Gout is the classic example of crystal-induced inflammation of synovial joints. It is a common condition, presenting in approximately 4% of the adult American population, and it is approximately 3 times more common in men than women. Deposition of monosodium urate crystals in the joint space leads to episodes of severe acute joint pain and swelling (particularly in the great toe, midfoot, ankle, and knee). These episodes tend to resolve completely and spontaneously within a week even in the absence of therapy. If not properly treated, however, this acute, self-limited form of the disease can evolve over many years into a chronic, destructive pattern resulting in more frequent and sustained periods of pain and resultant joint deformity. Accumulations of urate crystals elsewhere in the body can lead to subcutaneous deposits called tophi.
The critical initiating factor in gout is the precipitation of monosodium urate crystals in synovial joints. This occurs when body fluids become supersaturated with uric acid (generally at serum levels >7 mg/dL). Indeed, the degree of hyperuricemia correlates well with the development of gout, with annual incidence rates of about 5% for serum uric acid levels more than 9 mg/dL. Increased levels of serum uric acid result either from underexcretion (90% of patients) or overproduction (10%) of uric acid. A decreased glomerular filtration rate is the most frequent cause of decreased excretion of uric acid and may be due to numerous causes (see Chapter 16), but, regardless of etiology, impaired renal function is clearly related to the occurrence of gout. Diuretic administration is also a frequent cause of decreased excretion of uric acid. Overproduction defects can result from primary defects in the purine salvage pathway (eg, hypoxanthine phosphoribosyl transferase deficiency), leading to an increase in de novo purine synthesis and high flux through the purine breakdown pathway. Diseases causing increased cell turnover (eg, myeloproliferative disorders, psoriasis) and DNA degradation (eg, tumor lysis syndrome) are secondary causes of hyperuricemia.
Although the concentration of monosodium urate in joint fluid slowly equilibrates with that in the serum, formation of crystals is markedly influenced by physical factors such as temperature and blood flow. The propensity for gout to involve distal joints (eg, great toes and ankles), which are cooler than other body parts, probably reflects the presence of local physical conditions at these sites remote from the body core that favor crystal formation.
Monosodium urate crystals are not biologically inert. Their highly negatively charged surfaces function as efficient initiators of the acute inflammatory response. The crystals are potent activators of the classic complement pathway, generating complement cleavage products (eg, C3a, C5a) that are strong chemoattractants for neutrophil influx (Figure 24–2). The crystals also activate the kinin system and in that way induce local vasodilation, pain, and swelling. Phagocytosis of crystals by synovial macrophages activates the inflammasome (a complex of proteins that sense certain intracellular stressors and activate IL-1 maturation) and stimulates the release of proinflammatory cytokines (eg, IL-1, TNF, IL-8, PGE2). These products increase adhesion molecule expression on local vessel endothelium to facilitate neutrophil adhesion and migration and are also potent chemoattractants for neutrophils. Neutrophils also amplify their own recruitment by releasing leukotriene LTB4 upon phagocytosis of urate crystals (Figure 24–2).
Mechanisms in initiation and amplification of the acute inflammatory response in gout involve both cytokines and humoral mediators.
The intense inflammatory response in gout typically resolves spontaneously and completely over the course of several days, even without therapy. This down-modulation of the inflammatory response is a typical feature of acute inflammation, whereby the inflammatory response itself successfully removes the proinflammatory stimulus (Table 24–1). Numerous mechanisms appear to be responsible: (1) efficient phagocytosis of crystals, preventing activation of newly recruited inflammatory cells; (2) increased heat and fluid influx, altering local physical and chemical conditions to favor crystal solubilization; (3) coating of crystals with serum proteins, rendering the surface of the crystals less inflammatory; (4) secretion of a variety of anti-inflammatory cytokines (eg, TGF-β) by activated joint macrophages; and (5) phagocytosis of previously activated apoptotic neutrophils by macrophages in the joint, altering the balance of cytokines secreted by these macrophages in such a way that secretion of proinflammatory cytokines is inhibited while anti-inflammatory cytokine secretion is enhanced.
Table 24–1Mechanisms causing down-modulation of the inflammatory response in gout. ||Download (.pdf) Table 24–1 Mechanisms causing down-modulation of the inflammatory response in gout.
Efficient phagocytosis of crystals
Increased heat and fluid influx, favoring solubilization
Coating of crystals with serum proteins, shielding their pro-inflammatory surfaces
Secretion of anti-inflammatory cytokines (eg, TGF-β) by activated joint macrophages
Phagocytosis of apoptotic neutrophils, enhancing anti-inflammatory effects
Thus, gout represents an excellent example of an acute inflammatory response initiated by a proinflammatory force. The response is acute, highly focused, and self-limited rather than self-sustaining and associated with little tissue destruction in the acute phase. Flares of disease represent recurrence of crystals in a proinflammatory form in the joints. Myelomonocytic cells and humoral factors (eg, cytokines and the complement and kinin cascades) are critical mediators of the acute syndrome.
Podagra and Episodic Oligoarticular Arthritis
Podagra—severe inflammatory arthritis at the first metatarsophalangeal joint—is the most frequent manifestation of gout. Patients typically describe waking in the middle of the night with dramatic pain, redness, swelling, and warmth of the area. Flares of gout typically produce one of the most intense forms of inflammatory arthritis. The toes and, to a lesser extent, the midfoot, ankles and knees are the most common sites for gout flares. Gout attacks frequently occur in circumstances that increase serum uric acid levels, such as metabolic stressors leading to increased DNA or adenosine triphosphate (ATP) turnover (eg, sepsis or surgery) or dehydration. Agents that reduce prostaglandin synthesis (eg, nonsteroidal anti-inflammatory drugs), reduce neutrophil migration into the joints (eg, colchicine), or decrease the activation of myelomonocytic cells (eg, corticosteroids) reduce the duration of a gouty flare.
