Epidemiology
- Incidence: 2-30 per 100k/yr
- Prevalence: 30-120 per 100k
- Age: peak in 30’s-50’s
- Sex: 3:1 to 8:1 female predominance
- Genetics
- Familial Clustering: has been reported, as with other autoimmune diseases
- However, there are very few reports of first-degree relatives having scleroderma
- Association with between HLA-DR3, HLA-DR52a, HLA-DRB111, and HLA-DPB11303 and interstitial lung disease
- Familial Clustering: has been reported, as with other autoimmune diseases
Etiology
- Drug/Toxin-Induced Scleroderma
- Penicillamine (see Penicillamine, [[Penicillamine]])
- L-Tryptophan (see Eosinophilia-Myalgia Syndrome, [[Eosinophilia-Myalgia Syndrome]])
- Bleomycin (see Bleomycin, [[Bleomycin]])
- Pentazocine (see Pentazocine, [[Pentazocine]])
- Contaminated Rapeseed Oil (see Contaminated Rapeseed Oil, [[Contaminated Rapeseed Oil]]): outbreak in Madrid in 1981, associated with ingestion of rapeseed oil inadvertently contaminated with aniline
- Vinyl Chloride Exposure (see Vinyl Chloride, [[Vinyl Chloride]]): especially in men
- Benzene Exposure (see Benzene, [[Benzene]]): especially in men
- Toluene Exposure (see Toluene, [[Toluene]]): especially in men
- Trichloroethylene (see Trichloroethylene, [[Trichloroethylene]]): especially in men
- Silica Exposure: has been shown to increase risk of scleroderma (but etiologic role is unclear)
- Silicosis (see Silicosis, [[Silicosis]]): has been shown to even further increase risk of scleroderma, over that of exposure alone
- Idiopathic Scleroderma: unknown pathogenesis, but probably involves immunologic factors
(silicone breast implants have not been found to be associated with scleroderma)
Physiology
- Scl-70 Antibody: association with allele of the JHLA-DPB1 gene
- In patients with Scl-70-responsive T-cell clones, the presence of this antibody may drive the immune response
- BAL Cytokines Involved in Lung Inflammatory Cascade: IL-8 (increases neutrophil chemotaxis), TNF-alpha, MIP-1alpha, RANTES, endothelin-1, coagulation cascade proteins
- Increased Collagen Production: TGF-beta -> connective tissue growth factor
- Pulmonary HTN can occur due to:
- Pulmonary Vasculitis: PPH-like picture may occur in 10% of CREST cases (this is higher incidence than in diffuse scleroderma) in absence of ILD
- Advanced Interstitial Lung Disease:
Diagnosis
Erythrocyte Sedimentation Rate (ESR) (see Erythrocyte Sedimentation Rate, [[Erythrocyte Sedimentation Rate]])
- Usually Elevated
Complete Blood Count (see Complete Blood Count, [[Complete Blood Count]])
- Leukocytosis (see Leukocytosis, [[Leukocytosis]])
- Iron Deficiency Anemia (see Iron Deficiency Anemia, [[Iron Deficiency Anemia]])
- Microangiopathic Hemolytic Anemia (MAHA) (see Hemolytic Anemia, [[Hemolytic Anemia]]): can occur in association with renal involvement
CXCL4 Level
- Elevated: CXCL4 level is correlated with presence and progression of both pulmonary fibrosis and pulmonary hypertension [MEDLINE]
Serology
Anti-Nuclear Antibody (ANA)
- Significance of Positivity
- ANA is Positive in 90-100% of Scleroderma Cases
Anti-Centromere
- Target: L centromere proteins (CENP A-F)
- Significance of Positivity
- 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
Scl-70
- Target: DNA topoisomerase I
- Significance of Positivity
- Scl-70 is Positive in 28-70% of Scleroderma Cases: however, there is wide racial variation
- Scl-70 is Positive in 40% of Diffuse Cutaneous Scleroderma Cases with Associated Interstitial Lung Disease
- Scl-70 Increases the Risk of Scleroderma-Associated Interstitial Lung Disease by 16.7x
PM-Scl
- Significance of Positivity
- PM-Scl is Present in Scleroderma-Myositis Overlap Syndromes
- Anti-Nucleolar: targets RNA polymerase I
- Positive in 8-20% of scleroderma cases
