Infliximab (Remicade ) to Treat Dermatomyositis and Polymyositis

Tumor necrosis factor (TNF), a cytokine that has been implicated in the pathogenesis of many
diseases including inflammatory disorders, has been found to be elevated in the muscles of
patients with dermatomyositis (DM) and polymyositis (PM). A subset of patients with DM and PM
do not respond readily to conventional therapy. Therefore, a controlled trial using
infliximab, a chimeric IgG(1) kappa monoclonal antibody against TNF, may provide a
therapeutic option and advance understanding in the pathogenesis of these diseases. This
study is designed to determine the safety and efficacy of infliximab in patients with DM and
PM. We plan to enroll a maximum of 28 patients randomized at 1:1 ratio into 2 groups, placebo
vs. infliximab at 5 mg/kg body weight. In the first phase of the study the placebo and
infliximab infusions will be given at week 0, 2, 6 and 14. Primary outcome assessment will be
done at week 16. Those who respond according to the criteria set for improvement in MMT will
be given the option to remain on the same infusion (i.e. placebo or infliximab at 5 mg/kg
body weight) at weeks 22, 30 and 38. Placebo non-responders will be given infliximab at 5
mg/kg body weight in an open label fashion at weeks 16, 18, 22, 30 and 38. Patients who were
initially on 5 mg/kg body weight of infliximab who failed to respond based on the criteria
set will be placed on infliximab at 7.5 mg/kg body weight in an open label fashion on weeks
22, 30 and 38. Pharmacokinetic modeling will be done in both phases of the study. A muscle
biopsy will be done before treatment and again at 16 weeks of treatment. Microarray gene
expression profiling of the muscle biopsy specimens will be done before treatment and again
at 16 weeks. Clinical, functional and serological evaluations will be performed in every
visit to assess other responses to treatment. Patients will be followed for 30 weeks after
study termination to evaluate the long-term effects of the drug.

- INCLUSION CRITERIA:

Must be at least 18 years of age.

Diagnosis of probable or definite polymyositis or dermatomyositis as defined by Bohan and
Peter:

i. Symmetrical proximal muscle weakness;

ii. Muscle biopsy abnormalities at some time during their disease:

1. Muscle fiber destruction;

2. Muscle fiber regeneration;

3. Perivascular and interstitial inflammatory infiltrates with muscle fiber destruction.

iii. Elevation of serum creatine phosphokinase (CPK), Transaminases, lactic dehydrogenase
(LDH) or aldolase activity;

iv. Electromyography changes:

1. Fibrillation potentials (on needle insertion at rest);

2. Complex repetitive discharges (on needle insertion at rest);

3. Positive sharp waves (on needle insertion at rest);

4. Short duration, low amplitude complex (polyphasic) potentials on contraction.

v. Typical skin rash. The classic skin manifestations include a purplish discoloration of
the eyelids (heliotrope rash) or papular, erythematous, scaly lesions over the knuckles
(Gottron s papules);

DEFINITE: any 4 of the criteria

PROBABLE: any 3 of the criteria

- Patients must have a baseline total muscle strength score of less than or equal to 120
but not less than 80 on manual muscle testing (MMT) or at least 25% decrease in manual
muscle strength.

- Ability to provide informed consent to all aspects of the study after full information
is provided.

- Evidence of active disease as measured by weakness, and an elevated CK, aldolase,
SGOT, SGPT, LDH or an active MRI. MR imaging may demonstrate signal abnormalities in
affected muscles secondary to inflammation and edema on STIR images.

- Patients must be on a stable dose of prednisone equal to or less than 0.5 mg/kg/day
for 1 month prior to the study.

- Patients must be on at least 7.5 mg of methotrexate weekly or at least 75 mg of
azathioprine daily for at least 4 weeks prior to the study.

- Patients must not be on any other cytotoxic agents for at least 1 month prior to the
study.

- Women of childbearing potential and men whose partners are of childbearing potential
must practice an acceptable form of contraception.

- No prior history of treatment with monoclonal antibodies, i.e. no prior history of
infliximab therapy.

- Patients with active disease despite previous treatment with at least one other
immunosuppressive agent and/or intolerable side effects: e.g. high-dose prednisone (1
mg/kg/day), methotrexate 12.5 to 20 mg/wk, azathioprine 100-150 mg/day, cyclosporineA
2-2.5 mg/kg/day and cyclophosphamide 1-2 mg/kg/day.

EXCLUSION CRITERIA:

Patients with inclusion body myositis or cancer-related or drug-induced myopathy.

History of hepatitis or abnormal liver function tests which do not reflect muscle disease.

History of recurrent infections, any active acute or chronic infections requiring
antimicrobial therapy, or serious viral (e.g. Hepatitis B positivity, herpes zoster, herpes
simplex, HIV positivity, hepatitis C or A, CMV) or fungal infections such as
histoplasmosis, aspergillosis, coccidiodomycosis. Patients with positive PPD who have
cavitary lesions suspicious for active tuberculosis will be excluded. In addition, patients
with a positive PPD who decline INH prophylaxis will be excluded. Any patients with
suspected pneumonia, cellulitis, pneumocystis carini, and infection at central venous
catheter site will also be excluded.

Patients with suspicious lesions on chest radiography suggestive of an infectious or
neoplastic condition will be excluded.

Pregnant females, nursing mothers, or patients of childbearing age not practicing birth
control.

Preexisting or coexisting malignancy other than basal cell carcinoma and localized squamous
cell carcinoma of the skin.

Patients who have not had any recent age-appropriate malignancy screen within the past 3
months who refuse to have said age-appropriate malignancy screening procedures prior to the
start of the study.

History of cerebrovascular accidents, seizure disorder, aseptic meningitis, transverse
myelitis, central nervous system demyelinating disease such as multiple sclerosis.

Confounding medical illness that in the judgment of the investigators pose added risk for
study participants (e.g. chronic lung or hematological disease).

Anemia requiring maintenance blood transfusions; leukopenia with WBC less than 3,000/ul or
absolute neutrophil count less than 2,000/ul; platelet count less than 100,000/ul on at
least two different occasions.

History of (or current) autoimmune hemolytic anemia.

Current anticoagulant therapy.

History of lupus erythematosus (+)ANA: dsDNA, anti-Smith, anti-Ro/La and clinical
presentation consistent with lupus erythematosus.

Clotting/bleeding disorders history of arterial or venous thrombosis, stroke, miscarriages
and presence of antiphospholipid antibodies, protein C or protein S deficiency along with a
compatible history of a thrombotic event.

History of psychiatric illness that in the opinion of psychiatric consultants would pose an
added risk for study participants.

History of uncontrolled diabetes mellitus.

Prior use of infliximab.

Current use of a TNF-blocking agent (patient has to be off for 4 weeks). Prior use of
etanercept is accepted so long as patient has been off of it for 4 weeks.

Allergy to murine-derived products.

Poor venous access.

History of live vaccinations within the past 3 months.

History of drug abuse within the past 5 years.

History of congestive heart failure.

Echocardiographic evidence of dilated or hypertrophic cardiomyopathy.

Echocardiographic evidence of valvular stenosis or regurgitation that in the judgment of
the physician poses a risk for congestive heart failure.

History of significant arrhythmia requiring pacing or cardioversion.

EKG or echocardiographic evidence of ventricular hypertrophy and clinical signs of
congestive heart failure.