3Idiopathic Inflammatory Myopathies Epidemiology Annual incidence – 1:100,000Incidence of individual myositides has been limited by the different diagnostic criteria employed in various epidemiological studiesIBM is the most common myopathy after age 50 with prevalence of 3.5/100,000 casesDisease of adults (except for Juvenile DM)Women are more commonly affectedGenetic predisposition secondary to inherited Human Leukocyte Antigens (HLA) haplotypesThere 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
6Dermatomyositis (DM) Can present at any age, including infancy Affects female more than malesAcute (over several weeks) or insidiously (over months) progressive, painless, proximal weakness with or without characteristic skin rashProximal leg and arm muscles are usually the earliest and most severely affected muscle groupsMostly painlessSpeech, chewing and swallowing difficulties may be seenJDM commonly presents after a febrile episode and with a skin rashMultisystem involvement is more common in JDM
7Dermatomyositis : Skin involvement Distinct rashOccurs before or with the onset of muscle weaknessVariable degree of muscle versus skin involvementAmyopathic DM– isolated rash with no muscle involvementAdermatopathic DM – isolated myositisClassical DM findings:heliotrope rashGottron’s papulesdilated nail bed capillariesV-signshawl signmechanic’s handsSubcutaneous calcinosis seen in 30-70% cases of JDM, less common in adults
8DM : Skin findingsHeliotrope rash: purplish discoloration along the hairline of scalp and malar region of the face and eyelidsDilated capillary loops evident in the nail bed as well as small ulceration involving the distal aspect of the little fingerHeliotrope rash – moderate erythematous rash along the hairline of scalp and malar region of the face amd eyelidsGottrons sign – macular rash seen over the extensor surface of the knucklesDilated capillary loops evident in the nail bed as well as small ulceration involving the distal aspect of the little finger
9DM : Skin findingsGottron papules : erythematous lichenoid papular scaly rash, over the extensor surface of the hands and fingersGottrons sign
10DM : Skin findingsV sign: Erythematous rash around face, neck and anterior chestShawl sign: erythematous rash affecting upper back
11DM : Skin findingsMechanic’s hands: Cracking of the finger pad skin, commonly involving the first, second, and third fingers.
12Dermatomyositis – Lab features Serum CKElevated serum CK with levels ranging upto 50 times the upper limit of normalCK level may be normal in less than 10% ptsDo not co-relate with the severity of weaknessANA is detected in 24-60% of pts with DMMyositis specific antibodiesFound in a minority of patientsUseful in predicting response to therapy and prognosisCytoplasmic 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 prognosisSome 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.
13Dermatomyositis - Electrophysiology Motor and sensory nerve conduction studies are mostly normalNeedle 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 fibrosisMotor unit action potentials (MUAPs) are polyphasic, brief, and of low amplitudeEMG is helpful in assessing relapsing weakness during treatmentWorsening strength in the absence of fibrillation potentials suggests a steroid induced myopathy
14Dermatomyositis Histopathology and Pathogenesis HistologyEarliest finding : Membrane Attack Complexes around blood vesselsPathognomic : 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 capillariesPathogenesisHumorally mediated micro angiopathyantibodies directed against endothelial cells activate complement factors membrane attack complex (MAC) deposition on capillaries endothelial damage, capillary necrosis, perivascular inflammation, ischemia and myofibril necrosis
15Muscle BiopsyPerifascicular atrophy with perimysial inflammationMAC deposition around blood vessels (Immunoperoxidase stain)greenbergbook
18Polymyositis (PM)Exclusionary diagnosis in pts who do not have a rash or alternate muscle or nerve diseasePM is a disease of adults over age 20 yearsMore prevalent in femaleSubacute to insidiously progressive, proximal arm and leg weaknessMyalgias and tenderness are common but usually not the first presenting symptomsDysphagia is seen in one-third of patientsFacial weakness is occasionally present
