Systemic Sclerosis

See Also

Collagen Disorder

Definitions

Scleroderma
1. Chronic hardening and thickening of the skin
2. Caused by swelling and thickening of fibrous tissue leading to eventual skin atrophy
Systemic Sclerosis (SSc)
1. Small vessel vasculopathy, autoantibodies, and fibroblast dysfunction results in hardening and thickening of body tissue
2. In addition to skin involvement (Scleroderma), affects a wide range of internal organ systems
3. Causes pulmonary fibrosis, Raynaud's Syndrome, Digestive System Telangiectasias, renal Hypertension, Pulmonary Hypertension
CREST Syndrome
1. Variant of Systemic Sclerosis
2. Characterized by calcinosis, Raynaud Phenomenon, Esophageal Motility Disorders, sclerodactyly, and Telangiectasia

Epidemiology

Incidence: 10-20 cases per 1 million persons annually
Prevalence: Up to 250 cases per 1 million persons
Gender: More common in Women (5:1 ratio)
Age: Peaks age 40 to 50 years
Black patients (RR 2.5)
1. Worse prognosis, with higher risk of severe Interstitial Lung Disease and pulmonary artery Hypertension

Pathophysiology

Autoimmune Connective Tissue Disorder
1. Immune dysregulation and small vessel vasculopathy
2. Triggers fibroblasts to overproduce Collagen
Effects
1. Progressive fibrosis of skin and organ systems
2. Progressive Muscle atrophy and fibrosis
3. Esophagus changes
  1. Loss of peristalsis
  2. Sphincter reduction

Types

Limited cutaneous Systemic Sclerosis (60% of cases)
1. Typical skin involvement is distal to elbows and knees
2. Associated with Pulmonary Hypertension
3. Associated with CREST Syndrome
  1. Severe Gastroesophageal Reflux is common
  2. Raynaud's Phenomenon (often with digital ischemia) are common
  3. Telangiectasia
  4. Calcinosis cutis
  5. Sclerodactyly
Diffuse cutaneous Systemic Sclerosis (35% of cases)
1. Skin involvement may be proximal to elbows and knees and may affect face
2. Associated with Interstitial Lung Disease (pulmonary fibrosis)
3. May present with renal disease
4. Skin pigment may be altered
5. Tendons friction rubs may be present
Systemic Sclerosis sine Scleroderma (5% of cases)
1. Internal organ manifestations (visceral, vascular) only

Findings

General
1. Gradual symptom onset (often with delayed diagnosis)
2. Earliest findings are Fatigue, Hand Edema, Raynaud Phenomenon
Skin
1. Bilateral skin thickening, Scleroderma (75%)
  1. Skin hardening
  2. Skin contracted with immobility and symmetric deformity (tight skin)
  3. Rodnan Skin score quantifies skin thickening
    1. https://rheumcalc.com/mrss/
2. Hyperpigmentation (40%)
3. Nonpitting hand edema (40%)
4. Raynaud Phenomenon (95-97%, early presenting finding)
5. Telangiectasia (48-75%)
6. Skin Ulcers, esp. at Trauma sites (20-40%)
7. Pruritus
8. Alopecia
9. Reduced sweating
10. Reduced Joint mobility
  1. Risk of contractures
  2. Includes reduced jaw motion (with decreased mouth opening)
Gastrointestinal
1. Dry Mouth or Xerostomia (90%)
  1. Results from Salivary Gland fibrosis
  2. Common overlap syndrome with Sjogren's Syndrome
2. Upper gastrointestinal presentations (most common than lower GI)
  1. Esophageal Dysmotility (80-95%)
    1. Presents with GERD symptoms, Dysphagia, Anorexia
  2. Other, less common findings
    1. Delayed Gastric Emptying
    2. Gastric antral vascular ectasia (associated with Upper GI Bleeding)
3. Lower gastrointestinal symptoms (less common than upper GI)
  1. Diarrhea (associated with Bacterial overgrowth)
  2. Constipation
  3. Fecal Incontinence
  4. Malabsorption (risk for Vitamin B12 Deficiency, Folate Deficiency)
Pulmonary
1. Limited chest expansion
2. Dyspnea (80%)
  1. Associated with Pulmonary Arterial Hypertension, Interstitial Lung Disease
Musculoskeletal (40-90% of SSc patients)
1. Associated with significant Disability
2. Arthralgias (most common)
3. Flexion contractures
4. Small Joint Stiffness
5. Myalgias
6. Proximal Muscle Weakness
7. Tendon friction rubs (leathery popping Sensation with joint movement)
  1. Associated with more diffuse and severe disease
Renal Crisis (rare, but potentially lethal)
1. Rapidly progressive Acute Renal Failure
2. Severe Hypertension
  1. Normotensive renal crisis may occur but is rare
3. Headache
4. Vision changes
5. Encephalopathy
6. Seizures
7. Pulmonary Edema

