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Treatment of Myopathies

Treatment of Myopathies. Hanni Bouma. Overview. Inflammatory myopathies Dermatomyositis Polymyositis Inclusion body myositis Clinical features Investigations Treatment approach. Etiological Classification of Myopathies. Hereditary Muscular Dystrophies Duchenne’s Myotonias

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Treatment of Myopathies

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  1. Treatment of Myopathies Hanni Bouma

  2. Overview Inflammatory myopathies Dermatomyositis Polymyositis Inclusion body myositis Clinical features Investigations Treatment approach

  3. Etiological Classification of Myopathies Hereditary Muscular Dystrophies Duchenne’s Myotonias Channelopathies Congenital Myopathies Metabolic Myopathies Pompe’s disease Mitochondrial myopathies Acquired Inflammatory myopathies PM, DM, IBM Endocrine thyroid Associated with other systemic illness Drug-induced and toxic myopathies EtOH, steroids, statins

  4. Overview of the IM

  5. DM: Clinical Slow, progressive, symmetric limb-girdle weakness Activity-induced muscle pain Rash usually accompanies or precedes weakness (but not always) Associated features: Adults: Myocarditis, ILD, vasculitis, other CTDs (RA, Scl, CREST) Children: Contractures, subQ calcinosis, intestinal ulceration Cancers: adenocarcinomas, ovarian, breast, lung, lymphoma/leukemia

  6. DM: Investigations CK normal (20-30%) or increased up to 50x Does not correlate with severity of weakness Aldolase may be elevated while CK still normal ANA+ (24-60%) Myositis specific antibodies: Mi-2 (15%) acute onset, nailfold ulcers & good response to therapy Anti-Jo-1 (~20%) ILD, mechanic’s hands, arthritis, Raynaud’s EMG Muscle biopsy

  7. Other Investigations: DM Increased risk of Ca. within first 2-3 yrs of diagnosis Treatment of malignancy sometimes improves muscle strength Malignancy workup in all patients: CT CAP Mammogram Breast & pelvic exams Colonoscopy CXR, High res CT chest (ILD) EKG (myocardial inv’t) or Echo if CHF Swallowing assessment if dysphagia

  8. Polymyositis “Diagnosis of exclusion” Often mistaken diagnosis of PM in cases of DM w/o rash (yet), IBM w/o inclusions on biopsy Prox symmetric weakness Associated with other autoimmune disorders Myocarditis, arthritis, Raynaud’s, ILD

  9. IBM Most common myopathy over 50 yo Insidious onset; Dx. usually several yrs after onset Early dysphagia Different pattern of weakness: Distal UE, Prox LE Early atrophy & weakness of WF, FF & quads Hip girdle, ant. tibial muscles

  10. Diagnosis?

  11. PM Mediated by CD8+ T-cells which attack muscle fibres Endomysial mononuclear inflammatory cell infiltrate invading and surrounding non-necrotic muscle fibres

  12. DM Humorally-mediated microangiopathy • Perifascicular necrosis/atrophy (late finding) • Perivascular & perimysial inflammation: • macrophages, B cells, CD4+ cells

  13. IBM Similar to PM: CD8+ T cells & macrophages Modified Gomori trichrome stain Same features as PM + rimmed vacuoles + amyloid deposits

  14. Is it possible to have IBM without inclusions on biopsy? Question

  15. Treatment Overall lack of “EBM” to guide treatment; we don’t know: Which second linetherapies are most beneficial The doses required to see an effect The best time to initiate 2nd or 3rd line agents If some agents are more effective in certain types of myositis

  16. Treatment: Step 1Initiate corticosteroids Treatment of choice in DM & PM: Majority of patients will improve with pred, but response may be incomplete Start prednisone at ~1 mg/kg/day up to 100 mg qd In severe weakness, treatment often initiated w/ short course of IV Solumedrol 1 g x 3 days prior to pred

  17. Treatment: Step 1Post-initiation of steroids Close clinical F/U q2-4 weeks initially Maintain dose until muscle strength normalizes, improvement plateaus, or CK normalizes (at least 4-6 wks) Then slow taper: by 5 mg q2-3 weeks, below 20 mg by 2.5 q2wks *Most will need to stay on a small dose of pred (10 mg qd) or need a 2nd line agent to stay in remission

