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A. Characteristics of Inflammatory Myositis navigator

  1. Systemic connective tissue diseases
  2. There are many subsets of myositis syndromes
    1. Dermatomyositis
    2. Polymyositis
    3. Myositis with cancer
    4. Childhood inflammatory myositis
    5. Inclusion body myositis
    6. Overlap syndromes with myositis
    7. Other myositis: see Differential Diagnosis below
  3. Dermatomyositis [6]
    1. Occurs in both children and adults
    2. Female to Male ratio is 2:1
    3. Most common of the myositis syndromes in both adults and children
    4. Prevalence ~1 per 100,000
    5. Characteristic rash accompanying or more commonly preceding muscle weakness
    6. Primary antigenic target is endothelium of endomysial capillaries
    7. Childhood inflammatory myopathies may be due to maternal chimerism [18,19]
    8. Associated with malignancy [4,5,17]
  4. Polymyositis
    1. Very rare in children, typically >18 years at onset
    2. Very uncommon disorder, <0.5 per 100,000
    3. More commonly associated with other inflammatory disorders
    4. Common overlap syndromes including mixed connective tissue disease and scleroderma
    5. Cytotoxic T lymphocytes target MHC-I antigen expressing muscle cells
  5. Degenerative changes in muscle ± skin
    1. Acute or insidious progression of symmetric weakness
    2. Muscle atrophy eventually occurs
    3. A subset of dermatomyositis patients have normal muscle enzyme levels
    4. This entity has been called "amyopathic" dermatomyositis
    5. Patients with amyopathic dermatomysotis do have muscle function abnormalities [3]
  6. Raynaud's Phenomenon with nailfold capillary dropout in ~35% of patients 7 Inclusion Body Myositis
    1. Most common myopathy in persons >50 years
    2. Generally not part of overlap syndrome
    3. Cytotoxic T lymphocytes target MHC-I antigen expressing muscle cells
  7. Association with Neoplasms [4,5,17,20]
    1. Dermatomyositis is associated with a ~2-6X increased risk for malignancy
    2. Dermatomyositis most often found with ovarian, lung, pancreatic, gastric, colorectal, non-Hodgkin's lymphoma
    3. Polymyositis is associated with a ~1.5-2X increased risk for malignancy
    4. Polymyositis most often found with non-Hodgkin lymphoma, lung, and bladder cancers
    5. Patients with active neuropathy and myopathy have an increased risk for neoplasm
    6. 5-20% of patients >40 years old with dermatomyositis eventually develop neoplasms
    7. Inclusion body myositis associated with 2.4X increased risk of neoplasm [5]
  8. Other myositis syndromes listed below (Differential Diagnosis)

B. Etiology [2] navigator

  1. Polymyositis
    1. Unknown, probably autoimmune (associated with HLA-DR3, B8, others)
    2. Infiltration of muscle cells by CD8+ T cytotoxic T lymphocytes
    3. Muscle cells in various stages of necrosis and regeneration
    4. Focal or diffuse inflammation, usually with muscle cells
    5. Perivascular accumulation is not common
  2. Dermatomyositis [13]
    1. Considered a systemic vasculopathy with both cellular and antibody inflammatory components
    2. Deposition of IgM, IgG and C3b in blood vessel walls of skeletal muscle
    3. Autoantibodies (autoAbs) target endothelium of endomysial capillaries
    4. Epidermal atrophy, basal cell degeneration
    5. Capillary vascular dilatation with lymphocytic infiltration (perivascular) is common
    6. Accumulation of CD4+ T cells and B lymphocytes
    7. Linked to HLA B8, DRB1*0301, DQA1*0501, DQA1*0301 in juvenile dermatomyositis
    8. Type I interferon overexpression has been observed and likely contributes to pathogenesis
  3. Inclusing body myositis similar CD8 cells as polymyositis
  4. T Cell Activation
    1. Activated T cells are found in muscle biopsy specimens
    2. Mainly CD4+ T cells are found in dermatomyositis, whereas CD8+ T cells in polymyositis
    3. Oligo- and monoclonal populations of T cells are found in many patients with myositis
  5. Drug Induced Dermatomyositis
    1. Mainly with hydroxyurea
    2. Quinidine
    3. NSAIDs
    4. Penicillamine
    5. HMG-CoA reductase inhibitors