Labs
General

Complete Blood Count with Platelet Count
1. Anemia may be present (e.g. chronic GI Bleed, malabsorption)
Basic chemistry panel
1. Serum Creatinine and GFR
Urinalysis
1. Evaluate for Proteinuria (reflex to Urine Protein to Creatinine Ratio)
Creatine Kinase
1. Evaluate for Myositis when musculoskeletal symptoms are present

Labs
Autoantibodies

Screening
1. Antinuclear Antibody
  1. Non-specific, but present in 95% of Systemic Sclerosis (all subtypes)
  2. ANA Nucleolar Pattern
Confirmation with specific markers
1. Anti-centromere Antibody
  1. Most associated with limited cutaneous subtype (60-80% of cases)
  2. Present in 30% of overall Systemic Sclerosis patients
  3. Associated with an increased risk of Pulmonary Arterial Hypertension
2. Anti-Topoisomerase I Antibody (Anti-Scl-70)
  1. Associated with diffuse cutaneous subtype (esp. more severe cases)
  2. Associated with higher risk of Interstitial Lung Disease
  3. Associated with worse prognosis (increased mortality)
  4. Test Sensitivity: 43%
  5. Test Specificity: 100%
3. Anti-RNA Polymerase III Antibody
  1. Associated with diffuse cutaneous subtype
  2. Associated with HIGHER risk of significant renal involvement
  3. Associated with LOWER risk of Interstitial Lung Disease and Pulmonary Arterial Hypertension

Diagnosis
Systemic Sclerosis Classification Criteria (ACR/EULAR 2013)

Skin thickening of fingers (choose only the ONE highest positive score)
1. Score 9: Involves both hands extending proximal to MCP joints
2. Score 4: Sclerodactyly of fingers proximal to PIP joints (but distal to MCP)
3. Score 2: Puffy finger involvement distal to PIP joints
Fingertip lesions (choose only the ONE highest positive score)
1. Score 3: Fingertip pitting scars
2. Score 2: Fingertip ulcers
Lung Involvement (choose only the ONE highest positive score)
1. Score 2: Pulmonary Arterial Hypertension
2. Score 2: Interstitial Lung Disease
Other associated findings (choose ANY that apply)
1. Score 2: Abnormal nailfold capillaries
2. Score 2: Telangiectasia
3. Score 3: Raynaud's Phenomenon
4. Score 3: SSc-Related autoantibodies (Anticentromere, Anti-Topoisomerase I, anti-RNA Polymerase III)
Interpretation
1. Total score >=9 is consistent with definite Systemic Sclerosis
2. Excluding other conditions on differential diagnosis that better explain patient's findings
References
1. van den Hoogen (2013) Ann Rheum Dis 72(11):1747-55 +PMID: 24092682 [PubMed]

Differential Diagnosis

Amyloidosis
Eosinophilia-Myalgia Syndrome
Eosinophilic fasciitis (Shulman syndrome)
Nephrogenic Fibrosing Dermopathy (Nephrogenic Systemic Fibrosis)
Scleroderma diabeticorum
Scleromyxedema
Erythromyalgia
Porphyria
Lichen Sclerosis
Graft Versus Host Disease
Diabetic Cheioarthropathy
Spanish Toxic oil syndrome (1981 epidemic, related rapeseed oil Poisoning)
Isolated conditions (not part of overlap syndrome or complications/subcomponents of SSc)
1. Raynaud Phenomenon
2. Mixed Connective Tissue Disease
3. Idiopathic pulmonary arterial disease
4. Systemic Lupus Erythematosus
5. Myositis
6. Sjogren Syndrome

Associated Conditions

Overlap syndromes occur in 10-20% of Systemic Sclerosis patients
Sjogren’s Syndrome (SSc-SS, common)
Myositis (Scleromyositis, includes Dermatomyositis or Polymyositis)
Rheumatoid Arthritis (SSc-RA)
Systemic Lupus Erythematosus (SSc-SLE)
Mixed Connective Tissue Disease (MCTD, findings of SLE, Myositis)

Evaluation
Monitoring

Pulmonary Arterial Hypertension
1. Echocardiogram
  1. Obtain at SSc diagnosis and then yearly
2. NT-proBNP
  1. Obtain at SSc diagnosis and then yearly
3. Pulmonary Function Tests (Spirometry with DLCO)
  1. Obtain at SSc diagnosis and then yearly
  2. Particular attention to Forced Vital Capacity (FVC) over time
Interstitial Lung Disease
1. HIstory
  1. Dyspnea
  2. Dry cough
  3. Exercise intolerance
2. High resolution Chest CT
  1. Obtain at SSc diagnosis and then every 1-3 years
  2. ILD findings include honeycombing, ground-glass Nodules, fibrosis
Cardiovascular
1. History
  1. Syncope
  2. Palpitations
  3. Chest Pain
  4. Right Heart Failure symptoms
2. Electrocardiogram (consider at baseline and as needed)
3. Holter Monitor or similar (consider for Palpitations, Syncope)
4. Echocardiogram (perform for PAH evaluation; also evaluate for Diastolic Dysfunction as needed)

