Inflammatory Myopathies Dipika Aggarwal, MD PGY 4 Neurology

Idiopathic Inflammatory Myopathies Dermatomyositis (DM) Polymyositis (PM) Autoimmune Necrotizing Myopathy (NM) Inclusion Body Myositis (IBM)

Idiopathic Inflammatory Myopathies Epidemiology Annual incidence – 1:100,000 Incidence of individual myositides has been limited by the different diagnostic criteria employed in various epidemiological studies IBM is the most common myopathy after age 50 with prevalence of 3.5/100,000 cases Disease of adults (except for Juvenile DM) Women are more commonly affected Genetic predisposition secondary to inherited Human Leukocyte Antigens (HLA) haplotypes There are few reports of DM, PM, and IBM occurring in parents, children and siblings of affected individuals, suggesting a genetic predisposition to developing these disorders, possibly secondary to inherited HLA haplotypes. (combination of DNA sequences at adjacent locations (loci) on a chromosome that are inherited together

Idiopathic Inflammatory Myopathies

Idiopathic Inflammatory Myopathies

Dermatomyositis (DM) Can present at any age, including infancy Affects female more than males Acute (over several weeks) or insidiously (over months) progressive, painless, proximal weakness with or without characteristic skin rash Proximal leg and arm muscles are usually the earliest and most severely affected muscle groups Mostly painless Speech, chewing and swallowing difficulties may be seen JDM commonly presents after a febrile episode and with a skin rash Multisystem involvement is more common in JDM

Dermatomyositis : Skin involvement Distinct rash Occurs before or with the onset of muscle weakness Variable degree of muscle versus skin involvement Amyopathic DM– isolated rash with no muscle involvement Adermatopathic DM – isolated myositis Classical DM findings: heliotrope rash Gottron’s papules dilated nail bed capillaries V-sign shawl sign mechanic’s hands Subcutaneous calcinosis seen in 30-70% cases of JDM, less common in adults

DM : Skin findings Heliotrope rash: purplish discoloration along the hairline of scalp and malar region of the face and eyelids Dilated capillary loops evident in the nail bed as well as small ulceration involving the distal aspect of the little finger Heliotrope rash – moderate erythematous rash along the hairline of scalp and malar region of the face amd eyelids Gottrons sign – macular rash seen over the extensor surface of the knuckles Dilated capillary loops evident in the nail bed as well as small ulceration involving the distal aspect of the little finger

DM : Skin findings Gottron papules : erythematous lichenoid papular scaly rash, over the extensor surface of the hands and fingers Gottrons sign

DM : Skin findings V sign: Erythematous rash around face, neck and anterior chest Shawl sign: erythematous rash affecting upper back

DM : Skin findings Mechanic’s hands: Cracking of the finger pad skin, commonly involving the first, second, and third fingers .

Dermatomyositis – Lab features Serum CK Elevated serum CK with levels ranging upto 50 times the upper limit of normal CK level may be normal in less than 10% pts Do not co-relate with the severity of weakness ANA is detected in 24-60% of pts with DM Myositis specific antibodies Found in a minority of patients Useful in predicting response to therapy and prognosis Cytoplasmic antibodies directed against transitional proteins (tRNA synthetases and anti-signal recognition particle) Directed against nuclear proteins (Mi-2 and Mas antigens) Most common MSA are Jo-1 antibodies, associated with Interstitial Lung Disease, seen in 20% pts (MTX should be avoided) Mi-2 antibodies (15-20% DM pts); associated with acute onset, florid rash, good response to therapy and favourable prognosis Some pts have the so called “myositis specific antibodies”. MSA include: 1 cytoplasmic antibodies directed against transitional proteins (ie various t RNA synthetases and the anti-signal recognition particle) and 2. those directed against Mi-2 and Mas antigens. The most common of the anti symthetases is the Jo-1 antibody which is associated with ILD and Raynaud phenomena (so called anti-synthetase syndrome). This antibody is demonstrated in as many as 20% of patients with inflammatory myopathy pts. These antibodies may be useful in predicting prognosis. Mi-2 antibodies are found in 15-20% of DM pts. Mi-2 is a 240kDa nuclear protein of unknown function. Anti-Mi-2 antibodies have been associated with an acute onset, florid rash, good response to therapy and favourable prognosis. Antibodies directed against signal recognition particle have been associated with myocarditis and a necrotising myopathy on biopsy.

