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Chapter 31 Systemic Sclerosis and Related Syndromes

Manual of Rheumatology and Outpatient Orthopedic Disorders

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Chapter 31 Systemic Sclerosis and Related Syndromes

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Robert F. Spiera

Pathogenesis
Clinical features
Treatment
Related syndromes

Scleroderma is a systemic disorder characterized by microvascular injury and fibrosis in affected organs. It is a relatively uncommon disorder , with an estimated incidence of between 10 to 20 per million annually, affecting women more commonly than men and often beginning in the third or fourth decade of life. Environmental factors have been implicated in subsets of scleroderma patients , but in the majority of cases, the disease is idiopathic. There is at best a weak genetic contribution to disease susceptibility.

I. Pathogenesis. The etiology and pathogenesis of scleroderma are unknown. The principal pathologic processes in affected organs are microvascular injury and fibrosis with excess deposition of extracellular matrix, in particular, collagen. It is not clear whether the primary process is endothelial injury causing ischemia and secondary fibrotic changes, or alternatively whether the exuberant fibrosis results in vascular injury. Recently, the role of possible autonomic dysregulation in the pathogenesis of the disorder has gained attention. Inflammation seems to play a role early in the disease course, and inflammatory perivascular infiltrates primarily consisting of T cells are seen in the dermis, particularly at the border between the reticular dermis and subcutaneous fat. Inflammation similarly seems to play a role in early alveolar disease, and in some patients with muscle disease. Vascular lesions generally consist of luminal narrowing caused by intimal proliferation . There is evidence of endothelial cell injury and platelet activation. Cytokines, including transforming growth factor-beta, interleukin-1 (IL-1), IL-2, and platelet -derived growth factor, have been implicated in fibroblast dysregulation and excess collagen production. Locally acting vasoactive molecules, including endothelin (vasoconstricting) and nitrous oxide (vasodilating), may also play a role in the disease process and afford future avenues of potential therapeutic intervention.

Auto-antibodies can be found in up to 95% of patients with systemic sclerosis, although a pathogenetic role has not yet been identified; they may be an epiphenomenon of immune systemic activation and tissue injury. A role for cellular immunity is supported by the correlation of increased IL-2 and soluble IL-2 receptor levels with disease activity, and the clinical and pathologic similarities between scleroderma and graft -versus-host disease. In this regard, investigators have demonstrated cellular mosaicism in women with scleroderma, with retention of fetal cells in skin lesions, and in the peripheral blood of women with systemic sclerosis. This suggests that a graft-versus-host type of reaction, induced by retained fetal cells, might contribute to the pathogenesis of scleroderma in some patients.

II. Clinical features. Scleroderma is a heterogeneous disorder with great variation in its presentation and clinical course. The hallmark features are hardening of the skin and Raynaud's phenomena. The pattern of skin involvement, namely limited versus diffuse, can be used to distinguish subsets of the disease and has implications regarding the involvement of other organ systems and prognosis. Morbidity and overall prognosis are a function of the pattern and degree of internal organ involvement, and are variable among patients. The course of the illness is characterized either by inexorable progression or by initial progression and then remission in some cases. Some patients have intermittent flares. Constitutional symptoms, including weight loss and fatigue, are common, whereas fever is uncommon in the absence of infection. Specific organ system involvement is addressed below.

