Diagnosis

Systemic sclerosis

Etiology

Cause [o5z]

• Autoimmune disease of unknown etiology

• Genetic factors: family history, HLA (DRB1, DQA1, and DQB1)

• Environmental triggers:

  • Infections: CMV, EBV, Parvovirus B19

  • Silica exposure

  • Solvent exposure

  • Radiation exposure or radiotherapy

  • Drugs (bleomycin, carbidopa, pentazocine, cocaine, penicillamine, vitamin K)

Classification [o5z]

• Localized scleroderma: primarily affects the skin and subcutaneous tissue

  • Morphea (dermal fibrosis with patches of thickened skin)

  • Linear scleroderma

  • Scleroderma en coup de sabre

• Systemic sclerosis: systemic manifestations and internal organ involvement

  • Limited systemic sclerosis (CREST syndrome)

  • Diffuse systemic sclerosis

Pathophysiology [fse][o5z]

1. Triggers --> endothelial cell injury --> aberrant autoimmune response

   • Activated macrophages, monocytes, and dendritic cells

   • T- and B cells produce pro-fibrotic/pro-inflammatory cytokines and autoantibodies

2. Fibroblast activation --> pro-thrombotic cascade

3. Occlusion of the microvasculature --> widespread microangiopathy --> tissue hypoxia

   • Vascular smooth muscle cell proliferation

   • Tissue fibrosis --> loss of tissue architecture

   • Organ damage: Skin, GI-tract, lungs, heart, kidney, CNS

4. Clinical manifestation:

   • Raynaud phenomenon: cold --> vasospasms (early and common manifestation)

   • Skin: Perivascular inflammation --> dermal edema --> dermal fibrosis

   • Lungs: inflammation of the alveolar walls --> interstitial pneumonitis --> fibrosis --> --> vasculopathy (loss of pulmonary microvasculature) --> pulmonary arterial hypertension, pleuritis, pulmonary hemorrhage

   • Kidney: ischemic changes, glomerulonephritis, renal crisis

   • Musculoskeletal: Arthralgia, arthritis, myalgia, myositis, muscle fibrosis

   • Heart: constrictive pericarditis, pericardial fibrosis/effusion, myocardial fibrosis --> dilated cardiomyopathy, arrhythmia

   • Gastrointestinal: perioral skin tightening, reduced oral aperture, periodontitis, gingivitis, esophageal dysmotility (dysphagia, heartburn, esophagitis, stricture, Barrett's esophagus), gastroparesis, salivary gland fibrosis --> Sjögren syndrome, bloating, nausea, vomiting, anorexia, GI bleeding, diarrhea, constipation, pseudo-obstruction

   • General fibrosis: GI-tract, thyroid gland (hypothyroidism), salivary glands, penis

Complications [o5z]

• Fibrosis --> end-organ damage

• Digital ischemia --> gangrene --> amputation

• Gastrointestinal complications

• Pulmonary involvement --> pulmonary fibrosis

• Renal crisis

Epidemiology

Incidence per 100.000 [fse][usc][isd][zsw][hs5][8wy][stb]

Approach

• Blood test: Antinuclear antibodies, Anti-centromere, anti-Scl-70, anti-RNA polymerase

• Biopsy

• ECG

• Echocardiography

• CT

• Endoscopy

Diagnosic Criteria:

1. American College of Rheumatology 1980 [8mb]

   • Major Criterion: sufficient for diagnosis

     Proximal scleroderma: Symmetrical thickening/tightening of the skin affecting limbs, face, neck, or trunk.

   • Minor Criteria: two required for diagnosis

     1. Sclerodactyly: Skin thickening limited to the fingers.

     2. Digital pitting scars or loss of fingertip substance: Due to ischemia.

     3. Bilateral basilar pulmonary fibrosis: Radiographic evidence

2. LeRoy and Medsger Criteria for Early Systemic Sclerosis [te8]

   • Core Requirement: Raynaud’s phenomenon

   • Additional Criteria (at least one required):

     1. Abnormal nailfold capillaries:

        Dilated capillaries, hemorrhages, or avascular areas on nailfold capillaroscopy

     2. SSc-specific autoantibodies:

        Anticentromere, anti-topoisomerase I (anti-Scl70), or anti-RNA polymerase III antibodies.

3. American College of Rheumatology 2013: score ≤9 indicates systemic sclerosis [o5z]

   1. Bilateral skin thickening proximal to metacarpophalangeal joints: 9

   2. Skin thickening of fingers (counting only higher score)

      • Between distal and proximal interphalangeal joints: 4

      • Puffy fingers: 2

   3. Fingertip lesions (counting only the higher score)

      • Fingertip pitting scars: 3

      • Digital tip ulcers: 2

   4. Telangiectasia: 2

   5. Abnormal nailfold capillaries: 2

   6. Raynaud phenomenon: 3

   7. Lung disease (maximum score of 2)

      • ILD: 2

      • PAH: 2

   8. Positive systemic sclerosis-specific antibodies (anti-centromere, anti–Scl–70, and anti–RNA polymerase III): 3

Treatment

1. There are no curative treatment [o5z]

2. Non-medical treatment:

   • Patient education

   • Regular exercise

   • Healthy diet and lifestyle

   • Emotional support

3. Raynaud phenomenon: keep extremities warm, avoid smoking and stress, and eliminate β-blockers

   • Vasodilator therapy: nifedipine (30-120 mg/d), amlodipine (5-20 mg/d), pentoxifylline, nitroglycerin, and phosphodiesterase inhibitors

4. Skin disease: Methotrexate (15-25 mg/week), IV methylprednisolone (30 mg/kg/d for 3 days), Prednisone (1 mg/kg/d), Hydroxychloroquine, mycophenolate mofetil, cyclophosphamide, antihistamines and topical moisturizing agents

5. Musculoskeletal involvement: arthralgias, arthritis, mypsitis

   • NSAIDs, Low-dose prednisone (<10 mg/d), HCQ (200-400 mg daily), MTX, Antitumor necrosis factor agents

   • Physiotherapy to prevent contractures

6. Pulmonary involvement: interstitial lung disease --> leading cause of mortality

   • Supplemental oxygen, diuretics, and anticoagulation

   • Cyclophosphamide has shown benefit for up to 18 months

   • Mycophenolate mofetil (1.5-3 g/day)

   • Lung transplantation

   • Vasodilator therapy: phosphodiesterase-5 inhibitors (tadalafil 40 mg daily and sildenafil 20 mg orally 3 times daily), endothelin receptor antagonists (such as bosentan at 62.5-125 mg twice daily, prostacyclin analogs (epoprostenol, treprostinil, beraprost, and iloprost at 2.5-5 μg inhaled 6-9 times daily

7. Cardiac involvement: Arrhythmias --> antiarrhythmic agents and pacemaker

8. Gastrointestinal involvement: microstomia --> exercise, xerostomia --> good dental hygiene, secretagogues, hearthburn --> dietary adjustments (avoid late/large/spicy meals, elevated head), proton pump inhibitors, gastroparesis --> Motility agents (metoclopramide)

9. Scleroderma renal crisis: ACE inhibitors

Differential diagnoses

Acute intermittent porphyria, Amyloidosis, Cutaneous T-cell lymphoma, Eosinophilia, Eosinophilia-myalgia syndrome, Eosinophilic Fasciitis, Graft-versus-host disease, Lichen sclerosus, Lyme disease, Morphea, Nephrogenic systemic fibrosis, Phenylketonuria, Primary biliary cirrhosis, Progeria, Pulmonary hypertension, Reflex sympathetic dystrophy, Scleroderma, Sjogren syndrome, Werners syndrome