only by a tissue diagnosis. By convention, the diagnosis of SM depends heavily on bone marrow biopsy to meet the criteria of one major plus one minor or three minor findings (Table 347-3). The bone marrow provides the major criterion by revealing aggregates of mast cells, often in paratrabecular and perivascular locations with lymphocytes and eosinophils, as well as the minor criteria of abnormal mast cell morphology, aberrant mast cell membrane immunophenotype, or a codon 816 mutation in an extracutaneous tissue. A basal serum total tryptase level is a noninvasive approach to consider before bone marrow biopsy. The pro-β and α forms of tryptase are elevated in more than one-half of patients with SM and provide a minor criterion; the fully processed (“mature”) β form is increased in patients undergoing an anaphylactic reaction. A rare histolopathologic subvariant called “well differentiated systemic mastocytosis” (WDSM) is characterized by clusters of mature appearing fully granulated and round mast cells, lack of aberrant CD25 and CD2 expression, and lack of D816V KIT mutation in most patients. These patients often have a history of childhood onset cutaneous disease and their mast cells may display aberrant CD30 expression and other markers of clonality such as atypical (non-D816V) KIT mutations. Additional studies directed by the presentation include a bone densitometry, bone scan, or skeletal survey; computed tomography scan, or endoscopy; and a neuropsychiatric evaluation. Osteoporosis is increased in mastocytosis and may lead to pathologic fractures.

Some patients presenting with recurrent mast cell activation symptoms (particularly hypotensive syncopal anaphylactic episodes) have been found to have underlying mastocytosis. A subset of these patients may be found to have the D816V KIT mutation or aberrant mast cells displaying CD25, but lack other diagnostic criteria for SM. Such patients are termed to have “monoclonal mast cell activation syndrome.”

The differential diagnosis requires the exclusion of other flushing disorders. The 24-h urine assessment of 5-hydroxy-indoleacetic acid and metanephrines should exclude a carcinoid tumor or a pheochromocytoma, respectively. Some patients presenting with recurrent mast cell activation symptoms without an obvious increase in mast cell burden in skin or bone marrow have been shown to carry aberrant mast cells with clonality markers of D816V KIT mutation or surface CD25 expression. Most patients with recurrent IgE-induced or idiopathic anaphylaxis present with urticaria, angioedema, and/or wheezing, which are not manifestations of SM.

TREATMENT

FURTHER READING

INTRODUCTION

One of the central features of the immune system is the capacity to mount an inflammatory response to potentially harmful foreign materials while avoiding damage to self-tissues. Whereas recognition of self plays an important role in shaping the repertoires of immune receptors on both T and B cells and in clearing apoptotic and other tissue debris from sites throughout the body, the development of potentially harmful immune responses to self-antigens is, in general, prohibited. The essential feature of an autoimmune disease is that tissue injury is caused by the immunologic reaction of the organism against its own tissues. Autoimmunity, on the other hand, refers merely to the presence of antibodies or T lymphocytes that react with self-antigens and does not necessarily imply that the self-reactivity has pathogenic consequences. Autoimmunity is present in all individuals and increases with age; however, autoimmune disease occurs only in those individuals in whom the breakdown of one or more of the basic mechanisms regulating immune tolerance results in self-reactivity that can cause tissue damage.

Polyreactive autoantibodies that recognize many host antigens are present throughout life. These antibodies are usually of the IgM heavy chain isotype and are encoded by nonmutated germline immunoglobulin variable region genes. These antibodies are essential, as they remove apoptotic debris through non inflammatory pathways. Expression of these autoantibodies may be increased after some inciting events. When autoimmunity is induced by an inciting event, such as infection or tissue damage from trauma or ischemia, the autoreactivity is in general self-limited. When such autoimmunity does persist, however, pathology may or may not result. Even in the presence of organ pathology, it may be difficult to determine whether the damage is mediated by autoreactivity. After an inciting event, the development of self-reactivity may be the consequence of an ongoing pathologic process, may be nonpathogenic, or may exacerbate tissue inflammation and damage. Individuals with autoimmune disease may have numerous autoantibodies, only some or even none of which may be pathogenic. For example, patients with systemic sclerosis may have a wide array of antinuclear antibodies that are important in disease classification but are not clearly pathogenic; in contrast, patients with pemphigus may also exhibit a wide array of autoantibodies, one of which (antibody to desmoglein 1 and 3) is known to be pathogenic.

MECHANISMS OF AUTOIMMUNITY

Since Ehrlich first postulated the existence of mechanisms to prevent the generation of self-reactivity in the early 1900s, there has been a progressive increase in understanding of this prohibition in parallel with a progressive increase in understanding of the immune system. Burnet’s clonal selection theory included the idea that interaction of lymphoid cells with their specific antigens during fetal or early postnatal life would lead to elimination of such “forbidden clones.” This idea was refuted, however, when it was shown that autoimmune diseases could be induced in experimental animals by simple immunization procedures, that autoantigen-binding cells could be demonstrated easily in the circulation of normal individuals, and that self-limited autoimmune phenomena frequently developed after tissue damage from infection or trauma. These observations indicated that clones of cells capable of responding to autoantigens were present in the repertoire of antigen-reactive cells in normal adults and suggested that mechanisms in addition to clonal deletion were responsible for preventing their activation.

Currently, three general processes are thought to be involved in the maintenance of selective unresponsiveness to autoantigens (Table 348-1): (1) sequestration of self-antigens, rendering them inaccessible to the immune system; (2) specific unresponsiveness (tolerance or anergy) of relevant T or B cells; and (3) limitation of potential reactivity by regulatory mechanisms. Derangements of these normal processes may predispose to the development of autoimmunity (Table 348-2). In general, these abnormal responses require both an exogenous trigger, such as bacterial or viral infection or cigarette smoking, and the presence of endogenous abnormalities in the cells of the immune system. Microbial superantigens, such as staphylococcal protein A and staphylococcal enterotoxins, are substances that can stimulate a broad range of T and B cells through specific interactions with selected families of immune receptors, irrespective of their antigen specificity. If autoantigen-reactive T and/or B cells express these receptors, autoimmunity may develop. Alternatively, molecular mimicry or cross-reactivity between a microbial product and a self-antigen may lead to activation of autoreactive lymphocytes. One of the best examples of autoreactivity and autoimmune disease resulting from molecular mimicry is rheumatic fever, in which antibodies to the M protein of streptococci cross-react with myosin, laminin, and other matrix proteins as well as with neuronal antigens. Deposition of these autoantibodies in the heart initiates an inflammatory response, whereas their penetration into the brain can result in Sydenham’s chorea. Molecular mimicry between microbial proteins and host tissues has been reported in type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus (SLE), celiac disease, and multiple sclerosis. It is presumed that infectious agents may be able to overcome self-tolerance because they possess pathogen-associated molecular patterns (PAMPs). These molecules (e.g., bacterial endotoxin, RNA, or DNA) exert adjuvant-like effects on the immune system by interacting with Toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) that increase the immunogenicity and immunostimulatory capacity of the microbial material. The adjuvants activate dendritic cells, which in turn stimulate the activation of previously quiescent lymphocytes that recognize both microbial antigens and self-antigens. Similarly, cellular and tissue damage due to the release of damage-associated molecular patterns (DAMPs), including DNA, RNA nucleosomes, and other tissue debris, may activate cells of the inflammatory and immune systems through engagement of the same array of PRRs. This pathway may lead to autoimmune disease in individuals who have impairments in mechanisms for clearance of tissue debris.

Although previous work focused on the role of pathogenic microorganisms in triggering autoimmunity, more recent studies have focus on the role of the microbiome, the collection of non-pathogenic microorganisms that reside on various body surfaces. It has become clear that the interaction between specific constituents of these microbiota and the immune system can shape the nature of the immune response to either favor or discourage immune/inflammatory responses. Thus, some genera within the microbiome may favor a nonresponsive state dominated by regulatory T cells whereas others may favor the development of T effector cells and a proinflammatory state. Gender bias in autoimmune conditions may also be favored by differences in the dominant organisms within the microbiome.

Endogenous derangements of the immune system may also contribute to the loss of immunologic tolerance to self-antigens and the development of autoimmunity (Table 348-2). Some autoantigens reside in immunologically privileged sites, such as the brain or the anterior chamber of the eye. These sites are characterized by the inability of engrafted tissue to elicit immune responses. Immunologic privilege results from a number of events, including the limited entry of proteins from those sites into lymphatics, the local production of immunosuppressive cytokines such as transforming growth factor β, and the local expression of molecules (including Fas ligand) that can induce apoptosis of activated T cells. Lymphoid cells remain in a state of immunologic ignorance (neither activated nor anergized) with regard to proteins expressed uniquely in immunologically privileged sites. If the privileged site is damaged by trauma or inflammation or if T cells are activated elsewhere, proteins expressed at this site can become immunogenic and also be the targets of immunologic assault. In multiple sclerosis and sympathetic ophthalmia, for example, antigens uniquely expressed in the brain and eye, respectively, become the target of activated T cells.

Alterations in antigen presentation may also contribute to autoimmunity. Peptide determinants (epitopes) of a self-antigen that are not routinely presented to lymphocytes may be recognized as a result of altered proteolytic processing of the molecule and the ensuing presentation of novel peptides (cryptic epitopes). When B cells rather than dendritic cells present self-antigen, they may also present cryptic epitopes that can activate autoreactive T cells. These cryptic epitopes will not previously have been available to effect the silencing of autoreactive lymphocytes. Furthermore, once there is immunologic recognition of one protein component of a multimolecular complex, reactivity may be induced to other components of the complex after internalization and presentation of all molecules within the complex (epitope spreading). Finally, inflammation, environmental agents, drug exposure, or normal senescence may cause a post-translational alteration in proteins, resulting in the generation of immune responses that cross-react with normal self-proteins. For example, the induction and/or release of protein arginine deiminase enzymes results in the conversion of arginine residues to citrullines in a variety of proteins, thereby altering their capacity to induce immune responses. Production of antibodies to citrullinated proteins has been observed in rheumatoid arthritis and chronic lung disease as well as in normal smokers. These antibodies may be the target of autoantibodies that contribute to organ pathology. Alterations in the availability and presentation of autoantigens may be important components of immunoreactivity in certain models of organ-specific autoimmune diseases. In addition, these factors may be relevant to an understanding of the pathogenesis of various drug-induced autoimmune conditions. However, the diversity of autoreactivity manifesting in non-organ-specific systemic autoimmune diseases suggests that these conditions may result from a more general activation of the immune system rather than from an alteration in individual self-antigens.

Many autoimmune diseases are characterized by the presence of antibodies that react with antigens present in apoptotic material. Defects in the clearance of apoptotic material have been shown to elicit autoimmunity and autoimmune disease in a number of animal models. Moreover, such defects have been found in patients with SLE. Apoptotic debris that is not cleared quickly by the immune system can function as endogenous ligands for a number of PRRs on dendritic cells and B cells. Under such circumstances, dendritic cells and/or B cells are activated, and an immune response to apoptotic debris can develop. In addition, the presence of uncleared extracellular apoptotic material within germinal centers of secondary lymphoid organs in patients with SLE may facilitate the direct activation of autoimmune B cell clones or may function to select such clones during immune responses.

Deficiency in C1q, likewise, can predispose or exacerbate autoimmunity. C1q assists in the clearance of apoptotic debris binding to IgM autoantibodies and to inhibitory receptors on monocytes and dendritic cells. If C1q is not present, a mechanism of immune suppression is lost. Moreover, if antibodies have undergone class switch recombination to IgG, the apoptotic debris containing immune complexes will engage activating Fc receptors on myeloid cells to induce an inflammatory response. Studies in a number of experimental models have suggested that intense stimulation of T lymphocytes can produce nonspecific signals that bypass the need for antigen-specific helper T cells and lead to polyclonal B cell activation with the formation of multiple autoantibodies. For example, antinuclear, antierythrocyte, and antilymphocyte antibodies are produced during the chronic graft-versus-host reaction. In addition, true autoimmune diseases, including autoimmune hemolytic anemia and immune complex–mediated glomerulonephritis, can be induced in this manner. While such diffuse activation of helper T cell activity clearly can cause autoimmunity, nonspecific stimulation of B lymphocytes can also lead to the production of autoantibodies. Thus, the administration of polyclonal B cell activators, such as bacterial endotoxin, to normal mice leads to the production of a number of autoantibodies, including those to DNA and IgG (rheumatoid factor). A variety of genetic modifications resulting in hyperresponsiveness of B cells also can lead to the production of autoantibodies and, in animals of appropriate genetic background, a lupus-like syndrome. Moreover, excess B cell activating factor (BAFF), a B cell survival promoting cytokine, can impair B cell tolerance, cause T cell–independent B cell activation, and lead to the development of autoimmunity. SLE can also be induced in mice through exuberant dendritic cell activation, through a redundancy of TLR7 on the Y chromosome (as in BXSB-Yaa mice), or through exposure to CpG, a ligand for TLR9. The ensuing induction of inflammatory mediators can cause a switch from the production of nonpathogenic IgM autoantibodies to the production of pathogenic IgG autoantibodies in the absence of antigen-specific T cell help. Aberrant selection of the B or T cell repertoire at the time of antigen receptor expression can also predispose to autoimmunity. For example, B cell immunodeficiency caused by an absence of the B cell receptor–associated kinase (Bruton’s tyrosine kinase) leads to X-linked agammaglobulinemia. This syndrome is characterized by reduced B cell numbers. This leads to high levels of BAFF which alter B cell selection and results in greater survival of autoreactive B cells. Likewise, negative selection of autoreactive T cells in the thymus requires expression of the autoimmune regulator (AIRE) gene that enables the expression of tissue-specific proteins in thymic medullary epithelial cells. Peptides from these proteins are expressed in the context of major histocompatibility complex (MHC) molecules and mediate the central deletion of autoreactive T cells. The absence of AIRE gene expression leads to a failure of negative selection of autoreactive cells, autoantibody production, and severe inflammatory destruction of multiple organs. Individuals deficient in AIRE gene expression develop autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED).

Primary alterations in the activity of T and/or B cells, cytokine imbalances, or defective immunoregulatory circuits may also contribute to the emergence of autoimmunity. Diminished production of tumor necrosis factor (TNF) and interleukin (IL) 10 has been reported to be associated with the development of autoimmunity. Overproduction or therapeutic administration of type 1 interferon has also been associated with autoimmunity. Overexpression of costimulatory molecules on T cells similarly can lead to autoantibody production.

Autoimmunity may also result from an abnormality of immunoregulatory mechanisms. Observations made in both human autoimmune disease and animal models suggest that defects in the generation and expression of regulatory T cell (Treg) activity may allow the production of autoimmunity. It has been appreciated that the IPEX (immunodysregulation, polyendocrinopathy, enteropathy X-linked) syndrome results from the failure to express the FOXP3 gene, which encodes a molecule critical in the differentiation of Tregs. Administration of normal Tregs or of factors derived from them can prevent the development of autoimmune disease in rodent models of autoimmunity, and allogeneic stem cell transplantation ameliorates human IPEX. Abnormalities in the function of Tregs have been noted in a number of human autoimmune diseases, including rheumatoid arthritis and SLE, although it remains uncertain whether these functional abnormalities are causative or are secondary to inflammation. One of the mechanisms by which Tregs control immune/inflammatory responses is by the production of the cytokine IL-10. In this regard, children with a deficiency in the expression of IL-10 or the IL-10 receptor develop inflammatory bowel disease that mimics Crohn’s disease and that can be cured by allogeneic stem cell transplantation. Finally, recent data indicate that B cells may also exert regulatory function, largely through the production of IL-10. Deficiency of IL-10-producing regulatory B cells can prolong the course of multiple sclerosis in an animal model, and such cells are thought to be functionally diminished in human SLE.

It should be apparent that no single mechanism can explain all the varied manifestations of autoimmunity or autoimmune disease. Furthermore, genetic evaluation has shown that convergence of a number of abnormalities is often required for the induction of an autoimmune disease. Additional factors that appear to be important determinants in the induction of autoimmunity include age, sex (many autoimmune diseases are far more common in women), exposure to infectious agents, and environmental contacts. How all of these disparate factors affect the capacity to develop self-reactivity is currently being investigated intensively.

GENETIC CONSIDERATIONS

Evidence in humans that there are susceptibility genes for autoimmunity comes from family studies and especially from studies of twins. Studies in type 1 diabetes mellitus, rheumatoid arthritis, multiple sclerosis, and SLE have shown that ~15–30% of pairs of monozygotic twins show disease concordance, whereas the figure is <5% for dizygotic twins. The occurrence of different autoimmune diseases within the same family has suggested that certain susceptibility genes may predispose to a variety of autoimmune diseases. Genome-wide association studies have begun to identify polymorphisms in individual genes that are associated with specific autoimmune diseases. More than 100 genetic polymorphisms associated with one or more autoimmune diseases have been identified to date. It is notable that some genes are associated with multiple autoimmune diseases, whereas others are specifically associated with only one autoimmune condition. Moreover, recent genetic evidence suggests that clusters of genetic risk factors can commonly be found in groups of autoimmune diseases. Four general clusters have been identified: one group most frequently associated with Crohn’s disease, psoriasis, and multiple sclerosis; a second cluster most strongly associated with celiac disease, rheumatoid arthritis, and SLE; a third cluster most strongly associated with type 1 diabetes, multiple sclerosis, and rheumatoid arthritis; and a fourth cluster most strongly associated with type 1 diabetes, rheumatoid arthritis, celiac disease, Crohn’s disease, and SLE. These results imply that autoimmune diseases with widely different clinical presentations and patterns of organ involvement could involve similar immunopathogenic pathways or endophenotypes. For example, the same allele of the gene encoding PTPN22 is associated with multiple autoimmune diseases. Its product is a phosphatase expressed by a variety of hematopoietic cells that downregulates antigen receptor–mediated stimulation of T and B cells. The risk allele is associated with type 1 diabetes mellitus, rheumatoid arthritis, and SLE in some populations. In recent years, genome-wide association studies have demonstrated a variety of other genes that are involved in human autoimmune diseases. Most genes individually confer a relatively low risk for autoimmune diseases and are found in normal individuals. In addition, most polymorphisms associated with autoimmune diseases are in non-coding regions of DNA, implying that expression levels rather that altered function might convey most genetic risk for autoimmune diseases. Abnormalities in epigenetics or the mechanisms controlling and influencing gene expression has also been implicated in contributing to autoimmune diseases. No single gene or epigenetic modification has been identified that is essential for autoimmune diseases. In addition to this evidence from humans, certain inbred mouse strains reproducibly develop specific spontaneous or experimentally induced autoimmune diseases, whereas others do not. These findings have led to an extensive search for genes that determine susceptibility to autoimmune disease and for genes that might be protective.

