Inflammatory Muscle Disease

ד"ר סוהיל אעמרראומטולוגיה – הדסה הר הצופים

Classification of IMDAdult Polymyositis (PM)

Adult Dermatomyositis (DM)

Bohan & PeterCRITERIA

1-MUSCLE WEAKNESS2-ENZYMES3-EDT=EMG

4-MUSCLE BIOPSY all for PM

5-TYPICAL RASH for DM

Classification of IMDAdult Polymyositis

Adult DermatomyositisChildhood DermatomyositisPoly/Dermato-myositis associated with malignancyPoly/Dermato-myositis associated with Connective Tissue DiseaseInclusion Body myositisAmyopathic Dermatomyositis

EPIDEMIOLOGY

Annual Incidence: 2-10 case /millionPeak age : 10-15 and 45-55 years old

Female: Male ratio: 3:1 total 1:1 childhood DM

10:1 PM/DM assoc. CTD

Black: White (USA): 4:1

CLINICAL MANIFESTATIONSWeakness of muscles

- shoulder girdle - pelvic girdle - neck flexors

Myalgia is minimal

Constitutional symptoms-fatigue, fever…

CLINICAL MANIFESTATIONS

Rheumatic: arthralgia/arthritis 20-70%Pulmonary: interstitial lung disease 10%GIT: esophageal dysmotility 10-30%Cardiac: conduction blocks and arrhythmiaVascular: Raynaud’s phenomenon 20-40%Skin : Rash, livedo reticularis

RAYNAUD’S PHENOMENON

DERMATOLOGIC-SKIN RASH DERMATOMYOSITIS-:

HELIOTROPE RASH: purple /erythematous rash affecting eyelids,periorbital edema

-/+malar, forehead and nasolabial folds

LIVEDO RETICULARIS- cutis marmorata like

Heliotrope Rash

DERMATOLOGIC-SKIN RASHGOTTRON’S PAPULES :

Purple /erythematous raised lesions over knuckles and extensor regions

V-SIGN:

Erythematous rash over anterior chest and neck. (photosensitivity)

DERMATOLOGIC-SKIN RASHSHAWL-SIGN:

Erythematous rash over the shoulders, upper back and proximal arms

HOSTLER SIGN :

Erythema over lateral thigh

NAILFOLD PATHOLOGY:

Cuticular overgrowth and dilated capillary loops

PM/DM

DERMATOLOGIC-SKIN RASHMECHANIC’S HANDS:

Cracking/fissuring the finger pads

CALCINOSIS:

Subcutaneous calcifications ( exclusive in childhood dermatomyositis)

DM -childhood

DIFFERENTIAL DIAGNOSIS

-MYOPATHY- DRUG/TOXIN-NEURO-MUSCULAR

-ENDOCRINE DISEASE-INFECTIOUS MYOSITIS

-METABOLIC STORAGE MYOPATHIES

-MITOCHONDRIAL MYOPATHY-OTHERS

CRITERIA

1-MUSCLE WEAKNESS2-ENZYMES3-EDT=EMG

4-MUSCLE BIOPSY

DIAGNOSTIC CRITERIA1 .PROXIMAL MOTOR WEAKNESS:

symmetric, proximal muscles

2 .HIGH SERUM MUSCLE ENZYMES:

CPK, aldolase, myoglobin, AST, ALT, LDH

DIAGNOSTIC CRITERIA3 .EDT= electro-diagnostic tests

PM/DMNEUROPATHIC DISORDER

EMG-Poly-phasic action potentials

-short duration-low amplitude

-Poly-phasic action potentials

-long duration-large amplitude

NCVnormalabnormal

DIAGNOSTIC CRITERIA

4 .MUSCLE BIOPSY:

biopsy a clinically weak muscle, contralateral to an abnormal muscle ( by EDT), MRI directed.

a. Perivascular and endomysial inflammationCD8+ T cells in PM,

CD8+, CD4+ T and B cells in DM

.bb. Muscle fiber necrosis and regeneration

LABORATORY TESTSHIGH MUSCLE ENZYMES:- CPKELEVATED ESR , CRP:- 50%POSITIVE ANA:- 50-80%

AUTOANTIBODIES-:

anti- RNP (MCTD) anti-PM/Scl (OVERLAP)

Myositis-specific AUTOANTIBODIESANTI Jo-1 part of ANTI SYNTHETASE Ab’s

Antibodies to the antigen- Aminoacyl-tRNA synthetase, in 20-50% of PM>>DM

ANTI SRP = anti signal recognition particleIn 5% of PM

ANTI Mi-2 in 10% of DM .

ANTI-SYNTHETASE SYNDROME

associated with anti-Jo1 antibodies with acute onset of PM>> DM disease.

