Basics
Description
- Scleroderma means "hard skin. " It can be systemic or localized.
- Systemic sclerosis (SSc) or progressive systemic sclerosis (PSS)
- Diffuse cutaneous SSc: affects skin and internal organs (lungs, GI tract)
- Limited cutaneous SSc, also known as CREST: a variant form of SSc characterized by calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectases
- Localized
- Morphea
- Linear scleroderma
- En Coup de Sabre/Parry-Romberg syndrome
Epidemiology
- Systemic
- Age of onset: 30 " 50 years; very rare in children
- Sex ratio
- <7 years, male = female
- >7 years, female > male (3:1)
- 15 " 44 years, female > male (15:1)
- CREST
- Earlier age of onset than SSc
- Almost nonexistent in children
- Female > male
Incidence
- Systemic: 0.27 per million annually
- CREST: affects ’ Ό1/2 of patients with systemic disease
- Localized: approximately 10 more common than SSc in childhood
Pathophysiology
- Systemic involvement
- Vasculopathy: based on high association with Raynaud phenomenon; vascular injury leading to fibrotic changes as a part of overcorrection
- Serum factors: overexpression of endothelin, a potent vasoconstrictor with profibrotic activity
- Immune dysfunction: autoimmunity directed against connective tissue antigen such as laminin or type IV collagen, platelet-derived growth factor receptors stimulating fibrosis
- Localized form
- Alteration of normal glycosylation and hydroxylation of collagen
- May represent distinct early and late processes
- Early: increased hydrophilic glycosaminoglycan; increased T cells, macrophages, and plasma cells; mast cell hyperplasia
- Late: increased collagen content; collagen is embryonic with narrow fibrils and immature cross-banding; atrophy of rete pegs, epithelial tissue projecting into underlying connective tissue
Diagnosis
History
- Thickening of skin
- Tightness of joints
- Discoloration of skin
- Often insidious onset
- Morning stiffness
- Heartburn, dysphagia, reflux, cough with swallowing
Signs and symptoms:
- SSc
- Diagnostic criteria (1 major criterion or 2 minor criteria required)
- Major: sclerodermatous changes (tightness, thickening, induration) proximal to metacarpophalangeal or metatarsophalangeal joints
- Minor: sclerodactyly-sclerodermatous changes limited to digits (unable to pinch skin over the digit), digital pitting, bibasilar pulmonary fibrosis not due to primary lung disease
- CREST
- More severe calcinosis
- Distal symptoms more severe
- Associated with anti-centromere antibody
- Occasional evolution into another connective tissue disease such as mixed connective tissue disease (MCTD) or systemic lupus erythematosus (SLE)
- Localized
- Fibrosis limited to skin, subcutaneous (SC) tissue, and muscle
- Systemic features including Raynaud phenomenon and visceral involvement are extremely rare except in Parry-Romberg.
- Forms:
- Morphea: ≥1 oval or round indurations that become hard and whitish early on, have active inflammatory border with violaceous color. Various forms: plaque or guttate (limited number of lesions); generalized (extensive); nodular (SC)
- Linear: ≥1 linear areas affecting SC tissue, muscle, and bone; can cross joint lines and also affect limb growth
- En Coup de Sabre: involves face or scalp; may be associated with seizures
- Parry-Romberg syndrome: form of linear scleroderma; congenital dysplasia of SC tissue; neurologic changes such as transient ischemic attacks (TIAs) in brain matter under lesion, without its direct extension into the skull
Physical Exam
- Findings in SSc:
- Skin
- Stage 1: Edema " tense, nonpitting; perhaps warm or tender but often asymptomatic
- Stage 2: Sclerosis " waxy, hard texture; bound to SC structures, back of digits, face (loss of forehead wrinkles, reduced mouth orifice)
- Stage 3: Atrophy " shiny appearance, hypopigmented or hyperpigmented, calcium deposits in SC tissue
- Telangiectasias: macular dilatations that fill slowly, unlike spider telangiectasias
- Loss of SC tissue pulp of the fingers and ulcerations on fingertips with prolonged healing in SSc
- Raynaud phenomenon
- Primary phenomenon or Raynaud disease: not associated with underlying disease; milder; 75% are female.
- Secondary Raynaud phenomenon: associated with underlying disease such as SSc, SLE, Sj Άgren syndrome, MCTD, dermatomyositis, and polymyositis; more serious. Present in ’ Ό90% of SSc patients.