1. Vascular. Vascular disease is nearly universal in scleroderma. Microvascular injury is felt to play a major role in pathogenesis, and the distribution thereof largely determines what organ systems will be affected. The most clinically overt indication of vascular disease is the presence of Raynaud's phenomena, which occurs in 95% of patients with scleroderma. In fact, when the diagnosis of scleroderma is suspected, the absence of Raynaud's phenomena should caution the clinician to search for other possible etiologies of a sclerosing illness. Typical changes of Raynaud's phenomena are pallor, cyanosis, then erythema in response to cold stimuli, although other factors can stimulate these symptoms, such as stress or smoking. They can also occur spontaneously. As opposed to the spasm in the primary Raynaud's phenomena, patients with scleroderma have structural changes in the arteries secondary to intimal hyperplasia and adventitial fibrosis that lead to attenuation of the lumen. Vasoconstriction in these already compromised vessels can lead to significant ischemia distally and can result in digital infarction and progressive auto-amputation. Similar changes are felt to contribute to visceral disease in the lungs and kidneys. Studies have similarly suggested visceral Raynaud's phenomena in the heart and kidney. Nailfold capillary changes, including tortuosity of capillary loops and areas of loop dropout, can be readily observed by use of an ophthalmoscope at 40 power with oil immersion. Telangiectases, which develop later in the course of the disease and can involve the oral mucosa, face, lips, and hands, also represent microvascular change.
2. Skin. Thickened, tight skin is the hallmark feature of systemic sclerosis, and the term scleroderma itself in fact is derived from Greek roots meaning hard skin. Although systemic sclerosis without skin involvement has been described ( scleroderma sine scleroderma ), skin involvement in general is a readily recognizable, universal feature. In the earliest, edematous phase, there may be puffy, painless swelling in the hands and fingers. As the disease progresses, the skin becomes thickened and bound down, with loss of normal appendicular structures. The appearance can initially be erythematous, and later hypopigmented or hyperpigmented. Pruritus is a common complaint, and skin breakdown, particularly over extensor surfaces of the small joints of the hands, can result in poorly healing ulcerations with infections. The changes generally begin distally in the hands and progress proximally, with involvement of the neck and face, typical thinning of the lips, and a pursed appearance of the mouth resulting from perioral involvement. Telangiectases are commonly seen in the distal upper extremities and face. Subcutaneous calcifications occur mostly in the hands and near bony eminences. Overlying skin can become painful and inflamed, and calcifications can also lead to poorly healing wounds.

   The pattern of skin involvement is variable, but two distinct courses have been recognized, which allow stratification of patients into distinct subgroups with differing serologic associations, clinical courses, and patterns of organ involvement. In limited scleroderma, the cutaneous disease remains distal and does not extend proximally to the forearms, although the face and neck can be involved. There can be a spontaneous regression of skin involvement within 2 years of disease onset. The limited pattern has also been referred to as the CREST syndrome, an acronym for calcinosis, Raynaud's esophageal dysmotility, sclerodactyly, and telangiectases, which are typical features. Organ involvement tends to occur earlier in diffuse scleroderma, and renal crisis and interstitial fibrotic lung disease are major causes of morbidity and mortality. Early classification of the patient with systemic sclerosis is important in regard to both prognosis and identification of key organ systems at risk.

3. Pulmonary. Lung involvement is a major cause of mortality in systemic sclerosis. Interstitial disease often begins at the bases and can be progressive. Interstitial lung disease can occur early in the course of diffuse scleroderma, but it is a very late, indolent process when occurring in patients with the limited form. Symptoms generally include dyspnea and a nonproductive cough, and the examination can reveal the typical dry velcro rales of fibrotic lung disease. Chest radiographs can reveal increased interstitial markings , especially at the bases. High-resolution computed tomography (CT) has a greater sensitivity in terms of detecting early abnormalities, and pulmonary function testing can reveal diminished vital capacity, diffusion capacity, and compliance, even in patients without symptoms. Bronchoalveolar lavage in some patients is suggestive of alveolitis, and there is interest in identifying patients with an inflammatory component to their lung disease (i.e., lavage fluid containing primarily polys), who might be candidates for immunosuppressive therapy . Pulmonary hypertension can also occur, as a secondary phenomenon in the setting of interstitial lung disease or as a primary process independent of parenchymal lung involvement, particularly in patients with limited scleroderma. Echocardiography can estimate pulmonary arterial pressures noninvasively. Infection is also a major issue, particularly in patients with esophageal disease and dysphagia, who are often at risk for aspiration. The incidence of lung cancer in patients with scleroderma also seems to be increased.
4. Renal. Before the introduction of angiotensin-converting enzyme (ACE) inhibitors , hypertensive renal crisis was a major cause of mortality in patients with diffuse scleroderma. This syndrome is characterized by a hyperreninemic state with accelerated hypertension, rapidly progressive azotemia, microangiopathic hemolysis, and consumptive thrombocytopenia. Urinalysis reveals evidence of protein and red blood cells. In the absence of appropriate diagnosis and therapy, severe complications, including hypertensive retinopathy, encephalopathy, and renal failure, can ensue. In some patients, normotensive renal crisis can occur, and this may be associated with corticosteroid use. In a patient in whom scleroderma has been diagnosed, particularly a patient with rapidly progressive, diffuse disease, regular blood pressure monitoring is essential, and daily self-monitoring of blood pressure at home is advisable.
5. Gastrointestinal . Gastrointestinal involvement is common in scleroderma and is the cause of clinical symptoms in nearly 50% of patients. Any segment of the gastrointestinal tract can be involved. Early pathologic changes include vasculopathy and smooth-muscle atrophy and fibrosis, which eventually result in dysmotility. There is also evidence that neuropathic changes contribute to disordered myoelectric function, even before the development of atrophic or fibrotic changes.

