In:
PLOS Medicine, Public Library of Science (PLoS), Vol. 20, No. 6 ( 2023-6-29), p. e1004249-
Abstract:
Polymyalgia rheumatica (PMR) is a common inflammatory disease in elderly persons whose mechanism of pathogenesis has not been elucidated. Glucocorticoids are the main first-line treatments but result in numerous side effects. Therefore, there is a need to explore pathogenetic factors and identify possible glucocorticoid-sparing agents. We aimed to study the pathogenetic features of the disease and assess the efficacy and safety of Janus tyrosine kinase (JAK)-inhibitor tofacitinib in patients with PMR. Methods and findings We recruited treatment-naïve PMR patients from the First Affiliated Hospital, Zhejiang University School of Medicine, between September 2020 and September 2022. In the first cohort, we found that the gene expression patterns of peripheral blood mononuclear cells (PBMCs) in 11 patients (10 female, 1 male, age 68.0 ± 8.3) with newly diagnosed PMR were significantly different from 20 healthy controls (17 female, 3 male, age 63.7 ± 9.8) by RNA sequencing. Inflammatory response and cytokine–cytokine receptor interaction were the most notable pathways affected. We observed marked increases in expression of IL6R, IL1B, IL1R1, JAK2, TLR2, TLR4, TLR8, CCR1, CR1, S100A8, S100A12, and IL17RA, which could trigger JAK signaling. Furthermore, tofacitinib suppressed the IL-6R and JAK2 expression of CD4 + T cells from patients with PMR in vitro . In the second cohort, patients with PMR were randomized and treated with tofacitinib or glucocorticoids (1/1) for 24 weeks. All PMR patients underwent clinical and laboratory examinations at 0, 4, 8, 12, 16, 20, and 24 weeks, and PMR activity disease scores (PMR-AS) were calculated. The primary endpoint was the proportion of patients with PMR-AS ≤10 at weeks 12 and 24. Secondary endpoints: PMR-AS score, c-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) at weeks 12 and 24. Thirty-nine patients with newly diagnosed PMR received tofacitinib, and 37 patients received glucocorticoid. Thirty-five patients (29 female, 6 male, age 64.4 ± 8.4) and 32 patients (23 female, 9 male, age 65.3 ± 8.7) patients completed the 24-week intervention, respectively. There were no statistically significant differences in primary or secondary outcomes. At weeks 12 and 24, all patients in both groups had PMR-AS 〈 10. PMR-AS, CRP, and ESR were all significantly decreased in both groups. No severe adverse events were observed in either group. Study limitations included the single-center study design with a short observation period. Conclusions We found that JAK signaling was involved in the pathogenesis of PMR. Tofacitinib effectively treated patients with PMR as glucocorticoid does in this randomized, monocenter, open-label, controlled trial (ChiCTR2000038253). Trial registration This investigator-initiated clinical trial (IIT) had been registered on the website ( http://www.chictr.org.cn/ , ChiCTR2000038253 ).
Type of Medium:
Online Resource
ISSN:
1549-1676
DOI:
10.1371/journal.pmed.1004249
DOI:
10.1371/journal.pmed.1004249.g001
DOI:
10.1371/journal.pmed.1004249.g002
DOI:
10.1371/journal.pmed.1004249.g003
DOI:
10.1371/journal.pmed.1004249.t001
DOI:
10.1371/journal.pmed.1004249.t002
DOI:
10.1371/journal.pmed.1004249.s001
DOI:
10.1371/journal.pmed.1004249.s002
DOI:
10.1371/journal.pmed.1004249.s003
DOI:
10.1371/journal.pmed.1004249.s004
DOI:
10.1371/journal.pmed.1004249.s005
DOI:
10.1371/journal.pmed.1004249.s006
DOI:
10.1371/journal.pmed.1004249.s007
DOI:
10.1371/journal.pmed.1004249.s008
DOI:
10.1371/journal.pmed.1004249.s009
DOI:
10.1371/journal.pmed.1004249.s010
DOI:
10.1371/journal.pmed.1004249.s011
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2164823-2
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