- Presence predicts poorest 10-year survival and renal crises
- High specificity for scleroderma
- Ku: targets DNA binding proteins
- Anti-Nucleolar: targets RNA polymerase I
- PM-Scl is Present in Scleroderma-Myositis Overlap Syndromes
U1-RNP
- Target: small nuclear proteins
- Significance of Positivity
- U1-RNP is Positive in 8% of Cases
- U1-RNP is Positive in 14% of Limited Cutaneous Scleroderma Cases
- U1-RNP is Positive in 3% of Diffuse Cutaneous Scleroderma Cases
- U1-RNP is Correlated with the Presence of Interstitial Lung Disease and Joint Involvement
Anti-U3 Nucleolar RNP
- Significance of Positivity
- Anti-U3 Nucleolar RNP is Highly Specific for Scleroderma
- Anti-U3 Nucleolar RNP is More Common in African-Americans
- Anti-U3 Nucleolar RNP is Associated with Skeletal Muscle Disease and Pulmonary Hypertension
Rheumatoid Factor (RF)
- Present at Low Titer in 25% of Scleroderma Cases
Circulating Immune Complexes
- Positive in Patients with Pulmonary Involvement
Ventilation-Perfusion (V/Q) Scan
- Decreased Perfusion After Cold Exposure (Intrapulmonary Raynaud’s)
Clinical Variants of Scleroderma
- Morphea: single or multiple plaques of skin induration
- Linear Scleroderma: isolated skin involvement of extremity or face
- Limited Cutaneous Scleroderma: symmetric skin thickening limited to distal extremities and face
- Overall better prognosis (although pulmonary hypertension and biliary cirrhosis: occur in small subset)
- CREST Syndrome: calcinosis, Raynaud’s, esophageal dysmotility, sclerodactyly, and telangiectasia
- Diffuse Cutaneous Scleroderma: rapid development of symmetric skin thickening of proximal and distal extremities, face, and trunk
- Increased risk of visceral disease early in course
- Systemic Sclerosis without Scleroderma: visceral involvement without skin involvement
- Overlap Syndrome: presence of scleroderma with features of other connective tissue disease
- Undifferentiated Connective Tissue Disease: patients that do not meet criteria for any connective tissue disease
Clinical Criteria
- Major Criteria
- Thickening of Skin of Hands
- Minor Criteria
- Sclerodactyly: thickening of skin limited to the fingers
- Digital Pitting Scars or Loss of Substance from Finger Pads: depressed areas at tips of fingers or loss of digital pad tissue due to ischemia
- Bibasilar Pulmonary Fibrosis
Clinical Manifestations
Dermatologic Manifestations
- General Comments: dermatologic involvement is common
- Vasculitis: common
- Telangiectasia
- Sclerodactyly: fusion of dermis of fingers and hands to underlying fascia
Rheumatologic Manifestations
- Raynaud’s Phenomenon (see Raynaud’s Phenomenon, [[Raynauds 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)
Gastrointestinal Manifestations (common)
- Esophagitis:
- Esophageal Dilatation and Dysmotility: often with GERD (correlation between severity of GERD and severity of lung involvement)
- Evaluate with manometry/cine-esophagram
- Small Bowel/Colonic Dysmotility: may present with constipation, pseudo-obstruction
- Malabsorption:
Pulmonary Manifestations
General Comments
- Lung is the 4th most involved organ
- In rare cases, pulmonary involvement can precede skin involvement by years
Interstitial Lung Disease (see Interstitial Lung Disease-Etiology, [[Interstitial Lung Disease-Etiology]])
- Epidemiology
- ILD is the most common lung manifestation: extent of skin involvement does not predict the extent of lung involvement
- Present in 14-67% of cases by radiographic studies, 32-90% of cases by PFT studies, and 80% of cases by autopsy studies
- Diagnosis
- CXCL4 Levels: correlate with presence and progression of both pulmonary fibrosis and pulmonary hypertension [MEDLINE]
- ABG: increased A-a gradient hypoxemia/hypocapnia
- CXR: abnormal in 25-67% of cases
