Two New Approaches to Treating Rheumatoid Arthritis
Two New Approaches to Treating Rheumatoid Arthritis
Meanwhile, how about all of the patients who did not have the chance of receiving a biologic early in the disease course, but who were started on such an agent after multiple DMARDs failed? Clinical experience over the past 15 years has made it rather clear that most patients with established RA who are doing well on a biologic are not going to be able simply to stop treatment without a substantial risk for relapse. This mirrors experiences with the conventional DMARDs that were formally studied in the 1990s, but with the difference that both the clinical response upon starting biologics, and clinical worsening upon discontinuing them, tend to occur much more rapidly.
Recent trials have confirmed that discontinuing anti-TNF biologics in established RA usually leads to a flare of the disease. Thus, in the CERTAIN trial, certolizumab was given to patients with moderate disease. Responses were very good overall, as expected, but upon discontinuation of certolizumab, patients reverted to their baseline states.
Likewise, in the PRESERVE trial, patients with moderate RA were given etanercept, with clear clinical improvement but also with rapid return to the previous state after discontinuation. In this trial, a group of patients was continued on etanercept at one half of the usual dose (25 mg once weekly). Remarkably, this group of patients did almost exactly as well as the third (control) group who simply continued on the standard dose of 50 mg etanercept weekly. Thus, a "dosing-down" scheme appeared to be possible for these patients.
One limitation of that trial was that the patients were selected for moderate disease, and they were recruited from practice settings where they had not been given anti-TNF therapy, so it is not known whether these results can be extrapolated to patients for whom the anti-TNF was felt to be necessary. This question was addressed in the DOSERA study, a multicenter randomized, double-blinded trial in the Nordic countries plus Hungary. The study was fully sponsored by Pfizer, but originally designed by and subsequently carried out in close collaboration with a group of academic investigators.
In DOSERA, patients for whom etanercept therapy had been chosen on clinical grounds, sometimes years earlier, and who were also taking MTX were invited to participate. They were randomly assigned to continuation of both MTX and etanercept at the usual dose (50 mg weekly), continued on MTX plus placebo, or continued on MTX plus etanercept 25 mg weekly. The results confirmed that discontinuation of etanercept resulted in a flare of disease activity in most patients, but that the half-dose of etanercept maintained clinical responses nearly as effectively as the full dose.
In a differently designed trial, Fautrel and colleagues randomly assigned patients on MTX plus an anti-TNF agent (adalimumab or etanercept) to continue as usual or to increase the dosing interval of the anti-TNF agent. Several steps of increasing dosages were taken, and in the end, the anti-TNF drug could be stopped completely. In the initial report of this trial, it was clear that although dosing-down did not achieve formal noninferiority, the vast majority of patients was able to reduce the intensity of their anti-TNF treatment by dosing more sparsely while maintaining clinical responses.
Taken together, the results from these trials strongly suggest that dosing down of at least some biologics is a distinct possibility that could have important health-economic implications. Further studies of this possibility are greatly needed, particularly more long-term follow-up, attention to radiologic outcomes, patient-reported and quality-of-life outcomes, and formal health-economic analyses.
Another important question is whether the same principle can be applied to the other biologics. A recent uncontrolled study reported that dosing down with tocilizumab was successful in a small group of patients.
Dosing-Down of Biologics
Meanwhile, how about all of the patients who did not have the chance of receiving a biologic early in the disease course, but who were started on such an agent after multiple DMARDs failed? Clinical experience over the past 15 years has made it rather clear that most patients with established RA who are doing well on a biologic are not going to be able simply to stop treatment without a substantial risk for relapse. This mirrors experiences with the conventional DMARDs that were formally studied in the 1990s, but with the difference that both the clinical response upon starting biologics, and clinical worsening upon discontinuing them, tend to occur much more rapidly.
Recent trials have confirmed that discontinuing anti-TNF biologics in established RA usually leads to a flare of the disease. Thus, in the CERTAIN trial, certolizumab was given to patients with moderate disease. Responses were very good overall, as expected, but upon discontinuation of certolizumab, patients reverted to their baseline states.
Likewise, in the PRESERVE trial, patients with moderate RA were given etanercept, with clear clinical improvement but also with rapid return to the previous state after discontinuation. In this trial, a group of patients was continued on etanercept at one half of the usual dose (25 mg once weekly). Remarkably, this group of patients did almost exactly as well as the third (control) group who simply continued on the standard dose of 50 mg etanercept weekly. Thus, a "dosing-down" scheme appeared to be possible for these patients.
One limitation of that trial was that the patients were selected for moderate disease, and they were recruited from practice settings where they had not been given anti-TNF therapy, so it is not known whether these results can be extrapolated to patients for whom the anti-TNF was felt to be necessary. This question was addressed in the DOSERA study, a multicenter randomized, double-blinded trial in the Nordic countries plus Hungary. The study was fully sponsored by Pfizer, but originally designed by and subsequently carried out in close collaboration with a group of academic investigators.
In DOSERA, patients for whom etanercept therapy had been chosen on clinical grounds, sometimes years earlier, and who were also taking MTX were invited to participate. They were randomly assigned to continuation of both MTX and etanercept at the usual dose (50 mg weekly), continued on MTX plus placebo, or continued on MTX plus etanercept 25 mg weekly. The results confirmed that discontinuation of etanercept resulted in a flare of disease activity in most patients, but that the half-dose of etanercept maintained clinical responses nearly as effectively as the full dose.
In a differently designed trial, Fautrel and colleagues randomly assigned patients on MTX plus an anti-TNF agent (adalimumab or etanercept) to continue as usual or to increase the dosing interval of the anti-TNF agent. Several steps of increasing dosages were taken, and in the end, the anti-TNF drug could be stopped completely. In the initial report of this trial, it was clear that although dosing-down did not achieve formal noninferiority, the vast majority of patients was able to reduce the intensity of their anti-TNF treatment by dosing more sparsely while maintaining clinical responses.
Taken together, the results from these trials strongly suggest that dosing down of at least some biologics is a distinct possibility that could have important health-economic implications. Further studies of this possibility are greatly needed, particularly more long-term follow-up, attention to radiologic outcomes, patient-reported and quality-of-life outcomes, and formal health-economic analyses.
Another important question is whether the same principle can be applied to the other biologics. A recent uncontrolled study reported that dosing down with tocilizumab was successful in a small group of patients.
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