Gouty arthritis can be diagnosed by examination of synovial fluid from an actively inflamed joint under a polarizing microscope. Monosodium urate crystals can be seen as negatively birefringent needle-like structures that extend across the diameter of and are engulfed by polymorphonuclear neutrophils.
Firm, irregular subcutaneous deposits of monosodium urate crystals may occur in patients with chronic gout and are referred to as tophi. Tophi most often form along tendinous tissues on the extensor surfaces of joints and tendons as well as on the outer helix of the ear. Such tophi may extrude chalky material, containing urate crystals, onto the skin surface that can be viewed for diagnostic purposes under polarized microscopy.
Chronic Erosive Polyarthritis
In some patients, the total body burden of uric acid increases greatly over years; deposits of monosodium urate crystals occur at multiple joint sites. This may result in a persistent but more indolent inflammatory arthritis associated with remodeling of the thin synovial membrane into a thickened inflammatory tissue. Destructive and irreversible joint deformities resulting from bone and cartilage erosions often develop in this circumstance. Renal tubular injury and nephrolithiasis can also develop under these conditions.
Therapy for acute gouty arthritis consists of agents that decrease inflammatory cell recruitment and activation to the involved joints. In contrast, prevention or prophylaxis of recurrent attacks of gouty arthritis requires chronic therapy to decrease serum uric acid levels into the normal range, where dissolution of crystals is favored. Several agents are available that can accomplish this purpose. These include uricosuric agents (eg, probenecid), which enhance excretion of uric acid into the urine, allopurinol and febuxostat, which impede uric acid synthesis by inhibition of xanthine oxidase (a critical enzyme in the uric acid synthetic pathway), and pegloticase, which converts uric acid to allantoin, an inactive and soluble metabolite that is readily excreted by the kidneys. Conceptually, the xanthine oxidase inhibitors, allopurinol and febuxostat, are most appropriate for the treatment of uric acid overproduction (10% of patients), the uricosuric agent, probenecid, for the treatment of uric acid underexcretion (90% of patients), and pegloticase for the rare cases of refractory gout. However, agents that decrease uric acid production can be used for therapy of hyperuricemia irrespective of cause and are often more convenient in terms of dosage regimens.
4. What physical factors other than uric acid concentration influence crystal formation in gout?
5. What are some proinflammatory products released by synovial macrophages upon phagocytosis of urate crystals?
6. Suggest five reasons why the intense acute inflammatory response in gout typically resolves spontaneously over the course of several days even in the absence of therapy.
7. What are three metabolic conditions that can precipitate a gout flare?
8. Name three chronic sequelae of recurrent gout flares.
Immune Complex Vasculitis
Immune complex vasculitis is an acute inflammatory disease of small blood vessels that occurs in the setting of ongoing antigen load and an established humoral (antibody) immune response. Tissues affected include the skin (leukocytoclastic vasculitic rash), joints (inflammatory arthritis of small and medium-sized synovial joints), and kidney (immune complex–mediated glomerulonephritis).
Antigens are frequently derived from exogenous sources, including infections (eg, streptococcal skin infections, hepatitis B virus) and numerous drugs (especially antibiotics). An intense inflammatory response to such antigens accounts for one of the names (“hypersensitivity vasculitis”) given to this disorder. Release of endogenous antigens in the setting of an autoimmune response (eg, SLE; see later discussion) may similarly initiate the vasculitic process.
Any antigen that elicits a humoral immune response may give rise to circulating immune complexes if the antigen remains present in abundant quantities once antibody is generated. Immune complexes are efficiently cleared in most circumstances by the reticuloendothelial system and are rarely pathogenic. Their pathogenic potential is realized when circulating immune complexes are deposited in the subendothelium, where they set in motion the complement cascade and activate myelomonocytic cells. The propensity for immune complexes to deposit is a function of the relative amounts of antigen and antibody and of the intrinsic features of the complex (ie, composition, size, and solubility). The solubility of immune complexes is not a fixed property, because it is profoundly influenced by the relative concentrations of antigen and antibody, which generally change as an immune response evolves. For physicochemical reasons, soluble immune complexes formed at slight antigen excess are not effectively cleared by the reticuloendothelial system and are of a size that allows them to gain access to and be deposited at subendothelial and extravascular sites (Figure 24–3). When antibody is present in excess, immune complexes are rapidly cleared by the reticuloendothelial system and deposition does not occur.
Immune complex formation. Impact of concentrations of antigens and antibodies.
Thus, if foreign antigens (eg, drugs or infectious organisms) induce an antibody response in the setting of slight antigen excess, significant numbers of immune complexes of the appropriate size are formed and they may then be deposited in small vessels in various target organs (in skin, joints, kidney, blood vessel walls) where they activate several effector pathways (eg, FcR receptor, classic complement cascade) and where they may lead to the characteristic skin rashes (eg, palpable purpura), arthritis, and glomerulonephritis, which are the hallmarks of small-vessel vasculitis. As the immune response progresses and titers of specific antibody rise, or as the offending agent is removed, complexes are more effectively cleared, leading to resolution of the vasculitis.