19Polymyositis – work upElevated CK in range of 5 to 50 times the normal. Unlike DM, CK is always elevated in PMPositive ANA (16-40% )Myositis specific antibodiesuseful in predicting response to therapy and prognosisAnti SRP antibodies: severe, fulminant, steroid resistant PMAnti Jo-1 antibodies: associated with ILDElectro diagnostic tests show evidence of muscle irritationIncreased insertional activity, positive sharp waves, polyphasic MUAPsDo not distinguish PM from other IIMSkeletal muscle MRI – increased signal consistent with muscle edema and inflammationSRP 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
20Polymyositis Histopathology and Pathogenesis Histologyfiber size variabilityscattered necrotic and regenerating fibersendomysial inflammation consisting of cytotoxic T cells and macrophagesPathogenesisHLA- restricted, antigen specific, cell mediated immune response directed against muscle fibers?? Triggerviral 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 osmolysisUnlike DM - MAC, complement or immuno globulins are not deposited on the microvasculature in PMOther inflammatory cells – myeloid dendritic cells, and plasma cells which account for the increased expression of immunoglobulin genes on microarray experiments
21Muscle BiopsyEndomysial inflammatory cell infiltrate surrounding and invading non necrotic muscle fibresDimachkie- inflammatory infiltrates surrounding and invading non necrotic fibers.Amato and russellEndomysial mononuclear inflammatory cell infiltrate surrounding and invading non necrotic muscle fibres
23Autoimmune Necrotizing Myopathy (NM) Increasing recognized autoimmune myopathylittle or no inflammatory infiltratemore common in femalessub acute progressive proximal weakness without rashrapid onset than PM; markedly severe in 30% casesmyalgia and dysphagia
24Autoimmune Necrotizing Myopathy Subtypes Paraneoplastic NMrare, rapidly progressivesevere variantassociated with adenocarcinomaNM with thick “pipestem” capillariesassociated with subacute weaknessbrain infarction due to vascultisConnective Tissue DiseaseSRP autoantibodies associated NMSevere, fulminanttreatment refractorycardiac complications (myocarditis)Statin induced autoimmune NM (SANAM)affects between 46 to 89 year old ptsonset may be delayed upto 10 yrs following statin initiationmay occur several months after discontinuationOften therapy resistant
25Autoimmune Necrotizing Myopathy – work up Elevated CK – more than 10 times the normalPositive ANA – suggestive of underlying CTDMSA – SRP autoantibodiesEMG – irritative myopathy
26NM - Histopathology and Pathogenesis HistologyScattered necrotic myofibers with myophagocytesAbsence or paucity of T-lymphocytic inflammationUnlike DM, perivascular inflammation is scant, and there are no endothelial tubulo reticular inclusionsThick-walled and enlarged “pipestem” capillaries is diagnostic of NM with pipestem capillariesSRP-associated NM: bimodal distribution of fiber sizes, increased endomysial connective tissue, and reduced endomysial capillary number with enlargement and thickeningPathogenesisUnknowndeposition of complement MAC on small arterioles and capillaries with thickened endothelial walls suggests humorally mediated microangiopathyAnti 200/ 100 antibodiesAutoantigen is 3-hydroxy -3- methylglutaryl-coenzyme A reductase (HMGCR) proteinStatin upregulate HMGCR protein levels, thus triggering anti- HMGCR auto immunityAnti-200/100 (anti-HMGCR)• Autoantigen for anti-200/100 is 3-hydroxy -3-methylglutaryl-coenzyme A reductase (HMGCR)• HMGCR is a target of statinsMammen AL, et al. Arthritis Rheum 2011;63(3):• Statins upregulate HMGCR proteinlevels• Regenerating muscle fibres expresshigh levels HMGCRIn 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 couldtrigger anti-HMGCR autoimmunity
27Scattered necrotic fibers, some undergoing phagocytosis Muscle BiopsyScattered necrotic fibers, some undergoing phagocytosisDimachkie – multiple necrotic fibers undergoing phagocytosisBook – scattered necrtic fibers, some in process of undergoing phagocytosis
28Associated conditions There is an increased incidence of interstitial lung disease, autoimmune disorders, cancer and cardiac disorders in patients with DM , PM and NMCardiacconductions defects, arrhythmiasventricular and septal wall motion abnormalitiesPericarditis and congestive heart failure (less common)Myocarditis (seen in 1/3rd pts), associated SRP autoantibodiesPulmonary10-25% of patients have ILDJo-1 antibodies are present in at least 50% of ILD casesPrompt chest imaging and pulmonary function testsPulmonary consultation
