Epidemiology

Demographics

• 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

Risk Factors

Genetic Factors

• Genome-Wide Association Studies
  • 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

Drugs

• Bleomycin (see Bleomycin)
  • Epidemiology
    • Bleomycin Induces Scleroderma-Like Skin and Lung Changes In Animal Models
    • Human Cases Have Been Reported
• Cocaine (see Cocaine)
  • Epidemiology: potential association with the development of scleroderma
• Penicillamine (see Penicillamine
• Pentazocine (see Pentazocine)
  • Epidemiology: potential association with the development of scleroderma
• Taxanes (see Taxanes)
  • Epidemiology: potential association with the development of scleroderma
  • Agents
    • Docetaxel (Taxotere) (see Docetaxel)
    • Paclitaxel (Taxol) (see Paclitaxel)

Environmental Exposures

• Contaminated Rapeseed Oil (see Contaminated Rapeseed Oil)
  • Epidemiology: outbreak of scleroderma-like illness in Madrid in 1981, associated with ingestion of rapeseed oil inadvertently contaminated with aniline
• Contaminated L-Tryptophan (see Eosinophilia-Myalgia Syndrome)
  • Epidemiology
    • 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
    • Benzene (see Benzene): hydrocarbon
    • Paint Thinners: hydrocarbon
    • TCE: chlorinated solvent which has a similar structure to polyvinyl chloride (PVC)
    • Toluene (see Toluene)
    • Trichloroethane (TCA) (see Trichloroethane): chlorinated solvent
    • Xylene (see Xylene)
• Polyvinyl Chloride (PVC)n (see Polyvinyl Chloride)
  • Epidemiology
    • Exposure to Vinyl Chloride Monomer is Associated with the Development of a Scleroderma-Like Disease
    • Especially in Men
• Silica (Silicon Dioxide) Dust (see Silicosis)
  • 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

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Physiology

• Antitopoisomerase-I Antibody (Anti-Scl-70 Antibody) (see Antitopoisomerase-I Antibody)
  • XXXX

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Diagnosis

Erythrocyte Sedimentation Rate (ESR) (see Erythrocyte Sedimentation Rate)

• Usually Elevated

Complete Blood Count (see Complete Blood Count)

• Leukocytosis (see Leukocytosis)
• Iron Deficiency Anemia (see Iron Deficiency Anemia)
• Microangiopathic Hemolytic Anemia (MAHA) (see Hemolytic Anemia): can occur in association with renal involvement

CXCL4 Level

• Elevated: CXCL4 is anti-androgenic chemokine
  • CXCL4 Level is Correlated with More Advanced Skin Involvement [MEDLINE]
  • CXCL4 Level is Correlated with Presence and Progression of Both Pulmonary Fibrosis and Pulmonary Hypertension [MEDLINE]

Serology

Antinuclear Antibody (ANA) (see Antinuclear Antibody)

• Significance of Positivity
  • ANA is Positive in 90-100% of Scleroderma Cases

Anticentromere Antibody (ACA) (see Anticentromere Antibody)

• 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

Antitopoisomerase-I Antibody (Anti-Scl-70) (see Antitopoisomerase-I Antibody)

• 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

Anti-PM/Scl Antibody

• 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-U1-RNP Antibody

• 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 Antibody

• 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) (see Rheumatoid Factor)

• Present at Low Titer in 25% of Scleroderma Cases

Circulating Immune Complexes (see xxxxx)

• Positive in Patients with Pulmonary Involvement

Ventilation-Perfusion (V/Q) Scan (see Ventilation-Perfusion Scan)

• Decreased Perfusion After Cold Exposure (Intrapulmonary Raynaud’s)

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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

Clinical Classification

Prescleroderma

• Digital Ischemia (see Mucocutaneous Ulcers)
• Nailfold Capillary Changes: early or active pattern is typical
• Raynaud Phenomenon (see Raynaud Phenomenon)
• Antibodies
  • Antitopoisomerase-I Antibody (Anti-Scl-70) (see Antitopoisomerase-I Antibody)
  • Anticentromere Antibody (ACA) (see Anticentromere Antibody)
  • Anti-RNA Polymerase I/II/III Antibody (see xxxxx)

