1. Idiopathic Inflammatory Myopathies Dr. Mark I. Boulos PGY 1 – Neurology Rheumatology Rounds Tuesday, June 5, 2007 2. Objectives Discuss how one can differentiate the idiopathic inflammatory myopathies (IIMs) from other neurological conditions Review the major causes of myopathies Review the following for the IIMs: Clinical features Antibody markers EMG findings Current treatment strategies Discuss steroid-induced myopathy versus disease activity Discuss the use of MRI in the IIMs 3. Case 58F office clerk from Trinidad Initially presented to the SMH MS Clinic with: Unstable gait Intermittent hand tremor Blurring of vision Headaches Subtle UMN findings in left leg Non-specific T2 hyperintensities on brain MRI Diagnosed with “Possible (but not definite) MS” 4. A few months later… Returned to neurologist complaining of: Difficulty getting up from a chair or a squatting position Difficulty combing hair and reaching for objects with her arms Weakness was slowly progressing On neurological examination, only abnormality was proximal muscle weakness Normal cranial nerves, sensation, reflexes & tone No fasciculations or atrophy No muscle or joint tenderness No cutaneous lesions 5. What’s going on? Based on these findings, which of the following diagnoses should be initially considered? Upper motor neuron disease process (e.g. Multiple Sclerosis) Anterior horn cell disease (e.g. ALS) Peripheral neuropathy Neuromuscular junction disease (e.g. Myasthenia gravis) Myopathy 6. Answer: E. Myopathy Proximal muscle weakness, in the absence of fasciculations, atrophy, cranial nerve and sensory findings is strongly suggestive of a myopathic process 7. Lower vs. Upper Motor Neuron Weakness *Disuse atrophy can develop after initial presentation Down-going Up-going (Babinski’s sign) Toes Decreased or absent Increased (spasticity) Tone Present Absent Fasciculations Present Absent* Atrophy Diminished or absent Hyperactive +/- clonus Reflexes Lower Motor Neuron (Anterior horn cells to peripheral nerves) Upper Motor Neuron (Brain to corticospinal tract) 8. Distinguishing Lower Motor Weakness from Muscle Weakness Weakness due to neuropathy: lower motor neuron disease. Weakness due to myopathy: nerve function intact. Absent May be present Sensory signs/symptoms Often preserved Diminished Reflexes Absent May be present Fasciculations Proximal > distal Distal > proximal Distribution Due to Myopathy Due to Neuropathy 9. Source: www.uptodate.com 10. Common Conditions that can Result in Myopathy Non-inflammatory myopathies Hypothyroidism Hypokalemia Alcoholism Drugs AZT HMG-CoA reductase inhibitors (statins) Corticosteroids… More on this later! 11. Idiopathic Inflammatory Myopathies Heterogeneous group of disorders characterized by: Proximal muscle weakness Non-suppurative inflammation of skeletal muscle with predominantly lymphocytic infiltrates 12. Idiopathic Inflammatory Myopathies Clinical Classification Polymyositis (PM) Dermatomyositis (DM) Inclusion Body Myositis (IBM) Juvenile Dermatomyositis Myositis associated with malignancy Myositis associated with collagen vascular disease Bohan & Peter (1975). NEJM. Tanimoto et al. (1995). J Rheumatology . 13. Epidemiology 2-8 cases per million per year Female:male = 2:1 Bimodal distribution: 10-15 years (pediatric variant) 45-60 years Age of onset for myositis associated with another condition is similar to that in the other condition IBM and myositis associated with malignancy are common after the age of 50 years Wortmann RL. Primer on Rheum Dis . 12th edition. 2001:369–376. 14. Usually insidious onset over 3-6 months No identifiable precipitant Shoulder and pelvic girdle muscles affected most severely Neck muscles (esp. flexors) involved in 50% of patients Ocular and facial muscles almost never affected Distal muscles are spared in majority of pts Dysphagia & dysphonia may occur Polymyositis Wortmann RL. Primer on Rheum Dis . 12th edition. 2001:369–376. 