> Table of Contents > Scleroderma
Scleroderma
Ann M. Lynch, PharmD, RPh, AE-C
Deborah M. DeMarco, MD, FACP
image BASICS
DESCRIPTION
  • Scleroderma (systemic sclerosis [SSc]) is a chronic disease of unknown cause characterized by diffuse fibrosis of skin and visceral organs and vascular abnormalities.
  • Most manifestations have vascular features (e.g., Raynaud phenomenon), but frank vasculitis is rarely seen.
  • Can range from a mild disease, affecting the skin, to a systemic disease that can cause death in a few months
  • The disease is categorized into two major clinical variants (1).
    • Diffuse: distal and proximal extremity and truncal skin thickening
    • Limited
      • Restricted to the fingers, hands, and face
      • CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclero-dactyly, telangiectasia)
  • System(s) affected: include, but not limited to skin; renal; cardiovascular; pulmonary; musculoskeletal; gastrointestinal
Geriatric Considerations
Uncommon >75 years of age
Pediatric Considerations
Rare in this age group
Pregnancy Considerations
  • Safe and healthy pregnancies are common and possible despite higher frequency of premature births.
  • High-risk management must be standard care to avoid complications, specifically renal crisis.
  • Diffuse scleroderma causes greater risk for developing serious cardiopulmonary and renal problems. Pregnancy should be delayed until disease stabilizes.
EPIDEMIOLOGY
Incidence
  • In the United States: 1 to 2/100,000/year
  • Predominant age
    • Young adult (16 to 40 years); middle-aged (40 to 75 years), peak onset 30 to 50 years
    • Symptoms usually appear in the 3rd to 5th decades.
  • Predominant sex: female > male (4:1)
Prevalence
In the United States: 1 to 25/100,000
ETIOLOGY AND PATHOPHYSIOLOGY
Pathophysiology involves both a vascular component and a fibrotic component. Both occur simultaneously. The inciting event is unknown, but there is an increase in certain cytokines after endothelial cell activation that are profibrotic (TGF-&bgr; and PDGF).
  • Unknown
  • Possible alterations in immune response
  • Possibly some association with exposure to quartz mining, quarrying, vinyl chloride, hydrocarbons, toxin exposure
  • Treatment with bleomycin has caused a scleroderma-like syndrome, as has exposure to rapeseed oil.
Genetics
Familial clustering is rare, but has been seen.
RISK FACTORS
Unknown
image DIAGNOSIS
PHYSICAL EXAM
  • Skin
    • Digital ulcerations
    • Digital pitting
    • Tightness, swelling, thickening of digits
    • Hyperpigmentation/hypopigmentation
    • Narrowed oral aperture
    • SC calcinosis
  • Peripheral vascular system
    • Telangiectasia
  • Joints, tendons, and bones
    • Flexion contractures
    • Friction rub on tendon movement
    • Hand swelling
    • Joint stiffness
    • Polyarthralgia
    • Sclerodactyly
  • Muscle
    • Proximal muscle weakness
  • GI tract
    • Dysphagia
    • Esophageal reflux due to dysmotility (most common systemic sign in diffuse disease)
    • Malabsorptive diarrhea
    • Nausea and vomiting
    • Weight loss
    • Xerostomia
  • Kidney
    • Hypertension
    • May develop scleroderma renal crisis: acute renal failure (ARF)
  • Pulmonary
    • Dry crackles at lung bases
    • Dyspnea
  • Nervous system
    • Peripheral neuropathy
    • Trigeminal neuropathy
  • Cardiac (progressive disease)
    • Conduction abnormalities
    • Cardiomyopathy
    • Pericarditis
    • Secondary cor pulmonale
DIFFERENTIAL DIAGNOSIS
  • Mixed connective tissue disease/overlap syndromes
  • Scleredema
  • Nephrogenic systemic fibrosis
  • Toxic oil syndrome (Madrid, 1981, affecting 20,000 people)
  • Eosinophilia-myalgia syndrome
  • Diffuse fasciitis with eosinophilia
  • Scleredema of Buschke
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Nail fold capillary microscopy—drop out is most significant finding
  • CBC
  • Creatinine
  • Urinalysis (albuminuria, microscopic hematuria)
  • Antinuclear antibodies (ANA): positive in >90% of patients
  • Anti-Scl-70 (anti-topoisomerase [ATA]) antibody is highly specific for systemic disease and confers a higher risk of interstitial lung disease (ILD).