   Esophageal abnormalities are often the predominant complaint. Reflux is common and is related to lower esophageal sphincter incompetence and impaired esophageal motility . Erosive esophagitis and even strictures can develop. Dysphagia and odynophagia are common and can interfere with nutrition. Cine-esophagography or manometric evaluations can help distinguish the pattern of esophageal involvement. Stomach involvement is less commonly symptomatic, but gastroparesis can contribute to dyspepsia and a sense of bloating. Gastric telangiectases occur but are uncommonly a cause of bleeding. Intestinal hypermotility can lead to bloating and cramps in addition to bacterial overgrowth, malabsorption, and diarrhea. Colonic manifestations often include constipation or pseudo-obstruction. Wide-mouthed colonic diverticula are common but are often not of clinical significance.

6. Cardiac . Myocardial fibrosis can occur in scleroderma and is a poor prognostic feature. The early lesion appears to be contraction band necrosis and is likely related to local microvascular disease and intermittent ischemia resulting from spasm. Fibrotic replacement of normal myocardium can cause arrhythmias, which indicate a poor prognosis. Effusive pericarditis can occur but is not a common feature. Pulmonary hypertension can occur in the setting of fibrotic lung disease or as a primary vascular problem in patients with limited scleroderma. Systemic hypertension can also contribute to myocardial dysfunction.
7. Musculoskeletal. Arthralgias and morning stiffness are common and are often related to involvement of periarticular structures rather than arthritis per se. Contractures, particularly of the hands but also in large joints such as the shoulders, can lead to major functional limitations and are related to fibrosis of tendon sheaths or to sclerodermatous involvement of the overlying skin. Tendon friction rubs about the hands and feet are a typical feature in patients with diffuse scleroderma. Radiographs can reveal acro-osteolysis of digital tufts, which is likely related to repeated digital ischemia. Subcutaneous calcinosis can be seen as well.

   Myopathy can occur secondary to fibrotic disease and atrophy, and less commonly as a result of an inflammatory myositis or an obliterative endarteropathy.

8. Serologies and laboratory investigations. Antinuclear antibodies can be found in 90% of patients. Anti-centromere antibodies can be found in more than 50% of patients with limited scleroderma (CREST syndrome). Anti-topoisomerse-1 (SCL-70) antibodies are found in 30% of patients with diffuse disease. The diagnosis is made on a clinical basis, however, and should not rely on serologic confirmation. Serologies provide supportive but not diagnostic information.

   Other laboratory investigations are helpful in defining organ system involvement (e.g., creatine phosphokinase and aldolase in patients with weakness and possible myositis, or urinalysis and serum creatinine to screen for renal involvement), or monitoring for toxicities of ongoing therapies.

III. Treatment. No drugs have been proved to have a disease-modifying role in scleroderma in terms of altering the progression of the underlying pathogenic process. d-Penicillamine has been of interest, given its ability to interfere with cross-linking of collagen, which would in theory retard progression of this fibrosing illness. Some retrospective studies have suggested an improvement in skin and lung disease and survival in comparison with historical controls. A recent trial, however, comparing very low-dose (62.5 mg daily) with high-dose (750 to 1,000 mg daily) penicillamine did not show benefit in the higher-dose group . Colchicine has been of interest also, owing to its antifibrotic properties in vitro. Other agents currently under investigation include high-dose methotrexate, cyclosporin A, interferon- t , and recombinant human relaxin. Photophoresis is also being used in some centers, although it has not been approved by the Food and Drug Administration for use in scleroderma.

