Tapering csDMARD or TNFi first: is the risk of flares different for ACPA-positive or ACPA-negative rheumatoid arthritis?

Abstract

According to the European Alliance of Associations for Rheumatology (EULAR) recommendations, glucocorticoids should be tapered first, followed by biological DMARDs (bDMARDs) and conventional synthetic DMARDs (csDMARDs).1 In the total RA population, the optimal order of tapering (bDMARDs first or csDMARDs first) regarding clinical outcomes is not evident from the limited number of studies that have investigated this.2 3 As the RA population is heterogeneous, there might be patient factors that are relevant for the choice of tapering order. ACPA-positive but not ACPA-negative patients have shown to benefit from concomitant use of methotrexate with a tumour necrosis factor inhibitor (TNFi) compared with TNFi monotherapy.4 5 Thus, ACPA-positive patients might be at a higher risk of flares when combination therapy is discontinued compared with ACPA-negative patients. [...]we aimed to explore differences in flare rates between tapering strategies separately for ACPA-positive and ACPA-negative patients with RA with well-controlled disease using both a TNFi and a csDMARD. Flare-free survival curves for ACPA-positive (A) and ACPA-negative (B) patients with RA comparing a tapering csDMARD-first strategy (orange straight line) versus a TNFi-first strategy (blue dotted line), including 95% CIs. Noteworthy is the fact that we observed an equal risk of flares in the ACPA-positive and the ACPA-negative population, which was confirmed by the SEAM-RA (Study of Etanercept and Methotrexate in Combination or as Monotherapy in Subjects with Rheumatoid Arthritis) trial but contradictive to the results of the RETRO (Reduction of Therapy in patients with Rheumatoid arthritis in Ongoing remission) trial.7–9 Possibly, ACPA-negative patients who require biologicals are a selective group of ACPA-negative patients for which tapering treatment is more difficult than for those who do not require biologicals.

Correspondence to Judith W Heutz; [email protected]

In well-controlled rheumatoid arthritis (RA), tapering of disease-modifying antirheumatic drugs (DMARDs) can be considered. According to the European Alliance of Associations for Rheumatology (EULAR) recommendations, glucocorticoids should be tapered first, followed by biological DMARDs (bDMARDs) and conventional synthetic DMARDs (csDMARDs).¹ In the total RA population, the optimal order of tapering (bDMARDs first or csDMARDs first) regarding clinical outcomes is not evident from the limited number of studies that have investigated this.^{2 3} As the RA population is heterogeneous, there might be patient factors that are relevant for the choice of tapering order. One factor could be the presence of anti-citrullinated protein antibodies (ACPA). ACPA-positive but not ACPA-negative patients have shown to benefit from concomitant use of methotrexate with a tumour necrosis factor inhibitor (TNFi) compared with TNFi monotherapy.^{4 5} Thus, ACPA-positive patients might be at a higher risk of flares when combination therapy is discontinued compared with ACPA-negative patients. Therefore, we aimed to explore differences in flare rates between tapering strategies separately for ACPA-positive and ACPA-negative patients with RA with well-controlled disease using both a TNFi and a csDMARD.

Data from the TApering Strategies in Rheumatoid Arthritis (TARA) trial were used.² The TARA trial was a multicentre randomised controlled trial in patients with established RA with a well-controlled disease (Disease Activity Score 44 (DAS44) ≤2.4 and swollen joint count (SJC) ≤1) for at least 6 months, achieved with both a csDMARD and TNFi. Patients were randomised to either gradually taper their csDMARD (mostly methotrexate) in the first year, followed by gradually tapering their TNFi (mostly etanercept or adalimumab) in the second year, or vice versa (online supplemental figure S1). The csDMARD was tapered to 50% of the original dose at baseline. At 3 months, the dose was reduced to one-quarter of the original dose. At 6 months, the csDMARD was discontinued. The TNFi was tapered by doubling the dose interval at baseline. At 3 months, the dose was tapered to 50% of the original dose, and at 6 months the TNFi was discontinued. Cox regression analyses were used to compare cumulative flare-free survival over 2 years between both tapering strategies in ACPA-positive and ACPA-negative patients separately. A flare was defined as DAS>2.4 and/or SJC>1, similar to the original TARA trial.² In case of a flare, the previous effective dose was restarted. This is in line with the OMERACT flare definition, in which a flare is defined as worsening of signs and symptoms leading to change in therapy.⁶ Stata V.18 was used. P values <0.05 were considered statistically significant.

Baseline characteristics of the included patients are listed in online supplemental table S1. In the 135 ACPA-positive patients, 66 tapered their TNFi first and 69 tapered their csDMARD first. The cumulative risk of flare after 2 years was similar for the two tapering strategies (HR 1.2, 95% CI 0.8 to 1.8, figure 1A). Although there appeared to be a visual difference between 12 and 21 months, the 95% CIs of the survival curves overlapped (figure 1A). After 2 years, this trend had disappeared and the overall flare risk was similar between the groups. In the 53 ACPA-negative patients, 29 tapered their TNFi first and 24 tapered their csDMARD first. Again, the cumulative risk of flare was similar for both tapering strategies (HR 0.9, 95% CI 0.5 to 1.9, figure 1B). As a sensitivity analysis, we corrected for baseline DAS, because this differed between tapering strategies in the ACPA-negative population (0.7 (TNFi first) vs 1.2 (csDMARD first), p<0.05). This yielded similar results (online supplemental table S2). Furthermore, no differences in flare-free survival percentages between ACPA-positive and ACPA-negative patients were seen (34% and 38%, respectively; HR 0.9, 95% CI 0.6 to 1.4).