Dermatomyositis - Electrophysiology Motor and sensory nerve conduction studies are mostly normal Needle examination shows non specific findings of irritative myopathy (increased insertional activity, fibrillation potentials and positive sharp waves, complex repetitive discharges) Muscle fibrosis in advanced cases may result in reduced insertional activity due to fibrosis Motor unit action potentials (MUAPs) are polyphasic, brief, and of low amplitude EMG is helpful in assessing relapsing weakness during treatment Worsening strength in the absence of fibrillation potentials suggests a steroid induced myopathy

Dermatomyositis Histopathology and Pathogenesis Histology Earliest finding : Membrane Attack Complexes around blood vessels Pathognomic : perifascicular atrophy with or without perimysial and perivascular inflammatory infiltrate (macrophages , B cells , CD4+ T cells , plasmacytoid dendritic cells) Electron microscopy: tubulo reticular inclusions in the intramuscular arterioles and capillaries Pathogenesis Humorally mediated micro angiopathy antibodies directed against endothelial cells activate complement factors  membrane attack complex (MAC) deposition on capillaries  endothelial damage, capillary necrosis, perivascular inflammation, ischemia and myofibril necrosis

Muscle Biopsy Perifascicular atrophy with perimysial inflammation MAC deposition around blood vessels (Immunoperoxidase stain) greenberg book

Muscle Biopsy Wash u

Idiopathic Inflammatory Myopathies

Polymyositis (PM) Exclusionary diagnosis in pts who do not have a rash or alternate muscle or nerve disease PM is a disease of adults over age 20 years More prevalent in female Subacute to insidiously progressive, proximal arm and leg weakness Myalgias and tenderness are common but usually not the first presenting symptoms Dysphagia is seen in one-third of patients Facial weakness is occasionally present

Polymyositis – work up Elevated CK in range of 5 to 50 times the normal. Unlike DM, CK is always elevated in PM Positive ANA (16-40% ) Myositis specific antibodies useful in predicting response to therapy and prognosis Anti SRP antibodies: severe, fulminant, steroid resistant PM Anti Jo-1 antibodies: associated with ILD Electro diagnostic tests show evidence of muscle irritation Increased insertional activity, positive sharp waves, polyphasic MUAPs Do not distinguish PM from other IIM Skeletal muscle MRI – increased signal consistent with muscle edema and inflammation SRP antibodies are seen in severe, fulminant, steroid resistant PM or NM, they predict a rapid course leading to muscle fibrosis and marked cardiac involvement and thus indicate need for aggressive therapy

Polymyositis Histopathology and Pathogenesis Histology fiber size variability scattered necrotic and regenerating fibers endomysial inflammation consisting of cytotoxic T cells and macrophages Pathogenesis HLA- restricted, antigen specific, cell mediated immune response directed against muscle fibers ?? Trigger viral infections (inconclusive hypothesis) MHC 1 expressed endogenous peptide “auto antigen”  activation of CD8+ cytotoxic T cells and macrophages that invade myocytes  destroy muscle fibres through perforin pathway causing pore formation and osmolysis Unlike DM - MAC, complement or immuno globulins are not deposited on the microvasculature in PM Other inflammatory cells – myeloid dendritic cells, and plasma cells which account for the increased expression of immunoglobulin genes on microarray experiments

Muscle Biopsy Endomysial inflammatory cell infiltrate surrounding and invading non necrotic muscle fibres Dimachkie- inflammatory infiltrates surrounding and invading non necrotic fibers. Amato and russell Endomysial mononuclear inflammatory cell infiltrate surrounding and invading non necrotic muscle fibres

Idiopathic Inflammatory Myopathies

Autoimmune Necrotizing Myopathy (NM) Increasing recognized autoimmune myopathy little or no inflammatory infiltrate more common in females sub acute progressive proximal weakness without rash rapid onset than PM; markedly severe in 30% cases myalgia and dysphagia

