1. Inflammatory Myopathies
Susan Wallis, MD

2. Idiopathic inflammatory myopathies
Polymyositis
Dermatomyositis
Juvenile dermatomyositis
Inclusion body myositis
Myositis associated with collagen vascular disease
Myositis associated with malignancy

3. Idiopathic inflammatory myopathies
Polymyositis
Dermatomyositis
Juvenile dermatomyositis
Inclusion body myositis
Myositis associated with collagen vascular disease
Myositis associated with malignancy

4. 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.

5. 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

6. Epidemiology Bimodal age distribution in PM/DM Inclusion body
Between years in children
Between in adults
Inclusion body
More common after age 50 years
Female predominance

7. 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
The HLA genes vary in different populations.
Metabolic causes hyperthyroid, hyperparathyroid, hypophos, hypoglycemia

8. Symmetric weakness of limb girdle muscles and anterior neck flexors.
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.
The weakness is progressive over weeks to months with or without dysphagia or respiratory muscle involvment.
Necrosis and regeneration
N Engl J Med 292:344, 1975

9. 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.
3. Muscle enzymes including CK, aldolase, AST/ALT and LDH

10. 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
High dose steroids should be at least mg prednisone/day for 3-4 months.

11. 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.

12. Clinical features Progressive painless weakness Fatigue Fever
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

13. Other clinical features
Weight loss
Nonerosive inflammatory polyarthritis in rheumatoid-like distribution
Except in Jo-1 positive, can be erosive and deforming.
Raynaud’s phenomenon
Interstitial lung disease
Cardiac abnormalities
Amyopathic dermatomyositis

14. Deforming arthritis of anti-Jo 1 antibody patient

15. 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.

16. Dermatologic manifestations
Gottron’s sign is differentiated from SLE in which the rash is typically between the joints.

18. Nailfold capillaries
Upper left is normal. Upper right is scleroderma with dilation of isolated capillary loops with loss of surrounding structures. The lower left is an adult dermatomyositis with distortion of normal architecture, alteration in morphology of blood vessels, including dilated enlarged giant loops. The lower right child dermatomyositis with dilated capillary loops and arborized clusters.

19. Cardiac Myocarditis Cor pulmonale
With secondary arrhythmias and CHF
Myocardial fibrosis
Cor pulmonale
Secondary to ILD
Accelerated atherosclerosis associated with prolonged steroid use
Seldom symptomatic

20. 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
Studies range from 25-60% of IIM patients have ILD

21. Pulmonary evaluation CT scan PFTs BAL Biopsy
Increased interstitial markings
PFTs
Decreased TLV and DLCO
BAL
Abnormal number of leukocytes
Biopsy
Mononuclear cell infiltration, destruction of alveolar spaces and fibrosis

22. GI Tract Pharyngeal muscle involvement
Dyphonia
Dysphagia
Postprandial symptoms of bloating, pain and distension
Pneumatosis cystoides intestinalis

23. 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.

24. Pathology

25. Inflammation Dermatomyositis Polymyositis and inclusion body myositis
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

26. Just a quick review of muscle anatomy
Just a quick review of muscle anatomy. The individual myofibrils or myocytes are surrounded by an endomysial membrane. Groups of myocytes are arranged into a bundle or fascicle and surrounded by the perimysium. In myositis, clusters of inflammatory cells may be found between unaffected myocytes (endyomysium) or fascicles (perimysium) and surrounding blood vessels. Also within myocytes.

27. Normal appearing muscle cell invaded by T cells.
Green staining for CD8 cells
The different distribution of invading inflammatory cells.

28. Polymyositis
pleiad.umdnj.edu/.../muschtml/musc008.htm
Endomysial inflammatory infiltrate surrounding and invading non-necrotic muscle fibers

29. Dermatomyositis
Necrotic and regenerating muscle fibers in perifascicular regions

30. Chronic dermatomyositis
Small fibers in the periphery of the fascicle (perifascicular atrophy) and increase in fibrous tissue separating the bundles of myofibers.

31. Inclusion body myositis
The pink section is showing basophilic rimmed vacuoles. The blue shows a vacuole filled with granules

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

33. 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.

34. 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, 2006;39(3):
Most commonly the anti-aminoacyl-tRNA, SRP and MI2

35. Other examples of myositis specific antibodies
Other examples of myositis specific antibodies. Here is the list of the anti-aminoacyl-tRNA antibodies and what the other 2 are.
Autoimmunity, May 2006; 39(3): 161–170

36. Just a reminder of where these antigens are found in protein synthesis

37. Clinical syndromes associated with specific antibodies

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

39. Common characteristics
Myopathy
Interstitial lung disease
Raynaud’s phenomenon
Polyarthritis
Fever
Mechanic’s hands

40. Retrospective study of 74 patients who met Peter-Bohan criteria.
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):

41. Prevalence of symptoms of patients with antisynthetase syndrome
Autoimmunity 2006; 39(3):

42. Interstitial lung disease
Autoimmunity 2006; 39(3):

43. They found that patients with the anti-ARS syndrome mostly developed ILD preceeding diagnosis
Autoimmunity 2006; 39(3):

44. 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.

45. 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:

46. Anti-Mi-2
Antibodies directed to a nuclear macromolecular complex involved in transcription.
Strong specificity for dermatomyositis.
Usually good response to treatment.

47. Schematic representation of each antibody associated clinical presentation.

48. Myositis Associated Antibodies
Anti-PM-Scl
Anti-RNP
Anti-Ro
Anti-La
Anti-Ku
To touch briefly on other antibodies. There are myositis associated antibodies that are seen in pateints with myositis and other conditions.

49. Myositis-associated antigens
Antigens that are seen in myositis but also in other diseases
Autoimmunity, May 2006; 39(3): 161–170

50. 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.
One commonly found is the anti-Scl antibody that is seem in an overlap with scleroderma

51. 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.
Most commonly seen here is the anti-RNP that comes on the ENA panel done here that is suggestive of an overlap with connective tissue disease.

52. Joint, Bone, Spine. 2006;73:

53. Cellular Immunity Lymphocyte accumulation
T cell receptor restriction in inflamed muscle
Cytokine activation
Increased expression of antigen presenting cells

54. 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.

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

56. Immunopathological changes in dermatomyositis
Disease probably starts with complement activation. The MAC is deposited in and around the endothelial wall of the endomysial capillaries. This leads to ischemia (from hypoperfusion) and microinfarcts in the periphery of the fascicle. Migration of B cells, Cd4 and CD8 t-cells is faciliated by ICAM and VCAM that have been upregulated by cytokines. The atrophic fibers express STAT-1, TGFbeta, MCH-1
Neuromuscular Disorders 16 (2006) 223–236

57. Polymyositis CD8+ invade healthy non-necrotic muscle fibers.
MHC-class I antigen expressing muscle cells.

58. 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):

59. 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:

60. 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.

61. 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);

62. 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.

63. Muscle biopsies showing localization of CD4, CD8 and BV3-expressing cells (brown cells).
Arthritis and rheumatism 2007;56(1)

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

65. Patient evaluation

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

67. STIR image of active dermatomyositis

68. 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
The international myostitis assessment and clinical studies group have developed a core set of measures

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

70. Anti-inflammatory and immunosuppressive
Steroids
Azathioprine
CellCept
Methotrexate
Cytoxan
Cyclosporin

71. 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.

72. Other treatments Steroid sparing Non-responders Methotrexate Imuran
Rituxan
IVIG
Cyclosporin
Cellcept
Cyclophosphamide (also for ILD)
Plasmapheresis
?TNF inhibitors
Cellcept is an inhibitor of inosine monophosphate dehydrogenase which inhibits de novo guanosine nucleotide synthesis. T/B cells are dependent on this pathway for proliferation.
Cytoxan is an alkylating agent that prevents cell division by cross-linking DNA strands and decreases DNA synthesis.

73. 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.

74. 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.

75. Poor prognostic factors
Older age
Malignancy
Delayed steroid treatment
Dysphagia with aspiration
ILD

76. Bibliography
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Chinoy H, et al. In adult onset myositis, the presence of interstitial lung disease and myositis specific/associated antibodies are governed by HLA class II haplotype, rather than by myositis subtype. Arthritis Research and Therapy 2006;8(1):R13.
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