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Sparks et al. (1) are to be congratulated on an important and timely study. They found that the use of JAKi was associated with worse outcome of Covid-19 infection, and they interpret this as a harmful effect of the treatment in that particular setting. But this question deserves further consideration. Assuming that the observation is correct, what could the mechanism be? As the authors correctly point out, some JAKis did show benefits for patients with severe Covid-19 infection (2, 3). We therefore propose an alternative explanation of the observed data.
Some guidance documents (4,5), and certainly medical practice traditions, frequently have patients discontinue immunomodulatory treatments when a potentially severe infection is diagnosed, and it seems safe to assume that the vast majority of patients in the study did, in fact, stop their treatment when they became aware of the infection. While this would of course apply to all antirheumatic therapies, there are important differences in the impact this might have. Biologicals have half-lives in the order of weeks, and the effect of stopping the treatment is therefore limited in the acute setting. For MTX, pharmacodynamic aspects also lead to a long latency in the impact of discontinuing the drug. In contrast, JAKi have short half-lives and discontinuing the treatment will almost immediately lead to the re-activation of the relevant signaling pathways.
We therefore propose, as an alternative possible explan...
We therefore propose, as an alternative possible explanation of the findings by Sparks et al, that it is the discontinuation of JAKi when SARS-CoV-2 infection is diagnosed, rather than the treatment itself, that is harmful.
Needless to say, this possibility needs to be tested in clinical studies before leading to changes in practice, and would most likely only be addressed sufficiently in a prospective, randomized trial.
(1) Sparks JA, Wallace ZS, Seet AM, et al. Ann Rheum Dis. 2021 May 28:annrheumdis-2021-220418. doi: 10.1136/annrheumdis-2021-220418. PMID: 34049860; PMCID: PMC8172266.
(2) Kalil AC, Patterson TF, Mehta AK, et al. N Engl J Med. 2021 Mar 4;384(9):795-807. doi: 10.1056/NEJMoa2031994. PMID: 33306283; PMCID: PMC7745180.
(3) Guimarães PO, Quirk D, Furtado RH, et al. N Engl J Med. 2021 Jun 16. doi: 10.1056/NEJMoa2101643. PMID: 34133856.
(4) Landewé RB, Machado PM, Kroon F, et al. Annals of the Rheumatic Diseases 2020;79:851-858.
(5) Leipe, J., Hoyer, B.F., Iking-Konert, C. et al. Z Rheumatol 79, 686–691 (2020). https://doi.org/10.1007/s00393-020-00878-0