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, CSLBehring, 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 pickup 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
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
 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?
Clinical Patterns of Muscle Disorders
Weakness
Proximal
Distal
Asymmetric
Symmetric
Episodic
Trigger
Diagnosis
PATTERN
MP1 - Limb girdle
+
MP2 – Distal*
+
+
Most myopathies –
hereditary and acquired
+
Distal myopathies
(also neuropathies)
MP3 - Proximal arm / distal leg
“scapuloperoneal”
+
Arm
+
Leg
+
(FSH)
MP4 - Distal arm / proximal
leg
+
Leg
+
Arm
+
MP5 - Ptosis / Ophthalmoplegia
+
MP6 - Neck – extensor*
+
+
INEM, MG
MP7 - Bulbar (tongue,
pharyngeal, diaphragm)*
+
+
MG, LEMS, OPD
(also ALS)
MP8 - Episodic weakness/
Pain/rhabdo + trigger
+
+
+
+
MP9 - Episodic weakness
Delayed or unrelated to exercise
+
+
+
+/-
Primary periodic paralysis
Channelopathies:
Na+
Ca++
Secondary periodic paralysis
+
+/-
Myotonic dystrophy, channelopathies,
PROMM, rippling (also stiff-person,
neuromyotonia)
MP10 - Stiffness/ Inability to relax
*Overlap patterns with neuropathic disorders
+
(MG)
+
(others)
FSH, Emery-Dreifuss,
acid maltase, congenital scapuloperoneal
IBM
Myotonic dystrophy
+
(others)
OPD, MG, myotonic dystrophy, mitochondria
McArdle’s, CPT, drugs, toxins
Adapted from Barohn RJ, Dimachkie MM, Jackson RJ. Neurol Clin 2014;32(3):569-593
Clinical Patterns of Neuropathic Disorders
Weakness
Proximal
Distal
+
Asymm
Symm
Sensory
Symptoms
+
+
+
GBS/CIDP
NP2 - Distal sensory loss
with/without weakness
+
+
+
CSPN, metabolic, drugs,
hereditary
NP3 - Asymmetric distal
weakness with sensory loss
+
+
+
Multiple – vasculitis, HNPP,
MADSAM, infection
Single - Mononeuropathy,
radiculopathy
+
+
+
Polyradiculopathy, plexopathy
NP5 - Asymmetric distal
weakness w/out sensory loss
+
+
NP6 – Symmetric sensory
loss & upper motor neuron
signs
+
+
+
+
PATTERN
NP1 - Symmetric prox &
distal weakness w/sensory
loss
NP4 - Asymmetric prox &
distal weakness w/sensory
loss
+
NP7 - Symmetric weakness
without sensory loss*
+\-
NP8 - Focal midline proximal
symmetric weakness*
+ Neck/trunk
extensor
or
+ Bulbar
+ Diaphragm
NP9 – Asymmetric
proprioceptive loss w/out
weakness
NP10 – Autonomic
dysfunction
*Overlap patterns with myopathy and NMJ disorders
+
+
Severe
Proprioceptive
Loss
+
UMN
Signs
Autonomic
Symps/Signs
Diagnosis
+/-
+ UMN – ALS/PLS
- UMN – MMN
+
B12/Copper defic;
Friedreich’s,
ALD
Prox & Distal
SMA
Distal
Hereditary motor neuropathy
+
+
+
+
+
ALS
ALS/PLS
+
Sensory neuronopathy
(ganglionopathy)
CISP
+
Diabetes, GBS, amyloid,
prophyria
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:
̶
̶
̶
̶
̶
̶
MHC expression on myocyte surface
Endomysial inflammation
APCs present Ag to naive CD8+ cells which mature to
cytotoxic cells in an HLA-I/MHC restricted fashion
Surround & commonly (63%) invade non-necrotic fibers
expressing MHC antigens
Necrosis, phagocytosis & regenerating myofibers
Granzyme, perforin and granulysin
Polymyositis
Probable PM
Endomysial Inflammation
(CD8+ predominant) surrounds
Myofibers w/o invasion
or diffuse MHC-1 expression
Definite PM
Focal endomysial myofiber
invasion 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
Immune NM with or
without statin use
Cholesterol
biosynthesis
PM
Drug Therapy
• 1st Line
̶
̶
Prednisone
IV methylprednisolone
• 2nd Line
̶
• 3rd Line
̶ Rituximab*(Oddis)
̶ Cyclophosphamide
̶ Tacrolimus PM/ILD (Oddis)
̶ Cyclosporine
Methotrexate
Azathioprine*
Mycophenolate mofetil
IVIG (positive in DM)*
• 4th Line / Experimental
̶
̶ ?Tocilizumab
̶
̶ Acthar gel
̶
̶ Chlorambucil
̶ ? Infliximab ?Trigger
̶ MEDI-545 completed
*RCT
Bunch TW, et al. Ann Intern Med. 1980;92:365-369; Dalakas MC, et al. N Engl J Med. 1993;329:1993-2000;
̶ Group. Ann Neurol. 2011;70:427-436;
Oddis CV, et al. Arthritis Rheum. 2013;65:314-324; Muscle Study
Oddis CV, et al. Lancet. 1999;353:1762-1763; Higgs BW, et al. Ann Rheum Dis. 2014;73:256-262.
Inclusion Body Myositis
The 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
IBM
IBM
Age of
Onset
Rash
Pattern of
Weakness
CK
Muscle
Biopsy
Cellular
Infiltrate
Response
to Therapy
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
microscopy
Commonly
Associated
Conditions
Autoimmune
disorder: SS, SLE,
thrombocytopenia
& sarcoidosis
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)
J Rheumatol. 2008 Mar;35(3):445-7
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)
Int J Rheum Dis. 2013 Jun; 16(3):331–8
Netherlands: prevalence 4.9 per million vs, age-adjusted
prevalence in > 50 yrs old 16 per million
Neurol Clin. 2014. Aug;32(3):817-842
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 phenotype
Estephan, 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 Estephan, Barohn, Dimachkie et al. JCNMD 2011
 1 +HF/+ADF leg only at 1y
Sporadic Inclusion Body Myositis
Associated 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%
Salajegheh et al PlosOne 2011
respectively
Greenberg et al. Ann Neurol. 2013
Pluk 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:
̶
̶
̶
̶
MHC class I expression on myocyte surface
Endomysial CD8+ cytotoxic T cells, myeloid DC and
macrophages invasion
Necrosis, phagocytosis & regenerating myofibers
Granzyme, perforin and granulysin
 Unlike PM: less necrosis & more frequently invasion of nonnecrotic (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+
Dalakas & Sekul 1993