C. Autoantibodies (autoAbs) navigator

  1. Found in a minority of these patients
  2. Anti-Jo1
    1. Positive in10-20% of cases [13], all patients are HLA-DRw52+
    2. Patients often have lung disease
    3. Thumb subluxation also occurs in this group
    4. Generally patients have poor response to therapy
    5. Not found in patients with scleroderma, sclerodermatomyositis, or other diseases
    6. Target antigen is histidyl-transfer RNA synthetase (50K subunit homodimer)
  3. Anti-Mi2
    1. Target is a 220K protein
    2. Usually positive in dermatomyositis
    3. Good response to therapy in most patients with Anti-Mi2
  4. Anti-SRP
    1. AutoAbs to signal recognition particle (SRP)
    2. Associated with acute onset of polymyositis, usually without weakness
    3. Generally poor response to therapy
  5. AutoAbs to other tRNA synthetases and a variety of other nuclear + cytoplasmic targets

D. Symptoms / Signs navigator

  1. Acute or Insidious Onset
  2. Initial Symptoms
    1. Proximal symmetric muscle weakness and tender muscles
    2. Dysphagia
    3. Polyarthralgias - true arthritis usually associated with anti-Jo1
    4. Raynaud's Phenomenon - more common in dermatomyositis
    5. Systemic Symptoms: fever, malaise and weight loss
  3. Skin Changes in Dermatomyositis [1,6]
    1. V Sign across chest: dusky and erythematous (face, neck, upper torsoe)
    2. Shawl Sign across back
    3. Periorbital edema with heliotrope hue; heliotrope rash over the eyelides is classic
    4. Gottron's Sign - pink to violaceous scaling areas on MCPs, elbows, knees, not PIPs
    5. Gottron's Papules - violaceous rash with papules usually on knuckles
    6. Periungal Erythema
    7. Rash often precedes muscle symptoms by up to 1 year
    8. Some patients never develop muscle symptoms (only rash), although subclinical muscle inflammation is often present; this is called amyopathic dermatomyositis
    9. Raynaud's phenomenon is present in ~35% of patients
  4. Rhabdomyolysis - in severe cases, with acute renal failure
  5. Cardiac Disease
    1. Relatively uncommon
    2. Conduction system abnormalities predominate, often asymptomatic
    3. Heart block, supraventricular tachyarrhythmias, or (dilated) cardiomyopathy
    4. Glucocorticoid Side Effects - hypertension, cardiomyopathy, etc.
  6. Pulmonary Disease
    1. Chronic Interstitial Fibrosis - dyspnea on exertion
    2. Subacute Interstitial Pneumonitis - cough, dyspnea, hypoxemia
    3. Rapidly Progressive Interstitial Pneumonitis -Hammond-Rich Syndrome [7]
    4. Adult Respiratory Distress Syndrome (non-infectious) [8]
    5. Aspiration Pneumonia - often due to muscle weakness
    6. Bronchiolitis obliterans (with organizing pneumonia)
    7. Complications of infection (including ARDS) - associated with immunosuppression
    8. Most patients with lung disease are anti-Jo1 antibody positive
  7. Clinical Features of Juvenile Dermatomyositis [6]
    1. Constitutional: fever (>40%), lymphadenopathy (20%), lethargy (10%)
    2. Pulmonary: dyspnea (>20%)
    3. Gastrointestinal: dysphagia >20%, other: >30%
    4. Musculoskeletal: weakness 95%, myalgia/arthralgia >50%, arthritis >40%, contractures >25%
    5. Raynaud's Disease: >10%
    6. Cutaneous: Gottron's papules >80%, heliotrope rash >85%, nailfold capillary changes 91% malar or facial rash >55%, mouth (35%) or skin (25%) ulcers, limb edema >20%, calcinosis 20%
    7. Lipodystrophy: >10%

