Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: The selective Janus kinase (JAK) inhibitor tofacitinib inhibits progression of structural damage in rheumatoid arthritis (RA). These results suggest the possibility that tofacitinib improves osteoclastic bone destruction of RA. However, the detailed mechanism of tofacitinib for bone metabolism in RA is poorly understood. The purpose of this study is to clarify the effect of tofacitinib on bone metabolism, especially osteoclast regulating factor in RA.
Methods: Fourteen patients with active RA who inadequate response to DMARDs (mean age: 54.6 years, mean disease duration: 4.1 years, mean simplified disease activity index: 26.9, ACPA positive: 86%, oral steroid use: 29%, mean oral steroid dose: 10mg/day, MTX use: 93%, mean MTX dose:10.9mg/week, biologic DMARDs naïve: 57%) were started on treatment with tofacitinib 5mg twice daily (BID). Disease activity was assessed using the simplified disease activity index (SDAI). Next, the following soluble biomarkers of bone remodeling were measured by ELISA at the baseline and after 2, 4 and 12 weeks. (i) bone formation marker: osteocalcin (IRMA SRL, corp.); (ii) bone resorption maker: type I collagen cross-linked N-telopeptides (NTx) (ELISA , SLR corp.); (iii) osteoclat regulator: soluble receptor activator of nuclear factor kappa B ligand (sRANKL) (human RANKL ELISA kit, Biomedica) and osteoprotegerin (OPG) (human osteoprotegerin ELISA kit, Biomedica)
Results: After treatment of tofacitinib, SDAI score among all fourteen patients decreased significantly from 26.9±12.4 (mean±SD) at the base line to 14.7±9.9 at week 4 (p<0.0001), to 8.3±6.1 at week 12 (p<0.0001). Average of osteocalcin levels increased significantly from 6.9±4.3 ng/mL at the baseline to 8.8±6.1 at week 12 (p=0.0142), whereas average of NTx levels tend to decrease from 18.2±5.9 nmol BCE/L at the baseline to 16.7±5.8 at week 12. At the baseline, sRANKL levels were significantly correlated with CRP levels (Spearman r2=0.488, P=0.0054). Average of sRANKL levels decreased significantly from 0.15±0.11 pmol/L at the baseline to 0.09±0.05 at week 2 (p=0.0097), to 0.11±0.10 at week 4 (p=0.0311), to 0.08±0.05 at week 12 (p=0.0014). On the other hand, statistically significant changes in OPG levels were not observed during 12 weeks. Consequently, average of sRANKL/OPG ratio decreased significantly from 4.81±4.82 at the baseline to 2.62±1.84 at week 2 (p=0.0186), to 3.11±2.81 at week 4 (p=0.0191), to 2.11±1.72 at week 12 (p=0.0052). Interestingly, decreasing effects of sRANKL level or sRANKL/OPG ratio were greater in patient with the high sRANKL level (>0.14 pmol/L: mean value of 70 RA patients in previous our study) at the base line.
Conclusion: Here, we show for the first time that tofacitinib has improved inflammatory bone metabolism immediately through the regulation of sRANKL levels and sRANKL/OPG balance in patients with RA. It had been reported that tofacitinib regulated synovitis through inhibition of IL-17 production by CD4+ T cells and IL-6 production by synovial fibroblasts in RA (Maeshima K. et al. Arthritis Rheum.64:1790-8.2012). Thus, tofacitinib might control of RANKL induction via inhibition of IL-17 and IL-6 production in RA synovium.
To cite this abstract in AMA style:Kitano M, Kitano S, Furukawa T, Yokoyama Y, Nishioka A, Sekiguchi M, Azuma N, Matsui K, Sano H. Early Effects of Tofacitinib on Bone Homeostasis in Patients with Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/early-effects-of-tofacitinib-on-bone-homeostasis-in-patients-with-rheumatoid-arthritis/. Accessed June 22, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/early-effects-of-tofacitinib-on-bone-homeostasis-in-patients-with-rheumatoid-arthritis/