Systemic Sclerosis (Scleroderma)

The answer first

Systemic sclerosis (SSc, scleroderma) is a chronic multisystem autoimmune disease defined by three things happening together: microvascular injury, immune activation with autoantibody production, and fibroblast dysregulation causing excessive collagen deposition — the three-hit hypothesis. Those three processes explain every clinical feature, from Raynaud phenomenon and digital ulcers through to interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), gut dysmotility and scleroderma renal crisis. ^[1]

The single most important classification at the bedside is limited versus diffuse cutaneous disease, because it predicts the timing and type of internal-organ involvement: ^[1]

1. Limited cutaneous SSc (formerly CREST) — skin thickening confined to distal to the elbows and knees and the face; anti-centromere antibody; longstanding Raynaud; a later risk of pulmonary arterial hypertension, calcinosis and telangiectasia.
2. Diffuse cutaneous SSc — skin thickening proximal to the elbows or knees or on the trunk; anti-Scl-70 (anti-topoisomerase I) or anti-RNA polymerase III antibody; earlier and more severe internal-organ disease including ILD, cardiac disease and scleroderma renal crisis ^[1].

Three rules that change outcome: ^[1]

• Scleroderma renal crisis is an emergency in which an ACE inhibitor saves lives and kidneys. New-onset hypertension with AKI (and often microangiopathic haemolytic anaemia) in early diffuse disease demands captopril immediately, up-titrated against blood pressure, even if the blood pressure is normal and even as the creatinine rises ^[4]. Prednisolone at 15 mg per day or more is a recognised trigger — avoid it ^[3].
• Dyspnoea in systemic sclerosis demands a same-visit lung and heart assessment. ILD and PAH are the leading disease-specific causes of death and are often clinically silent until advanced. Screen with PFTs and HRCT for ILD, and with annual transthoracic echo (and confirm by right heart catheterisation) for PAH.
• There is no disease-modifying cure. Management is organ-based: immunosuppression (mycophenolate, cyclophosphamide) and antifibrotic therapy (nintedanib) for ILD ^[5][6]; vasodilator therapy for Raynaud and digital ulcers; PAH-specific therapy for pulmonary hypertension; and ACE inhibitors for renal crisis. Autologous haematopoietic stem cell transplant is considered for selected patients with severe early diffuse disease ^[8][9].

Survival has improved markedly over the past three decades, driven by ACE inhibitors for renal crisis, modern PAH therapy, ILD screening and immunosuppression. Five-year survival is now around 80 to 85 per cent overall, but it varies widely by subtype, antibody and organ involvement — which is why structured surveillance, not episodic care, defines good management. ^[1]

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References11ShowHide

1. [1]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.PMID 24122180
2. [2]Kowal-Bielecka O, Fransen J, Avouac J, et al. Update of EULAR recommendations for the treatment of systemic sclerosis Ann Rheum Dis, 2017.PMID 27941129
3. [3]Steen VD, Medsger TA Jr. Long-term outcomes of scleroderma renal crisis Ann Intern Med, 2000.PMID 11033587
4. [4]Steen VD, Costantino JP, Shapiro AP, Medsger TA Jr. Outcome of renal crisis in systemic sclerosis: relation to availability of angiotensin converting enzyme (ACE) inhibitors Ann Intern Med, 1990.PMID 2382917
5. [5]Tashkin DP, Roth MD, Clements PJ, et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial Lancet Respir Med, 2016.PMID 27469583
6. [6]Distler O, Highland KB, Gahlemann M, et al. Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease N Engl J Med, 2019.PMID 31112379
7. [7]Korn JH, Mayes M, Matucci Cerinic M, et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist Arthritis Rheum, 2004.PMID 15593188
8. [8]van Laar JM, Farge D, Sont JK, et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial JAMA, 2014.PMID 25058083
9. [9]Sullivan KM, Goldmuntz EA, Keyes-Elstein L, et al. Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma N Engl J Med, 2018.PMID 29298160
10. [10]Shah AA, Rosen A, Hummers LK, Wigley F, Casciola-Rosen L. Close temporal relationship between onset of cancer and scleroderma in patients with RNA polymerase I/III antibodies Arthritis Rheum, 2010.PMID 20506513
11. [11]Shah AA, Rosen A Cancer and systemic sclerosis: novel insights into pathogenesis and clinical implications Curr Opin Rheumatol, 2011.PMID 21825998