Scleroderma

Scleroderma (systemic sclerosis) is an autoimmune condition characterized by diffuse collagen deposition and fibrosis. The clinical presentation varies from limited skin involvement to diffuse involvement of internal organs. Diagnosis is established by a combination of physical findings and serology. There is no curative treatment. Management options are limited and include immunosuppressive medications as well as specific organ- or symptom-directed drugs. The overall 5-year survival of patients with scleroderma is about 80%.

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Overview

Definition

Scleroderma, also known as systemic sclerosis (SS), is an autoimmune disorder in which there is progressive deposition of collagen in the skin and internal organs causing tightening and fibrosis.

Epidemiology

  • Women are 5 times more likely to be affected than men.
  • Women more likely to present:
    • Younger
    • With limited disease
    • With pulmonary hypertension
  • Peak age at presentation: 35–50 years
  • More severe in African American patients

Etiology

  • Etiology is unknown.
  • Genetics likely play a role.
  • Suspected environmental triggers include:
    • Infectious (cytomegalovirus (CMV), herpesvirus, parvovirus)
    • Environmental:
      • Silica exposure
      • Solvents (vinyl chloride, benzene)
    • Drugs (bleomycin)
    • Radiation exposure

Pathophysiology and Clinical Presentation

Pathophysiology

  • Not completely understood
  • 3 interlinked complex processes are the basis for pathogenesis:
    • Abnormal activation of both humoral and cell immunity → autoimmune disorder
      • Microvascular endothelial injury likely caused by anti-endothelial antibodies
      • Perivascular accumulation of T and B lymphocytes, macrophages, and fibroblast precursors
      • Secretion of cytokines and growth factors by inflammatory cells
    • Abnormal stimulation of fibroblast activation and proliferation within small arteries and arterioles 
    • Progressive deposition of collagen and other extracellular matrix molecules within the skin and internal organs

Clinical variants

  • Diffuse cutaneous SS: 
    • Puffy hands
    • Involves skin proximal to the knees and elbows (trunk, neck, and face)
    • Early and extensive involvement of internal organs in the course of the disease
    • Rapid progression with diffuse skin thickening and lung, renal, and cardiac involvement
  • Limited cutaneous SS:
    • Puffy fingers distal to metacarpophalangeal joints
    • Limited to skin distal to elbows and knees
    • Prominent vascular symptoms:
      • Raynaud’s phenomenon
      • Telangiectasias
      • Pulmonary arterial hypertension (PAH; late symptom)
    • Also referred to as CREST syndrome:
      • Calcinosis
      • Raynaud’s phenomenon
      • Esophageal dysmotility 
      • Sclerodactyly (tight skin over digits)
      • Telangiectasias 
  • SS sine scleroderma (rare):
    • No detectable skin involvement
    • Raynaud’s phenomenon, digital ulcers, and PAH
  • SS with overlap syndrome:
    • Symptoms of any of the other subsets
    • Overlap with other rheumatologic diseases:
      • Lupus
      • Rheumatoid arthritis
      • Polymyositis
      • Sjögren’s syndrome

Clinical symptoms

Diffuse and limited cutaneous SS:

  • Constitutional symptoms:
    • Fever
    • Fatigue
    • Weight loss 
  • Skin:
    • Swelling with non-pitting edema
    • Skin thickening/tightening:
      • Sclerodactyly 
      • Perioral skin → reduced mouth opening
      • Around small joints → contractures
    • Hyper-/hypopigmentation
    • Pruritus
  • Hands:
    • Prolonged Raynaud’s phenomenon
    • Calcinosis cutis (calcium deposition under the skin → hard bumps)
    • Digital ulceration
    • Gangrene
    • Nail bed telangiectasia

Diffuse forms with or without cutaneous involvement:

  • Gastrointestinal (90%):
    • Dysphagia
    • Gastroesophageal reflux disease
    • Hoarseness
    • Malabsorption
    • Vascular ectasia → watermelon stomach
  • Pulmonary (80%):
    • Interstitial lung disease (ILD) → pulmonary fibrosis
    • Pulmonary arterial hypertension 
    • Pulmonary embolism
  • Cardiac:
    • Restrictive cardiomyopathy
    • Constrictive pericarditis
    • Arrhythmias 
  • Genitourinary:
    • Dyspareunia
    • Erectile dysfunction
  • Renal:
    • Hypertension
    • Chronic kidney disease
    • Scleroderma renal crisis:
      • Life-threatening acute renal failure
      • Malignant hypertension
  • Musculoskeletal:
    • Arthralgia/arthritis
    • Joint contractures
    • Tendon friction rubs
    • Tendinitis
  • Neuromuscular:
    • Muscle atrophy
    • Weakness
    • Myopathy
    • Neuropathies

Related videos

Diagnosis

Physical exam

  • 1st step in evaluation
  • Look for characteristic skin and hand changes.

