Scleroderma Scleroderma and and

Inflammatory MyositisInflammatory Myositis

Scleroderma Scleroderma and and

Inflammatory MyositisInflammatory Myositis

Kathryn Dao, MD

Arthritis Center

February 16, 2006

SclerodermaSclerodermaSclerodermaScleroderma

“Skleros-” = hard “-derma” = skin Incidence 1-2/100,000 in USA Peak age of onset 30-50 y.o. Female:male 7-12: 1 Disease manifestation is a result of host

factors + environment (concordance is similar in monozygotic and dizygotic twins)

SclerodermaSclerodermaThree major disease subsets: based on extent of skin dz Localized Scleroderma

Morphea: manifests as focal patches Linear scleroderma: band-like (linear) areas of

thickening. (Coup de Sabre) Limited disease AKA "CREST" syndrome

Calcinosis, Raynauds, Esophageal dysmotility Sclerodactyly, Telangiectasias

Diffuse disease - skin abnormalities extending to the proximal extremities (AKA - PSS)

(Scleroderma sine scleroderma)

DDX of Tight SkinDDX of Tight SkinDDX of Tight SkinDDX of Tight Skin

Pseudosclerodactyly IDDM, Hypothyroidism

Drugs: Tryptophan, bleomycin, pentazocine, vinyl chloride, solvents

Eosinophilic fasciitis Overlap syndromes Scleredema

DDX of Tight SkinDDX of Tight SkinDDX of Tight SkinDDX of Tight Skin

Scleromyxedema (popular mucinosis)

Scleroderma-like conditions Eosinophil myalgia

syndrome (tryptophan) Porphyria cutanea

tarda Toxic oil syndrome Nephrogenic fibrosing

dermopathy

ACR Systemic Sclerosis ACR Systemic Sclerosis Preliminary Classification Criteria*Preliminary Classification Criteria*

ACR Systemic Sclerosis ACR Systemic Sclerosis Preliminary Classification Criteria*Preliminary Classification Criteria*

Major Criterion Proximal Scleroderma

Minor Criteria Sclerodactyly Digital pitting or scars or loss of finger pad Bibasilar pulmonary fibrosis

* One major and two minor required for diagnosis

Scleroderma: OnsetScleroderma: OnsetScleroderma: OnsetScleroderma: Onset

Raynauds Swollen or puffy digits Loss of skin folds, no hair

growth Digital pulp sores/scars Arthralgias >> Arthritis

SclerodermaSclerodermaA disorder of Collagen, VesselsA disorder of Collagen, Vessels

SclerodermaSclerodermaA disorder of Collagen, VesselsA disorder of Collagen, Vessels

Etiology: unknown? Autoimmune disorder suggested by the

presence of characteristic autoantibodies such as ANA, anti-centromere and anti-SCL-70 antibodies.

Pathology: Early dermal changes lymphocytic infiltrates

primarily of T cells Major abnormality is collagen accumulation

with fibrosis.

SclerodermaSclerodermaA disorder of Collagen, VesselsA disorder of Collagen, Vessels

SclerodermaSclerodermaA disorder of Collagen, VesselsA disorder of Collagen, Vessels

Small to medium-sized blood vessels, which show bland fibrotic change Vasculopathy, NOT vasculitis!

Small thrombi may form on the altered intimal surfaces.

Microvascular disease Normal

PSS

Cold

Cold

PSS - ClinicalPSS - Clinical

Skin: Skin thickening is most noticeable in the hands,

looking swollen, puffy, waxy. Thickening extends to proximal extremity, truncal

and facial skin thickening is seen. Raynaud's phenomenon is present. Digital pits or scarring of the distal digital pulp

Musculoskeletal: Arthralgias and joint stiffness are common. Palpable tendon friction rubs associated with an

increased incidence of organ involvement. Muscle weakness or frank myositis can be seen.

Skin ScoresExtent of skin involvment predictive of survival:

% Survival at 5 yr 10 yr

Sclerodactyly 79-84 47-75

Truncal 48-50 22-26

J Rheumatol 1988;15:276-83.

Gastrointestinal: Esophageal dysmotility, dysphagia, malabsorptive or blind loop syndrome, constipation.

PSS - ClinicalPSS - Clinical

Renal: Kidney involvement is an ominous finding and important cause of death in diffuse scleroderma. A hypertensive crisis (AKA renal crisis) may herald the onset of rapidly progressive renal failure.

