Last updated: November 3, 2014
Synonyms: Progressive systemic sclerosis (PSS); diffuse scleroderma; limited scleroderma (see also CREST syndrome); localized scleroderma (morphea, linear scleroderma).
ICD-9 Code: Progressive systemic sclerosis and CREST 710.1; PSS with lung involement 517.2; Circumscribed scleroderma 701.0
ICD-10 Code: Progressive systemic sclerosis M34.0; PSS with lung involement M34.81; CREST M34.1; Morphea L94.0
Definition: Scleroderma is a multisystem disorder characterized by skin thickening and vascular abnormalities. In addition to skin, the most commonly affected organs are lung and kidney. Three major disease subsets are recognized, based on the extent of skin disease. Limited disease is defined as skin fibrosis in distal extremities and some areas of the face and neck. Limited disease is also known as CREST syndrome. Diffuse disease includes patients with skin abnormalities extending to the proximal extremities (i.e., above the elbow or knee) and trunk. Localized disease manifests as patches (morphea) or band- like (linear scleroderma) areas of skin thickening.
Etiology: The cause of scleroderma remains unknown. Immunologic abnormalities are suggested by the presence of characteristic autoantibodies such as ANA, anticentromere, and anti-Scl-70 antibodies. Early dermal changes include lymphocytic infiltrates consisting primarily of T cells, but the major abnormality is collagen accumulation with fibrosis. In addition, other striking abnormalities are seen in small- to medium-sized blood vessels, which show immunologically bland fibrotic change. The theory that the vasculature is the primary target is supported by significant experimental data. In addition to these intrinsic abnormalities, the association of scleroderma-like syndromes with epidemic exposures to certain toxins (e.g., toxic oil syndrome related to tainted oil, eosinophilia-myalgia syndrome due to tryptophan) suggests that an environmental trigger may start the process in a susceptible individual.
Pathology: Small arteries in the skin, lung, and kidney show proliferation of subintimal tissues and fibrotic change. Small thrombi may form on the altered intimal surfaces. Luminal narrowing or occlusion characterize these small vessels, with a lesser role by vasospasm. Increased accumulation of fibrotic tissue, primarily collagen, is seen in the dermis and is accompanied by loss of normal skin appendages such as hair follicles. Skeletal muscle and myocardium may show atrophy of the muscle fibers and replacement by fibrotic tissue. Infrequently, histologic evidence of myositis is seen.
Demographics: Scleroderma is a rare disease. Approximately 80% of patients are females, and one-half present before the age of 40. Some studies suggest a higher incidence and severity of disease in black females than in whites. A much higher prevalence is seen in the United States than in northern Europe or in Asia, a difference that at present remains unexplained.
Cardinal Findings: A variety of organ systems may be involved in scleroderma.
—Skin: Skin changes are the hallmark of this disease in most patients. Skin thickening is most noticeable in the hands, which in early stages may appear swollen or puffy. The skin is not easily pinched into small folds and may be indurated or bound down to underlying tissues. Normal skinfolds (e.g., over the knuckles) may be obliterated, and hair no longer grows over sclerodermatous skin. In the diffuse form, proximal extremity, truncal, and facial skin thickening is seen. The area around the mouth is often affected, with thinning of the lips and an inability to open the mouth fully. The lack of facial wrinkling may make patients appear younger than their actual age. Involved skin may show both hypo- and hyperpigmentation resulting in “salt and pepper” skin changes. Skin changes are often accompanied by Raynaud’s phenomenon, and fingertips may be cool and dusky, with loss of the usual digital pulp. With time, hyperkeratosis develops under the nails, which may be another clue to Raynaud phenomenon. Digital pits or scarring of the distal digital pulp is characteristic; some patients may have open ulcerations. Subcutaneous calcinosis can manifest as hard white lesions that uncommonly ulcerate with exudation of chalky material from open ulcers (see Calcinosis). Rarely, patients are seen without skin changes but with organ (usually GI) involvement only (scleroderma sine scleroderma).
—Musculoskeletal: Arthralgias and joint stiffness are common. Uncommonly, patients may initially display rheumatoid-like synovitis, with subsequent development of sclerodermal skin findings. Palpable tendon friction rubs are best felt over the flexor and extensor surface of the wrists, knees, or above the ankles and produce a palpable grating sensation with movement. Tendon friction rubs may be seen early in diffuse disease and are associated with increased incidence of organ involvement. Muscle weakness may be from muscle atrophy, fibrosis, or less commonly frank myositis.
—GI: Esophageal dysmotility with substernal dysphagia is common. Incompetence of the gastroesophageal sphincter leads to symptomatic reflux esophagitis. Common symptoms are heartburn and a sensation that food or pills are lodged in the chest behind the sternum. Involvement of the small bowel is less common and can produce a malabsorptive or blind loop syndrome. Colon abnormalities may contribute to constipation. Wide-mouthed diverticula commonly occur in the large intestine.
