JAK inhibitor placed relative to DMARDs (Recommendation 10)
A paper published in the New England Journal of Medicine suggested cardiovascular risks and malignancy risks were higher with the JAK inhibitor, tofacitinib, compared with TNF-alpha inhibitors.
The task force therefore felt the need to evaluate the place of JAK inhibitors next to biologic DMARDs “once phase one with methotrexate plus glucocorticoids has failed,” Dr. Smolen said.
After a systematic literature review of around 4,500 papers, the researchers evaluated 88 safety papers including the ORAL Surveillance study. “This very clearly showed that tocilizumab was not noninferior according to the noninferiority criteria with an upper limit of 1.8 [hazard ratio] and this was independent of dose, compared with TNF-alpha inhibitor,” said Dr. Smolen. “The major adverse cardiovascular events [MACE] were not different, nor were malignancies and overall mortality.”
Dr. Smolen also referred to the ENTRACTE trial that compared etanercept with tocilizumab, and again, there was no evidence of an increased risk of MACE nor mortality for tocilizumab compared with a TNF-alpha inhibitor.
“The increased MACE risk in the ORAL Surveillance trial is unlikely due to inhibition of IL-6 and must be due to some other effects than IL-6 signaling,” he said.
As such, the agreed-on recommendation was that, “if the treatment target is not achieved with the first csDMARD strategy, when poor prognostic factors are present, a bDMARD should be added; JAK inhibitors may be considered but pertinent risk factors must be taken into account [aged over 65 years, history of current or past smoking, either cardiovascular or malignancy risk factors, and risk factors for thromboembolic events].”
There was a high level of agreement by the group for this recommendation.
Switching DMARDs
The task force considered their recommendations on switching DMARDs based on a systematic literature review of 47 papers.
EULAR previously strongly recommended a combination of csDMARDs with bDMARDs (including JAK inhibitors), and this recommendation remains the same except for a note added about risks of tsDMARDs.
Recommendation 10 relates to failure of phase 2 treatment and what to do when the first bDMARD or a tsDMARD has failed (including as per new recommendations, a JAK inhibitor), and if one TNF or IL-6 receptor inhibitor therapy has failed. In this case, patients may receive an agent with another mode of action or a second TNF/IL-6 receptor inhibitor, said Dr. Smolen.
Recommendation 11 has been combined with recommendation 12, he added. “If a patient is in persistent remission after having tapered glucocorticoids, one can consider tapering bDMARDs, or tsDMARDs especially if this treatment is combined with a csDMARD.
“We decided to put more emphasis on the stopping of glucocorticoids, namely not saying ‘tapering’ but ‘discontinued,’ and if the patient is in sustained remission, then consider reduction of DMARDs [biologic, targeted synthetic or conventional synthetic DMARDs],” he explained. “This is left to the discretion of the patient and the physician as to which one should be tapered first. We don’t recommend to taper everything because the patient might be affected by flares but this needs further discussion.”
Dr. Smolen ended his presentation by looking ahead to the next set of recommendations: “With the current rate of evidence development, we expect an update of the recommendations to be necessary in about 3-4 years.”
This article was updated on 6/9/2022.