medwireNews: Results of the ORAL Strategy trial suggest that tofacitinib given in combination with methotrexate, but not alone, is noninferior to adalimumab plus methotrexate for the treatment of patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate.
“Current practice is to add a biological DMARD [disease-modifying antirheumatic drug] such as adalimumab to methotrexate, but the 2016 update of the European League Against Rheumatism (EULAR) recommendations propose that the addition of a targeted synthetic DMARD, such as tofacitinib to methotrexate, might be an alternative,” said Roy Fleischmann (University of Texas Southwestern Medical Center, Dallas, USA) and study co-authors.
The ORAL (Oral Rheumatoid Arthritis Trial) Strategy investigators randomly assigned 1146 patients with active RA to receive methotrexate in combination with either the oral Janus kinase (JAK) inhibitor tofacitinib at a dose of 5 mg twice daily or the subcutaneous tumor necrosis factor inhibitor adalimumab at a dose of 40 mg every other week, or 5 mg oral tofacitinib monotherapy twice daily.
As presented at the EULAR 2017 annual meeting and published simultaneously in The Lancet, 46% of 376 patients receiving tofacitinib plus methotrexate achieved at least a 50% improvement in ACR criteria (ACR50) at 6 months, as did 44% of 386 patients in the adalimumab plus methotrexate group.
The difference in the proportion of patients with an ACR50 response was 2%, and the lower bound of the confidence interval, at –6%, was above the prespecified noninferiority boundary of –13%, meaning that “tofacitinib and methotrexate was deemed non-inferior to adalimumab and methotrexate,” say the researchers.
In a group of patients who are methotrexate incomplete responders, whether you add tofacitinib or you add adalimumab, you would get the same effect
However, tofacitinib monotherapy was not found to be noninferior to either tofacitinib plus methotrexate or adalimumab plus methotrexate. A total of 38% of 147 patients in the monotherapy group experienced an ACR50 response, giving a difference of –8% versus the tofacitinib combination and –6% versus the adalimumab combination, where the lower limit of the confidence intervals was below the prespecified noninferiority boundary.
The proportion of patients with low disease activity at 6 months, as assessed by the Simplified Disease Activity Index, was also comparable in the two combination therapy groups, whereas a lower proportion of patients receiving monotherapy versus either combination therapy had low disease activity at this timepoint.
A total of 30% of patients in the tofacitinib plus methotrexate arm experienced treatment-related adverse events, compared with 35% of patients in the adalimumab plus methotrexate arm and 26% of those in the tofacitinib monotherapy arm. A corresponding 7%, 10%, and 6% discontinued treatment due to adverse events.
The most common adverse events occurring across all treatment groups were upper respiratory tract infections, alanine aminotransferase elevation, nasopharyngitis, urinary tract infections, and nausea. “No new or unexpected safety issues were reported for either treatment in this study,” note the researchers.
Taken together, these findings “suggest that the addition of tofacitinib to methotrexate is preferable to switching to tofacitinib monotherapy,” write Fleischmann and colleagues.
The authors of an accompanying comment, David Scott (King’s College London, UK) and Matt Stevenson (University of Sheffield, UK), believe that the ORAL Strategy findings are “extremely encouraging” as they “show the ongoing benefits of innovation in drug treatment.”
However, they note that the trial did not include a cost analysis, and “JAK inhibitors will only be used to any extent if their cost-effectiveness is similar or better than biologics.”
And the commentators highlight that “[o]ral JAK inhibitors also increase serious infections.
“Caution is therefore needed when JAK inhibitors are used routinely.”
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