William J. Koopman

T cell receptor peptide vaccination in rheumatoid arthritis : A placebo-controlled trial using a combination of Vβ3, Vβ14, and Vβ17 peptides

OBJECTIVE Restricted T cell receptor (TCR) gene usage has been demonstrated in animal models of autoimmune disease and has resulted in the successful use of TCR peptide therapy in animal studies. This clinical trial was undertaken to determine the safety and efficacy of a combination of Vbeta3, Vbeta14, and Vbeta17 TCR peptides in Freunds incomplete adjuvant (IFA) in patients with rheumatoid arthritis (RA). METHODS A double-blind, placebo-controlled, multicenter, phase II clinical trial was undertaken using IR501 therapeutic vaccine, which consists of a combination of 3 peptides derived from TCRs (Vbeta3, Vbeta14, and Vbeta17) in IFA. A total of 99 patients with active RA received either 90 microg (n = 31) or 300 microg (n = 35) of IR501 or IFA alone (n = 33) as a control. The study medication and placebo were administered as a single intramuscular injection (1 ml) at weeks 0, 4, 8, and 20. RESULTS Treatment with IR501 was safe and well tolerated. None of the patients discontinued the trial because of treatment-related adverse events. Efficacy was measured according to the American College of Rheumatology 20% improvement criteria. Using these criteria, patients in both IR501 dosage groups showed improvement in disease activity. In the most conservative analysis used to evaluate efficacy, an intent-to-treat analysis including all patients who enrolled, the 90-microg dosage group showed a statistically significant improvement compared with control patients at the 20-week time point after the third injection. Trends toward improvement were shown in both the 90-microg and the 300-microg dosage groups at week 24 after the fourth injection. CONCLUSION IR501 therapeutic vaccine therapy was safe and well tolerated, immunogenic, and demonstrated clinical improvement in RA patients. Additional clinical trials are planned to confirm and extend these observations.

A quantitative assay for IgA rheumatoid factor

We developed a solid-phase radioimmunoassay capable of detecting nanogram quantities of human IgA rheumatoid factor (RF) in biological fluids. Human IgM RF, IgG RF, IgG, IgA, IgM and whole serum did not significantly interfere with the IgA RF assay. Patients with sero-positive rheumatoid arthritis (RA) had significantly higher concentrations of IgA RF than sero-negative RA patients or healthy adult controls. Concentrations of IgA RF in paired sera and synovial fluids from sero-positive RA patients were comparable. Levels of IgA RF demonstrated a moderately good correlation with levels of IgM RF in sero-positive RA sera (r = 0.673). However, the ratio of IgA RF concentration to IgM RF concentration in sero-positive RA sera varied widely.

Effects of nonsteroidal antiinflammatory drugs on bone loss in chronic inflammatory disease.

Several controlled clinical trials have indicated that nonsteroidal antiinflammatory drugs may slow alveolar bone loss in periodontitis. Demonstration of this efficacy is dependent on the development of accurate, sensitive, and specific quantitative methods for the assessment of bony change, such as digital subtraction radiography. Further studies of such methodologies are required to more fully investigate the effect of nonsteroidal antiinflammatory drugs in rheumatoid arthritis.

Results of a Phase II Rheumatoid Arthritis Clinical Trial Using T-Cell Receptor Peptides

Restricted T-cell receptor gene use has been found in animal models of autoimmune disease. This observation has resulted in the successful use of T-cell receptor peptide therapy in animal studies. Initial phase I studies in patients with rheumatoid arthritis (RA) indicated that this therapy was safe and well tolerated. A double-blind, placebo-controlled, multicenter phase II rheumatoid arthritis clinical trial was undertaken using IR501 therapeutic vaccine, which consists of a combination of three peptides derived from T-cell receptors (Vβ3, Vβ14, Vβ17) in incomplete Freund’s adjuvant (IFA). These T-cell receptors were previously reported to be restricted in RA patients. A total of 99 patients received either 90μg (31 patients) or 300μg (35 patients) of IR501 therapeutic vaccine or IFA alone (33 patients) as a control. IR501 therapeutic vaccine was administered as a 1.0-ml intramuscular injection at weeks 0, 4, 8, and 20. Patients were followed for 32 weeks. The results of the trial indicated that the treatment was safe, with none of the patients discontinuing the trial because of treatment-related adverse events. No significant adverse events attributable to the study drug were observed. Patients in both dose groups treated with IR501 therapeutic vaccine showed improvement in disease condition. Most importantly, the 90-μg dose group showed a statistically significant improvement when compared to control patients after the third and fourth injections. More than 50% of the treated patients showed improvement compared to 19% of controls, as measured in accordance with the American College of Rheumatology definition for clinical response (ACR 20 criteria).

Molecular genetic studies of rheumatoid arthritis

Bam HI DR-beta and DQ-beta restriction fragment length polymorphisms (RFLPs) were found with increased frequency in white persons with seropositive rheumatoid arthritis as compared with control subjects. DR-beta 4.8-, 5.2-, and 7.0-kilobase (kb) RFLPs were observed in 86.5 percent of rheumatoid arthritis patients and in 56 percent of control subjects (p = 0.001, relative risk [RR] = 5.0). The 6.0-kb RFLP was present in 79 percent of rheumatoid arthritis patients and 32 percent of control subjects (p = 0.0002, RR = 8.0). The 4.8-, 5.2-, and 7.0-kb RFLPs correlated with DR4, -7, -9, and -w53 phenotypes and the 6.0-kb RFLP correlated only with DR4. Thus, these RFLPs do not appear to be disease-specific. A DQ-beta 3.2-kb RFLP was found in 63.5 percent of rheumatoid arthritis patients and in 38.0 percent of control subjects (p = 0.01, RR = 2.8). This fragment was frequently found in persons expressing DR1 and DQw1 phenotypes. Probes consisting of the first exon of the DR-beta-I and DR-beta-IV genes, respectively, only hybridized with the 5.2- and 6.0-kb RFLPs. These data suggest that more than one gene within the major histocompatibility complex contributes to susceptibility to seropositive rheumatoid arthritis in white persons.