ACR 2020 Debate: JAK Inhibitors vs Biologics After Methotrexate Failure in RA

The 2015 American College of Rheumatology (ACR) guidelines for the treatment of rheumatoid arthritis (RA) recommends the use of tumor necrosis factor (TNF) inhibitors before Janus kinase (JAK) inhibitors in patients with inadequate response to conventional disease-modifying antirheumatic drugs (csDMARDs).¹ However, several recent studies^2,3 have suggested the potential efficacy and superiority of JAK inhibitors over biologics in the treatment of RA. 

In light of the evolution of treatment options for RA in last few decades, the topic at the Great Debate at this year’s all-virtual ACR annual meeting was whether JAK inhibitors should or should not be used before biologics after methotrexate failure in RA. Vibeke Strand, MD, adjunct clinical professor in the Division of Immunology/Rheumatology at the Stanford University School of Medicine in California, argued in favor of the early use of JAK inhibitors, while Michael E. Weinblatt, MD, professor of medicine at the Harvard Medical School and Brigham and Women’s Hospital in Boston, provided his opinion on the use of anti-TNF therapies before JAK inhibitors in methotrexate-resistant RA. 

JAK Inhibitors vs Anti-TNF Therapies in RA

The debate opened with Dr Strand highlighting the role of JAK inhibitors in the modulation of distinct cytokine pathways, which they do not continuously inhibit for 24 hours. She noted the 3 JAK inhibitors, including baricitinib, upadacitinib, and tofacitinib, which are currently approved by the Food and Drug Administration (FDA) for RA treatment in the United States.

Dr Weinblatt began his presentation by indicating the 5 FDA approved anti-TNF therapies and emphasizing the 22 years of strong clinical experience with anti-TNF therapies.

Clinical Efficacy and Remission

Among patients with RA, both baricitinib and upadacitinib were found to be superior to adalimumab, while tofacitinib and filgotinib were noninferior to adalimumab, Dr Strand stated. Studies, including ORAL Strategy⁴ and FINCH1,⁵ have indicated sustained ACR responses and Clinical Disease Activity Index (CDAI) remission with JAK inhibitors plus methotrexate in patients with RA with prior inadequate response or intolerance to methotrexate.

Dr Strand also offered data from a study,⁶ presented at the European League Against Rheumatism (EULAR) 2020 meeting, which showed superior improvements in RA signs and symptoms with upadacitinib vs abatacept in patients with prior inadequate response or intolerance to biologic DMARDs (bDMARDs).

In his presentation, Dr Weinblatt quoted findings from the COMET trial,⁷ which suggested that etanercept plus methotrexate showed clinical remission and radiographic nonprogression within 1 year in patients with early, severe RA. On the other hand, Dr Strand suggested that remission was more likely to occur and occurred earlier with JAK inhibitor treatment.

Dr Strand went on to describe the early onset of benefit with JAK inhibitors (maximal benefit at 3 months) in RA, regardless of population. A compelling argument was the rapid onset of action of JAK inhibitors, with ACR20 and ACR50 responses reported as early as 1 and 2 weeks, respectively.

Dr Weinblatt pointed out that both TNF and JAK inhibitors showed similar clinical effects with comparable efficacy, had similar long-term retention rates, and were associated with improvements in patient-reported outcomes (PROs). However, he argued that anti-TNF doses can be modified or withdrawn in patients with low disease activity or in remission. In addition, with anti-TNF therapy, nonsteroidal anti-inflammatory drug (NSAID) and steroid doses may also be reduced.

Patient-Reported Outcomes

As reported by Emery and colleagues,⁷ 24% of patients who received methotrexate alone vs 9% of those who received etanercept plus methotrexate stopped working during the study period, Dr Weinblatt noted.

Dr Strand also spoke on the importance of functioning and overall health of patients with RA, highlighting the improvements in Health Assessment Questionnaire, pain, and fatigue with the first JAK inhibitor, and suggesting that early initiation led to better patient responses in the disease process. She added that these patients were reported to be typically active within or outside the home. With upadacitinib, clinically meaningful improvements were reported in 55% to 75% of patients with RA, with 11% to 50% showing PRO scores greater than normative values at 3 months.⁸

The convenience of JAK inhibitors as being orally administered was also noted.

Safety and Toxicity

Dr Weinblatt recognized the safety issues linked to anti-TNF therapies, which included risk for infections, such as bacterial sepsis and opportunistic infections, demyelinating syndromes, and hematologic toxicity; however, he pointed that anti-TNF therapies were generally well tolerated among patients.