15. Cardiac disturbances Asymptomatic ECG changes Conduction disturbances Supraventricular arrhythmias Cardiomyopathy Congestive heart failure Respiratory involvement Interstitial fibrosis Interstitial pneumonitis Polymyositis (continued) Systemic symptoms Arthralgias Fever, malaise Raynaud’s phenomenon Wortmann RL. Primer on Rheum Dis . 12th edition. 2001:369–376. 16. Features of Polymyositis as well as cutaneous manifestations The skin lesions may precede or follow the muscle syndrome Gottron’s sign - symmetric violaceous erythematous eruption over knuckles Heliotrope rash - reddish violaceous eruption on upper eyelids +/- oedema Shawl sign – erythematous rash over neck, upper chest and shoulders Dermatomyositis Wortmann RL. Primer on Rheum Dis . 12th edition. 2001:369–376. 17. Gottron’s Sign 18. Heliotrope rash 19. Shawl Sign Source: DermAtlas, Johns Hopkins University www.dermatlas.med.jhmi.edu 20. Inclusion Body Myositis Mainly affects older individuals Symptoms begin insidiously and progress slowly Symptoms are often present 5-6 years before diagnosis Differs from Polymyositis in that IBM: May include focal, distal or asymmetric weakness Neurogenic or mixed neurogenic / myopathic changes on EMG Dysphagia is noted in more than 20% of patients May continue to progress slowly & steadily; in others, symptoms plateau Wortmann RL. Primer on Rheum Dis . 12th edition. 2001:369–376 . 21. Differs from adult form because of co-existence of vasculitis and ectopic calcification Vasculitis can involve skin, kidneys, GI tract, muscle and brain Calcification is frequently present in muscles of subcutaneous tissues Juvenile Dermatomyositis Wortmann RL. Primer on Rheum Dis . 12th edition. 2001:369–376. 22. Malignancy may precede or follow the onset of muscle weakness Associated malignancy may be more common in DM Association is rare in childhood Sites and types of malignancy are those expected for patient‘s age and gender MYOSITIS ASSOCIATED WITH MALIGNANCY Wortmann RL. Primer on Rheum Dis . 12th edition. 2001:369–376. 23. Overlap of muscle weakness and one of the collagen vascular diseases such as scleroderma, SLE and MCTD PAN and RA rarer association MYOSITIS ASSOCIATED WITH OTHER COLLAGEN VASCULAR DISEASES Wortmann RL. Primer on Rheum Dis . 12th edition. 2001:369–376. 24. Back to our case… What investigations can be done for this patient to confirm our diagnosis? 25. High clinical suspicion for Polymyositis … Diagnosis confirmed by: CK levels EMG findings Muscle biopsy 26. Polymyositis / Dermatomyositis Diagnostic criteria Proximal muscle weakness Elevated serum CK Myopathic changes on EMG Muscle biopsy demonstrating lymphocytic inflammation Dermatomyositis: Skin rash as well as criteria above Definitive diagnosis with four criteria having been met Probable with three Possible with two Bohan & Peter (1975). NEJM. 27. Elevation of CK sometime during course of disease (often >10 times normal) AST, ALT, and LDH are elevated in most cases Laboratory Findings Wortmann RL. Primer on Rheum Dis . 12th edition. 2001:369–376. 28. EMG classically reveals the following triad: Increased insertional activity, fibrillations and sharp positive waves Spontaneous, bizarre, high frequency discharges Polyphasic motor-unit potentials of low amplitude and short duration Complete triad seen in 40% of patients 10-15% of patients have completely normal EMGs EMG Findings Wortmann RL. Primer on Rheum Dis . 12th edition. 2001:369–376. 29. Muscle Biopsy: Histology and Immunochemistry Dermatomyositis B cells, macrophages CD4 T cells Decreased capillaries Perifascicular atrophy Perivascular infiltrate Polymyositis Mononuclear cells CD8 T cells Endomysial infiltrate Myonecrosis Patchy, focal IBM Same as PM; also: Rimmed vacuoles Eosinophilic cytoplasmic inclusions Source: Dr. R. Shupak, St. Michael ‘s Hospital Pathogenesis of Idiopathic Inflammatory Myopathy Rheumatology Rounds: April 5, 2005 Rolak LA. Neurology Secrets. 2005: 63-7. 