A classic example of the altered pathogenicity of immune complexes at various antigen-antibody ratios is serum sickness. (Penicillin-induced hypersensitivity vasculitis represents a similar example.) When serum products from animals (eg, horses) are injected into humans for a therapeutic purpose (eg, as once was used for passive immunization against snake venom), the foreign serum proteins stimulate an immune response, with antibodies first appearing approximately 1 week after injection. Soon thereafter, immune complexes appear, followed by the development of fever, arthritis, rash, and glomerulonephritis, consistent with deposition of soluble immune complexes and myelomonocytic cell activation at multiple tissue sites. As the antibody titers rise, immune complexes are no longer formed at great antigen excess but approach the zone of equivalence and then the zone of antibody excess. The latter complexes are effectively cleared and thus lose their pathogenicity as the immune response evolves. Provided that antigen administration is not sustained, the inflammatory disease will resolve spontaneously as those immune complexes that were deposited early (during the soluble phase) are cleared. Such significant clinical effects of immune complexes usually occur only when the initial antigen load is great (eg, a large bacterial load or drug administration).
Clinical Manifestations of Immune Complex Vasculitis
Affected tissues are all highly enriched in small blood vessels, which are the target of injury in this syndrome.
Cutaneous Small-Vessel (Leukocytoclastic) Vasculitis
A common clinical presentation of immune complex–induced vasculitis in the skin is palpable purpura, which appears as red or violaceous papules. Cutaneous immune complex vasculitis seldom causes severe pain or tissue breakdown and only rarely leads to long-term injury (see Chapter 8).
The most common pattern of joint involvement with immune complex disease is that of a severe, rapid-onset and self-limited symmetric polyarthritis. As the immune complexes undergo phagocytosis and are cleared, the immune response remits unless further waves of immune complexes are deposited.
Glomeruli are beds of small blood vessels in the kidney where immune complexes are likely to be deposited. Acute immune complex glomerulonephritis causes proteinuria, hematuria, and formation of red blood cell casts, due to disruption of the glomerular basement membrane caused by subendothelial complex deposition. In cases of extensive immune complex–mediated injury, immune complex vasculitis can cause oliguria and acute kidney injury.
The most effective treatment for immune complex vasculitis is elimination of the inciting antigen (eg, by discontinuation of an offending drug). Medications that reduce the degree of activation of myelomonocytic cells (eg, corticosteroids) are also helpful.
Contrast between Immune Complex Vasculitis, Granulomatosis with Polyangiitis [Formerly Wegener Granulomatosis], & Polyarteritis Nodosa
The vasculitides are a diverse group of inflammatory syndromes characterized by inflammatory destruction of blood vessels. However, not all forms of vasculitis are caused by immune complex deposition. This fact is highlighted by the current classification system for the systemic vasculitides, which segregates diseases on the basis of the size of the blood vessel involved (Table 24–2), by the presence of circulating autoantibodies, and by the histologic presence or absence of immune complexes.
Table 24–2Classification of vasculitic syndromes based on vessel size. ||Download (.pdf) Table 24–2 Classification of vasculitic syndromes based on vessel size.
|Vessel Size ||Examples ||Epidemiology and Demographics |
|Small vessel ||Immune complex mediated; Henoch-Schönlein purpura ||Common, evanescent. Predominantly in children, relatively common compared with other autoimmune conditions |
|Medium vessel ||Polyarteritis nodosa ||Rare; ~5 cases per million |
|Large vessel ||Giant cell arteritis ||Only in patients older than 50 years; ~100 cases per million |
It is useful to contrast the clinical and pathophysiologic features of immune complex vasculitis (see prior discussion) with those of the “pauci-immune” vasculitic processes, which include granulomatosis with polyangiitis [GPA] and polyarteritis nodosa. The clinical hallmarks of GPA include granulomatous inflammation of the upper airway (eg, sinusitis) and lower airway (eg, trachea, lungs), as well as a necrotizing vasculitis involving the kidneys and many other organs. Although immune complex deposition is not a prominent feature in the pathophysiology of GPA, a specific group of antibodies highly specific to this disease may play an important propagating role. These “ANCA” antibodies [antineutrophil cytoplasmic antibodies], directed against components situated within neutrophil cytoplasmic granules, may bind to and activate neutrophils at the interface of the plasma and vessel wall and cause them to degranulate and damage vascular walls at these sites.
In contrast, neither ANCA antibodies nor immune complex deposition plays a central role in the pathogenesis of polyarteritis nodosa, a vasculitis affecting medium-sized muscular arteries and arterioles. In this condition, the pathologic hallmark is an intense and destructive myelomonocytic cellular infiltrate in the blood vessel wall (called fibrinoid necrosis), leading to vessel occlusion, marked luminal narrowing and obsolescence. The dominant pathologic features of this disease, therefore, are organ and tissue ischemia–mediated dysfunction related to decreased perfusion and subsequent impaired oxygen delivery from severely damaged medium-sized vessels. Common manifestations of this condition include infarction of nerve trunks (eg, mononeuritis multiplex), bowel ischemia (eg, mesenteric insufficiency causing abdominal angina), kidney ischemia (eg, renal insufficiency), and deep cutaneous ulcerations. The different vasculitic syndromes, therefore, express unique phenotypes, clinical symptoms and signs, and pathologic features reflecting their distinct underlying pathophysiologic mechanisms.
9. In what two immunologic settings does immune complex vasculitis occur?
10. What are the three most prominent organ systems affected by immune complex vasculitis? Describe the typical manifestations in each.
11. What three physical properties determine whether immune complexes will be deposited in vessel walls?
12. What happens once subendothelial deposition has occurred?
13. Why does pathogenicity of immune complexes generally decrease as antibody titers rise?
Systemic Lupus Erythematosus
SLE is the prototypic systemic autoimmune rheumatic disease, characterized by chronic inflammatory injury to, and subsequent damage of, multiple organ systems. A key feature of this disease is the unique adaptive immune response, driven by antigens contained in self tissues, which is apparently responsible for much of the widespread pathologic consequences of the disease. Clinically, SLE is episodic in nature, with a course characterized by flares and remissions. It is also highly variable in severity, ranging from mild to life threatening. Tissues frequently affected include the skin, joints, kidneys, blood cell lines, serosal surfaces, and brain.
