International Myositis Classification Criteria Project (IMCCP) Workshop Held on November 11, 2005

International Myositis Classification Criteria Project (IMCCP) Workshop

Held on November 11, 2005

MEETING SUMMARY

This document summarizes a meeting of available members of the Steering and Working

Committees of the International Myositis Classification Criteria Project who met on Friday

November 11, 2005 from 8:30 AM to 3:30 PM at the Washington Dulles Airport Marriott Hotel,

Dulles, Virginia (attendees listed in Appendix 1). The purpose of the meeting was to define

approaches and variables to be collected in a retrospective study to develop new classification

criteria for the idiopathic inflammatory myopathies and their subgroups.

In prior meetings, it was decided that this project is needed because of the lack of reliable

information on sensitivity and specificity of all current criteria sets, because of the many different

unvalidated criteria now being used, and due to the availability of novel technologies and

approaches today that offer new opportunities to revise our thinking and definitions of myositis. For

those who are members of the International Myositis Assessment and Clinical Studies Group

(IMACS) and who wish to view all the documents and slides presented at the IMCCP Planning

Meeting in 2004, see https://dir-apps.niehs.nih.gov/imacs/index.cfm?action=home.meetings

It was decided that a combined interdisciplinary effort addressing both adult-onset and childhood-

onset myositis would be ideal and that there should be two primary goals for the project:

I. Criteria should be developed for use by basic and clinical researchers that

distinguish the idiopathic inflammatory myopathies (IIM) from other major

mimicking conditions with high sensitivity and specificity; and

II. Criteria should be developed for use by basic and clinical researchers that

separate the major subgroups of the IIM from each other with high sensitivity

and specificity.

1. Introduction – Ingrid Lundberg, Chair of the Project, summarized the developments that led to

the current meeting emphasizing the growing split among different specialities in terms of how the

idiopathic inflammatory myopathies and their major subgroups are viewed and defined and how

this could lead to great difficulties in future meta-analyses and attempts to correlate findings from

one trial or study to another. She discussed the activities of the first Steering Committee held in

November 2004 that lead to this meeting. She also described current interest and joint funding by

the European League Against Rheumatism (EULAR) and the American College of Rheumatology

(ACR) to support these efforts to develop criteria that would be recognized by these and possibly

other groups.

2. Matthew Liang reviewed his background from previous work on development or revision of

criteria in other disorders and the general processes that would be followed during the meeting

and then led the Nominal Group Technique throughout the sessions.

3. Fred Miller reviewed the organization and conduct of the pilot study which retrospectively

collected data from 50 variables on 34 subjects with myositis and 14 subjects without myositis in

order to assess the availability and feasibility of collection of certain of these variables (see

Appendix 2). He then introduced the Nominal Group Technique and its advantages and how it

was going to be used at this meeting.

4. Variables were considered by Nominal Group Technique in the following categories:

A. Clinical Muscle Variables

B. Skin Variables

Summary of the International Myositis Classification Criteria Project Workshop held 11/11/2005

C. Other Clinical Variables

D. Laboratory Variables

E. Muscle Biopsy Variables

A common approach was used for each category: first, Tony Lachenbruch reviewed his statistical

analyses of the variables from the pilot study. Then Matt Liang, Ingrid Lundberg, Fred Miller or

Lisa Rider led the group in repeated round-robin fashion asking for possible additional useful

variables. Finally each member was given the opportunity to mark a set number of proposed

variables that should be eliminated from the list for a variety of reasons including:

a. They were likely to often be missing in the retrospective medical record review

b. They were difficult to define

c. They were redundant

d. They were too rarely endorsed

e. They were non-discriminatory

f. They were costly to obtain, either financially or due to inconvenience, or

g. They were likely to differ in various ethnic populations

The proposed variable list obtained by this process, and including those variables from prior

proposed and published criteria, needed to assess their sensitivity and specificity, is listed in

Appendix 3.

5. Fred Miller presented the subgroups proposed by the Steering Committee to include within the

umbrella rubric of idiopathic inflammatory myopathies and those diagnostic groups to include as

non-idiopathic inflammatory myopathies. Attendees added to the list of potential myositis

subgroups and non-myositis diagnoses. Following the meeting, however, the number of myositis

subgroups was restricted due to sample size considerations for the study (see G7 in Appendix 3).

6. Tony Lachenbruch gave a brief presentation of the general issues to consider in defining cases

and variables and listed some power analyses for our consideration of the number of cases to

study. These questions included: How many variables should we collect? In which way should we

choose patients and over what period of time? Subsequent discussions by members of the

Steering Committee resolved that 750 IIM cases (divided as evenly as possible among the IIM

subgroups below) and 500 non-IIM comparators (divided as evenly as possible among the non-IIM

diagnostic groups below) should be initially studied, with a first request for 5-10 cases of IIM and 5-

10 cases of non-IIM from each participant. Following the collection of data on these initial cases

(by either a paper form or by an Excel database), an assessment of these data will be made to

determine the number and types of additional cases that may be needed to achieve adequate

power to complete the study. The criteria for choosing subjects for the study, in order of priority,

should be:

i. The subject has been diagnosed for at least 6 months to allow for an adequate

assessment of response to corticosteroid or other immunosuppressive therapy

ii. The physician is certain of the diagnosis – only cases with known idiopathic

inflammatory myopathy or, as comparators, known non-IIM cases (but in which

myositis was considered in the initial differential diagnosis) are chosen

iii. The most complete data are available - >60% of all variables present

iv. The most recent cases are chosen first – these would likely result in more

consistent evaluations and therapy

7. Ingrid Lundberg then led the group in discussing the overall work plan for the meeting and

timeline for the project, in hopes that it could be completed in the next two years:

Oct. 2004 – First planning meeting held at NIH

Sept. 2005 – Pilot project performed on 50 variables

Early 2006 – Variables and project plans finalized, including glossary of the variables

Late 2006 – Complete data collection of initial 1250 pts

Summary of the International Myositis Classification Criteria Project Workshop held 11/11/2005

Late 2006 – Complete analyses of initial data to determine needs for additional data collection

Mid 2007 – Complete all data collection

Late 2007 – Completion of all data analyses

Late 2007 – Experts determine final proposed criteria and possible future plans

8. Ingrid Lundberg and Matthew Liang closed the meeting by defining some other aspects of the

process for the development of these criteria and future plans.

a. The next step was to summarize the meeting and preliminary variable list with

definitions of the variables and distribute this by email to the larger number of

experts interested in this project, but who could not all attend this meeting, for

their comments and suggestions. Members of the working and steering

committees represent many collaborative study groups and are encouraged to

involve their respective groups in the project.

b. A concern was raised that the participants in this project should represent

different specialties with a balance among disciplines and it is particularly

important that neurology is balanced with rheumatology. Furthermore, the

participants recruited so far represent North America, Mexico, Europe and

Australia, but additional representatives from Asia and South America are

particularly needed. The participants of the meeting were asked to nominate

other experts to be invited for the future work. A list of participants that have

accepted to participate in this project as well as nominated experts to be

contacted is attached as a separate file. This larger group would be invited to join

the International Myositis Classification Criteria Project, to vote on variables to

define the final list, and then contribute cases to the study. It is to be emphasized

that many of the current participants represent larger collaborative study groups,

including IMACS, ENMC, Muscle Study Group, European JDM Network, PRINTO

and CARRA. It is intended to engage a broad participation in the medical record

review from each of these and other collaborative groups. As a consequence of

the workshop we have also extended the Steering committee with one

dermatologist and two neurologists.

c. The process should include the development of an extensive glossary with

standardized nomenclature as the variables are finalized.

d. Different approaches to analyze the data were discussed including heuristic

methods, major and minor criteria lists, probable and definite criteria,

classification and regression tree (CART) approaches, regression methods,

random forests classification – or, if funds permit, a combination of these could

be used.

e. It may be useful to define a pathology subcommittee of at least 3 members to

blindly review muscle biopsies and record findings using a specified format.

f. Other as yet unresolved issues that will eventually need to be addressed include:

possible training to enhance consistency in use of terms and collection of data

elements; possible subcommittees for MRI, autoantibodies, biopsies and

immunohistochemistry studies, if funding for these projects is obtained; how to

handle missing data (EMG, biopsies etc.); how to address international ethics

issues (possibly use a central Institutional Review Board (IRB) in the U.S. and

ethics exemptions when possible for retrospective anonymized chart reviews);

which of multiple statistical approaches are best; data collection and validation

methods; approval or acceptance of the developed criteria by neurology,

dermatology and other academies and groups.

Summary of the International Myositis Classification Criteria Project Workshop held 11/11/2005

Appendix 1 - Steering and Working Committee Members of the International Myositis

Classification Criteria Project who attended the Workshop held on November 11, 2005.

NAME

EMAIL ADDRESS

WORKING COMMITTEE MEMBERS

VINAY CHAUDHRY [email protected]

LISA CHRISTOPHER [email protected]

MARY CRONIN [email protected]

KATALIN DANKO [email protected]

BRIAN FELDMAN BRIAN.FELDMAN@SICKKIDS.CA

IGNACIO GARCIA DE LA TORRE [email protected]

GERALD HENGSTMANN G.HENGSTMAN@NEURO.UMCN.NL

RENATO MANTEGAZZA RMANTEGAZZA@ISTITUTO-BESTA.IT

CHET ODDIS [email protected]U

PAUL PLOTZ [email protected]

ANGELO RAVELLI ANGELORAVELLI@OSPEDALE-GASLINI.GE.IT

MICHAEL ROSE [email protected]

IRA TARGOFF [email protected]

JIRI VENCOVSKY [email protected]

VICTORIA WERTH [email protected]U

ROBERT WORTMANN ROBERT-WORTM[email protected]

STEERING COMMITTEE MEMBERS

ANTHONY AMATO [email protected]

PETER LACHENBRUCH [email protected]

MATTHEW LIANG MLIANG@PARTNERS.ORG

INGRID LUNDBERG (CHAIR) [email protected]

FRED MILLER [email protected]

CLARISSA PILKINGTON C.PILKINGTON@BTCONNECT.COM;

[email protected]C.UK

LISA RIDER [email protected]IH.GOV

OBSERVER FROM THE MYOSITIS ASSOCIATION

THERESA CURRY [email protected]

Summary of the International Myositis Classification Criteria Project Workshop held 11/11/2005

Appendix 2. Pilot study on 50 variables from 34 subjects with myositis and 14 subjects without

myositis to assess variable availability from retrospective chart review.

Category Variable

IIM %

(N)

present

IIM

%(N)

missing

Not IIM

%(N)

present

Not IIM

%(N)

missing

Sensitivity% Specificity%

Clinical

Muscle 1M Weakness, Prox UE 97 (33) 0 71 (10) 0 97 29

2M Wrist or FF weakness 56 (19) 6 (2) 2 (15) 1 (7) 56 79

3M Wrist/FF > shoulder abduct 18 (6) 9 (3) 7 (1) 14 (2) 18 79

4M Weakness, Prox LE 97 (33) 0 50 (7) 0 97 50

5M Hip abductor weakness 88 (30) 6 (2) 43 (6) 7 (1) 88 50

6M Weakness distal LE 41 (14) 0 21 (3) 14 (2) 41 64

7M Knee extensor weaker than hip 18 (6) 6 (2) 7 (1) 14 (2) 18 79

8M Neck flexor weakness 85 (29) 0 43 (6) 0 85 57

9M Neck extensor weakness 21 (7) 21 (7) 7 (1) 21 (3) 21 71

10M Symmetric weakness 85 (29) 0 57 (8) 7 (1) 85 36

11M Muscle pain at rest 32 (11) 18 (6) 29 (4) 0 32 71

12M Muscle tenderness 35 (12) 9 (3) 7 (1) 7 (1) 35 86

13M Muscle atrophy distal forearms 18 (6) 3 (1) 0 0 18 100

14M Thigh atrophy 32 (11) 3 (1) 0 0 32 100

Clinical Skin 1S Heliotrope 38 (13) 0 0 0 38 100

2S Gottron's papules 44 (15) 0

14 (2 DM

sine) 0 44 86

3S Erythema extensor surfaces 35 (12) 0 29 (4) 0 35 71

4S V-sign 21 (7) 0 7 (1)

