1. Inflammatory Muscle Disease ד"ר סוהיל אעמר ראומטולוגיה – הדסה הר הצופים

2. Classification of IMD Adult Polymyositis (PM)
Adult Dermatomyositis (DM)

3. Bohan & Peter CRITERIA 1-MUSCLE WEAKNESS 2-ENZYMES 3-EDT=EMG
4-MUSCLE BIOPSY
all for PM
5-TYPICAL RASH
for DM

4. Classification of IMD Adult Polymyositis Adult Dermatomyositis
Childhood Dermatomyositis
Poly/Dermato-myositis associated with malignancy
Poly/Dermato-myositis associated with Connective Tissue Disease
Inclusion Body myositis
Amyopathic Dermatomyositis

5. EPIDEMIOLOGY Annual Incidence: 2-10 case /million
Peak age : and years old
Female: Male ratio: 3:1 total
1:1 childhood DM
10:1 PM/DM assoc. CTD
Black: White (USA): :1

6. CLINICAL MANIFESTATIONS
Weakness of muscles
-shoulder girdle
- pelvic girdle
- neck flexors
Myalgia is minimal
Constitutional symptoms-fatigue, fever…

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

9. RAYNAUD’S PHENOMENON

10. DERMATOLOGIC-SKIN RASH
DERMATOMYOSITIS:-
HELIOTROPE RASH: purple /erythematous rash affecting eyelids,periorbital edema
+/- malar, forehead and nasolabial folds
LIVEDO RETICULARIS- cutis marmorata like

12. Heliotrope Rash

13. DERMATOLOGIC-SKIN RASH
GOTTRON’S PAPULES:
Purple /erythematous raised lesions over knuckles and extensor regions
V-SIGN :
Erythematous rash over anterior chest and neck. (photosensitivity)

19. DERMATOLOGIC-SKIN RASH
SHAWL-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

21. PM/DM

23. DERMATOLOGIC-SKIN RASH
MECHANIC’S HANDS:
Cracking/fissuring the finger pads
CALCINOSIS:
Subcutaneous calcifications ( exclusive in childhood dermatomyositis)

28. DM -childhood

29. DIFFERENTIAL DIAGNOSIS
-MYOPATHY- DRUG/TOXIN
-NEURO-MUSCULAR
-ENDOCRINE DISEASE
-INFECTIOUS MYOSITIS
-METABOLIC STORAGE MYOPATHIES
-MITOCHONDRIAL MYOPATHY
-OTHERS

30. CRITERIA
1-MUSCLE WEAKNESS
2-ENZYMES
3-EDT=EMG
4-MUSCLE BIOPSY

31. DIAGNOSTIC CRITERIA 1. PROXIMAL MOTOR WEAKNESS:
symmetric, proximal muscles
2. HIGH SERUM MUSCLE ENZYMES:
CPK, aldolase, myoglobin, AST, ALT, LDH

32. DIAGNOSTIC CRITERIA 3. EDT= electro-diagnostic tests PM/DM
NEUROPATHIC DISORDER
PM/DM
-Poly-phasic action potentials
-long duration
-large amplitude
-short duration
-low amplitude
EMG
abnormal
normal
NCV

33. DIAGNOSTIC CRITERIA 4. MUSCLE BIOPSY:
biopsy a clinically weak muscle, contralateral to an abnormal muscle ( by EDT), MRI directed.
a. Perivascular and endomysial inflammation
CD8+ T cells in PM,
CD8+, CD4+ T and B cells in DM
b. Muscle fiber necrosis and regeneration

34. LABORATORY TESTS HIGH MUSCLE ENZYMES:- CPK ELEVATED ESR , CRP:- 50%
POSITIVE ANA: %
AUTOANTIBODIES:-
anti- RNP (MCTD)
anti-PM/Scl (OVERLAP)

35. Myositis-specific AUTOANTIBODIES
ANTI 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 particle
In 5% of PM
ANTI Mi-2 in 10% of DM.

36. ANTI-SYNTHETASE SYNDROME
associated with anti-Jo1 antibodies with acute onset of PM>> DM disease.
Associated with ILD %, deforming and non-erosive arthritis, Mechanic’s hands and Raynaud’s phenomenon

37. Myositis-specific AUTOANTIBODIES
Steroid response
prognosis
HLA
Clinical
association
prevalence
Ab’s
moderate
DR3
Anti-synthetase syndrome
20-50%
(PM)
Anti-Jo-1
poor
bad
(cardiac)
DR5
Severe PM 5%
Anti-SRP
good
DR7
Classical DM
5-10%
(DM)
Anti-Mi-2

38. INFLAMMATORY MUSCLE DISEASE
1.Adult Polymyositis
2.Adult Dermatomyositis
3.Childhood Dermatomyositis
4.Poly/Dermato-myositis associated with Connective Tissue Disease
5.Poly/Dermato-myositis associated with malignancy
6.Inclusion Body myositis
7.Amyopathic Dermatomyositis

