Raynaud’s phenomenon, the most frequent extracutaneous complication of SSc, is characterized by episodes of reversible vasoconstriction in the fingers and toes, sometimes also affecting the tip of the nose and earlobes. Attacks, triggered by a decrease in temperature, as well as emotional stress and vibration, typically start with pallor, followed by cyanosis of variable duration. Hyperemia ensues spontaneously or with rewarming of the digit. The progression of the three color phases reflects the underlying vasoconstriction, ischemia, and reperfusion. Up to 5% of the general population has Raynaud’s phenomenon. In the absence of signs or symptoms of an underlying condition, Raynaud’s phenomenon is classified as primary (Raynaud’s disease), which represents an exaggerated physiologic response to cold. Secondary Raynaud’s phenomenon occurs in SSc and other connective tissue diseases, hematologic and endocrine conditions, and occupational disorders, and can complicate treatment with beta blockers and anticancer drugs such as cisplatin and bleomycin. Distinguishing primary Raynaud’s disease from secondary Raynaud’s phenomenon can present a diagnostic challenge. Raynaud’s disease is supported by the following: absence of an underlying cause, a family history of Raynaud’s phenomenon, absence of digital tissue necrosis or ulceration, and a negative ANA test. Secondary Raynaud’s phenomenon tends to occur at an older age (>30 years), is more severe (episodes more frequent, prolonged, and painful), and is associated with ischemic digital ulcers and loss of digits (Fig. 353-5).
Digital necrosis. Sharply demarcated necrosis of the fingertip secondary to ischemia in a patient with limited cutaneous systemic sclerosis (SSc) associated with severe Raynaud’s phenomenon.
Nailfold capillaroscopy using a low-power stereoscopic microscope or opthalmoscope permits visualization of nailbed cutaneous capillaries under immersion oil (Fig. 353-6). Raynaud’s disease is associated with evenly spaced parallel vascular loops, whereas in secondary Raynaud’s phenomenon, nailfold capillaries are distorted with widened and irregular loops, dilated lumen, microhemorrhages, and areas of vascular “dropout.” Thus, nailfold capillaroscopy can be helpful in differentiating primary from secondary Raynaud’s phenomenon and in establishing the early diagnosis of SSc.
SSc-associated nailfold capillary alterations. Normal nailfold pattern in healthy subjects. Note regularly-arrayed and uniform-size “hairpin” microvessels; “early pattern” showing dilations of microvessels and symmetrically increased microvessels (giant capillaries) representing the first morphological sign of systemic sclerosis; “active pattern” with giant capillaries, collapse with microhemorrages and loss of capillaries; “late pattern” showing massive loss of capillaries, fibrosis (white/yellow background) and neoangogenesis with secondary dilations (nailfold videocapillaroscope VIDEOCAP; magnification 220×). (Courtesy of Professor Maurizio Cutolo, University of Genoa.)
Bilateral symmetrical skin thickening is the hallmark of SSc that distinguishes it from other connective tissue diseases. Skin involvement starts in the fingers and characteristically advances from distal to proximal extremities in an ascending fashion. Some patients note diffuse tanning in the absence of sun exposure as a very early manifestation. In dark-skinned individuals, vitiligo-like hypopigmentation may occur. Because pigment loss spares the perifollicular areas, the skin may have a “salt-and-pepper” appearance, most prominently on the scalp, upper back, and chest. Dermal sclerosis obliterating hair follicles, sweat glands, and eccrine and sebaceous glands cause hair loss, decreased sweating, and dry and itchy skin on the extremities. Transverse creases on the dorsum of the fingers disappear (Fig. 353-7). Fixed flexion contractures of the fingers cause reduced hand mobility and lead to muscle atrophy. Skin and subjacent tendon fibrosis accounts for fixed contractures of the wrists, elbows, and knees. Thick ridges at the neck due to firm adherence of skin to the underlying platysma muscle interfere with neck extension.
Sclerodactyly. Note skin induration on the fingers, and fixed flexion contractures of proximal interphalangeal joints, in a patient with limited cutaneous systemic sclerosis (lcSSc).
In established SSc, the face assumes a characteristic “mauskopf” appearance with taut and shiny skin, loss of wrinkles, and occasionally an expressionless facies due to reduced mobility of the eyelids, cheeks, and mouth. Thinning of the lips with accentuation of the central incisor teeth and prominent perioral radial furrowing (rhytides) complete the picture. Reduced oral aperture (microstomia) interferes with eating and oral hygiene. The nose assumes a pinched, beak-like appearance. In late-stage disease, the skin becomes thin and atrophic, and is firmly bound to the subcutaneous fat (tethering). Dilated skin capillaries 2–20 mm in diameter (telangiectasiae), reminiscent of hereditary hemorrhagic telangiectasia, are frequently seen on the face, hands, lips, and oral mucosa (Fig. 353-8). The number of telangiectasias correlates with the severity of microvascular disease, including PAH. Breakdown of atrophic skin leads to chronic ulcerations at the extensor surfaces of the proximal interphalangeal joints, the volar pads of the fingertips, and bony prominences such as elbows and malleoli. Ulcers are often painful, heal slowly, and become secondarily infected, resulting in osteomyelitis. Healing of ischemic fingertip ulcerations leaves characteristic fixed digital “pits.” Loss of soft tissue at the fingertips due to ischemia may be associated with striking resorption of the terminal phalanges (acro-osteolysis) (Fig. 353-9).
