Myositis 2019
- 1. Inflammatory Myositis Vivian Stone, MD Medicine Noon Conference 4/4/2019
- 2. Objectives • Idiopathic Inflammatory Myopathies – DM – PM – Immune mediated necrotizing myopathy • Inclusion Body Myositis • Differential Diagnosis
- 3. Idiopathic inflammatory myopathies • Heterogeneous group of autoimmune disorders predominately affecting skeletal muscles, resulting in muscle inflammation and weakness • Other organ systems often involved – Skin, cardiac, GI, and pulmonary systems • Most common forms – Polymyositis and dermatomyositis – Immune mediated necrotizing myopathy – Inclusion body myositis – more degenerative, less inflammatory
- 4. Idiopathic inflammatory myopathies • Heterogeneous group of autoimmune disorders predominately affecting skeletal muscles, resulting in muscle inflammation and weakness • Other organ systems often involved – Skn, cardiac, GI, and pulmonary systems • Most common forms – Polymyositis and dermatomyositis – Immune mediated necrotizing myopathy – Inclusion body myositis – more degenerative, less inflammatory
- 5. Epidemiology • DM – bimodal incidence – Peaks in childhood and again 50-70 y/o • PM – rare in childhood, mainly after 2nd decade in life • Prevalence for both – 1 per 100,000 in the general population • Female predominance – 2: 1
- 6. Bohen and Peter classification (1975) • Symmetric proximal muscle weakness • Elevation in skeletal muscle enzymes • Abnormal EMG • Muscle biopsy abnormalities – Degeneration/regeneration, perifascicular atrophy, necrosis, inflammatory infiltrate • Typical skin rash of DM These criteria were before testing for myositis specific antibodies, and before inclusion body myositis was recognized as a separate d/o. Thus, use of these criteria may characterize patients as having DM or PM that in fact have other diagnoses. Newer classification criteria have been proposed, but Bohen and Peter classification is the most widely used
- 7. Overlap Syndrome • DM and PM may overlap with features of other CTD • Especially... – SLE – Scleroderma – MCTD • Less commonly… – Rheumatoid arthritis – Sjogrens syndrome
- 8. Laboratory Features • Elevated muscle enzymes – CPK up to 50x upper limit normal – Aldolase – LDH – AST/ALT • Elevated ESR, CRP • Anemia of chronic disease
- 9. Muscle Biopsy • Required to make definitive diagnosis • Also important to r/o other causes of myopathy • Useful to do EMG and/or MRI to help guide where to biopsy • EMG findings – abnormal in 70-90% – Polyphasic, short, motor unit potentials, pos sharp waves, fibrillation, repetitive discharges • MRI findings - edema, inflammation (hyperintense T2 weighted images)
- 10. DM - Muscle pathology • Humorally mediated • Perifascicular cellular infiltrate • Perivascular inflammation • Perifascicular atrophy and fibrosis • CD4 T cells, B cells and pDCs (IFN)
- 11. PM – Muscle pathology • Cell-mediated immune mechanisms • Cell infiltrate within the fascicles and invading muscle fibers • Increased numbers of cytotoxic CD8+ T cells
- 12. Immune-mediated necrotizing myopathy • Degeneration and regeneration • Sparse lymphocytic inflammation Hoogendijk et al., Neuromuscular Discord., 2004
- 13. Antibodies in DM/PM • Autoantibodies to nuclear antigens or cytoplasmic antigens are present in up to 55% – Neg ANA with + cytoplasmic staining is a clue • Myositis-specific autoantibodies – Antisynthetase • Jo1, PL7, PL12, EJ, OJ, KS, ZO, Ha – Dermatomyositis • Mi2, MDA5, TIF1ƴ, NXP-2 – Immune mediated necrotizing myopathy • Anti-HMGCR (anti-200/100) – assoc with prior statin use • SRP – Inclusion body myositis • NT5C1a • Myositis associated (overlap syndromes) – PM-Scl, U1RNP, Ro, 56kDa, KJ, Fer, Mas, MJ, hPMS1
- 14. Muscular manifestations • Symmetric proximal muscle and truncal weakness • Relatively slowly progressive – Over weeks to months • Difficulty – Rising from chair, climbing steps, lifting objects, combing hair • Distal muscle groups only involved late in course • Facial muscles unaffected • Pharyngeal and respiratory muscles may be affected • Often painless, although some pain may be seen early in course
- 15. Dermatologic Manifestations • Skin lesions are photosensitive • Pruritis can be present (different from SLE) • Variety of characteristic rashes • Periungal erythema with abnormal capillary loops (similar to those seen in scleroderma) • Psoriasiform changes of scalp • Calcinosis