The strongest consistent association for susceptibility to autoimmune disease is with particular MHC alleles. It has been suggested that the association of MHC genotype with autoimmune disease relates to differences in the ability of different allelic variations of MHC molecules to present autoantigenic peptides to autoreactive T cells. An alternative hypothesis involves the role of MHC alleles in shaping the T cell receptor repertoire during T cell ontogeny in the thymus. In addition, specific MHC gene products may themselves be the source of peptides that can be recognized by T cells. Cross-reactivity between such MHC peptides and peptides derived from proteins produced by common microbes may trigger autoimmunity by molecular mimicry. However, MHC genotype alone does not determine the development of autoimmunity. Identical twins are far more likely to develop the same autoimmune disease than MHC-identical nontwin siblings; this observation suggests that genetic factors other than the MHC affect disease susceptibility. Studies of the genetics of type 1 diabetes mellitus, SLE, rheumatoid arthritis, and multiple sclerosis in humans and mice have identified several independently segregating disease susceptibility loci in addition to the MHC. Genes that encode molecules of the innate immune response are also involved in autoimmunity. In humans, inherited homozygous deficiency of the early proteins of the classic pathway of complement (C1q, C4, or C2) as well as genes involved in the type 1 interferon pathway are very strongly associated with the development of SLE.

IMMUNOPATHOGENIC MECHANISMS IN AUTOIMMUNE DISEASES

The mechanisms of tissue injury in autoimmune diseases can be divided into antibody-mediated and cell-mediated processes. Representative examples are listed in Table 348-3.

The pathogenicity of autoantibodies can be mediated through several mechanisms, including opsonization of soluble factors or cells, activation of an inflammatory cascade via the complement system, and interference with the physiologic function of soluble molecules or cells.

In autoimmune thrombocytopenic purpura, opsonization of platelets targets them for elimination by phagocytes. Likewise, in autoimmune hemolytic anemia, binding of immunoglobulin to red cell membranes leads to phagocytosis and lysis of the opsonized cell. Goodpasture’s syndrome, a disease characterized by lung hemorrhage and severe glomerulonephritis, represents an example of antibody binding leading to local activation of complement and neutrophil accumulation and activation. The autoantibody in this disease binds to the α₃ chain of type IV collagen in the basement membrane. In SLE, activation of the complement cascade at sites of immunoglobulin deposition in renal glomeruli is considered to be a major mechanism of renal damage. Moreover, the DNA- and RNA-containing immune complexes in SLE activate TLR9 and TLR7, respectively, in plasmacytoid dendritic cells and promote the production of type 1 interferon and proinflammatory, cytokines conducive to amplification of the autoimmune response.

Autoantibodies can also interfere with normal physiologic functions of cells or soluble factors. Autoantibodies to hormone receptors can lead to stimulation of cells or to inhibition of cell function through interference with receptor signaling. For example, long-acting thyroid stimulators—autoantibodies that bind to the receptor for thyroid-stimulating hormone (TSH)—are present in Graves’ disease and function as agonists, causing the thyroid to respond as if there were an excess of TSH. Alternatively, antibodies to the insulin receptor can cause insulin-resistant diabetes mellitus through receptor blockade. In myasthenia gravis, autoantibodies to the acetylcholine receptor can be detected in 85–90% of patients and are responsible for muscle weakness. The exact location of the antigenic epitope, the valence and affinity of the antibody, and perhaps other characteristics determine whether activation or blockade results from antibody binding.

Antiphospholipid antibodies are associated with thromboembolic events in primary and secondary antiphospholipid syndrome and have also been associated with fetal wastage. The major antibody is directed to the phospholipid–β₂-glycoprotein I complex and appears to exert a procoagulant effect. In pemphigus vulgaris, autoantibodies bind to desmoglein 1 and 3, components of the epidermal cell desmosome, and play a role in the induction of the disease. These antibodies exert their pathologic effect by disrupting cell–cell junctions through stimulation of the production of epithelial proteases, with consequent blister formation. Cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA), found in granulomatosis with polyangiitis, is an antibody to an intracellular antigen, the 29-kDa serine protease (proteinase-3). In vitro experiments have shown that IgG anti-c-ANCA causes cellular activation and degranulation of primed neutrophils.

It is important to note that autoantibodies of a given specificity may cause disease only in genetically susceptible hosts, as has been shown in experimental models of myasthenia gravis, SLE, rheumatic fever, and rheumatoid arthritis. Furthermore, once organ damage is initiated, new inflammatory cascades are initiated that can sustain and amplify the autoimmune process. Finally, some autoantibodies seem to be markers for disease but have, as yet, no known pathogenic potential.

AUTOIMMUNE DISEASES

Manifestations of autoimmunity are found in a large number of pathologic conditions. However, their presence does not necessarily imply that the pathologic process is an autoimmune disease. A number of attempts to establish formal criteria for the classification of diseases as autoimmune have been made, but none is universally accepted. One set of criteria is shown in Table 348-4; however, this scheme should be viewed merely as a guide in consideration of the problem.

To classify a disease as autoimmune, it is necessary to demonstrate that the immune response to a self-antigen causes the observed pathology. Initially, the detection of antibodies to the affected tissue in the serum of patients suffering from various diseases was taken as evidence that these diseases had an autoimmune basis. However, such autoantibodies are also found when tissue damage is caused by trauma or infection and in these cases are secondary to tissue damage. Thus, autoimmunity must be shown to be pathogenic before a disease is categorized as autoimmune.

To confirm autoantibody pathogenicity, it may be possible to transfer disease to experimental animals by the administration of autoantibodies from a patient, with the subsequent development of pathology in the recipient similar to that seen in the patient. This scenario has been documented, for example, in Graves’ disease. Some autoimmune diseases can be transferred from mother to fetus and are observed in the newborn babies of diseased mothers. The symptoms of the disease in the newborn usually disappear as the levels of maternal antibody decrease. An exception, however, is congenital heart block, in which damage to the developing conducting system of the heart follows in utero transfer of anti-Ro antibody from the mother to the fetus. This antibody transfer can result in a permanent developmental defect in the heart.

In most situations, the critical factors that determine when the development of autoimmunity results in autoimmune disease have not been delineated. The relationship of autoimmunity to the development of autoimmune disease may be associated with the fine specificity of the antibodies or T cells or their specific effector capabilities. In many circumstances, a mechanistic understanding of the pathogenic potential of autoantibodies has not been established. In some autoimmune diseases, biased production of cytokines by helper T (T_H) cells may play a role in pathogenesis. In this regard, T cells can differentiate into specialized effector cells that predominantly produce interferon γ (T_H1), IL-4 (T_H2), or IL-17 (T_H17) or that provide help to B cells (T follicular helper, T_FH) (Chap. 342). T_H1 cells facilitate macrophage activation and classic cell–mediated immunity, whereas T_H2 cells are thought to have regulatory functions and are involved in the resolution of normal immune responses as well as in the development of responses to a variety of parasites. T_H17 cells produce a number of inflammatory cytokines, including IL-17 and IL-22, and seem to be prominently involved in host resistance to certain fungal infections. T_FH cells help B cells by constitutively producing IL-21. In a number of autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, type 1 diabetes mellitus, and Crohn’s disease, there appears to be biased differentiation of T_H1 and T_H17 cells, with resultant organ damage. Studies suggest an accentuated differentiation of T_H17 cells associated with animal models of inflammatory arthritis, whereas increased differentiation of T_FH cells has been associated with animal models of SLE. Importantly, genetically determined or environmentally induced features of the target organ may determine susceptibility of the target organ to autoantibodies or autoreactive T cell-mediated damage.

ORGAN-SPECIFIC VERSUS SYSTEMIC AUTOIMMUNE DISEASES

The spectrum of autoimmune diseases ranges from conditions specifically affecting a single organ to systemic disorders that involve many organs (Table 348-5). Hashimoto’s autoimmune thyroiditis is an example of an organ-specific autoimmune disease (Chap. 375). In this disorder, a specific lesion in the thyroid is associated with infiltration of mononuclear cells and damage to follicular cells. Antibody to thyroid constituents can be demonstrated in nearly all cases. Other organ- or tissue-specific autoimmune disorders include pemphigus vulgaris, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Goodpasture’s syndrome, myasthenia gravis, and sympathetic ophthalmia. One important feature of some organ-specific autoimmune diseases is the tendency for overlap, such that an individual with one specific syndrome is more likely to develop a second syndrome. For example, there is a high incidence of pernicious anemia in individuals with autoimmune thyroiditis. More striking is the tendency for individuals with an organ-specific autoimmune disease to develop multiple other manifestations of autoimmunity without the development of associated organ pathology. Thus, as many as 50% of individuals with pernicious anemia have non-cross-reacting antibodies to thyroid constituents, whereas patients with myasthenia gravis may develop antinuclear antibodies, antithyroid antibodies, rheumatoid factor, antilymphocyte antibodies, and polyclonal hypergammaglobulinemia. Part of the explanation may relate to the genetic elements shared by individuals with these different diseases.

Systemic autoimmune diseases differ from organ-specific diseases in that pathologic lesions are found in multiple diverse organs and tissues. The hallmark of these conditions is the demonstration of associated relevant autoimmune manifestations that are likely to have an etiologic role in organ pathology. SLE represents the prototype of these disorders because of its abundant autoimmune manifestations. SLE is a disease of protean manifestations that characteristically involves the kidneys, joints, skin, serosal surfaces, blood vessels, and central nervous system (Chap. 349). The disease is associated with a vast array of autoantibodies whose production appears to be a part of a generalized hyperreactivity of the humoral immune system. Other features of SLE include generalized B cell hyperresponsiveness and polyclonal hypergammaglobulinemia. Current evidence suggests that both hypo- and hyperresponsiveness to antigen can lead to survival and activation of autoreactive B cells in SLE. The autoantibodies in SLE are thought to arise as part of an accentuated T cell–dependent B cell response since most pathogenic anti-DNA autoantibodies exhibit evidence of extensive somatic hypermutation.

TREATMENT

FURTHER READING

DEFINITION AND PREVALENCE

Systemic lupus erythematosus (SLE) is an autoimmune disease in which organs and cells undergo damage initially mediated by tissue-binding autoantibodies and immune complexes. In most patients, autoantibodies are present for a few years before the first clinical symptom appears. Ninety percent of patients are women of child-bearing years; people of all genders, ages, and ethnic groups are susceptible. Prevalence of SLE in the United States is 20–150 per 100,000 women depending on race and gender; highest prevalence is in African-American and Afro-Caribbean women, and lowest prevalence is in white men.

PATHOGENESIS AND ETIOLOGY

The proposed pathogenic mechanisms of SLE are illustrated in Fig. 349-1. The abnormal immune responses underlying SLE may be summarized as leading to production of increased quantities and immunogenic forms of nucleic acids, their accompanying proteins, and other self-antigens. The process may begin with autoimmunity-inducing activation of innate immunity, partly through binding of DNA/RNA/proteins by toll-like receptors in those cells. The changes include dendritic cells producing interferon α (IFNα), activated macrophages producing inflammatory cytokines/chemokines such as interleukin (IL12), tumor necrosis factor α (TNFα), and the B cell maturation/survival factor BLys/BAFF, neutrophils releasing DNA/protein-containing nets, and natural killer (NK) cells unable to kill autoreactive T and B cells or to produce the transforming growth factor β (TGFβ) needed for development of regulatory T cells. Upregulation of genes induced by IFNs is a genetic “signature” in peripheral blood cells of 50–80% of SLE patients. The innate immune system interacts with the B and T cells of adaptive immunity, which further drive autoimmune responses. T lymphocytes have altered metabolism (abnormal mitochondrial electron transport, membrane potential, and oxidative stress), increased glucose utilization, increased pyruvate production, activation of mTOR, and increased autophagy. T and B cells are more easily activated and driven into apoptosis than are normal cells, probably due to autoantibodies binding them plus abnormal signaling after engagement of surface molecules resulting in abnormally low production of IL2, which is required for T cell survival. B cells present antigen and secrete IL6 and IL10, further promoting autoreactive B cell survival (which is also favored by estrogen). Lupus phagocytic cells have reduced capacity to clear immune complexes, apoptotic cells, and their DNA/RNA/Ro/La and phospholipid containing surface blebs. The result is persistence of large quantities of autoantigens and resultant large quantities of autoantibodies with increased numbers of activated B cells and plasmablasts/plasma cells, and autoreactive T cells with shifts away from regulatory populations toward increased numbers and functions of Th1, T17, and Tfh cells, all of which promote production of autoantibodies and tissue damage. This damage begins with deposition of autoantibodies and/or immune complexes, followed by destruction mediated by complement activation and release of cytokines/chemokines. Non-immune tissue-fixed cells are then activated to produce more inflammation and damage, such as basal cells of the dermis, synovial fibroblasts, renal mesangial cells, podocytes and tubular epithelium, and endothelial cells throughout the body. Meanwhile, the initial immune attack is attracting into the target tissues additional B and T cells, monocytes/macrophages, dendritic cells, and plasma cells. Inflammation also causes release of vasoactive peptides, oxidative damage, growth factors and fibrosing factors. Sclerosis/fibrosis with irreversible tissue damage can occur in multiple tissues including kidneys, lungs, blood vessels, and skin. Each of these processes depends on the individual’s genetic background, environmental influences, and epigenetics. Autoantibodies of SLE are referred to in Fig. 349-1 and described in Table 349-1.

SLE is a multigenic disease. Rare single-gene defects confer high hazard ratios (HRs) for SLE (5–25), including homozygous deficiencies of early components of complement (C1q,r,s; C2; C4) and a mutation in TREX1 (encoding a DNAase) on the X chromosome. In most genetically susceptible individuals, normal alleles of multiple genes each contribute a small amount to abnormal immune/inflammation/tissue damage responses; if enough predisposing variations are present, disease results. Approximately 60 genes with alleles increasing risk for SLE and/or lupus nephritis (examples listed in Fig. 349-1 which includes most with HR ≥1.5) have been identified in recent genome-wide association studies in different racial groups. Individually, they confer an HR for SLE of 1.5–3 and even in combination account for only 18% of disease susceptibility, suggesting that environmental exposures and epigenetics play major roles. Predisposing, antigen-presenting human leukocyte antigen (HLA) molecules are most commonly found, in multiple ethnic groups (HLA DRB1 ^*0301 and ^*1501 and DR3), as well as multiple genes across the major histocompatibility complex (MHC) 120-gene region. Non-HLA genetic factors are listed in Fig. 349-1 and include polymorphisms that affect innate and adaptive immunity pathways. Note the large number that influences IFN production—the most characteristic gene expression pattern of SLE patients. Other genes affect clearance of apoptotic cells or immune complexes, influence neutrophil adherence (ITGAM), and DNA repair (TREX-1). Some polymorphisms influence clinical manifestations; such as single nucleotide polymorphisms (SNPs) of STAT4 that associate with severe disease, anti-DNA, nephritis, and antiphospholipid syndrome (APS), and an allele of FCGRIIA encoding a receptor that binds immune complexes poorly and predisposes to nephritis. Some gene effects are in promoter regions (e.g., IL-10), and others are conferred by copy numbers (e.g., C4A, TLR7). In addition, multiple epigenetic changes characterize SLE, including hypomethylation of DNA in CD4+ T cells, B cells, and monocytes, including genes that control production of type 1 interferons, and histone modifications. Some of these changes are mediated by microRNAs associated with SLE including some that control DNA Methyl transferases (DNMTs), such as mIR-146a, that control methylation of DNA in CD4+ T cells and IFN production. Some gene polymorphisms contribute to several autoimmune diseases, such as STAT4 and CTLA4. All of these gene polymorphisms/transcription/epigenetic combinations influence immune responses to the external and internal environment; when such responses are too high and/or too prolonged and/or inadequately regulated, autoimmune disease is favored.

Female sex is permissive for SLE with evidence for hormone effects, genes on the X chromosome, and epigenetic differences between genders playing a role. Females of many mammalian species make higher antibody responses than males. Women exposed to estrogen-containing oral contraceptives or hormone replacement have an increased risk of developing SLE (HR 1.2–2). Estradiol binds to receptors on T and B lymphocytes, increasing activation and survival of those cells, especially autoreactive subsets, thus favoring prolonged immune responses. Genes on the X chromosome that influence SLE, such as TREX-1, may play a role in gender predisposition, possibly because some genes on the second X in females are not silent. People with XXY karyotype (Klinefelter’s syndrome) have a significantly increased risk for SLE.

Several environmental stimuli may influence SLE (Fig. 349-1). Exposure to ultraviolet light causes flares of SLE in ~70% of patients, possibly by increasing apoptosis in skin cells or by altering DNA and intracellular proteins to make them antigenic. Some infections and lupus-inducing drugs activate autoreactive T and B cells; if such cells are not appropriately regulated, prolonged autoantibody production occurs. Most SLE patients have autoantibodies for 3 years or more before the first symptoms of disease, suggesting that regulation controls the degree of autoimmunity for years before quantities and qualities of autoantibodies, pathogenic B and T cells, and activated tissue-fixed cells such as macrophages cause clinical disease. Epstein-Barr virus (EBV) may be one infectious agent that can trigger SLE in susceptible individuals. Children and adults with SLE are more likely to be infected by EBV than age-, sex-, and ethnicity-matched controls. EBV contains amino acid sequences that mimic sequences on human spliceosomes (RNA/protein antigens) often recognized by autoantibodies in people with SLE. Current tobacco smoking increases risk for SLE (HR 1.5). Prolonged occupational exposure to crystalline silica (e.g., inhalation of soap powder dust or soil in farming activities) increases risk (HR 4.3) in African-American women. Drinking alcohol (2 glasses of wine a week or ½ of an alcoholic drink daily) reduces the risk of SLE. Thus, interplay between genetic susceptibility, environment, gender, race, and abnormal immune responses results in autoimmunity (Chap. 348).

PATHOLOGY

In SLE, biopsies of affected skin show deposition of Ig at the dermal-epidermal junction (DEJ), injury to basal keratinocytes, and inflammation dominated by T lymphocytes in the DEJ and around blood vessels and dermal appendages. Clinically unaffected skin may also show Ig deposition at the DEJ. These patterns are not specific for dermatologic SLE; however, they are highly suggestive.