30. Source: Dr. R. Shupak, St. Michael ‘s Hospital Pathogenesis of Idiopathic Inflammatory Myopathy Rheumatology Rounds: April 5, 2005 31. Back to our case… CK previously elevated in range of 600-800 IU/L EMG study demonstrated “diffuse myopathic process, associated with muscle necrosis and/or muscle fibre splitting” Muscle biopsy "consistent with polymyositis" 32. Differential Diagnosis of the Motor Unit by EMG 33. Back to our case… Are there any other laboratory investigations that can be carried out? 34. Myositis-Specific Autoantibodies (MSA) Source: Dr. R. Shupak, St. Michael ‘s Hospital Pathogenesis of Idiopathic Inflammatory Myopathy Rheumatology Rounds: April 5, 2005 35. Myositis-Specific Autoantibodies Source: Dr. R. Shupak, St. Michael ‘s Hospital Pathogenesis of Idiopathic Inflammatory Myopathy Rheumatology Rounds: April 5, 2005 36. MSA And Associated Disease Features Ab Ag P revalence Disease Anti Jo1 HisRS 15-40 antisynthetase antiPL7 ThrRS 5 antisynthetase antiPL12 AlaRS 5 antisynthetase antiPL12 tRNA-Ala 5 antisynthetase antiOJ IleRS 5 antisynthetase AntiEJ GLyRS 5 antisynthetase AntiSRP SRP protein 5 severe acute PM Anti Mi-2 nuclear helicase 10 classic DM Anti KJ ?protein 1 ILD Source: Dr. R. Shupak, St. Michael ‘s Hospital Pathogenesis of Idiopathic Inflammatory Myopathy Rheumatology Rounds: April 5, 2005 Briani et al. (2006). Autoimmunity. 37. Myositis-Associated Antibodies (MAA) MAA are found in the sera of 20-50% of patients Commonly encountered in other connective tissue diseases. Source: http://www.emedicine.com/neuro/topic85.htm Sjögren syndrome and systemic lupus erythematosus (SLE) Ro/SSA 60 kd Ro/SSA 52 kd La/SSB Connective tissue–disease overlap syndrome snRNP Other connective tissue diseases Anti-Ku Scleroderma Anti-PM/Scl Myositis Overlapping with… MAA 38. What treatments are available for our patient? Back to our patient… 39. Immunotherapeutic strategies The immunotherapies for inflammatory myopathies can be divided into three major categories: Selective, antigen-specific immunotherapies Semi-specific therapies Conventional, non-specific immunosuppressive or anti-inflammatory therapies Dalakas MC. (2006). Neuromuscular Disorders. 40. 1) Selective, antigen-specific immunotherapies Target the trimolecular complex (TMC) of T–cell stimulation, which is part of the ‘immunological synapse’ In principle, each component of the TMC can be targeted Dalakas MC. (2006). Neuromuscular Disorders. 41. 1) Selective, antigen-specific immunotherapies Of limited practical application at the present time Antigen is unknown Such immunotherapy needs to be tailored to individual patients, because the T-cell response to various auto-antigens is very complex Growing evidence that the autoimmune response is not static but dynamic, spreading overtime to include new autoantigens (‘epitope spreading’) Dalakas MC. (2006). Neuromuscular Disorders. 42. 2) Semi-specific therapies Semi-specific therapies using agents and biologicals aimed at various targets of the immunopathological network Dalakas MC. (2006). Neuromuscular Disorders. 43. 3) Conventional, non-specific immunosuppressive agents At the present time, include: Steroids Azathioprine Mycophenolate Methotrexate Cyclophosphamide Cyclosporin Dalakas MC. (2006). Neuromuscular Disorders. 44. Therapeutic targets in PM, DM, IBM and the available biological agents directed against them 1. Intracellular signalling pathways (a) anti-CD52 (Alemtuzumab), (b) anti-LFA1/ICAM, (Efalizumab), (c) anti-LFA3/CD2 (Alefacept) Preliminary results are encouraging (d) anti-IL2R antagonist (CD25) (Daclizumab) Well-tolerated; promising results in 2 trials of MS patients (e) Calcineurin inhibitors ( Tacrolimus and Cyclosporin) In several small series of PM & DM patients, Tacrolimus has shown to be effective as a steroid-sparing agent in some patients A controlled study has not been done Dalakas MC. (2006). Neuromuscular Disorders. 