Limited Cutaneous Scleroderma

• Interstitial Lung Disease (see Interstitial Lung Disease)
  • Epidemiology: may occur in some cases
• Nailfold Capillary Pattern Typical of Scleroderma: predominantly nailfold capillary loops with capillary dropout
• Pulmonary Hypertension (see Pulmonary Hypertension): may occur late in course in 10-15% of cases
• Renal Disease: rarely occurs
• Skin Involvement Limited to Hands/Feet/Forearms (Acral Distribution) and Face/Neck (to a Lesser Extent)
• CREST Syndrome: variable
  • Calcinosis Cutis (see Calcinosis Cutis)
  • Raynaud Phenomenon (see Raynaud Phenomenon): may be present for years-decades
  • Esophageal Dysmotility (see Esophageal Motility Disorders)
  • Sclerodactyly (see Sclerodactyly):
  • Telangiectasias (see Telangiectasias)
• Antibodies
  • Anticentromere Antibody (ACA) (see Anticentromere Antibody): occurs in 50 to 60%
  • Anti-PM/Scl Antibody (see xxxxx): occurs in 5-10% of cases
  • Antitopoisomerase-I Antibody (Anti-Scl-70) (see Antitopoisomerase-I Antibody): occurs in 5-10% of cases

Diffuse Cutaneous Scleroderma

• General Comments
  • Patients with Diffuse Cutaneous Scleroderma are More Likely to Have Visceral Involvement than Patients with Limited Cutaneous Scleroderma
• Interstitial Lung Disease (see Interstitial Lung Disease)
  • Epidemiology: occurs early in course and typically significant
• Gastrointestinal Disease
  • Epidemiology: occurs early in course and typically significant
• Myocardial Disease
  • Epidemiology: occurs early in course and typically significant
• Nailfold Capillary Pattern Typical of Scleroderma
  • Early: dilatation
  • Active Disease: dilatation and dropout
  • Late in Course: tortuosity and dropout
• Raynaud Phenomenon (see Raynaud Phenomenon): skin changes usually occur within 1 year
• Renal Disease
  • Epidemiology: occurs early in course and typically significant
• Skin Involvement in Trunk and Acral Distribution
• Tendon Friction Rubs
• Antibodies
  • Antitopopisomerase-I Antibody (Anti-Scl-70) (see Antitopoisomerase-I Antibody): occurs in 30% of cases
  • Anti-RNA Polymerase I/II/III Antibody (see xxxxx): occurs in 12-15% of cases

Scleroderma Sine Scleroderma

• Absence of Skin Involvement
• Renal Disease
  • Epidemiology: may occur on initial presentation
• Interstitial Lung Disease (see Interstitial Lung Disease)
  • Epidemiology: may occur on initial presentation
• Gastrointestinal Disease
  • Epidemiology: may occur on initial presentation
• Myocardial Disease
  • Epidemiology: may occur on initial presentation
• Raynaud Phenomenon (see Raynaud Phenomenon)
  • Epidemiology: may be present
• Antibodies
  • Anticentromere Antibody (ACA) (see Anticentromere Antibody): may be present
  • Antitopoisomerase-I Antibody (Anti-Scl-70) (see Antitopoisomerase-I Antibody): may be present
  • 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
• Acute Myocardial Infarction (MI) (see Congestive Heart Failure)
  • Physiology
    • Patchy Myocardial Fibrosis Believed to Result from Recurrent Small Vessel Vasospasm
    • Longer History of Raynaud Phenomenon is Associated with an Increase in the Degree of Myocardial Fibrosis (Arthritis Rheum, 2007) [MEDLINE]
  • Clinical
    • Diastolic Dysfunction: occurs in 18% of cases (Ann Rheum Dis, 2008) [MEDLINE]
    • Systolic Dysfunction: occurs in 1% of cases (Ann Rheum Dis, 2008) [MEDLINE]
• Heart Blocks
  • Epidemiology
    • Common
  • Physiology
    • Myocardial Fibrosis
  • Clinical
    • First Degree Atrioventricular Block (First Degree Heart Block) (see Second Degree Atrioventricular Block-Mobitz Type I)
    • Second Degree Atrioventricular Block-Mobitz Type II (see Third Degree Atrioventricular Block)
• Myocarditis (see Pericardial Effusion)
• Pericarditis (see MEDLINE]
  • 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)

