• The most frequent symptoms are (in descending order) Raynaud phenomenon, gastroesophageal reflux with or without dysmotility, skin changes, swollen fingers, and arthralgias.
  
• Patients with Raynaud phenomenon and features atypical for primary Raynaud phenomenon should be evaluated for the possibility of scleroderma or another connective tissue disease.
  
• A negative antinuclear antibody test (by indirect immunofluorescence) makes the diagnosis of scleroderma very unlikely.
  
• The degree of skin involvement is highly variable. Many patients with limited scleroderma have only subtle cutaneous findings (eg, mild sclerodactyly).
  
• The current classification criteria do not include many patients with milder forms of scleroderma.
  
• Some patients may have overlapping clinical features with other systemic autoimmune rheumatic disorders such as polymyositis/dermatomyositis, Sjögren syndrome, systemic lupus erythematosus, and rheumatoid arthritis.

Systemic sclerosis (scleroderma) is a chronic multisystem disease that belongs to the family of systemic autoimmune disorders. The word scleroderma literally means “hard skin” and describes the most dramatic clinical feature of the disease—namely, skin fibrosis. Scleroderma effects approximately 20 new patients per million per year and has an estimated prevalence of approximately 250 patients per million in the United States. As with many other autoimmune disorders, scleroderma is approximately 4–5 times more common in women than men. The average age at the time of diagnosis is approximately 50 years.

The prevalence and manifestations of scleroderma vary among racial and ethnic groups. For example, the disease is approximately 100 times more common among the Choctaw Native Americans in Oklahoma, in whom the disease is characterized by diffuse skin disease and pulmonary fibrosis. Milder, “limited” disease is more common among older white women, and African American patients are more likely to be younger and have severe lung disease. The finding of various subtypes of scleroderma among different ethnic or racial groups, the presence of familial clustering, and the appearance of specific autoantibodies that are associated with specific HLA types define genetic influences on disease expression. New genetic studies examining both candidate gene approaches and genome-wide association studies confirm genetic influence in disease susceptibility. Certain environmental factors are also thought to play etiologic roles. For example, characteristic antibodies and scleroderma disease manifestations can develop in workers exposed to high levels of silica dust (ie, coal miners, stone masons).

Scleroderma is a rare disorder but is characterized by symptoms that occur frequently in the general population, such as Raynaud phenomenon, gastroesophageal reflux, fatigue, and musculoskeletal pain. Therefore, it is important for primary care practitioners to be aware of scleroderma because early recognition can reduce morbidity and detect treatable, life-threatening complications.

The American College of Rheumatology classification criteria for scleroderma include either thickened (sclerodermatous) skin changes proximal to the metacarpophalangeal joints or at least two of the following:

1. 
   

   Sclerodactyly.

   
   
2. 
   

   Digital pitting (loss of tissue on the finger pads due to ischemia).

   
   
3. 
   

   Bibasilar pulmonary fibrosis.

A diagnosis of scleroderma may also be made if the patient has three or more features of the CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) syndrome, although the term “limited scleroderma” is now preferred for this clinical subtype. Patients with definite Raynaud phenomenon who have abnormal nailfold capillary loops or the presence of autoantibodies known to be associated with scleroderma (see Laboratory Findings and Table 25–1) may be considered to have early scleroderma or a mild expression of the disease.

Although skin changes are usually the major diagnostic clue, scleroderma is a systemic disease that most commonly targets the peripheral circulation, muscles, joints, gastrointestinal tract, lung, heart, and kidney. Symptoms encountered in the early presentation of scleroderma include musculoskeletal discomfort, fatigue, weight loss, and heartburn associated with gastroesophageal reflux disease (GERD). When these symptoms are accompanied by the new onset of cold sensitivity or Raynaud phenomenon, then scleroderma should be considered and further diagnostic investigation is warranted.

Symptoms and Signs

Skin

Thickening of the skin is the most easily recognizable manifestation of scleroderma but is not prominent in all patients. Patients with scleroderma are typically classified based on the amount and location of skin involvement. Patients with “limited” cutaneous disease have skin changes on the face and distal to the knees and elbows. One subset of limited scleroderma, previously called the CREST syndrome, typically only involves the skin of the fingers (sclerodactyly) distal to the metacarpophalangeal joints (Plate 40). In contrast, diffuse scleroderma refers to the group of patients with proximal extremity or truncal skin thickening. The amount of skin thickening can be quantified by performing a “skin score,” in which the skin is pinched between the examiner’s thumbs in 17 specified areas of the patient’s body, scoring the thickness of the skin from 0 (normal) to 3 (very thick). The skin score provides a systematic approach to longitudinal disease evaluations and is commonly used in clinical trials to assess treatment efficacy. This score, however, has limitations, including (1) high inter-observer variability, (2) not scoring the quality of the skin or level of disease activity, (3) and lacking sensitivity to change over short periods of time. However, epidemiologic studies indicate that higher skin scores and changes in skin scores correlate with greater degrees of internal organ involvement and worse overall prognosis.

