Polymyositis & Dermatositis

diagnosis

DM Skin

• biopsy-epidermal thining

• vaculation in basal keratinocyte

• dermal vessel T cell infiltration in perivascular area

• immunoflurescence-complement and Ig deposition in dermo-epidermal junction

• Membrane attack complex

Differentiation from SLE- Complement is less common in DM than in SLE

• Muscle biopsy in DM (juvenile DM)• Perifascicular atrophy• Degeneration of type I and II muscle fibers• Regeneration of muscle fibers with associated basophilia• Centralization of nuclei in muscle fibers• Perivascular mononuclear infiltrate

• Muscle biopsy in pm: inflammatory exudate consisting of mononuclear T cells, which accumulate in the endomysium and surround and invade muscle fibers [1].

•

• Target muscle for biopsy- -deltoid and quadriceps

- Muscle weak in clinical exam

• Biopsying the muscle contralateral to one demonstrated to be

abnormal by EMG increases the likelihood of a diagnostic biopsy.

• avoid- – atriphied muscle

– recent EMG

– severely weak muscle

– Cuff muscle-artifectual report

• Role of MRI• MR imaging can demonstrate areas of muscle inflammation, edema with

active myositis, fibrosis, and

calcification.• selection of muscle for biopsy

• monitoring treatment response(serial MRI)

• Electromyography — The EMG shows evidence of increased membrane irritability in the form of a classic triad:

• Increased insertional activity and spontaneous fibrillations • (Spontaneous fibrillation is very occasionally recorded)• Abnormal myopathic low amplitude, short–duration polyphasic motor potentials• Complex repetitive discharge

• EMG abnormalities may support the diagnosis of DM or PM but are not diagnostic. Similar findings occur in various infectious, toxic, or metabolic myopathies. However, the EMG is of value in distinguishing weakness of myopathic origin from neuropathic disorders, such as amyotrophic lateral sclerosis, peripheral polyneuropathy, or myasthenia gravis.

• The EMG is also useful in directing the site of muscle biopsy

Myotonic discharges:

• High-frequency potential wax and wane in amplitude giving rise characteristic dive-bomber or kawasaki bajaj sound that is heard on the loudspeaker.

In denervation & reinnervation:• Profuse fibrillation and fasciculation are typical.

D)Decrement and increment:

• In myasthenia gravis, a characteristic decrementing response in evoked muscle action potential follows repetitive motor nerve stimulation (RNS).

• The reverse occurs, i.e. increment, following repetitive stimulation in LEMS.

• Muscle enzymes — Creatine kinase (CK), lactate dehydrogenase (LD), aldolase, aspartate aminotransferase (AST), and alanine aminotransferase (ALT)

• Blood should not be drawn after trauma or EMG

• In severe cases, the serum CK concentration may be elevated 50-fold.

• the degree of muscle dysfunction may be much greater than the enzyme levels would suggest.

• therapy should be guided primarily by patients' strength, not the concentration of their muscle enzyme

• The occurrence of muscle weakness with relatively normal enzyme levels is more likely to occur in DM than PM.

• Persistently low serum muscle enzyme levels in the setting of obvious muscle weakness may also occur in patients with advanced disease and significant loss of muscle mass

• In one study of 16 patients with JDM, elevations of serum LDH and AST were associated with disease flare [11] .

• The risk of disease flare within the next four months increased three-fold following a 20 percent rise in serum AST levels. However, an association with disease flares was not seen with either an elevation of serum ALT or CK.

• Autoantibodies:(ANA) in up to 80 % of patients with DM or PM

• Autoantibodies and connective tissue disorders — anti-Ro, anti-La, anti-Sm, or anti-ribonucleoprotein (RNP) antibodies strongly suggests a diagnosis of myositis associated or overlapping with another connective tissue disease

• Myositis-specific autoantibodies — 

• Anti-Jo-1 :most common myositis-specific autoantibody

• strongly associated with ILD, Raynaud's phenomenon, arthritis, and mechanic's hands

• correlations between anti-Jo-1-antibody levels and disease activity conflicting

• Anti-SRP antibodies – occur almost exclusively in PM.

– associated with severe myopathy and aggressive disease that is difficult to control, even with high-dose glucocorticoids and adjunct immunosuppressive agents.

• Anti-Mi-2 antibodies -associated with the relatively acute onset of classic DM with erythroderma

and the shawl sign .