In a case for the early use of JAK inhibitors, Dr Strand agreed that safety was similar to TNF inhibitors, with exceptions such as higher incidence of herpes zoster reactivation, venous thromboembolism events (VTEs), and gastrointestinal perforations. On a similar note, Dr Weinblatt referred to data from a paper published in Lancet Rheumatology⁹ that described the risk for hospitalizations due to serious infections with targeted synthetic vs bDMARDs in patients with RA. Risk for herpes zoster was found to be 2-fold higher with tofacitinib vs bDMARDs.

The topic of VTEs was heavily discussed by both experts. Dr Strand provided relevant data about the increased incidence of VTEs with JAK inhibitors in combination with bDMARDs, but balanced incidence with adalimumab vs methotrexate. She noted that most patients with VTEs had a prior event, and that glucocorticoids and NSAIDs may increase VTE risk. Dr Weinblatt supported his argument with evidence that both tofacitinib and adalimumab showed comparable risk for VTEs; however, he added the greater number of pulmonary embolisms and deaths observed with certain doses of tofacitinib (10 mg) vs anti-TNF therapies. Dr Weinblatt shared information from a 2019 report by the European Medicines Agency (EMA),¹⁰ which concluded that tofacitinib could increase blood clot risk in the lungs and deep veins in high-risk patients and must be prescribed with caution.

Summary

Dr Strand concluded that the availability of JAK inhibitors was an exciting development for treating rheumatic and autoimmune diseases, but they must be used early in RA. Head-to-head comparisons have established the efficacy of JAK inhibitors in RA; however, the safety risks must be weighed.

Dr Weinblatt ended his presentation with some of the known benefits of anti-TNF therapies, including dose flexibilities, 22-year clinical use, lower rates of herpes zoster, and cost effectiveness of biosimilars, although similar efficacy was seen between both drugs.

Fielding Questions

At the end of the debate, session participants posed a series of questions to both speakers.

One question addressed the effects of JAK inhibitors on reproduction. Dr Weinblatt provided evidence from animal studies on the negative outcomes with upadacitinib in pregnant women. On the other hand, Dr Strand responded by saying that pregnancy outcomes were similar between both treatments though more research is required.

Some other points of discussion were vaccinations with JAK inhibitors and its short half-life, comparative costs of both treatments, and the need for laboratory monitoring with JAK vs TNF inhibitors.  

The debate closed with the looming question of whether there will be any changes to the newly updated RA management guidelines, with regard to treatment with JAK inhibitors and biologics.

Overall, results of the poll – use of JAK inhibitors before/after biologics in RA – concluded that most participants were in favor of using anti-TNF therapies vs JAK inhibitors in RA.

Disclosures: Both Dr Strand and Dr Weinblatt declared affiliations with the pharmaceutical industry.

References

1. Singh JA, Saag KG, Bridges Jr. L, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2016;68(1):1-26.

2. Kotyla PJ. Are Janus kinase inhibitors superior over classic biologic agents in RA patients? Biomed Res Int. Published May 10, 2018. doi:10.1155/2018/7492904

3. Chatzidionysiou K. Beyond methotrexate and biologics in RA – efficacy of JAK inhibitors and their place in the current treatment armamentarium. Mediterr J Rheumatol. 2020;31(1):120-128.

4. Fleischmann R, Mysler E, Hall S, et al. Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial. Lancet. 2017;390(10093):457-468.

5. Combe B, Kivitz A, Tanaka Y, et al. Efficacy and safety of filgotinib for patients with rheumatoid arthritis with inadequate response to methotrexate: FINCH1 primary outcome results [abstract]. Arthritis Rheumatol. 2019;71(10).

6. Rubbert-Roth A, Enejosa J, Pangan A, et al. Efficacy and safety of upadacitinib versus abatacept in patients with active rheumatoid arthritis and prior inadequate response or intolerance to biologic disease-modifying anti-rheumatic drugs (SELECT-CHOICE): a double-blind, randomized controlled phase 3 trial. Ann Rheum Dis. 2020;79:1015-1016.

7. Emery P, Breedveld FC, Hall S, et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. 2008;372(9636):375:382.

8. Strand V, Schiff M, Tundia N, et al. Effects of upadacitinib on patient-reported outcomes: results from SELECT-BEYOND, a phase 3 randomized trial in patients with rheumatoid arthritis and inadequate responses to biologic disease-modifying antirheumatic drugs. Arth Res Ther. 2019;21:263.

9. Ajinkya P, Desai RJ, Gautam N, Kim SC. Risk of admission to hospital for serious infection after initiating tofacitinib versus biologic DMARDs in patients with rheumatoid arthritis: a multidatabase cohort study. Lancet Rheum. 2020;2(2):84-98.

10. European Medicines Agency (EMA). Annual Report 2019. Accessed November 11, 2020. https://www.ema.europa.eu/en/documents/annual-report/2019-annual-report-european-medicines-agency_en.pdf