  • Anticentromere antibody usually associated with CREST variant
  • Chest radiograph
    • Diffuse reticular pattern
    • Bilateral basilar pulmonary fibrosis
  • Hand radiograph
    • Soft tissue atrophy and acro-osteolysis
    • Can see overlap syndromes such as rheumatoid arthritis
    • SC calcinosis
Follow-Up Tests & Special Considerations
  • Pulmonary function tests (PFTs)
    • Decreased maximum breathing capacity
    • Increased residual volume
    • Diffusion defect
  • Antibodies to U3-RNP—higher risk for sclerodermaassociated pulmonary hypertension
  • Anti-PM-Scl antibodies (for myositis) (2)[B]
  • Anti-RNA polymerase III—higher risk for diffuse cutaneous involvement and renal crisis (3)[A]
  • ECG (low voltage): possible nonspecific abnormalities, arrhythmia, and conduction defects
  • Echocardiography: pulmonary hypertension or cardiomyopathy
  • Nail fold capillary loop abnormalities
  • Upper GI
    • Distal esophageal dilatation
    • Atonic esophagus
    • Esophageal dysmotility
    • Duodenal diverticula
  • Barium enema
    • Colonic diverticula
    • Megacolon
  • High-resolution CT scan for detecting alveolitis, which has a ground-glass appearance or fibrosis predominant in bilateral lower lobes
Diagnostic Procedures/Other
  • Skin biopsy
    • Compact collagen fibers in the reticular dermis and hyalinization and fibrosis of arterioles
    • Thinning of epidermis, with loss of rete pegs, and atrophy of dermal appendages
    • Accumulation of mononuclear cells is also seen.
  • Right-sided heart catheterization: Pulmonary hypertension is an ominous prognostic feature.
P.951

Test Interpretation
  • Skin
    • Edema, fibrosis, or atrophy (late stage)
    • Lymphocytic infiltrate around sweat glands
    • Loss of capillaries
    • Endothelial proliferation
    • Hair follicle atrophy
  • Synovium
    • Pannus formation
    • Fibrin deposits in tendons
  • Kidney
    • Small kidneys
    • Intimal proliferation in interlobular arteries
  • Heart
    • Endocardial thickening
    • Myocardial interstitial fibrosis
    • Ischemic band necrosis
    • Enlarged heart
    • Cardiac hypertrophy
    • Pulmonary hypertension
  • Lung
    • Interstitial pneumonitis
    • Cyst formation
    • Interstitial fibrosis
    • Bronchiectasis
  • Esophagus
    • Esophageal atrophy
    • Fibrosis
image TREATMENT
GENERAL MEASURES
  • Treatment is symptomatic and supportive.
  • Esophageal dilation may be used for strictures.
  • Avoid cold; dress appropriately in layers for the weather; be wary of air conditioning.
  • Avoid smoking (crucial).
  • Avoid finger sticks (e.g., blood tests).
  • Elevate the head of the bed during sleep to help relieve GI symptoms.
  • Use softening lotions, ointments, and bath oils to help prevent dryness and cracking of skin.
  • Dialysis may be necessary in renal crisis.
MEDICATION
First Line
  • ACE inhibitors (ACEIs): for preservation of renal blood flow and for treatment of hypertensive renal crisis
  • Corticosteroids: for disabling myositis, pulmonary alveolitis, or mixed connective tissue disease (not recommended in high doses due to increased incidence of renal failure)
  • NSAIDs: for joint or tendon symptoms. Caution with long-term concurrent use with ACEIs (potential renal complications)
  • Antibiotics: for secondary infections in bowel and active skin infections
  • Antacids, proton pump inhibitors: for gastric reflux
  • Metoclopramide: for intestinal dysfunction
  • Hydrophilic skin ointments: for skin therapy
  • Topical clindamycin, erythromycin, or silver sulfadiazine: for prevention of recurrent infectious cutaneous ulcers
  • Consider immunosuppressives for treatment of lifethreatening or potentially crippling scleroderma or interstitial pneumonitis such as cyclophosphamide for ILD (4)[B].