Figure 1. Flare-free survival curves for ACPA-positive (A) and ACPA-negative (B) patients with RA comparing a tapering csDMARD-first strategy (orange straight line) versus a TNFi-first strategy (blue dotted line), including 95% CIs. ACPA, anti-citrullinated protein antibody; csDMARD, conventional synthetic disease-modifying antirheumatic drug; RA, rheumatoid arthritis; TNFi, tumour necrosis factor inhibitor.

Our results demonstrate that in ACPA-positive and ACPA-negative patients with RA, the risk of flare was similar for a TNFi-first vs a csDMARD-first tapering strategy. However, this should be taken with caution, since these are results from a post hoc analysis. These results could imply that a patient’s ACPA status does not need to be considered when deciding on a tapering order. Noteworthy is the fact that we observed an equal risk of flares in the ACPA-positive and the ACPA-negative population, which was confirmed by the SEAM-RA (Study of Etanercept and Methotrexate in Combination or as Monotherapy in Subjects with Rheumatoid Arthritis) trial but contradictive to the results of the RETRO (Reduction of Therapy in patients with Rheumatoid arthritis in Ongoing remission) trial.^7–9 Possibly, ACPA-negative patients who require biologicals are a selective group of ACPA-negative patients for which tapering treatment is more difficult than for those who do not require biologicals. Other predictive factors for flare risk that were previously investigated could be validated in our data in the future.^{8 9} In conclusion, we believe that the current data can aid in treatment decisions regarding DMARD tapering in RA, though validation is warranted.

Ethics statements

Patient consent for publication

Not applicable.

Ethics approval

The original TARA study was approved by the local Medical Ethics Committee (Rotterdam). All patients gave written informed consent.

Footnote

JWH and AEML contributed equally.

Contributors AEML, JWH and EvM contributed to the conception and analysis plan of this study. AEML statistically analysed the data. JWH wrote the first version of the manuscript and AEML, PHPdJ, AHMvdHvM and EvM revised it critically. EvM supervised the study. AEML, JWH and EvM are the guarantors for this manuscript. All authors approved the final manuscript.

Funding This study was funded by ZonMw (grant number 171102014).

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

References

¹ Smolen JS, Landewé RBM, Bergstra SA, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis 2023; 82: 3–18. doi:10.1136/ard-2022-223356

² van Mulligen E, Weel AE, Hazes JM, et al. Tapering towards DMARD-free remission in established rheumatoid arthritis: 2-year results of the TARA trial. Ann Rheum Dis 2020; 79: 1174–81. doi:10.1136/annrheumdis-2020-217485

³ Curtis JR, Emery P, Karis E, et al. Etanercept or methotrexate withdrawal in rheumatoid arthritis patients in sustained remission. Arthritis Rheumatol 2021; 73: 759–68. doi:10.1002/art.41589

⁴ Greenwood M, Shipa M, Yeoh S-A, et al. Methotrexate reduces withdrawal rates of TNF inhibitors due to ineffectiveness in rheumatoid arthritis but only in patients who are seropositive. Ann Rheum Dis 2020; 79: 1516–7. doi:10.1136/annrheumdis-2020-217725

⁵ van Mulligen E, van der Helm-van Mil A, de Jong PHP. Methotrexate prolongs TNF inhibitor survival, but only in autoantibody-positive rheumatoid arthritis: a validation study. Ann Rheum Dis 2023; 82: e217. doi:10.1136/annrheumdis-2020-219499

⁶ Alten R, Pohl C, Choy EH, et al. Developing a construct to evaluate flares in rheumatoid arthritis: a conceptual report of the OMERACT RA flare definition working group. J Rheumatol 2011; 38: 1745–50. doi:10.3899/jrheum.110400

⁷ Haschka J, Englbrecht M, Hueber AJ, et al. Relapse rates in patients with rheumatoid arthritis in stable remission tapering or stopping antirheumatic therapy: interim results from the prospective randomised controlled RETRO study. Ann Rheum Dis 2016; 75: 45–51. doi:10.1136/annrheumdis-2014-206439

⁸ Curtis JR, Emery P, Kricorian G, et al. Factors associated with maintenance of remission following change from combination therapy to monotherapy in patients with rheumatoid arthritis. J Rheumatol 2023; 50: 1114–20. doi:10.3899/jrheum.2022-1008

⁹ Rech J, Hueber AJ, Finzel S, et al. Prediction of disease relapses by multibiomarker disease activity and autoantibody status in patients with rheumatoid arthritis on tapering DMARD treatment. Ann Rheum Dis 2016; 75: 1637–44. doi:10.1136/annrheumdis-2015-207900