Cutaneous vascular changes. A. Vascular changes at the nailfold in lcSSc. B. Telangiectasia on the face.
Acro-osteolysis. Note dissolution of distal terminal phalanges, commonly associated with ischemia, in a patient with long-standing limited cutaneous systemic sclerosis (lcSSc) and Raynaud’s phenomenon.
Dystrophic calcifications in the skin, subcutaneous, and soft tissues (calcinosis cutis) in the presence of normal serum calcium and phosphate levels occur in up to 40% of patients, most commonly in those with long-standing anti-centromere antibody-positive lcSSc. Calcific deposits, composed of calcium hydroxyapatite crystals, vary in size from tiny punctate lesions to large conglomerate masses can be readily visualized on plain radiographs, or dual-energy CT. These deposits occur when calcium precipitates in tissue damaged by inflammation, hypoxia, or local trauma. Common locations include the finger pads, palms, extensor surfaces of the forearms, and the olecranon and prepatellar bursae (Fig. 353-10). They can cause pain and nerve compression, ulcerate through the overlying skin with drainage of chalky white material, and secondary infections. Paraspinal sheet calcifications may cause neurologic complications.
Calcinosis cutis. Note soft tissue calcific deposit breaking through the skin in a patient with limited cutaneous systemic sclerosis (lcSSc).
The two principal forms of lung involvement in SSc, ILD, and pulmonary vascular disease are frequent and account for a majority of SSc-related deaths. Survival is particularly poor in SSc patients with concurrent presence of these two processes. Less common pulmonary complications of SSc include aspiration pneumonitis complicating chronic gastroesophageal reflux, pulmonary hemorrhage due to endobronchial telangiectasia, obliterative bronchiolitis, pleural reactions, restrictive physiology due to chest wall fibrosis, spontaneous pneumothorax, and drug-induced lung toxicity. The incidence of lung cancer is increased in SSc.
Interstitial Lung Disease
While evidence of ILD can be found in up to 65% of SSc patients by high-resolution computed tomography (HRCT), clinically significant ILD develops in 16–43%; the frequency varies depending on the detection method used. Risk factors for ILD include male sex, African-American race, diffuse skin involvement, severe gastroesophageal reflux, and the presence of topoisomerase I autoantibodies; in contrast, anti-centromere antibody-positive patients have a reduced risk of ILD. Additional risk factors include low forced vital capacity (FVC) or single-breath diffusing capacity of the lung for carbon monoxide (DLco) at initial presentation. Esophageal dilation with chronic acid reflux in SSc cause micro-aspiration, a risk factor for the development and progression of ILD. The most rapid progression in ILD generally occurs early in the disease course (within the first 3 years), when the FVC can decline by 30% per year.
Pulmonary involvement can remain asymptomatic until it is advanced. The most common presenting respiratory symptoms—exertional dyspnea, fatigue, and reduced exercise tolerance—are subtle and slowly progressive. A chronic dry cough may be present. Physical examination may reveal fine inspiratory “Velcro” crackles at the lung bases. Pulmonary function testing (PFT) is relatively sensitive for detecting early pulmonary involvement, and typically shows a restrictive ventilatory defect (FV<70% predicted and/or FEV1/FVC ratio >0.8), reduced total lung capacity (TLC) and diffusing capacity (DLco). A reduction in DLco that is significantly out of proportion to the reduction in lung volumes should raise suspicion for pulmonary vascular disease, but may also be due to anemia. Oxygen desaturation with exercise is common.
Chest radiography can be used as an initial screening tool to rule out infection and other causes of pulmonary involvement; however, compared to HRCT, it is relatively insensitive for detection of early ILD. It may demonstrate lower lobe subpleural reticular linear opacities and ground-glass opacifications, even in asymptomatic patients with normal PFTs (Fig. 353-11). Additional HRCT findings include mediastinal lymphadenopathy, pulmonary nodules, traction bronchiectasis, and uncommonly, honeycomb changes. The extent of interstitial changes on chest HRCT is a predictor of ILD progression and mortality. Bronchoalveolar lavage (BAL) can demonstrate inflammatory cells in the lower respiratory tract, and may be useful for ruling out tuberculosis and other infections. However, BAL does not appear to be useful for SSc diagnosis or for identifying reversible alveolitis, and is used primarily for research. Lung biopsy is indicated only in patients with atypical findings on chest radiographs. The histologic pattern on lung biopsy may predict the risk of progression of ILD, with NSIP, carrying a better prognosis than UIP.
Chest CT in systemic sclerosis. Top panel: Early interstitial lung disease with subpleural reticulations and ground glass opacities in the lower lobes. Patient in supine position. Bottom panel: Extensive lung fibrosis with coarse reticular honeycombing, and traction bronchiectasis. Note dilated esophagus. (Courtesy of Rishi Agrawal, Northwestern University.)