- 16. Gottron’s papules • 80% of patients with DM • Considered pathopneumonic
- 17. Heliotropic rash Violaceous eruption over upper eyelids, often with swelling
- 19. Mechanics hands Can be a manifestation of anti-synthetase syndrome Frequently mistaken for contact dermatiitis
- 20. Cutaneous calcinosis • More common in Juvenile DM (30%), rare in adult • Often occurs at sites of compression • Can be painful and lead to ulcerations and infection • Difficult to treat – can try CCB, bisphosphonates
- 21. Amyopathic DM • Cutaneous manifestations of DM • No elevation in muscle enzymes • No muscle weakness • 10-20% of DM cases • Can progress to myopathy, but less common – One small study – 18% of patients developed muscle weakness within 5 yrs of dx
- 22. Cardiac involvement • Estimated to be between 6-75% • Usually asymptomatic • Conduction abnormalities most common (32- 72%) • CHF and arrhythmias secondary to myocarditis are uncommon • CHF more common with chronic disease – thought to be complication of long-term steroid use • If clinically symptomatic -poor prognosis
- 23. Case • 45 y/o woman with 1 month hx of mild proximal muscle weakness in arms and legs, photosensitive skin rash. • Found to have elevated CPK and inflammatory markers. • Muscle and skin bx confirmed dx of DM • Started on prednisone 60mg daily
- 24. Case • During the next 2 weeks, she noted increasing DOE, unable to keep up with her family • At that time, crackles in both lung bases, and was noted to have decrease O2 sat with ambulation to 85% • CT chest showed interstitial lung disease with diffuse ground glass opacities
- 25. Pulmonary manifestations in DM/PM • Major cause of morbidity and mortality • Hypoventilation (5-20%) of patients – Occurs in patients with severe muscle weakness involving resp muscles – Restrictive pattern on PFTs with reduced lung volumes and atelectasis on CXR • Aspiration PNA (17%) – Frequently associated with dysphagia (with muscular involvement of pharynx and upper esophagus) • Interstitial lung disease (up to 46%)
- 26. ILD and PM/DM • May occur before, concomitantly or after the onset of skin or muscle symptoms • When associated with amyopathic DM, poorer prognosis with rapidly progressive course • Three patterns – Acute onset pulm sx, progressive hypoxia within 1 month of symptom onset – Chronic, slowly progressive symptoms – Asymptomatic progression (only abn imaging) • Major risk factor for premature death
- 27. Pulmonary Involvement in DM/PM • Patterns of lung involvement – Nonspecific interstitial pneumonia (NSIP) – Usual interstitial pneumonia – Bronchiolitis obliterans/Cryptogenic org PNA (BOOP/Cop) – Diffuse alveolar damage – Spontaneous pneumomediastinum
- 28. Anti-synthetase syndrome • Relatively acute disease onset • Constitutional sx (eg fever, weight loss) • Raynaud’s • Mechanics hands • Arthritis • ILD (can be more prominent than muscle sx) • Associated with antisynthetase antibodies that are highly specific for DM/PM (eg anti-Jo1) Does not require presence of all of the above to dx
- 29. Case - outcome • Day 1 of hospital – broch neg for infection – 1gm solumedrol x 3 days – Then transitioned to 125mg daily • Day 2 – Cyclophosphomide • Day 3 – Required intubation for worsening pulm status, decrease O2 sats – Started on IVIG x2 days • Despite above, continued to deteriorate – 100% O2 requirement • Day 7 – Died on day 7 from respiratory failure
- 30. Case - outcome • Day 1 of hospital – broch neg for infection – 1gm solumedrol x 3 days – Then transitioned to 125mg daily • Day 2 – Cyclophosphomide • Day 3 – Required intubation for worsening pulm status, decrease O2 sats – Started on IVIG x2 days • Despite above, continued to deteriorate – 100% O2 requirement • Day 7 – Died on day 7 from respiratory failure
- 31. Case - outcome • Day 1 of hospital – broch neg for infection – 1gm solumedrol x 3 days – Then transitioned to 125mg daily • Day 2 – Cyclophosphomide • Day 3 – Required intubation for worsening pulm status, decrease O2 sats – Started on IVIG high dose x2 days • Despite above, continued to deteriorate – 100% O2 requirement • Day 7 – Died on day 7 from respiratory failure
