Systemic Sclerosis

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[edit] Systemic Sclerosis

Virginia D. Steen

James C. Shaw

Systemic sclerosis (SSc) is a chronic, multisystem disorder of connective tissue characterized by degenerative and inflammatory changes that subsequently lead to intense fibrosis.The skin, blood vessels, synovium, skeletal muscle, and certain internal organs are affected, including the gastrointestinal (GI) tract, lungs, heart, and kidneys.

[edit] EPIDEMIOLOGY

SSc has a worldwide distribution.Approximately 20 new cases of SSc per million population occur annually, with an estimated 100,000 to 300,000 patients in the United States.Women are affected three to four times more often than men.The onset of disease usually occurs between ages 30 and 50, but younger and older adults can be affected.Child hood SSc is rare, although localized forms of scleroderma (linear, morphea) are more common in children.Familial cases have rarely been reported, and no strong genetic relationships have been found; however, other connective tissue diseases may be seen among first-degree relatives of patients with SSc.

The American College of Rheumatology's criteria for the classification of SSc require skin thickening proximal to the metacarpophalangeal joints or two of the following: sclerodactyly, digital pitting scars, or interstitial pulmonary fibrosis.These criteria have no relationship to the major clinical subsets of SSc, limited cutaneous and diffuse cutaneous scleroderma.These two major subsets have important differences in their disease onset and overall course (Box 139-1).The classic form of diffuse scleroderma has a rapid onset of symptoms, including Raynaud's phenomenon, polyarthritis, carpal tunnel syndrome, swollen hands and legs, and fatigue.Skin thickening progresses up the patient's arms and over the trunk, resulting in contractures and disability.Visceral involvement, including GI tract, lung, heart, and kidney, is common, particularly in the first 4 years of disease.

Limited scleroderma, or the CREST syndrome, is at the other end of the spectrum (Fig.139-1).These patients have a much less progressive disease and usually have Raynaud's phenomenon for a prolonged period before developing other symptoms.Puffy fingers, heartburn, and telangiectasias are clues to the diagnosis.Severe intestinal hypomotility, resulting in malabsorption and pseudoobstruction, and pulmonary hypertension are the most serious complications of limited scleroderma.Severe digital ischemia and calcinosis can cause disability.Anticentromere antibody is found in most patients.

Figure 139-1 A, Distal esophageal hypomotility, common to all scleroderma patients. B, Calcinosis, primarily occurring in fingers after many years of Raynaud's phenomenon. C, Cyanosis from Raynaud's phenomenon and sclerodactyly in patient with limited scleroderma. D, Multiple telangiectasias in patient with limited scleroderma.

The natural history of SSc varies considerably between the different subsets (Fig.139-2).Even within the major subsets, survival varies significantly, depending on the extent of internal organ involvement.The 10-year cumulative survival rate from onset of symptoms is 83% for limited scleroderma and 65% for patients with diffuse scleroderma.

Figure 139-2 Top, Cumulative survival from onset of symptoms in patients with limited and diffuse scleroderma with less than 2 years of symptoms.Five-year survival is 90% for limited scleroderma and 75% for diffuse scleroderma, (p<0.001). Bottom, Development of cutaneous skin thickening (skin score) and other organ involvement over time in patients with limited and diffuse scleroderma.

[edit] PATHOPHYSIOLOGY

The pathophysiology of SSc is not completely understood, but vascular and immunologic factors interact with connective tissue, causing an excessive amount of collagen production by fibroblasts (Fig.139-3).Small arterioles show subintimal hyperplasia and hyalinization.In patients with early diffuse disease, focal collections of T-cell lymphocytes can be identified in the deep dermis.Activated T cells produce cytokines, particularly interleukin-2 (IL-2) and transforming growth factor beta (TGF-β), which stimulate fibroblast proliferation and collagen production.Endothelial cell damage may result in increased permeability and the release and activation of cell growth factors.Platelet activation, platelet-derived growth factor (PDGF), and mast cells also have major effects of stimulating the fibroblast.

Figure 139-3 Vascular and immunologic factors that result in increased collagen in the pathogenesis of systemic sclerosis (see text for abbreviations).