E. Laboratory Evaluationnavigator

  1. ESR usually elevated - but >50mm/hr in ~20% of cases only
  2. Autantibodies
    1. Antinuclear Abs uncommon except in overlap syndromes (see below)
    2. Except for anti-Jo1, few autoantibodies are available routinely
    3. Consider obtaining anti-U1-RNP if ANA is positive
  3. Muscle enzyme elevation
    1. Creatine kinase (CK)
    2. Aldolase - probably the most specific muscle enzyme
    3. Transaminase: AST (SGOT) > ALT (SGPT) in muscle
    4. Lactate dehydrogenase (LDH) - probably the least specific enzyme
  4. Creatine Kinase (CK) elevation is quickest and most sensitive
    1. Initially CK is MM type only
    2. Regenerating muscle produces MB type CK so that there may be an elevated MB fraction
    3. Steroid myopathy does not cause a CK elevation
  5. Urine Hemoglobin increased with few RBCs (dipstick positive; microscopic negative)

F. Diagnosisnavigator

  1. Clinical Findings
    1. Proximal muscle weakness and tenderness
    2. Characteristic skin rash
  2. Elevated muscle enzymes
    1. Rapid screening with CK determination
    2. Urine may also be analyzed for myoglobin
  3. Nailfold Capillaroscopy
    1. Highly sensitive for diagnosis
    2. DermLite® or otoscopic light and water-soluble gel
    3. May detect changes of scleroderma, overlap myositis, or mixed connective tissue disease
    4. Easily done at bedside
  4. Electromyographic (EMG) abnormalities
    1. Small amplitude, short duration, polyphasic motor potentials
    2. Spontaneous fibrillations with positive spike waves at rest
    3. Increased spontaneous spike waves and irritability
  5. Nerve Conduction Studies
    1. Absence of neuropathy (except in Inclusion Body Myositis)
    2. Late onset atrophy of neurons may follow muscle atrophy
  6. Magnetic Resonance Imaging (MRI)
    1. Shows increased T2 signal in inflamed areas
    2. May distinguish between inclusion body myositis and others
    3. Special parameters are usually required for accurate reading (eg. STIR images)
  7. Muscle Biopsy
    1. Gold standard for diagnosis
    2. Perivascular infiltrates with capillary destruction - especially dermatomyositis
    3. Immunoglobulin and complement deposition - especially in dermatomyositis
    4. T lymphocyte infiltration - especially in polymyositis (CD8+ T clls)
  8. Skin biopsy - confirm diagnosis, differentiate from cutaneous lupus erythematosus

G. Differential Diagnosis [6] navigator

  1. Dermatomyositis
  2. Myositis associated with another autoimmune disease ("overlap myositis")
  3. Polymyositis
  4. Amyopathic dermatomyostis
  5. Focal Myositis
  6. Orbital Myositis
  7. Inclusion-Body Myositis
  8. Malignancy Associated Myositis
  9. Granulomatous Myositis
  10. Macrophagic Myofasciitis
  11. Eosinophilic Myositis

H. Therapy [1,2,9,15] navigator

  1. Range of motion exercise is critical
  2. Glucocorticoids
    1. Prednisone 0.5-2mg/kg per day initially for at least 1 month after symptoms resolve
    2. Taper gradually, about 10mg/month, over many months (taper up to 2 years for children)
    3. Maintenance therapy with prednisone 10-15mg/day usually required in adults
    4. If higher doses are required, or side effects develop, then begin a second line agent
    5. Up to 25% of patients will not respond to glucocorticoids
    6. High dose pulse methylprednisolone (SoluMedrol®) 500-1000mg IV may be effective
  3. Second Line Agents and Immunosuppresives
    1. Used as immunosuppressives and glucocorticoid-sparing
    2. Azathioprine (2.5-3.0mg/d) may be used as a steroid sparing agent
    3. Methotrexate (5-30mg / week) is more effective and better tolerated than azathioprine
    4. Alkylating Agents - most effective for progressive interstitial pneumonitis
    5. Cyclosporine - may be effective in refactory cases, childhood dermatomyositis
    6. Tacrolimus promising in patients with polymyositis and anti-Jo1 or anti-SNP Abs [16]
    7. Mycophenolate mofetil (Cellcept®) 1gm po bid may also be effective
    8. Hydrochloroquine (Plaquenil®) - see below
    9. Methotrexate also has good activity for skin disease (15-35mg per week IM) and in children
  4. Intravenous Ig (IVIg) [10,11,14]
    1. Tested in 15 steroid refractory dermatomyositis cases
    2. High dose IV Ig used, 2gm/kg, q month x 3 doses
    3. 8 patients receiving Ig responded well, 7 patients with placebo no response
    4. Additional responses when placebo group crossed over
    5. Efficacy in uncontrolled trials of resistant polymyositis [11]
    6. Recommended if methotrexate or azathioprine + glucocorticoids not effective
    7. Maintenance doses every 6-8 weeks
  5. Alkylating Agents [15]
    1. Cyclophosphamide - 1-2mg/kg po qd; iv pulse especially in cases with lung involvement
    2. Chlorambucil - 0.2mg/kg po qd
    3. Bone Marrow suppression and late leukemia (and other cancers) risk
  6. Plasmapheresis or leukophoresis [12]
    1. No benefit in steroid resistant cases
    2. May be added to cytotoxic (alkylating) agents in resistant cases
  7. Hydroxychloroquine (Plaquenil®)
    1. May be useful for skin rash but requires 2-4 weeks to work
    2. Can cause a myopathy itself (usually without myositis)
  8. Myoglobinuria
    1. CK >5000 generally should be treated with fluids and diuresis
    2. Alkalinization of urine (drip or bolus) may spare kidney function

