Etanercept (Enbrel^®)
Adalimumab (Humira™)
Infliximab (Remicade^®)

Etanercept (Enbrel^®)

OP0009 SUSTAINED EFFICACY AND SAFETY OF ETANERCEPT AND METHOTREXATE, COMBINED AND ALONE, IN RA PATIENTS: YEAR 3 TEMPO TRIAL RESULTS
L. Klareskog, D. Van der Heijde, J. Wajdula, R. Pedersen, S. Fatenejad

The TEMPO trial is a 3-year double-blind study that enrolled patients with early rheumatoid arthritis (RA) to compare the safety and efficacy of combination treatment with etanercept and methotrexate to either treatment alone. We previously highlighted the 1-year and the 2-year data. This abstract reports the 3-year data.

Briefly, 682 patients were randomized to receive etanercept 25 mg (2x weekly; n=223), MTX up to 20mg/week (n=228), or etanercept + MTX (n=231).

Results: The table below is a summary of the 3-year efficacy results. The combination therapy had a higher percentage of patients complete the study than etanercept or MTX monotherapy, 57%, 48%, and 39%, respectively. No new safety findings were reported or increased infections or malignancies after 3 years. Pulmonary tuberculosis developed in one patient in the combination treatment group.

Conclusion: These data are very similar to the 1-and 2-year data in that the combination treatment with etanercept and MTX is significantly more efficacious than either treatment alone. Additionally, no unexpected safety findings were reported.

Editorial Comments: These results are not surprising given the previously reported 1 and 2 year data from TEMPO, as well as other long term studies of the TNF inhibitors showing durability of response. Nonetheless, it is nice to see the data formally presented and reassuring that no new safety concerns have been raised in this study population. Although the combination of MTX and etanercept clearly results in a greater percentage of patients improving, many patients continue to respond well to monotherapy.

Almost half of patients treated with combination therapy continue to show a 70% improvement in the ACR composite response criteria, while similar numbers in the monotherapy arms are reaching only the 50% level of response. It is notable that the responses seen in all treatment arms remain high with similar levels to those initially reported in the first year. These results continue to demonstrate that aggressively dosed methotrexate performs very well in the relief of symptomatic RA. However, the previously reported two year radiographic data have shown discordance at that time point between relief of signs and symptoms and slowing radiographic progression with either etanercept or combination therapy better than methotrexate alone. Whether this divergence will ultimately translate to differences in functional outcomes or ultimate joint failure will require many years to demonstrate. One could argue that maintaining patients who continue to progress radiographically on MTX monotherapy in order to demonstrate such an outcome may be difficult to justify.

Additionally, predicting which patients require early combination therapy remains an important clinical question.

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Adalimumab (Humira™)

OP0013 THE EFFICACY AND SAFETY OF ADALIMUMAB (HUMIRA) PLUS METHOTREXATE VS. ADALIMUMAB ALONE OR METHOTREXATE ALONE IN THE EARLY TREATMENT OF RHEUMATOID ARTHRITIS (RA): 1- AND 2-YEAR RESULTS OF THE PREMIER STUDY
F. C. Breedveld, M. H. Weisman, A. F. Kavanaugh, S. B. Cohen, K. Pavelka, R. Van Vollenhoven, J. L. Perez, G. T. Spencer-Green

It is clear that early treatment intervention in patients with rheumatoid arthritis (RA) leads to better patients outcomes. The purpose of this abstract is to report the 1- and 2-year findings in the PREMIER study. This phase III study was designed to evaluate the safety and efficacy of adalimumab and methotrexate (MTX) combination therapy compared to monotherapy with either drug in patients recently diagnosed with RA.

Methotrexate nave patients with active RA of < 3 years duration were randomized to 1 of 3 treatment arms; 1) adalimumab 40 mg every other week (eow) + MTX, 2) adalimumab 40 mg eow as monotherapy, or 3) MTX alone. MTX dosages were rapidly optimized to a maximum of 20 mg weekly. ACR50 and total Sharp score were the primary endpoints.

Results: A total of 539 of 799 enrolled patients completed 2 years of therapy with the highest retention in the combination arm compared to MTX and adalimumab alone (76%, 66%, and 61%, respectively). Adverse events were similar across all 3 treatment arms. The table below gives both the 1 and 2 year results for each treatment arm.

Conclusion: Adalimumab in combination with methotrexate is significantly more efficacious for the treatment of early RA than either medication alone, both in clinical and radiographic outcome measures.

