TNFa

 

Rheumatoid Arthritis: Increasing Treatment Aggressiveness

 

Arthur Kavanaugh, MD

Clinicians attending this year's American College of Rheumatology Annual Scientific Meeting heard a number of presentations relevant to the treatment of rheumatoid arthritis (RA). Several posters focused on patient characteristics that may ultimately optimize the use of novel agents. Other posters provided key information on clinical efficacy and potential mechanisms of action. There was continued interest in developments in biologic agents, particularly inhibitors of tumor necrosis factor-alpha (TNF-alpha).

The Genetics of Rheumatoid Arthritis

Inhibitors of inflammatory cytokines such as TNF-alpha have been proven to have substantial efficacy as treatments for RA, both in therapeutic trials and in the clinic. Accompanying the progress in the use of inhibitors of these biologic agents has been the anticipation that progress in our understanding of the etiopathogenesis of RA might might allow refinement in the use of these interventions. For example, while a number of patients have a marked clinical response or even disease remission after treatment with TNF inhibitors, a small number of patients have no response to treatment.[1,2] Rheumatologists would certainly like to know whether there could be any way to identify patients who would have particular responses. In recent years, a number of genetic polymorphisms have been described that may have some relevance to RA.

T. Hohler, MD, and colleagues[3] from Mainz, Germany, presented a paper on genetic variation in the genes for TNF. They determined genetic polymorphisms in TNF-alpha microsatellites a, c, and d, and correlated these with the ability of cells from patients with these genetic differences to produce TNF. The authors found that genetic differences in TNF microsatellites correlated with the ability to make low, intermediate, or high levels of TNF in culture.

A. Gibson, MD, and colleagues[4] from Leiden in the Netherlands, and from Birmingham, Alabama, in the United States, described new genetic polymorphisms in the promoter for the cytokine interleukin 10 (IL-10). IL-10 is a cytokine that generally functions as an inhibitor of the proinflammatory cytokine cascade. Using subjects that had been identified on the basis of having cells that secreted high or low concentrations of IL-10, the authors identified a number of polymorphisms in the promoter region of the IL-10 gene.

These studies provide information that may ultimately help to define the subsets of patients who could be optimal candidates for certain tyes of biologic therapy, such as TNF inhibitors. By further identifying such persons, the benefits of these and other novel therapies might be increased while the risk of adverse effects might be diminished.

Increasing Aggressiveness of RA Treatment

In an update of work he had presented at an earlier ACR meeting, James O'Dell, MD, and Ted Mikuls, MD,[5] of the University of Nebraska presented data on the common prescribing habits of rheumatologists concerning disease-modifying antirheumatic drugs (DMARDs). Dr. O'Dell surveyed rheumatologists nationwide, focusing on the question of how commonly they used combinations of DMARDs in RA patients. He noted that the percentage of rheumatologists prescribing combinations of DMARDs increased from 90% in 1995 to 99% in 1997, and fell to 97% in 1999. Likewise, while 30% of rheumatologists used 3 DMARDs in combination in 1995, 67% said they did so in 1997, and 69% said they did so in 1999. Furthermore, the percentage of rheumatologists prescribing combination DMARD therapy for more than 30% of their RA patients increased from 16% in 1995 to 32% in 1997, and increased again to 47% in 1999.

These data show that rheumatologists have become more aggressive nationwide in their approach to the treatment of patients with RA. Further, it can be expected that many physicians will begin to use other novel therapies such as new DMARDs and biologic agents in their treatment paradigms.

Treatment With Leflunomide

Many rheumatologists have had the chance to gain some experience with leflunomide, a new DMARD that was introduced for the treatment of RA in the United States about a year ago. Results from 2 studies on leflunomide were presented.

Josef Smolen, MD,[6,7] from Vienna presented data on behalf of a number of his European colleagues on the effect of leflunomide treatment on the progression of RA, as shown by radiographic evidence. Previously, it was shown that at 1 year, leflunomide and sulfasalazine significantly slowed progression of visible x-ray damage as compared with placebo treatment. Dr. Smolen presented data on the 24-month follow-up on the same group of study patients. Analyzing the Larsen score of damage visible on x-ray, as well as the erosive joint count, it was shown that the ability of leflunomide to retard progression visible on x-ray is maintained through 24 months.

