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Newswise — WASHINGTON – Extending the time between doses, or tapering, TNF-inhibitor drugs in people with rheumatoid arthritis in remission can be done in some patients without significantly increasing disease activity or impairing joint function, according to new research findings presented this week at the American College of Rheumatology Annual Meeting in Washington, D.C.
Rheumatoid arthritis is a chronic disease that causes pain, stiffness, swelling, and limitation in the motion and function of multiple joints. Though joints are the principal body parts affected by RA, inflammation can develop in other organs as well. An estimated 1.3 million Americans have RA, and the disease typically affects women twice as often as men.
Once people with RA achieve remission, doctors often try to increase the interval between doses of drugs, which is called tapering, but doing so involves the risk of increasing disease activity and joint damage, reducing physical function, or causing a relapse. Researchers in France looked into how increasing the interval between injections of TNF-inhibitor drugs, which are both costly and may sometimes have serious side effects, might affect patients. They conducted an 18-month randomized, controlled trial involving 137 people with RA treated with biologic agents that inhibit TNF, who were in stable remission for at least six months. Seventy-eight percent of the participants were female, and all were using either etanercept (Enbrel®) or adalimumab (Humira®), for one year either alone or in combination with other drugs. Participants could be taking five milligrams or less of the corticosteroid drug prednisone daily.
Researchers split the participants into two randomized groups: One set using a progressive spacing out of injections of their TNF-inhibitor and one set who continued taking their injections at full doses at the approved time intervals. In the first group, doctors increased the time between two injections by 50 percent every three months up to a complete stop by the fourth interval. If the participants RA disease activity or physical function worsened, the patient stopped tapering doses of the drugs and was moved back to previous dose. To test the patient’s disease activity, function level and signs of relapse, doctors used standard scoring methods and health assessment questionnaires.
After 18 months, the researchers found that 82 percent of the RA participants were able to space out or stop their TNF-inhibitor injections without significant increases in either disease activity or functional impairment. However, the study did not demonstrate that the spacing approach was statistically equivalent to the traditional regimen. They also found that relapses occurred more frequently in the group that spaced injections compared to those who stayed on the same dosing schedule; but overall this did not result in differences in disease activity between the groups. The researchers are still analyzing X-rays to determine if the spacing strategy caused structural damage to their joints.
“A lot of effort has been dedicated to the development of new treatments for RA, leading to a substantial increase in RA costs. Nowadays, remission is achievable and treatment tapering needs to be considered and assessed,” says Bruno Fautrel, MD, PhD, lead investigator in the study and professor at the University of Paris Medical Center in France. “RA is a chronic disease and the risk-benefit balance of taking DMARDs to manage the condition should be explored. Issues that should be evaluated include the risk of tapering or stopping DMARDs given that reducing medication may lead to flares and potential structural damage. Additional issues that should be considered are drug toxicity from continued DMARD use and substantial economic burden to society. This study explored the balance and tested the feasibility of biologic DMARD tapering (i.e., either interruption of current treatment or identification of the minimal effective dose).”
Funding for this study was provided by French Ministry of Health. The study was also promoted by the Assistance Publique – Hôpitaux de Paris.
The American College of Rheumatology is an international professional medical society that represents more than 9,000 rheumatologists and rheumatology health professionals around the world. Its mission is to advance rheumatology. The ACR/ARHP Annual Meeting is the premier meeting in rheumatology. For more information about the meeting, visit www.acrannualmeeting.org or join the conversation on Twitter by using the official hashtag: #ACR2012.
Learn more about living well with rheumatic disease as well as rheumatologists and the role they play in health care. Also, discover the ACR’s Simple Tasks campaign, which highlights the severity of rheumatic diseases and the importance of early and appropriate referral to a rheumatologist.
Editor’s Notes: Bruno Fautrel, MD, PhD, will present this research during the ACR Annual Meeting at the Walter E. Washington Convention Center at 1:30 PM on Monday, November 12 in the on-site press conference room, Room 203 A-B.