The prevalence of SLE is approximately 30 cases per 100,000 in the general population in the United States. It occurs about nine times more frequently in women than in men and is most prevalent in blacks. Prevalence estimates rise to approximately 1 in 250 young African American women.
SLE is a complex disease because of an interplay between inherited susceptibilities (>20 different genetic loci are implicated) and poorly defined environmental factors. Genetic deficiencies of the proximal components of the classic complement pathway (eg, C1q, C1r, C1s, C4), although rare in most populations, are the strongest known risk factors defined for the development of lupus. Studies have demonstrated that the classic complement pathway is required for the efficient noninflammatory clearance of apoptotic cells by macrophages. The development of lupus in individuals with these deficiencies may relate to impaired clearance of apoptotic cells in this setting, with proinflammatory consequences (see later discussion). The mechanisms whereby environmental factors (eg, drugs, viral infections) function to initiate or propagate SLE are not yet well understood.
It is useful to view the pathogenesis of SLE in discrete phases even though these phases are not clearly separable clinically. Indeed, it is likely that events underlying initiation occur before the onset of clinically defined disease, which requires chronic amplification of the propagation phase to become clinically apparent.
The exuberant autoantibody response in lupus targets a highly specific group of self-antigens (Table 24–3). Although this group of autoantigens does not share common features (eg, structure, distribution, or function) in healthy cells, these molecules are unified during apoptotic cell death, when they become clustered and structurally modified in apoptotic surface blebs (Figure 24–4). Indeed, studies suggest that the initiating event in lupus is a unique form of apoptotic cell death that occurs in a proimmune context (eg, viral infection). Several environmental exposures have been persuasively associated with disease initiation in SLE. These include sunlight exposure (associated with both disease onset and flares), viral infection (Epstein-Barr virus exposure is strongly associated with SLE in children), and certain drugs. These are agents to which humans are commonly exposed, suggesting that those individuals who develop SLE have underlying abnormalities that render them particularly susceptible to disease initiation.
Table 24–3Autoantigens in systemic lupus erythematosus. ||Download (.pdf) Table 24–3 Autoantigens in systemic lupus erythematosus.
|Nuclear || |
|Cytoplasmic || |
Ribosomal protein P
Ro (52 kDa)
|Membrane associated || |
Although sharing no features in healthy cells, autoantigens become unified in apoptotic cells. Here, they become clustered at the surface of the apoptotic cells, and their structure is modified.
A critical susceptibility defect for the development and propagation of SLE appears to be impairment of normal clearance of apoptotic cells in tissues. Thus, in normal individuals, the fate of most apoptotic cells is rapid and efficient phagocytosis by macrophages, and antigens ingested in this way are rapidly degraded. Furthermore, phagocytosis of apoptotic cells inhibits secretion of proinflammatory cytokines from macrophages and induces secretion of several anti-inflammatory cytokines, contributing to the impaired ability of apoptotic cells to initiate a primary immune response. Last, the avid phagocytosis of apoptotic cells by normal macrophages prevents significant numbers from accessing dendritic cell populations, which are highly efficient initiators of primary immune responses. Together, these factors ensure that normal individuals do not efficiently immunize themselves with apoptotic material derived from their own tissues. In contrast, impaired clearance of apoptotic cells is observed in a subgroup of patients with SLE. Under conditions in which apoptotic material is not efficiently cleared by macrophages (eg, in C1q deficiency), suprathreshold amounts of this material may gain access to potent antigen-presenting cell populations under proimmune conditions and initiate a response to molecules whose structure has been modified during delayed apoptotic cell death.
Autoantibodies in lupus can cause tissue injury by a variety of mechanisms:
The most common pathogenic mechanism is generation and deposition of immune complexes, in which antigen is derived from damaged and dying cells. When the concentration and size of the relevant complexes favor subendothelial deposition, these markedly proinflammatory complexes initiate inflammatory effector functions that result in tissue damage (see prior discussion). Of particular importance is the ability of immune complexes to ligate the Fcγ receptor, which activates myelomonocytic cell effector functions. The deposition of immune complexes in the kidney, joints, and skin underlies several of the central clinical features of SLE.
Autoantibodies bind to extracellular molecules in the target organs and activate inflammatory effector functions at that site, with consequent tissue damage. Examples of this phenomenon include autoimmune hemolytic anemia and antibody-mediated thrombocytopenia as well as the photosensitive skin disease of the neonatal lupus syndrome (see later discussion).
Autoantibodies directly induce cell death by ligating cell surface molecules or by penetrating into living cells and exerting functional effects.
It is important to note that the intracellular antigens that drive the immune response in SLE can be derived from damaged or apoptotic cells. Such damage or apoptosis occurs commonly in the course of immune effector pathways. Thus, these effector pathways can generate additional antigen, further stimulating the immune system and generating still more antigen. This autoamplification is a central feature of the propagation phase of lupus.
Type I interferons have recently been shown to play a central role in amplification pathways in SLE, with clear evidence of increased type I interferon activity during active disease. Type I interferons induce the differentiation of monocytes into potent antigen-presenting dendritic cells. Additionally, type I interferons enhance signaling through toll-like receptors (TLRs), specifically increasing the pro-inflammatory signaling of SLE antigens containing nucleic acids through TLR 3, 7, and 9. Additionally, type I interferons sensitize target cells to death through various inflammatory effector pathways, increasing the antigen load presented to the immune system.
One of the characteristic features of an immune response is the establishment of immunologic memory, so that when the organism again encounters the antigen the immune system responds more rapidly and vigorously to lower concentrations than were required to elicit the primary response. Flares in SLE appear to reflect immunologic memory, occurring in response to rechallenge of the primed immune system with antigen. Apoptosis not only occurs during cell development and homeostasis (particularly of hematopoietic and epithelial cells) but also in many disease states. Thus, numerous stimuli (eg, ultraviolet light exposure, viral infection, endometrial and breast epithelial involution) may conceivably provoke disease flares.
SLE is a multisystem autoimmune disease that affects predominantly women during the childbearing years (mean age at diagnosis is 30 years). It is characterized clinically by periodicity, and the numerous exacerbations that occur over the years are termed flares. The symptoms are highly variable but tend to be stereotyped in a given individual (ie, the prominent clinical features often remain constant over years). Production of specific autoantibodies is a universal feature. Several organ systems are frequently affected. Prominent among these is the skin, in which photosensitivity and a variety of SLE-specific skin rashes (including a rash over the malar region, discoid pigmentary changes to the external ear, and erythema over the dorsum of fingers) are common. Like those who have other immune complex–mediated diseases, patients with SLE may manifest a nonerosive symmetric polyarthritis. Renal disease, which takes the form of a spectrum of glomerulonephritides, is a frequent major cause of morbidity and mortality. Patients may manifest a variety of hematologic disturbances (including hemolytic anemia, thrombocytopenia, and leukopenia), inflammation of serosal surfaces (including pleuritic and pericarditic chest pain and perotinitis), as well as several neurologic syndromes (eg, seizures, organic brain syndrome).
An intriguing neonatal SLE syndrome occurs in the offspring of mothers who have antibodies directed against the Ro, La, or U1-RNP proteins. In this condition, passive transfer of maternal autoantibodies across the placenta results in congenital heart block and photosensitivity in the neonate as a result of antibody-associated destruction of developing tissues such as cardiac conduction system and skin cells that transiently express these antigens.
14. What are the antigens against which antibodies are directed in SLE?
15. How many different genetic loci are believed to confer susceptibility to SLE? Which are the strongest ones?
16. What is believed to be the relationship of apoptosis to the initiation of SLE?
17. What prevents normal individuals from being immunized to apoptotic cell debris, and why does this host defense break down in patients with SLE?
18. What are three stimuli that typically provoke SLE flares?
19. What are the most prominently affected organ systems in SLE?
Sjögren syndrome is a prevalent and slowly progressive autoimmune rheumatic disorder in which the exocrine glands are the primary target tissue. Affected individuals frequently manifest intense dryness of their eyes (xerophthalmia) and mouth (xerostomia), giving rise to the alternate name keratoconjunctivitis sicca. Histologically, an intense mononuclear inflammatory infiltrate is observed in affected lacrimal and salivary glands, respectively. Like other autoimmune rheumatic diseases, prominent polyclonal hypergammaglobulinemia and high-titer levels of characteristic autoantibodies are frequent features of the syndrome.
Sjögren syndrome occurs in approximately 1–3% of the adult population. As with SLE, the prevalence is about nine times more frequent in women than men. The prototypic affected individual is a woman in the fourth or fifth decade of life. Sjögren syndrome occurs as both a primary disorder and as a secondary process, in the context of another well-defined autoimmune rheumatic disorder (especially SLE and rheumatoid arthritis).
Viruses have been implicated in the development of Sjögren syndrome but conclusive data are lacking. Epithelial cells in salivary glands can be infected by a number of viral pathogens (including Epstein-Barr virus, cytomegalovirus, hepatitis C, HIV, and coxsackievirus). In an autoimmune mouse model, CMV infection leads to initial infection of salivary glands, followed later by autoimmune salivary gland inflammation. Whether a similar process occurs during initiation of the human disease is not yet known.
Although the cause of Sjögren syndrome remains unclear, several pathways have been implicated in pathogenesis. Central among these is autoimmunity to epithelial tissues, with an immune response directed against several ubiquitously expressed antigens (eg, Fodrin, Ro, and La) as well as to some antigens expressed specifically in secretory epithelial cells (eg, type 3 muscarinic acetylcholine receptors [M3R]). The antibodies to M3R are believed to prevent stimulated secretion of saliva and tears and may be important generators of the hyposecretion that characterizes the disease. In addition, exocrine tissues are also infiltrated with activated cytotoxic lymphocytes, which induce death of duct and acinar epithelium, with progressive loss of functioning salivary tissue. The enrichment of HLA-DR3 in patients with Sjögren syndrome may reflect the enhanced ability of these molecules to present peptides contained within the pathogenic autoantigens.
The most prominent presenting symptoms in Sjögren syndrome are ocular and oral dryness. Intense xerophthalmia (ocular dryness) may express itself as eye irritation, with a foreign body sensation or with pain. Such impairment in tear production heightens the risk for corneal ulcer or perforation.
Impaired production of saliva, at rest and with stimulation when eating, contributes to the prominent symptom of xerostomia (dry mouth). Affected persons often relate difficulty in swallowing dry foods or in speaking at length. An altered sensation of taste or of oral burning may occur. Characteristically, individuals affected by Sjögren syndrome are susceptible to new-onset and severe dental caries at the gum line in mid-adult life. This reflects the loss of the essential antibacterial functions of saliva, with consequent excessive concentration of bacteria at dental surfaces.