In renal biopsies, the pattern and severity of injury are important in diagnosis and in selecting the best therapy. Most recent clinical studies of lupus nephritis have used the International Society of Nephrology (ISN) and the Renal Pathology Society (RPS) classification (Table 349-2). In the ISN/RPS classification, the addition of “a” for active and “c” for chronic changes gives physicians information regarding the potential reversibility of disease. The system focuses on glomerular disease, although the presence of tubular interstitial and vascular disease, as well as the chronicity score in both glomeruli and interstitium, are important in predicting clinical outcomes. In general, class III and IV disease, as well as class V accompanied by III or IV disease, should be treated with aggressive immunosuppression if possible, because there is a high risk for end-stage renal disease (ESRD) if patients are untreated or undertreated. In contrast, treatment for lupus nephritis is not recommended in patients with class I or II disease or with extensive irreversible changes. In the recent Systemic Lupus International Collaborating Clinic (SLICC) criteria for classification of SLE, a diagnosis can be established on the basis of renal histology in the presence of lupus autoantibodies, without meeting additional criteria totaling 4 (Table 349-3).

Histologic abnormalities in blood vessels may also determine therapy. Patterns of vasculitis are not specific for SLE but may indicate active disease: leukocytoclastic vasculitis is most common (Chap. 356).

Lymph node biopsies are usually performed to rule out infection or malignancies. In SLE, they show nonspecific diffuse chronic inflammation.

DIAGNOSIS

The diagnosis of SLE is based on characteristic clinical features and autoantibodies. Current criteria for classification are listed in Table 349-3, and an algorithm for diagnosis and initial therapy is shown in Fig. 349-2. The criteria are intended for confirming the diagnosis of SLE in patients included in studies; the author uses them in individual patients for estimating the probability that a disease is SLE. Any combination of four or more criteria, with at least one in the clinical and one in the immunologic category, well documented at any time during an individual’s history, makes it likely that the patient has SLE. (Specificity and sensitivity are ~93% and ~92%, respectively.) In many patients, criteria accrue over time. Antinuclear antibodies (ANA) are positive in >98% of patients during the course of disease; repeated negative tests by immunofluorescent methods suggest that the diagnosis is not SLE, unless other autoantibodies are present (Fig. 349-2). High-titer IgG antibodies to double-stranded DNA and antibodies to the Sm antigen are both specific for SLE and, therefore, favor the diagnosis in the presence of compatible clinical manifestations. The presence in an individual of multiple autoantibodies without clinical symptoms should not be considered diagnostic for SLE, although such persons are at increased risk.

INTERPRETATION OF CLINICAL MANIFESTATIONS

When a diagnosis of SLE is made, it is important to establish the severity and potential reversibility of the illness and to estimate the possible consequences of various therapeutic interventions. In the following paragraphs, descriptions of some disease manifestations begin with relatively mild problems and progress to those more life-threatening.

OVERVIEW AND SYSTEMIC MANIFESTATIONS

At its onset, SLE may involve one or several organ systems; over time, additional manifestations may occur (Tables 349-3 and 349-4). Most of the autoantibodies characteristic of each person are present at the time clinical manifestations appear (Tables 349-1 and 349-3). Severity of SLE varies from mild and intermittent to severe and fulminant. Approximately 85% of patients have either continuing active disease (on current treatment) or one or more flares of active disease annually. Permanent complete remissions (absence of symptoms with no treatment) are rare; however, low-level disease activity on treatments such as hydroxychloroquine and/or low dose prednisone is achievable in ~35% of patients. Systemic symptoms, particularly fatigue and myalgias/arthralgias, are present most of the time. Severe systemic illness requiring high dose glucocorticoid therapy can occur with fever, prostration, weight loss, and anemia with or without other organ-targeted manifestations.

MUSCULOSKELETAL MANIFESTATIONS

Most people with SLE have intermittent polyarthritis, varying from mild to disabling, characterized by soft tissue swelling and tenderness in joints and/or tendons, most commonly in hands, wrists, and knees. Joint deformities (hands and feet) develop in only 10%. Erosions on joint x-rays are rare but can be identified by ultrasound in 10–50% of patients. Some individuals have rheumatoid-like arthritis with erosions and fulfill criteria for both RA and SLE (“rhupus”). Joint pain is the most common reason that patients increase their dose of glucocorticoids. If pain persists in a single joint, such as knee, shoulder, or hip, a diagnosis of ischemic necrosis of bone (INB) should be considered, particularly if there are no other manifestations of active SLE, because INB prevalence is increased in SLE, especially in patients treated with systemic glucocorticoids. Myositis with clinical muscle weakness, elevated creatine kinase levels, positive magnetic resonance imaging (MRI) scan, and muscle necrosis and inflammation on biopsy can occur, although most patients have myalgias without frank myositis. Glucocorticoid therapies (commonly) and antimalarial therapies (rarely) can cause muscle weakness; these adverse effects must be distinguished from active inflammatory disease.

CUTANEOUS MANIFESTATIONS

Lupus dermatitis can be classified as acute, subacute, or chronic, and there are many different types of lesions encompassed within these groups. Discoid lupus erythematosus (DLE) is the most common chronic dermatitis in lupus; lesions are roughly circular with slightly raised, scaly hyperpigmented erythematous rims and depigmented, atrophic centers in which all dermal appendages are permanently destroyed. Lesions can be disfiguring, particularly on the face and scalp. Treatment consists primarily of topical or locally injected glucocorticoids and systemic antimalarials. Only 5% of people with DLE have SLE (although half have positive ANA); however, among individuals with SLE, as many as 20% have DLE. The most common acute SLE rash is a photosensitive, slightly raised erythema, occasionally scaly, on the face (particularly the cheeks and nose—the “butterfly” rash), ears, chin, V region of the neck and chest, upper back, and extensor surfaces of the arms. Worsening of this rash often accompanies flare of systemic disease. Subacute cutaneous lupus erythematosus (SCLE) consists of scaly red patches similar to psoriasis, or circular flat red-rimmed lesions. Patients with these manifestations are exquisitely photosensitive; most have antibodies to Ro (SS-A). Other SLE rashes include recurring urticaria, lichen planus-like dermatitis, bullae, and panniculitis (“lupus profundus”). Rashes can be minor or severe; they may be the major disease manifestation. Small ulcerations on the oral or nasal mucosa are common in SLE; the lesions resemble aphthous ulcers and may or may not be painful.

RENAL MANIFESTATIONS

Nephritis is usually the most serious manifestation of SLE, particularly because nephritis and infection are the leading causes of mortality in the first decade of disease. Because nephritis is asymptomatic in most lupus patients, urinalysis should be ordered in any person suspected of having SLE. The classification of lupus nephritis is primarily histologic (see “Pathology,” above, and Table 349-2). Renal biopsy is recommended for every SLE patient with any clinical evidence of nephritis; results are used to plan current and near-future therapies. Patients with dangerous proliferative forms of glomerular damage (ISN III and IV) usually have microscopic hematuria and proteinuria (>500 mg per 24 h); approximately one-half develop nephrotic syndrome, and most develop hypertension. If diffuse proliferative glomerulonephritis (DPGN) is inadequately treated, virtually all patients develop ESRD within 2 years of diagnosis. Therefore, aggressive immunosuppression is indicated (usually systemic glucocorticoids plus another immunosuppressive drug), unless damage is irreversible (Fig. 349-2, Table 349-5). African Americans are more likely to develop ESRD than are whites, even with the most current therapies. Overall in the United States, ~20% of individuals with lupus DPGN die or develop ESRD within 10 years of diagnosis. Such individuals require aggressive control of SLE and of the complications of renal disease and of therapy. Approximately 20% of SLE patients with proteinuria (usually nephrotic) have membranous glomerular changes without proliferative changes on renal biopsy. Their outcome is better than for those with DPGN, but patients with class V and nephrotic range proteinuria should be treated in the same way as those with classes III or IV proliferative disease. Lupus nephritis tends to be an ongoing disease, with flares requiring re-treatment or increased treatment over many years. For most people with lupus nephritis, accelerated atherosclerosis becomes important after several years of disease; attention must be given to control of systemic inflammation, blood pressure, hyperlipidemia, and hyperglycemia.

NERVOUS SYSTEM MANIFESTATIONS

There are many central nervous system (CNS) and peripheral nervous system manifestations of SLE; in some patients, these are the major cause of morbidity and mortality. It is useful to approach this diagnostically by asking first whether the symptoms result from SLE or another condition (such as infection in immunosuppressed individuals or side effects of therapies). If symptoms are related to SLE, it should be determined whether they are caused by a diffuse process (requiring immunosuppression) or vascular occlusive disease (requiring anticoagulation). The most common manifestation of diffuse CNS lupus is cognitive dysfunction, including difficulties with memory and reasoning. Headaches are also common. When excruciating, they often indicate SLE flare; when milder, they are difficult to distinguish from migraine or tension headaches. Seizures of any type may be caused by lupus; treatment often requires both antiseizure and immunosuppressive therapies. Psychosis can be the dominant manifestation of SLE; it must be distinguished from glucocorticoid-induced psychosis. The latter usually occurs in the first weeks of glucocorticoid therapy, at daily doses of ≥40 mg of prednisone or equivalent; psychosis resolves over several days after glucocorticoids are decreased or stopped. Myelopathy is not rare and is often disabling; rapid initiation of immunosuppressive therapy starting with high-dose glucocorticoids is standard of care.

VASCULAR OCCLUSIONS INCLUDING STROKE AND MYOCARDIAL INFARCTIONS

The prevalence of transient ischemic attacks, strokes, and myocardial infarctions is increased in patients with SLE. These vascular events are increased in, but not exclusive to, SLE patients with antibodies to phospholipids (antiphospholipid antibodies), which are associated with hypercoagulability and acute thrombotic events (Chap. 350). Ischemia in the brain can be caused by focal occlusion (either noninflammatory or associated with vasculitis) or by embolization from carotid artery plaque or from fibrinous vegetations of Libman-Sacks endocarditis. Appropriate tests for antiphospholipid antibodies (see below) and for sources of emboli should be ordered in such patients to estimate the need for, intensity of, and duration of anti-inflammatory and/or anticoagulant therapies. When it is most likely that a cerebral event results from clotting, long-term anticoagulation is the therapy of choice. Two processes can occur at once—vasculitis plus bland vascular occlusions—in which case it is appropriate to treat with anticoagulation plus immunosuppression.

In SLE, myocardial infarctions are primarily manifestations of accelerated atherosclerosis. The increased risk for vascular events is three- to tenfold overall, and is highest in women aged <49 years. Characteristics associated with increased risk for atherosclerosis include male gender, older age, hypertension, dyslipidemia, diabetes, dysfunctional proinflammatory high-density lipoproteins, repeated high scores for disease activity, high cumulative or daily doses of glucocorticoids, and high serum levels of homocysteine and leptin. Statin therapies reduce levels of low-density lipoproteins (LDL) in SLE patients; significant reduction of cardiac events by statins has been shown in SLE patients with renal transplants and recently in an epidemiologic study of large number of patients in Taiwan.

PULMONARY MANIFESTATIONS

The most common pulmonary manifestation of SLE is pleuritis with or without pleural effusion. This manifestation, when mild, may respond to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs); when more severe, patients require a brief course of glucocorticoid therapy. Pulmonary infiltrates also occur as a manifestation of active SLE and are difficult to distinguish from infection on imaging studies. Life-threatening pulmonary manifestations include interstitial inflammation leading to fibrosis, shrinking lung syndrome, and intraalveolar hemorrhage; all of these probably require early aggressive immunosuppressive therapy as well as supportive care. Pulmonary arterial hypertension occurs in a small proportion of SLE patients and should be treated in the same way as idiopathic pulmonary hypertension.

CARDIAC MANIFESTATIONS

Pericarditis is the most frequent cardiac manifestation; it usually responds to anti-inflammatory therapy and infrequently leads to tamponade. More serious cardiac manifestations are myocarditis and fibrinous endocarditis of Libman-Sacks. The endocardial involvement can lead to valvular insufficiencies, most commonly of the mitral or aortic valves, or to embolic events. It has not been proven that glucocorticoid or other immunosuppressive therapies lead to improvement of lupus myocarditis or endocarditis, but it is usual practice to administer a trial of high-dose steroids along with appropriate supportive therapy for heart failure, arrhythmia, or embolic events. As discussed above, patients with SLE are at increased risk for myocardial infarction, usually due to accelerated atherosclerosis, which probably results from immune attack, chronic inflammation, and/or chronic oxidative damage to arteries.

HEMATOLOGIC MANIFESTATIONS

The most frequent hematologic manifestation of SLE is anemia, usually normochromic normocytic, reflecting chronic illness. Hemolysis can be rapid in onset and severe, requiring high-dose glucocorticoid therapy, which is effective in most patients. Leukopenia is also common and almost always consists of lymphopenia, not granulocytopenia; lymphopenia rarely predisposes to infections and by itself usually does not require therapy. Thrombocytopenia may be a recurring problem. If platelet counts are >40,000/μL and abnormal bleeding is absent, therapy may not be required. High-dose glucocorticoid therapy (e.g., 1 mg/kg per day of prednisone or equivalent) is usually effective for the first few episodes of severe thrombocytopenia. Recurring or prolonged hemolytic anemia or thrombocytopenia, or disease requiring an unacceptably high dose of daily glucocorticoids, should be treated with additional strategies such as rituximab, platelet growth factors, and/or splenectomy (see “Management of Systemic Lupus Erythematosus” below).

GASTROINTESTINAL MANIFESTATIONS

Nausea, sometimes with vomiting, and diarrhea can be manifestations of an SLE flare, as can diffuse abdominal pain probably caused by autoimmune peritonitis and/or intestinal vasculitis. Increases in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are common when SLE is active. These manifestations usually improve promptly during systemic glucocorticoid therapy. Vasculitis involving the intestine may be life-threatening; perforations, ischemia, bleeding, and sepsis are frequent complications. Aggressive immunosuppressive therapy with high-dose glucocorticoids is recommended for short-term control; evidence of recurrence is an indication for additional therapies.

OCULAR MANIFESTATIONS

Sicca syndrome (Sjögren’s syndrome; Chap. 354) and nonspecific conjunctivitis are common in SLE and rarely threaten vision. In contrast, retinal vasculitis and optic neuritis are serious manifestations: blindness can develop over days to weeks. Aggressive immunosuppression is recommended, although there are no controlled trials to prove effectiveness. Complications of systemic and intraorbital glucocorticoid therapy include cataracts (common) and glaucoma.

LABORATORY TESTS

Laboratory tests serve (1) to establish or rule out the diagnosis; (2) to follow the course of disease, particularly to suggest that a flare is occurring or organ damage is developing; and (3) to identify adverse effects of therapies.

TESTS FOR AUTOANTIBODIES

Diagnostically, the most important autoantibodies to detect are ANA because the test is positive in >95% of patients, usually at the onset of symptoms (Tables 349-1 AND 349-3). A few patients develop ANA within 1 year of symptom onset; repeated testing may thus be useful. ANA tests using immunofluorescent methods are more reliable than enzyme-linked immunosorbent assays (ELISAs) and/or bead assays, which have less specificity. ANA-negative lupus exists but is rare in adults and is usually associated with other autoantibodies (anti-Ro or anti-DNA). High-titer IgG antibodies to double-stranded DNA (dsDNA) (but not to single-stranded DNA) are specific for SLE. ELISA and immunofluorescent reactions of sera with the dsDNA in the flagellate Crithidia luciliae have ~60% sensitivity for SLE. Titers of anti-dsDNA vary over time. In some patients, increases in quantities of anti-dsDNA herald a flare, particularly of nephritis or vasculitis, especially when associated with declining levels of C3 or C4 complement. Antibodies to Sm are also specific for SLE and assist in diagnosis; anti-Sm antibodies do not usually correlate with disease activity or clinical manifestations. Antiphospholipid antibodies are not specific for SLE, but their presence fulfills one classification criterion, and they identify patients at increased risk for venous or arterial clotting, thrombocytopenia, and fetal loss. There are three widely accepted tests that measure different antibodies (anticardiolipin, anti-β₂-glycoprotein, and the lupus anticoagulant). ELISA is used for anticardiolipin and anti-β₂-glycoprotein (both internationally standardized with good reproducibility); a sensitive phospholipid-based activated prothrombin time such as the dilute Russell venom viper test is used to identify the lupus anticoagulant. The higher the titers of IgG anticardiolipin (>40 IU is considered high), and the greater the number of different antiphospholipid antibodies that are detected, the greater is the risk for a clinical episode of clotting. Quantities of antiphospholipid antibodies may vary markedly over time; repeated testing is justified if clinical manifestations of the APS appear (Chap. 350). To classify a patient as having APS, with or without SLE, by international criteria requires the presence of one or more clotting episodes and/or repeated fetal losses plus at least two positive tests for antiphospholipid antibodies, at least 12 weeks apart; however, many patients with APS do not meet these stringent criteria, which are intended for inclusion of patients into studies.

An additional autoantibody test with predictive value (not used for diagnosis) detects anti-Ro/SS-A, which indicates increased risk for neonatal lupus, sicca syndrome, and SCLE. Women with child-bearing potential and SLE should be screened for antiphospholipid antibodies and anti-Ro, because both antibodies have the potential to cause fetal harm.

STANDARD TESTS FOR DIAGNOSIS

Screening tests for complete blood count, platelet count, and urinalysis may detect abnormalities that contribute to the diagnosis and influence management decisions.

TESTS FOR FOLLOWING DISEASE COURSE

It is useful to follow tests that indicate the status of organ involvement known to be present during SLE flares. These might include urinalysis for hematuria and proteinuria, hemoglobin levels, platelet counts, and serum levels of creatinine or albumin. There is great interest in identification of additional markers of disease activity. Candidates include levels of anti-DNA and anti-C1q antibodies, several components of complement (C3 is most widely available), activated complement products (an assay is commercially available that measures binding to the C4d receptor on erythrocytes and B cells), IFN-inducible gene expression in peripheral blood cells, serum levels of BLyS (B lymphocyte stimulator, also called BAFF), and urinary levels of TNF-like weak inducer of apoptosis (TWEAK), neutrophil gelatinase-associated lipocalin (NGAL), or monocyte chemotactic protein 1 (MCP-1). None is uniformly agreed upon as a reliable indicator of flare or of response to therapeutic interventions. It is likely that a panel of multiple proteins and nuclear products (and possibly levels of selected miRNAs and methylation profiles of DNA) will be developed to predict both impending flare and response to recently instituted therapies. Increased quantities of plasma cells, and increased expression of their gene signatures in whole blood, are associated with active disease and flares, but measurements are not commercially available. For now, the physician should determine for each patient whether certain available laboratory test changes predict flare (falling complement, rising anti-DNA, increased proteinuria, worsening anemia, etc.). If so, altering therapy in response to these changes may be advisable (30 mg of prednisone daily for 2 weeks has been shown to prevent flares in patients with rising anti-DNA plus falling complement). In addition, given the increased prevalence of atherosclerosis in SLE, it is advisable to follow the recommendations of the National Cholesterol Education Program for testing and treatment, including scoring of SLE as an independent risk factor, similar to diabetes mellitus.

MANAGEMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS

There is no cure for SLE, and complete sustained remissions are rare. There is an international effort to encourage practitioners and patients to aim for low-level disease activity (mild symptoms on the lowest possible doses of medications) which can be achieved for at least a year in 30–50% of SLE patients. Therefore, the physician should plan to induce remissions of acute flares and then maintain improvements with strategies that suppress symptoms to an acceptable level and prevent organ damage. Therapeutic choices depend on (1) whether disease manifestations are life-threatening or likely to cause organ damage, justifying aggressive therapies; (2) whether manifestations are potentially reversible; and (3) the best approaches to preventing complications of disease and its treatments. Therapies, doses, and adverse effects are listed in Table 349-5.

CONSERVATIVE THERAPIES FOR MANAGEMENT OF NON-LIFE-THREATENING DISEASE

Among patients with fatigue, pain, and autoantibodies indicative of SLE, but without major organ involvement, management can be directed to suppression of symptoms. Analgesics and antimalarials are mainstays. NSAIDs are useful analgesics/anti-inflammatories, particularly for arthritis/arthralgias. However, two major issues indicate caution in using NSAIDs. First, SLE patients compared with the general population are at increased risk for NSAID-induced aseptic meningitis, elevated serum transaminases, hypertension, and renal dysfunction. Second, all NSAIDs, particularly those that inhibit cyclooxygenase-2 specifically, may increase risk for myocardial infarction. Acetaminophen to control pain may be a good strategy, but NSAIDs are more effective in some patients. The relative hazards of NSAIDs compared with low-dose glucocorticoid therapy have not been established. Antimalarials (hydroxychloroquine, chloroquine, and quinacrine) often reduce dermatitis, arthritis, and fatigue. A randomized, placebo-controlled, prospective trial has shown that withdrawal of hydroxychloroquine results in increased numbers of disease flares; hydroxychloroquine also reduces accrual of tissue damage, including renal damage, over time. Some experts recommend a hydroxychloroquine blood level of ≥750 ng/mL to optimize responses in active SLE; after achieving response doses should be reduced. Because of potential retinal toxicity (occurring in 6% of patients after cumulative doses of 1000 g, ~5 years of continuing therapy), patients receiving antimalarials should undergo ophthalmologic examinations annually. A placebo-controlled prospective trial suggests that administration of dehydroepiandrosterone may reduce disease activity. If quality of life is inadequate despite these conservative measures, treatment with low doses of systemic glucocorticoids may be necessary. Belimumab is effective for 50% of patients with fatigue, rash, and/or the arthritis of SLE; it is expensive and should be considered after other approaches fail or are not tolerated. SLE patients most likely to respond to belimumab have robust clinical activity (a Systemic Lupus Erythematosus Disease Activity Index [SLEDAI] score of ≥10), positive anti-DNA, and low serum complement. SLEDAI is a widely used measure of SLE disease activity; scores >3 reflect clinically active disease. Lupus dermatitis should be managed with topical sunscreens, antimalarials, topical glucocorticoids and/or tacrolimus, and if severe or unresponsive, systemic glucocorticoids with or without mycophenolate mofetil, azathioprine, or belimumab.

LIFE-THREATENING SLE: PROLIFERATIVE FORMS OF LUPUS NEPHRITIS

Guidelines for management of lupus nephritis have been published recently by the American College of Rheumatology and the European League Against Rheumatism (encompassed and referenced in Fig. 349-2 and Table 349-5). The mainstay of treatment for any inflammatory life-threatening or organ-threatening manifestations of SLE is systemic glucocorticoids (0.5–1 mg/kg per day PO or 500–1000 mg of methylprednisolone sodium succinate IV daily for 3 days followed by 0.5–1 mg/kg of daily prednisone or equivalent). Evidence that glucocorticoid therapy is life-saving comes from retrospective studies from the predialysis era; survival was significantly better in people with DPGN treated with high-dose daily glucocorticoids (40–60 mg of prednisone daily for 4–6 months) versus lower doses. Currently, high doses are recommended for much shorter periods; recent trials of interventions for severe SLE use 4–6 weeks of 0.5–1 mg/kg per day of prednisone or equivalent. Thereafter, doses are tapered as rapidly as the clinical situation permits, usually to a maintenance dose ranging from 5 to 10 mg of prednisone or equivalent per day. Most patients with an episode of severe SLE require many years of maintenance therapy with low-dose glucocorticoids, which can be increased to prevent or treat disease flares. Frequent attempts to gradually reduce the glucocorticoid requirement are recommended because virtually everyone develops important adverse effects (Table 349-5). High-quality clinical studies regarding initiating therapy for severe, active SLE with IV pulses of high-dose glucocorticoids are not available. Most recent clinical trials in lupus nephritis have initiated therapy with high-dose IV glucocorticoid pulses (500–1000 mg daily for 3–5 days). This approach must be tempered by safety considerations, such as the presence of conditions adversely affected by glucocorticoids (e.g., infection, hyperglycemia, hypertension, osteoporosis). A current clinical trial is evaluating mycophenolate mofetil plus rituximab without maintenance daily glucocorticoids to treat lupus nephritis: if results are positive, the paradigm for short-term and long-term management of SLE is likely to change.

Cytotoxic/immunosuppressive agents added to glucocorticoids are recommended to treat serious SLE. Almost all prospective controlled trials in SLE involving cytotoxic agents have been conducted in combination with glucocorticoids in patients with lupus nephritis. Therefore, the following recommendations apply to treatment of nephritis. Either cyclophosphamide (an alkylating agent) or mycophenolate mofetil (a relatively lymphocyte-specific inhibitor of inosine monophosphatase and therefore of purine synthesis) is an acceptable choice for induction of improvement in severely ill patients; azathioprine (a purine analogue and cycle-specific antimetabolite) may be effective but is associated with more flares. In patients whose renal biopsies show ISN grade III or IV disease, early treatment with combinations of glucocorticoids and cyclophosphamide reduces progression to ESRD and death. Shorter-term studies with glucocorticoids plus mycophenolate mofetil (prospective randomized trials of 6 months, follow-up studies of 5 years) show that this regimen is similar to cyclophosphamide in achieving improvement. Comparisons are complicated by effects of race, since higher proportions of African Americans (and other non-Asian, nonwhite races) respond to mycophenolate than to cyclophosphamide, whereas similar proportions of whites and Asians respond to each drug. Regarding toxicity, diarrhea is more common with mycophenolate mofetil; amenorrhea, leukopenia, and nausea are more common with high dose cyclophosphamide. Importantly, rates of severe infections and death are similar in meta-analyses. Two different regimens of IV cyclophosphamide are available. For white patients with northern European backgrounds, low doses of cyclophosphamide (500 mg every 2 weeks for six total doses, followed by azathioprine or mycophenolate maintenance) are as effective as standard high doses, with less toxicity. Ten-year follow-up has shown no differences between the high-dose and low-dose groups (death or ESRD in 9–20% of patients in each group). It is not clear whether the data apply to U.S. populations, especially African Americans and Latinas. High-dose cyclophosphamide (500–1000 mg/m² body surface area given monthly IV for 6 months, followed by azathioprine or mycophenolate maintenance) is an acceptable approach for patients with severe nephritis (e.g., multiple cellular crescents and/or fibrinoid necrosis on renal biopsy, or rapidly progressive glomerulonephritis). Cyclophosphamide and mycophenolate responses begin 3–16 weeks after treatment is initiated, whereas glucocorticoid responses may begin within 24 h.

For maintenance therapy, mycophenolate and azathioprine probably are similar in efficacy and toxicity; both are safer than cyclophosphamide. In a recently published multicenter study, mycophenolate was superior to azathioprine in maintaining renal function and survival in patients who responded to induction therapy with either cyclophosphamide or mycophenolate. The incidence of ovarian failure, a common effect of high-dose cyclophosphamide therapy (but probably not of low-dose therapy), can be reduced by treatment with a gonadotropin-releasing hormone agonist (e.g., leuprolide 3.75 mg intramuscularly) prior to each monthly cyclophosphamide dose. Patients with high serum creatinine levels (e.g., ≥265 μmol/L [≥3.0 mg/dL]) many months in duration and high chronicity scores on renal biopsy are not likely to respond to any of these therapies. In general, it may be better to induce improvement in an African-American or Hispanic patient with proliferative glomerulonephritis with mycophenolate mofetil (2–3 g daily) rather than cyclophosphamide, with the option to switch if no evidence of response is detectable after 3–6 months of treatment. For whites and Asians, induction with either mycophenolate mofetil or cyclophosphamide is acceptable. Cyclophosphamide may be discontinued when it is clear that a patient is improving. The number of SLE flares is reduced by maintenance therapy with mycophenolate mofetil (1.5–2 g daily) or azathioprine (1–2.5 mg/kg per day). Both cyclophosphamide and mycophenolate mofetil are potentially teratogenic; patients should be off either medication for at least 3 months before attempting to conceive. Azathioprine can be used if necessary to control active SLE in patients who are pregnant. If azathioprine is used either for induction or maintenance therapy, patients may be prescreened for homozygous deficiency of the TMPT enzyme (which is required to metabolize the 6-mercaptopurine product of azathioprine) because they are at higher risk for bone marrow suppression.

Good improvement occurs in ~80% of lupus nephritis patients receiving either cyclophosphamide or mycophenolate at 1–2 years of follow-up. However, in some studies, at least 50% of these individuals have flares of nephritis over the next 5 years, and re-treatment is required; such individuals are more likely to progress to ESRD. Long-term outcome of lupus nephritis to most interventions is better in whites than in African Americans. Methotrexate (a folinic acid antagonist) may have a role in the treatment of arthritis and dermatitis but probably not in nephritis or other life-threatening disease. Small controlled trials (in Asia) of leflunomide, a relatively lymphocyte-specific pyrimidine antagonist licensed for use in rheumatoid arthritis, have suggested it can suppress disease activity in some SLE patients. Cyclosporine and tacrolimus, which inhibit calcium flux and therefore production of IL-2 and T lymphocyte functions, have not been studied in prospective controlled trials in SLE in the United States; several studies in Asia have shown they are effective in lupus nephritis. A recent trial in China showed that a combination of low dose mycophenolate mofetil (one gram daily) plus tacrolimus (4 mg daily) plus prednisone (pulse followed by 0.6 mg/kg/d) had a better response rate than high dose intravenous cyclophosphamide. Because calcineurin blockers have potential nephrotoxicity but little bone marrow toxicity, the author uses them for periods of a few months in patients with steroid-resistant cytopenias of SLE, in steroid-resistant patients who have developed bone marrow suppression from standard cytotoxic agents, or in patients with active SLE in spite of treatment with mycophenolate or cyclosphosphamide.

Most patients with SLE of any type should be treated with hydroxychloroquine since it prevents damage in skin and kidney and reduces overall damage scores. Patients with proteinuria > 500 mg daily should receive ACE inhibitors or ARBs, as they reduce the chance for ESRD.

Use of biologics directed against B cells for active SLE is under intense study. Use of anti-CD20 (rituximab), particularly in patients with SLE who are resistant to the more standard combination therapies discussed above, is controversial. Several open trials have shown efficacy in a majority of such patients, both for nephritis and for extrarenal lupus. However, recent prospective placebo-controlled randomized trials, one in renal and one in nonrenal SLE, did not show a difference between anti-CD20 and placebo when added to standard combination therapies. Belimumab, which is approved by the FDA for use in SLE without active renal disease (indication is serologically positive SLE which has failed standard treatments), is in clinical trials for active lupus nephritis. Drugs that kill plasma cells, used in multiple myeloma, are being studied in SLE, as are molecules and antibodies that prevent activation of B cells and/or T cells, such as Jak/Stat inhibitors.

SPECIAL CONDITIONS IN SLE THAT MAY REQUIRE ADDITIONAL OR DIFFERENT THERAPIES

Crescentic Lupus Nephritis

The presence of cellular or fibrotic crescents in glomeruli with proliferative glomerulonephritis indicates a worse prognosis than in patients without this feature. There are no large prospective multinational controlled trials showing efficacy of cyclophosphamide, mycophenolate, cyclosporine, or tacrolimus in such cases. Most authorities recommend high-dose cyclophosphamide as the induction therapy of choice; there is some evidence that high dose mycophenolate mofetil is equally effective.

Membranous Lupus Nephritis

Most SLE patients with membranous (INS-V) nephritis also have proliferative changes and should be treated for proliferative disease. However, some have pure membranous changes. Treatment for this group is less well defined. Some authorities do not recommend immunosuppression unless proteinuria is in the nephrotic range (although treatment with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers is recommended). In those patients, recent prospective controlled trials suggest that alternate-day glucocorticoids plus cyclophosphamide or mycophenolate mofetil or cyclosporine are all effective in the majority of patients in reducing proteinuria. It is more controversial whether they preserve renal function over the long term.

Pregnancy and Lupus

Fertility rates for men and women with SLE are probably normal. However, rate of fetal loss is increased (approximately two- to threefold) in women with SLE. Fetal demise is higher in mothers with high disease activity, antiphospholipid antibodies (especially the lupus anticoagulant), hypertension, and/or active nephritis. Suppression of disease activity can be achieved by administration of systemic glucocorticoids. A placental enzyme, 11-β-dehydrogenase 2, deactivates glucocorticoids; it is more effective in deactivating prednisone and prednisolone than the fluorinated glucocorticoids dexamethasone and betamethasone. Glucocorticoids are listed by the FDA as pregnancy category A (no evidence of teratogenicity in human studies); cyclosporine, tacrolimus, and rituximab are listed as category C (may be teratogenic in animals but no good evidence in humans); azathioprine, hydroxychloroquine, mycophenolate mofetil, and cyclophosphamide are category D (there is evidence of teratogenicity in humans, but benefits might outweigh risks in certain situations); and methotrexate is category X (risks outweigh benefits). Therefore, active SLE in pregnant women should be controlled with hydroxychloroquine and, if necessary, prednisone/prednisolone at the lowest effective doses for the shortest time required. Azathioprine may be added if these treatments do not suppress disease activity. Adverse effects of prenatal glucocorticoid exposure (primarily betamethasone, which is not recommended) on offspring may include low birth weight, developmental abnormalities in the CNS, and predilection toward adult metabolic syndrome. It is likely that each of these glucocorticoids and immunosuppressive medications gets into breast milk, at least in low levels; patients should consider not breastfeeding if they need therapy for SLE. In SLE patients with antiphospholipid antibodies and prior fetal losses, treatment with heparin (usually low-molecular-weight) plus low-dose aspirin has been shown in prospective controlled trials to increase significantly the proportion of live births. Aspirin alone may be used, although most consider it less effective than heparin-plus-aspirin. Warfarin is teratogenic. Studies with oral thrombin and Factor Xa inhibitors are in progress for APSs; however, their role in preventing fetal loss is not established. An additional potential problem for the fetus is the presence of antibodies to Ro, sometimes associated with neonatal lupus consisting of rash and congenital heart block with or without cardiomyopathy. The cardiac manifestations can be life-threatening; therefore the presence of anti-Ro requires vigilant monitoring of fetal heart rates with prompt intervention (delivery if possible) if distress occurs. Recent evidence shows that hydroxychloroquine treatment of an anti-Ro-positive mother whose infant develops congenital heart block significantly reduces the chance that subsequent fetuses will develop heart block. There is some evidence that dexamethasone treatment of a mother in whom first- or second-degree heart block is detected in utero sometimes prevents progression of heart block. Women with SLE usually tolerate pregnancy without disease flares. However, a small proportion develops severe flares requiring aggressive glucocorticoid therapy or early delivery.

Lupus and Antiphospholipid Syndrome

Patients with SLE who have venous or arterial clotting and/or repeated fetal losses and at least two positive tests for antiphospholipid antibodies have APS and should be managed with long-term anticoagulation (Chap. 350). With warfarin, a target international normalized ratio (INR) of 2.0–2.5 is recommended for patients with one episode of venous clotting; an INR of 3.0–3.5 is recommended for patients with recurring clots or arterial clotting, particularly in the CNS. Recommendations are based on both retrospective and prospective studies of posttreatment clotting events and adverse effects from anticoagulation. Thrombin and Factor Xa inhibitors are under study.

Microvascular Thrombotic Crisis (Thrombotic Thrombocytopenic Purpura, Hemolytic-Uremic Syndrome)

This syndrome of hemolysis, thrombocytopenia, and microvascular thrombosis in kidneys, brain, and other tissues carries a high mortality rate and occurs most commonly in young individuals with lupus nephritis. The most useful laboratory tests are identification of schistocytes on peripheral blood smears, elevated serum levels of lactate dehydrogenase, and antibodies to ADAMS13. Plasma exchange or extensive plasmapheresis is usually life-saving; most authorities recommend concomitant glucocorticoid therapy; there is no evidence that cytotoxic drugs are effective.

Lupus Dermatitis

Patients with any form of lupus dermatitis should minimize exposure to ultraviolet light, using appropriate clothing and sunscreens with a sun protection factor of at least 30. Topical glucocorticoids and antimalarials (such as hydroxychloroquine) are effective in reducing lesion severity in most patients and are relatively safe. Systemic treatment with retinoic acid is a useful strategy in patients with inadequate improvement on topical glucocorticoids and antimalarials; adverse effects are potentially severe (particularly fetal abnormalities), and there are stringent reporting requirements for its use in the United States. Extensive, pruritic, bullous, or ulcerating dermatitides usually improve promptly after institution of systemic glucocorticoids; tapering may be accompanied by flare of lesions, thus necessitating use of a second medication such as hydroxychloroquine, retinoids, or belimumab. Cytotoxic medications such as methotrexate, azathioprine, or mycophenolate mofetil may also be effective. In therapy-resistant lupus dermatitis there are reports of success with topical tacrolimus (caution must be exerted because of the possible increased risk for malignancies) or with systemic dapsone or thalidomide (the extreme danger of fetal deformities from thalidomide requires permission from and supervision by the supplier; peripheral neuropathy is also common).

PREVENTIVE THERAPIES

Prevention of complications of SLE and its therapy include providing appropriate vaccinations (the administration of influenza and pneumococcal vaccines has been studied in patients with SLE; flare rates are similar to those receiving placebo) and suppressing recurrent urinary tract infections. In patients receiving glucocorticoids, the higher the daily dose the lower the immune response to vaccination; however, the great majority of patients achieve protective levels. Vaccination with attenuated live viruses is generally discouraged in patients who are immunosuppressed; however, a recent study of vaccination of a small number of SLE patient with zostavax showed safety and efficacy. Strategies to prevent osteoporosis should be initiated in most patients likely to require long-term glucocorticoid therapy and/or with other predisposing factors. Postmenopausal women can be partially protected from steroid-induced osteoporosis with calcium supplementation, Vitamin D, and either bisphosphonates or denosumab. Safety of long-term use of these strategies in premenopausal women is not well established. Control of hypertension and appropriate prevention strategies for atherosclerosis, including monitoring and treatment of dyslipidemias, management of hyperglycemia, and management of obesity, are recommended. There is increasing evidence that statin therapies can reduce deaths from cardiac events in SLE patients. Finally, the physician must keep in mind that some cancers are increased in SLE patients including non-Hodgkin lymphomas and cancers of thyroid, lung, liver, and vulvar/vaginal tissues.

EXPERIMENTAL THERAPIES

Studies of highly targeted experimental therapies for SLE are in progress. They include (1) inhibition of IFN-α, which was promising in phase II clinical trials, (2) inhibition of IL12 and IL23 signaling; (3) inhibition of IL17; (4) inhibition of IL-6; (5) elimination of plasma cells; (6) inhibition of B/T cell second signal coactivation with CTLA-Ig or anti-CD40L; (7) inhibition of innate immune activation via TLR7 or TLR7 and 9; (8) induction of regulatory T cells with peptides from immunoglobulins or autoantigens or with low doses if IL2; and (9) inhibition of lymphocyte activation by blockade of Jak/Stat. A few studies have used vigorous untargeted immunosuppression with high-dose cyclophosphamide plus anti-T cell strategies, with rescue by transplantation of autologous hematopoietic stem cells for the treatment of severe and refractory SLE. One U.S. report showed an estimated mortality rate over 5 years of 15% and sustained remission in 50%. It is hoped that in the next edition of this text, we will be able to recommend more effective and less toxic approaches to treatment of SLE based on some of these strategies.

PATIENT OUTCOMES, PROGNOSIS, AND SURVIVAL

Survival in patients with SLE in the United States, Canada, Europe, and China is ~95% at 5 years, 90% at 10 years, and 78% at 20 years. In the United States, African Americans and Hispanic Americans with a mestizo heritage have a worse prognosis than whites, whereas Africans in Africa and Hispanic Americans with a Puerto Rican origin do not. The relative importance of gene mixtures and environmental differences accounting for ethnic differences is not known. Poor prognosis (~50% mortality in 10 years) in most series is associated with (at the time of diagnosis) high serum creatinine levels (>124 μmol/L [>1.4 mg/dL]), hypertension, nephrotic syndrome (24-h urine protein excretion >2.6 g), anemia (hemoglobin <124 g/L [<12.4 g/dL]), hypoalbuminemia, hypocomplementemia, antiphospholipid antibodies, male sex, ethnicity (African American, Hispanic with mestizo heritage), and low socioeconomic status. Data regarding outcomes in SLE patients with renal transplants show mixed results: some series show a twofold increase in graft rejection compared to patients with other causes of ESRD, whereas others show no differences. Overall patient survival is comparable (85% at 2 years). Lupus nephritis occurs in ~5% of transplanted kidneys. Disability in patients with SLE is common due primarily to chronic fatigue, arthritis, and pain, as well as renal disease. As many as 30–50% of patients may achieve low disease activity (defined as mild activity on hydroxychloroquine with or without low dose glucocorticoids); fewer than 10% experience remissions (defined as no disease activity on no medications). Both of these conditions may persist for a few years, but are usually not permanent, as flares of SLE occur. The leading causes of death in the first decade of disease are systemic disease activity, renal failure, and infections; subsequently, thromboembolic events become increasingly frequent causes of mortality.

DRUG-INDUCED LUPUS

This is a syndrome of positive ANA associated with symptoms such as fever, malaise, arthritis or intense arthralgias/myalgias, serositis, and/or rash. The syndrome appears during therapy with certain medications and biologic agents, is predominant in whites, has less female predilection than SLE, rarely involves kidneys or brain, is rarely associated with anti-dsDNA, is commonly associated with antibodies to histones, and usually resolves over several weeks after discontinuation of the offending medication. The list of substances that can induce lupus-like disease is long. Among the most frequent are the antiarrhythmics procainamide, disopyramide, and propafenone; the anti-hypertensive hydralazine; several angiotensin-converting enzyme inhibitors and beta blockers; the antithyroid propylthiouracil; the antipsychotics chlorpromazine and lithium; the anticonvulsants carbamazepine and phenytoin; the antibiotics isoniazid, minocycline, and nitrofurantoin (Macrodantin); the antirheumatic sulfasalazine; the diuretic hydrochlorothiazide; the antihyperlipidemics lovastatin and simvastatin. Biologics that can cause drug-induced lupus (DIL) include inhibitors of IFNs and TNF. In DIL, ANA usually appears before symptoms; however, many of the medications mentioned above induce ANA in patients who never develop symptoms of drug-induced lupus. It is appropriate to test for ANA at the first hint of relevant symptoms and to use test results to help decide whether to withdraw the suspect agent.

FURTHER READING

DEFINITIONS

Antiphospholipid syndrome (APS) is an autoantibody-mediated acquired thrombophilia characterized by recurrent arterial or venous thrombosis and/or pregnancy morbidity. It affects primarily females. APS may occur alone (primary) or in association with other autoimmune diseases, mainly systemic lupus erythematosus (SLE) (secondary). Catastrophic APS (CAPS) is a life-threatening rapidly progressive thromboembolic disease involving simultaneously three or more organs.

The major autoantibodies detected in patients’ sera are directed against phospholipids and/or phospholipid (PL)-binding plasma proteins such as prothrombin and β2 glycoprotein I (β2GPI). PLs are components of the cytoplasmic membrane of all living cells. The antibodies are directed against negatively charged PLs including among others cardiolipin, phosphocholine, and phosphatidylserine. The plasma protein β2GPI is a 43-kDa plasma apolipoprotein, which consists of 326 amino acids arranged in five domains (I through V). Domain V forms a positively charged patch, suitable to interact with negatively charged PLs. In plasma, β2GPI has a circular conformation with domain V binding to and concealing the B cell epitopes lying on domain I. Another group of antibodies termed lupus anticoagulant (LA) prolongs clotting times in vitro, which are not corrected by adding normal plasma (Table 350-1). Patients with APS often possess antibodies recognizing Treponema pallidum PL/cholesterol complexes, detected by Venereal Disease Research Laboratory (VDRL) tests and characterized as biologic false-positive serologic tests for syphilis (BFP-STS).

EPIDEMIOLOGY

The incidence of APS is estimated to be around 5 cases per 100,000 persons per year. Anti-PL antibodies occur in 1–5% of the general population. Their prevalence increases with age; however, it is questionable whether they are able to induce thrombotic events in elderly individuals. Moreover, one-third of patients with SLE and other autoimmune diseases (Chap. 349) possess these antibodies, with only 5–10% of them developing APS.

PATHOGENESIS

The initiating event for the induction of antibodies to PL-binding proteins seems to be infections, oxidative stress, and major physical stresses such as surgery or trauma. All these factors appear to induce increased apoptosis of the vessel endothelial cells and subsequent exposure of PLs. The latter, bound with serum proteins such as β2GPI or prothrombin, lead to neoantigen formation, which in turn triggers the induction of anti-PLs. The binding of anti-PLs to the disrupted endothelial cells leads to initiation of intravascular coagulation and thrombus formation. Complement activation has been also proposed as a mechanism of APS-related fetal injury.

CLINICAL MANIFESTATIONS AND LABORATORY FINDINGS

Clinical manifestations represent the consequences of venous or arterial thrombosis and/or pregnancy morbidity (Table 350-2). Venous thrombosis, superficial or deep, occurs primarily in the lower extremities often leading to pulmonary emboli. Thrombosis of the pulmonary arteries leads to pulmonary hypertension and thrombosis of the inferior vena cava to Budd-Chiari syndrome. Cerebral venous thrombosis, presents with signs and symptoms of intracranial hypertension and retinal vein thrombosis. Arterial thrombosis affects more commonly the arteries of the brain and is manifested as migraines, cognitive dysfunction, transient ischemic attacks, stroke, and retinal artery occlusion. Arterial thrombosis of the extremities presents with ischemic leg ulcers, digital gangrene, avascular bone necrosis, while thrombosis of other arteries leads to myocardial infarction, renal artery stenosis, glomerular lesions, and infarcts of spleen, pancreas, and adrenals.

Livedo reticularis consists of a mottled reticular vascular pattern that appears as a lace-like, purplish discoloration of the skin. It is probably caused by swelling of the venules due to obstruction of capillaries by thrombi. This clinical manifestation usually occurs together with vascular lesions in the central nervous system and with aseptic bone necrosis. Libman-Sacks endocarditis consists of very small vegetations, histologically characterized by organized platelet-fibrin microthrombi surrounded by growing fibroblasts and macrophages. Glomerular involvement is manifested with hypertension, mildly elevated serum creatinine levels, as well as mild proteinuria/hematuria. Histologically, in an acute phase, thrombotic microangiopathy is present in the glomerular capillaries. In a chronic phase, fibrous intima hyperplasia, fibrous and/or fibrocellular arteriolar occlusions, and focal cortical atrophy are present (Table 350-2). Pregnancy morbidity manifests with increased risk of recurrent miscarriages, intrauterine growth retardation, preeclampsia, eclampsia, and preterm birth. The major causes of these complications are infarctions of the placenta.

Premature atherosclerosis has been also recognized as a feature of APS. Musculoskeletal manifestations include in addition to bone necrosis, arthralgia/arthritis, bone marrow necrosis, muscle infarction, non-traumatic fractures, and osteoporosis. Coombs-positive hemolytic anemia and thrombocytopenia are laboratory findings associated with APS.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

The diagnosis of APS should be seriously considered in cases of thrombosis, cerebral vascular accidents in individuals <55 years of age, or pregnancy morbidity in the presence of livedo reticularis or thrombocytopenia. In these cases, aPL antibodies should be measured. The presence of at least one clinical and one laboratory criterion is compatible with the diagnosis, in the absence of other thrombophilia causes. Clinical criteria include: (1) vascular thrombosis defined as one or more clinical episodes of arterial, venous, or small vessel thrombosis in any tissue or organ; and (2) pregnancy morbidity, defined as (a) one or more unexplained deaths of a morphologically normal fetus at or beyond the tenth week of gestation; (b) one or more premature births of a morphologically normal neonate before the thirty-fourth week of gestation because of eclampsia, severe preeclampsia, or placental insufficiency; or (c) three or more unexplained consecutive spontaneous abortions before the tenth week of gestation. Laboratory criteria include (1) LA, (2) anticardiolipin (aCL), and/or (3) anti-β2GPI antibodies, at intermediate or high titers on two occasions, 12 weeks apart.

Differential diagnosis is based on the exclusion of other inherited or acquired causes of thrombophilia (Chap. 112), Coombs-positive hemolytic anemia (Chap. 96), and thrombocytopenia (Chap. 111). Livedo reticularis with or without a painful ulceration on the lower extremities may be also a manifestation of disorders affecting (1) the vascular wall, such as atherosclerosis, polyarteritis nodosa, SLE, cryoglobulinemia, and lymphomas; or (2) the vascular lumen, such as myeloproliferative disorders, hypercholesterolemia, or other causes of thrombophilia.

TREATMENT

ACKNOWLEDGMENT

I would like to thank Dr. P. G. Vlachoyiannopoulos for his contribution to the previous edition of the chapter.

FURTHER READING

INTRODUCTION

Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology characterized by a symmetric polyarthritis, the most common form of chronic inflammatory arthritis. Since persistently active RA often results in articular cartilage and bone destruction and functional disability, it is vital to diagnose and treat this disease early and aggressively before damage ensues. RA, a systemic disease, may also lead to a variety of extraarticular manifestations, including fatigue, subcutaneous nodules, lung involvement, pericarditis, peripheral neuropathy, vasculitis, and hematologic abnormalities, which must be managed accordingly.

Insights gained by a wealth of basic and clinical research over the past two decades have revolutionized the contemporary paradigms for the diagnosis and management of RA. Serum antibodies to cyclic citrullinated peptides (anti-CCPs) are routinely included with rheumatoid factor in the diagnostic evaluation of patients with suspected RA, and serve as biomarkers of prognostic significance. Advances in imaging modalities have assisted clinical decision-making by improving the detection of joint inflammation and damage. The science of RA has taken major leaps forward by illuminating new disease-related genes and environmental interactions and elucidating in more detail the molecular components and pathways of disease pathogenesis. The relative contribution of these molecular components and pathways has been further brought to light by the observed benefits of targeted biologic and small-molecule therapies. Despite this progress, incomplete understanding of the initiating events of RA and the factors perpetuating the chronic inflammatory response remains a sizable barrier to its cure and prevention.

The last two decades have witnessed a remarkable improvement in the outcomes of RA. The crippling arthritis of year’s past is encountered much less frequently today. Much of this progress can be traced to the expanded therapeutic armamentarium and the adoption of early treatment intervention. The shift in treatment strategy dictates a new mind-set for primary care practitioners—namely, one that demands early referral of patients with inflammatory arthritis to a rheumatologist for prompt diagnosis and initiation of therapy. Only then will patients achieve their best outcomes.

CLINICAL FEATURES

The incidence of RA increases between 25 and 55 years of age, after which it plateaus until the age of 75 and then decreases. The presenting symptoms of RA typically result from inflammation of the joints, tendons, and bursae. Patients often complain of early morning joint stiffness lasting more than 1 h that eases with physical activity. The earliest involved joints are typically the small joints of the hands and feet. The initial pattern of joint involvement may be monoarticular, oligoarticular (≤4 joints), or polyarticular (>5 joints), usually in a symmetric distribution. Some patients with inflammatory arthritis will present with too few affected joints to be classified as having RA—so-called undifferentiated inflammatory arthritis. Those with an undifferentiated arthritis who are most likely to be diagnosed later with RA have a higher number of tender and swollen joints, test positive for serum rheumatoid factor (RF) or anti-CCP antibodies, and have higher scores for physical disability.

Once the disease process of RA is established, the wrists, metacarpophalangeal (MCP), and proximal interphalangeal (PIP) joints stand out as the most frequently involved joints (Fig. 351-1). Distal interphalangeal (DIP) joint involvement may occur in RA, but it usually is a manifestation of coexistent osteoarthritis. Flexor tendon tenosynovitis is a frequent hallmark of RA and leads to decreased range of motion, reduced grip strength, and “trigger” fingers. Progressive destruction of the joints and soft tissues may lead to chronic, irreversible deformities. Ulnar deviation results from subluxation of the MCP joints, with subluxation, or partial dislocation, of the proximal phalanx to the volar side of the hand. Hyperextension of the PIP joint with flexion of the DIP joint (“swan-neck deformity”), flexion of the PIP joint with hyperextension of the DIP joint (“boutonnière deformity”), and subluxation of the first MCP joint with hyperextension of the first interphalangeal (IP) joint (“Z-line deformity”) also may result from damage to the tendons, joint capsule, and other soft tissues in these small joints. Inflammation about the ulnar styloid and tenosynovitis of the extensor carpi ulnaris may cause subluxation of the distal ulna, resulting in a “piano-key movement” of the ulnar styloid. Although metatarsophalangeal (MTP) joint involvement in the feet is an early feature of disease, chronic inflammation of the ankle and midtarsal regions usually comes later and may lead to pes planovalgus (“flat feet”). Large joints, including the knees and shoulders, are often affected in established disease, although these joints may remain asymptomatic for many years after onset.

Atlantoaxial involvement of the cervical spine is clinically noteworthy because of its potential to cause compressive myelopathy and neurologic dysfunction. Neurologic manifestations are rarely a presenting sign or symptom of atlantoaxial disease, but they may evolve over time with progressive instability of C1 on C2. The prevalence of atlantoaxial subluxation has been declining in recent years, and occurs now in <10% of patients. Unlike the spondyloarthritides (Chap. 355), RA rarely affects the thoracic and lumbar spine. Radiographic abnormalities of the temporomandibular joint occur commonly in patients with RA, but they are generally not associated with significant symptoms or functional impairment.

Extraarticular manifestations may develop during the clinical course of RA in up to 40% of patients, even prior to the onset of arthritis (Fig. 351-2). Patients most likely to develop extraarticular disease have a history of cigarette smoking, have early onset of significant physical disability, and test positive for serum RF or anti-CCP antibodies. Subcutaneous nodules, secondary Sjögren’s syndrome, interstitial lung disease (ILD), pulmonary nodules, and anemia are among the most frequently observed extraarticular manifestations. Recent studies have shown a decrease in the incidence and severity of at least some extraarticular manifestations, particularly Felty’s syndrome and vasculitis.

The most common systemic and extraarticular features of RA are described in more detail in the sections below.

CONSTITUTIONAL

These signs and symptoms include weight loss, fever, fatigue, malaise, depression, and in the most severe cases, cachexia; they generally reflect a high degree of inflammation and may even precede the onset of joint symptoms. In general, the presence of a fever of >38.3°C (101°F) at any time during the clinical course should raise suspicion of systemic vasculitis (see below) or infection.

NODULES

Subcutaneous nodules have been reported to occur in 30–40% of patients and more commonly in those with the highest levels of disease activity, the disease-related shared epitope (SE) (see below), a positive test for serum RF, and radiographic evidence of joint erosions. However, more recent cohort studies suggest a declining prevalence of subcutaneous nodules, perhaps, related to early and more aggressive disease-modifying therapy. When palpated, the nodules are generally firm; nontender; and adherent to periosteum, tendons, or bursae; developing in areas of the skeleton subject to repeated trauma or irritation such as the forearm, sacral prominences, and Achilles tendon. They may also occur in the lungs, pleura, pericardium, and peritoneum. Nodules are typically benign, although they can be associated with infection, ulceration, and gangrene.

SJÖGREN’S SYNDROME

Secondary Sjögren’s syndrome (Chap. 354) is defined by the presence of either keratoconjunctivitis sicca (dry eyes) or xerostomia (dry mouth) in association with another connective tissue disease, such as RA. Approximately 10% of patients with RA have secondary Sjögren’s syndrome.