Ruling Out Associated Malignancy

• Old age >65

• Dermatomyositis compared with PM

• Cutaneous necrosis on the trunk

• Cutaneous leukocytoclastic vasculitis

• Capillary damage on muscle biopsy

Five-year Survival

• 1971-85: 52-65%

• 2001-06: 75-95%

Causes of Death

Infection

Respiratory failure

Cardiovascular disease

Malignancies

Predictors of Outcome

• Delay in the initiation of treatment >6 mo

• Severe weakness at presentation

• Dysphagia

• Respiratory muscle weakness

• DPLD

• Associated malignancy

• Cardiac involvement

• ? Old age

Response to GC

• DM: Initial 87%

– 92% flared during tapering

• Myositis overlap: 87-100%

• PM: 50%

Response Patterns….

• Responsive to initial therapy and achieve

sustained disease control

– off all therapy

– with low dose maintenance therapy

Response Patterns

• Recurrent disease: after achieving control,

experience recurrences (flares) during or

after medication tapering

• Resistant disease: does not respond

– alternative approaches must be considered

Course of Treated Disease

• Chronic – 60%

• Polycyclic – 20%

• Monocyclic 20%Bronner IM et al. Ann Rheum Dis 2006; 65: 1456-61

Goals of Treatment

• To improve muscle strength

• To avoid the development of

extra-muscular complications

• In DM, resolution of skin

manifestations

• To improve QoL

General Principles

• Establish disease control:

– high doses for first several months

• Slow taper to lowest effective dose

– total duration between 9 and 12 months

Initial GC therapy

• Prednisone 1 mg/kg/day maximum daily dose of 80 mg

• PMP 1000 mg/dX3 d at the start of therapy

– Bedridden

– Respiratory failure

– Dysphagia

GC Taper

• Should begin after (4-) six weeks

• Insufficient clinical improvement

– Addition of a SSA if not begun with GC

A Standard Protocol…

• By 10 mg each week up to 40 mg/day

– 8 wk

• By 5 mg each week up to 20 mg/day

– 12 wk

• By 2.5 mg each week up to 10 mg/day

– 16 wk

A Standard Protocol

• By 1 mg every two weeks → 5 mg/day

– 26 wks

• Continuation of taper

– if good disease control achieved and maintained

• Further taper should not proceed > 1 mg decreases every two weeks

Initiation

• Simultaneously with pred

• Mandatory:– No improvement with pred over 4 to 6 weeks– Profound weakness– Significant extramuscular involvement:

• ILD• Dysphagia

MTX-Dosing

• Started with 15 mg/wk

– increasing weekly by 5mg/wk up to 25 mg/wk

• If improvement at 4 wk unsatisfactory

– Inj 25 mg/wk→ 30 mg → 37.5 mg/wk → ? 50

– Titrating carefully against toxicity

MTX-Prevention of Toxicity

• Folic acid 1 mg/d except MTX day

• Folinic acid 5 mg:

– MTX >25 mg/wk

– AEs not adequately prevented with folic acid

Preferential Indications for AZT

ILD

Liver disease

Unwillingness to stop alcohol

AZT • 50 mg/d X 1 wk

– Increased progressively to 1.5 to 3 mg/kg/d

– Usual maximum 200 mg

• CBC and ALT monthly initially, then 3 monthly

• Thiopurine methyltransferase (TPMT):

– Predictor of marrow suppression

– Low dose for hetero, avoided in homozygous

MonitoringDisease response

Drug toxicity

Intervals for Outpatient

• Weekly for 2 wks

• Fortnightly for 4 wks

• Monthly for 3 months

• Then at 2 to 3 mo intervals

Tools

• Customized history

• Customized examination

• Lab tests:– CBC– ALT– S creatinine (if on MTX)– CPK– CXR (less frequently)

Response to Treatment

• Assessed by:– Improvement of muscle strength– Resolution of skin lesions

• Rate:– Rapid: within several week– Slow: progress not evident > 3 mo

Muscle Strength Vs. Enzymes

• Muscle strength is a more reliable indicator of clinical progress than muscle enzymes

• Serum enzymes fall within two weeks, but normalization takes considerably longer

– Adjusting prednisone doses in attempts to normalize muscle enzyme concentration may lead to over-treatment

Muscle Testing• Quadriceps - crosses arms and rises from a chair, using

only the proximal leg muscles

• Hip flexors - lifts leg off the table while lying down without bending the knees

• Deltoids - extend the arms against the examiner's pressure with flexed elbow

• Neck flexors - pushes head forward while the examiner applies reverse pressure against the forehead

• ? Vital capacity

Other Monitoring Parameters

• Carefully during the tapering period:

– Recurrent weakness

• steroid myopathy also affects the proximal

– Extramuscular complications of DM or PM

– Features of drug toxicity

Recurrent Disease

• Definition: recurrences (flares) during or after medication tapering after full control

• Flare patterns:

– at > 10 mg/day prednisone

– at ≤10 mg/day prednisone

– off prednisone but on SSA

– off all immunosuppressives

1. Flare At > 10 mg/day Prednisone

• Prednisone, 1 mg/kg per day, to reestablish

disease control

• Addition of a SSA if neither has been used

• Treatment of the flare as resistant disease if

the patient is already taking SSA

– Usual course in our situation

2. Flare At ≤10 mg/day Prednisone

• pred to lowest dose to reestablish control

– The dose is based on severity of clinical findings

– If flare detected early, dose may be < 1 mg/kg/d (? 0.5 mg/kg)

– Minimum re-induction dose is 20 mg/day

• Increase AZT/MTX to a higher dose, if the dose

has not already been maximized

• Once control restored, taper slower than initial

– maintained on low dose prednisone (e.g., 5 mg/day) for ≥ 1 year

3. Flare off Pred but on SSA….

• Prednisone reinstituted at lowest dose to

reestablish control

– The dose selected on severity of clinical

findings

– May be ≤ 1 mg/kg (? 0.5 mg/kg) if flare

detected early

– Usual minimum -- 20 mg/day

Flare off Pred but on SSA

• SSA changed from MTX to AZT or vice

versa

• If treated previously with both MTX and

AZT, flare regarded as a manifestation of

resistance

4. Flare Off All Immunosuppressives

• Prednisone should be reinstituted

– Dose varying with the severity of the relapse

• The minimum starting dose is 20 mg/day

• A SSA should be resumed

Definition

• No (or minimal) response after 6

(?4) weeks

Apparent Failure

• Misdiagnoses: IBM, dystrophies, metabolic

• GC myopathy: lower pred dose

• Associated malignancy

Options for Resistant Disease• Rituximab

• IVIG

• MTX higher (>25 mg) doses and parenteral

• Combination of AZT & MTX

• Calcineurin inhibitors: cyclosporine, tacrolimus

• MMF

• Cyclophosphamide

• TNF inhibitors

General Measures

Education

Exercises

Prophylaxis against infections

Prevention of GIOP

Prevention of aspiration

Avoidance of UV light

Physical Therapy and Rehabilitation…

• Should begin early in course of treatment:

– regimens tailored to the severity of weakness

• Even during active disease, appropriate

exercise programs do not

– increase serum CK levels

– delay recovery of muscle strength

Physical Therapy and Rehabilitation…

• Bed or chair-bound patients: passive range of

motion exercises to prevent joint contractures

– Careful attention to positioning reduces the

risk of pressure sores

• Isometric and resistive exercises: as soon as the

patient has recovered strength to be able to

participate

Physical Therapy and Rehabilitation

• Patients with less severe weakness: participate

in an active exercise program

– progressing as tolerated from lower level

isometric exercises to more vigorous isotonic

exercises

• Patients with mild weakness: continue

reasonable levels of activity as tolerated

Prevention of Infections• Vaccinations:

– Pneumococcus– Influenza virus– Hepatitis B– ? Hemophilus influenzae B

• Pneumocystis jirovecii prophylaxis– Cotrimoxazole double strength once daily– If MTX being used, single strength

Skin Care• Sun protection

– Sunscreens

– Sun protective clothing

– Minimizing sun exposure

• Anti-malarials

• Prevention of sores

• Keeping skin dry and clean

• Pruritus: hydroxyzine, topical menthol, camphor etc.

Prevention of Osteoporosis…

• Exercises as permitted

• Calcium and vitamin D: for patients

receiving pred ≥5 mg daily for ≥3 months

– 1200 mg of elemental calcium total diet plus

supplement

– 800 IU of vitamin D daily

Prevention of Osteoporosis

• Postmenopausal women & men at high

risk for fracture (elderly, prior fragility

fracture): oral bisphosphonate

– alendronate 35 mg/week for prevention, 70

mg/week for treatment

– risedronate 35 mg/week

Final Weaning….

• Pred 5 mg/d continued for 1 to 3 mo

– 12 mo in resistant disease or HO flare

• Tapered by 1mg at 2 to 4 wk intervals to

complete withdrawal at 2 to 4 mo

Final Weaning

• Taper of MTX/AZT started if remission maintained for 3 to 12 (for resistant & flared) mo off steroid

– Tapered at monthly intervals to complete withdrawal after six months if no relapse

• unsuccessful in majority

– Careful assessment for signs of relapse

Duration of Treatment

• Minimum duration:

– Pred 9 mo.

– MTX/AZT 18 mo

– Successful in 20%

• Maximum duration: indefinite

– 41% were using >10 mg pred or other immunosuppressive after 5 years

Bronner IM et al. Ann Rheum Dis. 2006 Nov;65(11):1456-61.