Autoimmune Necrotizing Myopathy Subtypes Paraneoplastic NM rare, rapidly progressive severe variant associated with adenocarcinoma NM with thick “pipestem” capillaries associated with subacute weakness brain infarction due to vascultis Connective Tissue Disease SRP autoantibodies associated NM Severe, fulminant treatment refractory cardiac complications (myocarditis) Statin induced autoimmune NM (SANAM) affects between 46 to 89 year old pts onset may be delayed upto 10 yrs following statin initiation may occur several months after discontinuation Often therapy resistant

Autoimmune Necrotizing Myopathy – work up Elevated CK – more than 10 times the normal Positive ANA – suggestive of underlying CTD MSA – SRP autoantibodies EMG – irritative myopathy

NM - Histopathology and Pathogenesis Histology Scattered necrotic myofibers with myophagocytes Absence or paucity of T-lymphocytic inflammation Unlike DM, perivascular inflammation is scant, and there are no endothelial tubulo reticular inclusions Thick-walled and enlarged “pipestem” capillaries is diagnostic of NM with pipestem capillaries SRP-associated NM: bimodal distribution of fiber sizes, increased endomysial connective tissue, and reduced endomysial capillary number with enlargement and thickening Pathogenesis Unknown deposition of complement MAC on small arterioles and capillaries with thickened endothelial walls suggests humorally mediated microangiopathy Anti 200/ 100 antibodies Autoantigen is 3-hydroxy -3- methylglutaryl-coenzyme A reductase (HMGCR) protein Statin upregulate HMGCR protein levels, thus triggering anti- HMGCR auto immunity Anti-200/100 (anti-HMGCR) • Autoantigen for anti-200/100 is 3-hydroxy -3- methylglutaryl-coenzyme A reductase (HMGCR) • HMGCR is a target of statins Mammen AL, et al. Arthritis Rheum 2011;63(3):713-21. • Statins upregulate HMGCR protein levels • Regenerating muscle fibres express high levels HMGCR In pts with SANAM, Mamen identified the antigen to be the 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGCR) protein. In muscle biopsy tissue from antibody-positive patients, HMGCR expression was upregulated. Statins are known to dramatically upregulate HMGCR protein levels; thus, in some patients, increased HMGCR expression could trigger anti-HMGCR autoimmunity

Scattered necrotic fibers, some undergoing phagocytosis Muscle Biopsy Scattered necrotic fibers, some undergoing phagocytosis Dimachkie – multiple necrotic fibers undergoing phagocytosis Book – scattered necrtic fibers, some in process of undergoing phagocytosis

Associated conditions There is an increased incidence of interstitial lung disease, autoimmune disorders, cancer and cardiac disorders in patients with DM , PM and NM Cardiac conductions defects, arrhythmias ventricular and septal wall motion abnormalities Pericarditis and congestive heart failure (less common) Myocarditis (seen in 1/3rd pts), associated SRP autoantibodies Pulmonary 10-25% of patients have ILD Jo-1 antibodies are present in at least 50% of ILD cases Prompt chest imaging and pulmonary function tests Pulmonary consultation

Associated conditions (contd.) Malignancy Most studies suggest 15 to 25% of adult DM patients, older than 40 years, have preexisting, concurrent, or future malignancies Most common DM-associated malignancy Women: ovarian cancer Men: small cell lung cancer Other common malignancies are – pancreatic cancer, stomach and colorectal cancers and lymphoma Rarely, malignancy has been reported in JDM Malignancy is increased in PM and NM when compared with the general population Routine screening with careful skin examination for melanoma; CT scan of chest, abdomen and pelvis; and in women, mammogram and pelvic exam; in men, testicular and prostate examinations If primary screening is negative, repeat screening is recommended after 3-6 months; thereafter every 6 months for 4 years Treatment of the malignancy improves muscular involvement

Associated conditions (contd.) Gastro-intestinal system Dysphagia, aspiration and delayed gastric emptying due to smooth and skeletal muscle weakness Vasculopathy affecting the GI tract may cause bowel ischemia, necrosis and perforation more commonly seen in JDM Joints Polyarthritis has been reported in up to 45% of patients with PM

Treatment Immunosuppressive therapy is the mainstay of treatment First line Prednisone IV Methylprednisone Second line Methotrexate Azathioprine Intravenous Immunoglobulins Mycophenolate Third line/ Emerging drugs Cyclosporine Tacrolimus Rituximab Etanercept Cyclophosphamide

First line: Corticosteroids No controlled trails Usual dosing schedule 1mg/kg/day or 60-100mg daily for 2-4 weeks followed by every other day schedule Slower taper in more severe disease Intravenous steroids may be used in more severe cases initially followed by a slower taper response to therapy seen in 2-3 months no improvement is seen in 4-6 months or concerns for side effects or exacerbation during the taper , add second line agents Special points CXR, PPD – screening; if PPD positive initiate Rx with isoniazid DEXA at baseline and every 6 months; if bone density < 1.0 SD initiate Rx with alendronate Can be used in wide range of doses and routes An immediate response may suggest an alternative diagnosis like Polymyalgia Rheumatica

Second line of management Steroid sparing agents Methotrexate - Antifolate drug; inhibits lymphocyte proliferation - Initial dose of 7.5mg weekly, upto 25mg per week; therapeutic effect after 4-8 weeks - Side effects : myelosuppression, liver/ renal toxicity, interstitial pneumonitis, stomatitis, teratogenicity - Contra indications: Presence of Anti Jo-1 antibodies or ILD, severe renal/ hepatic impairement, pregnancy - Special points: folate co-administration, monitor CBC and LFT routinely, monitor PFTs at baseline and every 6 months Azathioprine - Antimetabolite; blocks T cell proliferation - Usual dose: 2 to 3 mg/kg/day ranging from 100 to 250mg / day - Delayed therapeutic response, 4-8 months (peaks at 1-2 years) - Side effects: myelosuppression, liver toxicity, acute hypersensitivity reaction/ flu like illness (12%), pancreatitis, teratogenicity - Contra indications: Pregnancy - Special points: monitor CBC and LFT every 2 weeks until stable dose, then once monthly; if leukopenia then decrease dose; if LFTs elevated x2 then discontinue Immunoglobulins have a complex immunomodulatory mechanism of action thought to involve reduced autoantibody production and binding, suppression of proinflammatory cytokines. Randomized controlled trials have shown efficacy of ivig in treatment-resistant DM patients. American Academy of Neurology guidelines recommend IVIg as possibly effective for treating nonresponsive D. IVIg is often used for patients with refractory disease or as a steroid-sparing agent. An initial dose of 2 g/kg is divided over 2 to 5 days.Maintenance dosing is 0.4 to 2 g/kg per month administered every 1 to 4 weeks.

Second line of management Steroid sparing agents Intravenous Immunoglobulins - complex immuno modulatory mechanism of action: reduced autoantibody production and binding, suppression of pro inflammatory cytokines - AAN guideline recommend IVIg as possibly effective for non responsive DM - Dose: initial dose of 2 g/kg divided over 2 to 5 days. Maintenance dosing of 0.4 to 2 g/kg per month administered every 1 to 4 weeks - Side effects: Flu like illness, headache, aseptic meningitis, risk of renal failure and thrombosis - Contra indications: Immunoglobulin A deficiency, renal insufficiency, significant atherosclerotic disease - Special points: very expensive Mycophenolate mofetil - Inhibits proliferation of T and B lymphocytes by blocking purine synthesis - Dose: 1 to 1.5gm twice daily - Side effects: myelosuppression, diarrhea, HTN, tremor - Contra indications : myelosuppression, pregnancy Immunoglobulins have a complex immunomodulatory mechanism of action thought to involve reduced autoantibody production and binding, suppression of proinflammatory cytokines. Randomized controlled trials have shown efficacy of ivig in treatment-resistant DM patients. American Academy of Neurology guidelines recommend IVIg as possibly effective for treating nonresponsive D. IVIg is often used for patients with refractory disease or as a steroid-sparing agent. An initial dose of 2 g/kg is divided over 2 to 5 days.Maintenance dosing is 0.4 to 2 g/kg per month administered every 1 to 4 weeks.

