Myosites du sujet âgé

Olivier Benveniste

Département de Médecine Interne

Centre de Référence Maladies Neuro-Musculaires Equipe Muscle Inflammatoire U974

Groupe Hospitalier Pitié-Salpêtrière

Myositis classification

Most of the literature is based on this paper:

Peter and Bohan criteria for PM or DM

1. Symmetrical proximal muscle weakness;

2. Muscle biopsy abnormalities : 1. Muscle fiber destruction;

2. Muscle fiber regeneration;

3. Perivascular and interstitial inflammatory infiltrates with muscle fiber destruction.

3. Elevation of CPK, Transaminases, LDH or aldolase activity;

4. Electromyography changes: 1. Fibrillation potentials (on needle insertion at rest);

2. Complex repetitive discharges (on needle insertion at rest);

3. Positive sharp waves (on needle insertion at rest);

4. Short duration, low amplitude complex (polyphasic) potentials on contraction.

5. Typical skin rash.

• DEFINITE: any 4 of the criteria

• PROBABLE: any 3 of the criteria

Example, 84 years old patient

– 75 y, proximal deficit, difficulties to climb stairs

– 79 y, proximal and distal muscle weakness (anterior

tibialis, quadriceps, finger and wrist flexors, ankle

dorsiflexors)

– 82 y, use a stick

– Swallowing tbs

Old patient 2

• CK: 450 U/l

• EMG: myogenic syndrome

• Muscular biopsy

• Diagnosis : polymyositis.

(definite with Peter and Bohan criteria)

• Treatment : 2 years

1) Corticosteroids

2) IVIg

• No success → 2nd biopsy →

sIBM features

Many proteins related to neurodegenerative diseases:

• b-amyloid and bAPP

• phosphorylated tau

• a1ACT

• a-synuclein

• prion protein

• ApoE

• ab-crystallin

• Parkin

• copper zinc superoxide dismutase

• manganese superoxide dismutase

• apoptotic regulators (Bcl-2, Bcl-x and BAX)

• Lipoprotein receptors

• Ubiquitins

Content of protein inclusions

Amyloid deposits

IBM AD

Werner Stenzel

Unanswered question

Dalakas M, Nat Clin Pract Neurol. 2006

Is IBM a degenerative or an inflammatory myopathy?

ICOS

Treg

IFN-g

CD28-

Plasma

cells

?

sIBM clinical features

Evaluation

Visit 1 Visit 2

9 months

Visit 3

4 years

Baseline visit: strength measurements

left

right

0 10 20 30 40 50 60 70 80 90 100

Grip

Wrist flexion

Wrist extension

Elbow flexion

Elbow extension

Ankle flexion

Ankle extension

Knee flexion

Knee extension

% predicted

*

*

*

*

*

*

Upper limb

Lower limb

Relation between knee extension strength and

6MWD

0

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80 100

Knee extension strength (% predicted normal)

6M

WD

(%

pre

dic

ted

no

rmal

)

Neurology 2014

• Finger flexor or quadriceps weakness, and

• Endomysial inflammation, and

• Invasion of nonnecrotic muscle fibres or rimmed vacuoles

→ 90% sensitivity and 96% specificity

http://www.ox.ac.uk/

Characteristics of 136 patients

Variable Result

Gender : male (n=136) 78 (57.3%)

Age at first symptoms, years (n=136) 61 [55-69]

First symptoms (n=136)

Muscle weakness only

Swallowing troubles only

Muscle weakness and swallowing troubles

119 (87.5%)

6 (4.4%)

11 (8.1%)

Previous diagnosis (n=136)

None

Polymyositis

Amyotrophic Lateral Sclerosis

Dystrophy

Other

94 (69.1%)

23 (16.9%)

3 (2.2%)

4 (2.9%)

12 (8.8%)

Delay between first symptoms and diagnosis, months

(n=136)

59 [29-95]

Survival from first signs

81 years

Description of received treatments

by 71 (52%) sIBM patients

Molecules and duration Results

Corticosteroids (prednisone, 1 mg/kg/day) 65 (92%)

(n=63)

Intravenous Immunoglobulins 40 (56%)

(n=39)

Azathioprine 19 (27%)

(n=17)

Methotrexate 23 (32%)

(n=21)

Combination of treatment

Corticosteroids only

Corticosteroids and other drugs

Other drugs only

19 (27%)

46 (65%)

6 (8%)

Duration of treatment, months [n=69]

41 [13.0-89.2] ~ 3.5 years

Status at the last visit Untreated

(n=65)

Treated

(n=71)

p

CK, u/ml (n=87) 367 [219 -649] 209 [117-559] 0.11

Grip test (n=76) 13.4 [11.0-17.2] 13.5 [9.0-18.0] 0.84

Walton (n=113) 4 [3-6] 6 [3-6] 0.007

RMI (n=88) 11 [9-13] 10 [4-11] 0.004

IWCI (n=71) 50 [30-65] 40 [25-50] 0.04

Current handicap for walking (n=136)

None

1 or 2 canes

Wheelchair

20 (31%)

26 (40%)

19 (29%)

13 (18%)

26 (37%)

32 (45%)

0.10

Comparison of treated and untreated

sIBM patients

Estimates of covariate effect on each

transition in the multi-state model

Transition HR (95%CI) p

Age at first symptoms

(> 60 yrs vs <60 yrs)

No handicap – walking with aid

No handicap – wheelchair

Walking with aid – wheelchair

Alive - Death

1.98 (1.27-3.08)

0.62 (0.19-2.07)

1.35 (0.68-2.71)

3.65 (1.22-10.92)

0.003

0.44

0.39

0.02

Treatment

(Yes vs No)

No handicap – walking with aid

No handicap – wheelchair

Walking with aid – wheelchair

Alive - Death

2.05 (1.30-3.25)

2.09 (0.70-6.24)

1.74 (0.92-3.30)

1.47 (0.67-3.22)

0.002

0.18

0.09

0.34

Discussion / conclusions

Onset

Diagnosis

=

Walk support

Wheelchair Death

5 y. 9 y.

