Idiopathic Inflammatory Myopathies
Dr. Mark I. Boulos
PGY 1 – Neurology Rheumatology Rounds
Tuesday, June 5, 2007
Objectives
1. Discuss how one can differentiate the
idiopathic inflammatory myopathies (IIMs) from other neurological conditions 2. Review the major causes of myopathies 3. Review the following for the IIMs: a) Clinical features b) Antibody markers c) EMG findings d) 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. C. D.
Anterior horn cell disease (e.g. ALS) Peripheral neuropathy 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. Upper Motor Neuron Weakness
Upper Motor Neuron
(Brain to corticospinal tract)
Lower Motor Neuron
(Anterior horn cells to peripheral nerves)
Reflexes Atrophy
Hyperactive +/- clonus Absent*
Diminished or absent Present
Fasciculations Absent Tone
Toes
Present Decreased or absent
Increased (spasticity)
Up-going (Babinski‟s sign) Down-going
*Disuse atrophy can develop after initial presentation
Distinguishing Lower Motor Weakness from Muscle Weakness
Due to Neuropathy
Distribution Fasciculations Reflexes Sensory signs/symptoms Distal > proximal May be present Diminished May be present
Due to Myopathy
Proximal > distal Absent Often preserved 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.
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. 2001:369–376.
Polymyositis
Cardiac disturbances
(continued)
Systemic symptoms
Asymptomatic ECG changes
Conduction disturbances Supraventricular arrhythmias
Arthralgias Fever, malaise Raynaud’s phenomenon
Cardiomyopathy Congestive heart failure
Interstitial fibrosis Interstitial pneumonitis
Respiratory involvement
Wortmann RL. Primer on Rheum Dis. 12th edition. 2001:369–376.
Dermatomyositis
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
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.
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. 2001:369–376.
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 patient„s age and gender
Wortmann RL. Primer on Rheum Dis. 12th edition. 2001:369–376.
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. 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.
2.
3. 4.
5.
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.
Laboratory Findings
Elevation of CK sometime during
course of disease (often >10 times normal)
AST, ALT, and LDH are elevated in
most cases
Wortmann RL. Primer on Rheum Dis. 12th edition. 2001:369–376.
EMG Findings
EMG classically reveals the following triad:
1.
Increased insertional activity, fibrillations and sharp positive waves Spontaneous, bizarre, high frequency discharges Polyphasic motor-unit potentials of low amplitude and short duration
2. 3.
Complete triad seen in 40% of patients 10-15% of patients have completely normal
EMGs
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
IBM Polymyositis Mononuclear cells Same as PM; also: CD8 T cells Rimmed Endomysial infiltrate vacuoles Myonecrosis Eosinophilic Patchy, focal cytoplasmic inclusions
Perivascular infiltrate
Source:
Rolak LA. Neurology Secrets. 2005: 63-7.
Dr. R. Shupak, St. Michael‘s Hospital Pathogenesis of Idiopathic Inflammatory Myopathy Rheumatology Rounds: April 5, 2005
Source:Dr. R. Shupak, St. Michael‘s Hospital
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
MSA And Associated Disease Features
Ab
Anti Jo1
antiPL7 antiPL12 antiPL12
Ag
HisRS
ThrRS AlaRS tRNA-Ala
Prevalence
15-40
5 5 5
Disease
antisynthetase
antisynthetase antisynthetase antisynthetase
antiOJ AntiEJ
AntiSRP Anti Mi-2
IleRS GLyRS
SRP protein nuclear helicase
5 5
5 10
antisynthetase antisynthetase
severe acute PM classic DM
Anti KJ
?protein
1
ILD
Briani et al. (2006). Autoimmunity.
Source: Dr. R. Shupak, St. Michael‘s Hospital Pathogenesis of Idiopathic Inflammatory Myopathy Rheumatology Rounds: April 5, 2005
Myositis-Associated Antibodies (MAA)
MAA are found in the sera of 20-50% of
patients
Commonly encountered in other connective tissue diseases.
MAA
Anti-PM/Scl Anti-Ku snRNP
Myositis Overlapping with…
Scleroderma Other connective tissue diseases 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
Back to our patient…
What treatments are available for our
patient?
Immunotherapeutic strategies
The immunotherapies for
inflammatory myopathies can be divided into three major categories:
1.
Selective, antigen-specific immunotherapies Semi-specific therapies Conventional, non-specific immunosuppressive or anti-inflammatory therapies
2.
3.
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.
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 Preliminary studies have shown effectiveness of Rituximab in DM patients
(b) Rituximab
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
A pilot study with Avonex was ineffective in IBM A controlled multicenter trial with higher doses is being considered
(c) Beta-interferon
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
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 activity Examples 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
Patient with increasing weakness and stable CK who receives high dose of steroids
Dalakas MC. (2006). Neuromuscular Disorders.
Possible Steroid-induced Myopathy
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?