Overview of Idiopathic Inflammatory Myopathies
Idiopathic Inflammatory Myopathies encompass conditions like Dermatomyositis, Polymyositis, Autoimmune Necrotizing Myopathy, and Inclusion Body Myositis. These conditions affect adults, with Dermatomyositis potentially presenting at any age and predominantly affecting females. Genetic predisposition may play a role, and different myositides have varying incidence rates. Dermatomyositis can involve characteristic skin rashes and distinct musculoskeletal symptoms, with multisystem involvement being more common in juvenile cases. Specific skin findings like heliotrope rash, Gottron's papules, and nail bed capillary abnormalities may aid in diagnosis.
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Idiopathic Inflammatory Myopathies Dipika Aggarwal, MD PGY 4 Neurology 1
Idiopathic Inflammatory Myopathies Dermatomyositis (DM) Polymyositis (PM) Autoimmune Necrotizing Myopathy (NM) Inclusion Body Myositis (IBM) 2
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 3
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 6
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 7
DM : Skin findings Dilated capillary loops evident in the nail bed as well as small ulceration involving the distal aspect of the little finger Heliotrope rash: purplish discoloration along the hairline of scalp and malar region of the face and eyelids 8
DM : Skin findings Gottron papules : erythematous lichenoid papular scaly rash, over the extensor surface of the hands and fingers 9
DM : Skin findings V sign: Erythematous rash around face, neck and anterior chest Shawl sign: erythematous rash affecting upper back 10
DM : Skin findings Mechanic s hands: Cracking of the finger pad skin, commonly involving the first, second, and third fingers 11
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 12
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 13
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 14
Muscle Biopsy MAC deposition around blood vessels (Immunoperoxidase stain) Perifascicular atrophy with perimysial inflammation 15
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 18
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 19
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 20
Muscle Biopsy Endomysial inflammatory cell infiltrate surrounding and invading non necrotic muscle fibres 21
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 23
Autoimmune Necrotizing Myopathy Subtypes Paraneoplastic NM rare, rapidly progressive severe variant associated with adenocarcinoma SRP autoantibodies associated NM Severe, fulminant treatment refractory cardiac complications (myocarditis) NM with thick pipestem capillaries associated with subacute weakness brain infarction due to vascultis Connective Tissue Disease 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 24
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 25
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 26
Muscle Biopsy Scattered necrotic fibers, some undergoing phagocytosis 27
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 28
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 29
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 30
Treatment Immunosuppressive therapy is the mainstay of treatment Prednisone IV Methylprednisone First line Methotrexate Azathioprine Intravenous Immunoglobulins Mycophenolate Second line Cyclosporine Tacrolimus Rituximab Etanercept Cyclophosphamide Third line/ Emerging drugs 31
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 32
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 33
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 34
Third line 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 Cyclosporine 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 Recent drug trials Etanercept Rituximab 35
Recent drug trials Randomized, Pilot Trial of Etanercept in Dermatomyositis; Muscle Study Group (Amato, et al) Neurology 2011 Etanercept: Tumor necrosis factor 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 36
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 37
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 38
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 39
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 41
IBM marked difficulty in flexing the fingers of the left hand as compared to the right Quadriceps atrophy 42
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 43
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 44
Muscle Biopsy Vacuole filled with granules (Modified Gomori trichrome stain) H&E stain 45
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 46
Prognosis Associated conditions Prognosis Unlike DM &PM, IBM is not associated with myocarditis, lung disease and malignancy Life expectancy not significantly altered Most patients are wheelchair bound by 10-15 years 15% pts have underlying autoimmune CTD like SLE, Sjogren s, Scleroderma and sacrcoidosis 47
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