tofacitinib and Osteoporosis

The inadequate response of some patients with rheumatoid arthritis (RA) to current therapies is an issue that needs to be addressed. Patients with refractory RA (RRA) are often accompanied by high Tumor necrosis factor (TNF) expression. We evaluated the synergistic therapeutic effects of the combination of Iguratimod (IGU) and Tofacitinib (TOF) on RRA and secondary osteoporosis.. Pathological changes in the ankle joints of collagen-induced arthritis (CIA) + TNF model rats were assessed using hematoxylin and eosin (HE) staining. Immunohistochemistry (IHC) and immunofluorescence (IF) were used to evaluate pyroptosis-related protein levels in the synovial tissues. Moreover, the knee joint was investigated by performing HE staining, IHC, and micro-computed tomography. Furthermore, in vitro, western blotting and enzyme-linked immunosorbent assay (ELISA) were performed to detect the effects of TOF and IGU on TNF-α-induced pyroptosis in fibroblast-like synoviocytes of RA.. After treatment with TOF and/or IGU, the arthritis scores, inflammatory cell infiltration in synovial tissues, and levels of interleukin (IL)-18, IL-1β, and IL-6 in the plasma were remarkably increased in the CIA + TNF model and dramatically decreased in the combination group. The expression of pyroptosis-related proteins was significantly lower in the combination group than in the CIA + TNF group, and a consistent trend was observed in vitro. Bone destruction was significantly alleviated, and the bone turnover rate was remarkably increased in the combination group compared to that in the CIA + TNF model.. TOF + IGU alleviated the severity of RRA in the CIA + TNF rat model, relieving joint inflammation, reducing bone erosion, and suppressing pyroptosis. The combined application of TOF and IGU may have a superimposed therapeutic effect on RRA and secondary osteoporotic bone remodeling.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Drug Combinations; Humans; Osteoporosis; Rats; Tumor Necrosis Factor-alpha; X-Ray Microtomography

Systemic inflammation is the main factor underlying secondary osteoporosis in patients with rheumatoid arthritis (RA). Janus kinase inhibitors (JAKi), such as tofacitinib (Tofa), can control systemic inflammation and may have beneficial effects on bone in various models. This might be due to direct effects on the bone microenvironment and not exclusively based on their anti-inflammatory function. Bone marrow adipocytes (BMAds) are abundant in the bone microenvironment. The effect of JAKi on BMAds is unknown, but evidence suggests that there is competition between human bone marrow-derived stromal cell (hBMSC) differentiation routes towards BMAds and osteoblasts (Ob) in osteoporosis.. The aims of the study are to determine whether Tofa influences BMAds and Ob derived from hBMSCs and to investigate the potential effects of Tofa on bone marrow adiposity in RA patients.. To determine the effect of Tofa on cellular commitment, hBMSCs were differentiated to BMAds or OBs for 3 days together with Tofa at 200, 400, or 800 nM and TNFα. This study was also conducted using differentiated BMAds. The impact of Tofa was determined by gene and protein expression analysis and cell density monitoring. In parallel, in a pilot study of 9 RA patients treated with Tofa 5 mg twice a day (NCT04175886), the proton density fat fraction (PDFF) was measured using MRI at the lumbar spine at baseline and at 6 months.. In non-inflammatory conditions, the gene expression of Runx2 and Dlx5 decreased in Ob treated with Tofa (p <0.05). The gene expression of PPARγ2, C/EBPα, and Perilipin 1 were increased compared to controls (p <0.05) in BMAds treated with Tofa. Under inflammatory conditions, Tofa did not change the expression profiles of Ob compared to TNFα controls. In contrast, Tofa limited the negative effect of TNFα on BMAd differentiation (p <0.05). An increase in the density of differentiated BMAds treated with Tofa under TNFα was noted (p <0.001). These findings were consolidated by an increase in PDFF at 6 months of treatment with Tofa in RA patients (46.3 ± 7.0% versus 53.2 ± 9.2% p <0.01).. Together, these results suggest a stimulatory effect of Tofa on BMAd commitment and differentiation, which does not support a positive effect of Tofa on bone.

Topics: Adipocytes; Arthritis, Rheumatoid; Bone Marrow; Clinical Studies as Topic; Humans; Inflammation; Osteoporosis; Pilot Projects; Piperidines; Pyrimidines

Mutations in DDX58 (DExD/H-box helicase 58), which encodes the cytoplasmic RNA sensor retinoic acid-inducible gene I (RIG-I), were recently identified in the rare autoimmune disease Singleton-Merten syndrome (SMS). We report the spontaneous development of psoriasis-like skin lesions as an SMS-like symptom in transgenic mice harboring one of the RIG-I SMS variants, E373A. Histological analysis revealed typical characteristics of psoriasis, including the abnormal proliferation and differentiation of keratinocytes leading to epidermal hyperplasia, and infiltrates consisting of neutrophils, dendritic cells and T cells. Levels of the IL-23/IL-17 immune axis cytokines were high in the skin lesions. Rag2-/- transgenic mice showed partial amelioration of the phenotype, with down-regulation of inflammatory cytokines, including IL-17A, suggesting the importance of lymphocytes for the pathogenesis similar to that of human psoriasis. Of note, IL-17A deficiency abolished the skin phenotype, and treatment using the JAK inhibitor tofacitinib not only prevented onset, but also improved the skin manifestations even after onset. Our study provides further evidence for the involvement of RIG-I activation in the onset and progression of psoriasis via type I interferon signaling and the IL-23/IL-17 axis.

Topics: Animals; Aortic Diseases; DEAD Box Protein 58; Dendritic Cells; Dental Enamel Hypoplasia; DNA-Binding Proteins; Epidermis; Hyperplasia; Interferon Type I; Interleukin-17; Interleukin-23 Subunit p19; Janus Kinase Inhibitors; Janus Kinases; Keratinocytes; Metacarpus; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscular Diseases; Neutrophils; Odontodysplasia; Osteoporosis; Piperidines; Psoriasis; Pyrimidines; T-Lymphocytes; Vascular Calcification