Transcript Inflammatory Myopathies

Inflammatory Myopathies
Susan Wallis, MD
Idiopathic inflammatory myopathies
• Polymyositis
• Dermatomyositis
• Juvenile dermatomyositis
• Inclusion body myositis
• Myositis associated with collagen
vascular disease
• Myositis associated with
malignancy
Idiopathic inflammatory myopathies
• Polymyositis
• Dermatomyositis
• Juvenile dermatomyositis
• Inclusion body myositis
• Myositis associated with collagen
vascular disease
• Myositis associated with
malignancy
Inflammatory myopathies
• Rare heterogeneous group of acquired
diseases characterized by inflammatory
infiltrate of skeletal muscle.
• Incidence of about 2-10 per 1 million
people per year in the United States.
• Potentially treatable.
Polymyositis/Dermatomyositis
• Heliotrope rash was first described in 1875
in France.
• In 1888 the first American biopsy
documented polymyositis in ruling out
Trichinella.
• 1930 Gottron reported skin lesions
• 1967 the pathology of inclusion body
myositis was described.
Hochberg et al. Rheumatology 3rd ed. 2003
Epidemiology
• Bimodal age distribution in PM/DM
– Between 10-15 years in children
– Between 45-60 in adults
• Inclusion body
– More common after age 50 years
• Female predominance
Differential diagnosis
• Drugs and toxins:
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Chloroquine
Colchicine
Corticosteroids
Heroin
Alcohol
Fibrates/statins
AZT
• Metabolic
• Malignancy
• Infectious agents:
– Bacteria
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Staphylococci
Clostridia
Rickettsias
Mycobacteria
– Parasites
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Toxoplasma
Trichnella
Schistosoma
Cysticerca
Borrelia
– Viruses
• Genetic
– HLA-DRB1
– HLA-DQA1
– TNF2(-308)
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Coxsackie
Echo
Influenze
Adeno
Criteria to define polymyositis and dermatomyositis
proposed by Bohan and Peter
1. Symmetric weakness of limb girdle muscles
and anterior neck flexors.
2. Skeletal muscle histologic examination
showing evidence of necrosis of types I and II
muscle fibers, phagocytosis, regeneration with
basophilia, large sarcolemmal nuclei and
prominent nucleoli, atrophy in a perifascicular
distribution, variation in fiber size, and an
inflammatory exudate.
N Engl J Med 292:344, 1975
3.
Elevation of levels of serum skeletal muscle enzymes
4.
Electromyographic (EMG) triad of short, small
polyphasic motor units; fibrillations, positive waves,
and insertional irritability; and bizarre high-frequency
discharges.
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Dermatologic features including a heliotrope rash with
periorbital edema; a scaly, erythematous dermatitis
over the dorsa of the hands, especially over the MCP
and PIP joints (Gottron's sign); and involvement of the
knees, elbows, medial malleoli, face, neck, and upper
torso.
Diagnostic criteria for IBM
• Pathologic criteria
– Electron microscopy:
Microtubular filaments
in the inclusions.
– Light microscopy:
• Lined vacuoles
• Intranuclear or
intracytoplasmic
inclusions or both
• Clinical criteria
– Proximal muscle
weakness
– Distal weakness
– EMG evidence of
generalized myopathy
– Increase in serum muscle
enzymes
– Failure of muscle
weakness to improve on
high-dose steroids
Polymyositis/Dermatomyositis
• Occur sporadically or in association with
other systemic autoimmune disease
• More common in women than men.
• DM common than PM.
• DM can clinically manifest with heliotrope
rash, Grotton’s papules, shawl rash,
erythematous nailfolds, dermatomyositis
sine myositis.
Clinical features
• Progressive painless weakness
– Difficulty lifting above head/combing hair
– Difficulty arising from a low chair or toilet
– Nasal regurgitation or choking when eating
– Hoarseness, change in voice
– *Ocular/facial muscle involvement is very
uncommon
• Fatigue
• Fever
Other clinical features
• Weight loss
• Nonerosive inflammatory polyarthritis in
rheumatoid-like distribution
– Except in Jo-1 positive, can be erosive and
deforming.
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Raynaud’s phenomenon
Interstitial lung disease
Cardiac abnormalities
Amyopathic dermatomyositis
Deforming arthritis of anti-Jo 1
antibody patient
Inclusion body myositis
• Can present with features identical to PM.
• Onset is typically insidious and
progression is slow.
• May differ from PM in that it may include
focal, distal or asymmetric weakness.
• Dyspagia is a late occurrence.
• CK only slightly increased and can be
normal in up to 25% of patients.
