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Systemic scleroderma

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What is Systemic Sclerosis (Scleroderma)?

Systemic Sclerosis (SSc), often referred to as scleroderma, is a chronic, complex autoimmune disease characterized by three cardinal features: vascular damage (microangiopathy), immune system activation (leading to autoantibody production), and excessive collagen deposition resulting in fibrosis (thickening and hardening) of the skin and internal organs (1, 2).

The term "scleroderma" literally means "hard skin," but SSc is a systemic condition, meaning it can affect various organ systems beyond the skin, including the gastrointestinal tract, lungs, heart, kidneys, and musculoskeletal system (1, 3). The clinical presentation and severity of SSc are highly variable among patients.

While the exact cause remains unknown, it is believed to result from an interplay of genetic susceptibility, environmental factors, and immune dysregulation (2).

Skin fibrosis (thickening and tightening) is a hallmark feature of Systemic Sclerosis (1).

Classification of Systemic Sclerosis

SSc is broadly classified based on the extent and pattern of skin involvement, which often correlates with the pattern of internal organ involvement and specific autoantibody profiles (1, 4):

  • Limited Cutaneous Systemic Sclerosis (lcSSc):
    • Skin thickening is restricted to areas distal to the elbows and knees (hands, forearms, feet, lower legs) and may also involve the face and neck.
    • Often associated with prominent Raynaud's phenomenon (may precede skin changes by years) and esophageal dysmotility.
    • Internal organ involvement tends to occur later and may include pulmonary arterial hypertension (PAH) and gastrointestinal issues.
    • Often associated with anti-centromere antibodies (ACA).
    • Formerly known in part as CREST syndrome (Calcinosis, Raynaud's, Esophageal dysmotility, Sclerodactyly, Telangiectasias), though lcSSc is the preferred term as it better reflects the systemic nature.
  • Diffuse Cutaneous Systemic Sclerosis (dcSSc):
    • Skin thickening is more widespread, affecting areas proximal to the elbows and knees (upper arms, thighs, trunk) in addition to distal areas and the face/neck.
    • Skin changes often progress more rapidly.
    • Higher risk of early and significant internal organ involvement, particularly interstitial lung disease (ILD), scleroderma renal crisis (SRC), severe gastrointestinal disease, and myocardial involvement.
    • Often associated with anti-topoisomerase I (Scl-70) or anti-RNA polymerase III antibodies.
  • Systemic Sclerosis Sine Scleroderma:
    • Patients exhibit Raynaud's phenomenon, characteristic autoantibodies, and internal organ involvement (e.g., ILD, PAH, GI disease) but lack clinically apparent skin thickening (1).
  • Overlap Syndromes: Patients may have features of SSc along with features of other connective tissue diseases like lupus, polymyositis, or rheumatoid arthritis.

Clinical Features

The signs and symptoms of SSc are diverse and depend on the subtype and organs affected (1, 3):

  • Raynaud's Phenomenon: Episodic vasospasm of digital arteries triggered by cold or stress, causing fingers/toes to turn white, then blue, then red upon rewarming. Present in >95% of patients, often the earliest symptom.
  • Skin Changes: Initial phase may involve puffy, swollen fingers/hands (edematous phase), followed by progressive thickening and tightening (fibrotic phase). Skin can become shiny, taut, and bound down, leading to reduced mobility (e.g., sclerodactyly - tightening of finger skin). Later, skin may soften somewhat (atrophic phase). Calcinosis (calcium deposits under the skin) and telangiectasias (dilated small blood vessels) can occur, especially in lcSSc.
  • Musculoskeletal: Arthralgia (joint pain), inflammatory arthritis, tendon friction rubs (a palpable or audible grating sensation over tendons, common in dcSSc), muscle weakness (myopathy).
  • Gastrointestinal: Affects >90% of patients. Symptoms include heartburn/reflux (GERD) due to esophageal dysmotility, difficulty swallowing (dysphagia), early satiety, bloating, constipation, diarrhea, and potential malabsorption or pseudo-obstruction.
  • Pulmonary: A leading cause of mortality. Main complications are:
    • Interstitial Lung Disease (ILD): Scarring/fibrosis of the lung tissue, causing cough and shortness of breath. More common and severe in dcSSc (especially Scl-70 positive).
    • Pulmonary Arterial Hypertension (PAH): High blood pressure in the lung arteries, leading to right heart strain/failure. Can occur in both lcSSc (often later) and dcSSc.
  • Cardiac: Myocardial fibrosis, pericarditis, arrhythmias, conduction system abnormalities, diastolic dysfunction.
  • Renal: Scleroderma Renal Crisis (SRC) - an uncommon but life-threatening complication characterized by abrupt onset of severe hypertension and rapidly progressive renal failure. More common in early dcSSc, particularly in those positive for anti-RNA polymerase III antibodies or on high-dose corticosteroids.
Raynaud's phenomenon, with distinct color changes in the digits upon cold exposure, is present in nearly all SSc patients (1).

