Idiopathic Inflammator Myopathie Dr.Mark Boulos June5 07fin

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!


Heterogeneous group of disorders characterized by: Proximal muscle weakness

Non-suppurative inflammation of skeletal muscle with predominantly lymphocytic infiltrates


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


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


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


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


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


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


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


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


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


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


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’)


2) Semi-specific therapies

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


3) Conventional, non-specific immunosuppressive agents

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


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



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


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



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



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



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



Therapeutic Targets


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)


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


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


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


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


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?

Self Improvement

Idiopathic Inflammator Myopathie Dr.Mark Boulos June5 07fin