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Scleroderma, Pediatric

Basics

Description

- CREST - Earlier age of onset than SSc - Almost nonexistent in children - Female > male

- 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

- 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)

- 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

- 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

- 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

- 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.

- Systemic - Colchicine: inhibits fibroproliferative process - Immunosuppressives - Steroids, chlorambucil, methotrexate, mycophenolate mofetil, cyclosporine, cyclophosphamide, rituximab

- Systemic forms - Physical exam for digital ulcerations, joint mobility, muscle bulk, and growth - Yearly pulmonary function tests - Yearly barium swallow - ECHO

- 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

  • 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
  • LocalizedMorpheaLinear sclerodermaEn Coup de Sabre/Parry-Romberg syndrome

Epidemiology

  • SystemicAge of onset: 30 " 50 years; very rare in childrenSex ratio<7 years, male = female>7 years, female > male (3:1)15 " 44 years, female > male (15:1)
  • CRESTEarlier age of onset than SScAlmost nonexistent in childrenFemale > 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 involvementVasculopathy: based on high association with Raynaud phenomenon; vascular injury leading to fibrotic changes as a part of overcorrectionSerum factors: overexpression of endothelin, a potent vasoconstrictor with profibrotic activityImmune dysfunction: autoimmunity directed against connective tissue antigen such as laminin or type IV collagen, platelet-derived growth factor receptors stimulating fibrosis
  • Localized formAlteration of normal glycosylation and hydroxylation of collagenMay represent distinct early and late processesEarly: increased hydrophilic glycosaminoglycan; increased T cells, macrophages, and plasma cells; mast cell hyperplasiaLate: 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:

  • SScDiagnostic criteria (1 major criterion or 2 minor criteria required)Major: sclerodermatous changes (tightness, thickening, induration) proximal to metacarpophalangeal or metatarsophalangeal jointsMinor: sclerodactyly-sclerodermatous changes limited to digits (unable to pinch skin over the digit), digital pitting, bibasilar pulmonary fibrosis not due to primary lung diseaseCRESTMore severe calcinosisDistal symptoms more severeAssociated with anti-centromere antibodyOccasional evolution into another connective tissue disease such as mixed connective tissue disease (MCTD) or systemic lupus erythematosus (SLE)
  • LocalizedFibrosis limited to skin, subcutaneous (SC) tissue, and muscleSystemic 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 growthEn Coup de Sabre: involves face or scalp; may be associated with seizuresParry-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:SkinStage 1: Edema " tense, nonpitting; perhaps warm or tender but often asymptomaticStage 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 tissueTelangiectasias: macular dilatations that fill slowly, unlike spider telangiectasiasLoss of SC tissue pulp of the fingers and ulcerations on fingertips with prolonged healing in SScRaynaud phenomenonPrimary 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 thumbCalcinosis, especially over extensor joint surfaces in systemic form onlyPitfallsFailure to recognize limited mouth opening in SScFailure to evaluate periungual nailfold changes with Raynaud phenomenon: capillary dropout and dilated loops; occasional redundant cuticular growth and digital pittingMusculoskeletal "Creaking " of thickened tendonsContractures, especially proximal interphalangeal joints and elbowsAssociated arthritisMuscle inflammation in ’ Ό30% of casesGIMucosal telangiectasias of mouthDecreased incisor distance/mouth opening secondary to skin tightness of the lipsSicca syndrome with parotitisLoosening of teeth secondary to periodontal membrane diseaseEsophageal disease: esophagitis, occasional ulceration or strictureLarge-bowel disease less commonCardiacPrimary cause of morbidityPossibly due to Raynaud phenomenon of coronary arteries and pulmonary artery hypertensionMyocarditis possiblePulmonaryInterstitial fibrosis with gradual obliteration of vascular bed and resulting cor pulmonaleParenchymal disease is almost universal; frequently asymmetric; may have hacking cough, dyspnea on exertion, pleural rub.Combined pulmonary vascular and pulmonary parenchymal diseasePrimary pulmonary vascular disease with right ventricular failureRenal: due to decreased renal plasma flow, proteinuria, hypertension, renal crisisCNS: cranial nerve involvement, especially sensory branch of trigeminal nerveSicca syndromeXerostomia (dry mouth)Keratoconjunctivitis sicca (dry eyes)

Diagnostic Tests & Interpretation

Lab

There are no specific diagnostic tests.

  • Nonspecific testsSystemic formAntinuclear antibody (ANA): often positiveHemoglobin: 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 diseaseAnti-centromere antibody: present in 22%, almost exclusively with CRESTMuscle biopsyLocalized formsEosinophilia: present in 25 " 50% during active diseaseANA: positive in 37 " 67%

Imaging

  • Chest radiographBibasilar pulmonary fibrosisRib notchingCalcifications (in CREST)
  • High-resolution chest CTGround-glass attenuationHoneycombing
  • Bone radiographAcro-osteolysis: resorption of tufts of distal phalanges, especially with severe Raynaud phenomenonPeriarticular or SC calcification (15 " 25% patients)Bony erosions

Diagnostic Procedures/Other

  • For sicca syndromeSchirmer test for dry eyesLip biopsyRose bengal staining of cornea
  • ECG1st-degree blockRight and left bundle-branch blockPremature atrial contractions (PACs) and premature ventricular contractions (PVCs): nonspecific T-wave changes, ventricular hypertrophy
  • Pulmonary function testsRestrictive lung disease: present in 34% of patients with SScEarliest 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

  • HistologicSkin: loss of SC fat, increased amount of fibroblastsMuscle: increased collagen and fat; negative immunofluorescenceEsophagus: 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:

  • LocalizedImiquimod, calcitriol ointment, psoralen ultraviolet A light (PUVA) therapy, methotrexate, mycophenolate mofetil, cyclosporine
  • SystemicColchicine: inhibits fibroproliferative processImmunosuppressivesSteroids, 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 therapyHelps retard development of contractures and muscle atrophyPitfall: insufficient physical therapy resulting in permanent joint contractures

Ongoing Care

Follow-up Recommendations

Patient Monitoring

  • Localized formsPhysical exam for joint mobility, muscle bulk, and growthDifficult to follow slow disease progression, thus photography of lesions every 3 " 6 months is recommended
  • Systemic formsPhysical exam for digital ulcerations, joint mobility, muscle bulk, and growthYearly pulmonary function testsYearly barium swallowECHO

Prognosis

  • In localized forms, natural course includes several phases:Initial: inflammationLate: sclerosisOccasional 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 SScMales > femalesNon-whites > whites
  • Most common cause of death in pediatric patients with SSc is secondary to cardiac, renal, and pulmonary complications.

Complications

  • LocalizedSkin thickeningJoint contracturesLeg length discrepanciesCNS 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.