Early in the course of diffuse scleroderma, the skin appears edematous and inflamed with erythema and pigmentary changes, and swelling in the fingers and hand may be confused with early rheumatoid arthritis. Hyperpigmented areas alternating with vitiligo-like areas of depigmentation impart to the skin a “salt and pepper” appearance. Diffuse hyperpigmention develops in some patients, making them appear tanned. This early inflammatory phase is associated with pruritus and discomfort that usually lasts for weeks to months. In vitro studies show that dermal fibroblasts derived from patients with scleroderma overproduce extracellular matrix that leads to increased tissue collagen deposition in the skin. Collagen cross-linking then causes progressive skin tightening. In the later stages of the disease, the involved skin becomes atrophic, dry, and scaly because of sebaceous gland damage. These dry thickened areas of skin may be intensely pruritic, causing the patient to excoriate the skin, which leads to more damage and thickening (lichenification). Skin uclers can form over areas of joint contractures and local trauma. Digital ischemic ulcers form on the distal fingers in 30–50% of patients (Plate 41). Pitted areas on the distal finger and loss of digital pad is common, while a picture of pseudo-clubbing is a less common manifestation of underlying osteolysis due to microvascular disease. Patients often have other prominent skin changes, including marked telangiectasias (dilated capillaries) that occur on the skin of the face, the palmar surface of the hands (Plate 42), and the mucous membranes. Telangiectasias tend to be more numerous in those patients with other scleroderma related vascular disease (ie, pulmonary arterial hypertension). Telangiectasia increase in numbers and location with a longer disease duration. A small proportion of patients have subcutaneous calcinosis, primarily on the fingers and along the extensor surfaces of the forearms.

Vascular Disease

Involvement of the vasculature is ubiquitous among patients with scleroderma. A widespread obliterative vasculopathy of peripheral arteries and the microcirculation is manifested pathologically by intimal thickening with marked luminal narrowing and evidence of local thrombi. Endothelial cell injury leads to abnormal vascular reactivity and altered tissue perfusion. Critical ischemia occurs in the tissues when vasoconstriction occludes these diseased vessels. Evidence suggests that this vascular disease is fundamental to organ damage and subsequent malfunction of the heart (cardiomyopathy), lung (pulmonary hypertension), kidney (scleroderma renal crisis [SRC]), and other organs in scleroderma (see below).

Raynaud phenomenon is the first manifestation of the disease in almost every patient. It tends to develop concurrently with other symptoms in those with diffuse disease and typically precedes other symptoms by years in those with limited skin disease. Stress and cold temperature induce an exaggerated vasoconstriction of the small arteries, arterioles, and arteriovenous shunts or thermoregulatory vessels of the skin of the digits. This is manifested clinically as pallor and cyanosis of the digits, followed by a reactive hyperemia after rewarming. Unlike episodes of uncomplicated primary Raynaud phenomenon, attacks of Raynaud phenomenon in patients with scleroderma are often painful and frequently lead to digital ulcerations, gangrene, or amputation.

Clinical features found to be predictive of an autoimmune rheumatic disease among patients with Raynaud phenomenon include the presence of antinuclear antibodies (ANA) and abnormal nailfold capillaries (see Special Examinations below). Patients over the age of 30 who develop new onset Raynaud phenomenon should be screened with an ANA test and nailfold capillary examination, particularly if they have severe, painful episodes of vasospasm, signs of digital ischemia or tissue damage, or any other systemic signs or symptoms of a secondary disease. Although patients with scleroderma almost always have a positive ANA, it is important to remember that the presence of a positive ANA does not, by itself, make the diagnosis of a connective tissue disorder (see Laboratory Findings below).

Lung Involvement

Two main forms of lung disease occur in patients with scleroderma: inflammatory alveolitis leading to interstitial fibrosis and pulmonary vascular disease leading to pulmonary arterial hypertension (see Chapters 63 and 64). These two processes can occur independently or concomitantly. Active interstitial lung disease occurs typically in patients with early diffuse scleroderma in the first 4 years of illness, whereas pulmonary hypertension more commonly affects those with long-standing disease. Lung involvement (both types) usually presents as dyspnea on exertion but can be asymptomatic early in the course of the lung disease. Therefore, routine screening tests for lung disease (complete pulmonary function testing [PFTs] and echocardiograms) are important because early intervention may prevent progression. In the case of interstitial fibrosis, physical examination reveals fine crackles at the lung bases. This finding, however, may not be present in early disease and its presence may indicate stable fibrosis and is not necessarily a sign of active disease. PFTs or high-resolution computed tomography (CT) scanning can detect very mild and early disease and are better indicators of disease activity (ie, change in forced vital capacity [FVC] over a short interval or ground glass opacities or fibrosis on CT). Approximately 80% of patients with scleroderma have restrictive ventilatory defects on PFTs, consistent with interstitial lung disease. However, only about 10–20% of these patients suffer from progressive severe interstitial lung disease. Predictors for progression of interstitial lung disease are the presence of diffuse skin disease, African American race, early decline in FVC, fibrosis on CT scan, and the presence of antitopoisomerase antibodies.