PULMONARY

Pleuritis, the most common pulmonary manifestation of RA, may produce pleuritic chest pain and dyspnea, as well as a pleural friction rub and effusion. Pleural effusions tend to be exudative with increased numbers of monocytes and neutrophils. ILD may also occur in patients with RA and is heralded by symptoms of dry cough and progressive shortness of breath. ILD can be associated with cigarette smoking and is generally found in patients with higher disease activity, although it may be diagnosed in up to 3.5% of patients prior to the onset of joint symptoms. Recent studies have shown the overall prevalence of ILD in RA to be as high as 12%. Diagnosis is readily made by high-resolution chest computed tomography (CT) scan, which shows infiltrative opacification in the periphery of both lungs. Usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP) are the main histological and radiologic patterns of ILD. UIP causes progressive scarring of the lungs that produces on chest CT scan honeycomb changes in the periphery and lower portions of the lungs. In contrast, the most common radiographic changes in NSIP are relatively symmetric and bilateral ground glass opacities with associated fine reticulations, with volume loss and traction bronchiectasis. In both cases, pulmonary function testing shows a restrictive pattern (e.g., reduced total lung capacity) with a reduced diffusing capacity for carbon monoxide (DL_CO). The presence of ILD confers a poor prognosis, which if present, is associated with a 10% increase in mortality. The prognosis of ILD in RA is not quite as poor as that of idiopathic pulmonary fibrosis (e.g., usual interstitial pneumonitis). ILD secondary to RA responds more favorably than idiopathic ILD to immunosuppressive therapy (Chap. 287). Pulmonary nodules are also common in patients with RA and may be solitary or multiple. Caplan’s syndrome is a rare subset of pulmonary nodulosis characterized by the development of nodules and pneumoconiosis following silica exposure. Respiratory bronchiolitis and bronchiectasis are other less common pulmonary disorders associated with RA.

CARDIAC

The most frequent site of cardiac involvement in RA is the pericardium. However, clinical manifestations of pericarditis occur in <10% of patients with RA despite the fact that pericardial involvement is detectable in nearly one-half of cases by echocardiogram or autopsy studies. Cardiomyopathy, another clinically important manifestation of RA, may result from necrotizing or granulomatous myocarditis, coronary artery disease, or diastolic dysfunction. This involvement too may be subclinical and only identified by echocardiography or cardiac magnetic resonance imaging (MRI). Rarely, the heart muscle may contain rheumatoid nodules or be infiltrated with amyloid. Mitral regurgitation is the most common valvular abnormality in RA, occurring at a higher frequency than the general population.

VASCULITIS

Rheumatoid vasculitis (Chap. 356) typically occurs in patients with long-standing disease, a positive test for serum RF or anti-CCP antibodies, and hypocomplementemia. The overall incidence has decreased significantly in the last decade to <1% of patients. The cutaneous signs vary and include petechiae, purpura, digital infarcts, gangrene, livedo reticularis, and in severe cases large, painful lower extremity ulcerations. Vasculitic ulcers, which may be difficult to distinguish from those caused by venous insufficiency, may be treated successfully with immunosuppressive agents (requiring cytotoxic treatment in severe cases) as well as skin grafting. Sensorimotor polyneuropathies, such as mononeuritis multiplex, may occur in association with systemic rheumatoid vasculitis.

HEMATOLOGIC

A normochromic, normocytic anemia often develops in patients with RA and is the most common hematologic abnormality. The degree of anemia parallels the degree of inflammation, correlating with the levels of serum C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Platelet counts may also be elevated in RA as an acute-phase reactant. Immune-mediated thrombocytopenia is rare in this disease.

Felty’s syndrome is defined by the clinical triad of neutropenia, splenomegaly, and nodular RA and is seen in <1% of patients, although its incidence appears to be declining in the face of more aggressive treatment of the joint disease. It typically occurs in the late stages of severe RA and is more common in whites than other racial groups. T cell large granular lymphocyte leukemia (T-LGL) may have a similar clinical presentation and often occurs in association with RA. T-LGL is characterized by a chronic, indolent clonal growth of LGL cells, leading to neutropenia and splenomegaly. As opposed to Felty’s syndrome, T-LGL may develop early in the course of RA. Leukopenia apart from these disorders is uncommon and most often a side effect of drug therapy.

LYMPHOMA

Large cohort studies have shown a two- to fourfold increased risk of lymphoma in RA patients compared with the general population. The most common histopathologic type of lymphoma is a diffuse large B cell lymphoma. The risk of developing lymphoma increases if the patient has high levels of disease activity or Felty’s syndrome.

ASSOCIATED CONDITIONS

In addition to extraarticular manifestations, several conditions associated with RA contribute to disease morbidity and mortality rates. They are worthy of mention because they affect chronic disease management.

Cardiovascular Disease

The most common cause of death in patients with RA is cardiovascular disease. The incidence of coronary artery disease and carotid atherosclerosis is higher in RA patients than in the general population even when controlling for traditional cardiac risk factors, such as hypertension, obesity, hypercholesterolemia, diabetes, and cigarette smoking. Furthermore, congestive heart failure (including both systolic and diastolic dysfunction) occurs at an approximately twofold higher rate in RA than in the general population. The presence of elevated serum inflammatory markers appears to confer an increased risk of cardiovascular disease in this population.

Osteoporosis

Osteoporosis is more common in patients with RA than an age- and sex-matched population, with prevalence rates of 20–30%. The inflammatory milieu of the joint probably spills over into the rest of the body and promotes generalized bone loss by activating osteoclasts. Chronic use of glucocorticoids and disability-related immobility also contributes to osteoporosis. Hip fractures are more likely to occur in patients with RA and are significant predictors of increased disability and mortality rate in this disease.

Hypoandrogenism

Men and postmenopausal women with RA have lower mean serum testosterone, luteinizing hormone (LH), and dehydroepiandrosterone (DHEA) levels than control populations. It has thus been hypothesized that hypoandrogenism may play a role in the pathogenesis of RA or arise as a consequence of the chronic inflammatory response. It is also important to realize that patients receiving chronic glucocorticoid therapy may develop hypoandrogenism owing to inhibition of LH and follicle-stimulating hormone (FSH) secretion from the pituitary gland. Because low testosterone levels may lead to osteoporosis, men with hypoandrogenism should be considered for androgen replacement therapy.

EPIDEMIOLOGY

RA affects ~0.5–1% of the adult population worldwide. There is evidence that the overall incidence of RA has been decreasing in recent decades, whereas the prevalence has remained the same because individuals with RA are living longer. The incidence and prevalence of RA varies based on geographic location, both globally and among certain ethnic groups within a country (Fig. 351-3). For example, the Native American Yakima, Pima, and Chippewa tribes of North America have reported prevalence rates in some studies of nearly 7%. In contrast, many population studies from Africa and Asia show lower prevalence rates for RA in the range of 0.2–0.4%.

Like many other autoimmune diseases, RA occurs more commonly in females than in males, with a 2–3:1 ratio. Interestingly, studies of RA from some of the Latin American and African countries show an even greater predominance of disease in females compared to males, with ratios of 6–8:1. Given this preponderance of females, various theories have been proposed to explain the possible role of estrogen in disease pathogenesis. Most of the theories center on the role of estrogens in enhancing the immune response. For example, some experimental studies have shown that estrogen can stimulate production of tumor necrosis factor α (TNF-α), a major cytokine in the pathogenesis of RA.

GENETIC CONSIDERATIONS

It has been recognized for over 30 years that genetic factors contribute to the occurrence of RA as well as to its severity. The likelihood that a first-degree relative of a patient will share the diagnosis of RA is 2–10 times greater than in the general population. There remains, however, some uncertainty in the extent to which genetics plays a role in the causative mechanisms of RA. Heritability estimates range from 40 to 50% and are approximately the same for autoantibody positive and negative individuals. The estimate of genetic influence may vary across studies due to gene–environment interactions.

The alleles known to confer the greatest risk of RA are located within the major histocompatibility complex (MHC). It has been estimated that about 13% of the genetic risk for RA resides within this locus. Most, but probably not all, of this risk is associated with allelic variation in the HLA-DRB1 gene, which encodes the MHC II β-chain molecule. The disease-associated HLA-DRB1 alleles share an amino acid sequence at positions 70–74 in the third hypervariable regions of the HLA-DR β-chain, termed the shared epitope. Carriership of the SE alleles is associated with production of anti-CCP antibodies and worse disease outcomes. Some of these HLA-DRB1 alleles bestow a high risk of disease (^*0401), whereas others confer a more moderate risk (^*0101, ^*0404, ^*1001, and ^*0901). Additionally, there is regional variation. In Greece, for example, where RA tends to be milder than in western European countries, RA susceptibility has been associated with the ^*0101 SE allele. By comparison, the ^*0401 or ^*0404 alleles are found in ~50–70% of northern Europeans and are the predominant risk alleles in this group. The most common disease susceptibility SE alleles in Asians, namely the Japanese, Koreans, and Chinese, are ^*0405 and ^*0901. Lastly, disease susceptibility of Native American populations such as the Pima and Tlingit Indians, where the prevalence of RA can be as high as 7%, is associated with the SE allele ^*1042. The risk of RA conferred by these SE alleles is less in African and Hispanic Americans than in individuals of European ancestry.

Genome-wide association studies (GWAS) have made possible the identification of several non-MHC-related genes that contribute to RA susceptibility. GWAS are based on the detection of single-nucleotide polymorphisms (SNPs), which allow for examination of the genetic architecture of complex diseases such as RA. There are ~10 million common SNPs within a human genome consisting of 3 billion base pairs. As a rule, GWAS identify only common variants, namely, those with a frequency of >5% in the general population.

Overall, several themes have emerged from GWAS in RA. First, among the more than 100 non-MHC loci identified as risk alleles for RA, they individually have only a modest effect on risk; they also contribute to the risk for developing other autoimmune diseases, such as type 1 diabetes mellitus, systemic lupus erythematosus, and multiple sclerosis. Second, although most of the non-HLA associations are described in patients with anti-CCP antibody-positive disease, there are several risk loci that are unique to anti-CCP antibody-negative disease. Third, risk alleles vary among ethnic groups. And fourth, the risk loci mostly reside in genes encoding proteins involved in the regulation of the immune response. However, the risk alleles identified by GWAS only account at present for ~5% of the genetic risk, suggesting that rare variants or other classes of DNA variants, such as variants in copy number, may be yet found that significantly contribute to the overall risk model.

Recently, imputation of SNP data from a GWAS meta-analysis shows amino acid substitutions in the MHC locus independently associated with the risk for RA are at positions 11, 71, and 74 in HLA-DRβ1, position 9 of HLA-B, and position 9 of HLA-DPβ1. The amino acids at positions 11, 71, and 74 are located in the antigen-binding grove of the HLA-DRβ1 molecule, highlighting positions 71 and 74 that form part of the original SE.

Among the best examples of the non-MHC genes contributing to the risk of RA is the gene encoding protein tyrosine phosphatase non-receptor 22 (PTPN22). This gene varies in frequency among patients from different parts of Europe (e.g., 3–10%), but is absent in patients of East Asian ancestry. PTPN22 encodes lymphoid tyrosine phosphatase, a protein that regulates T and B cell function. Inheritance of the risk allele for PTPN22 produces a gain-of-function in the protein that is hypothesized to result in the abnormal thymic selection of autoreactive T and B cells and appears to be associated exclusively with anti-CCP-positive disease. The peptidyl arginine deiminase type IV (PADI4) gene is another risk allele that encodes an enzyme involved in the conversion of arginine to citrulline and is postulated to play a role in the development of antibodies to citrullinated antigens. A polymorphism in PADI4 has been associated with RA only in Asian populations. Recently, polymorphisms in apolipoprotein M (APOM) have been demonstrated in an East Asian population to confer an increased risk for RA as well as risk for dyslipidemia, independent of RA disease activity.

Epigenetics is the study of heritable traits that affect gene expression but do not modify DNA sequence. It may provide a link between environmental exposure and predisposition to disease. The best-studied mechanisms include posttranslational histone modifications and DNA methylation. Although studies of epigenetic phenomena are limited, DNA methylation patterns have been shown to differ between RA patients and healthy controls, as well as patients with osteoarthritis. MicroRNAs, which are non-coding RNAs that function as post-transcriptional regulators of gene expression, represent an additional epigenetic mechanism that may potentially influence cellular responses. Many microRNAs have been identified as contributing to the activated phenotype of synovial fibroblasts such as miR146a or miR155.

ENVIRONMENTAL FACTORS

In addition to genetic predisposition, a host of environmental factors have been implicated in the pathogenesis of RA. The most reproducible of these environmental links is cigarette smoking. Numerous cohort and case control studies have demonstrated that smoking confers a relative risk for developing RA of 1.5–3.5. In particular, women who smoke cigarettes have a nearly 2.5 times greater risk of RA, a risk that persists even 15 years after smoking cessation. A twin who smokes will have a significantly higher risk for RA than his or her monozygotic co-twin, theoretically with the same genetic risk, who does not smoke. Interestingly, the risk from smoking is almost exclusively related to RF and anti-CCP antibody-positive disease. However, it has not been shown that smoking cessation, while having many health benefits, improves disease activity.

Researchers began to aggressively seek an infectious etiology for RA after the discovery in 1931 that sera from patients with this disease could agglutinate strains of streptococci. Certain viruses such as Epstein-Barr virus (EBV) have garnered the most interest over the past 30 years given their ubiquity, ability to persist for many years in the host, and frequent association with arthritic complaints. For example, titers of IgG antibodies against EBV antigens in the peripheral blood and saliva are significantly higher in patients with RA than the general population. EBV DNA has also been found in synovial fluid and synovial cells of RA patients. Because the evidence for these links is largely circumstantial, it has not been possible to directly implicate infection as a causative factor in RA.

Recent studies suggest that periodontitis may play a role in the pathogenesis of RA. Multiple studies provide evidence for a link between anti-CCP positive RA and cigarette smoking, periodontal disease, and the oral microbiome, specifically Porphyromonas gingivalis. It has been hypothesized that the immune response to P. gingivalis may trigger the development of RA and that induction of anti-CCP antibodies results from citrullination of arginine residues in human tissues by the enzyme peptidyl arginine deiminase (PAD). Interestingly, P. gingivalis is the only oral bacterial species known to harbor this enzyme. Some studies have shown a relationship between circulating antibodies to P. gingivalis and RA, as well as these antibodies and first-degree relatives at risk for this disease.

PATHOLOGY

RA affects the synovial tissue and underlying cartilage and bone. The synovial membrane, which covers most articular surfaces, tendon sheaths, and bursae, normally is a thin layer of connective tissue. In joints, it faces the bone and cartilage, bridging the opposing bony surfaces and inserting at periosteal regions close to the articular cartilage. It consists primarily of two cell types—type A synoviocytes (macrophage-derived) and type B synoviocytes (fibroblast-derived). The synovial fibroblasts are the most abundant and produce the structural components of joints, including collagen, fibronectin, and laminin, as well as other extracellular constituents of the synovial matrix. The sublining layer consists of blood vessels and a sparse population of mononuclear cells within a loose network of connective tissue. Synovial fluid, an ultrafiltrate of blood, diffuses through the subsynovial lining tissue across the synovial membrane and into the joint cavity. Its main constituents are hyaluronan and lubricin. Hyaluronan is a glycosaminoglycan that contributes to the viscous nature of synovial fluid, which along with lubricin, lubricates the surface of the articular cartilage.

The pathologic hallmarks of RA are synovial inflammation and proliferation, focal bone erosions, and thinning of articular cartilage. Chronic inflammation leads to synovial lining hyperplasia and the formation of pannus, a thickened cellular membrane containing fibroblast-like synoviocytes and granulation-reactive fibrovascular tissue that invades the underlying cartilage and bone. The inflammatory infiltrate is made up of no less than six cell types: T cells, B cells, plasma cells, dendritic cells, mast cells, and, to a lesser extent, granulocytes. The T cells comprise 30–50% of the infiltrate, with the other cells accounting for the remainder. The topographical organization of these cells is complex and may vary among individuals with RA. Most often, the lymphocytes are diffusely organized among the tissue resident cells; however, in some cases, the B cells, T cells, and dendritic cells may form higher levels of organization, such as lymphoid follicles and germinal center–like structures. Growth factors secreted by synovial fibroblasts and macrophages promote the formation of new blood vessels in the synovial sublining that supply the increasing demands for oxygenation and nutrition required by the infiltrating leukocytes and expanding synovial tissue.

The structural damage to the mineralized cartilage and subchondral bone is mediated by the osteoclast. Osteoclasts are multinucleated giant cells that can be identified by their expression of CD68, tartrate-resistant acid phosphatase, cathepsin K, and the calcitonin receptor. They appear at the pannus-bone interface where they eventually form resorption lacunae. These lesions typically localize where the synovial membrane inserts into the periosteal surface at the edges of bones close to the rim of articular cartilage and at the attachment sites of ligaments and tendon sheaths. This process most likely explains why bone erosions usually develop at the radial sites of the MCP joints juxtaposed to the insertion sites of the tendons, collateral ligaments, and synovial membrane. Another form of bone loss is periarticular osteopenia that occurs in joints with active inflammation. It is associated with substantial thinning of the bony trabeculae along the metaphyses of bones, and likely results from inflammation of the bone marrow cavity. These lesions can be visualized on MRI scans, where they appear as signal alterations in the bone marrow adjacent to inflamed joints. Their signal characteristics show they are water-rich with a low fat content and are consistent with highly vascularized inflammatory tissue. These bone marrow lesions are often the forerunner of bone erosions.

The cortical bone layer that separates the bone marrow from the invading pannus is relatively thin and susceptible to penetration by the inflamed synovium. The bone marrow lesions seen on MRI scans are associated with an endosteal bone response characterized by the accumulation of osteoblasts and deposition of osteoid. Thus, in recent years, the concept of joint pathology in RA has been extended to include the bone marrow cavity. Finally, generalized osteoporosis, which results in the thinning of trabecular bone throughout the body, is a third form of bone loss found in patients with RA.

Articular cartilage is an avascular tissue comprised of a specialized matrix of collagens, proteoglycans, and other proteins. It is organized in four distinct regions (superficial, middle, deep, and calcified cartilage zones)—chondrocytes constitute the unique cellular component in these layers. Originally, cartilage was considered to be an inert tissue, but it is now known to be a highly responsive tissue that reacts to inflammatory mediators and mechanical factors, which in turn, alter the balance between cartilage anabolism and catabolism. In RA, the initial areas of cartilage degradation are juxtaposed to the synovial pannus. The cartilage matrix is characterized by a generalized loss of proteoglycan, most evident in the superficial zones adjacent to the synovial fluid. Degradation of cartilage may also take place in the perichondrocytic zone and in regions adjacent to the subchondral bone.

