Through Genome-Wide Association Studies, Candidate Genes (Major Histocompatibility Complex (MHC), Fibrillin) Have Been Identified
Familial Clustering
Familial Clustering of Scleroderma Has Been Reported
Other Associated Genes
PTPN22 Gene
IRF8 Gene
TNFAIP3 (A20) Gene
IFN Regulatory Factor 5 Gene
STAT4 Gene
BANK1 Gene
CD247 Gene
TBX21 Gene
HLA-DPB1 and HLA-DPB2 Genes
IL-23 Receptor Gene
TNIP-1 Gene
Infection
Borrelia Burdorferi (see Lyme Disease): European studies have suggested an association of Borrelia Burdorferi infection with scleroderma (similar studies in the US fail to confirm this association)
Cytomegalovirus (CMV) (see Cytomegalovirus): CMV may induce some of the vascular, fibrotic, and immunologic features of scleroderma on various cell types
Epidemiology: outbreak of scleroderma-like illness in Madrid in 1981, associated with ingestion of rapeseed oil inadvertently contaminated with aniline
Outbreak of a scleroderma-like illness was noted in the late 1980’s, associated with L-tryptophan ingestion contaminated with 1,1′-ethylidenebis(tryptophan)
Sporadic Cases of Eosinophilia-Myalgia Syndrome without L-Tryptophan Exposure Has Also Been Reported
5-Hydroxytryptophan (5-OHTrp) (Contaminated by an Oxidation Product of 5-OHTrp Which Has Neurotoxic Properties) Has Also Been Associated with an Eosinophilia-Myalgia Syndrome-Like Disorder
Petroleum Derivatives
Convincing Association Exists Between Exposure to Petroleum Derivatives and the Development of Scleroderma
Silica Dust Exposure Has Been Implicated in the Development of Scleroderma, Based on Epidemiological Studies of Stone Masons, Gold Miners in South Africa, and Coal Miners in the US: however, since the use of vibrating machinery may cause Raynaud phenomenon and silica may cause interstitial lung disease, this association is uncertain
Silicone Breast Implants Have Not Been Found to Be Associated with the Development of Scleroderma
Microchimerism
While Normal Females Harbor Viable Immunologic Stem Cells of Fetal Origin for Years Following Pregnancy, the Number of Fetal Stem Cells is Higher in (Previously Pregnant) Female Patients with Scleroderma, as Compared to (Previously Pregnant) Controls
Graft vs Host Reaction: fetal cells mount an immune response against maternal tissues
Maternal Response to Fetal Cells May Be Subsequently Redirected Against Maternal Tissues
*Maternal Cells Crossing the Placenta and are Carried by the Fetus May Have an Immunomodulatory Role in Males with Scleroderma or Females (Who Have Never Been Pregnant) with Scleroderma
Anti-Centromere Antibody is Positive in 20-40% of Scleroderma Cases
Anti-Centromere Antibody is Positive in 57% of Limited Cutaneous Scleroderma
Anti-Centromere Antibody is Associated with the CREST Syndrome
Anti-Centromere Antibody is Positive in 70-80% of Limited Cutaneous Scleroderma Cases with Associated Pulmonary Hypertension
Anti-Centromere Antibody Appears to Be Protective Against the Development of Interstitial Lung Disease: it is rare to have both Scl-70 and anti-centromere antibodies
Specificity: anti-centromere antibody has high specificity for scleroderma
Anti-RNA Polymerase I/II/III Antibody (see xxxxx): may be present
Environmentally-Induced Scleroderma
Diffuse Skin Sclerosis with History of Exposure to an Environmental Agent Which Has Been Associated with Scleroderma
Overlap Syndrome
Features of Scleroderma Which Coexist with Features of Another Autoimmune Rheumatologic Disease (Systemic Lupus Erythematosus, Rheumatoid Arthritis, Dermatomyositis, Vasculitis, Sjogren’s Syndrome)
Cardiovascular Manifestations
General Comments
Cardiac Involvement in Scleroderma Has a Poor Prognosis: approximately 75% 5-year mortality rate
In all, 30 studies (288 patients) were included. Eleven therapeutic classes, surgery, and physical treatments were identified as potential treatment options for calcinosis cutis
On the basis of results of a small randomized controlled trial and 4 retrospective studies, low-dose warfarin should not be used for calcinosis cutis (level IB evidence)
The results of several studies suggest diltiazem and bisphosphonates might be useful treatment options (level IV)
Considering biologic therapies, rituximab has shown promising results in treating both dermatomyositis and systemic sclerosis, whereas tumor necrosis factor inhibitors might be useful for treating juvenile dermatomyositis (level IV)
