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39 Cards in this Set
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- Back
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Inflammatory muscle disorder: history and exam
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History
-Constitutional symptoms (systemic affect of cytokines) -If joints involved: prolonged a.m. stiffness (>45-60 min), insidious onset, pain improves with movement -Other organ involvement (e.g., rash) Exam -Objective findings of inflammation -Thorough neuro-muscular exam |
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Inflammatory muscle disorder: labs
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ESR and C-reactive protein are indicators of generalized inflammation
Autoantibodies can be helpful in selected cases Organ specific tests can suggest internal organ involvement (hepatic, renal) Muscle-specific enzymes Duration of symptoms is important for diagnosis - < 6 months = may be early rheumatic disease - 1 year = diagnostic clinical signs and lab abnormalities should be present - > 2 years = abnormalities almost always present |
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Endocrinopathies/metabolic problems leading to muscle complaints
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Thyroid disease
Parathyroid disease Adrenal disease Diabetes mellitus Acromegaly Diagnosis of endocrinopathy suggested by history and appropriate screening lab tests -TSH, calcium, phosphorous, glucose, sodium/potassium Dx of metabolic myopathy suggested by relationship of symptoms to exercise tolerance |
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Toxins/drugs leading to muscle complaints
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HMG-CoA reductase inhibitors (‘statins’)
Zidovudine (AZT) Ethanol Cyclosporine A Colchicine Steroids |
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Muscle pain syndromes
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Think polymyalgia rheumatica (PMR) when
-Age > 50 -Proximal muscle myalgias and stiffness without specific muscle weakness -High ESR (“50-50” club) -Anemia Fibromyalgia syndrome Somatoform pain disorders -Chronic pain unexplained by a known medical condition -Nonintentional -Psychological factors play a role in the onset, severity, or maintenance of the pain -Commonly seen (15%) and nonrecognized (70%) in a primary-care setting -Screen for mental disorders; Major depression associated with musculoskeletal pain |
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Myopathy exam
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Weakness: distribution, MRC grading scale
0 = no contraction 1 = contraction, no movement 2 = movement, but not against gravity 3 = movement against gravity 4 = vs some resistance 5 = normal Seated position to standing |
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Myopathy labs
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Blood tests
-Electrolytes (Na, K, Ca, Mg, PO4) -Muscle enzymes (CK, aldolase, AST, ALT, LDH) -- (AST, ALT, LDH: secreted by activated myoblasts) -Suggests rhabdomyolysis: urine dipstick analysis positive for blood, but no RBC on microscopic -Nope, no autoantibodies yet -Forearm Ischemic Exercise Test - FIET (lactate and ammonia production after ischemic exercise) |
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Forearm ischemic exercise test
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FIET (forearm ischemic exercise test)
Venous blood for measurements of lactate and ammonia, preferably from the nondominant arm without using a tourniquet. A blood pressure cuff is inflated around the dominant upper arm and maintained at a pressure of 20 to 30 mm of Hg above systolic pressure while the patient vigorously exercises the dominant forearm by squeezing a tennis ball or a rolled up, partially inflated blood pressure cuff. The cuff is kept inflated around the arm for 2 minutes or until exercise causes complete exhaustion of the extremity (whichever is longer), at which point it is released. Two minutes later, repeat lactate and ammonia levels from the dominant arm using a tourniquet. Normal: at least a threefold increase over baseline in venous lactate and ammonia. Glycogenoses (except for deficiency of acid maltase, phosphorylase b kinase, or branching enzyme): ammonia levels increase but lactate levels remain at baseline. Myoadenylate deaminase deficiency: lactate levels increase but ammonia levels remain at baseline. |
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Causes of elevated CK enzyme activity
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Physical trauma or muscle stress (MM isoenzyme)
-Muscle trauma – falls, EMG, surgery, IM injections -Strenuous exercise – marathons, forced march, weight lifting Drug effects (MM isoenzyme predominant) -On muscle itself – clofibrate, statins, EtOH, amphetamine, heroin, AZT -On CK metabolism/clearance – phenobarbital, morphine, diazepam Diseases altering -Muscle – noninflammatory myopathies (MM), myocardial infarction (MB), malignant hyperthermia (MM), infectious myopathies (MM), IIM (MM and some MB) -Blood supply to muscle – emboli to muscle (MM), vasculitis (MM), prolonged immobilization/coma (MM) -CNS (BB) – cerebral ischemia, trauma, infections Possible familial cases, especially African-Americans (MM) (can be 2-3x ULN) |
