Diagnosis and differential diagnosis of systemic sclerosis (scleroderma) in adults
- John Varga, MD
John Varga, MD
- John and Nancy Hughes Professor of Medicine
- Northwestern University Feinberg School of Medicine
Systemic sclerosis (SSc) is a multisystem disease characterized by widespread vascular dysfunction and progressive fibrosis of the skin and internal organs. The diagnosis of SSc and related disorders is based primarily upon the presence of characteristic clinical findings, and supported by specific serologic abnormalities. The various cutaneous and visceral manifestations of SSc are discussed separately. (See "Overview of the clinical manifestations of systemic sclerosis (scleroderma) in adults".)
SSc is a heterogenous disease, but two distinct clinical subsets are traditionally recognized based on the extent of skin involvement: limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc). Patients with lcSSc typically have skin involvement distal to the elbows and knees, and may display features of the CREST syndrome (Calcinosis cutis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia). Patients with dcSSc generally have skin involvement extending to the proximal limbs and/or trunk. The classification of scleroderma disorders is discussed in detail separately. (See "Overview and classification of scleroderma disorders".)
This topic will review the diagnosis and differential diagnosis of SSc in adults. Localized scleroderma, scleroderma-like conditions, and scleroderma disorders in childhood are presented separately. (See "Localized scleroderma in childhood" and "Overview and classification of scleroderma disorders", section on 'Localized scleroderma'.)
EVALUATION FOR SUSPECTED SYSTEMIC SCLEROSIS
Systemic sclerosis (SSc) should be suspected in patients with skin thickening, puffy or swollen fingers, hand stiffness, and painful distal finger ulcers. Symptoms of Raynaud phenomenon (RP) and gastroesophageal reflux are often present (see "Clinical manifestations and diagnosis of the Raynaud phenomenon").
With the physical examination, the clinician should look for evidence of the following findings:
- Kavanaugh A, Tomar R, Reveille J, et al. Guidelines for clinical use of the antinuclear antibody test and tests for specific autoantibodies to nuclear antigens. American College of Pathologists. Arch Pathol Lab Med 2000; 124:71.
- Reveille JD, Solomon DH, American College of Rheumatology Ad Hoc Committee of Immunologic Testing Guidelines. Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl-70, and nucleolar antibodies. Arthritis Rheum 2003; 49:399.
- Hu PQ, Fertig N, Medsger TA Jr, Wright TM. Correlation of serum anti-DNA topoisomerase I antibody levels with disease severity and activity in systemic sclerosis. Arthritis Rheum 2003; 48:1363.
- Nguyen B, Mayes MD, Arnett FC, et al. HLA-DRB1*0407 and *1304 are risk factors for scleroderma renal crisis. Arthritis Rheum 2011; 63:530.
- Nikpour M, Hissaria P, Byron J, et al. Prevalence, correlates and clinical usefulness of antibodies to RNA polymerase III in systemic sclerosis: a cross-sectional analysis of data from an Australian cohort. Arthritis Res Ther 2011; 13:R211.
- Joseph CG, Darrah E, Shah AA, et al. Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science 2014; 343:152.
- Moinzadeh P, Fonseca C, Hellmich M, et al. Association of anti-RNA polymerase III autoantibodies and cancer in scleroderma. Arthritis Res Ther 2014; 16:R53.
- Russo K, Hoch S, Dima C, et al. Circulating anticentromere CENP-A and CENP-B antibodies in patients with diffuse and limited systemic sclerosis, systemic lupus erythematosus, and rheumatoid arthritis. J Rheumatol 2000; 27:142.
- Kuwana M, Okano Y, Pandey JP, et al. Enzyme-linked immunosorbent assay for detection of anti-RNA polymerase III antibody: analytical accuracy and clinical associations in systemic sclerosis. Arthritis Rheum 2005; 52:2425.
- Koenig M, Joyal F, Fritzler MJ, et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud's phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum 2008; 58:3902.
- Pakozdi A, Nihtyanova S, Moinzadeh P, et al. Clinical and serological hallmarks of systemic sclerosis overlap syndromes. J Rheumatol 2011; 38:2406.
- Locke IC, Worrall JG, Leaker B, et al. Autoantibodies to myeloperoxidase in systemic sclerosis. J Rheumatol 1997; 24:86.
- Merkel PA, Polisson RP, Chang Y, et al. Prevalence of antineutrophil cytoplasmic antibodies in a large inception cohort of patients with connective tissue disease. Ann Intern Med 1997; 126:866.
- Derrett-Smith EC, Nihtyanova SI, Harvey J, et al. Revisiting ANCA-associated vasculitis in systemic sclerosis: clinical, serological and immunogenetic factors. Rheumatology (Oxford) 2013; 52:1824.
- Connolly MK. Systemic Sclerosis. In: Dermatology, Third, Bolognia JL, Jorizzo JL, Schaffer JV. (Eds), Elsevier Saunders, 2012. Vol 2.
- Poormoghim H, Lucas M, Fertig N, Medsger TA Jr. Systemic sclerosis sine scleroderma: demographic, clinical, and serologic features and survival in forty-eight patients. Arthritis Rheum 2000; 43:444.
- Diab S, Dostrovsky N, Hudson M, et al. Systemic sclerosis sine scleroderma: a multicenter study of 1417 subjects. J Rheumatol 2014; 41:2179.
- Simeón-Aznar CP, Tolosa-Vilella C, Gabarró-Juliá L, et al. Systemic sclerosis sine scleroderma and limited cutaneous systemic sclerosis: similarities and differences. Clin Exp Rheumatol 2014; 32:S.
- Marangoni RG, Rocha LF, Del Rio AP, et al. Systemic sclerosis sine scleroderma: distinct features in a large Brazilian cohort. Rheumatology (Oxford) 2013; 52:1520.
- 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; 72:1747.
- 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. Arthritis Rheum 2013; 65:2737.
- Lonzetti LS, Joyal F, Raynauld JP, et al. Updating the American College of Rheumatology preliminary classification criteria for systemic sclerosis: addition of severe nailfold capillaroscopy abnormalities markedly increases the sensitivity for limited scleroderma. Arthritis Rheum 2001; 44:735.
- Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1980; 23:581.
- LeRoy EC, Medsger TA Jr. Criteria for the classification of early systemic sclerosis. J Rheumatol 2001; 28:1573.
- Avouac J, Fransen J, Walker UA, et al. Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group. Ann Rheum Dis 2011; 70:476.
- Minier T, Guiducci S, Bellando-Randone S, et al. Preliminary analysis of the very early diagnosis of systemic sclerosis (VEDOSS) EUSTAR multicentre study: evidence for puffy fingers as a pivotal sign for suspicion of systemic sclerosis. Ann Rheum Dis 2014; 73:2087.
- Moinzadeh P, Aberer E, Ahmadi-Simab K, et al. Disease progression in systemic sclerosis-overlap syndrome is significantly different from limited and diffuse cutaneous systemic sclerosis. Ann Rheum Dis 2015; 74:730.
- EVALUATION FOR SUSPECTED SYSTEMIC SCLEROSIS
- Laboratory testing
- Additional studies
- Systemic sclerosis
- Systemic sclerosis sine scleroderma
- Systemic sclerosis classification criteria
- - 2013 Classification criteria
- - Preliminary criteria for early diagnosis
- DIFFERENTIAL DIAGNOSIS
- Causes of scleroderma-like skin changes
- Raynaud phenomenon
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS