Open AccessEpitope‐specific immunotherapy of rheumatoid arthritis: Clinical responsiveness occurs with immune deviation and relies on the expression of a cluster of molecules associated with T cell tolerance in a double‐blind, placebo‐controlled, pilot phase II trial
Author(s) -
Koffeman Eva C.,
Genovese Mark,
Amox Diane,
Keogh Elissa,
Santana Ernesto,
Matteson Eric L.,
Kavanaugh Arthur,
Molitor Jerry A.,
Schiff Michael H.,
Posever James O.,
Bathon Joan M.,
Kivitz Alan J.,
Samodal Rodrigo,
Belardi Francis,
Dennehey Carolyn,
van den Broek Theo,
van Wijk Femke,
Zhang Xiao,
Zieseniss Peter,
Le Tho,
Prakken Berent A.,
Cutter Gary C.,
Albani Salvatore
Publication year - 2009
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.24916
Subject(s) - medicine , rheumatoid arthritis , immunology , immune system , arthritis , placebo , epitope , immunotherapy , rheumatology , proinflammatory cytokine , immune tolerance , clinical trial , tumor necrosis factor alpha , inflammation , antigen , oncology , pathology , alternative medicine
Objective Induction of immune tolerance to maintain clinical control with a minimal drug regimen is a current research focus in rheumatoid arthritis (RA). Accordingly, we are developing a tolerization approach to dnaJP1, a peptide part of a pathogenic mechanism that contributes to autoimmune inflammation in RA. We undertook this study to test 2 hypotheses: 1) that mucosal induction of immune tolerance to dnaJP1 would lead to a qualitative change from a proinflammatory phenotype to a more tolerogenic functional phenotype, and 2) that immune deviation of responses to an inflammatory epitope might translate into clinical improvement. Methods One hundred sixty patients with active RA and with immunologic reactivity to dnaJP1 were enrolled in a pilot phase II trial. They received oral doses of 25 mg of dnaJP1 or placebo daily for 6 months. Results The dnaJP1 peptide was safe and well‐tolerated. In response to treatment with dnaJP1, there was a significant reduction in the percentage of T cells producing tumor necrosis factor α and a corresponding trend toward an increased percentage of T cells producing interleukin‐10. Coexpression of a cluster of molecules (programmed death 1 and its ligands) associated with T cell regulation was also found to be a prerequisite for successful tolerization in clinical responders. Analysis of the primary efficacy end point (meeting the American College of Rheumatology 20% improvement criteria at least once on day 112, 140, or 168) showed a difference between treatment groups that became significant in post hoc analysis using generalized estimating equations. Differences in clinical responses were also found between treatment groups on day 140 and at followup. Post hoc analysis showed that the combination of dnaJP1 and hydroxychloroquine (HCQ) was superior to the combination of HCQ and placebo. Conclusion Tolerization to dnaJP1 leads to immune deviation and a trend toward clinical efficacy. Susceptibility to treatment relies on the coexpression of molecules that can down‐regulate adaptive immunity.