29Associated conditions (contd.) MalignancyMost studies suggest 15 to 25% of adult DM patients, older than 40 years, have preexisting, concurrent, or future malignanciesMost common DM-associated malignancyWomen: ovarian cancerMen: small cell lung cancerOther common malignancies are – pancreatic cancer, stomach and colorectal cancers and lymphomaRarely, malignancy has been reported in JDMMalignancy is increased in PM and NM when compared with the general populationRoutine 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 examinationsIf primary screening is negative, repeat screening is recommended after 3-6 months; thereafter every 6 months for 4 yearsTreatment of the malignancy improves muscular involvement
30Associated conditions (contd.) Gastro-intestinal systemDysphagia, aspiration and delayed gastric emptying due to smooth and skeletal muscle weaknessVasculopathy affecting the GI tract may cause bowel ischemia, necrosis and perforation more commonly seen in JDMJointsPolyarthritis has been reported in up to 45% of patients with PM
31Treatment Immunosuppressive therapy is the mainstay of treatment First linePrednisoneIV MethylprednisoneSecond lineMethotrexateAzathioprineIntravenous ImmunoglobulinsMycophenolateThird line/ Emerging drugsCyclosporineTacrolimusRituximabEtanerceptCyclophosphamide
32First line: Corticosteroids No controlled trailsUsual dosing schedule1mg/kg/day or mg daily for 2-4 weeks followed by every other day scheduleSlower taper in more severe diseaseIntravenous steroids may be used in more severe cases initially followed by a slower taperresponse to therapy seen in 2-3 monthsno improvement is seen in 4-6 months or concerns for side effects or exacerbation during the taper , add second line agentsSpecial pointsCXR, PPD – screening; if PPD positive initiate Rx with isoniazidDEXA at baseline and every 6 months; if bone density < 1.0 SD initiate Rx with alendronateCan be used in wide range of doses and routesAn immediate response may suggest an alternative diagnosis like Polymyalgia Rheumatica
33Second 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 monthsAzathioprine- 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 discontinueImmunoglobulins 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 treatingnonresponsive 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.
34Second 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 expensiveMycophenolate 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, pregnancyImmunoglobulins 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 treatingnonresponsive 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.
35Third line Cyclosporine Cyclophosphamide Tacrolimus Recent drug trials Dose: 3 to 4 mg/kg per day; max 6mg/kg/dayC/I: HTN, renal dysfunction, malignancy, pregnancyS/E: HTN, renal failure, gingival hyperplasia, GI upsetMonitor BP, renal function, drug levelTacrolimusDose: 2mg oral titrated to clinical response/ toleranceC/I: ILD and Anti Jo-1 antibodies, renal/ hepatic impairementS/E: diarrhea, headache, tremors, insomnia, lymphomaCyclophosphamideDose: 1-2mg/kg per dayC/I: myelosuppression, pregnancyS/E: hemorrhagic cystitis, alopecia, GI upsetHigh fluid intake, monitor UA and CBC closelyRecent drug trialsEtanerceptRituximab
36Recent drug trials Randomized, Pilot Trial of Etanercept in Dermatomyositis; Muscle Study Group (Amato, et al) Neurology 2011Etanercept: Tumor necrosis factor α inhibitorRandomized, double blind, placebo controlled trial16 subjects randomized: 11 – etanercept; 5 – placeboDuration of study: 52 weeksEtanercept: 50 mg subcutaneous weeklyAll subjects tapered off prednisone over 24 weeksOutcome measures: adverse events, time from randomization to failure, average prednisone dose at 24 weeksResults:All 5 Placebo subjects: failed (median 148 days)6/11 Etanercept subjects: failed (median 358 day)5/11 Etanercept subjects: successfully tapered off PrednisoneAverage 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
37Recent drug trials Rituximab in the Treatment of Refractory Adult and Juvenile Dermatomyositis and Adult Polymyositis. Oddis et al, 2011Rituximab: B cell depleting agentRandomized, double blind, placebo phase trial195 subjects with refractory disease (76 PM, 76 DM and 48 JDM)Duration of study: 44 weeks2 groups:Group A ( Rituximab early)Group B ( Rituximab started 8 weeks later)Outcome measures:Primary end point: time to achieve definition of improvementSecondary end point: time to achieve 20% improvement in muscle strengthResultsNo significant difference in Group A and B in primary end point (20.2 and 20 weeks respectively)No difference in secondary end point83% of subjects met the primary end point/ DOI following Rituximab treatmentConclusion: The role of B cell depleting therapies in myositis warrants further study