39. Poly/Dermato-myositis associated with malignancy
Associated 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

40. Inclusion Body myositis (IBM)
POLYMYOSITIS
M>>F age >50
F>M all ages
Demography
Prox. And distal
proximal
Muscle involved
Asymmetric
Lower >upper
Symmetric
Legs=arms
Neuropathy
Cardiac, lung, joints
Extra-muscular
Myopathic/ neuropathic
myopathic
EMG

41. Inclusion Body myositis (IBM)
POLYMYOSITIS
CD8+ T cells, red-rimmed vacuoles with beta amyloid
CD8+ T cells infiltrate
Muscle Biopsy
ANA= rare
ANA=frequent
Auto-antibodies no
yes
Myositis-specific antibodies
frequent
Response to therapy

42. IMD-PROGNOSIS
5-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%

43. גורמי הרעת פרוגנוזה ב- IMD
גיל מבוגר
עיכוב באיבחון
עיכוב במתן טיפול סטרואידלי ואימונוספרסיבי
ממאירות
מעורבות אברים פנימיים
IBM
חוסר תגובה ראשונית לטיפול
נוכחות נוגדנים מריעים פרוגנוזה

44. INFLAMMATORY MUSCLE DISEASE
TREATMENT:
1. STEROIDS
2. IMMUNOSUPPRESSIVE AGENTS:
methotrexate, azathioprine, cytoxan, cellcept
3. IMMUNOMODULATORY AGENTS:
IVIG, Plasmapheresis
4. REHABILITATION

45. מחלות שריר דלקתיות- טיפול
טיפולים ביולוגים ?
נוגדי TNF
Anti CD 20
IL-6 antagonist

46. Cytokines in Inflammation
IL-1Ra
IL-10
sTNFR
IL-1b
TNFa
Pro-inflammatory
Anti-inflammatory

47. Synthesis and Function of TNF
Soluble TNF
Macrophage or Activated T Cell
Receptor-Bound TNF
Transmembrane TNF
TNF is a cell-surface protein produced by cells of the immune system (macrophages and activated T cells). It is a central cytokine that plays a major role in the innate immune response and is able to trigger an inflammatory cascade through the induction of secondary mediators. Activated TNF binds to one of 2 receptors, TNF-R1 and TNF-R2. Once TNF is bound to its receptors, mediators are activated (AP-1 and NFB) that induce increased vascular permeability, resulting in an acute inflammatory response.
Signal Induction
TNF Receptor
Target Cell

48. Inhibition of Cytokines
Normal interaction
Neutralization of cytokines
Inflammatory cytokine
Monoclonal antibody
Cytokine
receptor
Soluble receptor
Inflammatory signal
No signal
Activation of anti-inflammatory pathways
Receptor blockade
Monoclonal antibody
Inhibition of Cytokines
Cytokines exert their damaging effects by binding to specific receptors, and there are several potential approaches that can be employed to block these effects.
Cytokines can be neutralized through the use of antibodies or soluble receptors. With this approach, the cytokine never reaches the receptor on the cell of interest. This avenue for treatment of RA has been taken with soluble TNF- receptor fusion proteins, soluble IL receptors, monoclonal antibodies against TNF-, and monoclonal antibodies against IL-6.
Receptor antagonists or antibodies can bind to cytokine receptors on cells and prevent cytokines from binding. This blocks their actions on the cell in question. This approach to treatment of RA has been taken with recombinant IL-1Ra and an antibody against the IL-6 receptor.
Administration of anti-inflammatory cytokines can inhibit expression of inflammatory cytokines. This approach has been taken with IL-4 and IL-10.
Choy EHS, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med. 2001;344:
Anti-inflammatory
cytokine
Receptor antagonist
Suppression of
inflammatory
cytokines
No signal
Adapted with permission from Choy EHS, Panayi GS. N Engl J Med. 2001;344: Copyright © 2001 Massachusetts Medical Society. All rights reserved. 48

49. Humira- The first fully human antiTNFa
Chimeric
Humanized
Fully Human
Humanized Antibody 95% Human
Fully Human Antibody 100% Human
Chimeric Antibody 70% Human
Mouse
Human 49

50. אנטי TNF ETANERCEPT= Enbrel REMICADE= Infliximab HUMIRA= Adalimumab
מחלות שריר דלקתיות
אנטי TNF
ETANERCEPT= Enbrel
REMICADE= Infliximab
HUMIRA= Adalimumab

52. Research & treatment IMD

53. מרכז רפואי הדסה - הר הצופים
מחלות שריר דלקתיות
דר' סוהיל אעמר
Suhail Aamar MD, MSc.
מומחה בריאומטולוגיה
מרכז רפואי הדסה - הר הצופים
נובמבר 2013