Current and evolving therapies for

inflammatory myopathiesIRACON

November 26, 2016Ingrid E. Lundberg M.D. Ph.D.Ingrid E. Lundberg M.D. Ph.D.

Rheumatology Unit Rheumatology Unit Karolinska Institutet/Karolinska Institutet/

Karolinska University HospitalKarolinska University HospitalStockholm, SwedenStockholm, Sweden

Ingrid.Lundberg@ki.seIngrid.Lundberg@ki.se

Lay out of presentation• Myositis – clinical phenotypes• Outcome meaures• Standard treatment

– Pharmacological • Myositis – ILD• Dysphagia • Biologic treatment• Nonpharmacological treatment - Exercise

Myositis specific autoantibodies Clinical phenotypes in adults and children

Anti-synthetases

Anti-Mi-2

Anti-SRP

Anti-SAE

Anti-MDA5 Anti-p155/140TIF

PL-12OJKS

PL-7

EJ

Jo-1

Zo

Ha

NXP-2

Lung disease

Myositis

Hallmark DM

CADMSevere DM

(muscle, skin, soft tissue)

Cancer-DM

Severe necrotizing myopathyMSAs in adult and juvenile disease

Courtesy H. Gunawardena

Anti-HMGCR

Gunawardena H. Rheumatology 2009;48:607-12. Review.

Anti-cN-1A

Anti-FHL1

IBM

Severe myopathy

Goal of treatment• Restore muscle strength/endurance• Eliminate inflammation• Prevent damage• Restore lung function• Eliminate skin rash • Eliminate arthritisOverall goal: to improve function and health

related quality of life

Outcome measures

Disease activity

Damage Quality of life, SF-36

Miller et al Rheumatol 40:1262-1273, 2001Miller et al Rheumatol 40:1262-1273, 2001IMACS (IMACS (International Myositis International Myositis and Clinical Studies Group)and Clinical Studies Group)

IMACS IIM Disease Activity Core Set

• Global Assessments: Physician and patient/parent - VAS

• Muscle strength: MMT (proximal, distal & axial muscles) MMT8 max score 80

• Physical function: HAQ (CHAQ / CMAS)• Laboratory: Serum activity of ≥ 2 muscle enzymes

(CK, LD, aldolase, AST, ALT)• Extra-skeletal muscle disease activity

– Myositis Disease Activity Assessment (MDAAT, MITAX)Miller, Rider et al., 2001, Rheum.40:1262-73

https://dir-apps.niehs.nih.gov/imacs/index.cfm

IMACS IIM Disease Activity IMACS IIM Disease Activity Core SetCore Set

• Global Assessments: Physician and patient/parent - VAS

• Muscle strength: MMT (proximal, distal & axial muscles) MMT8 max score 80

• Physical function: HAQ (CHAQ / CMAS)• Laboratory: Serum activity of ≥ 2 muscle enzymes

(CK, LD, aldolase, AST, ALT)• Extra-skeletal muscle disease activity

– Myositis Disease Activity Assessment (MDAAT, MITAX)Miller, Rider et al., 2001, Rheum., 40: 1262-73

https://dir-apps.niehs.nih.gov/imacs/index.cfm

Manual Muscle Test-8max. score 80

IMACS WEBSITE: HTTPS://DIR-APPS.NIEHS.NIH.GOV/IMACS/

Preliminary Definition of Improvement

For adult and pediatric PM and DM • ≥ 3 of any of the core set measures

improved by ≥ 20%• with no more than 2 worse by ≥ 25% and this could not be MMT

Rider LG,Rider LG, Arthritis Rheum; 50:2281-90, 2004

Which is the most important outcome measure?

Choices

1. Physician global assessment- VAS2. Health assessment questionaire (HAQ)3. Serum CK levels4. Muscle strength 5. Patient global assessment

Correct answer

4. Muscle strength

Treatment of myositis• Multidisciplinary team: rheumatologist,

neurologist, dermatologist, pulmonologist, physical therapist

• Pharmacological therapy• Non-pharmacological therapy

• Few controlled trials• Absence of consensus recommendations• Clinical experience – case reports/series

Current treatment (PM/DM)Current treatment (PM/DM) Prednisolone 0.75 mg/kg/day (40 - 80 mg/day) In patients with severe muscle weakness,

dysphagia, lung disease, or ulcerative skin disease - Pulse methylprednisolon 1000mg x 3 days

Ca/vitamin D and bisphosphonates

Combine with Azathioprine, 2 mg/kg/day Bunch 1980

or Methotrexate 7,5 mg -25 mg/week or Mycophenolate mofetil (MMF) Rowin, Neurology 2006 or Cyclosporine A Vencovsky, Scand J Rheumatol 2000

Treatment of inflammatory myopathy

Glucocorticoids Immunosuppressive agents•Azathioprine•Methotrexate•Mycophenolate mofetil (MMF)•Cyclosporin A

50% are unresponsive to glucocorticoids

Side effects are common

Few patients fully recover their muscle function

Oddis C, Review J Int Med 2016

In treatment resistant myositis cases

Reevaluate diagnosis! Inclusion body myositis, muscle dystrophy,

metabolic myopathy? Cancer associated myositis?

