BL 3-11-14 9-10AM PM DM-Janson_Hirsh Flashcards
Polymyositis (PM) & Dermatomyositis (DM)
= 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
Dermatomyositis (DM) - other manifestations (different than PM)
In DM, inflammatory muscle disease is accompanied by typical skin rashes.
Causes of PM & DM
- 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.
Classification of PM/DM
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)
Inclusion body myositis (IBM)
- 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
Clinical Features - Muscle disease in DM/PM
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
Clinical Features - Skin Disease in DM/PM
- Gottron’s papules & sign
- Heliotrope rash
- V-sign & shawl-sign rash
- Mechanic’s hands
- Calcinosis cutis
- Periungual erythema, nail-fold telangiectasias, and cuticular overgrowth (more common in DM)
- Holster sign
Gottron’s papules & sign
Erythematous papular rash over metacarpal or interphalangeal joints
If occur over elbows & knees = Gottron’s sign
V-sign & shawl-sign rash
Erythematous V-shape rash over anterior chest
Shawl-sign = erythematous rash over shoulders & upper back
Mechanic’s hands
Cracked, dry-appearing skin over finger pads, esp/ on radial side of index fingers
- usually associated w/ anti-synthetase autoAbs
Calcinosis cutis
SubQ calcification
- occurs primarily in juvenile dermatomyositis
Holster sign
Poikiloderma on lateral aspects of thighs
Clinical Features - Extra-muscular Disease of DM/PM - Constitutional symptoms
weight-loss, fever, fatigue
Clinical Features - Extra-muscular Disease of DM/PM - GI symptoms
Dysphagia Intestinal perforation (via mesenteric vasculitis in juvenile DM)
Clinical Features - Extra-muscular Disease of DM/PM - Pulmonary symptoms
Interstitial lung disease (pulmonary fibrosis)
- 50 to 60% of anti-Jo-1 Ab cases
Aspiration pneumonia
Clinical Features - Extra-muscular Disease of DM/PM - Cardiac symptoms
Myocarditis
Conduction defects
Arrhythmias
Clinical Features - Extra-muscular Disease of DM/PM - Musculoskeletal symptoms
Nonerosive inflammatory arthritis
Clinical Features - Extra-muscular Disease of DM/PM - Vascular symptoms
Raynaud’s phenomenon
Vasculitis (in juvenile DM)
Clinical Features - Extra-muscular Disease of DM/PM - Anti-synthetase syndrome
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%)
Epidemiology of DM/PM
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)
Muscle enzymes lab findings in DM/PM
High CPK in vast majority of pts w/ active disease
Other indicators of muscle injury may be elevated:
- aldolase
- myoglobinemia
- LDH
- AST, ALT
Autoantibody lab findings in DM/PM
Myositis-specific antibodies (MSAs)
OR
Myositis-associated antibodies (MAAs)
Myositis-specific antibodies (MSAs) - types
Anti-synthetase antibodies
Anti-Mi-2 antibody
Anti-signal recognition particle (SRP) antibodies
Anti-synthetase antibodies
- 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
Anti-Mi-2 antibody
- 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
Anti-signal recognition particle (SRP) antibodies
- 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
Myositis-associated antibodies (MAAs)
Antinuclear antibody (+ANA) - in >70% of patients
Indicators of inflammation in PM/DM
Erythrocyte sedimentation rate (ESR) elevated in only 50%
Electromyography (EMG) findings in DM/PM
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.
MRI findings in DM/PM
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.
Biopsy Findings in DM/PM
Common to both PM & DM is finding chronic inflammatory infiltrate in muscle tissue, accompanied by muscle fiber necrosis & regeneration.
Specific Histological findings in PM
- 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)
Specific Histological findings in DM
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.
Etiology of PM/DM
Etiology unknown, but several theories:
- Cellular Immune Abnormalities (cell response against muscle tissue)
- Humoral Immune Abnormalities
- Nonimmune mechanisms
- Genetic Susceptibility
- Viral Infections
Cellular Immune Abnormalities Theory in PMDM
The following support cellular immune response against muscle:
- Muscle tissue infiltration by activated CD8+ CTL
- Increased # of activated Tcells in peripheral blood of PM/DM pts
- Proliferative response (i.e. recognition) of peripheral blood mononuclear cells to muscle tissue
- Lymphocytes from pts w/ PM show cytotoxicity to muscle tissue.
- 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.
Humoral Immune Abnormalities Theory in PM/DM
- Increased CD4+ (helper) T cells & B cells in DM muscle tissue.
- Evidence for immune complex-mediated damage:
- Production of myositis-specific antibodies (MSAs) & myositis-associated antibodies (MAAs):
- No current evidence supports that these Abs are pathogenic
Evidence for immune complex-mediated damage in PM/DM
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
Nonimmune mechanisms theory in Polymyositis (PM)
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.
Nonimmune mechanisms theory in Dermantomyolitis (DM)
Tissue hypoxemia from capillary loss & local tissue inflammation
Genetic Susceptibility in PM
Relatively strong association with: - HLA-DRB1 - HLA-DQA1 - HLA-DQB1 in those w/anti-synthetase antibodies in PM.
Viral Infections Theory in DM/PM
Viruses might initially trigger disease process before elimination by host’s immune response.
Evidence for viral infections as cause / trigger in PM & DM:
- Certain viral infections cause form of inflammatory myositis (influenza, coxsackievirus, echoviruses)
- Viral particles (detected by electron microscopy) & RNA sequences (detected by virus-specific gene probes) in muscle tissue of DM/PM pts
- HIV infection can be associated with PM
- Higher prevalence of Abs to coxsackie B virus in juvenile DM compared to controls.
- Isolation of enterovirus from a few pts w/PM/DM
- Spring onset pattern in pts w/anti-Jo-1 Abs
- Microarray mRNA profiling in DM:
- predominance of interferon-responsive pathways suggesting an antiviral response
Treatment for PM/DM
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
Corticosteroid (prednisone) therapy in PM/DM
1st line therapy
Immunosuppressive / Immunomodulatory Drugs - When to use for DM/PM
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)
Immunosuppressive / Immunomodulatory Drugs - types used
- Methotrexate
- Azathioprine
- Cyclophosphamide
- Mycophenolate
- Cyclosporine or Tacrolimus
- IVIG
- Rituximab (mAb against CD20 on B cells) with possible benefit in pts w/ refractory PM/DM
