Advances in Inclusion Body Myositis

Mazen M. Dimachkie, M.D.

Professor of Neurology

Director, Neuromuscular Division

Vice Chairman for Research

University of Kansas Medical Center

Dr. Dimachkie is on the speaker’s bureau or is a consultant for Baxalta, Catalyst, CSL-Behring, Mallinckrodt, Novartis and NuFactor. He has also received grants from Alexion, Biomarin, Catalyst, CSL-Behring, FDA/OPD, GSK, Grifols, MDA, NIH, Novartis & TMA.

Objectives

Case-based approach to illustrate diagnostic challenges and pattern approaches

Review diagnostic classifications of IIM & IBM

Examine differences between PM & IBM

Describe the clinical presentation of IBM

Discuss its prognosis & management

Overview recent & ongoing IBM research

Case History 68 yo RH woman: difficulty climbing stairs &

getting out from a chair x 2 yrs Falls x 2: knee buckling getting out of a pick-

up truck and going down steps Cannot open drawers or do buttons Chocking on food / pills S/P crycopharyngeal

myotomy (some help) Cramping (right thigh) but no fasciculation No numbness or tingling or weight loss

Case Examination O. Oculi 3+/5 and O. Oris 4/5 with air escape

Neck flexion 3+, extension 5/5, no scap. winging

Asymmetric atrophy of the forearm muscles L>R

Reflexes 1/4 at patella, others 2/4, absent Hoffman & jaw jerk, toes are down going

RS vibration scores: 1 at toes, 3 at ankles

What and Where?

Patterns?

SA EF EE WF FF FE HF KF KE APF ADF

Right 5 5 5 4 5 5 5 4 4 5 5

Left 5 4+ 5 3+ 4 4 5 4+ 4+ 5 5

Clinical Patterns of Muscle Disorders Weakness

PATTERN

Proximal Distal Asymmetric Symmetric Episodic Trigger Diagnosis

MP1 - Limb girdle + + Most myopathies –

hereditary and acquired

MP2 – Distal* + + Distal myopathies

(also neuropathies)

MP3 - Proximal arm / distal leg

“scapuloperoneal”

+

Arm

+

Leg

+

(FSH)

+

(others)

FSH, Emery-Dreifuss,

acid maltase, congenital scapuloperoneal

MP4 - Distal arm / proximal leg

+

Leg

+

Arm

+ IBM

Myotonic dystrophy

MP5 - Ptosis / Ophthalmoplegia + +

(MG)

+

(others)

OPD, MG, myotonic dystrophy, mitochondria

MP6 - Neck – extensor* + + INEM, MG

MP7 - Bulbar (tongue, pharyngeal, diaphragm)*

+ + MG, LEMS, OPD

(also ALS)

MP8 - Episodic weakness/

Pain/rhabdo + trigger

+ + + + McArdle’s, CPT, drugs, toxins

MP9 - Episodic weakness

Delayed or unrelated to exercise

+ + + +/- Primary periodic paralysis

Channelopathies:

Na+

Ca++

Secondary periodic paralysis

MP10 - Stiffness/ Inability to relax + +/- Myotonic dystrophy, channelopathies, PROMM, rippling (also stiff-person, neuromyotonia)

*Overlap patterns with neuropathic disorders Adapted from Barohn RJ, Dimachkie MM, Jackson RJ. Neurol Clin 2014;32(3):569-593

Clinical Patterns of Neuropathic DisordersWeakness

PATTERN

Proximal Distal Asymm Symm SensorySymptoms

Severe Proprioceptive

Loss

UMNSigns

AutonomicSymps/Signs

Diagnosis

NP1 - Symmetric prox & distal weakness w/sensory loss

+ + + + GBS/CIDP

NP2 - Distal sensory loss with/without weakness

+ + + CSPN, metabolic, drugs, hereditary

NP3 - Asymmetric distal weakness with sensory loss

+ + + Multiple – vasculitis, HNPP, MADSAM, infectionSingle - Mononeuropathy, radiculopathy

NP4 - Asymmetric prox & distal weakness w/sensory loss

+ + + + Polyradiculopathy, plexopathy

NP5 - Asymmetric distal weakness w/out sensory loss

+ + +/- + UMN – ALS/PLS- UMN – MMN

NP6 – Symmetric sensory loss & upper motor neuron signs

+ + + + + B12/Copper defic; Friedreich’s, ALD

NP7 - Symmetric weakness without sensory loss*

+\- + + Prox & Distal SMADistal Hereditary motor neuropathy

NP8 - Focal midline proximal symmetric weakness*

+ Neck/trunk extensor

or+ Bulbar

+ Diaphragm

+

+

+

+

ALS ALS/PLS

NP9 – Asymmetric proprioceptive loss w/out weakness

+ + + Sensory neuronopathy (ganglionopathy)CISP

NP10 – Autonomic dysfunction

+ Diabetes, GBS, amyloid, prophyria

*Overlap patterns with myopathy and NMJ disorders Adapted from Barohn RJ, Amato AA,. Neurol Clin 2013;31(2):343-361

Tests CK 306 to 531 IU/L Normal: TSH, ESR, ANA, serum immunofixation EMG: Mixed myopathic and neuropathic MUPs,

chronic moderate diffuse myopathy with irritability Muscle biopsy with severe freeze artifact: moderate

inflammatory myopathy, no vacuoles Outside physician started prednisone 60 mg/d in

July of 2008 tapered over 2-3 months to 20 mg/day Methotrexate 15 mg per week since July 2008 Response: more energy & ? better with stairs What are the diagnosis, management & prognosis?

Bohan and Peter Diagnostic Criteria Symmetric proximal weakness worsening over wks-mons Serum of creatine kinase elevation EMG:

small-amplitude, short-duration polyphasic muaps fibrillations, positive sharp waves, & increased insertional

irritability spontaneous, bizarre high-frequency discharges

Muscle biopsy abnormalities: degeneration and regeneration, necrosis, phagocytosis, perifascicular atrophy, and an interstitial mononuclear infiltrate

PM except the additional presence of skin rash indicates DM Exclude patients with:

slowly progressive course of muscle weakness Family history of muscular dystrophies other well-defined neuromuscular disorders (PMA, SMA,

metabolic, thyroid…)Bohan A, Peter JB. Polymyositis and dermatomyositis N EJM. 1975;292:344-347,403-407.Bohan A, Peter JB. A computer-assisted analysis of 153 patients with PM and DM. NEJM.1977;56:255-286.

IIM Classification Dermatomyositis (DM) 36%

Polymyositis (PM) initially 5% but final dx in 2% !!!

Necrotizing myopathy (NM) 19%

Sporadic inclusion body myositis 3%

Granulomatous myositis

Eosinophilic myositis

Infectious myositis

Overlap syndromes 10%

Non-specific myositis 29%

van der Meulen 2003

Polymyositis

• Affects mainly adults over the age of 20

• PM represents 2% of all IIM (van der Meulen 2003)

• 63% of patients with PM pathology have clinical PM, 37% have IBM phenotype (Chahin 2008)

• Incidence: South Australia 4.1 to 6.6 per million (4 x that of DM); Taiwan 4.4 per million (DM 7.1); Olmstead 3.45/million (DM 9.6; IBM 7.9)

• Prevalence: South Australia 72 per million (DM 19.7)

• Subacute to chronic onset of limb-girdle weakness

• Neck flexors and pharyngeal weakness, face spared

• Diagnosis of exclusion

Polymyositis Mimics

< 40 > 40

Fibromyalgia IBM

DM, NM SLE, RA

Dystrophin, calpain-3, dysferlin, DM 2

ANO5, Pompe, FSHD, etc PMR

DM 2 DM, NM

OS: RA, SLE, juvenile RA Fibromyalgia

IBM Pompe

Influenza A or B

PM - Laboratory Features

• Serum CK usually elevated 5-50 x LLN, aldolase increase

• May be associated with autoantibodies: Jo-1, PM-1 & SRP

• EMG/NCS: irritative myopathy

• Biopsy cell-mediated autoimmune sporadic disease:̶Q MHC expression on myocyte surface̶Q Endomysial inflammation ̶Q APCs present Ag to naive CD8+ cells which mature to

cytotoxic cells in an HLA-I/MHC restricted fashion̶Q Surround & commonly (63%) invade non-necrotic fibers

expressing MHC antigens̶Q Necrosis, phagocytosis & regenerating myofibers̶Q Granzyme, perforin and granulysin

Polymyositis

Probable PMEndomysial Inflammation(CD8+ predominant) surroundsMyofibers w/o invasionor diffuse MHC-1 expression

Definite PMFocal endomysial myofiberinvasion by T cells (CD8+)

MSA Antigens Autoantibody Antigen Antigen Function Clinical

Syndrome

Jo-1 Histidyl tRNA Protein Synthesis ILD (50%) Mechanics hands

Raynaud’s, joint

PL-7 Threonine tRNA Protein Synthesis ILD (90%)GI (15%)

PL-12 Alanyl tRNA Protein Syntheis ILD (90%)GI (20%)

SRP SRP RNA complex Protein translocation Acute severe NM

Mi-2 Helicase Nuclear transcription Nailfold lesions

MJ NXP-2 Nuclear transcription Calcinosis

Ku Thyroid autoantigen DNA protein kinase Scleroderma

HMGCR Reductase Cholesterol biosynthesis

Immune NM with or without statin use

PMDrug Therapy

• 1st LineQ̶ PrednisoneQ̶ IV methylprednisolone

• 2nd LineQ̶ MethotrexateQ̶ Azathioprine*Q̶ Mycophenolate mofetilQ̶ IVIG (positive in DM)*

• 3rd Line̶Q Rituximab*(Oddis)̶Q Cyclophosphamide̶Q Tacrolimus PM/ILD (Oddis)̶Q Cyclosporine

• 4th Line / Experimental̶Q ?Tocilizumab̶Q Acthar gel̶Q Chlorambucil̶Q ? Infliximab ?Trigger̶Q MEDI-545 completed̶Q

*RCTBunch TW, et al. Ann Intern Med. 1980;92:365-369; Dalakas MC, et al. N Engl J Med. 1993;329:1993-2000; Oddis CV, et al. Arthritis Rheum. 2013;65:314-324; Muscle Study Group. Ann Neurol. 2011;70:427-436; Oddis CV, et al. Lancet. 1999;353:1762-1763; Higgs BW, et al. Ann Rheum Dis. 2014;73:256-262.

Inclusion Body MyositisThe Begining

Adams et al. 1965: A myopathy with cellular inclusions

Chou 1967: Myxovirus-like structures in a case of human chronic polymyositis

Yunis & Samaha 1971: Inclusion body myositis

Vacuoles rimmed by basophilic material & nuclear & cytoplasmatic filamentous inclusions

Eosinophilic inclusions in vacuolated fibers

No viral trigger identified

Background 1978 Carpenter et al:

predominance in men slowly progressive weakness distal muscles involved, no skin lesions CK normal or mildly elevated Vacuoles and on EM tubulofilments prognosis different from other IIMs

Mendell et al 1991: small deposits of Congo red-positive staining material in vacuolated muscle fibers

IBM may have degenerative pathogenesis along with a cytotoxic process

1994 Askanas: ubiquitin in muscle tissue, & since then, other protein aggregates described

Age of Onset

Rash Pattern of Weakness

CK Muscle Biopsy

Cellular Infiltrate

Response to Therapy

Commonly Associated Conditions

IBM Elderly (most of

IIM > age 40-50)

No Asymmetry Finger

flexor, knee extensor, dysphagia

NL or up to 15xNL

Rimmed vacuoles;

endomysial inflammation with invasion

CD8+T-cells; macrophage

& Myeloid Dendritic Cells

No Autoimmune disorder: SS,

SLE, thrombocytopenia

& sarcoidosis

microscopy

IBM

Sporadic IBM: Epidemiology• Most frequent inflammatory myopathy > 40 - 50 yrs old

• IBM represents 16-30% of all IIM

• M/F = 2-3/1; sporadic, rarely familial

• Symptom onset before age 60 in 18% to 20%

• Olmsted County: age and sex adjusted (>30) prevalence 71 per million, incidence 7.9/million (3.45 for PM)

• Australia: prevalence 9.3 (West) to 51/million(South) vs. age-adjusted prevalence in ≥ 50 yrs old 35 - 139/million, incidence in South 2.9 per million (Sweden 2.2)

• Netherlands: prevalence 4.9 per million vs, age-adjusted prevalence in > 50 yrs old 16 per million

J Rheumatol. 2008 Mar;35(3):445-7

Neurol Clin. 2014. Aug;32(3):817-842

Int J Rheum Dis. 2013 Jun; 16(3):331–8

sIBM: Presentation

• Insidious onset with slow chronic progression

• Mean diagnostic delay of 5-8 yrs, getting shorter?

• Proximal & distal weakness: falls & dexterity loss

• Weakness asymmetric in a third

• Atrophy of weak muscles especially late

• Dysphagia 40% earlier on, almost all later on

• Mild to moderate facial weakness

• Muscle stretch reflexes at the patella

KUMC 51 IBM Case Series: Initial Symptoms

Limb-onset 42 (82%): 34: leg weakness 4: hand grip weakness 2: arm & leg weakness 2: foot drop

Bulbar-onset 9 (16%): 8/9: dysphagia as an initial symptom

7/8: isolated dysphagia for 3.4 years (1-10) 1/9: Facial weakness (20 years arm/leg

weakness) Estephan, Barohn, Dimachkie et al. JCNMD 2011

sIBM: Presenting Phenotypes 90%: asymmetry

85%: non-dominant side weaker

39/51 (¾ ): typical phenotype (+FF /+quads)

Typical phenotype spectrum: 13 - “Classic phenotype” (FF and quads weakest) 11 - Classic FF, no preferential quads weakness 6 - Classic quads, no preferential FF weakness 9 - No preferential FF or quads weakness

12/51 (¼): atypical phenotypeEstephan, Barohn, Dimachkie et al. JCNMD 2011

sIBM: Atypical Phenotype Spectrum 5/51: classic FF w/leg weakness sparing quads:

4/5 progressed to typical phenotype at 6y

4/51: LG phenotype: 2/4 progressed to non-preferential +FF weakness at 4 &14y 1/4 progressed to non-preferential +quads weakness at 10y 1/4 progressed to typical phenotype at 5y

3/51: other atypical phenotypes 1 FSH-like phenotype +FF at 6y typical phenotype at 10y 1 +FF arm only at 6.5y 1 +HF/+ADF leg only at 1y

Estephan, Barohn, Dimachkie et al. JCNMD 2011

Sporadic Inclusion Body MyositisAssociated Conditions

No systemic manifestation

No cardiac involvement

No ILD

No association with malignancy

Autoimmune disorders in up to 15%: SLE, Sjogren's syndrome, thrompocytopenia & sarcoidosis

sIBM: Laboratory Tests CK is NL or mildly increased 2 -15 x NL

EMG/NCS: irritative myopathy or “mixed pattern” Mild distal sensory neuropathy in 30%

30% of patients have large MUPs which can lead in some cases to misdiagnosis of ALS

20-30% IBM clinical phenotype mislabeled as PM due to inflammation without vacuoles (ENMC 2011)

May need > 1 biopsy to “prove” pathologically

Highly specific antibody to NT5C1A which is now commercially available; ? sensitivity

Chahin N 2008; Greenberg 2013

Cytosolic 5’-Nucleotidase 1A (cN1A) Ab

13/25 IBM 43 KD: 52% sensitivity, 100% spec.

cN1A most abundant in skeletal muscle

Catalyzes nucleotide hydrolysis to nucleosides

5’-nucleotidases may be involved in DNA repair

cN1A dot blot reactivity cutoff 2.5: 72% sensitive & 92% specific (sp 95%→ sens 57% @ co 3.5)

33% of sIBM patient sera by immunoblot vs. DM, PM & other NM d/o 4.2%, 4.5% & 3.2% respectively Salajegheh et al PlosOne 2011

Greenberg et al. Ann Neurol. 2013Pluk et al. Ann Neurol. 2013

Are cN1A Ab + sIBM cases more disabled? 25 (CD or CP) IBM cases, 72% NT5c1A seropositive

Female higher odds of seropositivity (OR=2.30)

Seropositive sIBM primary outcomes: longer time to get up and stand (p=0.012) more assistive devices need (OR=23.00; p=0.007) no difference on 6 min walk test

Exploratory outcomes in seropositive sIBM: lower total MRC sum score (p=0.03) & FVC more likely to have dysphagia (OR=10.67; p=0.03) IBMFRS 23.0 (17-36) vs 29.0 (22-35) (p=0.06) Facial weakness (50% vs 14%) (p=0.17)

Mozaffar et al. JNNP 2015

Specificity of cN1A Ab

Frequency in IBM 37%

Not in PM, DM or non-autoimmune neuromuscular diseases (<5%)

Anti-cN-1A reactivity was also observed in some other autoimmune diseases: Sjögren's syndrome (36%) Systemic lupus erythematosus (20%)

? distinct IBM-specific epitopes

Annals of the rheumatic diseases 02/2015; DOI: 10.1136/annrheumdis-2014-206691

sIBM: Muscle Pathology

Inflammatory like PM:̶Q MHC class I expression on myocyte surface̶Q Endomysial CD8+ cytotoxic T cells, myeloid DC and

macrophages invasion̶Q Necrosis, phagocytosis & regenerating myofibers̶Q Granzyme, perforin and granulysin

Unlike PM: less necrosis & more frequently invasion of non-necrotic (non-vacuolated) fibers

Degenerative: congophilic deposits, -amyloid precursor protein, tau (SMI-31), ubiquitin deposits, TDP-43, LC3, p62

Typical findings are rarely present: endomysial inflammation, small groups of atrophic fibers, myofibers with ≥1 rimmed vacuoles lined with granular material & eosinophilic cytoplasmic inclusion

IBM: Prognosis Relentless progression to disability: cane in 10/14 at 5 years+ and

wheelchair in 3/5 at 10 years+

4% strength decrease over 6 months, 9.2% per yr

Median of 14 years from onset, 75% significant walking difficulties &

37% used a wheelchair

KU chart review 7.5-year mean duration, 56% assistive device & 20%

requiring a wheelchair

Quad QMT decline 12.5% to 27.9% per yr

IBMFRS 13.8% per year to 22.3% per 4 years

Distance on 6MWT decline 34% over 4 years

Dalakas & Sekul 1993Dalakas & Sekul 1993

Benveniste et al. 2011Benveniste et al. 2011

Estephan et al. 2011 Estephan et al. 2011

Rose et al 2001Rose et al 2001

Neuromuscul Disord. 2013 May;23(5):404-12

Neuromuscul Disord. 2014 Jul;24(7):604-10

Griggs Diagnostic IBM Criteria 1995

A. Clinical features1.       Duration of illness > 6 months2.       Age of onset > 30 years old3.       Muscle weakness in proximal & distal arm & leg muscles and ≥ 1 of the following features:        a. Finger flexor weakness        b. Wrist flexor > wrist extensor weakness        c. Quadriceps muscle weakness (MRC ≤ 4) 

Griggs et al. Ann Neurol. 1995;38:705-713

Griggs Diagnostic IBM Criteria 1995

B. Laboratory features1.       Serum creatine kinase < 12 times normal2.       Muscle biopsy    a. Inflammatory myopathy with mononuclear cell invasion of nonnecrotic muscle fibers    b. Vacuolated muscle fibers    c. Either        - Intracellular amyloid deposits, or         - 15 to 18 nm tubulofilaments by EM3.       EMG must be consistent with inflammatory myopathy (long-duration potentials are acceptable)

 

Griggs et al. Ann Neurol. 1995;38:705-713

Natural history & history under treatment of sIBM: Pitié-Salpêtrière/Oxford study

N = 136, 57% male, 30% initial incorrect dx

6% definite sIBM inflammation, rimmed vacuoles and amyloid deposits

70% clinical sIBM phenotype & muscle biopsy showing inflammation (or MHC class I) & rimmed vacuoles but no amyloid deposits

24% clinical phenotype & either cells or vacuoles

Routine assessment for amyloid or protein aggregates not done: Congo-red or crystal violet or SMI-31 or p62 or TDP43 or 15–18 nm filaments

Brain. 2011 Nov;134(Pt 11):3176-84

2011-13 IBM diagnostic criteria

Clinical & Laboratory Features

Classification Pathological Features

Duration >12 months Age at onset > 45 yrs Quads weak ≥ hip flexand/orFF weak > should abd sCK not > 15xULN

Clinico-Pathologically Defined IBM

Endomysial inflammation &Rimmed vacuoles & eitherProtein accumulation (amyloid or other proteins)

or15-18nm filaments

Same as in Clinico-pathologically Defined IBM except Quads weak ≥ hip flexandFF weak > should abd

Clinically-Defined IBM

One or more of:Endomysial inflammationRimmed vacuoles↑ MHC1Protein accumulation* (amyloid or other proteins) 15-18nm filaments

Same as in Clinico-pathologically Defined IBM except Quads weak ≥ hip flexorFF weak > should abd

Probable IBMSame as clinically defined IBM

*amyloid = Congo-red, crystal violet, or thioflavine T/S other proteins = p62, SMI-31, or TDP-43

Case 1

What does this patient have?

ENMC 2011 Clinically-Defined IBM

What should she do?

Exercise, participate in research

SA EF EE WF FF FE HF KF KE APF ADF

Right 5 5 5 4 5 5 5 4 4 5 5

Left 5 4+ 5 3+ 4 4 5 4+ 4+ 5 5

Sporadic IBM: Resistive Exercise 12-week home exercise program in 7 IBM patients safe;

CK & pathology were unchanged

Exercise 5 days / week does not appear to be harmful

but strength not significantly improved

16-week home exercise program 2/d in 7 cases

resistance isometric + isotonic exercises

Improved all muscles! & in timed functional tests

Stationary cycle ergometer at 80% of the max. HR +

above resistance exercise in 7 IBM cases

Improved aerobic capacity & muscle strength in SA, HF,

HABD, KF; not KE, grip or timed tests

Arnardottir S at al. J Rehabil Med. 2003 Jan;35(1):31-5

Johnson et al. J Clin Neuromusc Dis. 2007;8:187-194

Johnson et al. J Clin Neuromuscul Dis 2009;10(4), 178-184

sIBM: Negative Research Studies

Refractory to prednisone (Lotz 1989)

Refractory to azathioprine (Lindberg 1994)

Refractory to IVIG* (Dalakas 1997)

Refractory to IVIG & CS* (Dalakas 2001)

Refractory to MTX* (Badrising 2002)

Refractory to cyclophosphamide

Refractory to total lymphoid irradiation

Refractory to β-interferon 1a MSG 2001*

Refractory to β-interferon 1a MSG 2004*

* RCT

sIBM: Pilot Studies

Oxandrolone some improvement in arm MVICT (Rutkove 2002)

Antithymocyte globulin improved QMT

(Lindberg 2003)

Etanercept improvement in handgrip was not clinically meaningful at 12 months (Barohn 2006)

Alemtuzumab: (Dalakas 2009) reduction in muscle CD3+ lymphocytes at 6 months No significantly improvement in strength or function ? Short-term stability

Arimoclomol (Barohn 2014)

Ongoing Research Studies• Attempt to increase muscle size and strength or

function; full listing on www.clinicaltrials.gov:

• BYM338 of Novartis to block Activin IIB Rc, n=240

• Follistatin gene transfer therapy of Mendell / TMA by injecting alternatively spliced follistatin to inhibit myostatin

• Arimoclomol Phase 2 Study

• IBMFRS (PROM): following enrolled patients over several years, Burns, Amato & Dimachkie

• Genetic study in IBM: UCL-ION, Hanna/Machado

158 (69) IBM & 127 (127) controls blood (muscle)

APOE ε4 not a susceptibility factor for sIBM

TOMM40 very long repeat allele with later onset age by 3.7 years (95%CI: 0.4, 6.9; p=0.027)

TOMM40 gene encodes mitochondrial pore protein Tom40 involved in transport of amyloid-β & other proteins into mitochondria

TOMM40 VL repeat effect more pronounced among APOE ε3/ε3: 4.9 years (95%CI: 1.1, 8.7; p=0.013)

Men 2.7 years later onset age than women, p 0.095

Rasch Analysis of IBMFRSUsing RUMM 2030 Software

Prospective study of 127 IBM cases from UK & USA

IBMFRS scale demonstrated good fit & reliability

Participant ability higher than scale difficulty level

3 items with disordered thresholds; resolved by grouping categories

IBMFRS passes Rasch analysis!

