Being able to identify the hallmark signs of disease is not always enough. Clinicians may recognize the taut and contracted, statue-like skin that characterizes scleroderma, but failure to identify the systemic manifestations of the disease can have deadly results. Scleroderma can affect multiple systems and virtually every body organ. Earlier diagnosis of the disease’s systemic form can help improve prognosis and ultimately increase survival rates for affected patients.
Systemic scleroderma (SSc), also known as systemic sclerosis, is a chronic connective tissue disease that is characterized by vasculopathy, autoimmunity, and inflammation.1,2 As SSc develops, the body’s fibroblasts produce too much collagen, leading to fibrosis of the skin and the internal organs.1,3 It was not until the 20th century that scleroderma was shown to affect the internal organs—resulting in the devastating outcomes that are now associated with SSc.
SSc is more prevalent than many clinicians realize. About 300,000 people in the United States have a form of scleroderma, and nearly one-third of these (perhaps 75,000 to 100,000) are believed to be affected by its systemic variant.1,4,5
When SSc invades the major internal organs, especially the lungs, kidneys, and heart, the prognosis is poor. SSc carries a survival rate of only 55% at 10 years postdiagnosis—the highest risk of fatality among connective tissue diseases.1 Therefore, when any form of scleroderma is suspected, it is imperative that the patient be examined for multisystem involvement.
Patient presentation varies, depending on the form of scleroderma. To recognize the symptoms, the clinician must first understand the various classifications of the disease. Scleroderma is often seen as a spectrum of illness, ranging from mild to life-threatening. The two major variants are localized scleroderma (with fibrosis restricted to the skin) and systemic scleroderma (in which fibrosis affects the internal organs).6
Localized scleroderma may manifest as linear scleroderma, with band-like thickened skin lesions that begin to develop during childhood and usually affect one area, such as an arm or a leg; involvement of the forehead, face, or scalp is referred to as en coup de sabre (“cut of the sword”). By contrast, morphia (which can be limited or generalized) appears as circumscribed sclerotic patches or plaques on the skin and can be intermittent. These lesions vary in size but are usually round or oval, with purple edges and a waxy appearance6 (see Figure 1).
Systemic scleroderma comprises both cutaneous and noncutaneous involvement (although scleroderma sine sclerosis, fibrosis of the internal organs with no skin lesions, is rare). Typically, limited systemic scleroderma affects only the hands, the face, and the distal extremities (see Figure 2). It was originally referred to as CREST syndrome, an acronym for calcinosis of the digits, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias.6 The lungs may eventually be affected.7
Diffuse systemic scleroderma usually begins with Raynaud’s phenomenon, followed by sclerosis of the proximal extremities, the trunk, and the face, and progresses to dysfunction of the lungs, kidneys, heart, and gastrointestinal (GI) system.1,8 For the purposes of this review, further mentions of “SSc” will refer to the diffuse form.
Although presentation varies in patients with SSc, vascular changes are among its earliest presenting signs (see Table 16,8,9 for a list of clinical manifestations). Raynaud’s phenomenon accounts for 70% of SSc patients’ first reported symptoms, and it occurs in 90% to 99% of patients with systemic disease.10,11
Raynaud’s phenomenon is the episodic constriction of blood vessels in response to environmental factors such as cold, stress, or emotional changes. This circulation disturbance is evidenced by color changes in the digits and the development of digital ulcers resulting from ischemia (found in almost half of all patients).11,12 It manifests as a series of changes in appearance: white or pale as a result of vasospasm, cyanotic from ischemia, then red or flushed as the blood flow returns.10,11
Raynaud’s phenomenon may be present for many years before any other clinically significant symptoms or systemic manifestations occur. Even among patients who do not experience all of the skin changes associated with Raynaud’s phenomenon, most report digital pallor11 (see Figure 3). Care of digital ulcers is required to prevent potentially serious sequelae, including osteomyelitis and soft-tissue necrosis12,13 (see Figure 4).
Once patients with SSc have begun to experience circulation problems and blood vessel damage, cutaneous changes result. Skin edema occurs, manifesting in swollen, pruritic hands and digits.14 Over time, the skin hardens and thickens over the digits, extremities, face, and trunk—all resulting from vascular dysfunction and oxidative stress, followed by immunologic activation and inflammation.1,3,15 The tight, fibrotic skin that results is the hallmark of SSc1,3 (see Figure 5).