Associated with ILD -40-60%, deforming and non-erosive arthritis, Mechanic’s hands and Raynaud’s phenomenon

Myositis-specific AUTOANTIBODIES

Ab’sprevalenceClinical association

HLAprognosisSteroid response

Anti-Jo-1

20-50%

(PM)

Anti-synthetase syndrome

DR3moderatemoderate

Anti-SRP

5%

(PM)

Severe PMDR5bad(cardiac)

poor

Anti-Mi-2

5-10%

(DM)

Classical DM

DR7goodgood

INFLAMMATORY MUSCLE DISEASE

1.Adult Polymyositis 2.Adult Dermatomyositis3.Childhood Dermatomyositis4.Poly/Dermato-myositis associated with Connective Tissue Disease 5.Poly/Dermato-myositis associated with malignancy6.Inclusion Body myositis7.Amyopathic Dermatomyositis

Poly/Dermato-myositis associated with malignancyAssociated neoplasms present within the first 2 years of PM/DM followup

In PM- 10%

In DM- 15%

Reports of: carcinoma-lung, stomach, ovary lymphoma

Routine screening in DM

Inclusion Body myositis(IBM)

POLYMYOSITISIBM

DemographyF>M all agesM>>F age >50

Muscle involvedproximalProx. And distal

SymmetricLegs=arms

AsymmetricLower >upper

Extra-muscular Cardiac, lung, joints

Neuropathy

EMGmyopathicMyopathic/ neuropathic

Inclusion Body myositis(IBM)POLYMYOSITISIBM

Muscle BiopsyCD8+ T cells infiltrate

CD8+ T cells, red-rimmed vacuoles with beta amyloid

Auto-antibodiesANA=frequentANA= rare

Myositis-specific antibodies

yesno

Response to therapy

frequentno

IMD-PROGNOSIS5-YEAR SURVIVAL IS AROUND 85% IN PM,

DM, PM/DM ASSOC. CTD.

MUCH LOWER IN PM/DM ASSOC. MALIGNANCY.

Anti-Mi2 Ab’s in DM – better 5-Y-S ,>90%Anti-Jo1 positive decrease 5-Y-S to 65%Anti-SRP Ab’s worsens 5-Y-S to 30%

IMD גורמי הרעת פרוגנוזה ב- גיל מבוגרעיכוב באיבחוןעיכוב במתן טיפול סטרואידלי ואימונוספרסיביממאירותמעורבות אברים פנימייםIBMחוסר תגובה ראשונית לטיפולנוכחות נוגדנים מריעים פרוגנוזה

INFLAMMATORY MUSCLE DISEASETREATMENT:

1 .STEROIDS

2 .IMMUNOSUPPRESSIVE AGENTS:

methotrexate, azathioprine, cytoxan, cellcept

3 .IMMUNOMODULATORY AGENTS:

IVIG, Plasmapheresis4 .REHABILITATION

מחלות שריר דלקתיות- טיפול

טיפולים ביולוגים ?

TNFנוגדי Anti CD 20

IL-6 antagonist

Cytokines in InflammationCytokines in Inflammation

Pro-inflammatory Anti-inflammatory

TNFIL-1

sTNFRIL-10

IL-1Ra

Macrophage or Activated T Cell

Soluble TNF

Target Cell

TNF Receptor

Signal Induction

Synthesis and Function of TNF

Transmembrane TNF

Receptor-Bound TNF

Adapted with permission from Choy EHS, Panayi GS.Adapted with permission from Choy EHS, Panayi GS. N Engl J Med N Engl J Med. 2001;344:907-916.. 2001;344:907-916.Copyright © 2001 Massachusetts Medical Society. All rights reserved.Copyright © 2001 Massachusetts Medical Society. All rights reserved.

Inhibition of Cytokines

Inflammatory Inflammatory cytokine cytokine

Normal interactionNormal interaction Neutralization of cytokinesNeutralization of cytokines

Receptor blockadeReceptor blockadeActivation ofActivation of

anti-inflammatory pathwaysanti-inflammatory pathways

Cytokine Cytokine receptorreceptor

Soluble Soluble receptorreceptor

Monoclonal Monoclonal antibodyantibody

Monoclonal Monoclonal antibodyantibody

Receptor Receptor antagonistantagonist

Anti-inflammatoryAnti-inflammatorycytokinecytokine

Suppression ofSuppression ofinflammatoryinflammatorycytokinescytokines

No signalNo signal

No signalNo signal

Inflammatory Inflammatory signalsignal

Humira- The first fully human antiTNFa

Chimeric Antibody

70% Human

Humanized Antibody

95% Human

Fully Human Antibody

100% Human

Mouse

Human

Chimeric Humanized Fully Human

49

מחלות שריר דלקתיות

TNFאנטי

ETANERCEPT= EnbrelREMICADE= InfliximabHUMIRA= Adalimumab

Research & treatmentIMD