61 y. 66 y. 75 y. 80 y.

• IS treatments don’t seem to ameliorate the handicap

- Are treated patients more severely affected?

- Are treatments deleterious?

• IS treatments don’t seem to delay the dates of wheelchair

or death

IBM: 6 controlled prospective studies

Authors N Intervention Efficacy

Dalakas, 1997

Walter, 2000

Dalakas, 2001

Muscle study Group, 2001

and 2004

Rutkove, 2002

Badsrising, 2002

19

22

34

57

19

44

IVIg or placebo

IVIg or placebo

CS + IVIg or placebo

Beta IFN or placebo

Oxandrolone or placebo

MTX or placebo

No, 3 mo

No, 6 mo

No, 3 mo

No, 6 mo

No, 3 mo

No, 12 mo

Treatment of IBM, in practice :

• Physiotherapy +++

• If « young » patient, rapid evolution, many inflammatory

infiltrates on biopsy…

• Prednisone (1 mg/kg/d)

• MTX

• For a limited duration (3 to 6 months)

• If swallowing troubles

• IVIg

• Cricoid myotomy

sIBM: Th1 Signature and Treg deficiency

FoxP3

CD4

Dapi

Y Allenbach, PLoS One 2014

% o

f p

os

itiv

e

ce

lls

sIBM Controls

sIBM

Effect of Rapamycin in our mouse model

PBS 1mg 3mg PBS 1mg 3mg

2.5E7

B c

ell

s

T c

ell

s

CD

4+

CD

8+

PBS

Rapa 3mg

Ce

ll c

ou

nt

1.5E7

0.5E7

% o

f T

reg

s

PBS Rapa 3mg

N Prevel: PLoS One 2014

Inclusion

criteria:

45 y.o.

Defined IBM

Exclusion Criteria:

• Allergy to rapamycin

• Intolerance to rapamycin

• Loss of walking capability

Rapamycin or

placebo

0,3 mg/Kg

For 12 months

n=44

Pre-study

observation

D0 D10 M1 M2 M3 M6 M12 M9

Clinical Evaluation of Muscle Strength • MRC scale

• RMI scale

• Walton scale

• IWCI

• IBMFRS

Clinical Research Evaluation • Myometric study of quads

• Whole body IRM

TOLERANCE

• Clinical evaluation

• Biological evaluation

Mode D’action

• Facs

• Dosage of cytokines

• Treg

MRI

Translational Medicine Grant

DGOS-Inserm

MRI

Efficacy and Safety of Bimagrumab/BYM338 at 52

Weeks on Physical Function, Muscle Strength, Mobility

in sIBM Patients (RESILIENT)

Phase 2, 3: 240 patients

Sponsor: Novartis Pharmaceuticals

ClinicalTrials.gov Identifier: NCT01925209

ClinicalTrials.gov

New classification of myositides

• Dermatomyositis, 30% paraneoplastic

• Inclusion body myositis

• Polymyositis

• Overlap myositis (Troyanov) – Myositis associated to a connective tissue disease

– Myositis with associated Abs (PmScl, Ku …)

– Myositis with specific Abs (anti-synthetases, anti-SRP…)

• Immune mediated necrotizing myopathies (Hoogendijk) with anti-SRP+, anti-HMGCoA Reductase+ (post-statines), or paraneoplastic

MDA-5

TIF-1g Cancer

Jo-1

PL-7

PL-12

EJ

OJ

Ku

PM-Scl

U1-RNP

SAE

HMGCR

SRP

Mi-2 NXP2

Ove

rlap

Myo

siti

s D

erm

atom

yositis

Po

lym

yosi

tis

Imm

un

e M

ed

iated

N

ecro

tizing M

yop

athy

Inclusion Body Myopathy

5’-Nucleotidase

KS

Zo

YRS

ASA

ILD Cancer

Arthritis, Sept 2010

• 225 patients

• 38 necrotizing myopathies

- 4 anti-synthetase

- 6 anti-SRP

- 16 anti-p200/100

• En ELISA HMGCoAR : 100% + patients anti-p200/100

• Specificity :

Immunoprecipitation

W blot

N = 1966 with 763 now under statines, 322 had statines, 881 no statines

Medicine 2014

Characteristics of the patients

Paris

n=45

Baltimore

n=50

Age (year) 44 ± 19 52 ± 16

Patients < 16 5 2

Women 81% 62%

Statines + 44% 72.7%

First signs:

- Muscle weakness: 87%

- Isolated increase of CK: 13% (n=5)

• Myalgia: 75%

• Muscle weakness: 87% (Paris) vs 95% (Baltimore) – Bilateral, proximal, severe ≤3/5: 72%

– Rapidly progressive in < 6 mo: 47%

– Axial: 61%

– Bedridden: 10%

– No facial weakness

– Dysphagia: 41%

• Amyotrophia: 15% – Scapula wings: 1 patient

Muscle involvement

Acknowledgements

• Werner Stenzel, Berlin, D

• David Hilton-Jones, Oxford, UK

• Baziel GM van Engelen, Nijmegen, NL

• Olivier Boyer, Rouen, F

and my colleagues from:

• Bruno Eymard

• Pascal Laforêt

• Baptiste Hervier

• Yves Allenbach