التفاصيل البيبلوغرافية
| العنوان: |
Efficacy and Safety of Tofacitinib in Patients with Polymyalgia Rheumatica (EAST PMR): An open-label randomized controlled trial. |
| المؤلفون: |
Ma, Xinlei, Yang, Fan, Wu, Jinzhi, Xu, Bei, Jiang, Mengdi, Sun, Yiduo, Sun, Chuanying, Yu, Ye, Xu, Danyi, Xiao, Lanlan, Ren, Chunyun, Chen, Chunyan, Ye, Zi, Liang, Junyu, Lin, Jin, Chen, Weiqian |
| المصدر: |
PLoS Medicine; 6/29/2023, Vol. 19 Issue 6, p1-15, 15p, 2 Diagrams, 2 Charts, 1 Graph |
| مصطلحات موضوعية: |
RANDOMIZED controlled trials, MONONUCLEAR leukocytes, PATIENT safety, POLYMYALGIA rheumatica, BLOOD sedimentation, OLDER people |
| مستخلص: |
Background: 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.cnTest/, ChiCTR2000038253). Xinlei Ma and co-workers investigate tofacitinib as a possible treatment for patients with polymyalgia rheumatica. Author summary: Why was this study done?: Polymyalgia rheumatica (PMR) is a common inflammatory disease in elderly persons whose pathogenesis is not elucidated. Glucocorticoids are the first-line drugs for patients with PMR but result in numerous side effects. New therapeutic agents are urgently needed. We investigated whether Janus tyrosine kinase (JAK) signaling was involved in the pathogenesis of PMR and if JAK-inhibitor tofacitinib was effective in the treatment of patients with PMR. What did the researchers do and find?: In this prospective study, we showed increased expression of many genes related to JAK signaling in PMR. We further found that patients with PMR receiving tofacitinib (n = 35) or glucocorticoid (n = 32) both had a proportion of 100% (PMR activity disease score (PMR-AS) ≤ 10) at weeks 12 and 24. PMR-AS, c-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were all significantly decreased at weeks 12, and 24 in both groups. No severe adverse events were observed. What do these findings mean?: These results suggest that JAK signaling is involved in the pathogenesis of PMR. In this study, tofacitinib monotherapy had similar benefits to glucocorticoid treatment in patients with PMR. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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