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Advances in Inclusion Body Myositis

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.

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Advances in Inclusion Body Myositis

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  1. 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.

  2. 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

  3. 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

  4. 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?

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

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

  7. 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?

  8. 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.

  9. IIM Classification • Dermatomyositis (DM) 36% • Polymyositis (PM) • initially 5% but final dx in 2% !!! • Necrotizing myopathy (NM) 19% • Sporadic inclusion body myositis 3% • Granulomatousmyositis • Eosinophilicmyositis • Infectious myositis • Overlap syndromes 10% • Non-specific myositis 29% van der Meulen 2003

  10. 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

  11. Polymyositis Mimics < 40 > 40 • FibromyalgiaIBM • 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

  12. 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

  13. 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+)

  14. MSA Antigens

  15. PMDrug Therapy • 3rd Line • Rituximab*(Oddis) • Cyclophosphamide • Tacrolimus PM/ILD (Oddis) • Cyclosporine • 4th Line / Experimental • ?Tocilizumab • Acthar gel • Chlorambucil • ? Infliximab ?Trigger • MEDI-545 completed • 1st Line • Prednisone • IV methylprednisolone • 2nd Line • Methotrexate • Azathioprine* • Mycophenolate mofetil • IVIG (positive in DM)* *RCT Bunch 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.

  16. 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

  17. 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

  18. IBM microscopy

  19. 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 yrsold 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 Int J Rheum Dis. 2013 Jun; 16(3):331–8 Neurol Clin. 2014. Aug;32(3):817-842

  20. 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

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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

  26. Cytosolic 5’-Nucleotidase 1A (cN1A) Ab Salajegheh et al PlosOne 2011 Greenberg et al. Ann Neurol. 2013 Pluk et al. Ann Neurol. 2013 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

  27. 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

  28. Specificity of cN1A Ab Annals of the rheumatic diseases 02/2015; DOI: 10.1136/annrheumdis-2014-206691 • 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

  29. 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 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

  30. IBM: Prognosis Dalakas & Sekul 1993 Benveniste et al. 2011 Estephan et al. 2011 Rose et al 2001 Neuromuscul Disord. 2013 May;23(5):404-12 Neuromuscul Disord. 2014 Jul;24(7):604-10 • 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

  31. Griggs Diagnostic IBM Criteria 1995 Griggs et al. Ann Neurol. 1995;38:705-713 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)

  32. Griggs Diagnostic IBM Criteria 1995 Griggs et al. Ann Neurol. 1995;38:705-713 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)

  33. 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

  34. 2011-13 IBM diagnostic criteria *amyloid = Congo-red, crystal violet, or thioflavine T/S other proteins = p62, SMI-31, or TDP-43

  35. Case 1 • What does this patient have? • ENMC 2011 Clinically-Defined IBM • What should she do? • Exercise, participate in research

  36. Sporadic IBM: Resistive Exercise Arnardottir S at al. J Rehabil Med. 2003 Jan;35(1):31-5 • 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 Johnson et al. J Clin Neuromusc Dis. 2007;8:187-194 Johnson et al. J Clin Neuromuscul Dis 2009;10(4), 178-184

  37. 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

  38. 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)

  39. 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

  40. 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

  41. Rasch Analysis of IBMFRSUsing RUMM 2030 Software Muscle & Nerve. Volume 48, Issue Supplement S1, S2-3, 2013 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!

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

  43. Phase II Study of Arimoclomol in IBMBackground: Degenerative Theory

  44. Results: Demographics Diagnosis of Griggs definite (10) or probable (14) IBM

  45. IBM FUNCTIONAL RATING SCALE

  46. Results:

  47. 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

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