The humoral immune system with B-cell activation is involved in SSc, although its relationship to endothelial cells and increased collagen production remains obscure.Several autoantibodies are specific to scleroderma and associated with unique subsets of clinical and genetic features.Because of the many toxin-induced scleroderma-like illnesses, a toxin or environmental factor could be responsible for triggering scleroderma, although none has yet been identified.

[edit] PATIENT EVALUATION

The first symptoms of scleroderma are usually Raynaud's phenomenon, puffy fingers, and polyarthritis involving the small joints of the hands.Thereafter the course and multisystem features are extremely variable.The physician must review the history and findings for each organ system to determine the expected course and best management of each patient's disease (Fig.139-4).

Figure 139-4 Clinical manifestations of systemic sclerosis (SSc). 1, Predominantly in diffuse scleroderma;2, predominantly in limited scleroderma;3, frequently seen in both subsets of scleroderma.

[edit] Physical Examination

[edit] Raynaud's Phenomenon.

Cold exposure and emotional stress may induce vasospasm, causing characteristic episodes of bilateral blanching or cyanosis of the digits (see Chapter 70 ).Infarction of tissue at the fingertips may lead to painful ulcerations or frank gangrene.In limited cutaneous disease, Raynaud's phenomenon usually antedates other evidence of SSc by years or even decades.In contrast, Raynaud's phenomenon is initially present in only 75% of patients with diffuse scleroderma.The finding of dilated nail fold capillaries with capillary ``dropout is typical for scleroderma and is a helpful differential finding in patients with primary Raynaud's phenomenon (Fig.139-5).

Figure 139-5 A, Pallor from vasoconstriction in Raynaud's phenomenon. B, Digital artery from patient with scleroderma and severe digital ischemia.(Magnification ×21.)C, Digital pitting scars on fingertips of patient with scleroderma, one of minor criteria for scleroderma. D, Abnormal nail fold capillaries in patient with scleroderma.(Magnification ×4.) Note loss of capillaries and dilation of capillary loops.

[edit] Skin.

In diffuse scleroderma an early manifestation is often bilateral symmetric swelling of the hands and legs (Fig.139-6).Patients frequently are evaluated for cardiac, endocrine, or kidney diseases because of striking peripheral edema.After a few weeks to several months, edema is replaced by induration, resulting in thick, hard skin.An inability to elicit a wrinkle when pinching the skin is a reliable method for determining skin thickening, which spreads rapidly from the fingers, up the arms, and onto the trunk, particularly the anterior chest and abdomen.After several years the progression of skin thickening stabilizes, and spontaneous skin softening occurs to some degree in most patients.In contrast, limited scleroderma patients tend to have puffiness primarily in the fingers, and skin thickening is limited to the distal extremities and face, rarely changing throughout the illness.

Figure 139-6 A, Swollen hands in patient with early diffuse scleroderma. B, Marked contractures with inability to make a fist in diffuse scleroderma. C, Acroosteolysis in fingers 1, 2, and 3 in longstanding scleroderma.

After many years, numerous small macular punctate telangiectasias appear on the fingers, face, lips, and tongue (see Fig.139-1, D).They occur most frequently in patients with limited scleroderma but also in those with late-stage diffuse scleroderma and disease for 5 to 10 years.Subcutaneous calcinosis is a late complication that occurs more often in limited than diffuse scleroderma (see Fig.139-1, B).Sites of minor trauma are often affected, such as the fingers, forearms, elbows, and knees.

[edit] Joints and Tendons.

Polyarthralgias affect both small and large joints and are especially frequent early in diffuse scleroderma.Joint pain, swollen fingers, and polyarthritis often lead to the premature diagnosis of rheumatoid arthritis.In diffuse scleroderma, rapid development of hand swellingand skin tightening often leads to severe flexion contractures, with clawlike hands and serious disability.Limited scleroderma patients have only mild, if any, contractures because the disease process is slower.Acroosteolysis, thought to be caused by hypovascularity, causes painless bone resorption, primarily of the distal phalanges (see Fig.139-6, C).

Carpal tunnel syndrome is common early in diffuse scleroderma and often is the symptom that brings the patient to a physician.Coarse, leathery tendon friction rubs palpated during motion of the extensor and flexor tendons of the fingers, distal forearms, knees, and ankles are found almost exclusively in patients with diffuse cutaneous disease.Their presence can foreshadow the development of diffuse cutaneous scleroderma.