Skin changes tend to peak within the first five years. Patients who experience them rapidly are at increased risk for severe internal organ involvement.6 With disease progression come facial changes, including a shrunken nose, microglossia, small lips, furrowing around the mouth, telangiectasias, hyperpigmentation (resembling that seen in patients with Addison’s disease), and sclerosis that limits facial expressions, leaving a mask-like appearance.6,10
Calcinosis, the buildup of calcium deposits under the skin, appears in the form of painful, hard nodules, especially in the digits, elbows, knees, and other joints. This occurs in 40% of SSc patients.11 In addition to the already thickened sclerotic skin, calcinosis causes flexion contractures leading to restricted mobility, articular deformities, and dissolution of the distal phalanges.10,16
In addition to vascular and cutaneous changes, patients affected by SSc may develop a multitude of musculoskeletal complaints, including nonspecific joint pain. These symptoms can manifest as arthritis and cause discomfort in the tendons and muscles. Patients may even develop myopathies and muscle weakness over time.17
GI tract complaints are almost universally seen in patients with SSc; more than 85% of patients experience dysphagia, phagodynia, or other esophageal problems.10 These symptoms usually result from peristaltic abnormalities: reflux, Barrett’s metaplasia, hypomotility, and/or fibrotic strictures. Subsequent complaints may include nausea, vomiting, abdominal pain, and constipation due to colonic hypomotility.18,19 In some patients, malabsorption syndrome can advance to a stage at which parenteral nutrition is required.12
Pulmonary impairment is another common manifestation, affecting possibly 80% to 90% of patients with SSc.2,7 Patients who present with dyspnea or a dry, irritating cough may have underlying lung fibrosis.6,11 Those who report shortness of breath, fatigue, fast heart rates, or blackouts may have pulmonary hypertension, which is seen in one in seven patients.11 Pulmonary hypertension reduces the five-year survival rate from 90% to as low as 50%, making it a significant cause of SSc-related death.10
The most devastating clinical manifestations in SSc patients are renal and heart involvement.20 Among all the possibilities of organ involvement, kidney damage incurs the worst prognosis and the highest mortality. Of patients not treated for this development, only 16% survive longer than one year; with treatment, such patients’ five-year survival is 45%.10
Sclerodermal renal crisis is apparent in patients who meet the diagnostic criteria of proteinuria, azotemia, arterial hypertension, a reduced glomerular filtration rate, hematuria, and microangiopathic hemolytic anemia.20-25 Patients may also present with retrosternal pain, possibly signifying myocardial fibrosis. This complication, in addition to kidney failure, can lead to arrhythmias and ultimately heart failure.
Particularly important components of the patient history include gender, race, age, family history, and work environment. Although anyone can develop scleroderma, women are four times more likely than men to develop SSc, and pregnancy increases women’s risk tenfold.11 For unknown reasons, African-Americans are more frequently affected than whites and are at increased risk for serious systemic involvement.4
Symptom onset is most common between ages 25 and 55, although children and elderly persons can be affected.11,26,27
Most research suggests that SSc is not directly inherited, although (as in the case of other autoimmune diseases) genetic factors can predispose people with additional external triggers.21,28,29 A positive family history is a strong risk factor for SSc. In a large cohort-based study, patients with SSc invariably had at least one first-degree relative who was also affected.29
Although the exact cause of SSc remains unknown, substantial research suggests that environmental factors, especially exposure to certain metals and chemical compounds (eg, solvents, pesticides, silica), play a major role in its development.1,16,30 Farmers, factory and construction workers, coal miners, and others may be exposed to these chemicals, so it is important to ask about potentially hazardous occupations.
Patients in whom any form of scleroderma is suspected should undergo a thorough physical examination. It is here that preliminary signs of internal organ involvement and fibrosis must be detected.
Clinicians should observe the skin for signs of inflammation. Any changes in the skin’s appearance or texture, including tight, hardened, and sclerotic changes of the hands, face, mouth, trunk, and/or digits, should also be noted. The examiner may notice furrowing around the mouth, telangiectasias, and hyperpigmentation.6,10 Signs of vascular damage may be identified, including digital discoloration and ulcers associated with Raynaud’s phenomenon.22
Examination of the skin (with palpation) will reveal information about the disease’s activity, involvement, and severity.31 Active cutaneous disease indicated by inflammatory signs (eg, edema) correlates with active internal disease, such as renal crisis or fibrosing alveolitis.10 Inactive skin disease manifests as sclerotic skin resembling a scar.31
If skin sclerosis is sufficient for suspicion of SSc, additional steps are required. In the ear-nose-throat examination, for example, the mucosal membranes should be observed for signs of Sjögren’s syndrome, since it is associated with SSc.32 The mouth should also be examined for telangiectasias and microglossia.