  18. Step 1: SteroidsSide effect considerations Monitor fasting glucose, K+ levels Septra for PCP prophylaxis If concurrent ILD or pred + other immunosuppressant Bone density scan at baseline & qyearly Calcium 1 g/day + Vit D 1000 IU/day Bisphosphonate used if postmenopausal Record BP at each visit (accelerated HTN & renal failure is a risk) Coexistence of scleroderma & other MCTDs Periodic eye exams for glaucoma & cataracts

  19. Question What should I do if there is no response after an adequate trial of high dose prednisone?

  20. Question How can I tell if the patient is weaker because of refractory disease or because of chronic steroid use?

  21. Treatment: Step 2Add immunosuppressant Indications: Moderate or severe weakness Other organ system inv’t (ILD, myocarditis) Increased risk of steroid complications (diabetic, OP, postmenopausal women) Failure to significantly improve after 2-4 months of steroids Any pt expected to need steroids for 10-12 mos or more * Must weigh risks of immunosuppression vs. possible benefits (faster improvement, steroid-sparing)

  22. Treatment: Step 2Immunosuppression Options: Azathioprine Methotrexate IVIG Cellcept Cyclophosphamide Generally used as 3rd line, if refractory to other Rx.: Rituximab PLEX Ciclosporine Tacrolimus

  23. Azathioprine Effective in DM/PM (retrospective studies), but takes 6-18 mos to work Prior to starting, can screen for TPMT deficiency (BM toxicity in homozygotes) or just monitor CBC Begin at 50 mg/d, increase by 50 mg q2wks up to 2-3 mg/kg/d

  24. AzathioprineMonitoring & SEs Major SEs: 12% develop systemic rxn (fever, abdo pain, N/V) w/i first few wks requiring discontinuation of drug; BM & liver toxicity (avoid allopurinol), pancreatitis, teratogenicity, oncogenicity, infection Monitor CBC, LFTs closely; D/C if LFTs double (esp. GGT) Leukopenia: can develop at 1 wk to as late as 2 yrs post-initiation; decrease dose if WBCs fall to <4, D/C altogether if <2.5 or ANC <1; usually reverses w/i 1 mo., can then rechallenge

  25. Methotrexate Most DM & PM respond to MTX (retrospective studies only) Begin at 7.5 mg/wk po, increase gradually by 2.5 mg each week up to 25 mg/wk If no improvement after 1 month on 25 mg, switch to weekly subQ & increase dose by 5 mg qwk up to 60 mg/wk

  26. MethotrexateMonitoring & SEs Major SEs: alopecia, stomatitis, pulmonary fibrosis, teratogenicity, oncogenicity, infection; renal, liver & BM toxicity Avoid MTX in pts with ILD or anti-Jo-1+ Avoid MTX in heavy drinkers Treat all pts with folate 5 mg qwk Monitor LFTs, CBC q2wks until on stable dose, then q1-3 mos Check GGT because AST/ALT can be elevated from muscle inv’t; consider liver Bx. if cumulative dose exceeds 2 g Monitor PFTs periodically

  27. IVIG One prospective, double-blind, placebo-controlled study in 15 pts w/ DM showed significant improvement Little RCTevidence of benefit as monotherapy but plenty of anecdotal evidence that IVIG is effective, even alone

  28. IVIG 2 g/kg over 2-5 days, repeated at monthly intervals for at least 3 mos Then decrease or spread out dose (40 g q2wks) SEs: Renal failure (esp. diabetics), flu-like Sx., rash, aseptic meningitis, MI, stroke, CHF

  29. Cyclophosphamide • Used often if ILD • SEs: infections, secondary malignancies, hemorrhagic cystitis, sterilization, BM toxicity, GI upset, alopecia • Usually given pulsed (0.5-1 g/ IV/m2/mo. for 6-12 mos), higher risk of cystitis po

  30. Mycophenolate mofetil Blocks purine synthesis in lymphs Actual benefit unknown Main advantage: lack of renal or liver toxicity Starting dose 1.0 g bid, increased to 1.5 bid if needed Limit 1 g/d if renal insufficiency Side effects: N/V, diarrhea, fever, leukopenia, severe infections possible