Intralesional sodium thiosulfate might be a promising alternative (level IV)
Ulcerations over the distal interphalangeal joints (DIP) and proximal interphalangeal joints (PIP) related to repetitive microtrauma over tightened skin
May occur as the initial presentation of the disease (without pre-existing lung manifestations)
Treatment and Prognosis: most cases die within months, despite steroid therapy
Case reports describe the use of cyclosporin A + either prednisolone or cyclophosphamide
Airway Disease
Clinical
Bronchiectasis (see Bronchiectasis): cylindrical bronchiectasis is common on HRCT in scleroderma patients
Physiology
May be due to recurrent aspiration or traction bronchiectasis associated with interstitial lung disease
Bronchiolitis Obliterans (BO) (see Bronchiolitis Obliterans): although bronchiolitis obliterans has been described in scleroderma, it is likely due to treatment with penicillamine, rather than due to scleroderma itself (see Penicillamine)
Follicular Bronchiolitis (see Follicular Bronchiolitis): usually seen on lung biopsy in association with NSIP pathology
Obstructive Lung Disease (see Obstructive Lung Disease): tobacco abuse may be a contributing factor (although obstruction may occur in non-smoker scleroderma patients)
In reported cases, rapidly progressive glomerulonephritis was observed in 2 of 4 reported cases (rapidly progessive glomerulonephritis is otherwise uncommon in scleroderma)
The Extent of Interstitial Lung Disease Seen on HRCT is Inversely Correlated with the Forced Vital Capacity (FVC) and is Predictive of Mortality (Am J Respir Crit Care Med, 2008) [MEDLINE]
Non-Specific Interstitial Pneumonia (NSIP) Pattern (Fibrotic Type) (see Non-Specific Interstitial Pneumonia): most common pathologic pattern
Peripheral Ground-Glass Infiltrates (Starting in Dependent/Posterior Area of Lower Lobes): early in course
Volume Loss, Reticular Infiltrates, and Traction Bronchiectasis: late in course
Findings are Usually Similar to Fibrotic NSIP Pattern Above, But May Appear Similar to Typical UIP (with Bibasilar Reticular Opacities, Traction Bronchiectasis, and Subpleural Honeycombing)
Restrictive Pattern with Decreased Lung Compliance (Not Due to Chest Wall Skin Changes): common
Decreased DLCO: isolated decrease in DLCO may be seen early in course
DLCO Changes with Ambient Temperature Have Been Reported: consistent with “intrapulmonary Raynaud” phenomenon
Serology
Anticentromere Antibodies are Protective Against the Development of Scleroderma-Associated Interstitial Lung Disease (see Anticentromere Antibody) (Respir Med, 1996) [MEDLINE]
Antitopoisomerase-I (Anti-Scl-70) Antibodies are Associated with an Increased Risk of Scleroderma-Associated Interstitial Lung Disease (see Antitopoisomerase-I Antibody): (Arthritis Rheum, 2003) [MEDLINE]: sensitivity of 45%, specificity of 81%
Anti-U3 Ribonucleoprotein, Anti-U11/U12 Ribonucleoprotein, Anti-Th/To Antibodies are Associated with an Increased Risk of Scleroderma-Associated Interstitial Lung Disease
Serum CXCL4 Level (see Serum CXCL4): serum CXCL4 level correlates with presence and progression of both pulmonary fibrosis and pulmonary hypertension (NEJM, 2014) [MEDLINE]
Bronchoscopy with Bronchoalveolar Lavage (BAL) (see Bronchoscopy)
Useful Mainly to Exclude Infection or Other Interstitial Lung Diseases
Increased BAL Granulocytes, Mostly Neutrophils and Eosinophils (or Sometimes Increased Lymphocytes or Mast Cells), May Be Seen: unclear clinical significance of these findings
BAL Cell Counts Do Not Predict Outcome (NEJM, 2006) [MEDLINE]
Lung Biopsy (see Lung Biopsy): usually not necessary
Cardiopulmonary Exercise Test (see Cardiopulmonary Exercise Test): desaturation with increased PVR (even in absence of overt cor pulmonale)
Exercise Worsens V/Q Matching (Resulting in an Increase in the A-a Gradient) and Increases the VD/VT Ratio
Scleroderma Lung Study II of Mycophenolate Mofetil vs Cyclophosphamide in Scleroderma-Associated Interstitial Lung Disease (Lancet Respir Med, 2016) [MEDLINE]
Mycophenolate Mofetil (x 2 yrs) was Equivalent to Cyclophosphamide (x 1 yr) Over the 2 Year Study
Mycophenolate Mofetil was Better Tolerated than Cyclophosphamide
