Dr. Arthur Kavanaugh discussed safety and efficacy evidence of the class of drugs known as TNF-alpha inhibitors, focusing specifically on infliximab and etanercept. He explained that the agents are comparable in safety and clinical efficacy. "These may be regarded as class effects, as they depend on the target, not on the individual agent," he said.

Slide 1. Clinical Efficacy of Infliximab at 30 Weeks in Refractory RA: Active Despite MTX Evidence comes from studies of the same disease with the same starting population, such as ATTRACT (Anti-TNF Treatment in RA with Concomitant Therapy). Participants in this study had highly refractory RA and active disease despite treatment with MTX. Tremendous improvement was seen when infliximab was added (Figure 1). A similar population was studied in another trial where patients were given etanercept plus MTX. Clinical efficacy was comparable.

Despite their success in RA, both agents have proven ineffective in treating sepsis and congestive heart failure. They are probably equivalent, but data are being gathered on their effectiveness in juvenile RA/adult-onset Still's disease, early RA, psoriatic arthritis, and spondyloarthropathy. "Both agents appear to be effective and their efficacy appears to be equivalent in treating rheumatic diseases," said Dr. Kavanaugh.

Some increase in mild infectious episodes, such as upper respiratory tract infections, has been seen in all studies of TNF-alpha inhibitors. No increase in serious infectious episodes has been seen.

Dr. Kavanaugh addressed the issue of tuberculosis (TB) in patients on TNF inhibitors by explaining that in animal models, TNF has a central role in protecting against microbacterial infections, thereby preventing reactivation of latent TB. Interestingly, the cases of TB and infliximab have mostly been reactivations of latent TB.

"About 75% of the cases of TB in patients taking infliximab have occurred outside the United States, although 80% of the drug is administered in the United States. Most cases occurred in areas where TB is very prevalent. Also, there is far greater use of infliximab in countries where TB is a greater concern," he explained. He recommended using American Thoracic Society Consensus Committee guidelines, which call for focused PBD testing and treatment options.
"In summary, the clinical efficacy and the safety of TNF inhibitors are the same," he stated.

Inhibiting Structural Damage in Rheumatoid Arthritis With Anti-TNF-Alpha Therapy

Differentiation of the TNF-Alpha Class Effect Dr. James Morgan took the opposite stance, declaring that a clear difference between the anti-TNF-alpha agents exists. "The difference is especially evident in studies of inflammatory bowel disease (IBD), where etanercept had no effect on IBD, but a single dose of infliximab put patients into remission," he stated.

Disparity among anti-TNF-alpha agents is also evident when treating psoriasis and psoriatic arthritis, with infliximab producing a far more significant response than etanercept. While efficacy of both drugs was similar in the ATTRACT trial, infliximab showed significant ability to stop joint erosions, while etanercept had no effect on joint space narrowing.

"The effect might be due to the fact that infliximab does not release TNF-alpha after it is bound, while etanercept does release TNF-alpha, which is physiologically active and stimulates endothelial cells to produce adhesion molecules," he explained.

"We don't have to think about these drugs as being better or worse than each other, but as simply different. In some circumstances, such as Crohn's disease and psoriasis, this may cause differences in efficacy," he concluded.

Concluding Words

Dr. David Yocum concluded by summarizing that MTX offers a prolonged duration of benefit compared with other DMARDs and slows the progression of RA. In the last several years, however, TNF inhibitors have been shown to relieve pain and suffering in a majority of patients, and significantly inhibit progressive structural damage in patients with established disease. Furthermore, these new agents demonstrate activity in patients with early disease as well.

Nonetheless, the early RA trial demonstrated that the use of MTX in early onset RA was as effective as etanercept during the first year of treatment and only slightly less effective during the second year. "Therefore, per the rationale presented by Dr. Wolfe, all patients with persistent synovitis should receive MTX early in the disease course. Those in whom MTX fails or produces an inadequate response should receive additional agents in combination with MTX. However, the most appropriate and effective agent to combine with MTX remains to be determined," Dr. Yocum explained.

Previous studies have demonstrated that cyclosporine, leflunomide, interleukin-1 receptor antagonist (IL-1ra), etanercept, and infliximab have combined clinical efficacy when added to MTX. Some studies have suggested that sulfasalazine may have added benefit, but others do not. Nonetheless, only infliximab in combination with MTX has demonstrated benefit on inhibiting radiographic progression. "In fact, patients with the most aggressive disease, as demonstrated by radiographic scoring, often achieve the maximal benefit on this combination," he said.

The efficacy of TNF antagonists is being examined in a variety of inflammatory diseases. While only etanercept is presently approved for juvenile RA, infliximab also appears effective. Data have shown the efficacy of infliximab in AS, Crohn's disease, and fistulizing disease. Early data from psoriatic arthritis, psoriasis, Wegener granulomatosis, graft-versus-host disease, and ulcerative colitis are exciting. Case reports in Behcet syndrome and scleroderma suggest these areas may be worth pursuing.

"Our patients deserve the best outcome possible. Anti-TNF-alpha therapies are assisting rheumatologists in accomplishing this goal," he concluded