PATHOGENESIS

The pathogenic mechanisms of synovial inflammation are likely to result from a complex interplay of genetic, environmental, and immunologic factors that produces dysregulation of the immune system and a breakdown in self-tolerance (Fig. 351-4). Precisely what triggers these initiating events and what genetic and environmental factors disrupt the immune system remains a mystery. However, a detailed molecular picture is emerging of the mechanisms underlying the chronic inflammatory response and the destruction of the articular cartilage and bone.

In RA, the preclinical stage appears to be characterized by a breakdown in self-tolerance. This idea is supported by the finding that autoantibodies, such as RF and anti-CCP antibodies, may be found in sera from patients many years before onset of clinical disease. However, the antigenic targets of anti-CCP antibodies and RF are not restricted to the joint, and their role in disease pathogenesis remains speculative. Anti-CCP antibodies are directed against deaminated peptides, which result from posttranslational modification by the enzyme PADI4. They recognize citrulline-containing regions of several different matrix proteins, including filaggrin, keratin, fibrinogen, and vimentin, and are present at higher levels in the joint fluid compared to the serum. Other autoantibodies have been found in a minority of patients with RA, but they also occur in the setting of other types of arthritis. They bind to a diverse array of autoantigens, including type II collagen, human cartilage gp-39, aggrecan, calpastatin, immunoglobulin binding protein (BiP), and glucose-6-phosphate isomerase.

In theory, environmental stimulants may synergize with other factors to bring about inflammation in RA. People who smoke display higher citrullination of proteins in bronchoalveolar fluid than those who do not smoke. Thus, it has been speculated that long-term exposure to tobacco smoke might induce citrullination of cellular proteins in the lung and stimulate the expression of a neoepitope capable of inducing self-reactivity, which in turns, leads to formation of immune complexes and joint inflammation. Exposure to silicone dust and mineral oil, which has adjuvant effects, has also been linked to an increased risk for anti-CCP antibody-positive RA. Similarly, periodontal pathogens, such as P. gingivalis, may play a pathogenic role and contribute to the citrullination of cellular proteins in the oral cavity. In addition to the possible link between the oral microbiome and RA, investigators are turning their attention toward the intestinal microbiota and whether its altered composition may predispose to disease.

How might microbes or their products be involved in the initiating events of RA? The immune system is alerted to the presence of microbial infections through Toll-like receptors (TLRs). There are 10 TLRs in humans that recognize a variety of microbial products, including bacterial cell-surface lipopolysaccharides and heat-shock proteins (TLR4), lipoproteins (TLR2), double-strand RNA viruses (TLR3), and unmethylated CpG DNA from bacteria (TLR9). TLR2, 3, and 4 are abundantly expressed by synovial fibroblasts in early RA and, when bound by their ligands, upregulate production of proinflammatory cytokines. Although TLR ligands may theoretically amplify inflammatory pathways in RA, their specific role in disease pathogenesis remains uncertain.

The pathogenesis of RA is built upon the concept that self-reactive T cells drive the chronic inflammatory response. In theory, self-reactive T cells might arise in RA from abnormal central (thymic) selection or intrinsic defects lowering the threshold in the periphery for T cell activation. Either mechanism might result in abnormal expansion of the self-reactive T cell repertoire and a breakdown in T cell tolerance. The support for these theories comes mainly from studies of arthritis in mouse models. It has not been shown that patients with RA have abnormal thymic selection of T cells or defective apoptotic pathways regulating cell death. At least some antigen stimulation inside the joint seems likely, owing to the fact that T cells in the synovium express a cell-surface phenotype indicating prior antigen exposure and show evidence of clonal expansion. Of interest, peripheral blood T cells from patients with RA have been shown to display a fingerprint of premature aging that mostly affects inexperienced naïve T cells. In these studies, the most glaring findings have been the loss of telomeric sequences and a decrease in the thymic output of new T cells. Although intriguing, it is not clear how generalized T cell abnormalities might provoke a systemic disease with a predominance of synovitis.

There is substantial evidence of a role for CD4+ T cells in the pathogenesis of RA. First, the co-receptor CD4 on the surface of T cells binds to invariant sites on MHC class II molecules, stabilizing the MHC-peptide–T cell receptor complex during T cell activation. Because the SE on MHC class II molecules is a risk factor for RA, it follows that CD4+ T cell activation may play a role in the pathogenesis of this disease. Second, CD4+ memory T cells are enriched in the synovial tissue from patients with RA and can be implicated through “guilt by association.” Third, CD4+ T cells have been shown to be important in the initiation of arthritis in animal models. Fourth, some, but not all, T cell–directed therapies have shown clinical efficacy in this disease. Taken together, these lines of evidence suggest that CD4+ T cells play an important role in orchestrating the chronic inflammatory response in RA. However, other cell types, such as CD8+ T cells, natural killer (NK) cells, and B cells are present in synovial tissue and may also influence pathogenic responses.

In the rheumatoid joint, by mechanisms of cell-cell contact and release of soluble mediators, activated T cells stimulate macrophages and fibroblast-like synoviocytes to generate proinflammatory mediators and proteases that drive the synovial inflammatory response and destroy the cartilage and bone. CD4+ T cell activation is dependent on two signals: (1) T cell receptor binding to peptide-MHC on antigen-presenting cells; and (2) CD28 binding to CD80/86 on antigen-presenting cells. CD4+ T cells also provide help to B cells, which in turn, produce antibodies that may promote further inflammation in the joint. The previous T cell–centric model for the pathogenesis of RA was based on a T_H1-driven paradigm, which came from studies indicating that CD4+ T helper (T_H) cells differentiated into T_H1 and T_H2 subsets, each with their distinctive cytokine profiles. T_H1 cells were found to mainly produce interferon γ (IFN-γ), lymphotoxin β, and TNF-α, whereas T_H2 cells predominately secreted interleukin (IL)-4, IL-5, IL-6, IL-10, and IL-13. The recent discovery of another subset of T_H cells, namely the T_H17 lineage, has revolutionized our concepts concerning the pathogenesis of RA. In humans, naïve T cells are induced to differentiate into T_H17 cells by exposure to transforming growth factor β (TGF-β), IL-1, IL-6, and IL-23. Upon activation, T_H17 cells secrete a variety of proinflammatory mediators such as IL-17, IL-21, IL-22, TNF-α, IL-26, IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Substantial evidence now exists from studies in both animal models and humans that IL-17 plays an important role not only in promoting joint inflammation, but also in destroying cartilage and subchondral bone. Nevertheless, secukinumab, an anti-IL17 receptor antibody, failed to show significant clinical benefit in a phase II trial involving patients with RA, raising new questions about the importance of IL-17 in perpetuating joint inflammation in this disease.

The immune system has evolved mechanisms to counterbalance the potential harmful immune-mediated inflammatory responses provoked by infectious agents and other triggers. Among these negative regulators are regulatory T (T_reg) cells, which are produced in the thymus and induced in the periphery to suppress immune-mediated inflammation. They are characterized by the surface expression of CD25 and the expression of the transcription factor forkhead box P3 (FOXP3) and the absence of CD127, the IL-7 receptor. T_regs orchestrate dominant tolerance through contact with other immune cells and secretion of inhibitory cytokines, such as TGF-β, IL-10, and IL-35. They are heterogeneous and capable of suppressing distinct classes (T_H1, T_H2, T_H17) of the immune response. In RA, the data that T_reg numbers are deficient compared to normal healthy controls are contradictory and inconclusive. Although some experimental evidence suggests that T_reg suppressive activity is lost due to dysfunctional expression of cytotoxic T lymphocyte antigen 4 (CTLA-4), the nature of T_reg defects in RA and their role in disease mechanisms remains unclear.

Cytokines, chemokines, antibodies, and endogenous danger signals bind to receptors on the surface of immune cells and stimulate a cascade of intracellular signaling events that can amplify the inflammatory response. Signaling molecules and their binding partners in these pathways are the target of small-molecule drugs designed to interfere with signal transduction and in turn, block these reinforcing inflammatory loops. Examples of signaling molecules in these critical inflammatory pathways include Janus kinase (JAK)/signal transducers and activators of transcription (STAT), spleen tyrosine kinase (Syk), mitogen-activated protein kinases (MAPKs), and nuclear factor-κB (NF-κB). These pathways exhibit significant cross-talk and are found in many cell types. Some signal transducers, such as JAK3, are primarily expressed in hematopoietic cells and play an important role in the inflammatory response in RA.

Activated B cells are also important players in the chronic inflammatory response. B cells give rise to plasma cells, which in turn, produce antibodies, including RF and anti-CCP antibodies. RFs may form large immune complexes inside the joint that contribute to the pathogenic process by fixing complement and promoting the release of proinflammatory cytokines and chemokines. In mouse models of arthritis, RF-containing immune complexes and anti-CCP-containing immune complexes synergize with other mechanisms to exacerbate the synovial inflammatory response.

RA is often considered to be a macrophage-driven disease because this cell type is the predominant source of proinflammatory cytokines inside the joint. Key proinflammatory cytokines released by synovial macrophages include TNF-α, IL-1, IL-6, IL-12, IL-15, IL-18, and IL-23. Synovial fibroblasts, the other major cell type in this microenvironment, produce the cytokines IL-1 and IL-6 as well as TNF-α. TNF-α is a pivotal cytokine in the pathobiology of synovial inflammation. It upregulates adhesion molecules on endothelial cells, promoting the influx of leukocytes into the synovial microenvironment; activates synovial fibroblasts; stimulates angiogenesis; promotes pain receptor sensitizing pathways; and drives osteoclastogenesis. Fibroblasts secrete matrix metalloproteinases (MMPs) as well as other proteases that are chiefly responsible for the breakdown of articular cartilage.

Osteoclast activation at the site of the pannus is closely tied to the presence of focal bone erosion. Receptor activator of nuclear factor-κB ligand (RANKL) is expressed by stromal cells, synovial fibroblasts, and T cells. Upon binding to its receptor RANK on osteoclast progenitors, RANKL stimulates osteoclast differentiation and bone resorption. RANKL activity is regulated by osteoprotegerin (OPG), a decoy receptor of RANKL that blocks osteoclast formation. Monocytic cells in the synovium serve as the precursors of osteoclasts and, when exposed to macrophage colony-stimulating factor (M-CSF) and RANKL, fuse to form polykaryons termed preosteoclasts. These precursor cells undergo further differentiation into osteoclasts with the characteristic ruffled membrane. Cytokines such as TNF-α, IL-1, IL-6, and IL-17 increase the expression of RANKL in the joint and thus promote osteoclastogenesis. Osteoclasts also secrete cathepsin K, a cysteine protease that degrades the bone matrix by cleaving collagen. Stimulation of osteoclasts also contributes to generalized bone loss and osteoporosis.

Increased bone loss is only part of the story in RA, as decreased bone formation plays a crucial role in bone remodeling at sites of inflammation. Recent evidence shows that inflammation suppresses bone formation. The proinflammatory cytokine TNF-α plays a key role in actively suppressing bone formation by enhancing the expression of dickkopf-1 (DKK-1). DKK-1 is an important inhibitor of the Wnt pathway, which acts to promote osteoblast differentiation and bone formation. The Wnt system is a family of soluble glycoproteins that binds to cell-surface receptors known as frizzled (fz) and low-density lipoprotein (LDL) receptor–related proteins (LRPs) and promotes cell growth. In animal models, increased levels of DKK-1 are associated with decreased bone formation, whereas inhibition of DKK-1 protects against structural damage in the joint. Wnt proteins also induce the formation of OPG and thereby shut down bone resorption, emphasizing their key role in tightly regulating the balance between bone resorption and formation.

DIAGNOSIS

The clinical diagnosis of RA is largely based on signs and symptoms of a chronic inflammatory arthritis, with laboratory and radiographic results providing important corroborating information. In 2010, a collaborative effort between the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) revised the 1987 ACR classification criteria for RA in an effort to improve early diagnosis with the goal of identifying patients who would benefit from early introduction of disease-modifying therapy (Table 351-1). Application of the newly revised criteria yields a score of 0–10, with a score of ≥6 fulfilling the requirements for definite RA. The new classification criteria differ in several ways from the older criteria set. The new criteria include as an item a positive test for serum anti-CCP antibodies (also termed ACPA, anti-citrullinated peptide antibodies), which carries greater specificity for the diagnosis of RA than a positive test for RF. The newer classification criteria also do not take into account whether the patient has rheumatoid nodules or radiographic joint damage because these findings occur rarely in early RA. It is important to emphasize that the new 2010 ACR-EULAR criteria are “classification criteria” as opposed to “diagnostic criteria” and serve to distinguish patients at the onset of disease who have a high likelihood of evolution to chronic disease with persistent synovitis and joint damage. The presence of radiographic joint erosions or subcutaneous nodules may inform the diagnosis in the later stages of the disease.

LABORATORY FEATURES

Patients with systemic inflammatory diseases such as RA will often present with elevated nonspecific inflammatory markers such as an ESR or CRP. Detection of serum RF and anti-CCP antibodies is important in differentiating RA from other polyarticular diseases, although RF lacks diagnostic specificity and may be found in association with other chronic inflammatory diseases in which arthritis figures in the clinical manifestations.

IgM, IgG, and IgA isotypes of RF occur in sera from patients with RA, although the IgM isotype is the one most frequently measured by commercial laboratories. Serum IgM RF has been found in 75–80% of patients with RA; therefore, a negative result does not exclude the presence of this disease. It is also found in other connective tissue diseases, such as primary Sjögren’s syndrome, systemic lupus erythematosus, and type II mixed essential cryoglobulinemia, as well as chronic infections such as subacute bacterial endocarditis and hepatitis B and C. Serum RF may also be detected in 1–5% of the healthy population.

The presence of serum anti-CCP antibodies has about the same sensitivity as serum RF for the diagnosis of RA. However, its diagnostic specificity approaches 95%, so a positive test for anti-CCP antibodies in the setting of an early inflammatory arthritis is useful for distinguishing RA from other forms of arthritis. There is some incremental value in testing for the presence of both RF and anti-CCP, as some patients with RA are positive for RF but negative for anti-CCP and vice versa. The presence of RF or anti-CCP antibodies also has prognostic significance, with anti-CCP antibodies showing the most value for predicting worse outcomes.

SYNOVIAL FLUID ANALYSIS

Typically, the cellular composition of synovial fluid from patients with RA reflects an acute inflammatory state. Synovial fluid white blood cell (WBC) counts can vary widely, but generally range between 5000 and 50,000 WBC/μL compared to <2000 WBC/μL for a noninflammatory condition such as osteoarthritis. In contrast to the synovial tissue, the overwhelming cell type in the synovial fluid is the neutrophil. Clinically, the analysis of synovial fluid is most useful for confirming an inflammatory arthritis (as opposed to osteoarthritis), while at the same time excluding infection or a crystal-induced arthritis such as gout or pseudogout (Chap. 365).

JOINT IMAGING

Joint imaging is a valuable tool not only for diagnosing RA, but also for tracking progression of any joint damage. Plain x-ray is the most common imaging modality, but it is limited to visualization of the bony structures and inferences about the state of the articular cartilage based on the amount of joint space narrowing. MRI and ultrasound techniques offer the added value of detecting changes in the soft tissues such as synovitis, tenosynovitis, and effusions, as well as providing greater sensitivity for identifying bony abnormalities. Plain radiographs are usually relied upon in clinical practice for the purpose of diagnosis and monitoring of affected joints. However, in selected cases, MRI and ultrasound can provide additional diagnostic information that may guide clinical decision making. Musculoskeletal ultrasound with power Doppler is increasingly used in rheumatology clinical practice for detecting synovitis and bone erosion.

Plain Radiography

Classically in RA, the initial radiographic finding is periarticular osteopenia. Practically speaking, however, this finding is difficult to appreciate on plain films and, in particular, on the newer digitalized x-rays. Other findings on plain radiographs include soft tissue swelling, symmetric joint space loss, and subchondral erosions, most frequently in the wrists and hands (MCPs and PIPs) and the feet (MTPs). In the feet, the lateral aspect of the fifth MTP is often targeted first, but other MTP joints may be involved at the same time. X-ray imaging of advanced RA may reveal signs of severe destruction, including joint subluxation and collapse (Fig. 351-5).

MRI

MRI offers the greatest sensitivity for detecting synovitis and joint effusions, as well as early bone and bone marrow changes. These soft tissue abnormalities often occur before osseous changes are noted on x-ray. Presence of bone marrow edema has been recognized to be an early sign of inflammatory joint disease and can predict the subsequent development of erosions on plain radiographs as well as MRI scans. Cost and availability of MRI are the main factors limiting its routine clinical use.

Ultrasound

Ultrasound, including power color Doppler, has the ability to detect more erosions than plain radiography, especially in easily accessible joints. It can also reliably detect synovitis, including increased joint vascularity indicative of inflammation. The usefulness of ultrasound is dependent on the experience of the sonographer; however, it does offer the advantages of portability, lack of radiation, and low expense relative to MRI, factors that make it attractive as a clinical tool.

CLINICAL COURSE

The natural history of RA is complex and affected by a number of factors including age of onset, gender, genotype, phenotype (i.e., extraarticular manifestations or variants of RA), and comorbid conditions, which make for a truly heterogeneous disease. There is no simple way to predict the clinical course. It is important to realize that as many as 10% of patients with inflammatory arthritis fulfilling ACR classification criteria for RA will undergo a spontaneous remission within 6 months (particularly seronegative patients). However, the vast majority of patients will exhibit a pattern of persistent and progressive disease activity that waxes and wanes in intensity over time. A minority of patients will show intermittent and recurrent explosive attacks of inflammatory arthritis interspersed with periods of disease quiescence. Finally, an aggressive form of RA may occur in an unfortunate few with inexorable progression of severe erosive joint disease, although this highly destructive course is less common in the modern treatment era.

Disability, as measured by the Health Assessment Questionnaire (HAQ), shows gradual worsening of disability over time in the face of poorly controlled disease activity and disease progression. Disability may result from both a disease activity–related component that is potentially reversible with therapy and a joint damage–related component owing to the cumulative and largely irreversible effects of soft tissue, cartilage and bone breakdown. Early in the course of disease, the extent of joint inflammation is the primary determinant of disability, while in the later stages of disease, the amount of joint damage is the dominant contributing factor. Previous studies have shown that more than one-half of patients with RA are unable to work 10 years after the onset of their disease; however, increased employability and less work absenteeism has been reported recently with the use of newer therapies and earlier treatment intervention.

The overall mortality rate in RA is two times greater than the general population, with ischemic heart disease being the most common cause of death followed by infection. Median life expectancy is shortened by an average of 7 years for men and 3 years for women compared to control populations. Patients at higher risk for shortened survival are those with systemic extraarticular involvement, low functional capacity, low socioeconomic status, low education, and chronic prednisone use.