Diagnosis

Diagnosing SSc involves integrating clinical findings, autoantibody profiles, and specific investigations (1, 5):

  • Clinical Evaluation: Thorough history focusing on Raynaud's, skin changes, and symptoms related to internal organs. Physical examination includes assessing the extent and severity of skin thickening (e.g., using the modified Rodnan skin score), checking for telangiectasias, calcinosis, digital ulcers, tendon friction rubs, and signs of organ involvement.
  • Laboratory Tests:
    • Antinuclear Antibody (ANA): Positive in >95% of SSc patients, usually in high titers with specific patterns (e.g., centromere, nucleolar, speckled) (1, 5). A negative ANA makes SSc less likely but does not exclude it completely.
    • SSc-Specific Autoantibodies: Crucial for diagnosis, classification, and prognosis. Key antibodies include:
      • Anti-centromere antibodies (ACA / Anti-CENP-B)
      • Anti-topoisomerase I (Anti-Scl-70) antibodies
      • Anti-RNA polymerase III antibodies
      • Others like anti-U1 RNP (seen in overlap), anti-Th/To, anti-U3 RNP (fibrillarin), anti-PM-Scl (seen in myositis overlap). These antibodies are generally mutually exclusive (1, 5, 6).
  • Nailfold Videocapillaroscopy: A non-invasive technique to visualize the capillaries at the base of the fingernails. Characteristic abnormalities (e.g., enlarged capillaries, capillary loss, hemorrhages) reflect the systemic microvascular damage and are highly suggestive of SSc or related conditions (1, 5).
  • Organ-Specific Investigations (Screening and Assessment):
    • Lungs: Pulmonary Function Tests (PFTs - especially FVC and DLCO) and High-Resolution Computed Tomography (HRCT) of the chest to detect and monitor ILD (1).
    • Heart: Echocardiogram to screen for PAH and assess cardiac function. ECG for arrhythmias. Cardiac MRI may be used (1).
    • Gastrointestinal: Barium swallow, esophageal manometry, endoscopy as indicated by symptoms.
    • Kidneys: Regular blood pressure monitoring and urinalysis (checking for proteinuria) are essential for early detection of SRC, especially in high-risk patients (1). Serum creatinine monitors kidney function.
  • Classification Criteria: The 2013 ACR/EULAR classification criteria for SSc can aid diagnosis, incorporating factors like skin thickening, finger pulp lesions, telangiectasias, abnormal nailfold capillaries, lung involvement (ILD/PAH), Raynaud's phenomenon, and SSc-related autoantibodies (5).

Role of Specific Antibodies (Anti-Centromere B, Anti-Topoisomerase I/Scl-70)

Identifying specific autoantibodies in SSc provides significant diagnostic and prognostic information (1, 6):

  • Anti-Centromere Antibodies (ACA / Anti-CENP-B):
    • Association: Strongly associated with Limited Cutaneous Systemic Sclerosis (lcSSc) (1, 6).
    • Clinical Correlations: Patients are more likely to have prominent vascular features like severe Raynaud's, digital ulcers, calcinosis, and telangiectasias. They have a lower risk of developing severe ILD or SRC compared to Scl-70 or RNAP III positive patients (1, 6).
    • Prognosis: Generally associated with a higher risk of developing Pulmonary Arterial Hypertension (PAH), often later in the disease course (1, 6). Overall survival may be better than in Scl-70 positive dcSSc, but PAH remains a serious complication.
    • Anti-centromere antibodies (ACA) are highly characteristic of limited cutaneous SSc (lcSSc) and associated with an increased risk of PAH (1, 6).

  • Anti-Topoisomerase I Antibodies (Anti-Scl-70):
    • Association: Strongly associated with Diffuse Cutaneous Systemic Sclerosis (dcSSc) (1, 6).
    • Clinical Correlations: Patients often have more rapid and extensive skin thickening, tendon friction rubs, and potentially joint contractures. They are at a significantly higher risk of developing severe Interstitial Lung Disease (ILD) (1, 6).
    • Prognosis: Generally associated with a poorer prognosis compared to ACA-positive patients, primarily due to the higher risk of progressive ILD and potential cardiac involvement (1, 6). Risk of SRC is lower than with RNAP III antibodies but still present.

Testing for these antibodies is a key part of the diagnostic workup, helping to classify the disease subtype and predict the likely pattern of organ involvement and long-term outlook.

Treatment Overview

Currently, there is no cure for SSc. Management focuses on a multidisciplinary approach aimed at (1, 7):

  • Managing symptoms (e.g., Raynaud's, GERD, pain).
  • Monitoring for and treating specific organ complications (e.g., ILD, PAH, SRC).
  • Slowing disease progression where possible, particularly skin and lung fibrosis.
  • Maintaining function and quality of life.

Treatment is highly individualized based on the disease subtype, severity, and specific organ systems involved. Strategies may include:

  • Vasoactive medications for Raynaud's phenomenon (e.g., calcium channel blockers, PDE5 inhibitors).
  • Proton pump inhibitors (PPIs) for GERD.
  • Immunosuppressive therapies (e.g., mycophenolate mofetil, cyclophosphamide, biologic agents like tocilizumab or rituximab, or antifibrotic agents like nintedanib) for significant ILD or sometimes severe skin disease (1, 7).
  • Specific therapies for PAH (e.g., endothelin receptor antagonists, PDE5 inhibitors, prostacyclin analogues).
  • ACE inhibitors for Scleroderma Renal Crisis (crucial for management) (1).
  • Physical and occupational therapy to maintain range of motion and function.

Differential Diagnosis

Conditions that may share features with SSc and need to be considered include (1, 8):

Condition Key Differentiating Features
Localized Scleroderma (Morphea) Fibrosis limited to the skin (patches or bands), without Raynaud's, typical SSc autoantibodies, or systemic organ involvement.
Eosinophilic Fasciitis Rapid onset of symmetrical limb swelling and induration ("peau d'orange" skin), often sparing hands/feet. Associated with peripheral eosinophilia. Fascial inflammation/thickening on biopsy/MRI. Raynaud's typically absent.
Nephrogenic Systemic Fibrosis (NSF) Occurs in patients with severe kidney disease, linked to gadolinium-based contrast agents. Causes skin thickening/hardening, often limbs/trunk, sparing the face. Raynaud's, typical SSc antibodies absent.
Mixed Connective Tissue Disease (MCTD) Overlap features of SSc (Raynaud's, puffy fingers), lupus, and polymyositis. High titers of anti-U1 RNP antibodies are characteristic.
Other CTDs (SLE, Myositis, RA) May have Raynaud's or some overlapping symptoms, but clinical picture and specific autoantibodies differ. Significant skin fibrosis is usually absent.
Diabetic Cheiroarthropathy Limited joint mobility and waxy skin thickening of hands in patients with long-standing diabetes. Raynaud's, typical SSc antibodies absent.

References

  1. Denton CP, Khanna D. Systemic sclerosis. Lancet. 2017;390(10103):1685-1699. doi:10.1016/S0140-6736(17)30933-9
  2. Allanore Y, Simms R, Dodds T, et al. Systemic sclerosis. Nat Rev Dis Primers. 2015;1:15002. doi:10.1038/nrdp.2015.2
  3. Varga J, Trojanowska M, Kuwana M. Pathogenesis of Systemic Sclerosis: Recent Insights of Molecular and Cellular Mechanisms. J Scleroderma Relat Disord. 2017;2(3):137-152. doi:10.5301/jsrd.5000269
  4. LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988;15(2):202-205.
  5. 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(11):2737-2747. doi:10.1002/art.38098
  6. Hamaguchi Y. Autoantibody profiles in systemic sclerosis: predictive value for clinical evaluation and prognosis. J Dermatol. 2010;37(1):42-53. doi:10.1111/j.1346-8138.2009.00762.x
  7. Kowal-Bielecka O, Fransen J, Avouac J, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017;76(8):1327-1339. doi:10.1136/annrheumdis-2016-209909
  8. Asano Y, Sato S. Vasculopathy in systemic sclerosis. Semin Immunopathol. 2015;37(5):479-490. doi:10.1007/s00281-015-0507-9 (Note: This reference covers vasculopathy, useful context for Raynaud's differentiation).