07. Inflammatory Myopathies

Definition

A group of rare, idiopathic disorders characterized by skeletal muscle inflammation leading to muscle weakness (usually symmetric and proximal), progressing over weeks to months, that can affect multiple organs and lead to severe impairment of QOL.

Etiology/Risk Factors

Incidence of 2 in 100,000 persons annually.

  • Female > male (2:1) except in inclusion body myositis (IBM) M>F
  • DM/PM: age >20 years (peak 40-50); IBM >50 years
  • DM is most common; PM <5% and is a diagnosis of exclusion
  • May be primary or secondary to malignancy (especially if older age of onset): increased risk of malignancy in adults, not children; DM 6-fold and PM 2-fold increase in cancer risk; Malignancy can be diagnosed before, at the time of, or after the diagnosis of myositis (even up to 5 years), with a peak incidence of 2 years before and after the diagnosis of myositis
    • Ensure age-appropriate evaluation for malignancy, with surveillance for 2-3 years following the diagnosis of myositis. Ovarian, lung, breast, GI adenocarcinomas and NHL are the most common malignancies in the US
    • Secondary DM/PM mirrors the distribution of cancer in a given population

Clinical Manifestations

  • Dermatomyositis (DM) and polymyositis (PM)
    • Symmetric proximal muscle weakness is the most common presenting sign. Patients often have difficulty ascending stairs, rising from a chair, lifting objects overhead.
    • On exam, distinguish true muscle weakness from functional motor impairment or pain not due to loss of muscle power.
    • Muscle bulk is usually preserved in myopathies, except in late stages.
    • Distal weakness should prompt evaluation for an alternate diagnosis, as should severe pain.
    • Skin manifestations pathognomonic for DM: heliotrope rash (red/violaceous eruption of upper eyelids), Gottron’s papules (non-scaling, erythematous to violaceous eruption over extensor surfaces of MCP, PIP, DIPs), mechanic’s hands (hyperkeratotic fingers with fissured skin), shawl sign (erythematous rash of shoulders and upper back), v-neck sign (erythematous rash of upper chest), calcinosis can be severe problem in juvenile DM, photosensitive facial rash mimicking that of SLE (but includes nasolabial folds).
  • Inclusion body myositis: asymmetric weakness and atrophy that may cause distal and proximal weakness (including wrist and finger flexors, quadriceps). Can see dysphagia, mild peripheral neuropathy, and loss of deep tendon reflexes in some patients. Insidious and progressive course and refractory to treatment.
  • Necrotizing myositis: more rapid and severe with higher CK elevation compared to DM or PM (CK can be >10K). Can be idiopathic vs autoimmune mediated (anti-HMGCR or anti-SRP). SRP associated with rare extramuscular manifestations in heart and lung (cardiac conduction abnormalities, interstitial lung disease). Of note, anti-HMGCR immune-mediated necrotizing myositis is associated with statin exposure, however compared to standard statin-associated myopathy, CK elevation/weakness persist after statin discontinuation and requires immunosuppression.
  • Overlap myositis syndromes: DM/PM may co-exist and overlap with scleroderma, SLE, MCTD, RA, Sjogren’s.
    • Anti-synthetase syndrome: seen in up to 30% patients with DM/PM; ILD, mechanic’s hands, Raynaud’s, myositis, fever, arthritis. Associated with anti-Jo-1 and other anti-synthetase antibodies.
  • Other conditions causing muscle weakness ± elevated muscle enzymes must be considered when evaluating for inflammatory myopathies: motor neuron disease (ALS), myasthenia gravis, Lambert-Eaton, muscular dystrophies, metabolic disorders (glycogen or lipid), toxin/drug-induced, endocrine (hypothyroidism), infectious.

Laboratory, Radiologic, and Histologic Evaluation

Diagnosis relies on combination of clinical symptoms, EMG/NCS, MRI, autoantibody status, and muscle histology pattern.

  • Laboratory features - Elevated plasma muscle enzymes: CK (10-50x elevation, low elevation or normal CK in IBM), LDH, AST/ALT (due to muscle inflammation, as opposed to liver injury), aldolase.
  • Many associated antibodies are linked to clinical features including Mi-2, MDA5 (rapidly progressive ILD), TIF-1 (malignancy), NXP-2 (malignancy), SAE (DM), CN1A (IBM), SRP and HMGCR (immune-mediated necrotizing myositis), Ku, PM/Scl, U-snRNP, Anti-SS-A/Ro, and SS-B/La in overlap myositis, and anti-tRNA, Jo-1, PL-7, Pl-12, Ha, OJ, KS, Zo, and EJ in anti-synthetase syndrome. Defer to neurology/rheumatology for ordering.
  • EMG: myopathic changes.
  • MRI detects areas of active inflammation (intramuscular edema) and is helpful for selecting a biopsy site. Of note, MRI cannot distinguish myositis from other causes of muscle injury (e.g. rhabdomyolysis) which can also result in muscle edema.
  • Muscle biopsy: standard for diagnosis, NPV 85%.
    • DM: perimysial inflammation, perifascicular atrophy, vasculitis with complement deposition and loss of capillaries.
    • PM: endomysial inflammation, CD8+ T-cells.
    • Necrotizing myopathy: marked necrosis, relative lack of lymphocytic infiltrate.
    • IBM: red-rimmed vacuoles containing beta-amyloid, +/- endomysial CD8+ T-cells.
    • PM, DM, and IBM all exhibit MHC1 upregulation on muscle fibers.
  • Radiologic screening for malignancy: formal guidelines on optimal malignancy screening are lacking. After diagnosis, patients should generally undergo full a review of systems, age-appropriate cancer screening, and CXR to evaluate for thoracic malignancy. If high-risk (cutaneous necrosis or vasculitis, male gender, advanced age, dysphagia, TIF-1 or NXP-2 antibody, poor response to therapy), screening CT C/A/P can be considered. FDG-PET/CT is being increasingly used to screen high-risk patients.

Management

  • In general, treatment is similar with corticosteroids ± steroid sparing therapy with methotrexate, azathioprine, or mycophenolate as the basis of treatment.
  • Rituximab, IVIG, and cyclophosphamide can be used for refractory disease.
    • DM usually responds well except in cases of malignancy or ILD.
  • Necrotizing myositis: escalation of therapy is often required. IVIG can be especially helpful.
  • Physical therapy is a crucial component to recovery.

Key Points

  • DM and PM are characterized by progressive symmetric proximal muscle weakness and may be associated with malignancy.
  • IBM is characterized by progressive asymmetric proximal and distal muscle weakness.
  • Necrotizing myositis can evolve rapidly and can be associated with statin use and anti-HMGCR antibody.

References

Schmidt J. Current Classification and Management of Inflammatory Myopathies. J Neuromuscul Dis. 2018;5(2):109-129. doi:10.3233/JND-180308

Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis. Lancet 2003;362: 971-982.

Joseph A, Brasington,R, Kahl L, et al. Immunologic Rheumatic Disorders. Journal of Allergy and Clinical Immunology 2010;125: S205-S215.

Limaye VS, Blumbergs P, Roberts-Thomson PJ. Idiopathic Inflammatory Myopathies. Internal Medicine Journal 2009; 39:179-190.

Mammen AL. Dermatomyositis and Polymyositis.  Annals of the New York Academy of Sciences 2010;1184: 134-153.