Idiopathic Inflammatory Myopathies

1
Idiopathic Inflammatory Myopathies

• Dr. Mark I. Boulos
• PGY 1 Neurology
• Rheumatology Rounds
• Tuesday, June 5, 2007

2
Objectives

• Discuss how one can differentiate the idiopathic
  inflammatory myopathies (IIMs) from other
  neurological conditions
• Review the major causes of myopathies
• Review the following for the IIMs
• Clinical features
• Antibody markers
• EMG findings
• Current treatment strategies
• Discuss steroid-induced myopathy versus disease
  activity
• Discuss the use of MRI in the IIMs

3
Case

• 58F office clerk from Trinidad
• Initially presented to the SMH MS Clinic with
• Unstable gait
• Intermittent hand tremor
• Blurring of vision
• Headaches
• Subtle UMN findings in left leg
• Non-specific T2 hyperintensities on brain MRI
• Diagnosed with Possible (but not definite) MS

4
A few months later

• Returned to neurologist complaining of
• Difficulty getting up from a chair or a squatting
  position
• Difficulty combing hair and reaching for objects
  with her arms
• Weakness was slowly progressing
• On neurological examination, only abnormality was
  proximal muscle weakness
• Normal cranial nerves, sensation, reflexes tone
• No fasciculations or atrophy
• No muscle or joint tenderness
• No cutaneous lesions

5
Whats going on?

• Based on these findings, which of the following
  diagnoses should be initially considered?
• Upper motor neuron disease process (e.g. Multiple
  Sclerosis)
• Anterior horn cell disease (e.g. ALS)
• Peripheral neuropathy
• Neuromuscular junction disease (e.g. Myasthenia
  gravis)
• Myopathy

6
Answer E. Myopathy

• Proximal muscle weakness, in the absence of
  fasciculations, atrophy, cranial nerve and
  sensory findings is strongly suggestive of a
  myopathic process

7
Lower vs. UpperMotor Neuron Weakness
Disuse atrophy can develop after initial
presentation
8
Distinguishing Lower Motor Weakness from Muscle
Weakness

• Weakness due to neuropathy lower motor neuron
  disease.
• Weakness due to myopathy nerve function intact.

9
Source www.uptodate.com
10
Common Conditions that can Result in Myopathy

• Non-inflammatory myopathies
• Hypothyroidism
• Hypokalemia
• Alcoholism
• Drugs
• AZT
• HMG-CoA reductase inhibitors (statins)
• Corticosteroids More on this later!

11
Idiopathic Inflammatory Myopathies

• Heterogeneous group of disorders characterized
  by
• Proximal muscle weakness
• Non-suppurative inflammation of skeletal muscle
  with predominantly lymphocytic infiltrates

12
Idiopathic Inflammatory Myopathies

• Clinical Classification
• Polymyositis (PM)
• Dermatomyositis (DM)
• Inclusion Body Myositis (IBM)
• Juvenile Dermatomyositis
• Myositis associated with malignancy
• Myositis associated with collagen vascular disease

Bohan Peter (1975). NEJM. Tanimoto et al.
(1995). J Rheumatology.
13
Epidemiology

• 2-8 cases per million per year
• Femalemale 21
• Bimodal distribution
• 10-15 years (pediatric variant)
• 45-60 years
• Age of onset for myositis associated with another
  condition is similar to that in the other
  condition
• IBM and myositis associated with malignancy are
  common after the age of 50 years

Wortmann RL. Primer on Rheum Dis. 12th edition.
2001369376.
14
Polymyositis

• Usually insidious onset over 3-6 months
• No identifiable precipitant
• Shoulder and pelvic girdle muscles affected most
  severely
• Neck muscles (esp. flexors) involved in 50 of
  patients
• Ocular and facial muscles almost never affected
• Distal muscles are spared in majority of pts
• Dysphagia dysphonia may occur

Wortmann RL. Primer on Rheum Dis. 12th edition.
2001369376.
15
Polymyositis (continued)

• Cardiac disturbances
• Asymptomatic ECG changes
• Conduction disturbances
• Supraventricular arrhythmias
• Cardiomyopathy
• Congestive heart failure
• Respiratory involvement
• Interstitial fibrosis
• Interstitial pneumonitis