Pulmonary Arterial Hypertension PAH resulting from vascular remodeling of small (<500 μm) pulmonary arteries develops in 8–12% of patients with SSc, and occurs as an isolated abnormality or in association with ILD. PAH is defined hemodynamically as a mean pulmonary artery pressure ≥25 mmHg with a pulmonary capillary wedge pressure ≤15 mmHg and pulmonary vascular resistance >3 Wood units. The natural history of SSc-associated PAH is variable, but often follows a downhill course with onset of right heart failure. The 3-year survival of SSc patients with untreated PAH is <50%. Risk factors include lcSSc, high numbers of cutaneous telangiectasia, older age at disease onset, and the presence of antibodies to centromere, U1-RNP, U3-RNP (fibrillarin), and B23. Mutations in the BMPR2 gene associated with idiopathic PAH are not found in patients with SSc-PAH.
Although patients with PAH are often asymptomatic in early stages, they may present with nonspecific symptoms of exertional dyspnea and reduced exercise capacity. With progression, angina, near-syncope, and symptoms and signs of right-sided heart failure appear. Physical examination may show tachypnea, a loud pulmonic component of the S2 heart sound, pulmonic/tricuspid regurgitation murmur, palpable right ventricular heave, elevated jugular venous pressure, and dependent edema. Doppler echocardiography provides a noninvasive screening method for estimating the pulmonary arterial pressure. In light of the poor prognosis of untreated PAH and better therapeutic response in patients with early diagnosis, all SSc patients should be screened for PAH at initial evaluation, followed by annual evaluation. Estimated pulmonary artery systolic pressure >40 mmHg at rest or tricuspid regurgitation jet velocities >3 m/sec suggest PAH. PFT may show a reduced DLco in isolation or out of proportion with the severity of restriction. Because echocardiography can over- or underestimate pulmonary artery pressures, cardiac catheterization is the gold standard required to confirm the diagnosis of suspected PAH, to assess its severity, including the degree of right heart dysfunction, to rule out veno-occlusive disease and other cardiac (post-capillary) causes of pulmonary hypertension, and to provide prognostic parameters. Yearly echocardiographic screening for PAH is recommended in most patients; an isolated decline in DLco may also be indicative of developing PAH. Distinguishing PAH from pulmonary hypertension secondary to pulmonary fibrosis and hypoxia in SSc can be difficult. Serum levels of N-terminal pro-brain natriuretic peptide (NT proBNP) correlate with the presence and severity of PAH in SSc, as well as survival. While NT proBNP measurements can be useful in screening for PAH and in monitoring the response to treatment, elevated levels are not specific for PAH and also occur in other forms of right and left heart disease. Despite more favorable hemodynamics, the prognosis of SSc-associated PAH is worse, and treatment response poorer, than that of idiopathic PAH, most likely due to frequent concurrence of ILD and cardiac complications in these patients.
Involvement of the gastrointestinal tract, which can affect any level, occurs in up to 90% of SSc patients with both lcSSc and dcSSc disease (Table 353-6). The pathologic findings of fibrosis, smooth muscle atrophy, and obliterative small-vessel vasculopathy are similar throughout the length of the gastrointestinal tract, and contribute to reduced quality of life, malnutrition, and increased mortality.
TABLE 353-6Prominent Gastrointestinal Manifestations of SSc and Their Management |Favorite Table|Download (.pdf) TABLE 353-6 Prominent Gastrointestinal Manifestations of SSc and Their Management
|SITE ||PRINCIPAL MANIFESTATION ||MANAGEMENT |
|Oropharynx || |
Diminished oral aperture
|Esophagus || |
Prokinetic drugs proton
|Stomach || |
Gastric antral vascular ectasia (GAVE, watermelon stomach)
Endoscopic laser cryotherapy
|Small and large intestines || |
Parenteral nutritional support
|Anorectum ||Sphincter incompetence ||Biofeedback, sacral nerve stimulation, surgery |
Upper Gastrointestinal Tract Involvement
Decreased oral aperture interferes with regular dental hygiene. Teeth are loosened due to loss of periodontal ligament attaching teeth to the alveolar bone. Additional oropharyngeal manifestations due to a combination of xerostomia, shortened frenulum, and resorption of the mandibular condyles are frequent and cause much distress. Most patients have symptoms of gastroesophageal reflux disease (GERD): heartburn, regurgitation, and dysphagia. A combination of reduced lower esophageal sphincter pressure resulting in reflux, impaired esophageal clearance of refluxed gastric contents due to diminished motility, and delayed gastric emptying accounts for GERD. Calcium channel antagonists and phosphodiesterase inhibitors used to treat Raynaud’s phenomenon can further aggravate reflux. Esophageal manometry shows abnormal motility in most patients, even in the absence of symptoms. Extra-esophageal manifestations of GERD include hoarseness, chronic cough, and microaspiration, which can result in infections and may aggravate underlying ILD. Chest CT characteristically shows a dilated patulous esophagus with intraluminal air. Endoscopy may be necessary to rule out opportunistic infections with Candida, herpes virus, and CMV. Severe erosive esophagitis may be found on endoscopy in patients with minimal symptoms. Esophageal strictures and Barrett’s esophagus may complicate chronic GERD. Because Barrett’s metaplasia is associated with increased risk of adenocarcinoma, SSc patients with Barrett’s require regular surveillance endoscopy with biopsy.
