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%.

Last updated: September 1, 2022

CONTENTS

Overview
Pathophysiology and Clinical Presentation
Diagnosis
Management
Differential Diagnosis
References

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

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
 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