Myopathies Inflammatoires, nouveaux concepts, nouveaux...
Transcript of Myopathies Inflammatoires, nouveaux concepts, nouveaux...
Myopathies Inflammatoires, nouveaux Myopathies Inflammatoires, nouveaux concepts, nouveaux traitementsconcepts, nouveaux traitements
Olivier BenvenisteDepartment of Internal Medicine
Institute of MyologyPitié-Salpêtrière Hospital
Paris
First myositis classification
1. Symmetrical proximal muscle weakness;2. Muscle biopsy abnormalities :
1. Muscle fiber destruction and regeneration; 2. Perivascular and interstitial inflammatory infiltrates with muscle fiber
destruction. 3. Elevation of CPK, Transaminases, LDH or aldolase activity;4. Electromyography changes:5. Typical skin rash.
• DEFINITE: any 4 of the criteria• PROBABLE: any 3 of the criteria
Neurology, 1995
EMG, MRI, auto-Abs
IMNM
Necrosis + regeneration without inflammation
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
First attempt of classification based on autoantibodies
Medicine, 2005
Use of commercial line blot assays
12 Abs
15 Abs
MDA‐5TIF‐1γ
CancerJo‐1
PL‐7
PL‐12
EJ
OJ
Ku
PM‐Scl
U1‐RNP
SAE
HMGCR
SRP
Mi‐2NXP2
Overlap
Myositis
Derm
atomyositis
Immune M
ediated Necrotizing M
yopathy
Inclusion Body Myopathy
5’‐Nucleotidase
KS
Zo
YRS
ASA
ILDCancer
MDA‐5TIF‐1γ
CancerJo‐1
PL‐7
PL‐12
EJ
OJ
Ku
PM‐Scl
U1‐RNP
SAE
HMGCR
SRP
Mi‐2NXP2
Overlap
Myositis
Derm
atomyositis
Immune M
ediated Necrotizing M
yopathy
Inclusion Body Myopathy
5’‐Nucleotidase
KS
Zo
YRS
ASA
ILDCancer
First description
1980
31%
Target of anti-Jo-1 Abs
Inhibition of histidyl-tRNA synthesis
Effect Kinetic
First series of cases
Myositis + interstitial pneumonia + Raynaud’s phenomenon + mechanic’s hands + arthritis = anti-synthetase syndrome
n=29-19 anti-Jo-1-4 anti-PL7-6 anti-PL12
Anti-synthetase Abs
• anti-aminoacyl-t-RNA-synthetase Abs:- Anti-JO1 (histidyl t-RNA),- PL7 (threonyl t-RNA), - PL12 (alanine t-RNA), - OJ (isoleucil t-RNA),
- EJ (glycyl t-RNA) etc…
• ANA
• Line blot assay
J Rheumatol 2012
• Follow-up: 4,5 years
– No need of DMARD: 14 patients (29%)
– Need of DMARD: 34 patients (71%)
• Predictive factors of DMARD need:
– Mechanic’s hands: p=0.02
– high CK (6000 vs. 1000): p=0.002
– NSIP score (7 vs. 4): p=0.04
– TLV (57% vs. 70%): p=0.02
PINS
233 patients
First description of Pathology
n=11
Perymisium disease (IMPP): fragmentation and inflammation (rich in macrophages)
Specificity and sensitivity of pathological criteria for anti-Jo-1+ patients
• Paris’ series of muscle biopsies: n=53• Berlin’ series of muscle biopsies: n=19• Controls
– DM: n=17– IMNM: n=21– sIBM: n=16
Collaboration with:Yves Allenbach, Baptiste HervierWerner Stenzel
1. Perifascicular necrosis (not observed in DM nor PM)
2. Perifascicular atrophy (DM like)
1 2
3. Perimysial fragmentation (alcaline phosphatase)
4. Perifascicular deposition of C5b9 at the sarcolemnal level
C5b9
3 4
5. Perifascicular HLA class I renforcement (DM like)
6. Perifascicular infiltrates with endomysial invasion (PM like)
CD8+
5 6
HLA I
Table 2: Perifascicular pattern in Jo-1 and DM patients
Pathologic features
DM
(n=20)
Jo-1
(n=19)
Myofiber necrosis in PF regions 7 (35%) 15 (79%)**
Myofiber atrophy in PF regions 17 (85%) 12 (63%)*
Perimysial fragmentation 9 (45%) 14 (74%)
Perimysial inflammatory infiltrates 20 (100%) 19 (100%)
HLA enhancement in PF regions 17 (85%) 15 (79%)
Sarcolemmal positivity for C5b9 in PF regions 10 (50%) 14 (74%)
*p <0.05; **p <0.01 calculated after multivariate analysis
NOD.Idd3/5 mice immunized with murine or human Jo-1 develop muscle inflammation and interstitial lung disease
Conclusion 1
• Clinico-pathological sign assembly defining an homogenous group
of patients
• Specific biomarkers = anti-synthetase autoantibodies
• Model in mice
• Correlation between biomarker levels and disease activity
Define an independent disease:
The anti-synthetase disease!
