SAN ANTONIO, Texas – Several significant published studies have furthered the field of rheumatology since last year's annual meeting of the American College of Rheumatology (ACR), according to John J. Cush, MD, Chief of Rheumatology and Immunology at Presbyterian Hospital in Dallas, Texas. Dr. Cush moderated a state-of-the-art lecture session October 20 at the 2004 ACR meeting in San Antonio, Texas.

The session highlighted basic scientific research that elucidates the complexity of some autoimmune conditions. Also highlighted were clinical studies that explore new biologic treatments and more effective ways to use the biologics that are currently available.

Michael E. Weinblatt, MD, Professor of Medicine and Attending Rheumatologist at Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts,

discussed the clinical trials publications. Gary Firestein, MD, Chief of Rheumatology, Allergy, and Immunology at the University of California-San Diego School of Medicine, discussed the basic research publications.

The outstanding publications in clinical research focused on investigative treatments for RA and on demonstrations of the efficacy of treatment strategies with approved tumor-necrosis factor inhibitors. Noting the role of costimulatory modulators that are required for T-cell activation in RA, Dr. Weinblatt pointed out a randomized controlled trial of CTLA4-Ig, or abatacept.1 Abatacept blocks CD28 on T cells, which is necessary for costimulation to be activated, and patients treated with this therapy showed a marked improvement in symptoms. Subsequently, the investigators conducted a Phase III study, the results of which were reported in a late-breaking presentation at the ACR meeting.

A randomized controlled trial of rituximab (Rituxan®) in RA showed that B-cell depletion is a feasible target in RA therapy and that, in contrast to cancer treatment, rituximab does not have to be combined with cyclosporine in order to be effective.2 "This is the first major randomized controlled trial of rituximab in RA," Dr. Weinblatt said. "The investigators showed that there was no difference in outcome in patients treated with rituximab and methotrexate compared to those treated with rituximab and cyclosporine."

Other investigators conducted a clinical trial of etanercept (Enbrel®) and anakinra (Kineret®) combination therapy in RA.3 While this trial found no difference in efficacy between the etanercept monotherapy and the combination therapy groups, a significant increase in serious infections was found in the combination therapy group.

The results of the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) tested the efficacy of etanercept combined with methotrexate.4 "The study showed that the combination was superior to either drug as monotherapy in all standard parameters," Dr. Weinblatt said. He added that the 2-year follow-up data for TEMPO were to be reported during a separate session at the current ACR meeting.

One genetic study showed that a genetic mutation associated with rheumatoid arthritis (RA) in a Japanese population does not have the same association in a United Kingdom population.5 "These findings suggest that different genetic mechanisms may be at work in RA and that more studies in other populations would help put the findings in perspective," Dr. Firestein said. He added that "another study indicates that a mutant mouse with an abnormal ZAP70 gene may help further the understanding of RA's pathogenesis." 6

Of particular interest was a study showing the mechanism by which antiphospholipid syndrome increases the risk of pregnancy loss in mouse models with antiphospholipid antibodies; the study also explored potential protective measures.7 Dr. Firestein noted that complement factors 4 and 5 (C4 and C5) are needed for the antiphospholipid antibodies to generate pregnancy loss. Certain treatments, including a C5-1 antagonist, a C5a receptor blocker, and antineutrophil antibodies, were associated with eliminating the risk for pregnancy loss in the mice. "It is clear that these antibodies are implicated in the whole cascade, and that they can be down-regulated with anticoagulants," Dr. Firestein said.

References:

  1. Kremer JM, Westhovens R, Leon M, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med. 2003;349:1907-1915.
  2. Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004;350:2572-2581.
  3. Genovese MC, Cohen S, Moreland L, et al, for the 20000223 Study Group. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum. 2004;50:1412-1419.
  4. Klareskog L, van der Heijde D, de Jager JP, et al, for the TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) study investigators. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet. 2004;363:675-681.
  5. Barton A, Bowes J, Eyre S, et al. A functional haplotype of the PADI4 gene associated with rheumatoid arthritis in a Japanese population is not associated in a United Kingdom population. Arthritis Rheum. 2004;50:1117-1121.
  6. S akaguchi N, Takahashi T, Hata H, et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature. 2003;426:454-460.
  7. Girardi G, Berman J, Redecha P, et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest. 2003;112:1644- 1654.