Presentation Number: L7
Tapering TNF-Blockers in Established Rheumatoid Arthritis Patients in DAS28 Remission: Results of a DAS28-Driven Step-Down Strategy Randomized Controlled Trial.
Bruno Fautrel (University of Paris Medical Center, Paris, France)
Thao Pham (Sainte Marguerite Hospital, Marseille, France)
Florence Tubach (Hôpital Bichat, Paris, France)
Toni Alfaiate (Assistance Publique – Hopitaux de Paris, France)
Jacques Morel (Hopital Lapeyronie, Montpellier, France)
Emmanuelle Dernis (Centre Hospitalier, Le Mans, France)
Xavier J. Puechal (Le Mans Hospital, Le Mans, France)
Philippe Gaudin (CHU Hôpital Sud, Grenoble Teaching Hospital, Echirolles, France)
Xavier Mariette (Bicêtre University Hospital, Le Kremlin Bicetre, France)
Background/Purpose: Step-down therapeutic strategies are often considered in established rheumatoid arthritis (RA) once remission is achieved but are associated with a potential risk of relapse or structural damage progression. A 18-month equivalence randomized controlled PROBE (prospective open blinded endpoint) trial was conducted in established RA patients treated with etanercept (ETA) or adalimumab (ADA) in stable DAS28 remission, comparing the impact of a DAS28-driven step-down strategy based on progressive injection spacing (S arm) to a strategy maintaining the therapy at full regimen (M arm).
Methods: Inclusion criteria were: RA according to the ACR1987 criteria, treatment with ETA or ADA for 1 year either as monotherapy or in combination, prednisone at a daily dose 5 mg/d, DAS28 remission (DAS28 2.6) for 6 months, no structural damage progression on X-rays since last X-ray assessment. Patients were randomized (blocks of variable sizes, after stratification on centre and TNF-blocker) in the 2 arms M or S and followed every 3 months for 18 months. In the S arm, the interval between 2 subcutaneous injections was increased by 50% every 3 months up to a complete stop in 4th step. If DAS28 remission was not maintained, dose tapering was suspended or reversed to the previous interval based on DAS28 level. The primary endpoint was disease activity, based on repeated DAS28 measures (every 3 months over 18 months) under the hypothesis of non-inferiority of the S arm, based on a mixed linear model. Secondary endpoints were DAS28 and HAQ evolution over 18 months and relapse (DAS28 increase > 0.6 and DAS28 > 2.6).
Results: 137 patients were included, 64 and 73 in the S and M arm respectively. Their main baseline characteristics were the following (mean ±sd or %): age 55 ±11 years, female 78%, RA duration 9.5 ±8.0 years, RF+ 68%, ACPA+ 78%, erosive disease 88%, DAS28 1.8 ±0.6, DAS44 1.0 ±0.5, HAQ 0.4 ±0.5, number of previous DMARDs 2.7 ±1.7, ETA 54 %, ADA 46 %. At 18 months, 15 % of the S-arm patients had completely stopped and 67% tapered TNF-blockers, other treatments remaining stable. The remaining 18% patients were unable to taper their treatment and remain at the initial injection interval. Disease activity on DAS28 and functional status (HAQ) were not significantly different between the 2 arms (figure). However, we failed to demonstrate the equivalence between the 2 strategies (p = 0.6) and due to the step-down strategy, a relapse occurred more frequently in the S than in the M arm (81% vs. 56%, p=0.0009).
Conclusion: Spacing of TNF-blockers was feasible in 82% of patients. Although we failed to demonstrate the equivalence between the 2 strategies, the spacing strategy did not result in a significant increase in disease activity or functional impairment. The impact of the spacing strategy on X-ray structural damage is currently being analysed.
ClinicalTrials.gov n°: NCT00780793
Disclosures: Bruno Fautrel, Abbott, BMS, Merck, MundiPharma, Pfizer, Roche, UCB.