Inflammatory%20Myopathies

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Inflammatory Myopathies

• Susan Wallis, MD

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Idiopathic inflammatory myopathies

• Polymyositis
• Dermatomyositis
• Juvenile dermatomyositis
• Inclusion body myositis
• Myositis associated with collagen vascular
  disease
• Myositis associated with malignancy

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Idiopathic inflammatory myopathies

• Polymyositis
• Dermatomyositis
• Juvenile dermatomyositis
• Inclusion body myositis
• Myositis associated with collagen vascular
  disease
• Myositis associated with malignancy

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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.

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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
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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

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Differential diagnosis

• Drugs and toxins
• Chloroquine
• Colchicine
• Corticosteroids
• Heroin
• Alcohol
• Fibrates/statins
• AZT
• Metabolic
• Malignancy
• Genetic
• HLA-DRB1
• HLA-DQA1
• TNF2(-308)

• Infectious agents
• Bacteria
• Staphylococci
• Clostridia
• Rickettsias
• Mycobacteria
• Parasites
• Toxoplasma
• Trichnella
• Schistosoma
• Cysticerca
• Borrelia
• Viruses
• Coxsackie
• Echo
• Influenze
• Adeno

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Criteria to define polymyositis and
dermatomyositis proposed by Bohan and Peter

• 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 292344, 1975
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• Elevation of levels of serum skeletal muscle
  enzymes
• Electromyographic (EMG) triad of short, small
  polyphasic motor units fibrillations, positive
  waves, and insertional irritability and bizarre
  high-frequency discharges.
• 5. 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.

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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

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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,
  Grottons papules, shawl rash, erythematous
  nailfolds, dermatomyositis sine myositis.

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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

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Other clinical features

• Weight loss
• Nonerosive inflammatory polyarthritis in
  rheumatoid-like distribution
• Except in Jo-1 positive, can be erosive and
  deforming.
• Raynauds phenomenon
• Interstitial lung disease
• Cardiac abnormalities
• Amyopathic dermatomyositis

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Deforming arthritis of anti-Jo 1 antibody patient
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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.

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Dermatologic manifestations
www.jfponline.com/Pages.asp?AID2763UID
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Nailfold capillaries
www.hakeem-sy.com/main/files/images/20_2.jpg
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Cardiac

• Myocarditis
• With secondary arrhythmias and CHF
• Myocardial fibrosis
• Cor pulmonale
• Secondary to ILD
• Accelerated atherosclerosis associated with
  prolonged steroid use

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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

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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

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GI Tract

• Pharyngeal muscle involvement
• Dyphonia
• Dysphagia
• Postprandial symptoms of bloating, pain and
  distension
• Pneumatosis cystoides intestinalis

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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.

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Pathology
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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

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Polymyositis
pleiad.umdnj.edu/.../muschtml/musc008.htm
Endomysial inflammatory infiltrate surrounding
and invading non-necrotic muscle fibers
www.neuropathologyweb.org/chapter13/chapter13
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Dermatomyositis

• Necrotic and regenerating muscle fibers in
  perifascicular regions

www.neuro.wustl.edu/.../pathol/dermmyo.htm
www.phoenixneurology.com
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Chronic dermatomyositis
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Inclusion body myositis
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Pathogenesis

• Humoral
• Autoantibodies
• Directed against cell components
• Directed at intracellular, ususally
  intracytoplasmic molecules
• Usually part of the protein synthesis machinery
• Cellular
• Genetic

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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.

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Autoantibodies

• Myositis specific antibodies (MSA)
• Present in 30-60 of patients with PM/DM
• Anti-aminoacyl-tRNA synthetases (ARS).
• Anti-SRP
• Anti-Mi-2
• Autoimmunity, 200639(3)161-170

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Autoimmunity, May 2006 39(3) 161170
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Clinical syndromes associated with specific
antibodies
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Antisynthetase syndrome

• Aminoacyl-tRNA-synthetase is a cytoplasmic enzyme
  involved in aminoacylation.
• The most common ARS is histidyl-RNA-synthetase,
  also called Jo-1.

www.arodia.com/.../orderByAttribute__caption
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Common characteristics

• Myopathy
• Interstitial lung disease
• Raynauds phenomenon
• Polyarthritis
• Fever
• Mechanics hands

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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
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Prevalence of symptoms of patients with
antisynthetase syndrome
Autoimmunity 2006 39(3)233-241
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Interstitial lung disease
Autoimmunity 2006 39(3) 233-241
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Autoimmunity 2006 39(3) 233-241
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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.

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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. 200673646-654
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Anti-Mi-2

• Antibodies directed to a nuclear macromolecular
  complex involved in transcription.
• Strong specificity for dermatomyositis.
• Usually good response to treatment.

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Myositis Associated Antibodies

• Anti-PM-Scl
• Anti-RNP
• Anti-Ro
• Anti-La
• Anti-Ku

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Myositis-associated antigens
Autoimmunity, May 2006 39(3) 161170
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Anti-PM-Scl antibodies

• Directed against a nucleolar macromolecular
  complex
• Primarily polymyositis or dermatomyositis/sclerode
  rma overlap
• Strongly associated with HLA-DR3
• Seen in 5-25 of patients with myositis.

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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.

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Joint, Bone, Spine. 200673646-654.
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Cellular Immunity

• Lymphocyte accumulation
• T cell receptor restriction in inflamed muscle
• Cytokine activation
• Increased expression of antigen presenting cells

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• 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.

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Dermatomyositis

• Complement activation
• C5b-C9 deposition in endomysial capillares
• Capillary necrosis
• Perivascular inflammation
• Ischemia
• Muscle fiber destruction

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Immunopathological changes in dermatomyositis
Neuromuscular Disorders 16 (2006) 223236
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Polymyositis

• CD8 invade healthy non-necrotic muscle fibers.
• MHC-class I antigen expressing muscle cells.

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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
  200097(16)9209-9214

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Genetic Factors

• HLA-DRB10301, HLA-DQA1
• Non-HLA class II genetic polymorphisms including
  IL-1 receptor antagonist and TNF-a.
• 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 200416707-713
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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.

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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
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• T cells recognize an antigen via complementary
  region of T cell receptors.
• TCR is a heterodimer of two a and two ß variable
  chain lesions.
• TCR genes are restricted and amino acid sequences
  are conserved when T cells are selectively
  recruited by specific autoantigens.

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Muscle biopsies showing localization of CD4, CD8
and BV3-expressing cells (brown cells).
Arthritis and rheumatism 200756(1)372-383
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Conclusion

• Restricted accumulation of T lymphocytes
  expressing selected TCR V-gene segments.
• Positive results from lung and muscle.
• Suggests common target antigens.
• Unidentified

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Patient evaluation
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Diagnosis

• Biopsy is gold standard
• EMG
• MRI
• STIR images for active myositis
• Confirmation of amyopathic dermatomyositis
• Documentation of flare

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Disease activity assessment

• Global activity- VAS
• Muscle strength
• Proximal and distal muscle evaluation
• Physical function
• HAQ
• Laboratory assessment
• gt2 serum muscle enzymes
• Extramuscular disease
• Assess cutaneous, GI, articular, cardiac and
  pulmonary activity

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If we do not know what causes it, how do we treat
it?

• Immunotherapy

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Anti-inflammatory and immunosuppressive

• Steroids
• Azathioprine
• CellCept
• Methotrexate
• Cytoxan
• Cyclosporin

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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.

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Other treatments

• Steroid sparing
• Methotrexate
• Imuran

• Non-responders
• Rituxan
• IVIG
• Cyclosporin
• Cellcept
• Cyclophosphamide (also for ILD)
• Plasmapheresis
• ?TNF inhibitors

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Additional follow-up

• Cancer screening
• Age appropriate
• CAP CT scan
• CA-125 and CA19-9
• Aggressive risk factor modification for
  atherosclerosis.
• PT tailored to patients needs starting with
  passive ROM, stretching advancing to aerobic
  activity after recovery.

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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.

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Poor prognostic factors

• Older age
• Malignancy
• Delayed steroid treatment
• Dysphagia with aspiration
• ILD

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