Third line Cyclosporine Cyclophosphamide Tacrolimus Recent drug trials Dose: 3 to 4 mg/kg per day; max 6mg/kg/day C/I: HTN, renal dysfunction, malignancy, pregnancy S/E: HTN, renal failure, gingival hyperplasia, GI upset Monitor BP, renal function, drug level Tacrolimus Dose: 2mg oral titrated to clinical response/ tolerance C/I: ILD and Anti Jo-1 antibodies, renal/ hepatic impairement S/E: diarrhea, headache, tremors, insomnia, lymphoma Cyclophosphamide Dose: 1-2mg/kg per day C/I: myelosuppression, pregnancy S/E: hemorrhagic cystitis, alopecia, GI upset High fluid intake, monitor UA and CBC closely Recent drug trials Etanercept Rituximab

Recent drug trials Randomized, Pilot Trial of Etanercept in Dermatomyositis; Muscle Study Group (Amato, et al) Neurology 2011 Etanercept: Tumor necrosis factor α inhibitor Randomized, double blind, placebo controlled trial 16 subjects randomized: 11 – etanercept; 5 – placebo Duration of study: 52 weeks Etanercept: 50 mg subcutaneous weekly All subjects tapered off prednisone over 24 weeks Outcome measures: adverse events, time from randomization to failure, average prednisone dose at 24 weeks Results: All 5 Placebo subjects: failed (median 148 days) 6/11 Etanercept subjects: failed (median 358 day) 5/11 Etanercept subjects: successfully tapered off Prednisone Average prednisone dosage after 24 weeks lower in etanercept group (1.2mg/day) as compared to placebo group (29.2mg/day) Conclusion: Etanercept may have steroid sparing effect; need further study

Recent drug trials Rituximab in the Treatment of Refractory Adult and Juvenile Dermatomyositis and Adult Polymyositis. Oddis et al, 2011 Rituximab: B cell depleting agent Randomized, double blind, placebo phase trial 195 subjects with refractory disease (76 PM, 76 DM and 48 JDM) Duration of study: 44 weeks 2 groups: Group A ( Rituximab early) Group B ( Rituximab started 8 weeks later) Outcome measures: Primary end point: time to achieve definition of improvement Secondary end point: time to achieve 20% improvement in muscle strength Results No significant difference in Group A and B in primary end point (20.2 and 20 weeks respectively) No difference in secondary end point 83% of subjects met the primary end point/ DOI following Rituximab treatment Conclusion: The role of B cell depleting therapies in myositis warrants further study

Other therapies Diet and lifestyle Dietary supplementation has limited role Oral creatine may be of potential benefit Assistive devices Single prong cane, Rolling walker, wheelchair to prevent falls Physical therapy To maintain strength and address ADLs Early mobilization to prevent flexion contractures of large joints

Prognosis The prognosis of the idiopathic inflammatory myopathies is generally favorable Overall, drug-free remissions are rare except in JDM Poor prognostic factors old age male gender non-Caucasian ethnicity longer symptom duration ILD, cardiac involvement associated malignancy dysphagia serum MSA (anti Jo-1 antibodies, anti SRP antibodies) Mortality remains two- to three fold higher than the general population; with cancer, lung, cardiac complications, and infections being the most common causes of death

Idiopathic Inflammatory Myopathies

Inclusion body myositis (IBM) Most common inflammatory myopathy after age 50 yrs Insidious onset, slowly progressive proximal leg and distal arm weakness Delayed diagnosis with average duration of symptoms prior to diagnosis is 6-7 yrs Male are affected more than female Hallmark: weakness and atrophy (2/3rd of the pts) Legs: knee extensors, ankle dorsiflexors Arms: wrist and finger flexors Upto 82% of patients have marked asymmetry Sparing of thenar and hypothenar muscles helps distinguish IBM from ALS Dysphagia occurs on 70% patients Mild to moderate facial weakness

IBM marked difficulty in flexing the fingers of the left hand as compared to the right Quadriceps atrophy Wash U – quadriceps atrophy Book – this pt has marked difficulty in flexing the fingers of the left hand as compared to the right.