Other epithelial surfaces may be similarly affected by diminished secretions and contribute to dryness. For example, patients may complain of skin and vaginal dryness. Dryness in the respiratory tract may give rise to hoarseness and recurrent bronchitis. Moreover, it is noteworthy that when immune activation is severe, patients experience systemic symptoms, including fatigue, arthralgia, myalgia, and low-grade fever. Other potentially affected organ systems include the kidneys, lungs, joints, and liver (resulting in interstitial nephritis, interstitial pneumonitis, nonerosive polyarthritis, and intrahepatic bile duct inflammation). As many as half of affected individuals experience autoimmune thyroid disease. Those patients with particularly severe disease are at increased risk for cutaneous vasculitis (including palpable purpura and skin ulceration) and lymphoproliferative disorders (eg, mucosa-associated lymphoid tissue [MALT] lymphoma).
Current therapy is aimed primarily at symptomatic improvement. Available agents include artificial tears, which serve as topical lubricants to aid with eye dryness. Maintaining oral hydration, with access to a regular supply of beverages, is encouraged. Use of sugar-free gum and lozenges may stimulate salivary flow. More recently, new cholinergic agonists have come to market aimed at improving oral hydration by stimulating increased salivary production, via muscarinic receptors, in affected submandibular salivary glands. Effective anti-inflammatory and immunosuppressive treatment for Sjögren syndrome has not yet been found, indicating that the components of the critical amplification loops have not yet been discovered. For those affected by severe disease sequelae (including systemic vasculitis and mononeuritis multiplex), administration of systemic immunosuppression is necessary.
The inflammatory myopathies—polymyositis and dermatomyositis—are characterized by the gradual development of progressive motor weakness affecting the arms and legs, as well as the trunk, in association with histologic evidence of muscle inflammation. While such inflammation predominantly involves striated muscle, it is important to recognize that smooth muscle and even cardiac muscle may similarly, though less commonly, be affected. Often, the afflicted patient experiences increasing difficulty when rising from a seated position, in getting out of bed, or in ascending a flight of stairs. It may become increasingly difficult to reach up and lift dishes from an upper shelf or to even brush one’s hair.
At the most severe end of the disease spectrum, affected persons may develop profound impairment in swallowing solid foods and in full lung expansion, arising from pathologic involvement of visceral muscle affecting the esophageal and diaphragmatic muscle tissues, respectively. These disease manifestations may result in nasal regurgitation of swallowed liquid beverages and in profound respiratory compromise. There is also a predilection for extramuscular involvement to occur, including of the lung parenchyma (interstitial pulmonary fibrosis) and peripheral joints (inflammatory polyarthritis), and in those with dermatomyositis, mild, moderate, or even severe inflammation of the integument. At the same time, diplopia (double vision resulting from a paretic ocular muscle) is distinctly uncommon in these two myositis disorders.
The inflammatory myopathies are relatively rare disorders. Polymyositis has been estimated to occur with an annual incidence rate of approximately 5 cases per million. Women are affected twice as often as men. Interestingly, dermatomyositis has a bimodal distribution in terms of age at onset; the first peak occurs in childhood, and the second peak occurs in mid and late adult life. Of note, polymyositis may clearly occur as a primary disorder in and of itself. However, the polymyositis phenotype may also occur as a secondary process, but when present in the context of another well-defined autoimmune rheumatic disorder, such as systemic lupus erythematosus, it is otherwise clinically and histologically indistinguishable.
Autoantibodies are present in approximately 60% of all patients with an inflammatory myositis. Two best examples are both anti Jo-1 antibodies (that target histidyl tRNA synthetase), which are found in approximately 20% of all patients with myositis and in approximately 70% of patients with a myositis/interstitial lung disease overlap syndrome, and anti-Mi-2 antibodies (that target CHD4, a DNA binding protein), which are specific to dermatomyositis. Since both nuclear and cytoplasmic antigens are targeted for an immune response in these diseases, both antinuclear antibodies (ANA) and anticytoplasmic antibodies (ANCA) can be found.
Recent studies suggest that one source of these autoantigens is the regenerating muscle cell itself, which expresses higher levels of myositis autoantigens than its normal counterpart. Some tumor cells also express these same antigens at high levels. An intriguing pathophysiologic hypothesis is that the immune response that targets similar antigens in both tumor and inflamed muscle cells might be responsible for the link between inflammatory myositis and malignancy.
Polymyositis and dermatomyositis share several similar pathologic features but possess distinct ones as well. These include patchy involvement, presence of inflammatory infiltrates, and areas of muscle damage and regeneration. In polymyositis, inflammation is located around individual muscle fibers (“perimyocyte”), and the infiltrate is T-cell (CD8+ > CD4+) and macrophage predominant. It has been suggested that the inflammation seen in polymyositis is driven by autoantigens expressed in the muscle environment, given the restricted T-cell repertoire in both circulating and muscle-infiltrating lymphocytes. Proinflammatory cytokines may induce a striking upregulation of MHC class I molecules seen on affected muscle cells but not adjacent normal myocytes. This MHC class I upregulation may lead to muscle damage through antigen-specific interactions with infiltrating CD8+ T cells, or through indirect mechanisms, by triggering a cell-damaging unfolded protein response (“UPR” or “ER stress”) in the muscle itself. Further damage occurs when infiltrating T cells degranulate and release perforin and proteolytic granzymes at specific sites of contact within the affected muscle.
In dermatomyositis, the pathology looks quite different, although the outcome—profound muscle weakness—is the same. The major pathologic hallmarks of this condition include atrophy at the periphery of muscle bundles (“perifascicular atrophy”), and a predominantly B-cell and CD4+ T-cell infiltrate localized to the perifascicular space and surrounding capillaries (which are reduced in number). Activation of the complement cascade is seen as well. Major involvement of the capillaries has led many experts to suggest that the primary disorder in dermatomyositis is a small-vessel vasculitis, with myositis occurring later as a result of tissue ischemia and repair. The characteristic skin and nailfold capillary changes seen in patients with dermatomyositis lend support to this notion.
