New recommendations reprioritize some common RA drugs.
Based on the work of “the largest Task Force ever convened for the development of EULAR recommendations,” the European League Against Rheumatism has compiled a meticulous update of their previous recommendations for the management of rheumatoid arthritis (RA), which includes several changes from previous 2010 and 2013 guidelines.
Recently updated this March and published in Annals of the Rheumatic Diseases, EULAR’s own journal, the 2016 recommendations included input from rheumatologists from 14 European countries, as well as experts from North America, Asia, Latin America and Australia, in addition to three patients, for a total of 50 participants. The effort was led by Josef S. Smolen, MD, of the Medical University of Vienna in Austria, himself a former president of EULAR. The process of compiling the report, according to Smolen, took about a year, and features an extensive, separately-published literature review.
The guidelines trim from 14 formal recommendations in the 2013 version down to 12 in this one, and expands from three overarching principles to four from the prior edition. Each principle and recommendation was stamped for inclusion based on a rigorous voting process, with no principle receiving less than 98% approval and only two of the dozen recommendations receiving less than 85%.
The recommendations hone in on the full range of RA treatments, primarily focusing on disease-modifying antirheumatic drugs (DMARDs). The report includes conventional synthetic DMARDs (csDMARDs) such as methotrexate (MTX), leflunomide, and sulfasalazine; glucocorticoids (GC); biological DMARDs (bDMARDs) including tumor necrosis factor inhibitors (TNFi) (such as adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab) and also abatacept, rituximab, tocilizumab, clazakizumab, sarilumab and sirukumab; biosimilar DMARDs (bsDMARDs); and targeted synthetic DMARDs (tsDMARDs) such as Janus kinase inhibitors (Jak inhibitors or Jakinibs) including tofacitinib and baricitinib.
The first recommendation, unchanged from the 2013 edition and receiving the highest level of ranked approval, is that “Therapy with DMARDs should be started as soon as the diagnosis of RA is made,” and the second point was that “Treatment should be aimed at reaching a target of sustained remission or low disease activity in every patient.”
Seemingly, the most contentious recommendation was the fourth: “MTX should be part of the first treatment strategy.” Previously, the 2013 version had added “…in patients with active RA” to the end of that phrase, but that was stricken for perceived redundancy. The recommendation is based, according to the report, on “efficacy, safety (especially in the presence of folic acid), the possibility to individualize dose and method of administration as well as relatively low costs,” continuing that MTX “continues to be the anchor (‘first’) drug for patients with RA both as monotherapy as well as in combination with other drugs…Moreover, MTX appears to reduce comorbidities and mortality in RA.” The report encourages rapid escalation of MTX, typically up to 25-30mg/week orally or subcutaneously, citing high response rates through such a treatment course, though it notes that such numbers should be lower for Asian patients: in China it is not recommended to exceed 20mg/week and in Japan, 16mg/week.
The recommendation was tied for the lowest approval percentage of them all, receiving 71% of the final vote. It also coincided with the fifth recommendation, that patients with a contraindication to MTX, or early intolerance, should instead be tried on leflunomide or sulfasalazine.
“The inclusion or exclusion of combinations of csDMARDs within the bullet points elicited long debates within the respective breakout group and the whole Task Force (and the withdrawal of one Task Force member),” according to the report.
The wording as it pertains to glucocorticoids has changed from “low-dose short-term” use of them to merely “short-term” because, in Smolen’s words, “There are data that a single IV of 250mg (which is not low dose) leads to excellent results and also that 30mg prednisone daily tapered rapidly gives good outcomes. For csDMARD combinations, the data show that when MTX is combined with glucocortiocids, there is no advantage of also adding further csDMARDs…but adverse events are much more frequent.”
The new update instead directs rheumatologists to attempt different csDMARDs if the first does not achieve targets (seventh recommendation), and to attempt the addition of a bDMARD or tsDMARD if that still does not move patients closer to treatment goals (eighth). According to the report, “early intolerance for a csDMARD should not be considered as a treatment failure, which would imply moving immediately to the next phase of the algorithm, but rather require reinstitution of another first csDMARD (replacement).”
The second of those two was expanded from the 2013 edition to include tsDMARDs in order to acknowledge the use of Jak inhibitors, which had previously been considered an option following a treatment failure with bDMARDs. “We recommend stratification by risk factors of rapid damage progression,” says Smolen, saying the reprioritization comes now that more data regarding Jak inhibitors have become available. “Also,” he says, “we generally recommend combining bDMARDs and Jakinibs with MTX or other csDMARDs, since the combination appears generally more efficacious than monotherapies.”
The ninth and tenth recommendations deal with potential difficulty of the previous two recommendations, logically suggesting that “bDMARDs and tsDMARDs should be combined with a csDMARD; in patients who cannot use csDMARDs as comedication, IL-6 pathway inhibitors and tsDMARDs may have some advantages compared with other bDMARDs,” and then “If a bDMARD or tsDMARD has failed, treatment with another bDMARD or a tsDMARD should be considered; if one TNF-inhibitor therapy has failed, patients may receive another TNF-inhibitor or an agent with another mode of action.”
The final two recommendations in the new EULAR update deal with tapering treatment if patients are in remission: the eleventh suggesting if GC use has already been tapered, and a patient is on both a bDMARD and a csDMARD that the bDMARD may be tapered; and the twelfth finally suggesting persistent remission creates an opening for the tapering of the csDMARD.
Though the report is expansive and direct, Smolen says there is still much to be learned in order to inform future recommendations. “We still do not know if Jakinibs work after other ones have failed, if IL-6 inhibitors work if others have failed, and there are also no efficacy data available for the use of TNF-inhibitors (or other bDMARDs) after agents with another mode of action have failed,” he told MD Magazine.
The full report, “EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update” was published this month in Annals of the Rheumatic Diseases.
Joseph Smolen photograph courtesy of the Vienna School of Clinical Research.
These inclusions resulted in the deletion of a previous recommendation. “In treatment-naïve patients we now recommend primarily using MTX plus short-term glucocorticoids. The recommendation to use combinations of csDMARDs has been deleted and we now more strongly recommend combining with glucocorticoids,” Dr. Smolen (pictured) explained to MD Magazine when reached for comment. The recommendation of GC is the new sixth recommendation, replacing the deleted one regarding csDMARD combinations.