4% strength decrease over 6 months, 9.2% per yr
Rose et al 2001

Median of 14 years from onset, 75% significant
walking difficulties & 37% used a wheelchair
Benveniste et al. 2011

KU chart review 7.5-year mean duration, 56%
assistive device & 20% requiring a wheelchair
Estephan et al. 2011

Quad QMT decline 12.5% to 27.9% per yr
Neuromuscul Disord. 2013 May;23(5):404-12

IBMFRS 13.8% per year to 22.3% per 4 years
Neuromuscul Disord. 2014 Jul;24(7):604-10

Distance on 6MWT decline 34% over 4 years
Griggs Diagnostic IBM Criteria 1995
A. Clinical features
1.
Duration of illness > 6 months
2.
Age of onset > 30 years old
3.
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 features
1.
Serum creatine kinase < 12 times normal
2.
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 EM
3.
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
Clinical &
Laboratory Features
Classification
Pathological Features
Duration >122011-13
months
Age at onset > 45 yrs
Quads weak ≥ hip flex
and/or
FF weak > should abd
sCK not > 15xULN
IBM diagnostic
criteria
Endomysial
inflammation &
Same as in Clinicopathologically Defined
IBM except
Quads weak ≥ hip flex
and
FF weak > should abd
One or more of:
Endomysial inflammation
Clinically-Defined Rimmed vacuoles
↑ MHC1
IBM
Protein accumulation*
(amyloid or other proteins)
15-18nm filaments
Same as in Clinicopathologically Defined
IBM except
Quads weak ≥ hip flex
or
FF weak > should abd
ClinicoPathologically
Defined IBM
Rimmed vacuoles & either
Protein accumulation
(amyloid or other proteins)
or
15-18nm filaments
Same as clinically defined
Probable IBM 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
Arnardottir S at al. J Rehabil Med. 2003 Jan;35(1):31-5
 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
Johnson et al. J Clin Neuromusc Dis. 2007;8:187-194
 Improved all muscles! & in timed functional tests
 Stationary cycle ergometer at 80% of the max.
HR + above resistance exercise in 7 IBM cases
Johnson et al. J Clin Neuromuscul Dis 2009;10(4), 178-184
 Improved aerobic capacity & muscle strength in
SA, HF, HABD, KF; not KE, grip or timed tests
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 IBMFRS
Using 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 IBM
Background: Degenerative Theory
Results:
Demographics
Baseline Characteristics of Participants N=24
Age - years
Mean ± SD
Gender - no. of patients (%)
Male
Race - no. of patients (%)
White
African American
American Indian/Alaska Native
Disease duration - years
Mean ± SD
67 +/- 8
17 (71%)
22 (92%)
1 (4%)
1 (4%)
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
Outcome Variable
Arimoclomol change
Placebo change
Results:
IBMFRS score, mean ± SD
4M (n=16+8)
-0.34±1.38
-0.88±1.157
8M (n=14+8)
-0.68±1.58
-2.50±3.31
12M (n=15+8)
-2.03±2.68
-3.50±3.35
Average MMT score, mean ± SD
4M (n=15+8)
-0.04±0.19
-0.12±0.20
8M (n=13+8)
-0.12±0.22
-0.26±0.27
12M (n=14+7)
-0.21±0.21
-0.35±0.20
MVICT sum score, mean ± SD
4M (n=14+8)
0.46±12.11
-0.30±14.49
8M (n=13+8)
7.20±19.65
-1.71±17.80
12M (n=14+8)
-1.21±20.76
0.52±17.98
Hand grip MVICT score (right), mean ± SD
4M (n=14+8)
0.76±2.74
0.50±2.46
8M (n=13+8)
1.26±2.63
-0.54±1.86
12M (n=14+8)
1.21±3.70
-0.24±2.94
DEXA body fat free mass percentage, mean ± SD
4M (n=15+8)
1.3±1.3
1.9±2.8
12M (n=14+8)
-2.0±3.8
-1.0±2.0
HSP70 levels (ng/100ng myosin), mean ± SD
4M (n=15+8)
-110.72±757.40
-34.70±336.35
p-value
0.239
0.055
0.538
0.561
0.147
0.232
0.633
0.347
0.946
0.608
0.064
0.339
0.949
0.339
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