[edit] Skeletal Muscle.

Patients typically have fatigue and weakness, but two specific types of myopathies exist.The most frequent is a bland, nonprogressive process characterized by mild proximal weakness, minimal elevation of serum creatine kinase (CK), and a noninflammatory fibrotic replacement of myofibrils on muscle biopsy.A second type is indistinguishable from polymyositis.These patients have impressive weakness, greatly increased CK, and classic inflammatory changes on electromyography (EMG) and muscle biopsy.

[edit] Gastrointestinal Tract.

GI involvement occurs in most patients and differs little between the diffuse and limited subgroups.Distal esophageal motor dysfunction leads to distal dysphagia, and the lower esophageal sphincter musculature does not close adequately, resulting in severe reflux of gastric contents and esophagitis.This may be complicated by ulcerations, candidal infection, and stricture.Symptomatic gastric emptying malfunction and duodenal hypomotility are much less common but contribute to postprandial abdominal pain and bloating.

Loss of smooth muscle function and hypomotility of the jejunum and ileum can result in bacterial overgrowth, which interferes with normal fat absorption.Malabsorption from bacterial overgrowth is associated with persistent diarrhea, marked weight loss, and intermittent episodes of abdominal distention and vomiting.These problems and pseudoobstruction may be life threatening.

[edit] Lungs.

Clinical evidence of pleural involvement, including pleurisy, pleural effusion, and pleural friction rub, is uncommon.Clinical or radiographic evidence of pulmonary interstitial fibrosis develops in most SSc patients.Common abnormalities on pulmonary function tests (PFTs) include a decline in forced vital capacity (restrictive lung disease) and a reduced diffusing capacity for carbon monoxide (DLco).Inflammatory alveolitis early in the disease results in pulmonary fibrosis, with respiratory symptoms occurring later.Progression is variable, however, and most patients have mild to moderate, nonprogressive restrictive lung dysfunction on PFTs.Serial PFTs, bronchoalveolar lavage, and high-resolution computed tomography (HRCT) scans can help to determine if alveolitis and progressive fibrosis are present early in the course.

In addition to a restrictive pattern on PFTs, patients may demonstrate an isolated decrease in the DLco, with the forced vital capacity remaining normal or near normal.Unless the DLcois less than 50%, this is not serious; however, patients with a very low DLcoare at high risk of developing isolated pulmonary arterial hypertension, which develops in about 10% of patients with limited scleroderma.Histologically, the small pulmonary arteries show intense subintimal hyperplasia without inflammation.The prognosis is grave, with the mean survival only 2 years.

[edit] Heart.

Clinical evidence of myocardial involvement is uncommon (less than 15%) and occurs more often in patients with diffuse scleroderma.In contrast, cardiac tests (e.g., electrocardiogram, echocardiogram, Holter monitor, nuclear studies) show evidence of asymptomatic abnormalities in a high proportion of patients.The symptomatic manifestations of myocardial disease include congestive heart failure and a variety of atrial and ventricular dysrhythmias.The mortality rate is high.Patchy replacement of the myocardium and conduction system by fibrous tissue is the rule in such cases.Interestingly, the vascular changes that occur in most other organs are not found in similar-sized blood vessels in the heart.Acute pericarditis or pericardial tamponade is more unusual than the common echocardiographic and pathologic evidence of asymptomatic pericardial involvement with effusion.

[edit] Kidneys.

Renal involvement is manifested by scleroderma renal crisis, a potentially fatal event.It affects approximately 20% of individuals with diffuse disease and typically occurs early (less than 4 years after disease onset) in the setting of rapidly progressive skin thickening.This complication was once the major cause of death in patients with diffuse cutaneous involvement.In contrast, renal crisis is rare in patients with limited cutaneous involvement.