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Myopathy: electromyogram
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Disease classification
-Myopathy vs neuropathy --Nerve problems have very high action potential sites -Inflamm vs noninflam myopathy --Inflammed muscle has higher likelihood of spontaneous electrical discharges, increased insertional activity --Noninflammatory shows no inflammatory changes Distribution / severity / progress Subclinical disease Look at electrical activity at rest and during contraction Look at duration, amplitude, how many fibers are recruited Low false negative |
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Myopathy: muscle biopsy
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Open or percutaneous
Proximal, affected muscle Stains: not a ‘shotgun’ approach Frequently vastus lateralis |
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Idiopathic inflammatory myopathies
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A heterogeneous group of systemic connective tissue diseases that share chronic muscle inflammation of unknown cause
The most common acquired muscle disease in adults, but are still rare Diagnosed by a combination of clinical, laboratory and pathologic features Clinicopathologic and immunologic phenotypes differ in risk factors, presentations, and outcomes Therapy is focused on immunosuppression to decrease inflammation and rehabilitation to improve function |
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Order of ordering myopathy tests
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History
Exam Blood FIET EMG Biopsy Myositis autoantibodies |
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Myopathy: autoantibodies
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Many only characterized over the past decade
Part of newer phenotype classifications of idiopathic inflammatory myopathies Can be useful diagnostically, prognostically |
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Idiopathic inflammatory myopathy: epidemiology
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Estimated annual incidence 5-10 / million
Estimated prevalence ~12/100,000 – likely increasing PM / DM peak in childhood (5-15 yrs) and midlife (30-50 yrs), whereas IBM peaks after age 50 Female:male ~2-3 : 1 in all forms except IBM (~1 : 3) African-Americans may be at increased risk and have poorer outcomes compared to Caucasians Case reports, epidemiologic studies and anecdotal clusterings of onset in time and space suggest enviromental influences |
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Idiopathic inflammatory myopathy: classification
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Polymyositis
-Histopathologic degeneration, regeneration, necrosis, and phagocytosis Nonspecific myositis -Nonspecific perimysial/perivascular infiltrates, but no diagnostic features of DM or PM Immune-mediated necrotizing myopathy -Absence of inflammatory infiltrate Clinicopathologic groups (adult or juvenile) -Polymyositis -Dermatomyositis -Myositis with other CTD -Cancer-associated myositis Serologic gropus (autoab's) |
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Polymyositis / Dermatomyositis Criteria
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First exclude all other myopathies
Symmetric proximal muscle weakness Elevation of serum activities of sarcoplasmic enzymes – CK, aldolase, LDH, ALT or AST Myopathic electromyography Characteristic muscle pathology required in PM: myofiber degeneration/regeneration, mononuclear cell infiltrates; perifasicular atrophy in DM Photosensitive rashes of DM: heliotrope rash (purpulish rash with lid edema) and Gottron’s papules (over joint) |
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Sporatic inclusion body myositis: demographics, clinical presentation, labs, associations
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15-28% of all IIM, most common acquired myopathy in those > 50
M : F 2-3 : 1, mean age 60 (range 15- to 90’s) Caucasians > African-Americans or Asians Insidious developing weakness, often LE then UE, and distal limb muscles (50%); asymmetric in 10-15%; myalgias in 40%; unexpected falling Characteristic: early quads (lose patellar reflex), iliopsoas, ankle dorsiflexors, volar forearm muscles Dysphagia in 40-50% CK < 12 ULN (normal in ~20%), EMG atypical in 30% (neuropathic component, or lack of inflammatory changes) Rimmed and unrimmed vacuoles, inclusion bodies, intracellular amyloid deposits, tubulofilamets With autoimmune disorders, HIV, Diab. No cardiac or malignancy associations |
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Polymyositis, dermatomyositis, inclusion body myositis histology
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Polymyositis:
Mononuclear cell infiltrates Variation in myofiber size Antigen-drive, perforin-mediated CD8+ T-cell myotoxicity Dermatomyositis: Perifasicular atrophy Vascular endothelial thickening and inflammation Complement/MAC/CD4+/plasmacytoid dendritic cell-mediated vasculopathy IMB: Rimmed vacuoles Antigen-drive, perforin-mediated CD8+ T-cell myotoxicity |
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Idiopathic inflammatory myositis: systemic manifestations
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Musculoskeletal
-Weakness -Muscle pain / tenderness -Muscle atrophy -Arthralgia -Arthritis Gastrointestinal -Dysphagia --Upper esophageal -Reflux -Dysmotility Cutaneous -Rashes -Calcification General -Fever , fatigue, wt loss, Raynaud’s Cardiac -Arrhythmias --35-75% have palpitations -Congestive failure / Myocardial dis. --LV dysfunction 12-42% --Cardiac findings assoc’d with anti-SRP --Troponin T and CK-MB from active myoblasts, thus troponin I best to follow --10-20% of PM / DM deaths Pulmonary -Atelectasis from muscle weakness -Aspiration pneumonia -Interstitial fibrosis --10-46% of adult PM/DM -->70% in pts with anti-synthetase Abs --5 yr survival 70-80% |
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Idiopathic inflammatory myositis: autoantibodies
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Positive ANA: 40 – 80%
Myositis-specific antibodies: 5 – 30% -Anti-synthetases (Jo-1, PL-7, PL-12, EJ) -Anti-signal recognition particle -Anti-Mi-2 -Anti-p155/140 (TIF1-gamma) -Anti-MJ (NXP-2) |
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Anti-synthetase syndrome
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Anti-Jo-1
An anti-synthetase (vs histidyl-tRNA synthetase) Myositis-specific Clinically: higher prevalence of arthritis, interstitial lung disease, fever, Raynaud’s, ‘mechanics hands’ Onset: acute, severe, often spring Moderate response to therapy Poor prognosis |
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Myositis and cancer
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Relative risk for cancer
-2-4 x in DM -1.5-2 x in PM -Anecdotal reports in IBM, children Most cancers within 2 years of myositis diagnosis Adenocarcinomas (esp ovary) increased in DM Risk factors -Age > 50 -Male gender -Severe rash -ESR > 35, and anti-p155/140 antibody ILD and other myositis autoantibodies are protective Age- and risk-appropriate evaluation for malignancy in adults with careful followup of any suggestive findings -Unclear role: CA-125 and transvaginal US screening ovarian CA |
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IIM Therapy
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First line:
-Corticosteroids -MTX -AZA Second line: -IVIg: if rapidly progressive or refractory, dysphagia, DM responds better than PM -Rituximab, Cyclosporin, Tacrolimus, Mycephenolate mofetil Third line: -Bone marrow or stem cell transplant -Cyclophosphamide (can be first line in pts with interstitial lung disease) -Biologics Adjunct therapy -Sunscreen and sun avoidance -HCQ -Ca and Vit D -Exercise and rehab (isometric to isotonic to isokinetic) |
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Sporadic inclusion body myositis: therapy
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Physical therapy program of graded strength training
Medical therapy: poor response is common -Who? --Insufficient published pts for subgroup analysis ( ? Treat all given possibility for improvement risks must outweigh benefits for each patient; treat the pt, not the CK level) --Common findings in “responders”: other autoimmune disease, higher CK or biopsy inflammation at baseline, absence of significant muscle repl. by fat and fibrosis -How? --Prednisone 1 mg/kg per day --If no response at 2-3 months, consider MTX or AZA for 3-6 months; ? IVIg: costly, benefit not proven --If decline continues, taper therapy off -Outcome? --Falling CK does not predict clinical benefit |
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Hypothyroidism and myopathy
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Prevalence ~ 7%, (>55)
Fewer signs and symptoms at presentation, but weakness in ~ 50% Pseudomyotonia Myopathy parallels degree and duration of hormone deficiency EMG may show inflammatory changes May mimic PM if severe |
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Hyperthyroidism and myopathy
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Prevalence ~ 2-4%; those > 60: 10-17% of all hyper-thyroid patients
Fewer clinical signs, weakness in ~ 25% CK often normal or minimally elevated EMG and bx may show a myopathic process |
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Steroid myopathy
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Activation of ubiquitin-proteasome pathway, mediating proteolysis of muscle contractile proteins
Usually with larger doses, longer duration, and more frequent dosing Likelihood higher with fluorinated steroids Affects mostly quads and hip girdle, but can affect respiratory muscles even when limb muscles strong Normal CK, myopathic EMG, Type II fiber atrophy or normal Muscle wasting leads to increased urinary creatine excretion: - % creatinuria (creatine/creatine + creatinine) is > 6% in 24 hr urine |
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Lipid lowering drugs and myopathy
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Except for bile acid sequestrants and plant sterols, any lipid-lowering agent can cause rhabdomyolysis
