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LETTER TO EDITOR
Ahead of print publication  

Tumor necrosis factor inhibitors versus janus kinase inhibitors in patients with incomplete response to methotrexate in rheumatoid arthritis


1 Department of Clinical Immunology and Rheumatology, King George's Medical University, Lucknow, Uttar Pradesh, India
2 Department of Neurology, SMS Hospital, Jaipur, Rajasthan, India
3 Department of Medicine, Sardar Vallabhbhai Patel Institute of Medical Sciences and Research and Smt, NHL Municipal Medical College, Ahmedabad, Gujarat, India

Date of Submission31-Oct-2021
Date of Acceptance14-Dec-2021
Date of Web Publication02-Feb-2022

Correspondence Address:
Kunal Chandwar,
Department of Clinical Immunology and Rheumatology, King George's Medical University, Lucknow - 226 003, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_251_21



How to cite this URL:
Chandwar K, Shah C, Srivastava P. Tumor necrosis factor inhibitors versus janus kinase inhibitors in patients with incomplete response to methotrexate in rheumatoid arthritis. Indian J Rheumatol [Epub ahead of print] [cited 2022 Oct 1]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=337586



Dear editor,

With the ever expanding armamentarium of biologics and targeted synthetic disease-modifying antirheumatic drugs (bDMARDs and tsDMARDs) in rheumatoid arthritis (RA), one is spoilt for choices between when and what to choose. With a lack of head-to-head trials, the confusion increases further. With the recent ACR guidelines recommending bDMARDs/tsDMARDs after incomplete response to methotrexate inadequate response (MTXIR) over triple therapy,[1] keeping Janus kinase inhibitors (JAKi) at an equal pedestal as other bDMARDs, it should be worthwhile to note how they fare as compared to other biological agents.

There are currently five JAKi available for the use in RA in different countries including tofacitinib, baricitinib, upadacitinib, peficitinib, and filgotinib. Of these, tofacitinib and peficitinib are pan JAKi, baricitinib is JAK1/2 selective, and upadacitinib and filgotinib are JAK1 selective.

JAKi have the advantage of having oral route of administration, much faster onset of action, more robust pain control, and almost equal efficacy to bDMARDs if not better. We have head-to-head trials with JAKi and adalimumab an Anti-TNF (Tumor Necrosis Factor) biologics and this gives us a chance to compare the efficacy of JAKi vis a vis adalimumab and between JAKi themselves.

The ORAL Standard[2] trial compared tofacitinib 5 mg and 10 mg bid doses to adalimumab 40 mg every 2 weeks and placebo in MTXIR patients, RA-BEAM trial[3] did the same for baricitinib 4 mg, SELECT-COMPARE[4] for upadacitinib 15 mg, and FINCH 1[5] for filgotinib 100 mg and 200 mg.

There were no available head-to-head trials for peficitinib.

Scientifically comparing heterogeneous population head-to-head would not be a wise decision but comparing the inclusion criteria and baseline characteristics of the patients included in the trial [Table 1]. The patients included were more similar than heterogeneous and with a lack of head-to-head trial between individual JAKi, a comparison between responses in trial may not be ideal but does indicate a trend that could guide future therapy with the caveat that actual head-to-head trial between available JAKi is the need of the hour where JAKi have turned out to be jack of all trades.
Table 1: Inclusion criteria and baseline characteristics of mentioned studies

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From the looks of it comparing the ACR20, ACR50, and ACR70 responses [Figure 1]c, filgotinib 200 mg can be seen to have the best response among the JAKis, but a closer look points out at the high placebo and adalimumab response in the FINCH trial [Figure 1]a and [Figure 1]b; the reason for such high placebo response is intriguing and has been attributed to increasing placebo response rates over the years[6] but that does not explain the high adalimumab response rates. While all JAKi demonstrated superiority over placebo, only baricitinib and upadacitinib proved a statistically significant difference to prove superiority over adalimumab[3],[4] while tofacitinib was not powered to do so and filgotinib could not, yet numerically ACR20, ACR50, and ACR70 responses, DAS28 responses, CDAI and HAQ-DI, and other patient-reported outcomes were better in JAKis compared to adalimumab across the trial. One criticism most JAKi trials face is using endpoints that are dependent on IL6-mediated markers, especially C-reactive protein (CRP) – as there is a robust decrease in CRP levels, American college of rheumatology response criteria (ACR), or DAS-28 responses will show a more significant reduction.
Figure 1: ACR20, ACR50, and ACR70 responses for (a) placebo, (b) adalimumab, and (c) Janus kinase inhibitors at 12 weeks in the trials and (d) absolute difference between placebo and Janus kinase inhibitors response at 12 weeks for ORAL Standard (2), RA-BEAM (3), SELECT-COMPARE (4), and FINCH1 (5) trial