Scleroderma Renal CrisisScleroderma Renal CrisisScleroderma Renal CrisisScleroderma Renal Crisis

Risk Factors diffuse skin involvement rapid progression of skin thickening disease course < 4 years anti-RNA-polymerase III-antibodies newly manifested anemia newly manifested cardiac involvement

pericardial effusion heart insufficiency

preceded high-dose corticoid therapy pregnancy

Am J Med 1984;76:779-786.

Scleroderma Renal CrisisScleroderma Renal CrisisScleroderma Renal CrisisScleroderma Renal Crisis

Microangiopathic hemolytic anemia +Microscopic hematuria

Fatal before the introduction of ACE-I, CCB Survival without ACE-I 16% @ 1 year, with

ACE-I 45% at 5 years Continue use of ACE-I even if dialysis

appears imminent

Ann Int Med 1990;113:352-357.

Pulmonary Manifestations of PSSPulmonary Manifestations of PSSPulmonary Manifestations of PSSPulmonary Manifestations of PSS

Dyspnea Pulmonary HTN primarily in CREST Ground glass (alveolitis) Interstitial fibrosis (bibasilar) High resolution CT vs Gallium Scan

Major cause of death RARE:

Pulmonary embolism Pulmonary vasculitis

Decreased DLCO is the Earliest Marker Increased A-a Gradient with Exercise Restrictive Pattern

VC, FEV1/FVC Pulmonary Vascular Disease

DLCO with Normal Volumes

PFT’s in Systemic SclerosisPFT’s in Systemic SclerosisPFT’s in Systemic SclerosisPFT’s in Systemic Sclerosis

Cardiac Findings in PSSCardiac Findings in PSSCardiac Findings in PSSCardiac Findings in PSS

Myocardial fibrosis Dilated cardiomyopathy Cor pulmonale Arrhythmias Pericarditis Myocarditis Congestive heart failure Myocardial infarction (Raynaud’s)

Comparison CREST v. PSSComparison CREST v. PSSComparison CREST v. PSSComparison CREST v. PSS Feature Limited CREST Diffuse PSS

 Calcinosis ++ +

 Arthralgia/Arthritis

 ++  ++++

 Pulmonary fibrosis

 ++  +++

 Pulmonary HTN  ++  +

 Tend friction rubs

 0 +++

 Renal crisis 0  +

 Centromere Ab  +++ +/0

 Anti-Scl 70 Ab + ++

+ Relative percentages: +++++ 81-100%; ++++ 61-80%; +++ 41-60%; ++ 21-40%; + 1-20%

Raynaud’s +++++ +++++

Telangiectasia +++++ ++++

Esophageal dysmotility

+++++ +++++

5 yr Survival +++++ ++++

Treatment of SclerodermaTreatment of SclerodermaTreatment of SclerodermaTreatment of Scleroderma Localized: none Raynauds: warmth, skin protection,

vasodilator therapy CREST: same as Raynauds PSS: none proven

No Value: Steroids, Penicillamine, MTX Cytoxan: for lung disease? Experimental: stem cell transplant, TNF-I

– Epoprostenol (Flolan): Prostacyclin– Bosentan (Tracleer): Endothelin receptor antagonist

Finger ulcers: difficult; vasodilators, Abx

Inflammatory Myositis:Inflammatory Myositis: Polymyositis/DermatomyositisPolymyositis/Dermatomyositis

Inflammatory Myositis:Inflammatory Myositis: Polymyositis/DermatomyositisPolymyositis/Dermatomyositis

F:M = 2:1 Acute onset Weakness (+ myalgia): Proximal > Distal Skeletal muscle: dysphagia, dysphonia Sx: Rash, Raynauds, dyspnea 65% elevated CPK, aldolase 50% ANA (+) 90% +EMG 85% + muscle biopsy

Proposed Criteria for MyositisProposed Criteria for MyositisProposed Criteria for MyositisProposed Criteria for Myositis1. Symmetric proximal muscle weakness2. Elevated Muscle Enzymes (CPK, aldolase,

AST, ALT, LDH)3. Myopathic EMG abnormalities4. Typical changes on muscle biopsy5. Typical rash of dermatomyositis

PM Dx is Definite with 4/5 criteria and Probable with 3/5 criteria

DM Dx Definite with rash and 3/4 criteria and Probable w/ rash and 2/4 criteria

Polymyositis ClassificationPolymyositis ClassificationBohan & PeterBohan & Peter

Polymyositis ClassificationPolymyositis ClassificationBohan & PeterBohan & Peter

1. Primary idiopathic dermatomyositis2. Primary idiopathic polymyositis3. Adult PM/DM associated with neoplasia4. Childhood Dermatomyositis (or PM)

often associated with vasculitis and calcinosis

5. Myositis associated with collagen vascular disease

MYOPATHY: HISTORICAL MYOPATHY: HISTORICAL CONSIDERATIONSCONSIDERATIONS

MYOPATHY: HISTORICAL MYOPATHY: HISTORICAL CONSIDERATIONSCONSIDERATIONS

Age/Sex/Race Acute vs. Insidious Onset Distribution: Proximal vs. Distal Pain? Drugs/Pre-existing Conditions Neuropathy Systemic Features

DDX MYOPATHIIESDDX MYOPATHIIESDDX MYOPATHIIESDDX MYOPATHIIES Toxic/Drugs

Etoh, Cocaine, Steroids, Plaquenil, Penicillamine, Colchicine, AZT, Statins, Clofibrate, Tryptophan, Taxol, Emetine

Infectious Coxsackie, HBV, HIV, Stept, Staph, Clostridium,

Toxoplasma, Trichinella Inflammatory Myopathies Congenital/metabolic myopathies Neuropathic/Motor Neuron Disorders-MG, MD Endocrine/Metabolic-hypothyroidism Inclusion body myositis

NONMYOPATHIC NONMYOPATHIC CONSIDERATIONSCONSIDERATIONSNONMYOPATHIC NONMYOPATHIC

CONSIDERATIONSCONSIDERATIONS

Fibromyalgia/Fibrositis/Myofascial Pain disorder

Polymyalgia Rheumatica Caucasians, > 55 yrs, M=F ESR > 100, normal strength, no

synovitis CTD (SLE, RA, SSc) Vasculitis Adult Still's Disease

INFLAMMATORY MYOSITISINFLAMMATORY MYOSITISImmunopathogenesisImmunopathogenesis

INFLAMMATORY MYOSITISINFLAMMATORY MYOSITISImmunopathogenesisImmunopathogenesis

Infiltrates - T cells (HLA-DR+) & monocytes Muscle fibers express class I & II MHC Ags T cells are cytotoxic to muscle fibers t-RNA antibodies: role? FOUND IN <50%

OF PTS Infectious etiology? Viral implicated HLA-B8/DR3 in childhood DM DR3 and DRW52 with t-RNA synthetase Ab

DERMATOMYOSITISDERMATOMYOSITIS5 Skin Features5 Skin Features

DERMATOMYOSITISDERMATOMYOSITIS5 Skin Features5 Skin Features

1. Heliotrope Rash: over eyelids Seldom seen in adults

2. Gottrons Sign/Papules (pathognomonic): MCPs, PIPs, MTPs, knees, elbows

3. V-Neck Rash: violaceous/erythema anterior chest w/ telangiectasias

4. Periungual erythema, digital ulcerations

5. Calcinosis

Why is it called a heliotropic rash?

CalcinosisCalcinosisCalcinosisCalcinosis

DIAGNOSTIC TESTINGDIAGNOSTIC TESTINGDIAGNOSTIC TESTINGDIAGNOSTIC TESTING

Physical Examiniation: Motor Strength (Gowers sign), Neurologic Exam

Acute phase reactants unreliable Muscle Enzymes

CPK: elevated >65%; >10% MB fraction is possible Muscle specific- Aldolase, Troponin, Carb. anhydraseIII AST > LDH > ALT Beware of incr. creatinine (ATN) and myoglobinuria

EMG: increased insertional activity, amplitude, polyphasics, neuropathic changes, incremental/decremental MU changes

DIAGNOSTIC TESTINGDIAGNOSTIC TESTINGDIAGNOSTIC TESTINGDIAGNOSTIC TESTING Muscle Biopsy (an URGENT not elective

procedure) Call the neuropathologist! 85% Sensitive. Biopsy involved muscle (MRI guided) Avoid EMG/injection sites or sites of trauma

Magnetic Resonance Imaging - detects incr. water signal, fibrous tissue, infiltration, calcification

Investigational: Tc-99m Scans, PET Scans Serologic Tests: ANA (+) 60%, Abs against t-

RNA synthetases

INFLAMMATORY MYOSITISINFLAMMATORY MYOSITISBiopsy FindingsBiopsy Findings

INFLAMMATORY MYOSITISINFLAMMATORY MYOSITISBiopsy FindingsBiopsy Findings

Inflammatory cells Edema and/or fibrosis Atrophy/ necrosis/ degeneration Centralization of nuclei Variation in muscle fiber size Rarely, calcification

