Use of Infliximab for the Treatment of Pemphigus Vulgaris

PV involves blistering of the outer layer of skin and mucous membranes, causing a separation
of epidermal cells. The disease occurs when the immune system produces antibodies to specific
proteins in the skin and mucous membranes; the cause for production of these autoantibodies
is unknown. Infliximab is a genetically engineered monoclonal antibody directed against tumor
necrosis factor (TNF)-alpha, a chemical messenger that activates an immune response.
Infliximab has been used to treat other autoimmune disorders, including rheumatoid arthritis,
ankylosing spondylitis, and Crohn's disease. This study will evaluate the safety and efficacy
of infliximab given in combination with prednisone for the treatment of adults with PV.

This study will last 26 weeks. At study entry, all patients will be taking a stable dose of
prednisone (or an equivalent corticosteroid) of 20 to 120 mg/day for at least 2 weeks prior
to study entry. Patients will be randomly assigned to one of two arms: experimental or
placebo comparator. The experimental treatment arm will receive infusions of infliximab, and
the control arm will receive placebo. Infusions will be given at study entry and Weeks 2, 6,
and 14. Before the start of each infusion, a physical exam, vital signs measurement, medical
and medication history, review of a disease activity log, a skin evaluation, and blood
collection will occur. During each infusion and for 1 hour postinfusion, patients' vital
signs will be monitored for any adverse events. Patients will need a responsible adult to
take them home after they are discharged from the treatment facility; this person should
remain with the patient overnight in case any problems arise from the treatment. The patient
will be contacted by phone that night and the next morning after infusion and will be asked
about any adverse effects they may have experienced. Those patients that experience adverse
effects may be asked to return to the treatment facility for examination. Prednisone doses
may be tapered by 15 percent every 2 weeks during the study at the investigator's discretion.

There will be a total of 9 study visits until Week 26: screening, study entry, Week 2, and
every 4 weeks thereafter. Each study visit will include a physical exam, vital signs
measurement, medical and medication history, a review of the disease activity log and adverse
events experienced since the last visit, skin assessments, and blood collection; patients
will also be asked to complete a tuberculosis (TB) questionnaire. Patients will be asked to
complete quality of life questionnaires at study entry and Weeks 10, 18, and 26. Skin
biopsies of unaffected skin will be done at study entry and Weeks 10, 18, and 26; if patients
have PV-associated lesions, additional skin biopsies of affected skin will be done at study
entry and Week 18.

Inclusion Criteria:

- Positive direct immunofluorescence of patient's skin showing IgG or complement C3
protein on cell surface with histopathology of lesional skin biopsies consistent with
diagnosis of pemphigus vulgaris

- Failure to completely respond to standard steroid therapy (equivalent to prednisone 1
to 2 mg/kg/day followed by tapering)

- Systemic corticosteroid therapy of at least 20 mg prednisone daily and no more than
120 mg/day

- Inability to reduce systemic corticosteroid dosage below 20 mg/day for at least 8
weeks

- Stable dosage of prednisone for at least 2 weeks prior to study entry

- Oral/mucosal disease or skin disease. Detailed information about this criterion can be
found in the protocol

- Willing to comply with the study protocol

- Willing to use acceptable means of contraception for the duration of the study and for
6 months after the end of the study

Exclusion Criteria:

- Positive tuberculosis (TB) test within 1 month prior to first administration of study
drug

- History of latent or active TB prior to screening

- Signs or symptoms suggestive of TB disease by medical history or physical examination
within 3 months prior to first administration of study drug

- Posterior/anterior/lateral chest radiograph within 3 months prior to screening showing
evidence of cancer, infection, or abnormalities (apical scarring) suggestive of
previous TB

- Serious infection, hospitalization for an infection, or treatment with intravenous
(IV) antibiotics for an infection within 2 months prior to screening. Patients who
have had less serious infections are eligible for this study at the discretion of the
investigator.

- History or presence of opportunistic infections within 6 months prior to screening

- History of receiving human/murine recombinant products

- Known allergy to murine products or other chimeric proteins

- Human immunodeficiency virus (HIV) infected

- Chronic hepatitis B or hepatitis C virus infection

- History of hepatitis C virus infection

- Cancer within the 5 years prior to study entry. Patients with completely resected
non-melanoma skin cancers are not excluded.

- History or presence of congestive heart failure

- History or presence of seizure or demyelinating disorder

- History of latent or active granulomatous infection, including TB, histoplasmosis, or
coccidioidomycosis

- Received a Bacillus Calmette-Guerin (BCG) vaccine within 12 months of screening

- History of lymphoproliferative disease, including lymphoma or signs and symptoms of
possible lymphoproliferative disease, such as lymphadenopathy of unusual size or
location or enlarged spleen

- Current signs or symptoms of severe progressive or uncontrolled kidney, liver, blood,
gastrointestinal, endocrine, lung, heart, neurologic, or cerebral disease

- Have had chronic or recurrent infectious disease including, but not limited to,
chronic kidney infection, chronic chest infection, sinusitis, recurrent urinary tract
infection, infected skin wound, or ulcer

- Previous treatment with infliximab, other monoclonal antibodies, or antibody fragments

- Previous treatment with etanercept or other anti-tumor necrosis factor (TNF) agents in
the 3 months prior to screening

- Treatment with methotrexate, azathioprine, mycophenolate mofetil, plasmapheresis, IV
immunoglobulin, pulse systemic corticosteroids, or other systemic immunosuppressive
agents within the 4 weeks prior to study entry

- History of alcohol or drug abuse within the 3 years prior to study entry

- History of noncompliance to medical regimens

- History of a systemic inflammatory disease other than pemphigus vulgaris

- History of a medical condition that would interfere with participation or increase the
risk to the participant

- Unable or unwilling to undergo blood draws because of poor tolerability or lack of
easy access

- Use of any investigational drug within 30 days prior to screening OR within 5
half-lives of the investigational agent, whichever is longer

- Participation in another investigative clinical trial

- Presence of transplanted solid organ. Participants who have received a corneal
transplant more than 3 months prior to screening are not excluded.

- Require certain medications

- Other conditions or circumstances that could interfere with participant's adherence to
the study requirements

- Pregnancy, breastfeeding, or plans to become pregnant