Dermatologic manifestations
www.jfponline.com/Pages.asp?AID=2763&UID=
Nailfold capillaries
www.hakeem-sy.com/main/files/images/20_2.jpg
Cardiac
• Myocarditis
– With secondary arrhythmias and CHF
– Myocardial fibrosis
• Cor pulmonale
– Secondary to ILD
• Accelerated atherosclerosis associated
with prolonged steroid use
Dyspnea
• Non-pulmonary: respiratory muscle
weakness, cardiac involvement
• Pulmonary:
– ILD: NSIP, UIP, diffuse alveolar damage,
cryptogenic organizing pneumonia
– Pulmonary hypertension
– Alveolar hemorrhage
– Infection: with or without aspiration
– Drug induced
Pulmonary evaluation
• CT scan
– Increased interstitial markings
• PFTs
– Decreased TLV and DLCO
• BAL
– Abnormal number of leukocytes
• Biopsy
– Mononuclear cell infiltration, destruction of
alveolar spaces and fibrosis
GI Tract
• Pharyngeal muscle involvement
– Dyphonia
– Dysphagia
• Postprandial symptoms of bloating, pain
and distension
• Pneumatosis cystoides intestinalis
Malignancy risk
• Strong association between malignancy
and dermatomyositis, but less clearly with
polymyositis.
– Ovarian, lung, pancreatic, stomach and
colorectal and non-Hodgkin lymphoma
• The overall risk is greatest in the first 3
years after diagnosis but is still increased
through all years of follow-up.
Pathology
Inflammation
• Dermatomyositis
– B cells and CD4 are abundant in the pervascular
region.
– MAC found in the perivascular areas and within
intrafascicular capillaries
– Damage to intrafascicular capillaries
• Polymyositis and inclusion body myositis
– Normal appearing muscle cells are invaded by T cells
• PM/DM
– Increased expression of costimulatory molecules
Polymyositis
pleiad.umdnj.edu/.../muschtml/musc008.htm
Endomysial inflammatory infiltrate surrounding and
invading non-necrotic muscle fibers
www.neuropathologyweb.org/chapter13/chapter13
Dermatomyositis
Necrotic and regenerating muscle fibers in
perifascicular regions
www.neuro.wustl.edu/.../pathol/dermmyo.htm
www.phoenixneurology.com
Chronic dermatomyositis
Inclusion body myositis
Pathogenesis
• Humoral
– Autoantibodies
• Directed against cell components
• Directed at intracellular, ususally intracytoplasmic
molecules
• Usually part of the protein synthesis machinery
• Cellular
• Genetic
Autoantibodies
• Autoantibodies have been identified in
patients with myositis.
– Not seen in inclusion body myositis
• Can help predict specific syndromes.
• Differentiate between types of idiopathic
myositis versus myositis associated with
other conditions.
Autoantibodies
• Myositis specific antibodies (MSA)
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Present in 30-60% of patients with PM/DM
Anti-aminoacyl-tRNA synthetases (ARS).
Anti-SRP
Anti-Mi-2
Autoimmunity, 2006;39(3):161-170
Autoimmunity, May 2006; 39(3): 161–170
Clinical syndromes associated
with specific antibodies
Antisynthetase syndrome
• Aminoacyl-tRNA-synthetase is a
cytoplasmic enzyme involved in
aminoacylation.
• The most common ARS is histidyl-RNAsynthetase, also called Jo-1.
www.arodia.com/.../orderByAttribute__caption
Common characteristics
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Myopathy
Interstitial lung disease
Raynaud’s phenomenon
Polyarthritis
Fever
Mechanic’s hands
Anti-aminoacyl-tRNA synthetase antibodies in clinical
course prediction of interstitial lung disease complicated
with idiopathic inflammatory myopathies
• Aim of the study to determine if these antibodies were
predictive of clinical course of ILD in idiopathic
inflammatory myositis patients.
• Retrospective study of 74 patients who met Peter-Bohan
criteria.
• The patients with ILD have a worse prognosis than those
without.
• Anti-ARS are strongly associated with ILD
Autoimmunity 2006; 39(3):233-241
Prevalence of symptoms of patients with antisynthetase
syndrome
Autoimmunity 2006; 39(3):233-241
Interstitial lung disease
Autoimmunity 2006; 39(3): 233-241
Autoimmunity 2006; 39(3): 233-241
Anti-SRP Antibodies
• Cytoplasmic antibody
• SRP is an RNA-protein complex that binds
newly synthesized proteins and guides
them to the endoplasmic reticulum for
translocation.
Clinical
• Very rare
• Chiefly proximal muscle involvement with
rhabdomyolysis
• Usually poor response to steroids
• ILD possible but uncommon
• Skin and joints spared
Joint, Bone, Spine. 2006;73:646-654
Anti-Mi-2
• Antibodies directed to a nuclear
macromolecular complex involved in
transcription.
• Strong specificity for dermatomyositis.
• Usually good response to treatment.
Myositis Associated Antibodies
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Anti-PM-Scl
Anti-RNP
Anti-Ro
Anti-La
Anti-Ku
Myositis-associated antigens
Autoimmunity, May 2006; 39(3): 161–170
Anti-PM-Scl antibodies
• Directed against a nucleolar macromolecular
complex
• Primarily polymyositis or
dermatomyositis/scleroderma overlap
• Strongly associated with HLA-DR3
• Seen in 5-25% of patients with myositis.