Laboratory studies

  • General:
    • Complete blood count (anemia):
      • Malabsorption
      • Iron deficiency
      • GI blood loss
    • Creatine kinase: myopathy/myositis
    • Urinalysis to assess kidney function:
      • Proteinuria
      • Cellular casts
    • Serum creatinine
  • Serology:
    • Antinuclear antibody (ANA): present in 95% of patients
    • Anti-centromere antibody: specific for limited SS
    • Anti-topoisomerase (anti-Scl 70): 
      • Specific for diffuse SS
      • Associated with interstitial lung disease
    • Anti-RNA polymerase III:
      • Specific for diffuse SS
      • Associated with rapidly progressive skin involvement and scleroderma renal crisis

Additional tests

  • Pulmonary function test (PFT):
    • Restrictive ventilatory defect
    • Decrease in single-breath diffusion capacity for carbon monoxide
  • High-resolution chest computed tomography (CT) scan: interstitial lung abnormalities
  • Echocardiogram: screening for PAH
  • Other studies depending on a particular organ involvement
Scleroderma CT

Chest CT scan showing lung fibrosis at the time of diagnosis of progressive systemic sclerosis

Image: “Chest computed tomography scan” by Division of Respiratory Medicine, Mito Medical Center, University of Tsukuba, Mito, Ibaraki 310-0015, Japan. License: CC BY 3.0

Skin biopsy

  • Rarely indicated
  • Can be performed to differentiate from other diseases (e.g., eosinophilic fasciitis, scleromyxedema, amyloidosis)

Management

There is no curative treatment for SS.

Management goals

  • Minimize symptoms.
  • Delay the progression of organ-specific complications.

Skin

  • Pruritus:
    • Prevent dryness (lubricating lotions; avoid drying soaps, heat).
    • Antihistamines
    • Low-dose prednisone
  • Skin sclerosis:
    • 1st line: methotrexate or mycophenolate mofetil
    • 2nd line: cyclophosphamide
    • For refractory cases: immune globulin or rituximab
    • Ultraviolet A light therapy also beneficial
  • Cutaneous calcinosis:
    • Oral minocycline
    • Surgical removal of lesions in some cases
  • Telangiectasia: laser therapy

Other organs

  • Kidneys:
    • Angiotensin-converting inhibitors
    • Avoid glucocorticoids.
  • Esophageal reflux: H2 blockers or proton-pump inhibitors
  • Raynaud’s phenomenon: 
    • Avoid cold.
    • Calcium-channel blockers
    • Prostacyclin analogs
  • Pulmonary hypertension: 
    • Endothelin receptor antagonist (bosentan)
    • Phosphodiesterase inhibitors (tadalafil)
    • Prostacyclin pathway agonists (epoprostenol)
  • Pulmonary fibrosis: 
    • Mycophenolate mofetil
    • Cyclophosphamide

Prognosis

  • Overall 5-year survival is 80%.
  • Mortality in patients with scleroderma is 4 times higher than in sex- and age-matched controls.
  • Major predictors of mortality:
    • Extensive skin involvement
    • Lung or cardiac disease
    • Renal disease
    • Younger age of onset
    • African descent

Differential Diagnosis

  • Hypothyroidism: a disorder associated with decreased production of thyroid hormones. One manifestation is myxedema, which produces skin changes similar to SS with coarseness and thickening. Patients also complain of fatigue. Diagnosed by measuring thyroid hormone and thyroid-stimulating hormone levels. The treatment is based on thyroid hormone replacement.
  • Diabetes: an endocrine disorder caused by insulin deficiency or insulin resistance. Long-standing diabetes mellitus type 1 may be associated with skin changes and sclerodactyly. Diagnosis is established by measurement of blood glucose levels. Treatment is focused on insulin replacement and blood glucose control.
  • Amyloidosis: a disorder of extracellular tissue deposition of fibrils. Infiltration of the skin can cause thickness and systemic deposition can result in symptoms very similar to those of diffuse scleroderma. Diagnosis is established by skin biopsy. Treatment modalities depend on the type of amyloidosis.
  • Chronic graft-versus-host disease: a disorder that typically follows allogeneic hematopoietic transplantation. Can be associated with scleroderma-like skin changes. Diagnosis is established by skin biopsy. Treatment involves steroids and immunosuppressive medications.

References

  1. Denton C.P. (2020). Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults. Retrieved January 28, 2021, from https://www.uptodate.com/contents/overview-of-the-treatment-and-prognosis-of-systemic-sclerosis-scleroderma-in-adults
  2. Denton C.P. (2019). Pathogenesis of systemic sclerosis (scleroderma). Retrieved January 28, 2021, from https://www.uptodate.com/contents/pathogenesis-of-systemic-sclerosis-scleroderma
  3. Ingegnoli F, Ughi N, Mihai C. Update on the epidemiology, risk factors, and disease outcomes of systemic sclerosis. Best Pract Res Clin Rheumatol. 2018;32(2):223. Epub 2018 Sep 14. 
  4. Jimenez S.A. (2020). Scleroderma. Retrieved January 28, 2021, from https://emedicine.medscape.com/article/331864-overview
  5. Varga J. (2020). Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults. Retrieved January 28, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-systemic-sclerosis-scleroderma-in-adults

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