I. Prognosis of Myositisnavigator

  1. Mortality is ~25% at 6-7 years after diagnosis
  2. Morbidity is usually due treatment side effects, especially glucocorticoids
  3. Poor Prognostic Factors
    1. Anti-synthetase antibodies
    2. Inclusion body myositis - poor and delayed response
    3. Lung Disease - intravenous pulse cyclophosphamide may be helpful
    4. Anti-SRP antibody positive patients
    5. Poor initial response to glucocorticoids
    6. Increasing patient age

References navigator

  1. Callen JP. 2000. Lancet. 355(9197):53 abstract
  2. Dalakas MC and Hohlfeld R. 2003. Lancet. 362(9388):971 abstract
  3. Park JH, Olsen NJ, King L Jr, et al. 1995. Arthritis Rheum. 38(1):68 abstract
  4. Sigurgeirsson B, Lindelof B, Edhag O, Allander E. 1992. NEJM. 326(6):363 abstract
  5. Buchbinder R, Forbes A, Hall S, et al. 2001. Ann Intern Med. 134(12):1087 abstract
  6. Feldman BM, Rider LG, Reed AM, Pachman LM. 2008. Lancet. 371(9631):2201 abstract
  7. Lazarus DS and Mark EJ. 1995. NEJM. 333(6):369 (Case Report)
  8. Clawson K and Oddis CV. 1995. Arthritis Rheum. 38(10):1519 abstract
  9. Jaffe MM, Love LA, Leff RL, et al. 1993. Am J Med. 94(4):379 abstract
  10. Dalakas MC, Illa I, Dambrosia JM, et al. 1993. NEJM. 329(27):1993 abstract
  11. Ratko TA, Burnett DA, Foulke GE, et al. 1995. JAMA. 273(23):1865 abstract
  12. Miller FW, Leitman SF, Cronin ME, et al. 1992. NEJM. 326:1380 abstract
  13. Vazquez-Abad D and Rothfield NF. 1996. Arthritis Rheum. 39(2):292 abstract
  14. Dalakas MC. 1997. Ann Intern Med. 126(9):721 abstract
  15. Langford CA, Klippel JH, Balow JE, et al. 1998. Ann Intern Med. 128(12):1021 abstract
  16. Oddis CV, Sciurba FC, Elmagd KA, Startzl TE. 1999. Lancet. 353(9165):1762
  17. Polisson RP, Crocker JT, Mueller PR, et al. 2005. NEJM. 353(12):1275 (Case Record) abstract
  18. Artlett CM, Ramos R, Jiminez SA, et al. 2000. Lancet. 356(9248):2155 abstract
  19. Reed AM, Picornell YJ, Harwood A, Kredich DW. 2000. Lancet. 356(9248):2156 abstract
  20. Hill CL, Zhang Y, Sigurgeirsson B, et al. 2001. Lancet. 357(9250):96 abstract