Pulmonary vascular disease with or without fibrosis can lead to pulmonary arterial hypertension and ultimately right heart failure. Estimates of the prevalence of pulmonary arterial hypertension among patients with scleroderma vary, but may be as high as 25%, although severe disease is only seen in roughly 10–15%. Typically, patients with isolated pulmonary arterial hypertension seek medical care complaining of dyspnea on exertion; however, signs of progressive, life-threatening right heart failure develop rapidly in later stages. Physical examination in these patients reveals systolic murmurs (from tricuspid regurgitation), a prominent P2 component of S2, right ventricular heaves, hepatomegaly and lower extremity edema.

Gastrointestinal Involvement

Gastrointestinal disease in scleroderma usually involves both the upper and lower gastrointestinal tract but is highly variable in its clinical expression. Patients with measurable gastrointestinal involvement can be relatively asymptomatic (eg, mild constipation). Alternatively, they may have profound gastrointestinal tract dysfunction, with malnutrition and significant morbidity. The majority of patients with scleroderma have symptomatic GERD with dysphagia. Complaints include a sensation of food getting stuck in the mid or lower esophagus, atypical chest pain, or cough. Patients often complain that they must drink liquids to swallow solid food, particularly dry food such as meat or bread. Reflux and dysphagia occur because of dysmotility of the esophagus and stomach (gastroparesis). This type of organ dysfunction results from abnormal motility caused by atrophy of the gastrointestinal tract wall smooth muscle that occurs with or without pathologic evidence of significant tissue fibrosis or obvious vascular insult to the bowel. If GERD is left untreated, the upper gastrointestinal disease can cause esophagitis, esophageal ulceration with bleeding, esophageal stricture, or Barrett esophagus. Bleeding can also occur secondary to mucosal A-V malformations or telangiectasia in the wall of the stomach (gastric antral vascular ectasia or GAVE).

The small and large intestines can also be affected by smooth muscle atrophy of the bowel wall causing abnormal motility of the gut. The most common symptom is the combination of constipation alternating with diarrhea and patients frequently give a history compatible with irritable bowel syndrome. Severe disease causes recurrent bouts of pseudo-obstruction, bowel distention with leakage of air into the bowel wall (pneumatosis coli intestinalis), and even bowel rupture. Lower bowel dysmotility slows the movement of bowel contents severely, allowing bacterial overgrowth, diarrhea, and malabsorption. Fecal incontinence develops in a small subset of patients.

Renal Involvement

Clinically important kidney disease occurs in only a minority of patients, but when it develops, renal disease poses a major threat to life. SRC develops in approximately 5% of patients. It is characterized by the sudden onset of malignant hypertension that, if untreated, can lead rapidly to renal failure and death. Prior to the discovery that angiotensin-converting enzyme (ACE) inhibitors can control hypertensive crises in scleroderma effectively, SRC was the leading cause of death. Despite the dramatic benefit of ACE inhibitors, significant morbidity or renal dysfunction can result from SRC. Patients in the early stages of diffuse scleroderma, particularly those treated with glucocorticoids and those who produce antibodies to RNA-polymerase III are at the greatest risk for SRC. Patients in whom SRC develops may have symptoms associated with the acute onset of severe hypertension, including headache, visual changes, or seizures. Some, however, are asymptomatic and have undetected hypertension and an abrupt rise in creatinine; therefore, patients at high risk (those with early, active diffuse skin involvement) must have their blood pressure monitored frequently. Renal biopsy specimens reveal changes similar to malignant hypertension, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, and eclampsia. There is intimal hyperplasia and vasospasm of cortical arteries. This leads to activation of the renin-angiotensin system and accelerated hypertension, proteinuria, microscopic hematuria, and thrombotic microangiopathy (schistocytes on peripheral blood smear).

Cardiac Involvement

Cardiac involvement in scleroderma can frequently be demonstrated by objective testing (eg, echocardiography, thallium scan, or electrocardiogram) but is usually subclinical in the early stages of disease. Cardiovascular morbidity is seen primarily in the late stages of diffuse scleroderma. Ischemia-reperfusion injury secondary to small arterial disease of the myocardium leads to contraction band necrosis and tissue fibrosis. This process can result in arrhythmias, a cardiomyopathy with diastolic dysfunction, or overt symptoms of heart failure. Although pericardial effusions are frequently detected by echocardiography, they are usually clinically silent. Large pericardial effusions are associated with pulmonary arterial hypertension and confer a poor prognosis. Symptoms from scleroderma cardiac disease include chest pain from pericarditis, palpitations from arrhythmias, or dyspnea on exertion from heart failure.

Musculoskeletal Involvement