Gastroparesis with early satiety, abdominal distention, and aggravated reflux symptoms are common. Barium contrast studies are neither sensitive nor specific for evaluation of gastric involvement in SSc. Gastric antral vascular ectasia (GAVE) in the antrum may occur. These subepithelial lesions, reflecting the diffuse small-vessel vasculopathy of SSc, are described as “watermelon stomach” due to their endoscopic appearance. Patients with GAVE can have recurrent episodes of gastrointestinal bleeding, resulting in chronic unexplained anemia.
Lower Gastrointestinal Tract and Anorectal Involvement
Weight loss and malnutrition due to impaired intestinal motility, malabsorption, and chronic diarrhea secondary to bacterial overgrowth are common. Fat and protein malabsorption and vitamin B12 and vitamin D deficiencies ensue, and may be further exacerbated by pancreatic insufficiency. Disturbed intestinal motor function can also lead to intestinal pseudo-obstruction, with symptoms that are indistinguishable from those of delayed gastric emptying. Patients present with recurrent episodes of acute abdominal pain, nausea, and vomiting, and radiographic studies show acute intestinal obstruction. A major diagnostic challenge is differentiating pseudo-obstruction, which responds to supportive care and intravenous nutritional supplementation, from mechanical obstruction. Colonic involvement may result in severe constipation, occasionally complicated by sigmoid volvulus. Fecal incontinence, gastrointestinal bleeding from telangiectasia, and rectal prolapse, can occur. In late-stage SSc, wide-mouth sacculations or diverticula occur in the colon, occasionally causing perforation and bleeding. An occasional radiologic finding is pneumatosis cystoides intestinalis due to air trapping in the bowel wall that may rarely rupture and cause benign pneumoperitoneum. Although the liver is rarely affected, primary biliary cirrhosis may coexist with SSc.
RENAL INVOLVEMENT: SCLERODERMA RENAL CRISIS
Scleroderma renal crisis presents with accelerated hypertension accompanied by acute kidney injury and progressive failure. This acute life-threatening complication of SSc occurs in 10–15% of patients, generally within 4 years of disease onset. Rarely, scleroderma renal crisis can be the initial presenting manifestation of SSc. Prior to the advent of angiotensin-converting enzyme (ACE) inhibitors, short-term survival in scleroderma renal crisis was <10%. The pathogenesis involves obliterative vasculopathy and luminal narrowing of the renal arcuate and interlobular arteries, with consequent intravascular hemolysis, along with evidence of activation of the complement pathways (Fig. 353-12). Progressive reduction in renal blood flow, aggravated by vasospasm, leads to juxtaglomerular renin secretion and activation of Angiotensin II, with further renal vasoconstriction resulting in a vicious cycle that culminates in accelerated hypertension. Risk factors for scleroderma renal crisis include African-American race, male sex, and diffuse or progressive skin involvement. Up to 50% of patients with scleroderma renal crisis have anti-RNA polymerase III antibodies, whereas patients with anti-centromere antibodies appear to be protected from this complication. Palpable tendon friction rubs, pericardial effusion, new unexplained anemia, and thrombocytopenia may be harbingers of impending scleroderma renal crisis. High-risk patients with early SSc should monitor their blood pressure daily. Because glucocorticoid use is associated with scleroderma renal crisis, prednisone in high-risk SSc patients should be taken only when absolutely required and at low doses (<10 mg/d).
Renal changes in scleroderma renal crisis. A. Renal biopsy demonstrating intimal proliferation and myxoid changes in medium-sized renal arteries. B. Film demonstrating fragmentation of red blood cells due to intravascular hemolysis in scleroderma renal crisis. (Courtesy of Drs. Edward Stern and Christopher Denton, Royal Free Hospital, London, UK.)
Patients characteristically present with accelerated hypertension (generally >150/90 mmHg) and progressive oliguric renal insufficiency. However, ~10% of patients with scleroderma renal crisis present with normal blood pressure. Normotensive renal crisis is generally associated with a poor outcome. Headache, blurred vision, congestive heart failure, and pulmonary edema may accompany elevation of blood pressure. Urinalysis typically shows mild proteinuria, granular casts, and microscopic hematuria; moderate thrombocytopenia and microangiopathic hemolysis with fragmented red blood cells can be seen. Progressive oliguric renal failure over several days generally follows. Scleroderma renal crisis is occasionally misdiagnosed as thrombotic thrombocytopenic purpura (TTP) or other forms of thrombotic microangiopathy. In such cases, renal biopsy and measuring vWF-cleaving protease activity may be of some benefit. Oliguria or a creatinine >3 mg/dL at presentation predicts poor outcome (permanent hemodialysis and mortality), as do biopsy findings of vascular thrombosis and glomerular ischemic collapse. Rarely, crescentic glomerulonephritis occurs in the setting of SSc and may be associated with myeloperoxidase-specific antineutrophil cytoplasmic antibodies. Membranous glomerulonephritis may occur in patients treated with d-penicillamine. Asymptomatic renal function impairment occurs in up to half of SSc patients. Such subclinical renal involvement is associated with other vascular manifestations of SSc and rarely progresses.