IBM – work up Serum CK may be normal or elevated up to 10 times normal ANA positive in 20% patients Nerve conduction studies - mild sensory axonal peripheral polyneuropathy in up to 30% of patients with IBM Needle examination - evidence of muscle irritation (increased insertional activity, positive sharp waves, polyphasic potentials) Skeletal muscle MRI scans – atrophy and signal abnormalities in affected muscle groups

IBM - Histopathology and Pathogenesis Histology Endomysial inflammation Small group of atrophic fibers Eosinophilic cytoplasmic inclusions ( better visualized with immunostain directed against phosphorylated tau) Multiple myofibers with one or more rimmed vacuoles lined with granular material (likely amyloid deposition-Congo Red stain) Pathogenesis ; unknown Autoimmune - presence of inflammatory cells on histology (cytotoxic T cells, myeloid dendritic cells, B cells and IBM autoantibody) Degenerative - no response to immunotherapy, presence of protein aggregates (amyloid, hyperphosphorylated tau, neurofilament heavy chain) within rimmed vacuolated muscle fibers

Vacuole filled with granules (Modified Gomori trichrome stain) Muscle Biopsy H&E stain Vacuole filled with granules (Modified Gomori trichrome stain) Multiple vacuolated fibers in IBM – H&E stain IBM muscle fiber with rimmed vacuoles – modified Gomori trichome Dimachkie

Treatment Refractory to all treatments Various RCT of IVIg with or w/o steroids, MTX, beta interferon, etanercept did not show any benefit Some patients may have transient and mild improvement with corticosteroids and exercise therapy early on in the course of the disease Several novel therapies are being evaluated – lithium chloride, arimoclomol, follistatin gene transfer therapy Arimoclomol: potent heat shock protein 70 inducer Inducing HSP levels may reverse the toxic cellular changes Recent two-center trial (KU and University College London) was conducted to assess the safety and tolerability of Arimoclomol in IBM as compared to placebo over 4 months of treatment Arimoclomol is well tolerated in this study population Li – induce autophagy and clearance of misfolded protein

Prognosis Associated conditions Prognosis Unlike DM &PM, IBM is not associated with myocarditis, lung disease and malignancy 15% pts have underlying autoimmune CTD like SLE, Sjogren’s, Scleroderma and sacrcoidosis Prognosis Life expectancy not significantly altered Most patients are wheelchair bound by 10-15 years

References Dimachkie MM, Barohn RJ. Idiopathic inflammatory myopathies. Semin Neurology 2012; 32:227-236 Dimachkie MM, Barohn RJ. Inclusion Body Myositis. Semin Neurology 2012; 32:237-245 Dimachkie MM. Idiopathic Inflammatory Myopathies. Journal of Neuroimmunology 231 (2011): 32-42 Amato AA, Russell JA. Inflammatory Myopathies. Neuromuscular Disorders 2008; Chapter 30: 681-713 Distad BJ, Amato AA. Inflammatory myopathies. Current Treatment Options in Neurology (2011) 13: 119-130 Oddis CV, Reed AM. Rituximab in the Treatment of Refractory Adult and Juvenile Dermatomyositis and Adult Polymyositis. Athritis and Rheumatism, 2013, Vol 65, 314-324 Amato AA. Randomized, Pilot Trial of Etanercept in Dermatomyositis; Muscle Study Group. Neurology 2011; 70: 427-436 Dalakas MC, Hohlfeld R. Polymyostis and Dermatomyositis. The Lancet 2003; Vol 362: 971-982 Titulaer MJ, Soffietti R, Dalmau J, et al. Screening for tumours in paraneoplastic syndromes: report of an EFNS task force. Eur J Neurol 2011;18(1):19–e3 Amato AA, Barohn RJ. Evaluation and treatment of inflammatory myopathies. J Neurol Neurosurg Psychiatry 2009; 80: 1060 – 1068 http://neuromuscular.wustl.edu Miller FW. Myositis-specific autoantibodies: touchstones for understanding the inflammatory myopathies. JAMA 1993;270:1846-1849