Renal crisis may present without warning.The patient develops malignant arterial hypertension with hyperreninemia and oliguric acute renal failure.It often follows a course of high-dose steroids.The urinalysis shows hematuria and proteinuria, and the serum CK rises daily.Even with aggressive treatment, these patients may develop rapidly progressive renal failure.Occasionally, the blood pressure remains normal; in these patients, microangiopathic hemolytic anemia with thrombocytopenia is prominent.This type of hemolysis also occurs with malignant hypertension and is an intravascular rather than an immune-mediated problem.The primary targets in renal crisis are interlobular and arcuate arteries and arterioles.Severe mucoid subintimal hyperplasia is evident histologically, and blood vessel walls may undergo fibrinoid necrosis.An inflammatory component and immune complex deposition are lacking.

[edit] Other Organs.

Sjögren's syndrome is seen in 20% of SSc patients but symptoms of Sjögren's syndrome, including dry eyes and dry mouth, may also be caused by glandular fibrosis.Both lymphocytic inflammation (Hashimoto's thyroiditis) and fibrous replacement of the thyroid have been observed and are often associated with clinical evidence of hypothyroidism.Biliary cirrhosis is found in a few women with limited scleroderma, but hepatic involvement is otherwise rare.Trigeminal sensory neuropathy has been described.

[edit] LABORATORY STUDIES

The routine laboratory tests from a typical SSc patient are generally unremarkable.Anemia and the erythrocyte sedimentationrate (ESR) are variable.Nearly all patients with SSc have serum antinuclear antibodies (ANAs), which are highly specific for SSc and associated with distinct clinical subsets of patients (Fig.139-7).Anticentromere antibody (centromeric staining on routine immunofluorescence) is highly specific for limited cutaneous scleroderma, and these patients rarely have pulmonary fibrosis.Antitopoisomerase I (or Scl-70) tends to identify individuals with diffuse cutaneous disease with more frequent pulmonary fibrosis and peripheral vascular difficulties.Anti-U1 ribonucleoprotein (RNP; high-titer, speckled ANA pattern) is associated with the classic mixed connective tissue disease.Also, several scleroderma-specific antibodies are not yet commercially available.Anti-RNA polymerase III identifies a large group of patients with diffuse disease who have severe skin thickening, and 25% progress to renal crisis.^[1] This will be an important prognostic test when it becomes available.Several other, less common but unique nucleolar antibodies also exist.One identifies a small subset of patients with limited scleroderma (anti-Th), another is present in more than half of the black patients with scleroderma (anti-U3 RNP), and a third (anti-PM Scl) is seen in a few patients with polymyositis- scleroderma overlap syndrome.

Figure 139-7 Autoantibody subsets in scleroderma.

[edit] DIFFERENTIAL DIAGNOSIS

The diagnosis of SSc is usually not difficult because of the characteristic cutaneous findings in scleroderma, except the early diffuse form.At that point, diagnosis is more difficult because of confusion with other forms of arthritis and other endocrine, cardiac, or renal diseases that result in similar types of edema.Many scleroderma-like diseases, although infrequent, can mimic scleroderma; localized forms of scleroderma, including morphea and eosinophilic fasciitis, are the most common (Box 139-2).The absence of Raynaud's phenomenon and atypical distribution of skin thickening are helpful clues.The chemically induced scleroderma-like illnesses include toxic oil syndrome and tryptophan-induced eosinophilic myalgia syndrome.

[edit] Localized Scleroderma

Localized scleroderma involves skin and subcutaneous tissue only.Three forms are recognized: morphea, generalized morphea, and linear scleroderma (Box 139-3).Lichen sclerosus is a related condition.The true incidence and mechanism of disease of localized scleroderma are unknown.It affects women three times as frequently as men, and the linear form tends to affect children and adolescents.The distribution in localized scleroderma suggests predisposed clones of fibroblasts present since birth that express their abnormal phenotype later in life.In early cases, patients may report areas of edema and pain with or without erythema.Low-grade arthralgia may also be present.Usually, however, the skin lesions are noticed because of appearance, and symptoms are absent.

In morphea, one or more patches of indurated skin have an erythematous or violaceous hue, especially at the borders.Lesions are asymmetric and favor the trunk.The epidermis is frequently atrophic, ivory white in color, with fine wrinkling (Fig.139-8).The distinction between morphea and generalized morphea is based on the amount and depth of involvement.Generalized morphea involves the subcutaneous fat, fascia, and occasionally muscle.In linear scleroderma an indurated, depressed band is present, usually on an extremity.Hyperpigmentation is common.Subcutaneous fatinvolvement may result in depressed, atrophic areas, and flexion contractures result when the process involves the skin over joints.