Although it is often silent, variable cardiac involvement in SSc is detected in 10–50% of patients screened with sensitive diagnostic tools. Clinical cardiac involvement, more frequent in dcSSc than in lcSSc, may be primary or secondary to PAH, ILD, or renal involvement, and is associated with poor outcomes. The endocardium, myocardium, and pericardium may each be affected separately or together. Pericardial involvement is manifested as pericarditis, pericardial effusions, constrictive pericarditis, and rarely, cardiac tamponade. Conduction system fibrosis occurs commonly and may be silent or manifested by heart block. Arrythmias including premature ventricular contractions, atrial fibrillation, and supraventricular tachycardia are common. Microvascular involvement, recurrent vasospasm, and ischemia-reperfusion injury contribute to patchy myocardial fibrosis, resulting in asymptomatic systolic or diastolic left ventricular dysfunction that may progress to overt heart failure. Acute or subacute myocarditis leading to left ventricular dysfunction may occur, and diagnosis requires cardiac magnetic resonance imaging (MRI) or endomyocardial biopsy. While conventional echocardiography has low sensitivity for detecting preclinical heart involvement in SSc, newer modalities such as tissue Doppler echocardiography (TDE), cMRI, and nuclear imaging (single photon emission CT [SPECT]) reveal a high prevalence of abnormal myocardial function or perfusion. The serum levels of N-terminal pro-BNP, a ventricular hormone elevated in SSc-PAH, may also have utility as markers of primary cardiac involvement.
Musculoskeletal complications are very common in SSc. Carpal tunnel syndrome may be a presenting disease manifestation. Generalized arthralgia and stiffness are prominent in early disease. Mobility of both small and large joints is progressively impaired, and fixed contractures develop at the proximal interphalangeal joints and wrists. Large joint contractures, seen in patients with dcSSc, are frequently accompanied by tendon friction rubs characterized by coarse leathery crepitation heard or palpated upon passive joint movement, that are due to extensive fibrosis and adhesion of the tendon sheaths and fascial planes at the affected joint. Tendon friction rubs are associated with increased risk for renal and cardiac complications and reduced survival. Synovitis detected by ultrasound or MRI is common; occasional SSc patients develop erosive polyarthritis in the hands, and some have a seropositive rheumatoid arthritis overlap. Muscle weakness is common and multifactorial: deconditioning, disuse atrophy, malnutrition, inflammation, and fibrosis may all contribute. A chronic non-inflammatory myopathy characterized by atrophy and fibrosis with mildly elevated muscle enzymes can be seen in late-stage SSc. Bone resorption in the terminal phalanges causes loss of the distal tufts (acro-osteolysis) (Fig. 353-9). Resorption of the mandibular condyles can lead to bite difficulties. Osteolysis can also affect the ribs and distal clavicles.
LESS RECONGIZED DISEASE MANIFESTATIONS
Dry eyes and dry mouth (sicca complex) are common in SSc. Biopsy of the minor salivary glands shows fibrosis rather than focal lymphocytic infiltration characteristic of primary Sjögren’s syndrome (Chap. 354). Hypothyroidism resulting from Graves’ or Hashimoto’s disease is common, particularly in lcSSc, and may be under-recognized. Whereas the central nervous system is generally spared, unilateral or bilateral sensory trigeminal neuropathy can occur. Erectile dysfunction is a frequent, and occasionally initial, disease manifestation. Inability to attain or maintain penile erection is due to vascular insufficiency and fibrosis of corporeal smooth muscle. Sexual performance is also adversely affected in women. While fertility is not impaired in SSc, pregnancy is associated with higher risk of adverse fetal outcomes. Furthermore, cardiopulmonary involvement may worsen during pregnancy, and new onset of scleroderma renal crisis has been described.
Epidemiologic studies indicate an increased cancer risk in SSc. Lung cancer and esophageal adenocarcinoma typically occur in the setting of long-standing ILD or GERD and may be caused by chronic inflammation and repair. In contrast, breast, lung, and ovarian carcinomas and lymphomas tend to occur in close temporal association with the onset of SSc, particularly in patients who have autoantibodies to RNA polymerase III. In this scenario, SSc may represent a paraneoplastic syndrome triggered by the anti-tumor immune response.
LABORATORY EVALUATION AND BIOMARKERS
Mild microcytic anemia is frequent and may indicate gastrointestinal bleeding caused by GAVE or chronic esophagitis. Macrocytic anemia may be caused by folate and vitamin B12 deficiency due to small-bowel bacterial overgrowth and malabsorption or by drugs such as methotrexate. Microangiopathic hemolytic anemia caused by mechanical fragmentation of red blood cells during their passage through microvessels coated with fibrin or platelet thrombi is a hallmark of scleroderma renal crisis. The erythrocyte sedimentation rate (ESR) is generally normal; an elevation may signal coexisting myositis or malignancy.
Antinuclear autoantibodies are detected in almost all patients with SSc. Anti-topoisomerase I (Scl-70) and anti-centromere antibodies are mutually exclusive and each is highly specific for SSc. Topoisomerase I antibodies are associated with increased risk of ILD and poor outcomes. Anti-centromere antibodies are associated with PAH, but only infrequently with significant cardiac, pulmonary, or renal involvement. Nucleolar immunofluorescence pattern may indicate antibodies to U3-RNP (fibrillarin), Th/To, or PM/Scl, whereas speckled immunofluorescence indicates antibodies to RNA polymerase III (Fig. 353-13).