The inflammatory myopathies characteristically begin over a number of weeks to a few months. The hallmark symptom of both polymyositis and dermatomyositis is weakness. This characteristically involves the upper and lower extremities and is predominantly proximal rather than distal in location. While muscle pain or myalgia may be present, weakness is the predominant symptom. Routine daily activities that one might otherwise take for granted can become quite a chore, or even an impossible ordeal, to perform. An example is standing up from a chair or toilet seat. In addition, the cutaneous features of dermatomyositis can be quite debilitating and include a painful, burning sensation of affected skin, as well as skin cracking and even breakdown with open ulceration.
There are four characteristic criteria for the diagnosis of polymyositis, which are: (1) weakness, (2) elevated laboratory parameters of muscle tissue (eg, creatine phosphokinase or aldolase), (3) an irritable electromyogram upon electrodiagnostic evaluation (producing sharp waves, spontaneous discharges), and (4) an inflammatory infiltrate upon histologic evaluation. In patients with dermatomyositis, a fifth criterion is a characteristic skin rash. Erythematous and/or violaceous discoloration may occur periorbitally or in a V-neck distribution on the trunk. These prototypic skin changes are termed periorbital heliotrope and shawl sign, respectively. Erythematous scaly eruptions may also occur over the extensor surface of the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints and are termed the Gottron sign. Extensive sheets of muscle and soft tissue calcification may occur in children beset with dermatomyositis. Though recent efforts to modify the original diagnostic criteria, by integration of newer imaging modalities, including magnetic resonance imaging, or use of newer autoantibodies with specificities for the inflammatory myopathies have been proposed, the original criteria remain the foundation for these two muscle disorders.
An important additional clinical feature of the inflammatory myopathies has been the finding of an association with cancer in multiple demographic groups and among diverse populations. In adult patients, the new diagnosis of an inflammatory myopathy not infrequently heralds the co-occurrence or subsequent development within 1–5 years of a malignancy. The veracity of this observation has been confirmed in several population-based studies that link the diagnoses of dermatomyositis and polymyositis with cancer in cancer registries. A diagnosis of dermatomyositis carries a 2-fold greater risk of incident malignancy, particularly stomach, lung, breast, colon, and ovarian cancers.
Corticosteroids are the front-line therapy for the inflammatory myopathies and are often required in high doses, for an extended period of time, to bring the marked inflammation in affected muscle tissues under control and to restore the patient’s full functional capacity. Therefore, careful review of the clinical and histologic evidence supporting the diagnosis of an inflammatory myopathy is indicated in order to be confident that the potential drug-associated toxicity to which the patient is exposed is warranted. In addition, the clinician also must recognize that a subset of treatment-refractory patients with presumed polymyositis may in fact be cases of a toxic myopathy (ie, related to the use of colchicine or a statin) or be attributable to a different myopathy (eg, inclusion body myositis). Second-line immunosuppressive agents integrated into treatment algorithms for the inflammatory myopathies include methotrexate, mycophenolate mofetil, intravenous immunoglobulin, and rituximab.
Rheumatoid arthritis is a chronic systemic inflammatory disease characterized by persistent symmetric inflammation of multiple peripheral joints. It is one of the most common inflammatory rheumatic diseases and is characterized by the development of a chronic inflammatory proliferation of the synovial linings of diarthrodial joints, which leads to aggressive cartilage destruction and progressive bony erosions. Untreated, rheumatoid arthritis often leads to progressive joint destruction, disability, and premature death.
The prevalence of rheumatoid arthritis in the United States is approximately 1% in the general population; similar prevalence rates have been observed worldwide. The disorder occurs approximately three times more frequently in women than in men and has its peak onset in the fifth to sixth decade of life.
Like SLE, rheumatoid arthritis is a systemic autoimmune disease in which abnormal activation of B cells, T cells, and innate immune effectors occurs. In contrast to SLE, the majority of inflammatory activity in rheumatoid arthritis occurs in the joint synovium. Although the cause of rheumatoid arthritis is unknown, a complex set of genetic and environmental factors appears to contribute to disease susceptibility. Because the incidence of rheumatoid arthritis has been observed to be similar in many cultures and geographic regions across the globe, it is assumed that the environmental exposures that provoke rheumatoid arthritis must be widely distributed. Early rheumatoid arthritis is closely mimicked by transient inflammatory arthritis precipitated by several microbial pathogens. Thus, although a role for infection in the development of rheumatoid arthritis has long been postulated, it is not yet satisfactorily proven. Specific class II MHC alleles (HLA-DR4), sharing a consensus QKRAA motif in the peptide-binding groove, have been highly related to disease susceptibility and to greater severity in rheumatoid arthritis.
Much of the pathologic damage that characterizes rheumatoid arthritis is centered around the synovial linings of joints. Normal synovium is composed of a thin cellular lining (one to three cell layers thick) and an underlying interstitium, which contains blood vessels but few cells. The synovium normally provides nutrients and lubrication to adjacent articular cartilage. Rheumatoid arthritis synovium, in contrast, is markedly abnormal, with a greatly expanded lining layer (8–10 cells thick) composed of activated cells and a highly inflammatory interstitium replete with B cells, T cells, and macrophages and vascular changes (including thrombosis and neovascularization). At sites where synovium and articular cartilage are contiguous, rheumatoid arthritis synovial tissue (called pannus) invades and destroys adjacent cartilage and bone.