Capillary Changes of the Nail Beds

• Clinical
  • XXXX

Digital Ulcers (see Mucocutaneous Ulcers)

• Clinical
  • Typically Located at the Tips of the Fingers
  • Ulcerations over the distal interphalangeal joints (DIP) and proximal interphalangeal joints (PIP) related to repetitive microtrauma over tightened skin

Dry Skin

• Clinical
  • XXXX

Lipoatrophy

• Clinical
  • XXXX

Loss of Appendicular Hair

• Clinical
  • XXXX

Pitting of the Fingertips

• Clinical
  • XXXX

Pruritus (see Pruritus)

• Clinical
  • Occurs Early in the Course of the Scleroderma

Sclerodactyly (see Sclerodactyly)

• Clinical
  • Fusion of the Dermis of Fingers to the Underlying Fascia

Skin Edema/Erythema

• Clinical
  • Occurs Early in the Course of the Scleroderma
  • Skin Edema/Erythema May Precede Skin Induration

Skin Thickening/Hardening

• Clinical
  • Progressive Skin Fibrosis is Associated with Worsening Lung Function in Patients with Diffuse Cutaneous Systemic Sclerosis (dcSSc)

Skin Hyperpigmentation/Depigmentation (“Salt and Pepper Skin”)

• Clinical
  • XXXX

Telangiectasias (see Telangiectasias)

• Clinical
  • XXXX

Vasculitis (see Vasculitis)

• Epidemiology
  • Common
• Clinical
  • XXXX

Gastrointestinal Manifestations

• General Comments
  • Gastrointestinal Manifestations are Common
    • While Gastrointestinal Involvement Occurs in 90% of Cases, Nearly 50% of These Patients are Asymptomatic
  • Any Part of the Gastrointestinal Tract May Be Involved
• Colonic Dysmotility
  • Clinical
    • Acute Colonic Pseudo-Obstruction (Ogilvie’s Syndrome) (see Acute Colonic Pseudo-Obstruction)
    • Constipation (see Constipation)
• Diarrhea/Fecal Incontinence (see Diarrhea)
• Esophageal Cancer (see Esophageal Cancer)
  • Epidemiology: increased risk
• Esophageal Dysmotility (see Esophageal Motility Disorders)
  • Diagnosis
    • Esophageal Manometry (see Esophageal Manometry)
      • Loss of Distal (Smooth Muscle) Peristalsis
      • Weak Lower Esophageal Sphincter Pressure (<10 mm Hg)
      • Normal Proximal Esophagus and Upper Esophageal Sphincter (Striated Muscle)
    • Esophogram (see xxxxx)
  • Clinical
    • Esophageal Dilation
• Gastroesophageal Reflux Disease (GERD) (see Gastroesophageal Reflux Disease)
  • Physiology
    • Due to Incompetence of the Lower Esophageal Sphincter
  • Clinical
    • Aspiration Pneumonia/Pulmonary Microaspiration (see Aspiration Pneumonia)
      • May Contribute to the Progression of Scleroderma-Associated Interstitial Lung Disease (Arthritis Rheum, 2001) [MEDLINE]
    • Barrett’s Esophagus
    • Esophagitis (see Esophagitis)
    • Esophageal Stricture (see Esophageal Stricture)
• Malabsorption
• Small Bowel Dysmotility

Hematologic Manifestations

Mild Thrombocytopenia (see Thrombocytopenia)