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The argument has been blunted to certain extent by a significant difference in CDAI response and patient-reported outcomes. When we see the absolute difference between JAKi and placebo response and also compare the baseline characteristics of the trial patients a clearer picture emerges – patients in ORAL Standard trial had the lowest baseline DAS-28 (CRP), shortest disease duration and HAQ-DI, patients in FINCH 1 had shorter disease duration, lowest baseline CRP levels probably explaining higher placebo and adalimumab response rate patients in both RA-BEAM and SELECT-COMPARE had high baseline hs-CRP and mean DAS-28 (CRP) levels. The ORAL Standard trial had lower response rate even for placebo and adalimumab and could be explained with the improving RA responses over the years since it was the earliest of the trails to be done but did prove equal efficacy of the tofacitinib 5 mg versus 10 mg regimens. When comparing the absolute difference between JAKi and placebo other than filgotinib 100 mg, which underperforms most JAKi have similar responses [Figure 1]d.

In terms of safety profile, most JAKi had similar safety profile, the recent finding from the Oral surveillance comparing TNF inhibitor and tofacitinib did show a numerically higher risk of malignancy and major adverse cardiovascular events during the long-term follow-up study, but a detailed analysis did point out that these patients had additional risk factors such as smoking and old age to predispose them to these events. The verdict is still out on the long-term safety data for other JAKi. Another point of concern is the decline of spermatogenesis in male patients with filgotinib 200 mg shown in animal models, but safety data are yet to confirm similar findings in human studies.

The answer to which is the best JAKi in RA may still be unresolved but newer JAKis are in the pipeline and with baricitinib and upadacitinib proving superiority over adalimumab and placebo they do come up as attractive options. Upadacitinib proved superiority over abatacept in RA and over adalimumab in psoriatic arthritis.[7],[8]

A head-to-head trial comparing JAKi with rituximab (anti-CD20) and tocilizumab (anti-IL6) could further enlighten the path to choose the best second-line drug for RA patients with incomplete response to MTXIR where bDMARDs/tsDMARDs are indicated. Exciting opportunities in treating RA await rheumatologist.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Fraenkel L, Bathon JM, England BR, St Clair EW, Arayssi T, Carandang K, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 2021;73:1108-23.  Back to cited text no. 1
    
2.
van Vollenhoven RF, Fleischmann R, Cohen S, Lee EB, García Meijide JA, Wagner S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 2012;367:508-19.  Back to cited text no. 2
    
3.
Taylor PC, Keystone EC, van der Heijde D, Weinblatt ME, Del Carmen Morales L, Reyes Gonzaga J, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med 2017;376:652-62.  Back to cited text no. 3
    
4.
Fleischmann R, Pangan AL, Song IH, Mysler E, Bessette L, Peterfy C, et al. upadacitinib versus placebo or adalimumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: Results of a phase III, double-blind, randomized controlled trial. Arthritis Rheumatol 2019;71:1788-800.  Back to cited text no. 4
    
5.
Combe B, Kivitz A, Tanaka Y, van der Heijde D, Simon JA, Baraf HS, et al. Filgotinib versus placebo or adalimumab in patients with rheumatoid arthritis and inadequate response to methotrexate: A phase III randomised clinical trial. Ann Rheum Dis 2021;80:848-58.  Back to cited text no. 5
    
6.
Bechman K, Yates M, Norton S, Cope AP, Galloway JB. Placebo response in rheumatoid arthritis clinical trials. J Rheumatol 2020;47:28-34.  Back to cited text no. 6
    
7.
Rubbert-Roth A, Enejosa J, Pangan AL, Haraoui B, Rischmueller M, Khan N, et al. Trial of upadacitinib or abatacept in rheumatoid arthritis. N Engl J Med 2020;383:1511-21.  Back to cited text no. 7
    
8.
McInnes IB, Anderson JK, Magrey M, Merola JF, Liu Y, Kishimoto M, et al. Trial of upadacitinib and adalimumab for psoriatic arthritis. N Engl J Med 2021;384:1227-39.  Back to cited text no. 8
    


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