A musculoskeletal exam may also prove helpful. Range of motion and joint mobility should be assessed, especially if sclerotic skin causes flexion contractures, producing shortened fingers or articular deformities.16
If suspicion of SSc persists, the disease can be further assessed through laboratory values and imaging. No one test ensures a definitive diagnosis, but serologic testing for autoantibodies is helpful.5,33
The provider may order an antinuclear antibody (ANA) test or rheumatoid factor testing to confirm connective tissue disease (CTD). However, it is important to remember that a positive ANA result is found in patients with other CTDs, including 30% of those with rheumatoid arthritis and 95% of those with systemic lupus erythematosus.33 Since anticentromere antibodies are present in 70% to 80% of patients, and antibodies against topoisomerase I DNA (anti-Scl-70) exist in about 40% of patients, confirmed presence of either has a specificity of 95% to 99% for the diagnosis of SSc.34
Imaging and other tests help to assess the involvement of SSc and the extent of associated fibrosis in internal organs. X-ray of the hands can reveal intra-articular calcifications and osteopenia, as well as soft-tissue calcinosis.11,17
Chest x-ray and CT can detect interstitial lung disease.33 Imaging will also help differentiate active alveolitis (ground-glass appearance) from pulmonary fibrosis (honeycombing).6 Clinicians may order pulmonary function testing to confirm restrictive lung disease. Doppler echocardiography will show cardiac and pulmonary vascular involvement and can confirm the presence of pulmonary hypertension. ECG, Holter monitoring, and ultrasonography can be used to further assess suspected myocardial disease and arrhythmias.35
GI changes, including esophageal stricture and Barrett’s esophagus, can be investigated through esophageal manometry and endoscopy.3,18 In addition to renal function testing, urinalysis and peripheral blood smear are necessary to confirm renal crisis, especially in patients with worsening hypertension or with new anemia not associated with blood loss.6
Diagnosis of SSc is made based on the patient’s clinical presentation, but the degree of organ involvement must also be determined by symptoms, history, physical examination, laboratory work-up, and imaging studies, as detailed above. The 1980 Preliminary Criteria for the Classification of Systemic Sclerosis36 is 97% sensitive and 98% specific for SSc,37,38 although additional criteria (eg, certain autoantibodies, nail-fold capillary changes) have been proposed to improve sensitivity for limited SSc.9,38 (For the major and minor criteria from the 1980 document, see Table 26,10,36).
Accurate, early classification of SSc is critical. Patients are most likely to respond to therapeutic efforts in the disease’s early stages, and prognosis depends on the degree of disease severity and organ involvement.37,38
No treatment modality has yet been found to reverse the fibrotic damage of SSc, but several therapies can slow disease progression.39 Because of the heterogeneous nature of the disease, management is individualized according to patient symptoms and organ involvement.40 Treatment is directed at preventing vascular damage, immune cell activation, and fibrosis.10,41 Table 32,12,41,42 shows treatment strategies to address all three disease processes.
In early SSc, vascular intervention and immunosuppressive treatment are most important because they can prevent later stages that involve fibrosis.2 Vasodilators (calcium channel blockers, such as amlodipine and nifedipine; ACE inhibitors, including enalapril and captopril; and angiotensin receptor blockers, such as losartan) have been found effective, particularly for treatment of Raynaud’s phenomenon and to prevent further renal damage.12,41 An abundance of recent evidence suggests that bosentan, an endothelium receptor antagonist, is helpful in treating pulmonary hypertension and preventing digital ulcers by regulating the inflammatory response.2,12,13,30,39,43
Cyclophosphamide is used for patients with interstitial lung disease and any associated alveolitis.5,41 In one randomized double-blind trial, methotrexate improved skin scores (ie, softened fibrosis), creatinine clearance, and overall well-being in 68% of patients who received it over a 24-week period.42
In later stages of SSc, suppressing fibrosis is the goal. d-Penicillamine is considered a first-line agent, because it interferes with collagen cross-linking.41 No conclusive data exist to support its dosing and efficacy, although findings vary from no effect to 70% benefit in improving skin scores and decreasing five-year mortality rates.2,6,41
Patient compliance will require education, as several months’ treatment may be required before results are evident. Supportive and symptomatic therapy will greatly improve quality of life as well.
Patients should be told that GI reflux and motility disorders can be controlled with proton pump inhibitors.41 They should also be advised to elevate the head when in bed and to eat small, frequent meals.
Arthralgias, arthritis, and deep tissue fibrosis that cause joint contractures and tendon friction rubs may be controlled by NSAIDs.41 The manifestations of Raynaud’s phenomenon can be minimized by avoiding exposure to cold temperatures and wearing warm clothes; smoking cessation is also advised.5
Colchicine may help alleviate inflammation, pain, and calcinosis. Physiotherapy can help prevent deformities, and an exercise routine is important to maintain joint mobility.5,41 Lubrication with emollients is essential for dry, sclerotic skin.
In addition, psychologic guidance through counseling is important for the patient’s self-confidence and self-image. SSc can be disfiguring, with the face and hands affected in almost all cases.11
Monitoring and Follow-Up
Emphasizing regular visits and routine screening procedures is crucial in the management of SSc. A team of specialists should be involved in treating the complex, diverse symptoms of SSc and in monitoring the disease to prevent further organ fibrosis and dysfunction.
Systemic sclerosis is a complex, multisystem disease. Because it is highly variable in expression and clinical presentation, diagnosis is difficult and often overlooked, even by the most attentive clinicians. Widespread involvement of SSc and potential fibrosis of organs beyond the skin (including the kidneys, heart, lungs, muscles, joints, and GI tract) contribute to SSc’s devastating morbidity and mortality.
Treatment is aimed at controlling the vasculopathy, autoimmunity, and fibrosis associated with the disease. Since there is no cure for SSc, close monitoring and management by a team of health care professionals are essential in slowing disease progression.
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