  • Nitrates and dihydropyridine calcium-channel blockers for Raynaud phenomenon
  • Avoidance of caffeine, nicotine, and sympathomimetics may ease Raynaud symptoms.
  • PDE-5 antagonists (e.g., sildenafil), prostanoids, and endothelin-1 antagonists are changing the management of pulmonary hypertension (5).
  • Alveolitis: immunosuppressants and alkylating agents (e.g., cyclophosphamide)
ADDITIONAL THERAPIES
  • Anti-TNF-&agr; therapy: Preliminary suggestion is that these may reduce joint symptoms and disability in inflammatory arthritis, but small sample sizes and observational biases lend to the need for further well-designed, adequately powered, longitudinal clinical trials.
  • Physical therapy to maintain function and promote strength
  • Heat therapy to relieve joint stiffness
SURGERY/OTHER PROCEDURES
  • Some success with gastroplasty for correction of GERD
  • Limited role for sympathectomy for Raynaud phenomenon
  • Lung transplantation for pulmonary hypertension and ILD
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Monitor every 3 to 6 months for end-organ and skin involvement and medications. Provide encouragement.
  • Echocardiology and PFTs yearly
DIET
Drink plenty of fluids with meals.
PATIENT EDUCATION
  • Stay as active as possible, but avoid fatigue.
  • Printed patient information available from the Scleroderma Federation, 1725 York Avenue, No. 29F, New York, NY 10128; (212) 427-7040
  • Advise the patient to report any abnormal bruising or nonhealing abrasions.
  • Assist the patient about smoking cessation, if needed.
PROGNOSIS
  • Possible improvement but incurable
  • Prognosis is poor if cardiac, pulmonary, or renal manifestations present early.
REFERENCES
1. van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against rheumatism collaborative initiative. Arthritis Rheum. 2013;65(11):2737-2747.
2. D'Aoust J, Hudson M, Tatibouet S, et al. Clinical and serologic correlates of anti-PM/Scl antibodies in systemic sclerosis: a multicenter study of 763 patients. Arthritis Rheumatol. 2014;66(6): 1608-1615.
3. Sobanski V, Dauchet L, Lefèvre G, et al. Prevalence of anti-RNA polymerase III antibodies in systemic sclerosis: new data from a French cohort and a systematic review and meta-analysis. Arthritis Rheumatol. 2014;66(2):407-417.
4. Roth MD, Tseng CH, Clements PJ, et al. Predicting treatment outcomes and responder subsets in scleroderma-related interstitial lung disease. Arthritis Rheum. 2011;63(9):2797-2808.
5. Volkmann ER, Saggar R, Khanna D, et al. Improved transplant-free survival in patients with systemic sclerosis-associated pulmonary hypertension and interstitial lung disease. Arthritis Rheumatol. 2014;66(7):1900-1908.
Additional Reading
&NA;
  • Herrick AL. Contemporary management of Raynaud's phenomenon and digits ischaemic complications. Curr Opin Rheumatol. 2011;23(6):555-561.
  • Kowal-Bielecka O, Landewé R, Avouac J, et al. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis. 2009;68(5):620-628.
  • Phumethum V, Jamal S, Johnson SR. Biologic therapy for systemic sclerosis: a systematic review. J Rheumatol. 2011;38(2):289-296.
  • Steen VD. Pregnancy in scleroderma. Rheum Dis Clin North Am. 2007;33(2):345-358, vii.
  • Valerio CJ, Schreiber BE, Handler CE, et al. Borderline mean pulmonary artery pressure in patients with systemic sclerosis. Arthritis Rheum. 2013;65(4):1074-1084.
See Also
&NA;
Morphea
Codes
&NA;
ICD10
  • M34.9 Systemic sclerosis, unspecified
  • M34.1 CR(E)ST syndrome
  • L94.0 Localized scleroderma [morphea]
Clinical Pearls
&NA;
  • Raynaud phenomenon is frequently the initial complaint.
  • Skin thickening, “puffy hands,” and GERD are often noted early in disease.
  • Patients must be followed proactively for development of pulmonary hypertension or ILD.