TREATMENT

APPROACH TO THE PATIENT

GLOBAL CHALLENGES

Developing countries are finding an increase in the incidence of noncommunicable, chronic diseases such as diabetes, cardiovascular disease, and RA in the face of ongoing poverty, rampant infectious disease, and poor access to modern health care facilities. In these areas, patients tend to have a greater delay in diagnosis and limited access to specialists, and thus greater disease activity and disability at presentation. In addition, infection risk remains a significant issue for the treatment of RA in developing countries because of the immunosuppression associated with the use of glucocorticoids and most DMARDs. For example, in some developing countries, patients undergoing treatment for RA have a substantial increase in the incidence of tuberculosis, which demands the implementation of far more comprehensive screening practices and liberal use of isoniazid prophylaxis than in developed countries. The increased prevalence of hepatitis B and C, as well as human immunodeficiency virus (HIV), in these developing countries also poses challenges. Reactivation of viral hepatitis has been observed in association with some of the DMARDs, such as rituximab. Also, reduced access to antiretroviral therapy may limit the control of HIV infection and therefore the choice of DMARD therapies.

Despite these challenges, one should attempt to initiate early treatment of RA in the developing countries with the resources at hand. Hydroxychloroquine, sulfasalazine and methotrexate are all reasonably accessible throughout the world where they can be used as both monotherapy and in combination with other drugs. The use of biologic agents is increasing in the developed countries as well as in other areas around the world, although their use is limited by high cost; national protocols restrict their use, and concerns remain about the risk for opportunistic infections.

SUMMARY

Improved understanding of the pathogenesis of RA and its treatment has dramatically revolutionized the management of this disease. The outcomes of patients with RA are vastly superior to those of the prebiologic modifier era; more patients than in years past are able to avoid significant disability and continue working, albeit with some job modifications in many cases. The need for early and aggressive treatment of RA as well as frequent follow-up visits for monitoring of drug therapy has implications for our health care system. Primary care physicians and rheumatologists must be prepared to work together as a team to reach the ambitious goals of best practice. In many settings, rheumatologists have reengineered their practice in a way that places high priority on consultations for any new patient with early inflammatory arthritis.

The therapeutic regimens for RA are becoming increasingly complex with the rapidly expanding armamentarium. Patients receiving these therapies must be carefully monitored by both the primary care physician and the rheumatologist to minimize the risk of side effects and identify quickly any complications of chronic immunosuppression. Also, prevention and treatment of RA-associated conditions such as ischemic heart disease and osteoporosis will likely benefit from a team approach owing to the value of multidisciplinary care.

Research will continue to search for new therapies with superior efficacy and safety profiles and investigate treatment strategies that can bring the disease under control more rapidly and nearer to remission. However, prevention and cure of RA will likely require new breakthroughs in our understanding of disease pathogenesis. These insights may come from genetic studies illuminating critical pathways in the mechanisms of joint inflammation. Equally ambitious is the lofty goal of biomarker discovery that will open the door to personalized medicine for the care of patients with RA.

FURTHER READING

INTRODUCTION

Acute rheumatic fever (ARF) is a multisystem disease resulting from an autoimmune reaction to infection with group A streptococcus. Although many parts of the body may be affected, almost all of the manifestations resolve completely. The major exception is cardiac valvular damage (rheumatic heart disease [RHD]), which may persist after the other features have disappeared.

GLOBAL CONSIDERATIONS

ARF and RHD are diseases of poverty. They were common in all countries until the early twentieth century, when their incidence began to decline in industrialized nations. This decline was largely attributable to improved living conditions—particularly less crowded housing and better hygiene—which resulted in reduced transmission of group A streptococci. The introduction of antibiotics and improved systems of medical care had a supplemental effect.

The virtual disappearance of ARF and reduction in the incidence of RHD in industrialized countries during the twentieth century unfortunately was not replicated in developing countries, where these diseases continue unabated. RHD is the most common cause of heart disease in children in developing countries and is a major cause of mortality and morbidity in adults as well. It has been estimated that between 15 and 19 million people worldwide are affected by RHD, with approximately one-quarter of a million deaths occurring each year. Some 95% of ARF cases and RHD deaths now occur in developing countries, with particularly high rates in sub-Saharan Africa, Pacific nations, Australasia, and South and Central Asia. The pathogenetic pathway from exposure to group A streptococcus followed by pharyngeal infection and subsequent development of ARF, ARF recurrences, and development of RHD and its complications is associated with a range of risk factors and, therefore, potential interventions at each point (Fig. 352-1). In affluent countries, many of these risk factors are well controlled, and where needed, interventions are in place. Unfortunately, the greatest burden of disease is found in developing countries, most of which do not have the resources, capacity, and/or interest to tackle this multifaceted disease. In particular, almost none of the developing countries has a coordinated, register-based RHD control program, which is proven to be cost-effective in reducing the burden of RHD. Enhancing awareness of RHD and mobilizing resources for its control in developing countries are issues requiring international attention.

EPIDEMIOLOGY

ARF is mainly a disease of children age 5–14 years. Initial episodes become less common in older adolescents and young adults and are rare in persons aged >30 years. By contrast, recurrent episodes of ARF remain relatively common in adolescents and young adults. This pattern contrasts with the prevalence of RHD, which peaks between 25 and 40 years. There is no clear gender association for ARF, but RHD more commonly affects females, sometimes up to twice as frequently as males.

PATHOGENESIS

ORGANISM FACTORS

Based on currently available evidence, ARF is exclusively caused by infection of the upper respiratory tract with group A streptococci (Chap. 143). Although classically, certain M-serotypes (particularly types 1, 3, 5, 6, 14, 18, 19, 24, 27, and 29) were associated with ARF, in high-incidence regions, it is now thought that any strain of group A streptococcus has the potential to cause ARF. The potential role of skin infection and of groups C and G streptococci is currently being investigated.

HOST FACTORS

Approximately 3–6% of any population may be susceptible to ARF, and this proportion does not vary dramatically between populations. Findings of familial clustering of cases and concordance in mono-zygotic twins—particularly for chorea—confirm that susceptibility to ARF is an inherited characteristic, with 44% concordance in mono-zygotic twins compared to 12% in dizygotic twins, and heritability more recently estimated at 60%. Most evidence for host factors focuses on immunologic determinants. Some human leukocyte antigen (HLA) class II alleles, particularly HLA-DR7 and HLA-DR4, appear to be associated with susceptibility, whereas other class II alleles have been associated with protection (HLA-DR5, HLA-DR6, HLA-DR51, HLA-DR52, and HLA-DQ). Associations have also been described with polymorphisms at the tumor necrosis factor α locus (TNF-α-308 and TNF-α-238), high levels of circulating mannose-binding lectin, and Toll-like receptors.

THE IMMUNE RESPONSE

The most widely accepted theory of rheumatic fever pathogenesis is based on the concept of molecular mimicry, whereby an immune response targeted at streptococcal antigens (mainly thought to be on the M protein and the N-acetylglucosamine of group A streptococcal carbohydrate) also recognizes human tissues. In this model, cross-reactive antibodies bind to endothelial cells on the heart valve, leading to activation of the adhesion molecule VCAM-1, with resulting recruitment of activated lymphocytes and lysis of endothelial cells in the presence of complement. The latter leads to release of peptides including laminin, keratin, and tropomyosin, which, in turn, activates cross-reactive T cells that invade the heart, amplifying the damage and causing epitope spreading. An alternative hypothesis proposes that the initial damage is due to streptococcal invasion of epithelial surfaces, with binding of M protein to type IV collagen allowing it to become immunogenic, but not through the mechanism of molecular mimicry.

CLINICAL FEATURES

There is a latent period of ~3 weeks (1–5 weeks) between the precipitating group A streptococcal infection and the appearance of the clinical features of ARF. The exceptions are chorea and indolent carditis, which may follow prolonged latent periods lasting up to 6 months. Although many patients report a prior sore throat, the preceding group A streptococcal infection is commonly subclinical; in these cases, it can only be confirmed using streptococcal antibody testing. The most common clinical features are polyarthritis (present in 60–75% of cases) and carditis (50–60%). The prevalence of chorea in ARF varies substantially between populations, ranging from <2 to 30%. Erythema marginatum and subcutaneous nodules are now rare, being found in <5% of cases.

HEART INVOLVEMENT

Up to 60% of patients with ARF progress to RHD. The endocardium, pericardium, or myocardium may be affected. Valvular damage is the hallmark of rheumatic carditis. The mitral valve is almost always affected, sometimes together with the aortic valve; isolated aortic valve involvement is rare. Damage to the pulmonary or tricuspid valves is usually secondary to increased pulmonary pressures resulting from left-sided valvular disease. Early valvular damage leads to regurgitation. Over ensuing years, usually as a result of recurrent episodes, leaflet thickening, scarring, calcification, and valvular stenosis may develop (Fig. 352-2). See Videos 352-1 and 352-2. Therefore, the characteristic manifestation of carditis in previously unaffected individuals is mitral regurgitation, sometimes accompanied by aortic regurgitation. Myocardial inflammation may affect electrical conduction pathways, leading to P-R interval prolongation (first-degree atrioventricular block or rarely higher level block) and softening of the first heart sound.

People with RHD are often asymptomatic for many years before their valvular disease progresses to cause cardiac failure. Moreover, particularly in resource-poor settings, the diagnosis of ARF is often not made, so children, adolescents, and young adults may have RHD but not know it. These cases can be diagnosed using echocardiography; auscultation is poorly sensitive and specific for RHD diagnosis in asymptomatic patients. Echocardiographic screening of school-aged children in populations with high rates of RHD is becoming more widespread and has been facilitated by improving technologies in portable echocardiography and the availability of consensus guidelines for the diagnosis of RHD on echocardiography (Table 352-1). Although a diagnosis of definite RHD on screening echocardiography should lead to commencement of secondary prophylaxis, the clinical significance of borderline RHD has yet to be determined.

JOINT INVOLVEMENT

The most common form of joint involvement in ARF is arthritis, i.e., objective evidence of inflammation, with hot, swollen, red, and/or tender joints, and involvement of more than one joint (i.e., polyarthritis). Polyarthritis is typically migratory, moving from one joint to another over a period of hours. ARF almost always affects the large joints—most commonly the knees, ankles, hips, and elbows—and is asymmetric. The pain is severe and usually disabling until anti-inflammatory medication is commenced.

Less severe joint involvement is also relatively common and has been recognized as a potential major manifestation in high-risk populations in the most recent revision of the Jones criteria. Arthralgia without objective joint inflammation usually affects large joints in the same migratory pattern as polyarthritis. In some populations, aseptic monoarthritis may be a presenting feature of ARF, which may, in turn, result from early commencement of anti-inflammatory medication before the typical migratory pattern is established.

The joint manifestations of ARF are highly responsive to salicylates and other nonsteroidal anti-inflammatory drugs (NSAIDs). Indeed, joint involvement that persists for more than 1 or 2 days after starting salicylates is unlikely to be due to ARF.

CHOREA

Sydenham’s chorea commonly occurs in the absence of other manifestations, follows a prolonged latent period after group A streptococcal infection, and is found mainly in females. The choreiform movements affect particularly the head (causing characteristic darting movements of the tongue) and the upper limbs (Chap. 428). They may be generalized or restricted to one side of the body (hemi-chorea). In mild cases, chorea may be evident only on careful examination, whereas in the most severe cases, the affected individuals are unable to perform activities of daily living. There is often associated emotional lability or obsessive-compulsive traits, which may last longer than the choreiform movements (which usually resolve within 6 weeks but sometimes may take up to 6 months).

SKIN MANIFESTATIONS

The classic rash of ARF is erythema marginatum (Chap. 16), which begins as pink macules that clear centrally, leaving a serpiginous, spreading edge. The rash is evanescent, appearing and disappearing before the examiner’s eyes. It occurs usually on the trunk, sometimes on the limbs, but almost never on the face.

Subcutaneous nodules occur as painless, small (0.5–2 cm), mobile lumps beneath the skin overlying bony prominences, particularly of the hands, feet, elbows, occiput, and occasionally the vertebrae. They are a delayed manifestation, appearing 2–3 weeks after the onset of disease, last for just a few days up to 3 weeks, and are commonly associated with carditis.

OTHER FEATURES

Fever occurs in most cases of ARF, although rarely in cases of pure chorea. Although high-grade fever (≥39°C) is the rule, lower grade temperature elevations are not uncommon. Elevated acute-phase reactants are also present in most cases.

EVIDENCE OF A PRECEDING GROUP A STREPTOCOCCAL INFECTION

With the exception of chorea and low-grade carditis, both of which may become manifest many months later, evidence of a preceding group A streptococcal infection is essential in making the diagnosis of ARF. Because most cases do not have a positive throat swab culture or rapid antigen test, serologic evidence is usually needed. The most common serologic tests are the anti-streptolysin O (ASO) and anti-DNase B (ADB) titers. Where possible, age-specific reference ranges should be determined in a local population of healthy people without a recent group A streptococcal infection.

CONFIRMING THE DIAGNOSIS

Because there is no definitive test, the diagnosis of ARF relies on the presence of a combination of typical clinical features together with evidence of the precipitating group A streptococcal infection, and the exclusion of other diagnoses. This uncertainty led Dr. T. Duckett Jones in 1944 to develop a set of criteria (subsequently known as the Jones criteria) to aid in the diagnosis. The most recent revision of the Jones criteria (Table 352-2) require the clinician to determine if the patient is from a setting or population known to experience low rates of ARF. For this group, there is a set of “low-risk” criteria; for all others, there is a set of more sensitive criteria.

TREATMENT

PROGNOSIS

Untreated, ARF lasts on average 12 weeks. With treatment, patients are usually discharged from hospital within 1–2 weeks. Inflammatory markers should be monitored every 1–2 weeks until they have normalized (usually within 4–6 weeks), and an echocardiogram should be performed after 1 month to determine if there has been progression of carditis. Cases with more severe carditis need close clinical and echocardiographic monitoring in the longer term.

Once the acute episode has resolved, the priority in management is to ensure long-term clinical follow-up and adherence to a regimen of secondary prophylaxis. Patients should be entered onto the local ARF registry (if present) and contact made with primary care practitioners to ensure a plan for follow-up and administration of secondary prophylaxis before the patient is discharged. Patients and their families should also be educated about their disease, emphasizing the importance of adherence to secondary prophylaxis.

PREVENTION

PRIMARY PREVENTION

Ideally, primary prevention would entail elimination of the major risk factors for streptococcal infection, particularly overcrowded housing. This is difficult to achieve in most places where ARF is common.

Therefore, the mainstay of primary prevention for ARF remains primary prophylaxis (i.e., the timely and complete treatment of group A streptococcal sore throat with antibiotics). If commenced within 9 days of sore throat onset, a course of penicillin (as outlined above for treatment of ARF) will prevent almost all cases of ARF that would otherwise have developed. In settings where ARF and RHD are common but microbiologic diagnosis of group A streptococcal pharyngitis is not available, such as in resource-poor countries, primary care guidelines often recommend that all patients with sore throat be treated with penicillin or, alternatively, that a clinical algorithm be used to identify patients with a higher likelihood of group A streptococcal pharyngitis. Although imperfect, such approaches recognize the importance of ARF prevention at the expense of overtreating many cases of sore throat that are not caused by group A streptococcus.

SECONDARY PREVENTION

The mainstay of controlling ARF and RHD is secondary prevention. Because patients with ARF are at dramatically higher risk than the general population of developing a further episode of ARF after a group A streptococcal infection, they should receive long-term penicillin prophylaxis to prevent recurrences. The best antibiotic for secondary prophylaxis is benzathine penicillin G (1.2 million units, or 600,000 units if ≤27 kg) delivered every 4 weeks. It can be given every 3 weeks, or even every 2 weeks, to persons considered to be at particularly high risk, although in settings where good compliance with an every-4-week dosing schedule can be achieved, more frequent dosing is rarely needed. Oral penicillin V (250 mg) can be given twice daily instead but is less effective than benzathine penicillin G. Penicillin-allergic patients can receive erythromycin (250 mg) twice daily.

The duration of secondary prophylaxis is determined by many factors, in particular the duration since the last episode of ARF (recurrences become less likely with increasing time), age (recurrences are less likely with increasing age), and the severity of RHD (if severe, it may be prudent to avoid even a very small risk of recurrence because of the potentially serious consequences) (Table 352-4). Secondary prophylaxis is best delivered as part of a coordinated RHD control program, based around a registry of patients. Registries improve the ability to follow patients and identify those who default from prophylaxis and to institute strategies to improve adherence.

FURTHER READING

DEFINITION AND CLASSIFICATION

Systemic sclerosis (SSc) is a complex and clinically heterogeneous orphan disease with protean clinical manifestations, a chronic and frequently progressive course, and significant disability, disfigurement and mortality. Virtually every organ can be affected (Fig. 353-1).

There is marked variability among SSc patients in patterns of skin involvement, organ complications, rates of disease progression, response to treatment, and survival. The early stages of SSc are associated with prominent inflammatory features; however, over time, structural alterations in multiple vascular beds and progressive visceral organ dysfunction due to fibrosis and atrophy come to dominate the clinical picture. Classification criteria for diagnosis of SSc are shown in Table 353-1.

Although thick and indurated skin (scleroderma) is the distinguishing hallmark of SSc, skin changes also occur in localized forms of scleroderma, along with multiple metabolic, inherited and autoimmune disorders (Table 353-2). Patients with SSc can be broadly segregated into two major subsets defined by the pattern of skin involvement, clinical and laboratory features, and natural history (Table 353-3). Diffuse cutaneous SSc (dcSSc) is typically associated with extensive skin induration starting in the fingers (sclerodactyly) and ascending from distal to proximal limbs and the trunk. In these patients, interstitial lung disease (ILD) and acute renal involvement develop relatively early. In contrast, in patients with limited cutaneous SSc (lcSSc), Raynaud’s phenomenon generally precedes other disease manifestations, sometimes by years. In these patients, skin involvement remains confined to the fingers, distal limbs, and face, while the trunk is spared. The constellation of calcinosis cutis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia, was historically termed the CREST syndrome. In lcSSc, visceral organ involvement tends to show insidious progression, and digital ischemic ulcers, pulmonary arterial hypertension (PAH), hypothyroidism, and primary biliary cirrhosis may occur as late complications. In some patients, Raynaud’s phenomenon and characteristic clinical and laboratory features of SSc occur in the absence of detectable skin thickening. This syndrome has been termed SSc sine scleroderma.