Glucocorticoid induced myopathy? Consider a new muscle biopsy Consider MRI

With persisting disease activity

Combination of immunusuppressive drugs

High dose intravenous immunoglobulin in DM Dalakas -93

Biologics?

Myositis and interstitial lung disease

(ILD)• ILD in 60 – 70% of dermatomyositis and polymyositis

• May be the first clinical symptom of myositis• High morbidity and mortality (7-44%)

Sato et al Arthritis Rheum 2005;52:1571-1576Fathi et al ARD, 2004, 63:297-301Hallowell et al Curr Opin Rheum, 2014;26,684

Treatment of interstitial lung disease

No controlled trials, case series and case reports

Prednisolone + • Cyclophosphamide Ge Y, Clin Rheumatol 2015

• or Cyclosporine A Kameda H, J Rheumatol 2005;32:1719

• or Tacrolimus Oddis CV, Lancet 1999;353:1762, Wilkes, Arthritis Rheum, 2005, Kurtia T Rheumatol 2015;

• or Mycophenylate mofetil • Swigris, Chest, 2006; Campbell, ACR 2009, Fischer A J Rheumatol 2013

Follow FVC, DLCO and HRCT, every 3 to 6 months

ILD in myositis• Prognosis: Longitudinal follow-up study:

total lung capacity (TLC) improved in 33%, remained stable in 39% and deteriorated in 28%(With conventional immunosuppressives)

Fathi et al A&R 2008, 59, 677

Myositis specific autoantibodies Clinical phenotypes in adults and children

Anti-synthetases

Anti-Mi-2

Anti-SRP

Anti-SAE

Anti-MDA5 Anti-p155/140TIF

PL-12OJKS

PL-7

EJ

Jo-1

Zo

Ha

NXP-2

Lung disease

Myositis

Hallmark DM

CADMSevere DM

(muscle, skin, soft tissue)

Cancer-DM

Severe necrotizing myopathyMSAs in adult and juvenile disease

Courtesy H. Gunawardena

Anti-HMGCR

Gunawardena H. Rheumatology 2009;48:607-12. Review.

Anti-cN-1A

Anti-FHL1

IBM

Severe myopathy

Necrotizing myopathy with anti–HMG-CoA reductase

autoantibodies • If patient is on a statin- stop the statin• Prednisolone + (methotrexate,

azathioprine or mycofenolate mofetil)• After 8-12 weeks: If still weak consider:

high dose intravenous immunoglobulin (IVIG) or rituximab

Mammen A NEJM, 2016;374,664-9

Dysphagia -treatmentAspiration pneumonia, nutrition problems •Videoradiography and manometry of the swallowing act•Collaborate with speech therapist and ENT specialists•Pharyngoesophageal dilatation•Cricopharyngeo myotomy•Percutaneous endoscopic gastrostomy (PEG)

How about new biologics in myositis?

Rituximab –targeting B cells

• 19/22 dermatomyositis – improved• 17/22 anti-Synthetase syndrome (anti-Jo-1 positive

myositis) improved• 5/10 anti-SRP positive myositis improved• 6/6 polymyositis improved Levine TD, Arthritis Rheum 2005; Lambotte O, J Rheumatol 2005; Noss EH, J Rheumatol 2006, Chung L, Arch Dermatol. 2007; Frikha F Rheumatol, 2009, Sem M Rheumatol 2009, Christopher-Stine L, abstract ACR 2009

Rituximab in Myositis (RIM)Rituximab in the Treatment of Refractory Adult and Juvenile Dermatomyositis and Adult Polymyositis

Chester V. Oddis, MDAnn M. Reed, MD and the RIM Study Group

Slides courtesy C OddisOddis et al Arthritis Rheum, 2013, 65(2):314-24

RIM study • Double blind placebo controlled trial with a

cross-over design- all patients were treated• Rituximab at w 0/1 or w 8/9• 200 pts (76 PM, 76 DM and 48 JDM)• Multicenter• Primary endpoint: time to achieve definition

of improvement (DOI) Oddis et al Arthritis Rheum, 2013, 65(2):314-24

RIM Study Summary• Results: Time to improvement: 20.2 or 20.0

weeks (no difference between groups)

• 83% of refractory adult and juvenile myositis patients met the definition of improvement (DOI) in this trial

• SAEs 26% (infections most common)