Figure 139-8 Morphea.Note ivory color and surrounding subtle erythema.

The ANA is positive in up to 50% of patients with localized scleroderma but is not a good predictor of disease activity.Eosinophilia and an elevated ESR may also be seen.Biopsy of involved skin shows features similar to those of SSc.

In extensive cases, differentiating between localized and systemic scleroderma is important because of differences in prognosis.Physical findings and laboratory testing usually allow a correct diagnosis.Several diseases may demonstrate sclerodermoid skin changes and need to be considered (Box 139-4).

Localized scleroderma is a self-limited disease of several years' duration.Permanent defects occur when the disease involves joints and produces contractures and when hemiatrophy of the face results from subcutaneous involvement.Physical therapy can help prevent contractures.Reconstructive dermatologic surgery, including autologous fat injections, may help correct atrophic defects of the face.Small trials with topical calcipotriene and UVA-1 have shown clinical and histologic improvement of sclerotic skin.

[edit] Lichen Sclerosus

Lichen sclerosus (LS) is a chronic skin disease of unknown etiology, usually affecting the vulva.Women are thought to be affected more than men, although one study of 76 patients with LS showed no gender difference.A subset of patientswith LS comprises prepubertal girls with involvement of the vulva and perineum.Most often, LS develops in postmenopausal women and in men between ages 40 and 60.^[2]

Pruritus and a burning sensation are the most common symptoms associated with LS, especially with genital involvement.Plaques and patches of slightly sclerotic (indurated) skin, with atrophy and wrinkling of the epidermis, are typical (Fig.139-9).The atrophic patches can become bullous and hemorrhagic or can erode repeatedly and heal with scarring.

Figure 139-9 Lichen sclerosus.Note white patches on labia minora and perineum.

The differential diagnosis includes localized scleroderma (morphea), atrophic lichen planus, and cutaneous diskoid lupus erythematosus.Skin biopsy for routine staining usually shows characteristic sclerosis in the upper dermis.

A potent (class I) topical corticosteroid is the treatment of choice.Topical testosterone has been shown to be less effective than clobetasol.The goal of treatment is palliation because LS tends to be chronic.Most prepubertal girls improve spontaneously at menarche.Squamous cell carcinoma can develop within the lesions in up to 10% of older patients with LS.Periodic examination and biopsy of suspicious areas are indicated.

[edit] TREATMENT

Treatment of SSc continues to be a major challenge.The wide spectrum of manifestations, severity, and disease courses means great interpatient variability.The relative rarity of SSc makes performing double-blind, controlled trials difficult.In addition, spontaneous improvement may occur, rendering interpretation of therapeutic results impossible without untreated comparison groups.

[edit] Disease-modifying Agents

Many drugs are being studied for SSc treatment because no single agent has been convincingly effective.Vascular abnormalities, immune mechanisms, and collagen production are possible areas for therapeutic intervention; thus far, no effective agent has been found (Fig.139-10).The immunomodulating agentd-penicillamine interferes with cross-linking of collagen and is the most widely used drug in the treatment of scleroderma.Patients show significant improvement in skin thickening after 2 years of therapy and improved 5-year survival compared with similar untreated patients.^[3] However, penicillamine, methotrexate, and photopheresis have not demonstrated consistent effectiveness.Relaxin, a biorecombinant version of the hormone, is in phase III trials, with earlier studies showing promising effects on skin thickening.

Figure 139-10 Possible pathogenesis of systemic sclerosis (SSc) and location of possible sites where drugs might be useful for therapeutic intervention. IL, Interleukin;PDGF, platelet-derived growth factor;TGF-β, transforming growth factor beta;CTAP, connective tissue activating peptide.

[edit] Management of Affected Organ Systems

Although no cure or remittive drug for SSc exists, patients can be treated in many ways to manage and improve different aspects of their disease.Abstinence from smoking, avoidance of cold temperatures, and common-sense measures are usually effective against Raynaud's phenomenon.More severe episodes accompanied by fingertip ulcers require calcium channel blockers, especially nifedipine and amilodopine, that relax vascular smooth muscle.Local management of fingertip ulcers includes soaking, antibiotic ointment, and oral antistaphylococcal antibiotics, as indicated.For deeper infections, surgical debridement of devitalized tissue and intravenous antibiotics may be necessary.