Although disease-modifying therapy has been elusive , major strides have recently been made in treating specific organ complications of systemic sclerosis.

1. Vascular. Avoidance of smoking and cold exposure is paramount. Systemic vasodilators, including calcium channel blockers (e.g., extended-release nifedipine started at 30 mg daily or diltiazem started at 120 mg daily) and alpha blockers (e.g., prazosin started at 1 mg twice daily), are helpful in reducing the severity and frequency of vasospastic episodes . Topical nitrates can be of use. Iloprost, a prostacyclin analog administered IV, has been of value in patients with ischemic ulcerations related to Raynaud's phenomena, but it is not presently available in the United States. Sympathetic blockade may be quite effective in controlling severe or persistent vasospasm. Surgical approaches, in particular digital sympathectomy, can be useful in salvaging digits at risk. Hygiene is critical, as is aggressive therapy of secondary superinfection and avoidance of trauma. Surgical amputation is generally avoided; auto-amputation of distally infarcted digits may occur. Anti-platelet therapy, such as aspirin (81 to 325 mg daily), or even full-dose anticoagulation has been advocated to improve perfusion in those patients with a low-flow state in their digits.
2. Skin. d-Penicillamine has been used in patients with rapidly progressive skin disease, although results are not impressive. Colchicine, potassium p -aminobenzoate, dimethyl sulfoxide, and photophoresis have also been used but are of uncertain value and are not supported by clinical trial evidence. No therapy has been proved to relieve calcinosis, although small case series have recently suggested a possible role for diltiazem in that regard. Colchicine (0.6 mg twice daily) seems to be helpful in the setting of inflammatory ulcerating lesions. Surgical debulking of calcinosis is generally not pursued, as recurrence is common, but it can be of value in instances of recurrent infection or extreme pain.
3. Pulmonary. Pulmonary fibrosis is a major cause of mortality in systemic sclerosis. Unfortunately, established fibrotic disease is not amenable to therapy other than supportive modalities. Early stages, however, may be more treatable, and there are some data supporting a role for cyclophosphamide in patients with alveolitis, which may be the earliest lesion. Bronchoalveolar lavage may be useful in determining whether an inflammatory alveolitis that could warrant such aggressive therapy is present. Pulmonary hypertension has a dismal prognosis and traditionally has been refractory to therapy. Vasodilators, generally with high-dose calcium channel blockers, and anticoagulation afford symptomatic benefit. More recently, administration of prostacyclin and nitric oxide by continuous IV infusion pumps has been shown to improve function and survival in patients with primary pulmonary hypertension and is now also being used in patients with systemic sclerosis. There is little published experience in lung transplantation in scleroderma.
4. Renal. ACE inhibitors have had a profound impact on scleroderma renal crisis. Blood pressure should be monitored closely in patients with diffuse disease, and periodic assessment of renal function is important, as approximately 10% of patients experience normotensive renal crisis that is responsive to ACE inhibitors. Standard ACE inhibitors, such as enalapril started at 5 mg daily or captopril started at 25 mg three times daily, are employed, and the dose is aggressively titrated upward to achieve adequate blood pressure control. In a normotensive renal crisis, the dose is increased to the maximum tolerated by blood pressure or until the parameters of active disease are controlled (e.g., microangiopathy, progressive azotemia, urinary sediment abnormalities). In a minority of patients, IV enalapril started at 1.25 mg every 6 hours is necessary. Renal transplantation has been performed successfully in scleroderma patients.
5. Gastrointestinal. Proton pump inhibitors (20 mg of omeprazole daily or 30 mg of lansoprazole daily) represent a tremendous advance in the management of reflux and esophagitis, and they now are being used for long-term therapy in patients with systemic sclerosis. Prokinetic agents such as cisapride (started at 10 mg four times daily) can help with early satiety and in reflux as well. In some patients, endoscopic dilation of strictures helps to relieve symptoms of dysphagia. Octreotide and erythromycin may be of value in improving gastric and intestinal motility. Bacterial overgrowth causes bloating and diarrhea and may require periodic empiric courses of antibacterial agents; quinolones such as ciprofloxacin (500 mg daily for 2 weeks) or tetracycline (250 mg twice daily) have been useful.
6. Cardiac. Pericarditis is not a frequent cause of symptoms or cardiovascular compromise, but when necessary it can be treated with antiinflammatory drugs or corticosteroids (often first with 30 mg of prednisone daily). Asymptomatic effusions do not usually require therapy. Other cardiac complications, such as arrhythmias and congestive heart failure, are treated in standard medical fashion.
7. Musculoskeletal. Arthralgias or tendon friction rubs can be treated with nonsteroidal antiinflammatory drugs, although these must be used cautiously given the gastrointestinal and renal concerns in this patient population. Low-dose corticosteroids (7.5 mg or less of daily prednisone) are helpful, but there are some concerns regarding an association of prednisone therapy with the development of renal crisis in patients with diffuse disease. Physical therapy and occupational therapy should be a mainstay of management, with particular attention to maintaining range of motion, muscle strengthening, the use of paraffin baths, and splinting when appropriate. Surgical reconstruction can be helpful in selected patients with severe contractures causing functional limitation.