Anti-U1-RNP
• Sm-RNPs are ribonucleoproteins
composed of 11 peptides and five small
RNAs called U1, U2, U4, U5 and U6.
– Anti-U1-RNP is primary marker of an overlap
syndrome.
• Found in 5-60% of patients with
connective tissue disease and myositis.
Joint, Bone, Spine. 2006;73:646-654.
Cellular Immunity
• Lymphocyte accumulation
• T cell receptor restriction in inflamed
muscle
• Cytokine activation
• Increased expression of antigen
presenting cells
• Factors that activate complement and the
antigenic targets are unknown.
• Lymphocytic infiltrates are B cells, CD4+
cells and plasmacytoid/dendritic cells.
• Complement activation upregulates
cytokines, chemokines and adhesion
molecules.
Dermatomyositis
Complement activation
C5b-C9 deposition in endomysial capillares
Capillary necrosis
Perivascular inflammation
Ischemia
Muscle fiber destruction
Immunopathological changes in
dermatomyositis
Neuromuscular Disorders 16 (2006) 223–236
Polymyositis
• CD8+ invade healthy non-necrotic muscle
fibers.
• MHC-class I antigen expressing muscle
cells.
MHC-class I
• MHC-class I expression is absent in
normal muscle
• Strongly up-regulated in pathologic
conditions, especially in inflammatory
myopathies.
• A mouse model of overexpression of MHC
class I molecules alone in skeletal muscle
led to a self-sustaining inflammatory
process.
PNAS 2000;97(16):9209-9214
Genetic Factors
• HLA-DRB1*0301, HLA-DQA1
• Non-HLA class II genetic polymorphisms
including IL-1 receptor antagonist and
TNF-α.
• Gene studies have been difficult to
perform given rarity of disease.
• Previous studies have combined DM and
PM patients to increase power.
Current Opinion in Rheumatology 2004;16:707-713
T cell receptors
• All the inflammatory myopathies are
characterized by the presence of T cells
and macrophages in muscle tissue.
• Exogenous or endogenous antigen?
• Previous studies looking at the TCR
repertoire in myositis patients has been
inconclusive.
Restricted T Cell Receptor BV Gene Usage in the
Lungs and Muscles of Patients with Idiopathic
Inflammatory Myopathies
• Aim of study to compare TCR expression
in 3 compartments that could be involved
in patients with myositis: muscle, lung and
peripheral blood.
• Identify a common TCR
Englund P et al. Arthritis and Rheumatism 2007; 56(1);372-383
• T cells recognize an antigen via
complementary region of T cell receptors.
• TCR is a heterodimer of two α and two β
variable chain lesions.
• TCR genes are restricted and amino acid
sequences are conserved when T cells are
selectively recruited by specific
autoantigens.
Muscle biopsies showing
localization of CD4, CD8
and BV3-expressing cells
(brown cells).
Arthritis and rheumatism 2007;56(1)372-383
Conclusion
• Restricted accumulation of T lymphocytes
expressing selected TCR V-gene
segments.
• Positive results from lung and muscle.
• Suggests common target antigens.
– Unidentified
Patient evaluation
Diagnosis
• Biopsy is gold standard
• EMG
• MRI
– STIR images for active myositis
– Confirmation of amyopathic dermatomyositis
– Documentation of flare
Disease activity assessment
• Global activity- VAS
• Muscle strength
– Proximal and distal muscle evaluation
• Physical function
– HAQ
• Laboratory assessment
– >2 serum muscle enzymes
• Extramuscular disease
– Assess cutaneous, GI, articular, cardiac and
pulmonary activity
If we do not know what
causes it, how do we treat it?
Immunotherapy
Anti-inflammatory and
immunosuppressive
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Steroids
Azathioprine
CellCept
Methotrexate
Cytoxan
Cyclosporin
Corticosteroids is mainstay of
treatment in most cases
• Start 1-2 mg/kg/day
• Continue until CPK returns to normal, then
slow taper.
• For severe acute disease, consider pulse
dose steroids.
Other treatments
• Steroid sparing
– Methotrexate
– Imuran
• Non-responders
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Rituxan
IVIG
Cyclosporin
Cellcept
Cyclophosphamide
(also for ILD)
– Plasmapheresis
– ?TNF inhibitors
Additional follow-up
• Cancer screening
– Age appropriate
– CAP CT scan
– CA-125 and CA19-9
• Aggressive risk factor modification for
atherosclerosis.
• PT tailored to patient’s needs starting with
passive ROM, stretching advancing to
aerobic activity after recovery.
Prognosis
• Older studies (before the availability of
steroids) revealed a 50% mortality from
complications.
• Current estimates of mortality, excluding
patients with malignancy, is less than 10%
at 5 years after initial diagnosis.
Poor prognostic factors
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Older age
Malignancy
Delayed steroid treatment
Dysphagia with aspiration
ILD
Bibliography
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Clinical implications of autoantibody screening in patients with autoimmune myositis. Autoimmunity 2006;
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