  31. Treatment: Step 3If refractory to other modalities… Rituximab -> monoclonal Ab against CD20, depletes B cells Dose 750 mg/m2 (up to 1 g) x 1, repeat in 2 wks & then q6-9mos Warnings re: PML risk…

  32. Treatment: Step 3If refractory to other modalities… Ciclosporine & tacrolimus -> renal toxicity, HTN, electrolyte imbalance, GI upset, hypertrichosis, gingival hyperplasia, cancers, tremor, infection PLEX -> few small open label series suggested benefit in DM, PM & IBM Controlled trial of 36 pts w/ DM & PM comparing PLEX, leukopheresis & sham apheresis showed no improvement

  33. Side Effects & Monitoring SI

  34. Non-medical therapies PT & OT Dietician consult if on steroids Aerobic exercise programs Prevents contractures May help w/ steroid SEs (weight gain, OP, type 2 fibre atrophy) Speech therapy Esp if concomitant dysphagia

  35. Question What is the value of monitoring serum CK levels in the treatment of DM & PM?

  36. Question How does the treatment of IBM differ from that of PM & DM?

  37. IBM Glucocorticoids have limited role In largest published series, muscle strength continued to deteriorate in all of 25 pred-treated patients followed for at least 2 yrs CK levels often normalize, but this doesn’t correlate with clinical benefit Exception: Cases of IBM ass’d w/ other CTDs (Sjogren’s, SLE, cutaneous DM) may have clinically important benefit from steroids MTX, Imuran: minor benefit at best

  38. IBM: suggested approach If ++inflammation seen on Bx., consider trial of steroids +/- Imuran (3 mos) early in disease Discontinue all therapy if continued decline in strength For most patients, no treatment Cricopharyngeal myotomy may be helpful if severe dysphagia

  39. References • Dr. Erin O’Ferrall! • Amato & Barohn. Evaluation and treatment of inflammatory myopathies. Journal of Neurology, Neurosurgery & Psychiatry. 2009; 80: 1060-1068. • UptoDate

  40. Lambert-Eaton Myasthenic Syndrome Hanni Bouma

  41. Symptoms • Slowly progressive proximal muscle weakness (legs>>arms) • Muscle fatigability or cramping after exercise • Autonomic dysfunction: • Dry mouth** • ED • Blurred vision, constipation • CN dysfunction (less prominent than in MG & rarely the presenting symptom) • Ptosis most common • Diplopia, dysarthria, dysphagia, difficulty chewing • Respiratory failure late in course

  42. Signs • Proximal muscle weakness without atrophy • Functional difficulties often worse than exam findings • Depressed or absent reflexes • Isometric contraction of relevant muscle can temporarily bring out reflexes or improve muscle weakness (postactivation facilitation) • More sustained physical exercise  muscle fatigability • Paradoxical eyelid elevation with sustained upgaze • Symmetric, sluggish pupillary responses • Reduced salivation

  43. Pathophysiology • VGCC antibodies: interfere with normal calcium influx required for Ach release  reduced Ach release from presynaptic nerve terminals

  44. Epidemiology • Annual incidence & prevalence 0.48 & 2.32 per million • ½ of cases associated w/ malignancy • Usually starts after age 50 • SCLC most commonly (84%), Hodgkin’s lymphoma • Presence of LEMS implies better prognosis in SCLC pts • In non-paraneoplastic forms, younger age of onset

  45. Treatment • 1) Treatment of underlying malignancy • causes remission of LEMS in many but not all paraneoplastic forms; may be only intervention necessary • 2) Symptomatic therapies • increase amt. of Ach available at postsynaptic membrane • 3) Immunologic therapies • reduce aberrant immune response causing formation of VGCC antibodies • Regimens similar to those used in MG

  46. Aminopyridines • MoA: significant prolongation of nerve terminal membrane depolarization  calcium channels kept open longer, which improves release of Ach • 3,4-Diaminopyridine:limited CNS penetration, few SEs (perioral & extremity paresthesias, seizures at higher doses)

  47. Guanidine • MoA: inhibits VGKC & enhances release of Ach • First beneficial agent for symptomatic treatment of LEMS • Significant bone marrow, liver & renal toxicity at higher doses • Max dose 1000 mg/d.

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