• Epidemiology
  • XXXX

Neurologic Manifestations

• Fatigue (see Fatigue)
  • Epidemiology
    • Occurs Early in the Course of Disease
• Headache (see Headache)
  • Epidemiology
    • Less Common
• Inflammatory Myositis
• Ischemic Cerebrovascular Accident (CVA) (see Ischemic Cerebrovascular Accident)
  • Epidemiology
    • Less Common
• Transverse Myelitis (see Transverse Myelitis)
  • Epidemiology
    • Has Been Reported (Arch Neurol, 2004) [MEDLINE]
• Myopathy (see Myopathy)
• Peripheral Neuropathy (see Peripheral Neuropathy)
  • Clinical
    • Autonomic Neuropathy
    • Cranial Nerve Involvement
    • Entrapment Neuropathy
• Radiculopathy
  • Epidemiology
    • Less Common
• Seizures (see Seizures)
  • Epidemiology
    • Less Common

Otolaryngologic Manifestations

Oropharyngeal Carcinoma (see Acute Respiratory Distress Syndrome)

• Epidemiology
  • XXXX
• 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

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)

Aspiration Pneumonia (see Aspiration Pneumonia)

• Epidemiology
  • Scleroderma Manifests an Increased Risk of Aspiration
• Physiology
  • Likely Due to Esophageal Dysmotility (Achalasia)/Gastroesophageal Reflux

Diffuse Alveolar Hemorrhage (DAH) (see 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 (see xxxx)
  • In reported cases, rapidly progressive glomerulonephritis was observed in 2 of 4 reported cases (rapidly progessive glomerulonephritis is otherwise uncommon in scleroderma)

Interstitial Lung Disease (ILD) (see Interstitial Lung Disease)

• Epidemiology
  • Interstitial Lung Disease is the Most Common Pulmonary Manifestation in Scleroderma
    • Interstitial Lung Disease Occurs in 26% of Patients with Limited Cutaneous Scleroderma (NEJM, 2014) [MEDLINE]
    • Interstitial Lung Disease Occurs in 48% of Patients with Diffuse Cutaneous Scleroderma (NEJM, 2014) [MEDLINE]
  • Risk Factors for Early Development of Interstitial Lung Disease (Arthritis Rheum, 2007) [MEDLINE]
    • African-American Ethnicity
    • Cardiac Involvement
    • Higher Skin Score
    • Higher Creatine Phosphokinase (CK)
    • Hypothyroidism (see Hypothyroidism)
• Diagnosis
  • Arterial Blood Gas (ABG) (see Arterial Blood Gas)
    • Hypocapnia (see Hypocapnia)
    • Increased A-a Gradient Hypoxemia (see Hypoxemia)
  • Chest X-Ray (CXR) (see Chest X-Ray)
    • Low Sensitivity for the Diagnosis of Interstitial Lung Disease
    • Basilar-Predominant Symmetric, Reticular, or Ground-Glass Infiltrates
  • High-Resolution Chest CT (HRCT) (see High-Resolution Chest Computed Tomography)
    • General Comments
      • 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
      • Honeycombing is Rare
    • Usual Interstitial Pneumonia (UIP) Pattern (see Usual Interstitial Pneumonia): occasional pathologic pattern
      • 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)
    • Centrilobular Fibrosis Pattern: rare pathologic pattern
      • Centrally-Distributed Patchy Ground-Glass or Consolidative Opacities
  • Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests)
    • 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
• Clinical
  • Bibasilar Fine (“Velcro”) Crackles: common
  • Chest Pain (see Mycophenolate Mofetil): first-line agent
    • 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
  • Corticosteroids (see corticosteroids)
    • Low Dose Corticosteroids (Prednisone ≤10 mg/day) Should Be Reserved for Patients with Specific Non-Pulmonary Indications (Pruritus, Arthritis)
    • Due to Risks of Scleroderma Renal Crisis and Opportunistic Infection, Corticosteroids Should Probably Not Be Used with Cyclophosphamide
  • Azathioprine (Imuran) (see Azathioprine): third-line agent
  • Refractory Disease
    • Rituximab (Rituxan) (see Rituximab)
  • Lung Transplant (see Lung Transplant)
  • Investigational
    • Hematopoietic Stem Cell Transplant (HSCT) (see Hematopoietic Stem Cell Transplant): investigational
    • Abatacept (Orencia) (see Abatacept): investigational
    • Nintedanib (Ofev) (see Nintedanib): investigational
    • Pirfenidone (Esbriet) (see Pirfenidone): investigational
    • Tocilizumab (Actemra) (see Tocilizumab): investigational
  • Agents with No Benefit in Scleroderma-Associated Interstitial Lung Disease
    • Anti-Tumor Necrosis Factor-α Therapy (see Anti-Tumor Necrosis Factor-α Therapy)
    • Corticosteroids Monotherapy (see corticosteroids)
    • D-Penicillamine (see Penicillamine)
    • Methotrexate (see Methotrexate)
• Prognosis
  • Presence of Interstitial Lung Disease Increases the Mortality Rate in Scleroderma (Arthritis Rheum, 2000) [MEDLINE]
    • 9-Year Survival Rate in Scleroderma with Severe Interstitial Lung Disease: 30%
    • 9-Year Survival Rate in Scleroderma without Severe Organ System Involvement: 72%
  • Systematic Review of Factors Predicting the Outcome of Scleroderma-Associated Interstitial Lung Disease (Chest, 2014) [MEDLINE]
    • Lower FVC, Older Age, and Lower DLCO Predicted Mortality Rate
    • Extent of Disease on HRCT Predicted Both ILD Progression and Mortality Rate
  • Bronchoalveolar Lavage Cell Counts Do Not Reliably Predict Outcome in Scleroderma-Associated Interstitial Lung Disease