Nonsteroidal antiinflammatory drugs (NSAIDs) are used for joint and tendon sheath involvement.In addition to medication, early aggressive physical and occupational therapy that emphasizes stretching is important to prevent or minimize contractures.Carpal tunnel symptoms, which often occur before the diagnosis of scleroderma, can be successfully treated with resting wrist splints and local steroid injections without requiring surgery.Inflammatory myositis is treated with corticosteroids and sometimes requires the addition of immunosuppressive drugs, but the bland, fibrotic myopathy is best managed with strengthening exercises alone.

Esophageal dysmotility most often causes heartburn and lower dysphagia.The new proton pump inhibitors can completely eliminate heartburn and reflux symptoms.Prokinetic drugs are used to stimulate esophageal muscle contraction but have limited effectiveness.Primary small bowel involvement and bacterial overgrowth result in abdominal distention (or bloating), diarrhea, weight loss, and malabsorption.Broad-spectrum antibiotics (e.g., ampicillin, metronidazole, ciprofloxacin) may have a dramatic effect on these symptoms.Prokinetic agents also may be useful.Poor nutrition may require hyperalimentation.The first approach to patients with pseudoobstruction should be conservative (nonsurgical decompression) with nasogastric suction, bowel rest, and observation.

Pulmonary interstitial disease has become a major therapeutic problem in SSc.Fortunately, most patients have mild, nonprogressive involvement that does not require treatment.Attempts to reverse advanced, fixed fibrosis have been unsuccessful.In contrast, treatment of inflammatory alveolitis identified by bronchoalveolar lavage may prevent further fibrosis.When used at the appropriate time, cyclophosphamide may halt the progression of lung disease.The only option for patients with advanced end-stage pulmonary interstitial fibrosis is a lung transplant.

Isolated pulmonary arterial hypertension without significant interstitial fibrosis has the worst prognosis of all scleroderma visceral problems.Until recently, no therapy has altered the progression of this complication; it is uniformly fatal within 5 years.Continuous intravenous infusion of prostacyclins offers some hope for improving the high pulmonary artery pressures.Single-lung transplant can reverse this deadly process.

Pericarditis, congestive heart failure, and serious dysrhythmias are potential complications of SSc.All are treated as they would be independent of scleroderma.Mild to moderate pericardial effusions and other asymptomatic cardiac abnormalities usually do not progress and require no treatment.

Renal crisis is treated with angiotensin-converting enzyme (ACE) inhibitors, which have dramatically improved the outcome.^[4] Patients now have an 80% 1-year and 60% 5-year survival.The key to successful treatment is early detection and normalization of the blood pressure.In some cases, renal failure ensues despite early and vigorous intervention.Fortunately, however, more than 50% of those patients progressing to dialysis who remain on ACE inhibitor therapy have enough improvement in renal function to discontinue dialysis 6 to 18 months later.

Although an effective cure for scleroderma has not been determined, important advances in the management of visceral involvement have led to improved survival.

[edit] REFERENCES

[edit] ADDITIONAL READINGS

• Follansbee WP: The cardiovascular manifestations of systemic sclerosis (scleroderma),. Curr Probl Cardiol 1986; 11:245.
• LeRoy EC: A brief overview of the pathogenesis of scleroderma (systemic sclerosis). Ann Rheum Dis 1992; 51:286.
• LeRoy EC,et al.: Scleroderma (systemic sclerosis): classificationsubsets and pathogenesis. J Rheumatol 1988; 15:202.
• Masi AT,et al.: Preliminary criteria for the classification of systemic sclerosis (scleroderma),. Arthritis Rheum 1980; 23:581.
• Silver R,et al.: Cyclophosphamide and low dose prednisone therapy in systemic sclerosis (scleroderma) patients with interstitial lung disease,. J Rheumatol 1993; 20:838.
• Steen VD: Epidemiology of rheumatic disease: systemic sclerosis. Rheum Dis Clin North Am 1990; 16:641.