45. Therapeutic targets in PM, DM, IBM and the available biological agents directed against them 1. Intracellular signalling pathways (continued) (f) Against TOR kinase via FK-506 binding protein (Rapamycin) Appears promising in patients with DM resistant to other therapies (g) Inhibition of purine biosynthesis by T and B cells (Mycophenolate Mofetil) Anecdotal reports suggest effectiveness in IBM (h) Anti-thymocyte globulin Randomized pilot study showed effectiveness in IBM Dalakas MC. (2006). Neuromuscular Disorders. 46. 2. B cells and autoantibodies (a) IVIg Effective in DM based on a controlled trial (b) Rituximab Preliminary studies have shown effectiveness of Rituximab in DM patients A multi-center controlled study in PM and DM funded by the NIH will begin shortly 3. Complement (a) IVIg (b) Anti C5 monoclonal antibody (Eculizumab) Now undergoing clinical trials in DM patients Therapeutic targets in PM, DM, IBM and the available biological agents directed against them Dalakas MC. (2006). Neuromuscular Disorders. 47. 3. Cytokines/chemokines/adhesion molecules Anti-TNF-a agents: (i) Etanercept (Embrel) Tried in uncontrolled series in some patients with PM, DM, and IBM with limited results (ii) Remicade Tried anecdotally in PM, DM, and IBM patients, but a controlled study has not been conducted Preliminary studies suggest that it can be of help to some patients with inflammatory myopathie (iii) Atalimumab (Humira) There are no reports on its effectiveness in DM, PM, or IBM Therapeutic targets in PM, DM, IBM and the available biological agents directed against them Dalakas MC. (2006). Neuromuscular Disorders. 48. 4 . Cytokines/chemokines/adhesion molecules (b) Anti-IL1 receptor antagonist (Anakinra) Has not been tried in DM, PM, or IBM (c) Beta-interferon A pilot study with Avonex was ineffective in IBM A controlled multicenter trial with higher doses is being considered Therapeutic targets in PM, DM, IBM and the available biological agents directed against them Dalakas MC. (2006). Neuromuscular Disorders. 49. T cell transmigration (a) IVIg (b) Natalizumab (Tysabri) Recently approved for Multiple Sclerosis Will likely be tried in DM, PM, or IBM sometime soon Therapeutic targets in PM, DM, IBM and the available biological agents directed against them Dalakas MC. (2006). Neuromuscular Disorders. 50. Therapeutic Targets Dalakas MC. (2006). Neuromuscular Disorders. 51. Treatment Strategy for DM & PM Step 1: Prednisone (in aggressive cases, combination with another agent listed in steps 2 & 3 may be preferred) Step 2: IVIg Step 3: Immunosuppressants, such as Azathioprine, Methotrexate, Mycophenolate or Cyclosporine Step 4 : Newer agents (Rituximab, Tacrolimus, Rapamycin) Dalakas MC. (2006). Neuromuscular Disorders. 52. More on IVIg… Only drug whose efficacy in IIM has been proven in controlled trials In a double blind study of IVIg therapy at 2 gm/kg given in two days in patients with refractory dermatomyositis: Improvement in strength first noticeable about 15 days after the first IVIg infusion Clear improvement after the second infusion Marked improvement is also noticed in cutaneous features Repeated infusions may be required every 6–12 weeks to maintain improvement Dalakas MC et al. (1993). NEJM. 53. This just in… IVIg & IBM Mild benefits in strength in patients with IBM A trial of IVIg may be helpful in patients with worsening of muscle strength or life-threatening dysphagia Sparks S et al. (2007). BMC Neurology. 54. Treatment Failure Failure to respond to therapy may suggest Inclusion body myositis Neoplasm-related myopathy Steroid-resistance or steroid-induced myopathy May also indicate: Wrong diagnosis (consider re-biopsy) Inadequate dose of prednisone or early taper Early discontinuation of prednisone without keeping a ‘maintenance‘ low dose therapy Dalakas MC. (2006). Neuromuscular Disorders. 