Management

General
1. Rheumatology referral (early, when SSc is suspected)
2. Consult other specialties as indicated
  1. Cardiology
  2. Pulmonology
  3. Nephrology
  4. Gastroenterology
  5. Dermatology
  6. Physical Medicine and Rehabilitation (PMR)
3. Occupational Therapy
  1. Oral motor function (esophageal motility, Swallowing)
  2. Upper extremity function
4. Lifestyle
  1. Target measures that improve quality of life and reduce progression and Disability
  2. Smoking Cessation
  3. Aerobic Exercise (e.g. stationary bike)
Skin Ulcers
1. First-line agents
  1. Phosphodiesterase 5 Inhibitor (e.g. Tadalafil)
  2. Intravenous Iloprost (Aurlumyn)
2. Prevention and treatment of recurrent Skin Ulcers
  1. Endothelin Receptor Antagonists (Bosentan)
  2. Avoid medications that cause Vasoconstriction
    1. Beta Blockers
    2. Triptans and Ergotamine
    3. Oral Contraceptives
Raynaud Phenomenon
1. See Raynaud Phenomenon
2. First-Line Agents
  1. Dihydropyridine Calcium Channel Blocker (e.g. Amlodipine)
3. Second-Line Agents
  1. Phosphodiesterase 5 Inhibitor (e.g. Tadalafil)
  2. Intravenous Iloprost (Aurlumyn)
Skin Fibrosis
Gastrointestinal complications
1. Esophageal Dysmotility
  1. Chew food well and drink adequate liquids with food
  2. Monitor for and prevent progressive GERD, esophageal ulcers, strictures
  3. Gastric acid reduction
    1. H2 Blocker (e.g. Famotidine)
    2. Proton Pump Inhibitor (e.g. Omeprazole 20 mg orally twice daily)
  4. Promotility agents (e.g. Metoclopramide, Erythromycin)
    1. Consider in Dysphagia, early satiety, bloating (e.g. Delayed Gastric Emptying)
2. Small Intestinal Bacterial overgrowth
  1. No specific treatment
  2. Assess and manage malabsorption, Malnutrition and weight loss
3. Gastric antral vascular ectasia
  1. Endoscopy with argon plasma coagulation
  2. Antacid management (and other medical management)
Interstitial Lung Disease
1. See Pulmonary Fibrosis
2. First-line agents
  1. Mycophenolate Mofetil (preferred)
  2. Cyclophosphamide
  3. Rituximab
  4. Avoid Corticosteroids as first line management
3. Alternative agents
  1. Tocilizumab (Actemra)
  2. Nintedanib (Ofev)
4. Additional prevention
  1. Influenza Vaccine
  2. Covid-19 Vaccine
  3. Pneumococcal Vaccine
  4. Shingles Vaccine (non-live)
Pulmonary Arterial Hypertension
1. See Pulmonary Hypertension
2. First-Line
  1. Phosphodiesterase 5 Inhibitor (e.g. Tadalafil 40 mg) AND
  2. Endothelin Receptor Antagonists (e.g. Ambrisentan 10 mg)
3. Severe Treatment-resistant disease
  1. Prostaglandins
  2. Epoprostenol (Veletri)
  3. Soluble Guanylate Cyclase Stimulators
Renal Crisis
1. ACE Inhibitors
  1. Started immediately at time of renal crisis diagnosis
    1. However, not recommended for prevention prior to renal crisis (worse outcomes)
  2. Target Blood Pressure <120/70 mmHg
  3. Inpatient management with short acting ACE Inhibitor
    1. Reduce systolic Blood Pressure by 20 mmHg in first 24 hours
    2. Convert to long-acting ACE Inhibitor once titrated to BP target
2. Alternatives
  1. Angiotensin Receptor Blockers
  2. Calcium Channel Blockers
Musculoskeletal Involvement
1. Maintain activity and mobility
2. Consider Methotrexate
  1. No evidence for Corticosteroids or other immune modulators

Complications

Esophageal Dysmotility
1. Substantial Gastroesophageal Reflux Disease
2. Barrett's Esophagus
Pulmonary fibrosis (Interstitial Lung Disease)
Pulmonary Arterial Hypertension
Scleroderma renal crisis
Digital infarction
Small Intestinal Bacterial overgrowth
Cardiovascular fibrosis
1. Common
  1. Diastolic Dysfunction
  2. Arrhythmia and Palpitations
2. Other complications
  1. Myocarditis or Pericarditis
  2. Conduction blocks
  3. Pericardial Effusion

Prognosis

Systemic Sclerosis has the highest mortality among Rheumatologic Disorders (related to pulmonary complications)
1. Delayed diagnosis is common, but earlier diagnosis is associated with a better prognosis
2. Cummulative survival is 87% at 5 years, 74% at 10 years after Raynaud Phenomenon symptom onset
Age at diagnosis <40 years is associated with more aggressive and diffuse disease
1. Age >60 years at onset is associated with slower progression (but more cardiopulmonary complications)
Diffuse cutaneous involvement progresses more rapidly with more internal, sytemic involvement
1. Limited cutaneous involvement is associated with a slower course

Resources

Scleroderma Foundation
1. http://www.scleroderma.org

References