Epitope-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.

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 alpha 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.

Multiple joint effusions associated with high-dose imatinib therapy in a patient with chronic myelogenous leukaemia.

Imatinib mesylate is a small molecule tyrosine kinase inhibitor that has significant efficacy in the treatment of chronic myelogenous leukaemia (CML). However, it is likely that patients with CML will require prolonged and perhaps life-long therapy. In general, the side-effects of imatinib therapy have been mild to moderate, with the large majority of patients tolerating prolonged periods of therapy. However, a minority of patients are completely intolerant of therapy, while others are able to remain on therapy despite significant side-effects. Here, we describe a novel form of fluid retention presenting as multiple joint effusions in a patient with advanced phase CML on high-dose imatinib, as well as successful measures that were undertaken to control this adverse event. Although fluid retention, including periorbital oedema, pleural and pericardial effusions, as well as life-threatening cerebral oedema have been previously described and attributed to imatinib, this is the first case of imatinib-associated polyarticular effusions that we are aware of. Further work will be required to confirm a casual relationship between imatinib therapy and this novel side-effect, as well as to determine the underlying pathophysiologic mechanisms.

MRI of large intraosseous lesions in patients with inflammatory arthritis.

OBJECTIVE: The purpose of our study was to evaluate on MRI the occurrence of large cystlike intraosseous lesions in patients with inflammatory arthritis. SUBJECTS AND METHODS: We prospectively reviewed contrast-enhanced MR images of 128 hands and wrists in 44 patients with clinical presentation of inflammatory arthritis. Large lesions (> or = 1 cm) found on MR images were further evaluated for the presence of a cortical break and intraarticular extension. These data were correlated with clinical and laboratory findings and the duration of arthritis. RESULTS: We found 26 patients with rheumatoid arthritis, seven with psoriatic arthritis, two with systemic lupus erythematosus, one with HIV-associated arthritis, one with mixed connective tissue disorder, one with paraneoplastic-associated arthritis, one with inflammatory bowel disease arthritis, and five patients with early unclassified inflammatory arthritis. Twelve patients had 16 large intraosseous lesions, none of which were detected on available radiographs (availability of radiographs for large erosions was 75%). A cortical break with intraarticular extension of the large lesions was seen in 12 cases. Four lesions were not intraarticular. CONCLUSION: Even large intraosseous lesions may be occult on radiography. MRI is a superior technique for detecting these lesions in the small joints of the hand and wrist in inflammatory arthritis. Although large intraosseous erosions often communicate with joints, we observed four large purely intraosseous enhancing lesions without intraarticular connection. Patients with large erosions have a longer duration of inflammatory arthritis.