The pathophysiology of the widespread inflammatory disease Polymyalgia Rheumatica (PMR), which affects elderly people, is unknown. The shoulder, neck, and pelvic girdle all experience discomfort and morning stiffness due to the condition.
The first-line treatment for PMR patients is glucocorticoids, although they have a lot of negative effects. Therefore, it is necessary to investigate pathogenetic aspects and find potential glucocorticoid-sparing medications.
A recent study examined the pathogenetic aspects of the condition and evaluated the effectiveness and security of the JAK-inhibitor tofacitinib in PMR patients. Researchers focused on determining if JAK signaling had a role in the development of PMR and whether tofacitinib, a JAK inhibitor, was beneficial in treating patients with PMR.
PMR pathophysiology is linked to polymorphisms in interleukin 6 (IL-6). In the synovial tissue of six PMR patients, IL-6 is shown to be strongly expressed, according to a recent article. According to reports, PMR’s therapeutic target is suppressing the IL-6 receptor. Tocilizumab, an inhibitor of the IL6 receptor, has recently been demonstrated to be an effective treatment option for treating new-onset PMR and glucocorticoid-dependent PMR.
This project had 2 phases: an observational study and a Phase II- randomized, monocenter, open-label, controlled, noninferiority trial. The study involved diagnosed PMR patients from the First Affiliated Hospital, Zhejiang University School of Medicine, between September 2020 and September 2022.
The pathogenetic characteristics of patients with PMR were examined in the first cohort. Patients in the second cohort received tofacitinib or glucocorticoids for 24 weeks of treatment.
Twenty healthy controls (HCs) and 11 patients with newly diagnosed PMR had their peripheral blood mononuclear cells (PBMCs) isolated. Researchers additionally collected PBMCs from five PMR patients receiving tofacitinib treatment and were in remission. Researchers then used a CD4+T cell isolation kit to separate the CD4+T cells. Tofacitinib or DMSO was used to culture CD4+T cells in soluble CD3 (1 g/ml) and CD28 (1 g/ml) media. Twenty-four hours later, T cells were harvested.
In the first cohort, scientists found that the gene expression patterns of peripheral blood mononuclear cells (PBMCs) in 11 patients significantly differed from 20 healthy controls ) by RNA sequencing. Inflammatory response and cytokine–cytokine receptor interaction were the most notable pathways affected.
Scientists noted, “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 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.
Thirty-nine patients with newly diagnosed PMR received tofacitinib, and 37 received glucocorticoid. Thirty-five patients and 32 patients completed the 24-week intervention, respectively. 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.
Scientists noted, “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.”
“We further found that patients with PMR receiving tofacitinib or glucocorticoid 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) significantly decreased at weeks 12 and 24 in both groups. No severe adverse events were observed.”
“Tofacitinib monotherapy had similar benefits to glucocorticoid treatment in patients with PMR.”
Journal Reference:
- Ma X, Yang F, Wu J, Xu B, Jiang M, Sun Y, et al. (2023) Efficacy and Safety of Tofacitinib in Patients with Polymyalgia Rheumatica (EAST PMR): An open-label randomized controlled trial. PLoS Med 20(6): e1004249. DOI: 10.1371/journal.pmed.1004249