• Systemic symptoms
• Arthralgias
• Fever, malaise
• Raynauds phenomenon

Wortmann RL. Primer on Rheum Dis. 12th edition.
2001369376.
16
Dermatomyositis

• Features of Polymyositis as well as cutaneous
  manifestations
• The skin lesions may precede or follow the muscle
  syndrome
• Gottrons sign - symmetric violaceous
  erythematous eruption over knuckles
• Heliotrope rash - reddish violaceous eruption on
  upper eyelids /- oedema
• Shawl sign erythematous rash over neck, upper
  chest and shoulders

Wortmann RL. Primer on Rheum Dis. 12th edition.
2001369376.
17
Gottrons Sign
18
Heliotrope rash
19
Shawl Sign
Source DermAtlas, Johns Hopkins University
www.dermatlas.med.jhmi.edu
20
Inclusion Body Myositis

• Mainly affects older individuals
• Symptoms begin insidiously and progress slowly
• Symptoms are often present 5-6 years before
  diagnosis
• Differs from Polymyositis in that IBM
• May include focal, distal or asymmetric weakness
• Neurogenic or mixed neurogenic / myopathic
  changes on EMG
• Dysphagia is noted in more than 20 of patients
• May continue to progress slowly steadily in
  others, symptoms plateau

Wortmann RL. Primer on Rheum Dis. 12th edition.
2001369376.
21
Juvenile Dermatomyositis

• Differs from adult form because of co-existence
  of vasculitis and ectopic calcification
• Vasculitis can involve skin, kidneys, GI tract,
  muscle and brain
• Calcification is frequently present in muscles of
  subcutaneous tissues

Wortmann RL. Primer on Rheum Dis. 12th edition.
2001369376.
22
MYOSITIS ASSOCIATED WITH MALIGNANCY

• Malignancy may precede or follow the onset of
  muscle weakness
• Associated malignancy may be more common in DM
• Association is rare in childhood
• Sites and types of malignancy are those expected
  for patients age and gender

Wortmann RL. Primer on Rheum Dis. 12th edition.
2001369376.
23
MYOSITIS ASSOCIATED WITH OTHER COLLAGEN VASCULAR
DISEASES

• Overlap of muscle weakness and one of the
  collagen vascular diseases such as scleroderma,
  SLE and MCTD
• PAN and RA rarer association

Wortmann RL. Primer on Rheum Dis. 12th edition.
2001369376.
24
Back to our case

• What investigations can be done for this patient
  to confirm our diagnosis?

25
High clinical suspicion for Polymyositis

• Diagnosis confirmed by
• CK levels
• EMG findings
• Muscle biopsy

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Polymyositis / Dermatomyositis

• Diagnostic criteria
• Proximal muscle weakness
• Elevated serum CK
• Myopathic changes on EMG
• Muscle biopsy demonstrating lymphocytic
  inflammation
• Dermatomyositis Skin rash as well as criteria
  above
• Definitive diagnosis with four criteria having
  been met
• Probable with three
• Possible with two

Bohan Peter (1975). NEJM.
27
Laboratory Findings

• Elevation of CK sometime during course of disease
  (often gt10 times normal)
• AST, ALT, and LDH are elevated in most cases

Wortmann RL. Primer on Rheum Dis. 12th edition.
2001369376.
28
EMG Findings

• EMG classically reveals the following triad
• Increased insertional activity, fibrillations and
  sharp positive waves
• Spontaneous, bizarre, high frequency discharges
• Polyphasic motor-unit potentials of low amplitude
  and short duration
• Complete triad seen in 40 of patients
• 10-15 of patients have completely normal EMGs

Wortmann RL. Primer on Rheum Dis. 12th edition.
2001369376.
29
Muscle BiopsyHistology and Immunochemistry

• IBM
• Same as PM also
• Rimmed vacuoles
• Eosinophilic cytoplasmic inclusions

• Dermatomyositis
• B cells, macrophages
• CD4 T cells
• Decreased capillaries
• Perifascicular atrophy
• Perivascular infiltrate

• Polymyositis
• Mononuclear cells
• CD8 T cells
• Endomysial infiltrate
• Myonecrosis
• Patchy, focal

Source Dr. R. Shupak, St. Michaels Hospital
Pathogenesis of Idiopathic Inflammatory
Myopathy Rheumatology Rounds April 5, 2005
Rolak LA. Neurology Secrets. 2005 63-7.
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Source Dr. R. Shupak, St. Michaels Hospital
Pathogenesis of Idiopathic Inflammatory
Myopathy Rheumatology Rounds April 5, 2005
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Back to our case

• CK previously elevated in range of 600-800 IU/L
• EMG study demonstrated diffuse myopathic
  process, associated with muscle necrosis and/or
  muscle fibre splitting
• Muscle biopsy "consistent with polymyositis"

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Differential Diagnosis of the Motor Unit by EMG
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Back to our case

• Are there any other laboratory investigations
  that can be carried out?

34
Myositis-Specific Autoantibodies (MSA)
Source Dr. R. Shupak, St. Michaels Hospital
Pathogenesis of Idiopathic Inflammatory
Myopathy Rheumatology Rounds April 5, 2005
35
Myositis-Specific Autoantibodies
Source Dr. R. Shupak, St. Michaels Hospital
Pathogenesis of Idiopathic Inflammatory
Myopathy Rheumatology Rounds April 5, 2005
36
MSA And Associated Disease Features

• Ab Ag Prevalence Disease
• Anti Jo1 HisRS 15-40 antisynthetase
• antiPL7 ThrRS 5 antisynthetase
• antiPL12 AlaRS 5 antisynthetase
• antiPL12 tRNA-Ala 5 antisynthetase
• antiOJ IleRS 5 antisynthetase
• AntiEJ GLyRS 5 antisynthetase
• AntiSRP SRP protein 5 severe acute PM
• Anti Mi-2 nuclear helicase 10 classic DM
• Anti KJ ?protein 1 ILD

Source Dr. R. Shupak, St. Michaels Hospital
Pathogenesis of Idiopathic Inflammatory Myopathy
Rheumatology Rounds April 5, 2005
Briani et al. (2006). Autoimmunity.
37
Myositis-Associated Antibodies(MAA)

• MAA are found in the sera of 20-50 of patients
• Commonly encountered in other connective tissue
  diseases.

Source http//www.emedicine.com/neuro/topic85.htm
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Back to our patient

• What treatments are available for our patient?

39
Immunotherapeutic strategies

• The immunotherapies for inflammatory myopathies
  can be divided into three major categories
• Selective, antigen-specific immunotherapies
• Semi-specific therapies
• Conventional, non-specific immunosuppressive or
  anti-inflammatory therapies

Dalakas MC. (2006). Neuromuscular Disorders.
40
1) Selective, antigen-specific immunotherapies

• Target the trimolecular complex (TMC) of Tcell
  stimulation, which is part of the immunological
  synapse
• In principle, each component of the TMC can be
  targeted

Dalakas MC. (2006). Neuromuscular Disorders.
41
1) Selective, antigen-specific immunotherapies

• Of limited practical application at the present
  time
• Antigen is unknown
• Such immunotherapy needs to be tailored to
  individual patients, because the T-cell response
  to various auto-antigens is very complex
• Growing evidence that the autoimmune response is
  not static but dynamic, spreading overtime to
  include new autoantigens (epitope spreading)

Dalakas MC. (2006). Neuromuscular Disorders.
42
2) Semi-specific therapies

• Semi-specific therapies using agents and
  biologicals aimed at various targets of the
  immunopathological network

Dalakas MC. (2006). Neuromuscular Disorders.
43
3) Conventional, non-specific immunosuppressive
agents

• At the present time, include
• Steroids
• Azathioprine
• Mycophenolate
• Methotrexate
• Cyclophosphamide
• Cyclosporin

Dalakas MC. (2006). Neuromuscular Disorders.
44
Therapeutic targets in PM, DM, IBM and the
available biological agents directed against them

• 1. Intracellular signalling pathways
• (a) anti-CD52 (Alemtuzumab), (b) anti-LFA1/ICAM,
  (Efalizumab), (c) anti-LFA3/CD2 (Alefacept)
• Preliminary results are encouraging
• (d) anti-IL2R antagonist (CD25) (Daclizumab)
• Well-tolerated promising results in 2 trials of
  MS patients
• (e) Calcineurin inhibitors (Tacrolimus and
  Cyclosporin)
• In several small series of PM DM patients,
  Tacrolimus has shown to be effective as a
  steroid-sparing agent in some patients
• A controlled study has not been done

Dalakas MC. (2006). Neuromuscular Disorders.
45
Therapeutic targets in PM, DM, IBM and the
available biological agents directed against them

• 1. Intracellular signalling pathways (continued)
• (f) Against TOR kinase via FK-506 binding protein
  (Rapamycin)
• Appears promising in patients with DM resistant
  to other therapies
• (g) Inhibition of purine biosynthesis by T and B
  cells (Mycophenolate Mofetil)
• Anecdotal reports suggest effectiveness in IBM
• (h) Anti-thymocyte globulin
• Randomized pilot study showed effectiveness in IBM

Dalakas MC. (2006). Neuromuscular Disorders.
46
Therapeutic targets in PM, DM, IBM and the
available biological agents directed against them

• 2. B cells and autoantibodies
• (a) IVIg
• Effective in DM based on a controlled trial
• (b) Rituximab
• Preliminary studies have shown effectiveness of
  Rituximab in DM patients
• A multi-center controlled study in PM and DM
  funded by the NIH will begin shortly
• 3. Complement
• (a) IVIg
• (b) Anti C5 monoclonal antibody (Eculizumab)
• Now undergoing clinical trials in DM patients

Dalakas MC. (2006). Neuromuscular Disorders.
47
Therapeutic targets in PM, DM, IBM and the
available biological agents directed against them

• 3. Cytokines/chemokines/adhesion molecules
• Anti-TNF-a agents
• (i) Etanercept (Embrel)
• Tried in uncontrolled series in some patients
  with PM, DM, and IBM with limited results
• (ii) Remicade
• Tried anecdotally in PM, DM, and IBM patients,
  but a controlled study has not been conducted
• Preliminary studies suggest that it can be of
  help to some patients with inflammatory myopathie
• (iii) Atalimumab (Humira)
• There are no reports on its effectiveness in DM,
  PM, or IBM

Dalakas MC. (2006). Neuromuscular Disorders.
48
Therapeutic targets in PM, DM, IBM and the
available biological agents directed against them

• 4. Cytokines/chemokines/adhesion molecules
• (b) Anti-IL1 receptor antagonist (Anakinra)
• Has not been tried in DM, PM, or IBM
• (c) Beta-interferon
• A pilot study with Avonex was ineffective in IBM
• A controlled multicenter trial with higher doses
  is being considered

Dalakas MC. (2006). Neuromuscular Disorders.
49
Therapeutic targets in PM, DM, IBM and the
available biological agents directed against them

• T cell transmigration
• (a) IVIg
• (b) Natalizumab (Tysabri)
• Recently approved for Multiple Sclerosis
• Will likely be tried in DM, PM, or IBM sometime
  soon

Dalakas MC. (2006). Neuromuscular Disorders.
50
Therapeutic Targets
Dalakas MC. (2006). Neuromuscular Disorders.
51
Treatment Strategy for DM PM

• Step 1 Prednisone (in aggressive cases,
  combination with another agent listed in steps 2
  3 may be preferred)
• Step 2 IVIg
• Step 3 Immunosuppressants, such as Azathioprine,
  Methotrexate, Mycophenolate or Cyclosporine
• Step 4 Newer agents (Rituximab, Tacrolimus,
  Rapamycin)

Dalakas MC. (2006). Neuromuscular Disorders.
52
More on IVIg

• Only drug whose efficacy in IIM has been proven
  in controlled trials
• In a double blind study of IVIg therapy at 2
  gm/kg given in two days in patients with
  refractory dermatomyositis
• Improvement in strength first noticeable about 15
  days after the first IVIg infusion
• Clear improvement after the second infusion
• Marked improvement is also noticed in cutaneous
  features
• Repeated infusions may be required every 612
  weeks to maintain improvement

Dalakas MC et al. (1993). NEJM.
53
This just in IVIg IBM

• Mild benefits in strength in patients with IBM
• A trial of IVIg may be helpful in patients with
  worsening of muscle strength or life-threatening
  dysphagia

Sparks S et al. (2007). BMC Neurology.
54
Treatment Failure

• Failure to respond to therapy may suggest
• Inclusion body myositis
• Neoplasm-related myopathy
• Steroid-resistance or steroid-induced myopathy
• May also indicate
• Wrong diagnosis (consider re-biopsy)
• Inadequate dose of prednisone or early taper
• Early discontinuation of prednisone without
  keeping a maintenance low dose therapy

Dalakas MC. (2006). Neuromuscular Disorders.
55
Other Management Considerations

• Prevention of medication side effects
• Physical therapy
• Speech therapy
• Psychiatric support

56
Back to our case

• Neurologist planned to start patient on
  Prednisone 60mg daily (1mg/kg/d)
• Side effects explained
• Calcium and vitamin D supplementation started
• DEXA scan arranged
• Baseline bloodwork (CK, CBC, Cr, Glucose, HbA1c)
  to be completed prior to starting Prednisone

57
One month later

• Patient returned complaining of
• Blurry vision in her eyes
• Epigastric pain
• Increase in weight
• Mild improvement in strength of upper extremity,
  but no improvement in lower extremity
• Neurologist decides to
• Transfer patients care to a Rheumatologist
• Start Losec
• Refer patient to ophthalmologist for formal eye
  examination

58
Two months later

• Saw Rheumatologist at SMH
• Weakness worsening
• Disease progression or steroid-induced myopathy?
• Methotrexate added
• Prednisone tapered to 40gmg/d
• Malignancy screening
• Mammogram Pap smear arranged
• Arthritis Society OT visit arranged
• Referred for repeat EMG (inconclusive)

59
Steroid myopathy versus disease activity

• Not common
• However, may be difficult to distinguish
  steroid-induced myopathic weakness from weakness
  related to
• Disease activity
• Decreased mobility
• Infection
• Concomitant systemic illness

Dalakas MC. (2006). Neuromuscular Disorders.
60
Steroid myopathy versus disease activityExamples
of two differing scenarios

• Weakness that may need more prednisone
• Increasing CK levels, no overt signs of steroid
  toxicity with reduced or unchanged dosage of
  steroids, and no evidence of a systemic illness
  or infection
• Possible Steroid-induced Myopathy
• Patient with increasing weakness and stable CK
  who receives high dose of steroids

Dalakas MC. (2006). Neuromuscular Disorders.
61
Steroid myopathy versus disease activity

• When the signs are not clear
• One may arbitrarily raise the prednisone dosage
• Answer can be evident in about 28 weeks,
  according to the change in the patients strength
• Helpful clinical sign - strength of neck extensor
  muscles
• Usually worsens with exacerbation of the disease
• Remains unchanged with steroid-induced muscle
  intoxication
• Electromyography, seeking for increased
  spontaneous activity could be another sign
  suggestive of active disease

Dalakas MC. (2006). Neuromuscular Disorders.
62
How can MRI help my patient?
63
Use of MRI in Patients with Inflammatory
Myopathies

• MRI is the method of choice for imaging of muscle
  abnormalities
• It is very sensitive in localizing nonhomogeneous
  inflammation in inflammatory myopathies
• During treatment of inflammatory myopathies, the
  extent and severity of inflammation may decrease
  at varying rates
• MRI can be used to track these changes

Park JH, Olsen NJ. (2001). Curr Rheumatol Rep.
64
Use of MRS in Patients with Inflammatory
Myopathies

• With P-31 MRS, biochemical defects are
  quantified, which may all be related to weakness
  and fatigue
• Low levels of ATP and phosphocreatine (PCr)
• Elevated concentrations of ADP and inorganic
  phosphate (Pi)
• The metabolic abnormalities detected with P-31
  MRS are more persistent and can be used for
  objective patient evaluation after the
  disappearance of inflammation and normalization
  of serum levels of muscle enzymes

Park JH, Olsen NJ. (2001). Curr Rheumatol Rep.
65
Advances in MRI

• New advances in MRI include
• Diffusion-weighted imaging
• Permits assessment of fluid motion in muscles
• Blood-oxygen-level-dependent (BOLD) imaging
• Evaluates tissue oxygenation

Olsen NJ, Qi J, Park JH. (2005). Curr Rheumatol
Rep.
66
Back to our case

• Patient has been followed by Rheumatologist on a
  monthly basis
• Weakness was concluded to be secondary to
• Steroid-induced myopathy
• Deconditioning
• Depression
• Patients strength improved with Prednisone taper
• Energy levels improved after seeing a
  psychiatrist and starting an antidepressant
  medication
• Patient declined formal PT rehabilitation

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Happy Ending

• Patients polymyositis remains symptomatically,
  clinically and biochemically quiescent
• Recent bloodwork showed normal CK, AST, LDH, CBC,
  glucose, Cr lytes
• She is much more animated and motivated
• She is exercising more
• Continues to see her psychiatrist

68
Thanks for your attention!

• Questions?