Muscle & Nerve. Volume 48, Issue Supplement S1, S2-3, 2013

Neuromuscular Disorders 01/2013 23(12):1044–1055

Phase II Study of Arimoclomol in IBMBackground: Degenerative Theory

Results:Demographics

Baseline Characteristics of Participants N=24Age - years Mean ± SD 67 +/- 8Gender - no. of patients (%) Male 17 (71%)Race - no. of patients (%) White 22 (92%) African American 1 (4%)

American Indian/Alaska Native 1 (4%)

Disease duration - years Mean ± SD 8 +/- 4

Diagnosis of Griggs definite (10) or probable (14) IBM

IBM FUNCTIONAL RATING SCALE

1. SWALLOWING 4 Normal 3 Early eating problems –

occasional choking 2 Dietary consistency changes 1 Frequent choking 0 Needs tube feeding

2. HANDWRITING (with dominant hand prior to IBM onset)

4 Normal 3 Slow or sloppy; all words are

legible 2 Not all words are legible 1 Able to grip pen but unable to

write 0 Unable to grip pen

3. CUTTING FOOD AND HANDLING UTENSILS

4 Normal 3. Somewhat slow and clumsy,

but no help needed 2 Can cut most foods, although

clumsy & slow; some help needed

1 Food must be cut by someone but can still feed slowly

0 Needs to be fed

4. FINE MOTOR TASKS (opening doors, using keys, picking up small objects) 4 Independent 3 Slow or clumsy in completing task 2 Independent but requires modified techniques or assistive devices 1 Frequently requires assistance from caregiver 0 Unable 5. DRESSING 4 Normal 3 Independent but with increased effort or decreased efficiency 2 Independent but requires assistive devices or modified techniques (Velcro snaps, shirts without buttons, etc.) 1 Requires assistance from caregiver for some clothing items 0 Total dependence

6. HYGIENE (Bathing and toileting) 4 Normal 3 Independent but with increased effort or decreased activity 2 Independent but requires use of assistive devices (shower chair, raised toilet seat, etc.) 1 Requires occasional assistance from caregiver 0 Completely dependent

7. TURNING IN BED & ADJUSTING COVERS 4 Normal 3 Somewhat slow & clumsy but no help needed 2 Can turn alone or adjust sheets but with great difficulty 1 Can initiate but not turn or adjust sheets alone

8. SIT TO STAND 4 Independent (without use of arms) 3 Performs with substitute motions (leaning forward, rocking) but without use of arms) 2 Requires use of arms 1 Requires assistance from device/person 0 Unable to stand

9. WALKING 4 Normal 3 Slow or mild unsteadiness 2 Intermittent use of assistive device (AFO, cane, walker) 1 Dependent on assistive device 0 Wheelchair dependent

10. CLIMBING STAIRS 4 normal 3 Slow with hesitation or increased effort; uses handrail intermittently 2 Dependent on handrail 1 Dependent on handrail and additional support (cane or person) 0 Cannot climb stairs

Results:

Outcome Variable Arimoclomol change Placebo change p-value

IBMFRS score, mean ± SD

4M (n=16+8) -0.34±1.38 -0.88±1.157 0.239

8M (n=14+8) -0.68±1.58 -2.50±3.31 0.055

12M (n=15+8) -2.03±2.68 -3.50±3.35 0.538

Average MMT score, mean ± SD

4M (n=15+8) -0.04±0.19 -0.12±0.20 0.561

8M (n=13+8) -0.12±0.22 -0.26±0.27 0.147

12M (n=14+7) -0.21±0.21 -0.35±0.20 0.232

MVICT sum score, mean ± SD

4M (n=14+8) 0.46±12.11 -0.30±14.49 0.633

8M (n=13+8) 7.20±19.65 -1.71±17.80 0.347

12M (n=14+8) -1.21±20.76 0.52±17.98 0.946

Hand grip MVICT score (right), mean ± SD

4M (n=14+8) 0.76±2.74 0.50±2.46 0.608

8M (n=13+8) 1.26±2.63 -0.54±1.86 0.064

12M (n=14+8) 1.21±3.70 -0.24±2.94 0.339

DEXA body fat free mass percentage, mean ± SD

4M (n=15+8) 1.3±1.3 1.9±2.8 0.949

12M (n=14+8) -2.0±3.8 -1.0±2.0 0.339

HSP70 levels (ng/100ng myosin), mean ± SD

4M (n=15+8) -110.72±757.40 -34.70±336.35 0.466

Conclusions

IBM & PM share some histological similarities but IBM is more common and refractory to therapies

Protein aggregate deposits (TDP43, p62, SMI-31) in IBM but not routinely done

New IBM Ab (? Specificity); new ENMC 2011

IBM is likely a degenerative muscle disease, requires a different approach

Importance of mild to moderate intensity regular exercise, diet and participation in research studies