Oddis et al Arthritis Rheum, 2013, 65:314-24

• Anti-Jo-1 and anti-Mi-2 antibodies were predictors of response, Aggarwal R. Arthritis Rheumatol. 2014;66:740-9

Inhibition of T cells Abatacept in one case of polymyositis

Musuruana JL, et al Joint Bone Spin. 2011;78:309-11

30

ARTEMIS – Abatacept in myositisStudy design (delayed-start design)

Intravenous infusions of abatacept 10 mg/kg for 6 months

n=11 (5 DM, 6 PM)

n=9 (4 DM, 5 PM)

Lundberg IE et al Arthritis Rheum, ACR abstract no 2361, 2015

ARTEMIS- Objectives

• Primary Endpoint The number of responders, defined as improved

according the IMACS criteria, after treatment with abatacept for six months

Lundberg IE et al Arthritis Rheum, ACR abstract no 2361, 2015

ARTEMIS- Results (1)

• 8 (47%) achieved the definition of improvement (DOI) after 6 months of active treatment

Lundberg IE et al Arthritis Rheum, ACR abstract no 2361, 2015

ARTEMIS – Results (2) Three months after study start•5/10 (50%) patients were responders in the active treatment arm•1/7 (14%) patients were responders in the delayed onset arm

Lundberg IE et al Arthritis Rheum, ACR abstract no 2361, 2015

34

Results-clinical (3)(active treatment for 6 months)

Muscle strength, assessed by MMT-8, from (median) 70 to 73 p=0.008

ARTEMISAdverse events (AE)

• 36 reported AE• Eight AE (infections, flank pain and dizziness)

were judged as related to the drug (4 mild and 4 moderate

Lundberg IE et al Arthritis Rheum, ACR abstract no 2361, 2015

ARTEMIS- conclusions

Treatment of PM and DM patients with abatacept resulted in improved muscle performance and warrants further investigations

Lundberg IE et al Arthritis Rheum, ACR abstract no 2361, 2015

Inclusion body myositis Inclusion body myositis (IBM)(IBM)

Men > 50 years Slow onset Muscle weakness

Finger flexor Distal muscle Quadriceps

Muscle atrophy Swallowing problems Rimmed vacuoles

Resistant to glucocorticoids and other immunosuppressive treatment

Could we use physical exercise as a targeted therapy?

Alexanderson H et al Arthritis Rheum. 2007;57:768-77

7 weeks with resistance exercise

Deltoids Quadriceps Biceps

Gastrocnemius Abdominal

Improved muscle performance

8

10

12

14

16

18

20

22

24

26

28

VRM 10-15

qua

dricep

s be

fore righ

tre

VRM 10-15

qua

dricep

s after rig

ht

F

G

A

E

C

B

D

55

60

65

70

75

80

MMT before MMT after

Wiberg

Tägström

Lundberg

Gustavsson

Florell

Eliasson

BlomgrenBerndtson

Before training After training

P<0,05P<0,05

VRM 10-15 quadricepsMMT-8

Alexanderson H et al Arthritis Rheum. 2007;57:768-77

Physical exercise in myositis• Safe• Improved muscle performance, muscle

strength • Hicks J 1993, Escalante 1993, Alexanderson et al Scand J Rheum 2000

• RCT: Increased oxygen uptake (VO2 max) Wiesinger et al Br J Rheumatol 1998 , Alemo Munters L et al Arthritis Res Ther. 2013 Aug 13;15

• Increased capillary density• Alemo Munters L. et al Arthritis Res Ther. 2013 Aug 13;15(4)

• Reduced inflammation Nader el al Mol Med 2010

Summary treatment of myositis

Myositis is a complex disease Subgroup patients according to serotype and clinical

phenotype Immunosuppressive treatment combined with

physical exercise We need to identify predictive markers for treatment

response New therapies are needed Increased knowledge about molecular disease

mechanisms International collaborations

Welcome to join the Euromyositi registry, find more information on www.euromyositis.euContact: Hector.Chinoy@manchester.ac.uk; Ingrid.Lundberg@ki.se

Euromyositis register

May 2016: more than 4 500 patients from 23 centers world wide

To be used in research and in clinical practice

Maryam DastmalchiHelene AlexandersonMei Zong Andreas FasthEva LindroosChristina OttossonAnnaTjärnlundKarina GheorgheIngela Loell Li Alemo MuntersMalin RegardtJayesh PandyaPaulius VenalisInka AlbrechtLouise EkholmLara DaniJohn SvenssonChristina DorphQuan TangCecilia WickAntonella Notarnicola

Acknowledgement

SweMyoNet

ARTEMISJ Vencovsky, PragueP Gordon, London

Pulmonary diseaseM FathiJ GrunewaldJ Wahlström