   Inflammatory myositis is treated with substantial doses of corticosteroids (often first with 40 to 60 mg of prednisone daily) and other immunosuppressive therapies, such as methotrexate or azathioprine. Idiopathic myositis would be treated similarly.

IV. Related syndromes

1. Localized scleroderma. Morphea is characterized by plaques of asymmetric fibrotic dermal lesions that can be histologically indistinguishable from the lesions of scleroderma. It is not associated with visceral disease, and survival does not differ from that of the general population. The lesions often spontaneously regress within several years, although in rare patients morphea can become generalized. Linear scleroderma usually occurs in children, often as a linear, indurated patch of dermal fibrosis in a lower extremity . In some instances, facial hemiatrophy in the typical coup de sabre deformity can occur. No proven therapeutic interventions are available.
2. Eosinophilic fasciitis is characterized by thickening and inflammation of fascia, with puckering and tightness of the overlying skin. Pain, weakness, and contractures can occur. In many patients, there is an antecedent history of trauma. Diagnostic biopsy must be deep and include fascia, where eosinophilic and lymphocytic infiltrates can be identified. Laboratory findings often include eosinophilia and the presence of acute-phase reactants. The skin changes can resemble those of scleroderma, but the syndrome is not generally associated with Raynaud's phenomena or sclerodactyly. Also, visceral disease and antinuclear antibodies are much less common. The distinction is crucial, as eosinophilic fasciitis is often dramatically responsive to modest or high doses of corticosteroids and is often a self-limited illness.
3. Chemically induced symptoms. Scleroderma-like illnesses have been reported after exposure to bleomycin, vinyl chloride, and silica dust. An association between silicone gel-filled breast implants and the development of scleroderma has been suggested, but epidemiologic studies have not supported a causal relationship. A scleroderma-like illness appeared in Spain in 1981 and was ultimately linked to ingestion of a toxic rapeseed oil. Ingestion of contaminated tryptophan is felt to be the cause of the eosinophilia myalgia syndrome, characterized by myalgias, arthralgias, neuropathy, and skin changes resembling those of scleroderma, but with less prominent Raynaud's phenomena.
4. Mixed connective tissue disease. Patients with rheumatic diseases can often demonstrate overlapping features. Mixed connective tissue disease is an antibody-defined overlap connective tissue disease demonstrating features of lupus, systemic sclerosis, and myositis. Patients often present with puffy hands and arthralgias, and joint symptoms can be a prominent part of the clinical course. Raynaud's phenomena, esophageal dysmotility, and interstitial lung disease in addition to inflammatory myopathy can be seen. These patients have antinuclear antibodies that stain in a speckled pattern of immunofluorescence and detectable and often high titers of antibodies to ribonucleoproteins (anti-RNP). Patients with various features of rheumatoid arthritis, systemic sclerosis, lupus, polymyositis, and other rheumatic signs and symptoms but with nonspecific serologies are classified as having undifferentiated connective tissue disease. With observation, a classic disease may emerge. Therapy tends to be focused on the dominant disease manifestations.

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Copyright 2000 by Lippincott Williams & Wilkins
Stephen A. Paget, M.D., Allan Gibofsky, M.D., J.D. and John F. Beary, III, M.D.
Manual of Rheumatology and Outpatient Orthopedic Disorders

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