- Chest CT: basilar, posterior, and subpleural-predominant
- Ground-glass infiltrates vs reticulonodular infiltrates appear to correlate with type of BAL cellular infiltrate
- More reticulonodular infiltrates correlate with higher degrees of BAL neutrophilia
- Honeycombing occurs in 33% of cases (radiographic honeycombing correlates well with pathologic honeycombing)
- CT findings correlate well with PFT findings
- Ground-glass infiltrates vs reticulonodular infiltrates appear to correlate with type of BAL cellular infiltrate
- Calcified granuloma: (seen in 67% of CREST cases but only 14% in diffuse Scleroderma)
- HRCT: detects 45-75% of cases of scleroderma-associated ILD where initial CXR is normal
- Picture mimics that of IPF
- Gallium Scan no diagnostic value
- Technetium-DTPA Clearance Study: has been used to predict prognosis in some centers (more rapid clearance indicates more disrupted epithelial integrity consistent with interstitial lung disease -> predicts worse prognosis)
- PFT’s (abnormal in 90% of cases): restriction with decreased lung compliance (not due to chest wall skin changes)
- DLCO: isolated decrease may be seen, particularly early in course (DLCO changes have been seen with changes in ambient temperature: intrapulmonary Raynaud’s phenomenon)
- MIP, MEP: commonly decreased
- Loss of VC correlates with active alveolitis on BAL
- Rate of decline in VC are higher within 2 yrs of onset of disease: making early diagnosis important
- Lower FVC within 3 yrs of disease onset predicts a decline in PFT’s
- Exercise Testing: desaturation with increased PVR (even in absence of overt cor pulmonale)
- Exercise -> worsens V/W matching -> increased A-a gradient
- Exercise -> increased VD/VT
- FOB-BAL: alveolitis may occur prior to onset of pulmonary symptoms
- More reticulonodular infiltrates correlate with higher degrees of BAL neutrophilia
- BAL should not be used for diagnosis or monitoring of scleroderm-associated ILD
- TBB offers no diagnostic information
- Presence of Scl-70 Antibody: increases risk of scleroderma-associated ILD by 16.7x
- OLB: usually not necessary (if CT and clinical pattern of disease is atypical or extensive pleural disease is seen, OLB may be required)
- Most common pattern: non-specific interstitial pneumonia pattern (NSIP-type pattern)
- Less common pattern: usual interstitial pneumonia pattern (UIP-type pattern)
- Clinical
- Dyspnea (21-80% of cases)
- Non-productive dry cough
- Bibasilar fine “velcro” crackles
- Hemoptysis (rare)
- Clubbing (extremely rare)
- Absence of pleural rub
- Treatment
- Supportive Therapy: oxygen therapy, treatment of infection, etc
- Corticosteroids (equivalent to prednisolone 10 qday) + Cyclophosphamide (2 mg/kg/day PO, max: 150 mg/day): proven to improve lung function and prognosis
- Scleroderma Lung Study (placebo-controlled trial): PO cyclophosphamide improved FVC, skin scores, QOL, and dyspnea scores at 12 months
- Monitor: urinalysis (for hematuria), CBC, LFT’s
- Pulsed IV Cyclophosphamide (750-1000 mg/m2 q2-4 wks for 6-12 months): may have better side effect profile than PO cyclophosphamide
–Cyclophosphamide (Cytoxan) (see Cyclophosphamide, [[Cyclophosphamide]])
- Interferon-gamma (placebo-controlled trial): worse lung function at 12 months
- Mycophenolate Mofetil (Cellcept) (see Mycophenolate Mofetil, [[Mycophenolate Mofetil]]): equivalent benefit to cyclophosphamide
- PCP Prophylaxis (see Pneumocystis Jirovecii, [[Pneumocystis Jirovecii]]): probably recommended in conjunction with immunosuppressives
- Association of Corticosteroid Therapy with Renal Crises: however, this may be confounded by the fact that patients with more severe disease are more likely to receive steroids
- Lung Transplantation: has been used in cases where other organs are spared
- Prognosis
- Lung disease is the most common cause of death in scleroderma (accounting for 21% of deaths in some series)
- Prognosis depends on lung function (particularly DLCO and VC) and CT findings at presentation
- CT involvement <20% and VC >70% pred -> limited disease: lower risk of progression and death
- CT involvement >20% and VC <70% pred -> extensive disease: higher risk of progression and death
- Crude Mortality Rates: 3.9%/yr for men and 2.6%/yr for women
- 5-Year Survival: 85%
- 10-Year Survival: 60%
Pulmonary Hypertension (see Pulmonary Hypertension, [[Pulmonary Hypertension]])
- Epidemiology
- Incidence of pulmonary hypertension in Scleroderma: 7-12%
- However, pulmonary vascular disease in seen in 30% of cases in autopsy studies
- Isolated pulmonary pulmonary hypertension occurs mainly in Limited Cutaneous Scleroderma and CREST syndrome
- Pathology: concentric fibrosis of small arterioles (absence of plexiform lesions and fibrinoid necrosis, which are seen in idopathic pulmonary arterial hypertension)
- Diagnosis
- CXCL4 Levels: correlate with presence and progression of both pulmonary fibrosis and pulmonary hypertension [MEDLINE]
- Positive Anti-Centromere Antibody: present in 70-80% of Limited Cutaneous Scleroderma cases with associated pulmonary hypertension
- Normal CXR/Chest CT and FOB-BAL
- PFT’s: decreased DLCO (risk of pulmonary hypertension increases with DLCO <50% pred)
- Technetium-DTPA Clearance Study: usually normal in pulmonary vascular disease (while increased clearance is seen in interstitial lung disease) -> may help to differentiate cases with isolated decreased DLCO on PFT’s
- Echo: 47-88% sensitivity for detection of pulmonary hypertension in scleroderma (less accurate at borderline low and high PA pressures)
- Stress Echo: may be useful to detect early (preclinical) pulmonary hypertension
- Swan: diagnostic
- NT-proBNP: elevated in scleroderma and inversely related to gas transfer -> may predct development of pulmonayr hypertension
- Clinical: dyspnea, hypoxemia
- Treatment
- Calcium-Channel Blockers: useful, if escalating doses are tolerated
- ACE-I: may be useful
- Prostacyclin Analogues (Flolan, inhaled iloprost): improve exercise tolerance and PA pressures
- Endothelin-1 Receptor Antagonist (bosentan): improve exercise capacity and hemodynamics in connective tissue disease-associated pulmonary hypertension
- Phosphodiesterase-5 Inhibitor (sildenafil): improve exercise capacity and hemodynamics in connective tissue disease-associated pulmonary hypertension
- Imatinib (platelet-derived growth factor antagonist): promising data from animal studies
- Prognosis: worse prognosis correlates with increasing pulmonary hypertension
- French PAH Network Study (2013): main prognostic Factors were age, male sex, and cardiac index [MEDLINE]
Secondary Pulmonary Hypertension Due to Scleroderma-Associated ILD (see Pulmonary Hypertension, [[Pulmonary Hypertension]])
- Right-Sided Heart Failure: elevated JVP, lower extremity edema, etc
Acute Lung Injury-ARDS (see Acute Lung Injury-ARDS, [[Acute Lung Injury-ARDS]])
- Diagnosis
- HRCT -> diffuse ground-glass infiltrates and/or consolidation, reticular infiltrates, honeycombing (mimics accelerated idiopathic pulmonary fibrosis)
- OLB: diffuse alveolar damage
- Clinical: acute respiratory deterioration
- 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
Thoracic Cage Restriction (see PFT-Restriction, [[PFT-Restriction]])
- Due to skin tightness over chest wall, limiting thoracic cage expansion during inspiration
- PFT’s: restriction
Obstructive Lung Disease (see Obstructive Lung Disease, [[Obstructive Lung Disease]])
- May occur in non-smoking patients without other lung disease
- PFT’s: obstruction has been reported in some cases of scleroderma (with decreased MVV, increased RV/TLC ratio, decreased FEF25-75 and FEV1/FVC ratio)
Bronchiolitis (see Bronchiolitis, [[Bronchiolitis]])
- xxx
Aspiration Pneumonia (see Aspiration Pneumonia, [[Aspiration Pneumonia]])
- Increased risk, due to esophageal dysmotility
Diffuse Alveolar Hemorrhage (DAH) (see Diffuse Alveolar Hemorrhage, [[Diffuse Alveolar Hemorrhage]])
- Epidemiology: uncommon -> only 4 reported cases of DAH associated with scleroderma
- Diagnosis
- CXR/Chest CT: alveolar infiltrates (diffuse or patchy)
- OLB: pulmonary capillaritis may be seen
- Clinical
- Hemoptysis
- In reported cases, rapidly progressive glomerulonephritis was observed in 2 of 4 reported cases (rapidly progessive glomerulonephritis is otherwise uncommon in scleroderma)
Pleuritis (see Pleural Effusion-Exudate, [[Pleural Effusion-Exudate]])
- Uncommon
- Diagnosis: pleural effusion or pleural fibrosis (10-25% of cases)
Scar Lung Carcinoma (see Lung Cancer, [[Lung Cancer]])
- Uncommon
- Pathology: bronchioloalveolar or adenocarcinoma
Cryptogenic Organizing Pneumonia (COP) (see Cryptogenic Organizing Pneumonia, [[Cryptogenic Organizing Pneumonia]])
- Uncommon
- Treatment: corticosteroids
Spontaneous Pneumothorax (see Pneumothorax, [[Pneumothorax]])
- Rare
Ocular Manifestations
- Scleritis
Renal Manifestations
- Hypertension (see Hypertension, [[Hypertension]]): measure plasma renin
- Scleroderma Renal Crisis (occurs in 13% of untreated cases): severe increases in BP
- 50% mortality rate in those with renal crisis within 5 yrs, even with treatment
- Predictors of renal crisis: higher than average skin score, large joint contractures, cardiac enlargement
Cardiac Manifestations
- Heart Blocks (see Heart Blocks, [[Heart Blocks]])
- Cardiomyopathy (see Congestive Heart Failure, [[Congestive Heart Failure]]): with systolic CHF
Hematologic Manifestations
- Mild Thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]])
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]
Treatment of Pulmonary Hypertension (see Pulmonary Hypertension, [[Pulmonary Hypertension]])
- Outcome of pulmonary HTN associated with scleroderma is worse than that from IPAH (despite pharmacologic therapy)
- Oxygen:
- Anticoagulants:
- Diuretics:
- Epoprostenol:
- Bosentan (endothelin-1 receptor inhibitor):
- Sildenafil: effective (acts synergistically with inhaled iloprost)
- Inhaled iloprost: may be effective by both vascular and anti-fibrotic mechanisms (Stratton, 2001)
Treatment of Hypertension
- ACE-Inhibitors:
- Diuretics:
Treatment of Raynaud’s
- Avoid Smoking: it can exacerbate vasospasm and precipitate digital ulcers, necrosis
- Avoid Beta Blockers: these can exacerbate Raynaud’s
- Long-Acting Calcium-Channel Blockers: can retard progression of digital ulcers
- Protective Measures: gloves with cold exposure, etc.
- Anticoagulation: may be used in cases with digital ulcers and ischemia
Treatment of Skin Disease
- UVA: may be useful
- 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
- Hachulla E, Gressin V, Guillevin L, et al. Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum 2005;52: 3792-800
- Mukerjee D, St George D, Coleiro B, et al. Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis 2003;62:1088-93
- Launay D, Mouthon L, Hachulla E, et al. Prevalence and characteristics of moderate to severe pulmonary hypertension in systemic sclerosis with and without interstitial lung disease. J Rheumatol 2007;34:1005-11
- de Groote P, Gressin V, Hachulla E, et al. 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
- Meune C, Avouac J, Wahbi K, et al. 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
- Hachulla E, Gressin V, Guillevin L, et al. 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]