—Cardiopulmonary: Insidious development of interstitial lung involvement is common early in the course of diffuse disease and may lead to a restrictive defect seen on pulmonary function testing. If fibrosis is present, auscultatory dry rales may be appreciated on examination. By contrast, patients with limited scleroderma may develop acute-onset pulmonary hypertension late in the disease. Increased pulmonary pressures can contribute to right-sided heart failure. Pulmonary artery hypertension is an important cause of morbidity and mortality among affected patients.
—Renal: Kidney involvement, most common in the diffuse form, is an ominous finding and important cause of death in diffuse scleroderma. Renal (or hypertensive) crisis may herald the onset of rapidly progressive renal failure.
This syndrome includes very high blood pressure, headaches, visual disturbances, and heart failure. Renal crisis risk factors include cold exposure, steroid use, dehydration, rapid progression of skin disease, and pregnancy. Microscopic hematuria may be observed, and microangiopathic hemolytic anemia is usually present. Before the use of the angiotensin-converting enzyme inhibitors, this syndrome was uniformly fatal. The more widespread use of angiotensin-converting enzyme inhibitors has dramatically reduced the numbers of renal deaths in diffuse scleroderma. More than half of patients with renal crisis do well and avoid long-term dialysis; <20% die of this infrequent complication.
—Eyes/mouth: Secondary Sjögren’s syndrome occurs in a significant number of patients with scleroderma who are usually anti-SSA antibody positive and exhibit dry eyes and dry mouth.
—Thyroid: Hypothyroidism, present in approximately one-fourth of patients, is often clinically unrecognized. The thyroid gland shows fibrotic change. Hyperthyroidism is rare.
Uncommon Manifestations: Exudative pleural or pericardial effusions are rare. Intestinal pseudo-obstruction has been reported. Primary biliary cirrhosis appears to be increased in patients with the limited variant of scleroderma.
Diagnostic Tests: The diagnosis is made largely by history and physical examination. Laboratory information may provide supportive or prognostic information. More than 90% of patients are positive for ANAs. The nucleolar ANA pattern is common in patients with diffuse scleroderma, and the centromere pattern is characteristic of the limited (CREST syndrome) variant. Antibodies to Scl-70 are directed against topoisomerase-1 and are associated with the diffuse form. It should be noted that these antibodies are not diagnostic of the particular subtype of disease. Patients tend to have either anticentromere (limited disease) or anti-Scl-70 (diffuse disease) antibodies but not both. Nailfold capillaroscopy should be performed early in patients with Raynaud’s phenomenon or suspected scleroderma to help define the prognosis (patients with abnormal nailfold capillaries with dilated vessels and vascular dropout tend to have a worse prognosis). Periodic pulmonary function testing, including force vital capacity (FVC) and diffusion capacity (DLCO), is indicated in patients with diffuse disease and is an effective way to assess for the presence and impact of interstitial lung disease. Routine hemogram, chemistries, and urinalysis are most often indicated as part of drug monitoring. Echocardiography is indicated to assess the presence of pulmonary artery hypertension. However, the definitive assessment of pulmonary artery pressures is right heart catheterization. Measurement of exercise tolerance (e.g., as is done with the 6 minute walk test) is a useful method to quantify and to assess pulmonary abnormalities (both interstitial lung disease and pulmonary artery hypertension)
Imaging: Chest radiographs should be performed to evaluate pulmonary symptoms and may aid in diagnosis of pulmonary fibrosis. High-resolution CT scans may be used to further evaluate pulmonary fibrosis and may show a honeycomb (with pulmonary fibrosis) or ground-glass (with alveolitis) appearance. Esophageal studies such as barium swallow with a cineesophagram can identify lower esophageal dysmotility.
Keys to Diagnosis: Tightening of the skin, especially of the hands (sclerodactyly), associated with Raynaud’s phenomenon strongly suggests scleroderma, either limited or diffuse.
Differential Diagnosis: Eosinophilic fasciitis is a scleroderma variant in which skin tightening is most common in the extremities but spares the hands, feet, and face and is not associated with Raynaud’s phenomenon. Tight skin may also be caused by exposure to vinyl chloride, solvents, rapeseed oil, bleomycin, pentazocine, and tryptophan (eosinophil-myalgia syndrome). Pseudosclerodactyly refers to waxy or tight skin changes seen with diabetes or hypothyroidism. Scleromyxedema causes waxy tightening of the extremities and trunk. It is often associated with myopathy, monoclonal gammopathy, lymphoma, arthritis, neuropathy, and Sjögren’s syndrome. The cause is unknown.