Lung Cancer (see Lung Cancer)

• Epidemiology
  • Scleroderma Increases the Risk of Lung Cancer by Approximately 5-Fold, as Compared to Age/Gender-Matched Controls
• Pathology
  • Bronchioloalveolar/Adenocarcinoma

Pleural Effusion/Pleuritis (see Pleural Effusion-Exudate)

• Epidemiology
  • Pleural Effusion is Uncommon in Scleroderma: present in <10% of cases (Br J Rheumatol, 1998) [MEDLINE]
• Diagnosis
  • Pleural Effusion/Pleural Fibrosis
• Clinical
  • Usually Asymptomatic
  • Pleural Friction Rub (see Pleural Rub)

Pulmonary Hypertension (see Pulmonary Hypertension)

• Epidemiology
  • Pulmonary Hypertension Develops in Approximately 10% of Patients with Scleroderma
  • Risk Factors
    • Long-Standing Disease (>5 yrs)
    • Limited Cutaneous Scleroderma
    • Older Age at Onset of Scleroderma
    • Telangiectasias
    • Elevated Serum BNP (see Elevated Serum Brain Natriuretic Peptide)
    • Exercise-Associated Pulmonary Hypertension During Course of Disease
    • DLCO <60% Predicted
    • FVC Percent/DLCO Ratio >1.6
    • Serology
      • Absence of Antitopoisomerase-I Antibody (Anti-Scl-70 Antibody) (Arthritis Rheum, 2003) [MEDLINE]
      • Anticentromere Antibody (ACA) (see Anticentromere Antibody)
      • Anti-U1-Ribonucleoprotein Antibody
      • Nucleolar Pattern Antinuclear Antibodies (see Antinuclear Antibody)
• Diagnosis
  • Normal Chest X-Ray/Chest CT (see Chest X-Ray and Chest Computed Tomography): usually normal
  • Bronchoscopy with Bronchoalveolar Lavage (BAL) (see Bronchoscopy): usually normal
  • Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests): decreased DLCO
  • Echocardiogram (see Echocardiogram)
  • Stress Echocardiogram (see xxxxx): may be useful to detect early or exercise-associated pulmonary hypertension
  • Swan-Ganz Catheter (see Swan-Ganz Catheter): diagnostic
  • Serum Brain Natriuretic Peptide (BNP) (see Elevated Serum Brain Natriuretic Peptide): may be elevated
  • 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]
    • Anticentromere Antibody (ACA) (see Anticentromere Antibody)
    • Anti-U1-Ribonucleoprotein Antibody
    • Nucleolar Pattern Antinuclear Antibodies (see Antinuclear Antibody)
• Clinical
  • Dyspnea (see Dyspnea)
  • Hypoxemia (see Hypoxemia)
• Treatment
  • Oxygen (see Oxygen)
  • Supportive Care
    • Treatment of Infections
    • Vaccinations
  • 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
  • Endothelin Receptor Antagonists (see Endothelin Receptor Antagonists)
  • Phosphodiesterase Type 5 Inhibitors (see Phosphodiesterase Type 5 Inhibitors)
  • Riociguat (Adempas) (see Riociguat)
    • 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
  • Prostacyclin Analogues
    • Epoprostenol (Flolan) (see Epoprostenol)
    • Iloprost (see Iloprost)
    • Treprostinil (see Treprostinil)
    • Selexipag (Uptravi) (see Selexipag)
  • Lung Transplant (see Lung Transplant)
• Prognosis
  • 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)