Editorial Comments: The PREMIER study of adalimumab in combination with methotrexate confirms other studies that have shown TNF antagonists in combination with aggressively dosed methotrexate are more effective in the relief of signs and symptoms and in inhibiting radiographic progression than monotherapy.

This study evaluated a group of patients with very active RA of relatively short duration and showed both one and two year results of signs and symptoms and radiographic progression. The results demonstrated significantly more patients achieving ACR 50/70 and even ACR90 levels of clinical response in the patients treated with a combination of Adalimumab at 40 mg eow + aggressively dosed MTX., results that were maintained over the two years of the study. It will be important to see ACR and DAS responses at longer time points and to evaluate drop-out rates over time.

Importantly, combination therapy significantly reduced radiographic progression by approximately 70% compared to patients receiving MTX alone. While monotherapy with adalimumab and methotrexate were similar in terms of clinical responses, a reduction in radiographic progression was demonstrated with adalimumab. The results of this study combined with data presented for other TNF antagonists in early or established RA, demonstrate that a more aggressive treatment approach for patients with active disease has resulted in improved clinical and radiographic responses. A 90% improvement in the composite ACR response was achieved by almost a quarter of patients treated with the combination regimen, with ACR 70 responses maintained over 6 months (a major clinical response) in almost half of patients at 2 years.

The fact that these outcomes are possible and achievable by significant numbers of patients demonstrates the possible outcomes for patients with active RA when managed using more aggressive combination regimens. Defining which patients are most appropriate for combination therapy from the outset of their disease is now even more important to define.

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Infliximab (Remicade™)
OP0010 MANY EARLY RHEUMATOID ARTHRITIS PATIENTS WITH A GOOD CLINICAL RESPONSE TO INFLIXIMAB CAN DISCONTINUE ANTI-TNF-ALPHA THERAPY WITHOUT RELAPSE
A. E. Van der Bijl, Y. P. Goekoop-Ruiterman, F. C. Breedveld, J. M. Hazes, P. J. Kerstens, J. K. De Vries-Bouwstra, D. Van Zeben, C. F. Allaart, B. A. Dijkmans

With any therapy comes the question of whether the treatment benefits can be sustained once medication is discontinued. Using the experiences of treatment Group 4 from the BeST study (initial combination therapy with methotrexate and infliximab), this abstract attempts to address this question.

128 patients with active RA, previously untreated and disease duration of < 2 years, were initially treated with infliximab (IFX) 3mg/kg at week 0, 2, 6, and every 8 weeks. The dose was escalated if the DAS44 score was > 2.4 or was discontinued if the score was < 2.4 for at least 6 months. Efficacy was assessed using HAQ and DAS44 scores while radiographic progression was monitored with the Sharp-van der Heijde Score (SHS).

Results: : Review of the study data after 2 years showed that 67/128 patients (52%) were able to discontinue the IFX treatment after approximately 1 year (12.6 mos) and to maintain good clinical response (DAS44 < 2.4) regardless of increases in IFX dosing earlier in the study. A mean dose of 12.2mg/week MTX was continued. The responders had a mean change in the 2-year SHS score of 1.63, SD 3.7.

In 10/128 (8%) patients, IFX was reintroduced a median of 2.1 months after discontinuation and 13 (10%) patients were maintained on variable doses of IFX throughout the 2 years. The 23 patients maintained on IFX had a mean change in the 2-year SHS score of 2.53, SD 4.2. IFX and MTX failures had a mean change in the 2-year SHS score of 4.17, SD 6.0.

Conclusions: In over 50% of patients receiving initial infliximab and methotrexate combination treatment within the BeST study, infliximab was successfully discontinued. Thus far, these patients have sustained clinical improvement approximately 1 year after stopping infliximab. Additionally, these patients have shown less joint damage over this same time period compared to non-responders and patients on continued infliximab treatment.

Editorial Comments: It is remarkable that such a large percentage of patients were able to successfully discontinue IFX and maintain improvement over 12 months on MTX alone. By comparison, in groups 1 and 2 (see Abstract OP0007 above) only 30% of patients initially treated with MTX alone were able to achieve and maintain a DAS44 <2.4 at 2 years without the addition of other agents. It will be interesting to see the numbers of patients who can remain off of IFX over the next several months to years. A sustained benefit from early IFX therapy would add credibility to the hypothesis that early aggressive intervention may modulation or educate the immune response resulting in a less severe inflammatory disease state.

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