BL 3-11-14 9-10AM PM DM-Janson_Hirsh Flashcards

Question

Anti-Mi-2 antibody

Answer 1

- Type of Myositis-specific antibodies (MSAs) - Directed against a nuclear helicase - In ~7% of patients w/ classic DM - Erythroderma & shawl-sign - Associated w/ good prognosis

Answer 2

- Type of Myositis-specific antibodies (MSAs) - involved in translocation of newly synthesized proteins into ER - occur only in PM Associated w/ severe myopathy & cardiac disease - myopathy is often refractory to corticosteroids & immunosuppressive agents

Answer 3

``` Antinuclear antibody (+ANA) - in >70% of patients ```

Answer 4

Erythrocyte sedimentation rate (ESR) elevated in only 50%

Answer 5

Myopathic pattern - increased insertional activity (abnormally increased activity when EMG needle is inserted) - spontaneous fibrillations - decreased amplitude of motor unit action potentials - complex repetitive discharges Always obtain EMG on one side & muscle biopsy on contralateral side as not to complicate interpretation of biopsy.

Answer 6

Can show areas of - muscle inflammation - edema w/ active myositis - fibrosis - calcinosis Can be used to guide optimal site for biopsy & define response to therapy.

Answer 7

Common to both PM & DM is finding chronic inflammatory infiltrate in muscle tissue, accompanied by muscle fiber necrosis & regeneration.

Answer 8

- Endomysial distribution w/ mononuclear inflammatory cells surrounding & invading non-necrotic muscle fibers throughout fascicle. PM appears to be a direct CD8+ T cell-mediated muscle injury. Inflammatory cell infiltrates: - primarily CD8+ T cells & Macs - also rare CD4+ T cells & DCs - CD8+ cytotoxic T lymphocytes (CTLs) recognize MHC class I on muscle fibers & mediate muscle fiber damage - Normal (non-necrotic) skeletal muscle cells do not constitutively express MHC class I molecules, though expression can be induced by pro-inflammatory cytokines (INF-γ, TNF-α)

Answer 9

Dermatomyositis is considered in part to be a complement-mediated vasculopathy. Inflammatory infiltrate - CD4+ T cells - B cells - Macs - DCs = concentrated in perivascular, septal regions, & around periphery (rather than throughout fascicle as in PM) - most highly concentrated in perivascular regions of muscle Vascular deposition of Ig & complement's membrane attack complex frequently seen. Atrophy of muscle fibers in perifascicular pattern (perifascicular atrophy) is highly characteristic of DM.

Answer 10

Etiology unknown, but several theories: - Cellular Immune Abnormalities (cell response against muscle tissue) - Humoral Immune Abnormalities - Nonimmune mechanisms - Genetic Susceptibility - Viral Infections

Answer 11

The following support cellular immune response against muscle: 1. Muscle tissue infiltration by activated CD8+ CTL 2. Increased # of activated Tcells in peripheral blood of PM/DM pts 3. Proliferative response (i.e. recognition) of peripheral blood mononuclear cells to muscle tissue 4. Lymphocytes from pts w/ PM show cytotoxicity to muscle tissue. 5. Cytokine production: IL-1, TNF-α, & INF-α over-expressed in muscle tissue - In DM, many of CD4+ cells are plamacytoid DCs that produce type I interferons - High levels of type I interferon-inducible gene products are present in DM.

Answer 12

1. Increased CD4+ (helper) T cells & B cells in DM muscle tissue. 2. Evidence for immune complex-mediated damage: 3. Production of myositis-specific antibodies (MSAs) & myositis-associated antibodies (MAAs): - No current evidence supports that these Abs are pathogenic

Answer 13

Vascular Ig & complement deposition in DM. Vasculitis in DM causing: - skin ulcers - nail-fold changes - intestinal perforation (esp. in juvenile DM) Decreased density of muscle capillaries & evidence for ischemic muscle injury in DM ---> suggests possible immune complex vascular injury in muscle tissue

Answer 14

MHC class I is over expressed in myocytes MHC class I assembly occurs in ER ER stress/overload response likely has role in muscle fiber damage /destruction - -> initiates upregulation of nuclear factor κB (NFκB) - --> induces of inflammatory cytokines (IL-1, TNF-α) - ---> cell death if ER’s functions severely impaired Also, tissue hypoxia from local tissue inflammation.

Answer 15

Tissue hypoxemia from capillary loss & local tissue inflammation

Answer 16

``` Relatively strong association with: - HLA-DRB1 - HLA-DQA1 - HLA-DQB1 in those w/anti-synthetase antibodies in PM. ```

Answer 17

Viruses might initially trigger disease process before elimination by host’s immune response.

Answer 18

1. Certain viral infections cause form of inflammatory myositis (influenza, coxsackievirus, echoviruses) 2. Viral particles (detected by electron microscopy) & RNA sequences (detected by virus-specific gene probes) in muscle tissue of DM/PM pts 3. HIV infection can be associated with PM 4. Higher prevalence of Abs to coxsackie B virus in juvenile DM compared to controls. 5. Isolation of enterovirus from a few pts w/PM/DM 6. Spring onset pattern in pts w/anti-Jo-1 Abs 7. Microarray mRNA profiling in DM: - predominance of interferon-responsive pathways suggesting an antiviral response

Answer 19

Since muscle damage & other manifestations of PM/DM are caused by autoimmune inflammatory response, treatment is directed at suppressing this process though immunosuppressive therapy. Includes: - Corticosteroids (prednisone) - Immunosuppressive / Immunomodulatory Drugs - Physical therapy for muscle strengthening

Answer 20

1st line therapy

Answer 21

Used in conjunction w/ corticosteroids in pts... - who do not respond well to corticosteroid therapy alone - in whom steroid taper cannot be achieved - in whom steroid therapy results in significant adverse effects (e.g. exacerbation of diabetes)

Answer 22

- Methotrexate - Azathioprine - Cyclophosphamide - Mycophenolate - Cyclosporine or Tacrolimus - IVIG - Rituximab (mAb against CD20 on B cells) with possible benefit in pts w/ refractory PM/DM

BL 3-11-14 9-10AM PM DM-Janson_Hirsh Flashcards

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