SSc-associated autoantibodies: immunofluorescence patterns. Indirect immunofluorescence on HEp-2 substrate shows distinct patterns: A. anti-centromere; B. anti-Scl-70/topoisomerase I; C. anti-PM/Scl; D. anti-Th/To; E. anti-RNA polymerase III; F. anti-fibrillarin/U3RNP antibodies. Except for anti-centromere (discrete dots in metaphase nucleus), variations of nucleolar staining are clues to autoantibody specificity. However, immunoassays employing purified autoantigens are recommended to confirm specificity of these autoantibodies. (Courtesy of Marvin Fritzler and Susan Copple, Inova Diagnostics Inc., San Diego, California.)
DIAGNOSIS, STAGING, AND MONITORING
The diagnosis of SSc is made primarily on clinical grounds and is generally straightforward in patients with established disease. The presence of skin induration with a characteristic symmetric distribution pattern associated with typical visceral organ manifestations establishes the diagnosis with a high degree of certainty. In lcSSc, a history of Raynaud’s phenomenon and GERD symptoms, coupled with sclerodactyly and nailfold capillary changes, often in combination with cutaneous telangiectasia and calcinosis cutis, help to establish the diagnosis. Primary Raynaud’s disease is a benign condition that must be differentiated from early or limited SSc. Nailfold microscopy is particularly helpful in this situation, because in contrast to SSc, nailfold capillaries are normal. Diagnosing SSc at an early stage may be a challenge. In dcSSc, initial symptoms are often nonspecific, Raynaud’s phenomenon may be absent, and physical examination may only show upper extremity edema and puffy fingers. Patients with early SSc might be diagnosed as arthritis, SLE, myositis, or, most commonly, undifferentiated connective tissue disease. Within weeks to months, Raynaud’s phenomenon and advancing skin induration appear. SSc-specific autoantibodies provide a high degree of diagnostic certainty. Raynaud’s phenomenon with fingertip ulcerations or other evidence of digital ischemia, coupled with telangiectasia, distal esophageal dysmotility, unexplained ILD or PAH, or accelerated hypertension with renal failure in the absence of clinically evident skin induration, suggests the diagnosis of SSc sine scleroderma.
APPROACH TO THE PATIENT: Management of Systemic Sclerosis OVERVIEW: GENERAL PRINCIPLES
To date, with the possible exception of hematopoietic stem cell therapy (HSCT), no therapy has been shown to significantly alter the natural history of SSc. In contrast, multiple interventions are highly effective in alleviating the symptoms, slowing the progression of the cumulative organ damage, and reducing disability. A significant reduction in disease-related mortality has been noted during the past 25 years. In light of the marked heterogeneity in disease manifestations, and natural history, the management of SSc mandates a “personalized medicine” approach that is specifically tailored to each individual patient’s unique needs.
The following general principles should guide management (Table 353-7): prompt and accurate diagnosis; classification and risk stratification based on clinical and laboratory evaluation, including prognostic and predictive biomarkers; early recognition of organ-based complications and assessment of their extent, severity, and likelihood of deterioration; regular monitoring for disease progression, new complications, and response to therapy; adjusting therapy; and patient education. In order to minimize irreversible organ damage, management should be proactive, with regular screening and initiation of appropriate, intervention at the earliest possible opportunity. In light of the complex and multisystemic nature of the SSc, a team-oriented management approach integrating appropriate specialists should be pursued. Generally, a combination of drugs that impact different aspects of the disease is used. Patients should be encouraged to become familiar with potential complications and understand therapeutic options, including interventional trials, and natural history, and empowered to partner with their treating physicians. This requires a long-term relationship between patient and physician, with ongoing counseling, encouragement, and two-way dialogue. DISEASE-MODIFYING THERAPY: IMMUNOSUPPRESSIVE AGENTS
Immuno-suppressive agents used in other autoimmune diseases have generally shown modest or no benefit in SSc. Glucocorticoids alleviate stiffness and aching in early inflammatory-stage dcSSc, but do not influence the progression of skin or internal organ involvement. Since their use is associated with an increased risk of scleroderma renal crisis, glucocorticoids should be given only when absolutely necessary, at the lowest dose possible, and for brief periods only.
Cyclophosphamide has been extensively studied in light of its efficacy in the treatment of vasculitis (Chap. 356), SLE (Chap. 349), and other autoimmune diseases (Chap. 348). Both oral and intravenous cyclophosphamide have been shown to reduce the progression of SSc-associated ILD, with stabilization and, rarely, modest improvement of pulmonary function, HRCT findings, respiratory symptoms, and skin induration. The benefits of cyclophosphamide need to be balanced against its potential toxicity, including bone marrow suppression, opportunistic infections, hemorrhagic cystitis and bladder cancer, premature ovarian failure, and late secondary malignancies.
Methotrexate had modest effect on SSc skin involvement in small studies. Mycophenolate mofetil was evaluated in both open label and randomized control trials. Both skin induration and ILD improved in patients treated with MMF, and the drug was well tolerated. Tocilizumab, a monoclonal antibody directed against the IL-6 receptor that blocks IL-6 signaling, also showed benefit in randomized SSc trials. Open-label studies and small trials provide support for the use of rituximab, a monoclonal antibody directed against the mature B cell marker CD20, along with extracorporeal photopheresis and IV immunoglobulin. Randomized trials in SSc evaluating the efficacy of abatacept, a fusion protein that inhibits T cell co-stimulation and function, are on-going. The use of cyclosporine, azathioprine, plaquenil, thalidomide, and rapamycin is currently not well supported by the literature. Intensive immune ablation using high-dose chemotherapy, followed by autologous stem cell reconstitution, in selected patients was associated with durable remission and improved long-term survival in randomized clinical trials; however, this regimen carries potential morbidity and mortality, as well as significant cost. Antifibrotic Therapy
Because tissue fibrosis underlies organ damage in SSc, drugs that interfere with the fibrotic process represent a rational therapeutic approach. In older retrospective studies, d-penicillamine was shown to stabilize skin induration, prevent new internal organ involvement, and improve survival. However, a randomized-controlled clinical trial in early active SSc found no difference in the extent of skin involvement between patients treated with standard-dose (750 mg/d) or very low-dose (125 mg every other day) d-penicillamine. Recent clinical trials show benefit of pirfenidone and of nintedanib in patients with idiopathic pulmonary fibrosis, with significant slowing of the loss of lung function. Whether these anti-fibrotic drugs have comparable efficacy and tolerability in patients with SSc-associated ILD and other fibrotic manifestations of the disease is under investigation. Vascular Therapy
The goal of Raynaud’s therapy is to control episodes, prevent and enhance the healing of ischemic complications, and slow the progression of obliterative vasculopathy. Patients should dress warmly, minimize cold exposure, and avoid drugs that precipitate or exacerbate vasospastic episodes. Extended-release dihydropyridine calcium channel blockers such as amlodipine and diltiazem ameliorate Raynaud’s phenomenon, but their use is often limited by side effects (palpitations, dependent edema, worsening gastroesophageal reflux). While ACE inhibitors do not reduce the frequency or severity of episodes, Angiotensin II receptor blockers such as losartan are effective and well tolerated. Patients with Raynaud’s phenomenon unresponsive to these therapies may require the addition of α1-adrenergic receptor blockers (e.g., prazosin), 5-phosphodiesterase inhibitors (e.g., sildenafil), topical nitroglycerine, and intermittent IV infusions of prostaglandins. Low-dose aspirin and dipyridamole prevent platelet aggregation and may have a role as adjunctive agents. In patients with ischemic digital tip ulcerations, the endothelin-1 receptor antagonist bosentan reduces the risk of new ulcers. Digital sympathectomy and intradigital injections of botulinum type A (Botox) may be considered in patients with severe on-going ischemia. Empirical long-term therapy with statins and antioxidants may retard the progression of vascular damage and obliteration. There is limited evidence-based information for the treatment of cardiac complications of SSc, which should be guided by specialists experienced in their diagnosis and management. While selective beta blockers such as metorpolol can precipitate vasospasm, non-dihydropyridine calcium channel blockers can be used for rate control in atrial arrhythmias, and non-selective alpha/beta blockers such as carvediol for improving myocardial perfusion and left ventricular systolic function.
TABLE 353-7Key Principles in Management |Favorite Table|Download (.pdf) TABLE 353-7 Key Principles in Management
Establish early and accurate diagnosis.
Detect and evaluate internal organ involvement.
Define clinical disease stage and activity.
Tailor individualized therapy to each patient’s unique needs.
Assess treatment response, and adjust therapy as needed; monitor for disease activity, progression and new complications.