Diagnostic Criteria: Prior classification schema for scleroderma has been proposed that includes patients with diffuse or limited forms of the disease while excluding other syndromes such as eosinophilic fasciitis (Table 41). However, it is estimated that 10% of patients in clinical practice who appear to have scleroderma do not fulfill these criteria.
Proposed Criteria for the Classification of Patients with Scleroderm
|A. Major criteria
Proximal scleroderma: skin thickening/induration proximal to the metacarpopha- langeal (or metatarsophalangeal) joints, in areas including face, neck, proximal extremities, and trunk
B. Minor criteria
|A diagnosis of scleroderma requires 1 major or 2 minor criteria.|
Therapy: Treatment of Raynaud’s phenomenon should include care to keep hands and feet warm with gloves or other coverings; these may be required at night as well as during the day. Tobacco should be discontinued and betablockers should be avoided. Biofeedback training or stress reduction techniques may be effective in limiting frequency or severity of the vasospastic episodes. Major dental procedures or appliances present a problem because of limitation of mouth excursion. Gastric reflux measures should be instituted, including elevating the head of the bed and avoiding late evening meals.
—Raynaud’s phenomenon: Vasodilating agents may be used, especially long- acting dihyropyridine calcium channel blockers such as nifedipine. High blood pressure is best treated with angiotensin-converting enzyme inhibitors.
—Corticosteroids: In the early stages of diffuse disease, when hands appear puffy or edematous, low doses of prednisone may be useful. However, data suggest that high doses of corticosteroids can lead to renal crisis or failure. Thus, steroids should be avoided in most patients.
—Penicillamine: Data from several uncontrolled studies show a reduction in skin thickening with penicillamine treatment. Beneficial effects on pulmonary and GI abnormalities have also been reported in retrospective studies. Thus, penicillamine is generally recommended in patients with early disease who manifest progressive skin changes, pulmonary compromise, or renal disease. A recent study did not show any clinical difference between low-dose (250–750 mg/day) and high-dose (1,000–1,500 mg/day) penicillamine. Unfortunately, a placebo-treated group was not included.
—Others: Use of other immunosuppressive drugs is not promising; no controlled trials suggest their benefit. Some investigators anecdotally advocate the use of cyclophosphamide with progressive pulmonary fibrosis and cyclosporine for rapidly advancing early disease. Agents such as chlorambucil, MTX, recombinant human relaxin, extracorporeal photopheresis, antithymocyte globulin, interferon alpha, minocycline, and Potaba (potassium aminobenzoate) have been tried but remain unproven. The efficacy and safety of autologous stem cell transplantation in scleroderma is under study. Methotrexate has been proven useful in treating the skin manifestations of children with localized scleroderma (morphea)
—Pulmonary Artery Hypertension treatment: There are several classes of therapy that are useful for the treatment of PAH, including endothelin receptor antagonists (bosentan, ambrisentan), phosphodiesterase 5 inhibitors (sildenafil, tadalafil) and prostanoids (iloprost, trepostinil, epoprostenol)
Surgery: Surgery is not generally indicated. Renal transplants have been relatively successful, and few patients have received heart or lung transplants.
Prognosis: The outcome is most closely related to the extent of significant organ involvement, especially lung and kidney. In one study, 5-year survival in patients without organ involvement was >90%; patients with pulmonary or renal involvement had survival rates of 70% and 50%, respectively. Patients with diffuse skin involvement show shorter survival times than those with limited involvement. Patients with diffuse disease are at risk of early progressive end-organ damage, and those with limited disease are at a small but significant risk of developing pulmonary hypertension or small bowel malabsorption.
van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis. 2013 Nov;72(11):1747-55. PMID:24092682 Walker KM1, Pope J; Scleroderma Clinical Trials Consortium; Canadian Scleroderma Research Group. Expert agreement on EULAR/EUSTAR recommendations for the management of systemic sclerosis. J Rheumatol. 2011 Jul;38(7):1326-8. PMID:21459952 Varga J. Systemic sclerosis: an update. Bull NYU Hosp Jt Dis. 2008;66(3):198-202. PMID:18937632 Denton CP, Black CM. Management of systemic sclerosis. In: Hochberg MC, Silman AJ, Smolen JS, et al., eds. Rheumatology, 3rd ed. Edinburgh: Mosby, 2003:1493–1506.
Masi AT, Rodnan GP, Medsger TA Jr, et al. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980;23:581–590.
Mayes MD. Scleroderma epidemiology. Rheum Dis Clin North Am 1996;22:751–764.PMID:8923594
Krieg T, Takehara K. Skin disease: a cardinal feature of systemic sclerosis. Rheumatology. 2009;48 Suppl 3:iii14-8. PMID:19487217