- Triple phase: blanching of digits with sharp border to normal-colored skin (arterial vasoconstriction) followed by cyanosis (venostasis) then erythema; tingling/numb sensation of the digits (reflex hyperemia to vasodilatation)
- Usually fingers; also toes, nose, ears, and tongue; often spares thumb
- Calcinosis, especially over extensor joint surfaces in systemic form only
- Pitfalls
- Failure to recognize limited mouth opening in SSc
- Failure to evaluate periungual nailfold changes with Raynaud phenomenon: capillary dropout and dilated loops; occasional redundant cuticular growth and digital pitting
- Musculoskeletal
- "Creaking " of thickened tendons
- Contractures, especially proximal interphalangeal joints and elbows
- Associated arthritis
- Muscle inflammation in ’ Ό30% of cases
- GI
- Mucosal telangiectasias of mouth
- Decreased incisor distance/mouth opening secondary to skin tightness of the lips
- Sicca syndrome with parotitis
- Loosening of teeth secondary to periodontal membrane disease
- Esophageal disease: esophagitis, occasional ulceration or stricture
- Large-bowel disease less common
- Cardiac
- Primary cause of morbidity
- Possibly due to Raynaud phenomenon of coronary arteries and pulmonary artery hypertension
- Myocarditis possible
- Pulmonary
- Interstitial fibrosis with gradual obliteration of vascular bed and resulting cor pulmonale
- Parenchymal disease is almost universal; frequently asymmetric; may have hacking cough, dyspnea on exertion, pleural rub.
- Combined pulmonary vascular and pulmonary parenchymal disease
- Primary pulmonary vascular disease with right ventricular failure
- Renal: due to decreased renal plasma flow, proteinuria, hypertension, renal crisis
- CNS: cranial nerve involvement, especially sensory branch of trigeminal nerve
- Sicca syndrome
- Xerostomia (dry mouth)
- Keratoconjunctivitis sicca (dry eyes)
Diagnostic Tests & Interpretation
Lab
There are no specific diagnostic tests.
- Nonspecific tests
- Systemic form
- Antinuclear antibody (ANA): often positive
- Hemoglobin: 25% have anemia due to chronic disease or vitamin B12 and folate deficiencies resulting from chronic malabsorption in sclerodermatous gut.
- Eosinophilia: present in 50%
- Sclero-70 (Scl-70 or topoisomerase 1) antibodies: present in 26% of adults; more common with diffuse disease than with peripheral vascular disease
- Anti-centromere antibody: present in 22%, almost exclusively with CREST
- Muscle biopsy
- Localized forms
- Eosinophilia: present in 25 " 50% during active disease
- ANA: positive in 37 " 67%
Imaging
- Chest radiograph
- Bibasilar pulmonary fibrosis
- Rib notching
- Calcifications (in CREST)
- High-resolution chest CT
- Ground-glass attenuation
- Honeycombing
- Bone radiograph
- Acro-osteolysis: resorption of tufts of distal phalanges, especially with severe Raynaud phenomenon
- Periarticular or SC calcification (15 " 25% patients)
- Bony erosions
Diagnostic Procedures/Other
- For sicca syndrome
- Schirmer test for dry eyes
- Lip biopsy
- Rose bengal staining of cornea
- ECG
- 1st-degree block
- Right and left bundle-branch block
- Premature atrial contractions (PACs) and premature ventricular contractions (PVCs): nonspecific T-wave changes, ventricular hypertrophy
- Pulmonary function tests
- Restrictive lung disease: present in 34% of patients with SSc
- Earliest changes are decreased forced vital capacity (FVC) and small airway disease.
- Decreased diffusing capacity of the lung for carbon monoxide (DLCO): present in 18% of patients with SSc at the time of diagnosis
Pathologic Findings
- Histologic
- Skin: loss of SC fat, increased amount of fibroblasts
- Muscle: increased collagen and fat; negative immunofluorescence
- Esophagus: Atrophic muscle replaced by fibrous tissue more commonly affects smooth muscle of lower 2/3 of esophagus.
- Esophageal manometry and pH probe: decreased or absent peristalsis of distal esophagus " distal dilatation, hiatal hernia, stricture
- Dilatation of second and third part of duodenum and proximal jejunum
Differential Diagnosis
- Graft-versus-host disease (GVHD)
- Phenylketonuria
- Borrelia infection: acrodermatitis chronica atrophicans
- Porphyria cutanea tarda
- Scleredema
- Stiff skin syndrome (mucin deposition in the dermis, hardening of the subcutaneous tissue with normal-looking epidermis)
- Eosinophilic fasciitis
Treatment
Medication
Disease modification: Many agents have been tried; however, there are few controlled trials, and no proven treatment exists. Medications include the following:
- Localized
- Imiquimod, calcitriol ointment, psoralen ultraviolet A light (PUVA) therapy, methotrexate, mycophenolate mofetil, cyclosporine
- Systemic
- Colchicine: inhibits fibroproliferative process
- Immunosuppressives
- Steroids, chlorambucil, methotrexate, mycophenolate mofetil, cyclosporine, cyclophosphamide, rituximab
- Pitfall: Avoid excessive use of immunosuppressive therapy late in disease when inflammatory component has resolved.
