Scleroderma (Progressive Systemic Sclerosis)

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

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

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
    • 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

Hematologic Manifestations


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]