Ezetimibe: case reports of tendinopathy, and myopathy, with and without statins Nicotinic acid: rare cause of myalgias, increased CK Clofibrate, gemfibrozil, fibric acid derivatives: can cause cramps, acute or subacute painful proximal myopathy, incr CK, + myoglobinuria Fibrate use may have a higher relative risk than statin use |
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Statins and myopathy
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Myalgias ~5-10%, myositis ~1%, rhabdo ~0.1%
- no agreed upon case definition - 13 million Rx’s in US Asx’c incr CK, transient or persistent myalgias with normal or incr CK, rhabdomyolysis (alone, or with gemfibrozil, CyA, niacin, itraconazole, erythromycin) Statin-associated autoimmune (necrotizing) myopathy - antibodies to HMG CoA Reductase (HMGCR) Tendinopathy Case reports: SLE, DM, vasculitis, hypersensitivity with eosinophilia, Churg-Strauss-like vasculitis Tremendous variation in time to normalize CK after d/c’d, but can take weeks |
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Statins and myopathy etiology
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Precise mechanism(s) incompletely understood
-Decreased cholesterol content of skeletal myocyte membranes inducing instability -Depletion of isoprenoids or CoQ10 -Mitochondrial dysfunction SLCO1B1 gene variants -Encodes OATP1B1: mediates hepatic uptake of statins and other drugs Isoprenylation is responsible for the post-translational modification of up to 2% of cellular proteins -Statins may unmask subclinical metabolic defects |
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Statin-induced necrotizing myopathy
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Subset of patients with immune-mediated necrotizing myopathy
200/100 kDa doublet targeted by autoantibody Highly associated with statin use -Proximal weakness during or after statin treatment -Elevated CK -Weakness & elevated CK that persisted/worsened despite drug discontinuation -Requiring aggressive immunosuppression for treatment -Muscle biopsy: necrotizing myopathy without significant inflammation 100 kDa target identified as HMGCR Statins induce HMGCR expression; regenerating muscle cells express high HMGCR levels, sustaining the process |
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Statins and myopathy: mangement
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Inconsistent recommendations
Most agree to discontinue statin inf CK>10xULN Consider CoQ10 supplementation |
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Drug induced myopathies: alcohol
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acute myopathy: with acute intoxication
-Weakness, myalgias, rhabdomyolysis, marked increase in CK with myoglobinuria -EMG myopathic with inflammatory features and biopsy shows necrosis and varying degrees of inflammation -Rx is conservative care. chronic proximal myopathy: with chronic EtOH use. -Muscle atrophy, more in legs than arms -Normal CK, noninflammtory myopathic EMG, and biopsy showing only type II fiber atrophy. |
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Drug induced myopathies: colchicine
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Causes a vacuolar myopathy
Proximal weakness, and increased CK Renal insufficiency is a major risk factor, and colchicine dose should always be adjusted accordingly |
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Dystrophies overview
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In common: progressive weakness and muscle degeneration
Diverse group of inherited disorders -Patterns of inheritance and penetrance -Age of onset -Progression -Severity -Muscles involved Elevation of CK in some EMG to exclude neuropathic causes Muscle biopsy: fiber size variation and necrosis, macrophage invasion, ultimately replacement by fat and connective tissue |
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Duchenne and becker muscular dystrophies
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Duchenne: the sarcolemmal protein dystrophin is usually absent
- X-linked, but 5-10% of female carriers show some weakness and fewer develop dilated cardiomyopathy - Early childhood onset - Some degree of mental impairment is usual - Weakness of hip and knee extensors leads to Gower’s sign - Most with enlarged calves Becker: dystrophin is either reduced in amount or abnormal in size - More benign, onset in early teens, but symptoms in some delayed even longer |
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Emery-Dreifuss muscular dystrophy
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Triad of:
- Early contractures, even prior to any weakness - Humero-peroneal muscle wasting and weakness - Cardiomyopathy, that usually presents as conduction disturbance – can occur in the absence of any weakness X-linked: Usual complete absence of the nuclear membrane emerin Autosomal dominant: absence of lamin |
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Muscular dystrophies treatment
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Surgery for contractures
Attention to respiratory care and treatment of cardiac complications Beware of risk of myoglobinuria (Duchenne and Becker) - No succinylcholine as anaesthetic ? Gene therapy |