Cyclophosphamide (Cytoxan) (see Cyclophosphamide): second-line agent
Pneumocystis Jirovecii Prophylaxis (see Pneumocystis Jirovecii): recommended in conjunction with cyclophosphamide
Serum CXCL4 Level (see Serum CXCL4): serum CXCL4 level correlates with presence and progression of both pulmonary fibrosis and pulmonary hypertension [MEDLINE]
Serology
Absence of Antitopoisomerase-I Antibody (Anti-Scl-70 Antibody) (Arthritis Rheum, 2003) [MEDLINE]
Avoid Anticoagulation: due to risk of bleeding with telangiectasias
Diuretics: as indicated for fluid overload
Immunosuppression: usually not effective for scleroderma-associated pulmonary hypertension
Calcium Channel Blockers (see Calcium Channel Blockers): not likely to be useful in most patients, but may be considered the small subset of patients with pulmonary vasoreactivity on a vasodilator trial
Study of Effect of Riociguat on Connective Tissue Disease-Associated Pulmonary Hypertension (Ann Rheum Dis, 2017) [MEDLINE]: most patients had scleroderma-associated pulmonary hypertension
Riociguat Improved 6MWT Distance, WHC FC, Pulmonary Vascular Resistance, and Cardiac Index: improvements in 6MWT distance and WHO FC persisted at 2 yrs
Presence of Pulmonary Hypertension is a Risk Factor Increased Mortality in Scleroderma
Mortality Rate for Scleroderma-Associated Pulmonary Hypertension is Worse than that of Idiopathic Pulmonary Arterial Hypertension (IPAH): especially when associated with concomitant scleroderma-associated interstitial lung disease
Secondary Pulmonary Hypertension Due to Scleroderma-Associated ILD (see Pulmonary Hypertension)
Epidemiology: occurs early in the course of disease
Raynaud Phenomenon (see Raynaud Phenomenon): early nail bed capillary dilatation (abnormal loops with capillary “dropout”) may be seen before frank Raynaud’s
Calcinosis
Tendon Friction Rub Over Wrist: highly specific for scleroderma (but not sensitive)
Prognosis
Determined by extent of visceral disease
Mortality Rate: 0.9-1.5 per million men in US
Mortality Rate: 2.1-3.8 per million women in US
5-year Survival: 48-73%
5-year Survival after Any lung Involvement Occurs: 38-45%
Treatment
Treatment of Esophageal Dysmotility with GERD Symptoms
H2-blockers
PPI
Treatment of Interstitial Lung Disease
Steroids: case reports of decreased BAL cellularity, improved symptoms, increased lung volumes with steroid treatment
Long-term efficacy of steroid treatment is unclear
Cyclophosphamide: associated with improved pulmonary function and survival benefit in patients with scleroderma and alveolitis [Ann Intern Med 2000, 132: 947-954]
Imatinib (600 mg qday for 1 year): effective (increased TLC and DLCO), but has high incidence of adverse effects (fatigue, edema, nausea, vomiting, diarrhea, rash, proteinuria) [Arthritis Rheum 2011; 63: 3540-6]
Clinical Efficacy
Comparative Trial of Mycophenolate Mofetil vs Cyclophosphamide in Scleroderma-Associated Interstitial Lung Disease (Lancet Respir Med, 2016) [MEDLINE]: randomized, controlled trial of mycophenolate mofetil in scleroderma-related interstitial lung disease
Mycophenolate Mofetil Treatment (x 2 yrs), as Compared to Cyclophosphamide (x 1 yr), Resulted in Significant Improvements in Lung Function Over the 2 Year Course of the Study
Mycophenolate Mofetil was Associated with Less Toxicity and Better Tolerance than Cyclophosphamide
Mycophenolate Mofetil Exhibited a Longer Time to Patient Withdrawal than Cyclophosphamide
Mycophenolate Mofetil Had a Lower Incidence of Leukopenia/Thrombocytopenia than Cyclophosphamide
Stem Cell Transplant: effective in small series, may be useful
D-Penicillamine: prevents cross-linking of collagen and has immunosuppressive and anti-inflammatory properties
Improved 5 year survival, if given early in course
PFT improvement has been seen (but is preliminary)
29% of treated cases require discontinuation of drug due to SE
References
General
Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum. 2000;43(11):2437 [MEDLINE]
Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum 2005;52: 3792-800
Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis 2003;62:1088-93
Prevalence and characteristics of moderate to severe pulmonary hypertension in systemic sclerosis with and without interstitial lung disease. J Rheumatol 2007;34:1005-11
Evaluation of cardiac abnormalities by Doppler echocardiography in a large nationwide multicentric cohort of patients with systemic sclerosis. Ann Rheum Dis 2008;67:31-6
Cardiac involvement in systemic sclerosis assessed by tissue-doppler echocardiography during routine care: a controlled study of 100 consecutive patients. Arthritis Rheum 2008;58:1803-9
Diffuse Alveolar Damage: Uncommon Manifestation of Pulmonary Involvement in Patients With Connective Tissue Diseases. Chest 2006; 130:553–558
Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum 2005;52: 3792-800
Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis 2003;62:1088-93
Survival in systemic sclerosis-associated pulmonary arterial hypertension in the modern management era. Ann Rheum Dis. 2013 Dec 1;72(12):1940-6 [MEDLINE]
Proteome-wide Analysis and CXCL4 as a Biomarker in Systemic Sclerosis. N Engl J Med. 2014 Jan 30;370(5):433-43. doi: 10.1056/NEJMoa1114576. Epub 2013 Dec 18 [MEDLINE]
Diagnosis
Autoantibodies in systemic sclerosis. Semin Arthritis Rheum. 2005;35(1):35 [MEDLINE]
Clinical
General
xxxx
Cardiovascular Manifestations
Pattern and distribution of myocardial fibrosis in systemic sclerosis: a delayed enhanced magnetic resonance imaging study. Arthritis Rheum. 2007;56(11):3827 [MEDLINE]
Evaluation of cardiac abnormalities by Doppler echocardiography in a large nationwide multicentric cohort of patients with systemic sclerosis. Ann Rheum Dis. 2008;67(1):31. Epub 2007 Jan 31 [MEDLINE]
Gastrointestinal Manifestations
Esophageal involvement and pulmonary manifestations in systemic sclerosis. Arthritis Rheum. 2001;45(4):346 [MEDLINE]
Neurologic Manifestations
Transverse myelitis in systemic sclerosis. Arch Neurol. 2004;61(1):126 [MEDLINE]
Pulmonary Manifestations
Lung involvement in systemic sclerosis (scleroderma): relation to classification based on extent of skin involvement or autoantibody status. Respir Med. 1996;90(4):223 [MEDLINE]
A study of the frequency of pericardial and pleural effusions in scleroderma. Br J Rheumatol. 1998;37(12):1320 [MEDLINE]
Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl-70, and nucleolar antibodies. Arthritis Rheum. 2003;49(3):399 [MEDLINE]
Esophageal involvement and pulmonary manifestations in systemic sclerosis. Arthritis Rheum. 2001;45(4):346 [MEDLINE]
Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum. 2003;48(2):516 [MEDLINE]
Spontaneous pneumothorax in scleroderma. J Clin Rheumatol. 2004 Aug;10(4):207-9 [MEDLINE]
Pulmonary involvement in systemic sclerosis: associations with genetic, serologic, sociodemographic, and behavioral factors. Arthritis Rheum. 2007;57(2):318 [MEDLINE]
Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med. 2008;177(11):1248. Epub 2008 Mar 27 [MEDLINE]
Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. N Engl J Med. 2014;370(5):433. Epub 2013 Dec 18 [MEDLINE]
Systemic sclerosis increases the risks of deep vein thrombosis and pulmonary thromboembolism: a nationwide cohort study. Rheumatology (Oxford). 2014;53(9):1639 [MEDLINE]
Risk of Pulmonary Embolism and Deep Venous Thrombosis in Systemic Sclerosis: A General Population-Based Study. Arthritis Care Res (Hoboken). 2016 Feb;68(2):246-53 [MEDLINE]
Treatment
Calcinosis Cutis
Treatment of calcinosis cutis in systemic sclerosis and dermatomyositis: A review of the literature. J Am Acad Dermatol. 2020 Feb;82(2):317-325. doi: 10.1016/j.jaad.2019.07.006 [MEDLINE]
Lung Disease
Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006;354(25):2655 [MEDLINE]
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;4(9):708 [MEDLINE]
Combination therapy with Bosentan and Sildenafil improves Raynaud’s phenomenon and fosters the recovery of microvascular involvement in systemic sclerosis. Clin Rheumatol. 2016 Jan;35(1):127-32. doi: 10.1007/s10067-015-3119-3. Epub 2015 Dec 3 [MEDLINE]
Peripheral Arterial Disease
Improvement of peripheral artery disease with Sildenafil and Bosentan combined therapy in a patient with limited cutaneous systemic sclerosis: A case report. Medicine (Baltimore). 2017 Jun;96(25):e6988. doi: 10.1097/MD.0000000000006988 [MEDLINE]
Prognosis
Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum. 2000;43(11):2437 [MEDLINE]
Predictors of mortality and progression in scleroderma-associated interstitial lung disease: a systematic review. Chest. 2014 Aug;146(2):422-36 [MEDLINE]