• Not a syndrome, not a PM nor a DM!
Criteria for anti-synthetase disease
Item Sub-Item(s) Weight/Score
Inflammatory myopathy - Proximal weakness- High CK level- Compatible muscle pathology
Interstitial Lung Disease - NSIP- UIP
Skin - Mechanic’s hands- Rash
Raynaud’s phenomenon
Joint pain - Arthralgia- arthritis
Antisynthetase autoAbs Anti-Jo-1 (PL1), PL7, PL12, OJ, EJ…
To be determined: score with its specificity and sensitivity
MDA‐5TIF‐1γ
CancerJo‐1
PL‐7
PL‐12
EJ
OJ
Ku
PM‐Scl
U1‐RNP
SAE
HMGCR
SRP
Mi‐2NXP2
Overlap
Myositis
Derm
atomyositis
Immune M
ediated Necrotizing M
yopathy
Inclusion Body Myopathy
5’‐Nucleotidase
KS
Zo
YRS
ASA
ILDCancer
First description
• PS3-273 / #261 - Redefining the immune histolochemical pattern of Anti-SRP auto-antibody positive patients: a subgroup presents significant inflammation.Yves Allenbach (Berlin, Germany)
• Signal Recognition Particule
• ANA
• Commercial line blot assay
Anti-SRP Abs
54
TranslocationER
First series of cases
• 13 PM patients
• « Some of these cases were unusually severe and/or of rapid onset »
• « Anti-SRP antibodies may serve as a marker for a second (after Jo1),
distinct subgroup of adult PM »
– 7 patients with severe myopathy – ± cardiomyopathy (30%)– High CK level (> 10 000 U/L) – Sometimes skin rash or interstitial lung disease– Muscle fiber necrosis and regeneration and little or no
inflammationC5b9HE
EMG, MRI, auto-Abs
IMNM
Necrosis + regeneration without inflammation
P 0 002
PATHOGENIC ROLE OF ANTI-SRP AUTOANTIBODIES IN IMMUNE-MEDIATED NECROTIZING MYOPATHY
Running title: PATHOGENICITY OF ANTI-SRP AUTOANTIBODIES
Laurent Drouot,1,2* Coralie Bloch-Queyrat,3* Louiza Arouche-Delaperche,4,5 Yves Allenbach,3,4,5 Jérémie
Martinet,1,2,6 Thierry Maisonobe,7 Serge Herson,3,4 Lucille Musset,8 Gillian Butler-Browne,5 Olivier
Boyer,1,2,6 Olivier Benveniste3,4,5
1 Inserm, U905, Rouen, France
2 Normandy University, IRIB, Rouen, France
3 Assistance Publique - Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Internal
Medicine and Clinical Immunology, Hospital University Department: inflammation, immunopathology and
biotherapy (DHU i2B) Paris, France
4 Sorbonne Universités, University Pierre et Marie-Curie-Paris 6, Paris, France
5 Myology Research Center UMR 974, Inserm, U974, Paris, France
6 Rouen University Hospital, Laboratory of Immunology, Rouen, France
7 Assistance Publique - Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of
neuropathology, Paris, France
8 Assistance Publique - Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Laboratory of
Immunochemistry & Autoimmunity, Paris, France
Patient’s sera Purified IgG
Purifier anti-SRP Purifier anti-SRPIncubated with
rSRP (p54)
MonoclonalAnti-SRP
2nd Antibody
Human muscle (p54)
1 and 3: colomn affinity-purified human anti-SRP
2 and 4: commercial goat anti-SRP Ab
Atrophic effect of anti-SRP Abs on human myotubes
• PS3-278/#311 Effects of auto-antibodies anti- signal recognition particle (SRP) and anti-Hydroxyméthylglutaryl-CoA reductase (HMGCR) on muscle cells. Louiza Arouche-Delaperche (Paris, France)
*** P<0.001
** P<0.01, *** P<0.001
* P<0.05, ** P<0.01, *** P<0.001
C57BL/6 Rag-/- mice
*** P<0.001
HE
anti-human IgG Ab
anti-H-2Kb Ab(MHC-I)
Anti-C5b9
Anti-NCAM
Merge
Anti-SRP purified IgG
Anti-SRP aAbs from IMNM patients can:
1. Recognize their muscle molecular target at the level of the ER
2. Trigger in vitro atrophy of differentiated myotubes
3. Induce a muscle disease after passive transfer to recipient mice
Anti-SRP are pathogenic
Conclusion 2
• Clinico-pathological sign assembly defining an homogenous group
of patients
• Specific biomarkers = anti-SRP autoantibodies
• Pathogenicity of the anti-SRP autoantibodies
• Model in mice
• Correlation between biomarker levels and disease activity
Define an independent (humoral mediated) disease:
The anti-SRP disease!
• Not a syndrome, not a PM nor a DM!
MDA‐5TIF‐1γ
CancerJo‐1
PL‐7
PL‐12
EJ
OJ
Ku
PM‐Scl
U1‐RNP
SAE
HMGCR
SRP
Mi‐2NXP2
Overlap
Myositis
Derm
atomyositis
Immune M
ediated Necrotizing M
yopathy
Inclusion Body Myopathy
5’‐Nucleotidase
KS
Zo
YRS
ASA
ILDCancer
Arthritis, Sept 2010
• 225 patients
• 38 necrotizing myopathies- 4 anti-synthetase- 6 anti-SRP
- 16 anti-p200/100
• ELISA HMGCR : 100% + patients anti-p200/100
• Specificity :
Immunoprecipitation
W blot
Medicine 2014
Characteristics of the patients
Parisn=45
Baltimoren=50
Age (year) 49 ± 22 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)
•Age: 11-77 years old
•Majority of – Women
– Statine free patients
•Heterogeneous myopathic presentation– Asymptomatic (high CK): 13%
– Rapidly progressive (<6 mo): 47%
– Slowly progressive (LGMD like): 20%
•Immunosuppressant resistance
Conclusions: HMGCoAR+ patients from Paris
Auto-Abs and dermatomyositis
Anti-Mi-2
• Ac anti-Mi-2 :
• 1st description in1976, USA (Reichlin M, Clin. Immunol. Immunopathol. 1976):• Only DM, 20% of DM…• DM « dermatitis », corticosensitive• Few or no association with cancer
• Complexe Mi-2/NuRD :
• Epigenetic regulator• x fonctions
Ramirez J, Epigenetics, 2009
Arthritis 2006
• Negative predictive value: 93%• OR = 18 [95% IC 8-40]
Selva-O’Callaghan, Curr Opin Rheumatol, 2010
Rheumatology 2010
p155/140 = TIF1-γ = TRIM33 = Ret-fused gene 7 = PTC 7 = ectodermin
Arthritis 2005
Rheumatology 2010
p140 = melanoma differentiation-associated gene 5 = MDA5
J AM Acad Dermatol, 2011
• Fatigue, weight loss (-10 kg en 2 mo.)
• No fever
• Arthralgia (hands)
• Mechanic hands
• Palpebral oedema
• Dyspnea NYHAII, caugh+++
• Myalgia
37 years old patient
20
30
40
50
60
70
80
90
100
mai-11 Aout 2011 oct-11 janv-12 mars-12 mai-12 aout 2012 janv-13 juil-13
CVFCPTDLCO/VATest MarchePaO2
CT 60 CT 60MTX MTX CYP 5X
PE 5X
CT 60 CT 50 15 10 8
CICLOSPORINE
93-100%
65-100%
40-85%
20-50%
Death: 12-37%
In France: 6/28 (35%)
Hamaguchi al. 2012
5 series of anti-MDA5 patients
Mi2
Tif-1γ
MDA5
Gono T, Rheumatol. 2010Hoshino K, Rheumatol. 2010Hamaguchi Y, Arch Dermatol. 2011Hall JC, Arthritis Care Res. 2013
Pred 60 mg
7
IVIg
AZA 100
3815
N
360
Sept2008
Dec2008
May2009
Nov2011
Jan2012
Feb2013
May2011
Oct2009
5
//
Relapse
100150
Myalgia+++Swallowing
//
Livedo Ecchymosis
Ulcerations
Feb2012
Mar2012
MTX 20
Jun2012
14
Fistulisationcalcification
T2 STIR
12/2008 12/2011 04/2012Calcifications
Three patients with anti-NXP2 Abs
Dermatomyositis with anti-NXP2-AbAssociation with cancers ?
Arthritis & Rheumatology 13
MDA‐5TIF‐1γ
CancerJo‐1
PL‐7
PL‐12
EJ
OJ
Ku
PM‐Scl
U1‐RNP
SAE
HMGCR
SRP
Mi‐2NXP2
Overlap
Myositis
Derm
atomyositis
Immune M
ediated Necrotizing M
yopathy
Inclusion Body Myopathy
5’‐Nucleotidase
KS
Zo
YRS
ASA
ILDCancer
Neurology 2014
• Finger flexor or quadriceps weakness, and
• Endomysial inflammation, and
• Invasion of nonnecrotic muscle fibres or rimmed vacuoles
→ 90% sensitivity and 96% specificity
Aims: diagnosis criteria and outcomes for clinical trials
Acta Myologica, 2011; 30: 103‐8
Definite IBM
(n=17)
Possible IBM
(n=19)
PM/DM
(n=7)
Dystrophies
(n=8)
Controls
(n=6)p62 100% 33% 14%
(PM)0% 0%
TDP43 100% 33% 0% 0% 0%
SMI 31 93% 8% 0% 12.5%(Bethlem)
0%
Ubiquitin 81% 33% 28.5%(PM/DM)
12.5%(Dysf)
0%
Beta A4 12.6% 0% 0% 0% 0%APP 12.5% 0% 0% 0% 0%SMI 310 6% 8% 0% 0% 0%
Fine-tuning of the pathological diagnosis
Natural history
OnsetDiagnosis
=Walk support
Wheelchair Death
5 y. 9 y.
61 y. 66 y. 75 y. 80 y.
• 71 patients received Pred ± IVIg or MTX or Azat, during 3.5 years• 65 patients were untreated and were finally less severely disabled!
sIBMsIBMsIBMsIBMsIBMsIBMsIBMsIBMsIBMsIBM
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sIBM
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Ctrl
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sIBM
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sIBMsIBM
sIBMsIBM
IL-8
CCL-
3
CXCL
-10
CXCL
-9
IL-1
RA
IL-1
2
CCL-
2
sIBM: Th1 Signature and Treg deficiency
Positive Predictive Value
91%
Hierarchical clustering analysis of the 7
significant parameters after Benjamini-
Hochberg correction
Th1 SignatureLuminex analysis on serum samples
FoxP3CD4Dapi
Y Allenbach: PlosOne 2014
Allenbach et al., Am J Pathol 2009
Myosin in IFA
D0 D7 D24D14
Purified myosin in CFA +
Pertussis toxin Myosin in IFA
First Model of Autoimmune Experimental Myositis
0
0.5
1
1.5
2
2.5
3
3.5
Gastrocnemius Quadriceps Triceps
*
*
0
0.5
1
1.5
2
2.5
3
3.5
Gastrocnemius Quadriceps Triceps
EAM with Treg DepletionEAM Control
EAM and Treg depletionEAM l
**
Transfer
Effect of Rapamycin in our model
PBS 1mg 3mg PBS 1mg 3mg
2.5E7
B c
ells
T ce
lls
CD
4+
CD
8+
PBSRapa 3mg
Cel
l cou
nt
1.5E7
0.5E7
% o
f Tre
gs
PBS Rapa 3mg
N Prevel: Plos One 2014
Inclusion criteria:
18 y.o.Defined IM
Exclusion Criteria:• Allergy to rapamycin
• Intolerance to rapamycin
Rapamycin or placebo
0,3 mg/Kg
For 12 months
n=44
Pre-studyobservation
D0 D10 M1 M2 M3 M6 M12M9
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 2012 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 patientsSponsor: Novartis Pharmaceuticals ClinicalTrials.gov Identifier: NCT01925209
ClinicalTrials.gov
AcknowledgementsInternal MedicinePitié-SalpêtrièreParis
Y AllenbachB HervierA RigoletS Herson
Institute of MyologyPitié-SalpêtrièreParis
B EymardP LaforetT StojkovicA Behin
Neuro-muscular CentreOxford
D Hilton-Jones
NeuropathologyLa CharitéBerlin
W Stenzel
NeuropathologyPitié-SalpêtrièreParis
T MaisonobeS LouisN Romero
ImmunologyInserm U 905Rouen
L DrouotO Boyer
Team: Inflammatory MuscleInserm U 974Pitié-SalpêtrièreParis
F MingozziE MasatN PrevelL AroucheD Amelin