38Other therapies Diet and lifestyle Dietary supplementation has limited roleOral creatine may be of potential benefitAssistive devicesSingle prong cane, Rolling walker, wheelchair to prevent fallsPhysical therapyTo maintain strength and address ADLsEarly mobilization to prevent flexion contractures of large joints
39PrognosisThe prognosis of the idiopathic inflammatory myopathies is generally favorableOverall, drug-free remissions are rare except in JDMPoor prognostic factorsold agemale gendernon-Caucasian ethnicitylonger symptom durationILD, cardiac involvementassociated malignancydysphagiaserum 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
41Inclusion body myositis (IBM) Most common inflammatory myopathy after age 50 yrsInsidious onset, slowly progressive proximal leg and distal arm weaknessDelayed diagnosis with average duration of symptoms prior to diagnosis is 6-7 yrsMale are affected more than femaleHallmark: weakness and atrophy (2/3rd of the pts)Legs: knee extensors, ankle dorsiflexorsArms: wrist and finger flexorsUpto 82% of patients have marked asymmetrySparing of thenar and hypothenar muscles helps distinguish IBM from ALSDysphagia occurs on 70% patientsMild to moderate facial weakness
42IBMmarked difficulty in flexing the fingers of the left hand as compared to the rightQuadriceps atrophyWash U – quadriceps atrophyBook – this pt has marked difficulty in flexing the fingers of the left hand as compared to the right.
43IBM – work up Serum CK may be normal or elevated up to 10 times normal ANA positive in 20% patientsNerve conduction studies - mild sensory axonal peripheral polyneuropathy in up to 30% of patients with IBMNeedle 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
44IBM - Histopathology and Pathogenesis HistologyEndomysial inflammationSmall group of atrophic fibersEosinophilic 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 ; unknownAutoimmune - 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
45Vacuole filled with granules (Modified Gomori trichrome stain) Muscle BiopsyH&E stainVacuole filled with granules (Modified Gomori trichrome stain)Multiple vacuolated fibers in IBM – H&E stainIBM muscle fiber with rimmed vacuoles – modified Gomori trichomeDimachkie
46Treatment Refractory to all treatments Various RCT of IVIg with or w/o steroids, MTX, beta interferon, etanercept did not show any benefitSome patients may have transient and mild improvement with corticosteroids and exercise therapy early on in the course of the diseaseSeveral novel therapies are being evaluated – lithium chloride, arimoclomol, follistatin gene transfer therapyArimoclomol: potent heat shock protein 70 inducerInducing HSP levels may reverse the toxic cellular changesRecent 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 treatmentArimoclomol is well tolerated in this study populationLi – induce autophagy and clearance of misfolded protein
47Prognosis Associated conditions Prognosis Unlike DM &PM, IBM is not associated with myocarditis, lung disease and malignancy15% pts have underlying autoimmune CTD like SLE, Sjogren’s, Scleroderma and sacrcoidosisPrognosisLife expectancy not significantly alteredMost patients are wheelchair bound by years
48ReferencesDimachkie MM, Barohn RJ. Idiopathic inflammatory myopathies. Semin Neurology 2012; 32:Dimachkie MM, Barohn RJ. Inclusion Body Myositis. Semin Neurology 2012; 32:Dimachkie MM. Idiopathic Inflammatory Myopathies. Journal of Neuroimmunology 231 (2011): 32-42Amato AA, Russell JA. Inflammatory Myopathies. Neuromuscular Disorders 2008; Chapter 30:Distad BJ, Amato AA. Inflammatory myopathies. Current Treatment Options in Neurology (2011) 13:Oddis CV, Reed AM. Rituximab in the Treatment of Refractory Adult and Juvenile Dermatomyositis and Adult Polymyositis. Athritis and Rheumatism, 2013, Vol 65,Amato AA. Randomized, Pilot Trial of Etanercept in Dermatomyositis; Muscle Study Group. Neurology 2011; 70:Dalakas MC, Hohlfeld R. Polymyostis and Dermatomyositis. The Lancet 2003; Vol 362: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–e3Amato AA, Barohn RJ. Evaluation and treatment of inflammatory myopathies. J Neurol Neurosurg Psychiatry 2009; 80: 1060 – 1068Miller FW. Myositis-specific autoantibodies: touchstones for understanding the inflammatory myopathies. JAMA 1993;270: