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Idiopathic Inflammatory Myopathies
Dr. Mark I. BoulosPGY 1 – NeurologyRheumatology Rounds
Tuesday, June 5, 2007
Objectives1. Discuss how one can differentiate the
idiopathic inflammatory myopathies (IIMs) from other neurological conditions
2. Review the major causes of myopathies3. Review the following for the IIMs:
a) Clinical featuresb) Antibody markersc) EMG findingsd) Current treatment strategies
4. Discuss steroid-induced myopathy versus disease activity
5. Discuss the use of MRI in the IIMs
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”
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
What’s going on?
Based on these findings, which of the following diagnoses should be initially considered?
A. Upper motor neuron disease process (e.g. Multiple Sclerosis)
B. Anterior horn cell disease (e.g. ALS)
C. Peripheral neuropathy
D. Neuromuscular junction disease (e.g. Myasthenia gravis)
E. Myopathy
Answer: E. Myopathy
Proximal muscle weakness, in the absence of fasciculations, atrophy, cranial nerve and sensory findings is strongly suggestive of a myopathic process
Lower vs. UpperMotor Neuron Weakness
Upper Motor Neuron
(Brain to corticospinal tract)
Lower Motor Neuron
(Anterior horn cells to peripheral nerves)
Reflexes Hyperactive
+/- clonus
Diminished or absent
Atrophy Absent* Present
Fasciculations Absent Present
Tone Increased (spasticity) Decreased or absent
Toes Up-going (Babinski’s sign) Down-going
*Disuse atrophy can develop after initial presentation
Distinguishing Lower Motor Weakness from Muscle Weakness
Due to Neuropathy
Due to Myopathy
Distribution Distal > proximal Proximal > distal
Fasciculations May be present Absent
Reflexes Diminished Often preserved
Sensory signs/symptoms
May be present Absent
• Weakness due to neuropathy: lower motor neuron disease.
• Weakness due to myopathy: nerve function intact.
Source: www.uptodate.com
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!
Idiopathic Inflammatory Myopathies
Heterogeneous group of disorders characterized by: Proximal muscle weakness
Non-suppurative inflammation of skeletal muscle with predominantly lymphocytic infiltrates
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.
Epidemiology
2-8 cases per million per year
Female:male = 2:1
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. 2001:369–376.
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
Polymyositis
Wortmann RL. Primer on Rheum Dis. 12th edition. 2001:369–376.
Cardiac disturbances Asymptomatic ECG
changes
Conduction disturbances
Supraventricular arrhythmias
Cardiomyopathy
Congestive heart failure
Respiratory involvement Interstitial fibrosis
Interstitial pneumonitis
Polymyositis (continued) Systemic symptoms
Arthralgias Fever, malaise Raynaud’s phenomenon
Wortmann RL. Primer on Rheum Dis. 12th edition. 2001:369–376.
Features of Polymyositis as well as cutaneous manifestations The skin lesions may precede or follow the
muscle syndrome
Gottron’s 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
Dermatomyositis
Wortmann RL. Primer on Rheum Dis. 12th edition. 2001:369–376.
Gottron’s Sign
Heliotrope rash
Shawl Sign
Source: DermAtlas, Johns Hopkins University www.dermatlas.med.jhmi.edu
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. 2001:369–376.
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
Juvenile Dermatomyositis
Wortmann RL. Primer on Rheum Dis. 12th edition. 2001:369–376.
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 patient‘s age and gender
MYOSITIS ASSOCIATED WITH MALIGNANCY
Wortmann RL. Primer on Rheum Dis. 12th edition. 2001:369–376.
Overlap of muscle weakness and one of the collagen vascular diseases such as scleroderma, SLE and MCTD
PAN and RA rarer association
MYOSITIS ASSOCIATED WITH OTHER COLLAGEN VASCULAR DISEASES
Wortmann RL. Primer on Rheum Dis. 12th edition. 2001:369–376.
Back to our case…
What investigations can be done for this patient to confirm our diagnosis?
High clinical suspicion for Polymyositis…
• Diagnosis confirmed by:
• CK levels• EMG findings• Muscle biopsy
Polymyositis / Dermatomyositis Diagnostic criteria
1. Proximal muscle weakness
2. Elevated serum CK
3. Myopathic changes on EMG
4. Muscle biopsy demonstrating lymphocytic inflammation
5. 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.
Elevation of CK sometime during course of disease (often >10 times normal)
AST, ALT, and LDH are elevated in most cases
Laboratory Findings
Wortmann RL. Primer on Rheum Dis. 12th edition. 2001:369–376.
EMG classically reveals the following triad:
1. Increased insertional activity, fibrillations and sharp positive waves
2. Spontaneous, bizarre, high frequency discharges
3. 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
EMG Findings
Wortmann RL. Primer on Rheum Dis. 12th edition. 2001:369–376.
Muscle Biopsy:Histology and Immunochemistry
Dermatomyositis B cells,
macrophages
CD4 T cells
Decreased capillaries
Perifascicular atrophy
Perivascular infiltrate
Polymyositis Mononuclear cells
CD8 T cells
Endomysial infiltrate
Myonecrosis
Patchy, focal
IBM Same as PM;
also:
Rimmed vacuoles
Eosinophilic cytoplasmic inclusions
Source: Dr. R. Shupak, St. Michael‘s Hospital Pathogenesis of Idiopathic Inflammatory MyopathyRheumatology Rounds: April 5, 2005Rolak LA. Neurology Secrets. 2005: 63-7.
Source:Dr. R. Shupak, St. Michael‘s Hospital Pathogenesis of Idiopathic Inflammatory Myopathy Rheumatology Rounds: April 5, 2005
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"
Differential Diagnosis of the Motor Unit by EMG
Back to our case…
Are there any other laboratory investigations that can be carried out?
Myositis-Specific Autoantibodies (MSA)
Source: Dr. R. Shupak, St. Michael‘s Hospital Pathogenesis of Idiopathic Inflammatory Myopathy Rheumatology Rounds: April 5, 2005
Myositis-Specific Autoantibodies
Source: Dr. R. Shupak, St. Michael‘s Hospital Pathogenesis of Idiopathic Inflammatory Myopathy Rheumatology Rounds: April 5, 2005
MSA And Associated Disease Features
Ab Ag Prevalence DiseaseAnti 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. Michael‘s Hospital Pathogenesis of Idiopathic Inflammatory Myopathy Rheumatology Rounds: April 5, 2005Briani et al. (2006). Autoimmunity.
Myositis-Associated Antibodies(MAA) MAA are found in the sera of 20-50% of
patients Commonly encountered in other connective tissue
diseases.
MAA Myositis Overlapping with…
Anti-PM/Scl Scleroderma
Anti-Ku Other connective tissue diseases
snRNP Connective tissue–disease overlap syndrome
Ro/SSA 60 kd
Ro/SSA 52 kd
La/SSB
Sjögren syndrome and systemic lupus erythematosus (SLE)
Source: http://www.emedicine.com/neuro/topic85.htm
What treatments are available for our patient?
Back to our patient…
Immunotherapeutic strategies The immunotherapies for
inflammatory myopathies can be divided into three major categories:
1. Selective, antigen-specific immunotherapies
2. Semi-specific therapies
3. Conventional, non-specific immunosuppressive or anti-inflammatory therapies
Dalakas MC. (2006). Neuromuscular Disorders.
1) Selective, antigen-specific immunotherapies
Target the trimolecular complex (TMC) of T–cell stimulation, which is part of the ‘immunological synapse’ In principle, each component of the TMC can be
targeted
Dalakas MC. (2006). Neuromuscular Disorders.
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.
2) Semi-specific therapies
Semi-specific therapies using agents and biologicals aimed at various targets of the immunopathological network
Dalakas MC. (2006). Neuromuscular Disorders.
3) Conventional, non-specific immunosuppressive agents
At the present time, include: Steroids Azathioprine Mycophenolate Methotrexate Cyclophosphamide Cyclosporin
Dalakas MC. (2006). Neuromuscular Disorders.
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.
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.
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.
Therapeutic targets in PM, DM, IBM and the available biological agents directed against them
3. Cytokines/chemokines/adhesion molecules(a)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.
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.
Therapeutic targets in PM, DM, IBM and the available biological agents directed against them
5. 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.
Therapeutic targets in PM, DM, IBM and the available biological agents directed against them
Therapeutic Targets
Dalakas MC. (2006). Neuromuscular Disorders.
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.
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 6–12 weeks to maintain improvement
Dalakas MC et al. (1993). NEJM.
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.
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.
Other Management Considerations
Prevention of medication side effects Physical therapy Speech therapy Psychiatric support
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
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 patient‘s care to a Rheumatologist
Start Losec
Refer patient to ophthalmologist for formal eye examination
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)
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.
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.
Steroid myopathy versus disease activity When the signs are not clear…
One may arbitrarily raise the prednisone dosage
Answer can be evident in about 2–8 weeks, according to the change in the patient’s 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.
How can MRI help my patient?
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.
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.
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.
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
Patient‘s strength improved with Prednisone taper
Energy levels improved after seeing a psychiatrist and starting an antidepressant medication
Patient declined formal PT rehabilitation
Happy Ending…
Patient‘s 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
Thanks for your attention!
Questions?