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Unit 3 B&L > BL 3-11-14 9-10AM PM DM-Janson_Hirsh > Flashcards

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

1
Q

Polymyositis (PM) & Dermatomyositis (DM)

A

= the most common of the rare autoimmune inflammatory muscle diseases.

  • Characterized by chronic symmetric proximal muscle weakness & infiltration of muscle tissue by chronic inflammatory cells
  • other organs may be involved as well
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2
Q

Dermatomyositis (DM) - other manifestations (different than PM)

A

In DM, inflammatory muscle disease is accompanied by typical skin rashes.

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3
Q

Causes of PM & DM

A
  • Usually idiopathic
  • May occur in association w/ neoplastic disease or in “overlap” w/ other autoimmune diseases such as scleroderma, mixed CT disease (MCTD), Sjögren’s syndrome, and SLE.
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4
Q

Classification of PM/DM

A

Group I: Primary idiopathic polymyositis
Group II: Primary idiopathic dermatomyositis
Group III: PM/DM associated w/ neoplasia
Group IV: Childhood DM (more rarely PM)
Group V: PM/DM associated w/
another rheumatic / CTdisease
Other: Inclusion body myositis (IBM)

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5
Q

Inclusion body myositis (IBM)

A
  • Men > women
  • Age > 50 years
  • Insidious onset of muscle weakness predominantly involving finger flexors & thigh muscles
  • Negative autoAbs
  • Classic histopathologic changes of rimmed vacuoles & inclusion
  • Resistant to treatment w/ immunosuppressives
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6
Q

Clinical Features - Muscle disease in DM/PM

A

Main complaints:

  • Muscle weakness
  • Low endurance

Proximal extremity muscles affected earliest & most severely
–> early complaints of difficulty w/ standing, rising from chairs, climbing stairs, brushing/washing hair

Only half experience muscle pain or tenderness

If untreated, severe weakness develops affecting:

  • musculature of proximal extremities
  • striated muscle of upper third of esophagus
  • possibly muscles of respiration
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7
Q

Clinical Features - Skin Disease in DM/PM

A
  1. Gottron’s papules & sign
  2. Heliotrope rash
  3. V-sign & shawl-sign rash
  4. Mechanic’s hands
  5. Calcinosis cutis
  6. Periungual erythema, nail-fold telangiectasias, and cuticular overgrowth (more common in DM)
  7. Holster sign
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8
Q

Gottron’s papules & sign

A

Erythematous papular rash over metacarpal or interphalangeal joints
If occur over elbows & knees = Gottron’s sign

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9
Q

V-sign & shawl-sign rash

A

Erythematous V-shape rash over anterior chest

Shawl-sign = erythematous rash over shoulders & upper back

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10
Q

Mechanic’s hands

A

Cracked, dry-appearing skin over finger pads, esp/ on radial side of index fingers
- usually associated w/ anti-synthetase autoAbs

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11
Q

Calcinosis cutis

A

SubQ calcification

- occurs primarily in juvenile dermatomyositis

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12
Q

Holster sign

A

Poikiloderma on lateral aspects of thighs

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13
Q

Clinical Features - Extra-muscular Disease of DM/PM - Constitutional symptoms

A

weight-loss, fever, fatigue

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14
Q

Clinical Features - Extra-muscular Disease of DM/PM - GI symptoms

A 
Dysphagia
Intestinal perforation (via mesenteric vasculitis in juvenile DM)
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15
Q

Clinical Features - Extra-muscular Disease of DM/PM - Pulmonary symptoms

A

Interstitial lung disease (pulmonary fibrosis)
- 50 to 60% of anti-Jo-1 Ab cases

Aspiration pneumonia

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16
Q

Clinical Features - Extra-muscular Disease of DM/PM - Cardiac symptoms

A

Myocarditis
Conduction defects
Arrhythmias

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17
Q

Clinical Features - Extra-muscular Disease of DM/PM - Musculoskeletal symptoms

A

Nonerosive inflammatory arthritis

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18
Q

Clinical Features - Extra-muscular Disease of DM/PM - Vascular symptoms

A

Raynaud’s phenomenon

Vasculitis (in juvenile DM)

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19
Q

Clinical Features - Extra-muscular Disease of DM/PM - Anti-synthetase syndrome

A

Constellation associated w/ antisynthetase Abs (e.g. anti-Jo-1 antibody)

PM or DM presenting with:

  • fever (20%)
  • arthritis (50%)
  • mechanic’s hands (30%)
  • Raynaud’s phenomenon (40%)
  • interstitial lung disease (ILD, 60%)
20
Q

Epidemiology of DM/PM

A

Incidence: 10/1 million ppl per year
Sex: Females > Males (2-3:1)
Age: Two onset peaks: childhood & 5th decade
Race: In US, Af-Am > White (2-3:1)

21
Q

Muscle enzymes lab findings in DM/PM

A

High CPK in vast majority of pts w/ active disease

Other indicators of muscle injury may be elevated:

  • aldolase
  • myoglobinemia
  • LDH
  • AST, ALT
22
Q

Autoantibody lab findings in DM/PM

A

Myositis-specific antibodies (MSAs)
OR
Myositis-associated antibodies (MAAs)

23
Q

Myositis-specific antibodies (MSAs) - types

A

Anti-synthetase antibodies
Anti-Mi-2 antibody
Anti-signal recognition particle (SRP) antibodies

24
Q

Anti-synthetase antibodies

A
  • Type of Myositis-specific antibodies (MSAs)
  • Directed against aminoacyl-tRNA synthetases (family of enzymes that catalyze attachment of a particular amino acid to its transfer RNA)

Anti-Jo-1
= anti-histidyl-tRNA synthetase
- in ~20% of myositis pts

Abs against several other aminoacyl-tRNA synthetases occur less frequently (1-3%)

Clinical association: anti-synthetase syndrome

25
Q

Anti-Mi-2 antibody

A
  • 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
26
Q

Anti-signal recognition particle (SRP) antibodies

A
  • 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

27
Q

Myositis-associated antibodies (MAAs)

A 
Antinuclear antibody (+ANA) 
- in >70% of patients
28
Q

Indicators of inflammation in PM/DM

A

Erythrocyte sedimentation rate (ESR) elevated in only 50%

29
Q

Electromyography (EMG) findings in DM/PM

A

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.

30
Q

MRI findings in DM/PM

A

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.

31
Q

Biopsy Findings in DM/PM

A

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

32
Q

Specific Histological findings in PM

A
  • 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)
33
Q

Specific Histological findings in DM

A

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.

34
Q

Etiology of PM/DM

A

Etiology unknown, but several theories:

  • Cellular Immune Abnormalities (cell response against muscle tissue)
  • Humoral Immune Abnormalities
  • Nonimmune mechanisms
  • Genetic Susceptibility
  • Viral Infections
35
Q

Cellular Immune Abnormalities Theory in PMDM

A

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.
36
Q

Humoral Immune Abnormalities Theory in PM/DM

A
  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
37
Q

Evidence for immune complex-mediated damage in PM/DM

A

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

38
Q

Nonimmune mechanisms theory in Polymyositis (PM)

A

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.

39
Q

Nonimmune mechanisms theory in Dermantomyolitis (DM)

A

Tissue hypoxemia from capillary loss & local tissue inflammation

40
Q

Genetic Susceptibility in PM

A 
Relatively strong association with:
- HLA-DRB1
- HLA-DQA1
- HLA-DQB1 
in those w/anti-synthetase antibodies in PM.
41
Q

Viral Infections Theory in DM/PM

A

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

42
Q

Evidence for viral infections as cause / trigger in PM & DM:

A
  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
43
Q

Treatment for PM/DM

A

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
44
Q

Corticosteroid (prednisone) therapy in PM/DM

A

1st line therapy

45
Q

Immunosuppressive / Immunomodulatory Drugs - When to use for DM/PM

A

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)
46
Q

Immunosuppressive / Immunomodulatory Drugs - types used

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

Unit 3 B&L (18 decks)

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