• Clinical
  • Right-Sided Congestive Heart Failure (CHF): elevated JVP, lower extremity edema, etc

Pulmonary Veno-Occlusive Disease (VOD)/Pulmonary Capillary Hemangiomatosis (see Pulmonary Veno-Occlusive Disease and Pulmonary Capillary Hemangiomatosis)

• Epidemiology: rare case reports

Spontaneous Pneumothorax (see Pneumothorax)

• Epidemiology
  • Scleroderma-Associated Pneumothorax is Rare and Usually Occurs in Patients with Interstitial Lung Disease (J Clin Rheumatol, 2004)[MEDLINE]
• Physiology
  • Rupture of Subpleural Bleb

Thoracic Cage Restriction (see Pulmonary Function Tests)

• Physiology
  • Due to Skin Tightness Over the Chest Wall, Limiting Inspiratory Thoracic Cage
• Diagnosis
  • Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests): restriction

Venous Thromboembolism (see xxxx)

• xxxx

Renal/Genitourinary Manifestations

General Comments

• Approximately 60-80% of Diffuse Cutaneous Scleroderma Patients Have Pathologic Evidence of Renal Involvement

Erectile Dysfunction (ED) (see Erectile Dysfunction)

• Epidemiology: very common

Hypertension (see Hypertension)

• Diagnosis
  • Serum Renin (see Serum Renin)

Scleroderma Renal Crisis

• Epidemiology
  • Scleroderma Renal Crisis Occurs in Approximately 10-15% of Cases
  • Scleroderma Renal Crisis is Far More Common in Patients with Diffuse Cutaneous Scleroderma, as Compared to Limited Cutaneous Scleroderma
  • Scleroderma Renal Crisis Usually Occurs During the Early Stages of Disease
  • Predictors of Scleroderma Renal Crisis
    • Cardiomegaly
    • Higher Than Average Skin Score
    • Large Joint Contractures
• Diagnosis
  • Microangiopathic Hemolytic Anemia (see Hemolytic Anemia)
  • Thrombocytopenia (see Thrombocytopenia)
  • Urinalysis (see Urinalysis): mild proteinuria, few cells or casts
• Clinical
  • Abrupt Moderate-Severe Hypertension (see Hypertension): some cases are normotensive
  • Acute Respiratory Distress Syndrome (ARDS) (see Acute Respiratory Distress Syndrome)
  • Blurred Vision (see Blurred Vision)
  • Headache (see Headache)
  • Oliguric Acute Kidney Injury (AKI) (see Acute Kidney Injury)
  • Seizures (see Seizures)
• Prognosis: 50% 5-year mortality rate in patients with renal crisis, even if properly treated

Rheumatologic Manifestations

• Arthralgias (see Arthralgias)
  • Epidemiology: occurs early in the course of disease
• Myalgias (see Myalgias)
  • 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

Treatment of Hypertension

• ACE-Inhibitors:
• Diuretics:

Treatment of Raynaud Phenomenon (see Raynaud Phenomenon)

• 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
  • Bosentan (Tracleer) (see Bosentan)
  • XXXX
  • Sildenafil (Viagra, Revatio) (see Sildenafil)
  • XXXX

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

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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]

Raynaud Phenomenon (see Raynaud Phenomenon)

• 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]