Myosites du sujet âgé

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1 Myosites du sujet âgé Olivier Benveniste Département de Médecine Interne Centre de Référence Maladies Neuro-Musculaires Equipe Muscle Inflammatoire U974 Groupe Hospitalier Pitié-Salpêtrière

2 Myositis classification Most of the literature is based on this paper:

3 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

4 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

5 CK: 450 U/l EMG: myogenic syndrome Muscular biopsy Old patient 2 Diagnosis : polymyositis. (definite with Peter and Bohan criteria) Treatment : 2 years 1) Corticosteroids 2) IVIg No success 2 nd biopsy

6 sibm features

Content of protein inclusions Many proteins related to

bapp IBM phosphorylated tau a1act a-synuclein prion protein

manganese superoxide dismutase apoptotic regulators (Bcl-2,

7 Content of protein inclusions Many proteins related to neurodegenerative diseases: Amyloid deposits b-amyloid and bapp IBM 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 AD Werner Stenzel

8 Unanswered question Is IBM a degenerative or an inflammatory myopathy? Treg CD28- ICOS? Plasma cells IFN-g Dalakas M, Nat Clin Pract Neurol. 2006

9 sibm clinical features

11 Evaluation 9 months Visit 1 Visit 2 4 years Visit 3

12 Baseline visit: strength measurements % predicted Upper limb Grip * left Wrist flexion * right Wrist extension * Elbow flexion * Elbow extension Lower limb Ankle flexion * Ankle extension Knee flexion * Knee extension

13 Relation between knee extension strength and 6MWD 6MWD (% predicted normal) Knee extension strength (% predicted normal)

14 Neurology 2014 Finger flexor or quadriceps weakness, and Endomysial inflammation, and Invasion of nonnecrotic muscle fibres or rimmed vacuoles 90% sensitivity and 96% specificity

16 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 Previous diagnosis (n=136) None Polymyositis Amyotrophic Lateral Sclerosis Dystrophy Other Delay between first symptoms and diagnosis, months (n=136) 119 (87.5%) 6 (4.4%) 11 (8.1%) 94 (69.1%) 23 (16.9%) 3 (2.2%) 4 (2.9%) 12 (8.8%) 59 [29-95]

17 Survival from first signs 81 years

18 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 Duration of treatment, months [n=69] 19 (27%) 46 (65%) 6 (8%) 41 [ ] ~ 3.5 years

19 Comparison of treated and untreated sibm patients Status at the last visit Untreated (n=65) Treated (n=71) p CK, u/ml (n=87) 367 [ ] 209 [ ] 0.11 Grip test (n=76) 13.4 [ ] 13.5 [ ] 0.84 Walton (n=113) 4 [3-6] 6 [3-6] RMI (n=88) 11 [9-13] 10 [4-11] 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

20 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 ( ) 0.62 ( ) 1.35 ( ) 3.65 ( ) Treatment (Yes vs No) No handicap walking with aid No handicap wheelchair Walking with aid wheelchair Alive - Death 2.05 ( ) 2.09 ( ) 1.74 ( ) 1.47 ( )

21 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

22 IBM: 6 controlled prospective studies Authors N Intervention Efficacy Dalakas, IVIg or placebo No, 3 mo Walter, IVIg or placebo No, 6 mo Dalakas, CS + IVIg or placebo No, 3 mo Muscle study Group, 2001 and Beta IFN or placebo No, 6 mo Rutkove, 2002 Badsrising, Oxandrolone or placebo MTX or placebo No, 3 mo No, 12 mo

23 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

25 sibm: Th1 Signature and Treg deficiency % of positive cells Controls sibm sibm FoxP3 CD4 Dapi Y Allenbach, PLoS One 2014

26 B cells T cells CD4+ CD8+ Cell count % of Tregs Effect of Rapamycin in our mouse model PBS 1mg 3mg PBS 1mg 3mg 2.5E7 1.5E7 PBS Rapa 3mg 0.5E7 PBS Rapa 3mg N Prevel: PLoS One 2014

28 Translational Medicine Grant DGOS-Inserm 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 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 Pre-study observation D0 D10 M1 M2 M3 M6 M9 M12 MRI MRI

29 ClinicalTrials.gov 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: NCT

30 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+ (poststatines), or paraneoplastic

31 Polymyositis Overlap Myositis Ku SAE ASA YRS OJ KS Zo Jo-1 PL-12 EJ PL-7 U1-RNP PM-Scl ILD MDA-5 Mi-2 Cancer NXP2 TIF-1g Cancer Dermatomyositis 5 -Nucleotidase Inclusion Body Myopathy HMGCR SRP Immune Mediated Necrotizing Myopathy

32 Arthritis, Sept patients 38 necrotizing myopathies - 4 anti-synthetase - 6 anti-srp - 16 anti-p200/100

34 En ELISA HMGCoAR : 100% + patients anti-p200/100 Specificity : Immunoprecipitation W blot

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

36 Medicine 2014

37 Characteristics of the patients First signs: - Muscle weakness: 87% - Isolated increase of CK: 13% (n=5) Paris n=45 Baltimore n=50 Age (year) 44 ± ± 16 Patients < Women 81% 62% Statines + 44% 72.7%

38 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

39 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

The many faces of myositis. Marianne de Visser Academic Medical Centre Dept of Neurology Amsterdam The Netherlands

The many faces of myositis. Marianne de Visser Academic Medical Centre Dept of Neurology Amsterdam The Netherlands The many faces of myositis Marianne de Visser Academic Medical Centre Dept of Neurology Amsterdam The Netherlands Outline of the presentation Classification Diagnosis Therapy Prognosis Diagnostic criteria