Polymyositis: CD8+Tcells, endomysial infiltration

Dermatomyositis: Humoral response B cells, CD4+ T cells; perifascicular/perivascular infiltration

Autoantibodies in PM/DMAutoantibodies in PM/DMAutoantibodies in PM/DMAutoantibodies in PM/DM

Ab Freq (%) Clinical Syndrome

ANA 50 Myositis

U1-RNP 15 SLE + myositis

Ku <5 PSS + myositis

Mi2 30 Dermatomyositis

PM1 15 PSS – PM overlap

Jo-1 25 Arthritis+ ILD+ Raynaud

SS-B (La) <5 SLE,Sjogrens, ILD, PM

PL-12,7 <5 ILD + PM

Anti-synthetase syndrome: ILD, fever, arthritis, Raynauds, Mechanics hands– association with Jo-1

MALIGNANCY & MYOSITISMALIGNANCY & MYOSITISMALIGNANCY & MYOSITISMALIGNANCY & MYOSITIS

Higher association with DM, less common with polymyositis

Common tumors: Breast, lung, ovary, stomach, uterus, colon, NHL

60% the myositis appears 1st, 30% neoplasm 1st, and 10% contemporaneously

Studies found 20-32% with DM developed CA

Lancet 2001

Ann Int Med 2001.

Dermatomyositis and MalignancyDermatomyositis and MalignancyDermatomyositis and MalignancyDermatomyositis and Malignancy

All adults with DM should have age-appropriate screening annually during first several years after presentation: CXR Colonoscopy or sigmoidoscopy PSA/prostate exam in men Mammogram, CA-125, pelvic exam,

transvaginal ultrasonography in women

PM/DM ComplicationsPM/DM ComplicationsPM/DM ComplicationsPM/DM Complications

PULMONARY Aspiration pneumonitis Infectious pneumonitis Drug induced

pneumonitis Intercostal, diaphragm

involvement Fibrosing alveolitis RARE:

Pulmonary vasculitis Pulmonary neoplasia

CARDIAC Elev. CPK-MB Mitral Valve prolapse AV conduction

disturbances Cardiomyopathy Myocarditis

Recap: PM/DM DiagnosisRecap: PM/DM DiagnosisRecap: PM/DM DiagnosisRecap: PM/DM Diagnosis

Symmetric progressive proximal weakness

Elevated muscle enzymes (CPK, LFTs) Muscle biopsy evidence of myositis EMG: inflammatory myositis Characteristic dermatologic findings

INFLAMMATORY MYOSITISINFLAMMATORY MYOSITISTreatmentTreatment

INFLAMMATORY MYOSITISINFLAMMATORY MYOSITISTreatmentTreatment

Early Dx, physical therapy, respiratory Rx Corticosteroids : 60-80 mg/day

80% respond within 12 weeks

Steroid resistant Methotrexate Azathioprine

IVIG, Cyclosporin, Chlorambucil: unproven No response to apheresis

PROGNOSISPROGNOSISPROGNOSISPROGNOSIS

Poor in pts. with delayed Dx, low CPK, early lung or cardiac findings, malignancy

PT for muscle atrophy, contractures, disability Kids:50% remission, 35% chronic active

disease Adult < 20 yrs. do better than >55 yrs. Adults: Mortality rates between 28-47% @

7 yrs. Relapses & functional disability are common Death: due to malignancy, sepsis, pulm. or

cardiac failure, and complications of therapy

RHABDOMYOLYSISRHABDOMYOLYSISRHABDOMYOLYSISRHABDOMYOLYSIS Injury to the sarcolemma of skeletal muscle

with systemic release of muscle macromolecules such as CPK, aldolase, actin, myoglobin, etc

Maybe LIFE-THREATENING: from hyperkalemia, met. acidosis, ATN from myoglobinuria

Common causes: EtOH, Cocaine, K+ deficiency, infection, PM/DM, infection (clostridial, staph, strept), medications, exertion/exercise, cytokines

INCLUSION BODY MYOSITISINCLUSION BODY MYOSITISINCLUSION BODY MYOSITISINCLUSION BODY MYOSITIS Bimodal age distribution, maybe hereditary Males > females Slow onset, progressive weakness Painless, distal and proximal weakness Normal or mildly elevated CPK Poor response to corticosteroids Dx: light microscopy may be normal or show

CD8+ lymphs and vacuoles with amyloid. Tubulofilamentous inclusion bodies on electron microscopy