Improvement in quality of life is a key goal of therapy for patients with RA. It is commonly measured by questionnaires, such as the Health Assessment Questionnaire (HAQ) and the Short Form 36 (SF36). These questionnaires assess patients' ability to perform their activities of daily living and measure other aspects of their satisfaction with their health status.

It has previously been shown that quality of life, as measured by the HAQ and the SF-36 questionnaires, significantly improved after 12 months of treatment with leflunomide, as compared with placebo and with methotrexate. Peter Tugwell, MD,[8,9] on behalf of North American colleagues, presented data on measurement of quality of life in the 2-year follow-up of patients in a leflunomide trial. Dr. Tugwell showed that significant improvements in quality of life were maintained through 24 months.

Because of the length of follow-up in these studies, the data are very encouraging. Very few studies performed to date have generated data at 2 years of treatment. Of course, such long-term data are of great relevance to the practicing clinician, who will treat patients for RA for years. These encouraging results give additional support to the utility of leflunomide as a DMARD.

The data presented in these sessions had exciting implications for the treatment of RA. Using agents that are currently available, rheumatologists are becoming more aggressive in their approach to therapy. This may help to optimize the results achieved with these agents. For the novel therapy leflumonide, these studies offered encouraging support that this drug will have a place in the longer-term treatment of patients with RA. Finally, more is being learned about the genetic characteristics of patients with RA. This knowledge may allow future therapies to be used in the most appropriate groups of patients, thereby increasing efficacy and minimizing toxic effects.

References

  1. Kavanaugh A, Lipsky P. Treating rheumatoid arthritis with tumor necrosis factor inhibitors. J Musculoskel Med. 1998;15:33-41.
  2. Kavanaugh A, Cohen S, Cush J. Inhibitors of tumor necrosis factor in rheumatoid arthritis: will that dog hunt? J Rheumatol. 1998;25:2049-2053.
  3. Hohler T, Kaluza W, Grossmann S, et al. TNF-alpha microsatellites define haplotypes with high, intermediate and low TNF-alpha production. Presented at the American College of Rheumatology 63rd Annual Scientific Meeting; November 12-17, 1999; Boston, Mass. Abstract 126.
  4. Gibson AW, Keijsers V, Edberg JC, Huizinga TWJ, Kimberly RP. Novel genetic polymorphisms in the IL-10 promoter. Presented at the American College of Rheumatology 63rd Annual Scientific Meeting; November 12-17, 1999; Boston, Mass. Abstract 124.
  5. Mikuls T, O'Dell J. THE The treatment of rheumatoid arthritis: current trends in therapy. Presented at the American College of Rheumatology 63rd Annual Scientific Meeting; November 12-17, 1999; Boston, Mass. Abstract 51.
  6. Schiff M, Sharp J, Smolen JS, Emery P, Strand V, for the Leflunomide Investigators Study Group. Consistency of leflunomide effect for slowing the radiographic disease progression of active rheumatoid arthritis: results from three controlled trials. Presented at the American College of Rheumatology 63rd Annual Scientific Meeting; November 12-17, 1999; Boston, Mass. Abstract 63.
  7. Smolen JS, Larsen A, Kalden JR, et al, for the Multinational Leflunomide Study Group. Retardation of structural damage with leflunomide in rheumatoid arthritis assessed by Larsen methodology: 2-year results. Presented at the American College of Rheumatology 63rd Annual Scientific Meeting; November 12-17, 1999; Boston, Mass. Abstract 68.
  8. Tugwell P, Bombardier C, Strand V, et al, for the Leflunomide Study Group. Two-year treatment of active rheumatoid arthritis (RA) with leflunomide (LEF) improves function and health-related quality of life (HRQOL). Presented at the American College of Rheumatology 63rd Annual Scientific Meeting; November 12-17, 1999; Boston, Mass. Abstract 70.
  9. Tugwell P, Wells G, Strand V, et al. Clinical improvement as reflected in measures of function and health related quality of life: sensitivity and relative efficiency to detect a treatment effect in a 12 month placebo controlled trial comparing leflunomide with methotrexate. Presented at the American College of Rheumatology 63rd Annual Scientific Meeting; November 12-17, 1999; Boston, Mass. Abstract 71.  
 

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