Treatment of Psoriatic Arthritis with hOKT3γ(Ala-Ala): Psoriatic Arthritis Research Trial (PART)

Psoriatic Arthritis (PsA) is a chronic inflammatory seronegative arthritis which occurs in approximately 6-7% of individuals with psoriasis. Up to 57% of PsA patients develop erosive disease after eight-year follow-up, and 19% have moderate to severe functional impairment. While methotrexate is the gold-standard treatment for PsA, many individuals ultimately fail methotrexate or are unable to tolerate its' long-term use.

Both psoriasis and PsA are associated with specific MHC Class I alleles. Analysis of synovial fluid from PsA patients reveals an increase in CD8+ T lymphocytes and cytokine expression in the synovium is consistent with a Th1-type response. Furthermore, autologous reconstitution of SCID mice transplanted with uninvolved skin from psoriasis patients with lymphocyte subsets indicates that both peripheral CD4+ and intradermal CD8+ cells are required to induce psoriasis. These observations indicate that therapeutic stategies which target Th1 cells may be efficacious in the treatment of psoriasis and the associated arthritis. Non-FcR binding anti-CD3 antibodies have been shown to preferentially anergize Th1 and stimulate Th2 lymphocytes. To repolarize peripheral T cells, repeated rounds of stimulations are usually required.

In a phase I/II trial, hOKT3γ(Ala-Ala) was given to eight patients with PsA who had failed at least one remittive agent. The monoclonal antibody was given as a daily infusion for up to 14 days with a variable escalation of dose to a maximum of 4 mg. Of the seven patients who completed the trial, six had dramatic improvement in their tender and swollen joint counts. Indeed, 5 of 6 had no swollen joints at 30 days. Symptoms from hOKT3γ(Ala-Ala) were mild when given as an escalating dose. Emesis and fevers occured in one patient receiving an initial maximum dose.

We now propose a phase II/III blinded placebo controlled trial to demonstrate the safety and efficacy of hOKT3γ(Ala-Ala) in the treatment of PsA. Based on previous mechanistic studies and clinical experience, we postulate that hOKT3γ(Ala-Ala) will induce remission in patients by selectively anergizing Th1 populations. We will recruit 112 patients failing Methotrexate at seven academic centers and administer either antibody with a rapid dose escalation or placebo daily for 5 days once every 4 weeks for 4 cycles total. Patients will be followed for one year.

Mechanistic Studies: To complement the clinical trial, we propose an extensive array of mechanistic studies to address several questions including:

1. Does hOKT3γ(Ala-Ala) selectively induce the anergy of pathogenic Th1 cells in vivo?
2. Are other changes in T cell populations induced by hOKT3γ(Ala-Ala)?
3. Can specific gene products be identified which are either required for or predict angery?

The completion of the proposed investigations will determine the efficacy and in vivo immunomodulatory effects of a non-mitogenic anti-CD3 antibody in the treatment of a chronic T cell-mediated autoimmune disease. Preliminary evidence indicates that such treatment will preferentially induce anergy in Th1 populations leading to drug free remission in some patients.