- 32. Case - outcome • Day 1 of hospital – broch neg for infection – 1gm solumedrol x 3 days – Then transitioned to 125mg daily • Day 2 – Cyclophosphomide • Day 3 – Required intubation for worsening pulm status, decrease O2 sats – Started on IVIG x2 days • Despite above, continued to deteriorate – 100% O2 requirement • Day 7 – Died on day 7 from respiratory failure
- 33. Case - outcome • Day 1 of hospital – broch neg for infection – 1gm solumedrol x 3 days – Then transitioned to 125mg daily • Day 2 – Cyclophosphomide • Day 3 – Required intubation for worsening pulm status, decrease O2 sats – Started on IVIG x2 days • Despite above, continued to deteriorate – 100% O2 requirement • Day 7 – Died on day 7 from respiratory failure
- 34. Patient Presentation • 55 y/o woman with new onset photosensitive skin rash over nasolabial folds and eyelids, and symmetric proximal muscle weakness over the past 3-4 weeks. • She has lost 20 lbs, and denies any SOB, changes in her breathing or dysphagia • On exam, vital are stable, she has heliotrope rash and shawl sign as well as Gottron’s papules. Muscle strength is 2/5 with hip flexors and 3/5 shoulder forward flexion. • Lab work with elevated CPK 6000, elevated ESR and CRP, as well as transaminitis • Started on prednisone 60mg daily for dx of DM, confirmed by muscle bx
- 35. Patient Presentation • Despite prednisone 60mg daily, her muscle weakness and rash persisted • CPK, ESR and CRP remained elevated • Continued to lose weight, despite high doses of prednisone
- 36. Patient Presentation • Despite prednisone 60mg daily, her muscle weakness and rash persisted • CPK, ESR and CRP remained elevated • Continued to lose weight, despite high doses of prednisone • Additional testing?
- 37. Patient Presentation • Despite prednisone 60mg daily, her muscle weakness and rash persisted • CPK, ESR and CRP remained elevated • Continued to lose weight, despite high doses of prednisone • CT abd/pelvis revealed large ovarian mass -> bx done -> stage 4 ovarian ca
- 38. Malignancy and DM/PM • Increased risk of malignancy and inflammatory myopathies • Swedish pop-based cohort (788 pts) – 15% had cancer dx either at the same time or after dx of DM – 9% at the same time or after dx of PM • Australian pop-based cohort (537 patients) – Malig dx in 104 patients (19%) • Peak incidence of malig dx occurs within 2 yrs of dx of DM or PM
- 39. Risk factors for malignancy • Greater in DM than PM • Evidence of capillary damage on muscle bx • Cutaneous LCV • Older age (>65 y/o) – up to 48% have malignancy • Antibodies associated with cancer: – Anti-p155 ab, anti p155/140, anti MJ • Antibodies with negative associated for cancer – anti-synthetase antibodies, anti-Mi-2, anti-SRP – anti-RNP, anti-PM-Scl, anti-Ku
- 40. Types of Cancer • Ovarian (SIR 10.5) • Lung (SIR 5.9) • Pancreatic (SIR 3.8) • Non-Hodgkins Lymphoma (SIR 3.6) • Stomach (SIR 3.5) • Colorectal (SIR 2.5) • Breast (SIR 2.2) • Others Hill, CL et al. Lancet 2001
- 41. Screening for cancer • Age appropriate cancer screening in all patients • Complete physical, including breast, rectal and pelvic exam • Lab testing – CBC, ESR, CRP, Chem, UA looking for hematuria – Stool for occult blood, colonoscopy if age appropiate – Can consider tumor marker - CA 125 • Imaging – CXR, and in high risk pts – pan CT – Consider Pelvic or TV US in women with DM • Usually repeat screening for 2-3 yrs after dx, except for consider ovarian ca screening (can consider CA125 – twice yearly and US yearly), which can occur up to 5 yrs after initial dx of DM or PM – All above with PPV 78%, NPV 94% • ? Pet/CT – PPV 86%, NPV 96% – Am J Med 2010 – 6PM, 49 DM patients, 9 with cancer
- 42. Treatment • Systemic glucocorticoids – Usually 1mg/kg, max 80mg daily for at least 4-6 weeks – For severe disease –pulse solumedrol 1gm for 3 days – Taper slowly over 1 yr – no standard regimen • 10mg per week until at 40 • 5 mg per week until at 20 • 2.5 mg per week until at 10 • 1mg every 2 weeks until at 5mg • Watch for steroid-induced myopathy • More than 80 % with inflammatory myopathy will respond to GC alone, 50% for PM • Low threashold for steroid sparing agent
- 43. Steroid-sparing agents • Very few RCTs • Azathioprine – start 50mg/day, increase to 1.5- 3mg/kg/day – Screen for TMPT deficiency • Methotrexate – start 15mg weekly, increase to 25mg weekly – careful in patients with ILD • Hydroxychloroquine 200mg BID – For skin disease only • Many other agents have been used for refractory disease (mainly based on case series, anectodal reports) – Rituxan, IVIG, mychophenylate, cyclosporin, tacrolimus
- 44. Objectives • Idiopathic Inflammatory Myopathies – DM – PM – Immune mediated necrotizing myopathy • Inclusion Body Myositis • Differential Diagnosis
- 45. Inclusion Body Myositis • Considered one of the idiopathic inflammatory myopathies along with DM/PM • Prevalence 5-9 cases per million adults • Older age of onset – mean is approx 60 y/o • Male predominance • Insiduous onset of proximal muscle weakness – On average 6 yrs of sx prior to dx – Can be assymmetric in 10-15% of cases • Myalgias with weakness in 40% • Muscle atrophy can be severe • Dysphagia in 1/3
- 46. Inclusion body myositis - pathology • Basiphilic rimmed vacuoles • Inflammatory infiltrate more common early in disease • Over 90% of patients have filamentous inclusions on EM • Based on muscle pathology, often misdiagnosed as PM as about 20% do not have rimmed vacuoles. – Chahim and Engel, 2008
- 47. IBM Data Derived Diagnostic Criteria (DDC)-1 • All 3 of the following – Finger flexion OR knee extension weakness – Endomysial inflammation – Invasion of non-necrotic muscle fibers OR rimmed vacuoles • Sensitivty 90% • Specificity 96%
- 48. Lab Abnormalities • CKs elevations usually < 10x normal • Usually there is no elevation in inflammatory markers • Association with NT5C1a antibody • EMG – finding similar to DM/PM • MRI – finding often overlap with DM/PM, although may be more asymmetric in IBM • Less responsive to treatment than DM/PM
- 49. Differential diagnosis • Metabolic myopathy (glycogen storage diseases, lipid storage diseases, mitochondrial myopathies) – Early muscle fatigue, elevated muscle enzymes, normal strength initially that occasionally progresses to weakness • Polymyalgia Rheumatica – Older patients, elevated ESR, CRP – pain and stiffness predominant sx, as opposed to true weakness. Muscle enzyme normal • Drug related – Statins, colchicine, anti-malarials among others • Muscular dystrophies • Endocrine myopathies – Hypothyroidism – elevated CPKs (usually in the hundreds), and can see inflammation on muscle biopsy – DM muscle necrosis – usually focal
- 50. MKSAP Question • A 68-year-old man is admitted to the intensive care unit because of an exacerbation of chronic obstructive pulmonary disease (COPD). His course becomes complicated over the next 2 days by pneumonia and acute kidney injury, and he requires noninvasive positive-pressure ventilation. After 10 days, his medical condition stabilizes, but profound weakness of the extremities is noted. Besides COPD, the patient has a history of hypertension, hypothyroidism, and hyperlipidemia. One week before admission, he was started as an outpatient on prednisone, 60 mg/d, for his COPD; other medications include piperacillin-tazobactam, metoprolol, levothyroxine, and simvastatin.
- 51. MKSAP Question • On physical examination, blood pressure is 134/90 mm Hg, pulse rate is 90/min, and arterial oxygen saturation is 96% on nasal oxygen, 2 L/min. Neurologic examination shows profound symmetric weakness of bilateral upper and lower extremity muscles. Deep tendon reflexes and cranial nerve function are normal. • Laboratory studies show an elevated serum creatinine level at 1.5 mg/dL (114.5 µmol/L). Serum levels of creatine kinase and electrolytes are normal, as are results of liver chemistry studies.
- 52. MKSAP Question • Which of the following is the most appropriate therapy for this patient? A. Increased dosage of prednisone B. Intravenous administration of immune globulin C. Physical and occupational therapy D. Plasma exchange
- 53. MKSAP Question • Which of the following is the most appropriate therapy for this patient? A. Increased dosage of prednisone B. Intravenous administration of immune globulin C. Physical and occupational therapy D. Plasma exchange
- 54. Questions?
Editor's Notes
- #17: Violaceous flatt topped papules and plaques located over MCPs and PIPs