55. Other Management Considerations Prevention of medication side effects Physical therapy Speech therapy Psychiatric support 56. Back to our case… Neurologist planned to start patient on Prednisone 60mg daily (1mg/kg/d) Side effects explained Calcium and vitamin D supplementation started DEXA scan arranged Baseline bloodwork (CK, CBC, Cr, Glucose, HbA1c) to be completed prior to starting Prednisone 57. One month later … Patient returned complaining of: Blurry vision in her eyes Epigastric pain Increase in weight Mild improvement in strength of upper extremity, but no improvement in lower extremity Neurologist decides to: Transfer patient‘s care to a Rheumatologist Start Losec Refer patient to ophthalmologist for formal eye examination 58. Two months later … Saw Rheumatologist at SMH Weakness worsening… Disease progression or steroid-induced myopathy? Methotrexate added Prednisone tapered to 40gmg/d Malignancy screening Mammogram & Pap smear arranged Arthritis Society OT visit arranged Referred for repeat EMG (inconclusive) 59. Steroid myopathy versus disease activity Not common However, may be difficult to distinguish steroid-induced myopathic weakness from weakness related to: Disease activity Decreased mobility Infection Concomitant systemic illness Dalakas MC. (2006). Neuromuscular Disorders. 60. Steroid myopathy versus disease activity Examples of two differing scenarios Weakness that may need more prednisone Increasing CK levels, no overt signs of steroid toxicity with reduced or unchanged dosage of steroids, and no evidence of a systemic illness or infection Possible Steroid-induced Myopathy Patient with increasing weakness and stable CK who receives high dose of steroids Dalakas MC. (2006). Neuromuscular Disorders. 61. Steroid myopathy versus disease activity When the signs are not clear… One may arbitrarily raise the prednisone dosage Answer can be evident in about 2–8 weeks, according to the change in the patient’s strength Helpful clinical sign - strength of neck extensor muscles Usually worsens with exacerbation of the disease Remains unchanged with steroid-induced muscle intoxication Electromyography, seeking for increased spontaneous activity could be another sign suggestive of active disease Dalakas MC. (2006). Neuromuscular Disorders. 62. How can MRI help my patient? 63. Use of MRI in Patients with Inflammatory Myopathies MRI is the method of choice for imaging of muscle abnormalities It is very sensitive in localizing nonhomogeneous inflammation in inflammatory myopathies During treatment of inflammatory myopathies, the extent and severity of inflammation may decrease at varying rates MRI can be used to track these changes Park JH, Olsen NJ. (2001). Curr Rheumatol Rep. 64. Use of MRS in Patients with Inflammatory Myopathies With P-31 MRS, biochemical defects are quantified, which may all be related to weakness and fatigue Low levels of ATP and phosphocreatine (PCr) Elevated concentrations of ADP and inorganic phosphate (Pi) The metabolic abnormalities detected with P-31 MRS are more persistent and can be used for objective patient evaluation after the disappearance of inflammation and normalization of serum levels of muscle enzymes Park JH, Olsen NJ. (2001). Curr Rheumatol Rep. 65. Advances in MRI New advances in MRI include: Diffusion-weighted imaging Permits assessment of fluid motion in muscles Blood-oxygen-level-dependent (BOLD) imaging Evaluates tissue oxygenation Olsen NJ, Qi J, Park JH. (2005). Curr Rheumatol Rep. 66. Back to our case… Patient has been followed by Rheumatologist on a monthly basis Weakness was concluded to be secondary to: Steroid-induced myopathy Deconditioning Depression Patient‘s strength improved with Prednisone taper Energy levels improved after seeing a psychiatrist and starting an antidepressant medication Patient declined formal PT rehabilitation 67. Happy Ending… Patient‘s polymyositis remains symptomatically, clinically and biochemically quiescent Recent bloodwork showed normal CK, AST, LDH, CBC, glucose, Cr & lytes She is much more animated and motivated She is exercising more Continues to see her psychiatrist 68. Thanks for your attention! Questions?