TREATMENT TREATMENT OF SSc-ASSOCIATED ILD
ILD is a leading cause of death in patients with SSc. However, as SSc-associated ILD is not necessarily progressive, it is important to identify patients who are at high risk for disease progression in the absence of treatment. The extent of ILD on HRCT and the FVC at initial evaluation, and decline in PFTs during the preceding 12-month period, are helpful in identifying these patients. Patients at high risk for ILD should be monitored by performing PFTs every 6 months; serial HRCT imaging is not recommended. Cyclophosphamide, given IV or orally for 6 to 12 months, and mycophenolate mofetil slow the decline in lung function and improve respiratory symptoms; however, cyclophosphamide is associated with more frequent side effects. The safety and efficacy of anti-fibrotic drugs recently approved for idiopathic pulmonary fibrosis in the treatment of SSc-associated ILD are currently under investigation. In certain patients who show continued progression of ILD despite medical therapy, lung transplantation might be considered as a life-prolonging procedure, although significant GERD is a concern in SSc. Recurrence of SSc-ILD in transplanted lung allografts has not been reported. TREATMENT OF GASTROINTESTINAL COMPLICATIONS
Because oral problems including decreased oral aperture, decreased saliva production, gum recession, periodontal disease, and teeth loss are common, regular dental care is recommended. Gastroesophageal reflux is very common and may occur in the absence of symptoms. Patients should be instructed to elevate the head of the bed, eat frequent small meals, and avoid alcohol, caffeine, and known reflux exacerbants, or meals before bedtime. Proton pump inhibitors reduce acid reflux and in patients with SSc may need to be given in relatively high doses. Prokinetic agents such as metoclopramide, erythromycin (a motilin agonist), and domperidone may occasionally be helpful, but are frequently associated with side effects. Botulinum toxin injection sometimes ameliorates impaired gastric emptying. Anti-reflux procedures such as Nissen fundoplication can result in secondary achalasia and generally should be avoided. Episodic bleeding from GAVE (watermelon stomach) may be amenable to treatment with endoscopic ablation using laser or argon plasma photocoagulation, although bleeding frequently recurs. Some patients may require enteral feeding and/or decompression via percutaneous gastrostomy or jejunostomy. Small bowel bacterial overgrowth secondary to dysmotility causes abdominal bloating and diarrhea, and may lead to malabsorption and severe malnutrition. Treatment with short courses of rotating broad-spectrum antibiotics such as metronidazole, erythromycin, and rifaximin can eradicate bacterial overgrowth. Small bowel hypomotility may respond to octreotide; however, pseudo-obstruction is difficult to treat. Fecal incontinence, a frequent and under-reported complication, may respond to anti-diarrheal medication, biofeedback therapy, sphincter augmentation, and sacral neuromodulation. Potential malnutrition should be routinely assessed. TREATMENT OF PAH
In SSc, PAH carries an extremely poor prognosis and accounts for 30% of deaths. Because PAH is asymptomatic until advanced, patients with SSc should be screened at initial evaluation, and regularly thereafter. Treatment is generally started with an oral endothelin-1 receptor antagonist such as bosentan or a phosphodiesterase 5 inhibitor such as sildenafil. Recently, the soluble guanylate cyclase stimulator riociugat, which acts by increasing the production of nitric oxide, and the selective IP prostacyclin receptor agonist selexipag, were shown to improve PAH symptoms and survival. Patients may also require diuretics and digoxin. If hypoxemia is documented, supplemental oxygen should be prescribed in order to avoid secondary pulmonary vasoconstriction. Prostacyclin analogues such as epoprostenol or treprostinil can be given by continuous IV or SC infusion, or via intermittent nebulized inhalations. Combination therapy with different classes of agents acting additively or synergistically is often necessary. Lung transplantation remains an option for selected SSc patients with PAH who fail medical therapy, and 2-year survival rates (64%) are comparable to those of idiopathic ILD or PAH. MANAGEMENT OF RENAL CRISIS
Scleroderma renal crisis is a medical emergency. Since the outcome is largely determined by the extent of renal damage at the time that aggressive therapy is initiated, prompt recognition of impending or early scleroderma renal crisis is essential, and efforts should be made to avoid its occurrence. High-risk SSc patients with early disease, extensive and progressive skin involvement, tendon friction rubs, and anti-RNA polymerase III antibodies should be instructed to monitor their blood pressure daily and report significant alterations immediately. Potentially nephrotoxic drugs should be avoided, and glucocorticoids should be used only when absolutely necessary and at low doses. Patients presenting with scleroderma renal crisis should be immediately hospitalized. Once other causes of renal disease are excluded, treatment should be started promptly with titration of short-acting ACE inhibitors, with the goal of achieving rapid normalization of the blood pressure. In patients with persistent hypertension, addition of angiotensin II receptor blockers, calcium channel blockers, endothelin-1 receptor blockers, prostacyclins, and direct renin inhibitors should be considered. Up to two-thirds of patients with scleroderma renal crisis will require dialysis. Substantial renal recovery can occur, and dialysis can be discontinued in 30–50% of the patients. Kidney transplantation is appropriate for patients unable to discontinue dialysis after 2 years. Survival of transplanted SSc patients is comparable to that of other diseases, and recurrence of renal crisis is rare. SKIN CARE
Because skin involvement in SSc is never life-threatening and it stabilizes and may even regress spontaneously, disease management should not be dictated by its cutaneous manifestations. The inflammatory symptoms of early skin involvement can be controlled with antihistamines and short-term use of low-dose glucocorticoids (<5 mg/d of prednisone). Cyclophosphamide and methotrexate have modest effects on skin induration. Because the skin is dry, the use of hydrophilic ointments and bath oils is encouraged, and regular skin massage is helpful. Telangiectasia, which presents a cosmetic problem, especially on the face, can be treated with pulsed dye laser. Ischemic digital ulcerations should be protected by occlusive dressing to promote healing and prevent infection. Infected skin ulcers are treated with topical antibiotics and surgical debridement. While no therapy has been shown to be effective in preventing soft tissue calcific deposits or promoting their dissolution, reports support the use of diltiazem, minocycline, bisphosphonates, and topical or IV sodium thiosulfate (STS). Other therapies that have been used for calcinosis include carbon dioxide laser, extracorporeal shock-wave lithotripsy, and surgical high-speed microdrilling. TREATMENT OF MUSCULOSKELETAL COMPLICATIONS
Arthralgia and joint stiffness are very common and distressing manifestations in early-stage disease. Short courses of nonsteroidal anti-inflammatory agents, methotrexate, and cautious use of low-dose glucocorticoids alleviate symptoms. Physical and occupational therapy can be effective for preventing loss of musculoskeletal function and joint contractures, and should be initiated early.