Although the causes of rheumatoid arthritis remain unclear, several important components of pathogenesis have been identified. As discussed previously, it is useful to separate the initiating and propagating phases of the disease and to recognize that the established rheumatoid arthritis phenotype reflects a self-sustaining and amplified inflammatory state.
Concordance rates in twins vary between 15% and 35%, implicating genetic factors in the pathogenesis of rheumatoid arthritis. The most striking of these genetic factors defined to date involves a specific subset of MHC class II alleles whose presence appears to predominantly determine disease severity (patients homozygous for disease-associated alleles have the most severe disease). These MHC molecules function as antigen-presenting scaffolds, which present peptides to CD4 T cells. Disease-associated alleles (belonging to HLA-DR4/DR1 serotypes) share a sequence along their antigen-presenting groove, termed the “shared epitope.” It has been postulated that these alleles present critical antigens to the T cells, which play a role in initiating and driving progression of this disease. However, no specific antigens have yet been identified. Recent high-throughput genomewide genetic association studies have identified several new genetic risk factors for the development of RA. These genes (ie, PADI4, PTPN22, CTLA4, STAT4, and others) are involved in generating and propagating inflammatory responses and possibly autoantibody production as well.
Environmental and infectious factors—Although numerous bacterial and viral pathogens have been investigated as perhaps having a role in the initiation of rheumatoid arthritis, scrutiny has failed to identify a role for any specific infectious cause. It is conceivable that any of several different infectious agents might be able to induce non-pathogen-specific changes in the joint that are associated with disease initiation in susceptible individuals.
Autoimmunity—There is significant evidence supporting a role for autoimmunity in generating the rheumatoid arthritis phenotype, including the presence of antigen-driven autoantibodies such as IgG rheumatoid factors and anti-cyclic citrullinated peptide (anti-CCP) antibodies. Anti-CCP antibodies, in particular, are highly specific for RA and, as with the autoantibodies seen in SLE, can appear several years prior to the onset of disease. They appear to be a marker of a more destructive and aggressive RA phenotype, and their titers may be modulated by disease activity. The reasons these citrullinated peptides are targeted in RA are unknown, but potential explanations include an increase in a member of the peptidyl arginine deiminase family of enzymes (PADI, the enzymes that mediate the conversion of arginine to citrulline) activity in synovial tissue or altered activity of these enzymes due to genetic polymorphisms.
Cytokine elaboration in rheumatoid arthritis is markedly TH1 biased. Although the cytokine profile in rheumatoid arthritis synovium is highly complex, with numerous pro-inflammatory and anti-inflammatory cytokines expressed simultaneously (eg, TNF, IL-1, IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF]), studies have persuasively demonstrated that TNF is an important upstream principle in the propagation of the rheumatoid arthritis inflammatory lesion (see later). Thus, when pathways downstream of TNF are inhibited with soluble TNF receptors or monoclonal antibodies to TNF, a rapid and markedly beneficial effect on the inflammatory synovitis and overall state of well-being is noted in many patients. Interestingly, the effects of anti-TNF therapy were limited to the duration of therapy, and symptoms and signs of inflammation returned rapidly on discontinuation of therapy. Recent data also implicate TH17 cells in the pathogenesis of RA.
Rheumatoid arthritis is most typically a persistent, progressive disease presenting in women in the middle years of life. Fatigue and joint inflammation, characterized by pain, swelling, warmth, and morning stiffness, are hallmarks of the disease. Almost invariably, multiple small and large synovial joints are affected on both the right and left sides of the body in a symmetric distribution. Involvement of the small joints of the hands, wrists, and feet as well as the larger peripheral joints, including the hips, knees, shoulders, and elbows, is typical. Involved joints are demineralized, and joint cartilage and juxtaarticular bone are eroded by the synovial inflammation, inducing joint deformities. Although the lower spine is spared, cervical involvement can also occur, potentially leading to spinal instability. In highly active cases, extraarticular manifestations can occur. These include lung nodules, subcutaneous “rheumatoid” nodules (typically present over extensor surfaces), ocular inflammation (including scleritis), or small- to medium-sized arteritis.
Prompt and aggressive treatment to control inflammation in rheumatoid arthritis can slow or even stop progressive joint erosion. A number of immunomodulatory medications have shown benefit in treating rheumatoid arthritis. The primary pathway through which methotrexate—the drug most commonly used as single-agent therapy for rheumatoid arthritis—acts to diminish joint inflammation is still debated. One hypothesis suggests that methotrexate induces increased local release of adenosine, a short-acting anti-inflammatory mediator.
Rheumatoid arthritis is one of the first conditions in which biologic modifiers of defined pathogenic pathways such as anti-TNF therapy have been used successfully to treat disease. Inhibitors of TNF (etanercept, infliximab, and adalimumab) act by sequestering TNF, either to a recombinant soluble form of the TNF receptor (etanercept) or to monoclonal antibodies to TNF (infliximab, adalimumab). Although these agents have a high likelihood of achieving benefit in patients with rheumatoid arthritis, their use is still limited by their high cost and the potential risks of drug-associated toxicity (including susceptibility to life-threatening infections and induction of other autoimmune syndromes). Furthermore, although they are among the most potent agents yet described for the control of rheumatoid arthritis, there remain patients who fail to experience disease remission when treated only with TNF blockade. As a general principle of therapy in rheumatoid arthritis, it appears that using multiple agents with (presumably) different and complementary mechanisms of action can lead to additional benefit. T-cell–B-cell–APC interactions clearly play important roles in the propagation phase of RA, and it is therefore not surprising that additional biological agents have also shown efficacy in the treatment of RA, including—but not limited to—agents that inhibit B cells (eg, rituximab) and costimulation (eg, CTLA4-Ig).