Additional Treatment
General Measures
- Supportive care: Avoid trauma and excessive cold; keep extremities warm AND dry.
- Management of Raynaud phenomenon:
- Avoid beta-blockers, caffeine, and stimulating ADHD medications.
Additional Therapies
- Physical therapy
- Helps retard development of contractures and muscle atrophy
- Pitfall: insufficient physical therapy resulting in permanent joint contractures
Ongoing Care
Follow-up Recommendations
Patient Monitoring
- Localized forms
- Physical exam for joint mobility, muscle bulk, and growth
- Difficult to follow slow disease progression, thus photography of lesions every 3 " 6 months is recommended
- Systemic forms
- Physical exam for digital ulcerations, joint mobility, muscle bulk, and growth
- Yearly pulmonary function tests
- Yearly barium swallow
- ECHO
Prognosis
- In localized forms, natural course includes several phases:
- Initial: inflammation
- Late: sclerosis
- Occasional regression over 3 " 5 years
- Contractures and limb size difference can persist with linear scleroderma.
- Systemic form is progressive and ultimate prognosis depends on severity of skin tightness, joint contracture, and visceral involvement.
- Mortality with SSc
- Males > females
- Non-whites > whites
- Most common cause of death in pediatric patients with SSc is secondary to cardiac, renal, and pulmonary complications.
Complications
- Localized
- Skin thickening
- Joint contractures
- Leg length discrepancies
- CNS bleed in Parry-Romberg
Additional Reading
- Fain ET, Mannion M, Pope E, et al. Brain cavernomas associated with en coup de sabre linear scleroderma: two case reports. Pediatr Rheumatol Online J. 2011;9:18. [View Abstract]
- Fitch PG, Rettig P, Burnham JM, et al. Treatment of pediatric localized scleroderma with methotrexate. J Rheumatol. 2006;33(3):609 " 614. [View Abstract]
- Foeldvari I. Methotrexate in juvenile localized scleroderma. Arthritis Rheum. 2011;63(7):1779 " 1781. [View Abstract]
- Foeldvari I. Update on pediatric systemic sclerosis: Similarities and differences from adult disease. Curr Opin Rheumatol. 2008;20(5):608 " 612. [View Abstract]
- Herrick AL, Ennis H, Bhushan M, et al. Incidence of childhood linear scleroderma and systemic sclerosis in the UK and Ireland. Arthritis Care Res. 2010;62(2):213 " 218. [View Abstract]
- Martini G, Foeldvari I, Russo R, et al. Systemic sclerosis in childhood: Clinical and immunologic features of 153 patients in an international database. Arthritis Rheum. 2006;54(12):3971 " 3978. [View Abstract]
- Zulian F. New developments in localized scleroderma. Curr Opin Rheumatol. 2008;20(5):601 " 607. [View Abstract]
Codes
ICD09
- 710.1 Systemic sclerosis
- 517.8 Lung involvement in other diseases classified elsewhere
ICD10
- M34.9 Systemic sclerosis, unspecified
- M34.1 CR(E)ST syndrome
- L94.0 Localized scleroderma [morphea]
- L94.1 Linear scleroderma
- M34.83 Systemic sclerosis with polyneuropathy
- M34.81 Systemic sclerosis with lung involvement
- M34.82 Systemic sclerosis with myopathy
- M34.0 Progressive systemic sclerosis
- M34.89 Other systemic sclerosis
SNOMED
- 89155008 systemic sclerosis (disorder)
- 62382002 Calcinosis, Raynauds phenomenon, sclerodactyly, and telangiectasia syndrome (disorder)
- 201048007 Localized morphea (disorder)
- 22784002 Linear scleroderma (disorder)
- 7513007 Generalized morphea
- 196133001 Lung disease with systemic sclerosis (disorder)
- 236502006 Renal involvement in scleroderma
- 128460000 systemic sclerosis, diffuse (disorder)
- 299276009 Limited systemic sclerosis (disorder)
FAQ
- Q: Is a biopsy necessary?
- A: Biopsy is often useful to confirm diagnosis and assess degree of inflammation.
- Q: Is the sclero-70 antibody useful?
- A: Not for diagnosis; it is positive only in a subset of individuals with the systemic form and, therefore, useful for predicting more severe disease.