0 21 93

5S Shawl sign 24 (8) 0 0 0 24 100

6S Calcification 9 (3) 3 (1) 0 0 9 100

7S. Periungual eryth, petech, telan, cutic

over

41 (14) 0 7 (1) 0 41 93

8S Raynaud's 18 (6) 3 (1) 29 (4) 0 18 71

Clinical

Other 1O Family history AD 26 (9) 9 (3) 28 (4) 0 26 71

2O Acute onset 71 (24) 3 (1) 43 (6) 0 71 57

3O Arthritis 47 (16) 0 43 (6) 0 47 57

4O Polyarthralgia 44 (15) 0 50 (7) 0 44 50

5O Sjogren's syndrome 3 (1) 0 7 (1) 0 3 93

6O Systemic sclerosis 0 0 7 (1) 0 0 93

7O MCTD 0 0 0 0 0 0

8O Rheumatoid arthritis 0 3 (1) 43 (6) 0 0 57

9O SLE 3 (1) 0 29 (4) 0 3 71

10O Autoimmune thyroid disease 12 (4) 18 (6) 7 (1) 42 (6) 12 50

11O Objective improvement strength p

corticoid 79 (27) 6 (2) 43 (6) 43 (6) 79 14

12O No improvement strength p corticoid 3 (1) 35 (12) 14 (2) 43 (6) 3 43

Summary of the International Myositis Classification Criteria Project Workshop held 11/11/2005

Appendix 2 (cont.). Pilot study on 50 variables from 34 subjects with myositis and 14 subjects

without myositis to assess variable availability from retrospective chart review.

Category Variable

IIM %

(N)

present

IIM %

(N)

missing

Not IIM

%(N)

present

Not IIM

%(N)

missing

Sensitivity

Specificity

Laboratory

1L EMG c/w IIM 59 (20) 32 (11) 14 (2) 79 (11) 59 7

2L CK elevated 76 (26) 15 (5) 36 (5) 14 (2) 76 50

3L LD elevated 53 (18) 38 (13) 7 (1) 43 (6) 53 50

4L AST/SGOT elevated 65 (22) 24 (8) 29 (4) 29 (4) 65 43

5L ALT/SGPT elevated 59 (20) 15 (5) 29 (4) 14 (2) 59 57

6L Aldolase elevated 15 (5) 82 (28) 7 (1) 64 (9) 15 29

7L ANA + 62 (21) 12 (4) 50 (7) 14 (2) 62 36

8L Anti-Jo-1 autoantibody + 21 (7) 21 (7) 0 29 (4) 21 71

9L STIR/T2 MRI c/w inflammation 62 (21) 26 (9) 21 (3) 50 (7) 62 29

Muscle Bx 1B Inflammation & degen/regen on H&E 34 (25) 15 (5) 14 (2) 57 (8) 34 29

2B MHC I ag present on muscle fibers 21 (7) 76 (26) 0 92 (13) 21 7

3B Non-necrotic fibers surr/invaded by

MNC 44 (15) 15 (5) 7 (1) 57 (8) 44 36

4B Endomysial MNC infiltrates 65 (22) 15 (5) 21 (3) 57 (8) 65 21

6B Perimysial MNC infiltrates 18 (6) 35 (12) 7 (1) 57 (8) 18 36

7B Perifascicular atrophy 21 (7) 15 (5) 0 57 (8) 21 43

8B Rimmed vacuoles 12 (4) 32 (11) 0 57 (8) 12 43

Summary of the International Myositis Classification Criteria Project Workshop held 11/11/2005

Appendix 3

Development of Classification Criteria for the

Idiopathic Inflammatory Myopathies and their Major Subgroups

Proposed Data Collection Form and Preliminary Variable List for Comment

Variables in italics are from prior proposed criteria and are needed to assess their

sensitivity and specificity

In reviewing patients please use the following criteria for selecting cases for submission:

i. The subject has been diagnosed for at least 6 months to allow for an adequate

assessment of response to corticosteroid or other immunosuppressive therapy

ii. The physician is certain of the diagnosis – only cases with known idiopathic

inflammatory myopathy or, as comparators, known non-IIM cases (but in which

myositis was considered in the initial differential diagnosis) are chosen

iii. The most complete data are available - >60% of all variables present

iv. The most recent cases are chosen first – these would likely result in more

consistent evaluations and therapy

GENERAL INFORMATION

G0. IRB or Ethic’s Committee approval identifier and date of approval:

G1. Clinician submitting case:

G2. Case identifier/number:

G3. Gender: □ Female

□ Male

G4. Age at onset: (of first symptom assumed to be related to the disease

G5. Age at diagnosis

G6. Ethnicity: □ Of European descent

□ Of African descent

□ Of Asian descent

□ Of Native American descent

□ Of Pacific Island descent

□ Of Mixed descent

□ Unknown

Summary of the International Myositis Classification Criteria Project Workshop held 11/11/2005

G7. Study diagnosis and onset (adult onset = age >17) according to the clinician (check only one

diagnosis):

Idiopathic Inflammatory Myopathy (IIM), adults or children:

Myositis Onset: adult □ or childhood □

□ Polymyositis

□ Dermatomyositis

□ Inclusion body myositis

□ Non-specific myositis

□ Immune-mediated necrotizing myopathy

NOT Idiopathic Inflammatory Myopathy (Not IIM), adults or children, but in which the

diagnosis of idiopathic myositis was considered in the differential diagnosis:

Disease Onset: adult □ or childhood □

□ Non-inflammatory inclusion body myopathy

□ Dystrophy, specify diagnosis

□ Metabolic myopathy, specify diagnosis

□ Mitochondrial myopathy, specify diagnosis

□ Drug or toxin associated myopathy, specify diagnosis

□ Infectious myopathy, specify diagnosis

□ Endocrine myopathy, specify diagnosis

□ Other Neuromuscular disease, specify diagnosis

□ Other Rheumatic disease, specify diagnosis

□ Other Dermatologic disease, specify diagnosis

G8. Basis for study diagnosis (check and explain in detail all supporting reasons):

□ Muscle weakness

□ Muscle biopsy abnormalities

□ Elevated muscle enzymes

□ EMG abnormalities

Summary of the International Myositis Classification Criteria Project Workshop held 11/11/2005

□ Rashes

□ Other, specify

G9. Clinicia

n’s additional comments on the case:

G10. Other diagnoses in this case:

□ Hypothyroidism

□ Hyperthyroidism

□ Type I diabetes

□ Rheumatoid arthritis

□ Juvenile Rheumatoid arthritis

□ Systemic lupus erythematosus

□ Systemic sclerosis

□ Multiple sclerosis

□ Other, specify

Present

Absent Not available Comments

Clinical Muscle Variables

1M. Objective symmetric weakness,

usually progressive, of the proximal

upper extremities

2M, Objective shoulder abductor

weakness

3M. Objective elbow flexor weakness

4M. Objective elbow extensor weakness

5M. Wrist and finger flexors are weaker

than shoulder abductors

6M. Wrist flexors are weaker than wrist

extensors

7M. Objective finger flexor weakness

8M. Objective symmetric weakness,

usually progressive, of the proximal

lower extremities

9M. Objective hip flexor weakness

10M. Objective hip abductor weakness

11M. Objective knee extensor weakness

12M. Knee extensors are as weak or

weaker than hip girdle muscles

13M. Objective muscle weakness of

distal lower extremities

14M. Objective axial weakness

15M. Objective neck flexor weakness

16M. Neck flexors are weaker than neck

extensors

17M. Proximal muscles are weaker than

distal muscles

Summary of the International Myositis Classification Criteria Project Workshop held 11/11/2005

18M. Muscle pain at rest

19M. Muscle tenderness

20M. Muscle atrophy of distal forearms

21M. Muscle atrophy of thighs

22M. Scapular winging

23M. Involuntary muscle movement

Present Absent Not available Comments

Skin Variables

1S. Heliotrope rash

2S. Gottron´s papules

3S. Gottron’s sign

4S. Erythema of the neck (V-sign)

5S. Erythema of the back of neck and

shoulders (Shawl sign)

6S. Periorbital edema

7S. Linear extensor erythema

8S. Cutaneous, fascial or muscular

calcification

9S. Periungual erythema or nailfold

capillary abnormality

10S. Cuticular overgrowth

11S. Mechanic’s hands

12S. Facial erythema

Present Absent Not available Comments

Other Clinical Variables

1O. Family history of autoimmune

disease

2O. Family history of muscle disease

3O. Subacute onset (weeks to several

months) of symptoms

4O. History of episodic weakness

associated with exercise or fasting

5O. Arthritis

6O. Polyarthralgia

7O. Unexplained Fevers

8O. Interstitial lung disease

9O. Peripheral neuropathy

10O. Dysphagia or esophageal

dysmotility

11O. Objective improvement in strength

after corticosteroid therapy

12O. Objective improvement in strength

after other immunosuppressive therapy

Summary of the International Myositis Classification Criteria Project Workshop held 11/11/2005

Present Absent Not available Comments

Muscle Biopsy Variables

1B. Necrosis of type I and type II muscle

fibers, phagocytosis,

degeneration/regeneration of myofibers

with variation in myofiber size, endomysial,

perimysial, perivascular or interstitial

mononuclear cells (MNCs)

2B. Perifascicular atrophy

3B. Non-necrotic fibers surrounded and

invaded by MNCs

4B. MHC Class I antigen present on

scattered muscle fibers

5B. Endomysial inflammatory cells

surrounding, but not invading, myofibers

6B. Endomysial CD8+ cells surrounding

myofibers with MHC Class I expression on

myofibers

7B. Vacuolated muscle fibers

8B. Intracellular amyloid deposits or 15-18

nm tubulofilaments by electron microscopy

(EM)

9B. Many necrotic muscle fibers as the

predominant feature. Inflammatory cells

are sparse; perimysial infiltrate is not

evident.

10B. Rimmed vacuoles, ragged red fibers,

or cytochrome oxidase-negative fibers that

would suggest inclusion body myositis

(IBM)

11B. Membrane attach complex (MAC)

depositions on small blood vessels, or

reduced capillary density, or

tubuloreticular inclusions in endothelial

cells on electron microscopy, or MHC-1

expression of perifascicular fibers

12B. Endomysial mononuclear cell

infiltrates

13B. Perivascular mononuclear cell

infiltrates

14B. Perimysial mononuclear cell

infiltrates

15B. Fatty replacement of muscle

16B. Glycogen or fat vacuoles

Summary of the International Myositis Classification Criteria Project Workshop held 11/11/2005

Laboratory Variables

Value Normal range Comments

1L. Serum creatine kinase (CK) activity

2L. Serum lactate dehydrogenase (LDH)

activity

3L. Serum aspartate aminotransferase

(ASAT/AST/SGOT) activity

4L. Serum alanine aminotransferase

(ALAT/ALT/SGPT) activity

5L. Serum Aldolase activity

6L. Erythrocyte sedimentation rate (ESR)

7L. C-reactive protein (CRP)

Value Normal range (method) Comments

8L. Anti-Jo-1 autoantibodies

9L. Other myositis-specific autoantibody

10L. Anti-nuclear autoantibodies (ANA)

11L. Other autoantibodies

a. Ribonucleoprotein (RNP)

b. La

c. Ro

d. Smith (Sm)

Present Absent Not available Comments

12L. Electromyogram (EMG) - Increased

insertional and spontaneous activity in the

form of fibrillation potentials, positive

sharp waves, or complex repetitive

discharges

13L. EMG - Morphometric analysis reveals

the presence of short duration, small

amplitude, polyphasic MUAPs

14L. Electrocardiogram (EKG)

abnormalities consistent with myositis

14L. Muscle inflammation on STIR or T2-

weighted magnetic resonance imaging

(MRI)

15L. Muscle abnormalities on T1-

weighted MRI scanning consistent with

myositis

Other features important in making the diagnosis not listed above – please specify:

Summary of the International Myositis Classification Criteria Project Workshop held 11/11/2005