OBJECTIVE To investigate the effects of MIR149 rs2292832 and MIR499 rs3746444 gene polymorphisms on the efficacy of tofacitinib combined with iguratimod in the treatment of moderate‑to‑severe rheumatoid arthritis （RA）， to provide genetic reference for individualized treatment of moderate‑to‑severe RA patients.METHODS This was a prospective cohort study， and patients were grouped according to genotyping results. A total of 320 patients with moderate-to-severe RA diagnosed in the department of immunology of our hospital between January 2023 and January 2024 were enrolled. All patients received standardized treatment with tofacitinib （5 mg twice daily） combined with iguratimod （25 mg twice daily） for 24 weeks treatment course. Clinical efficacy outcomes， including American College of Rheumatology （ACR） 20/50/70 responses， disease activity score‑28 based on C‑reactive protein （DAS28-CRP）， erythrocyte sedimentation rate （ESR） and C-reactive protein （CRP）， were compared among patients with different genotypes. Combined-genotype analysis and multivariate Logistic regression analysis were also performed.RESULTS The MIR149 rs2292832 CC-genotype patients exhibited significantly higher ACR20， ACR50 and ACR70 response rates （88.90%， 67.78%， 45.56%） than those carrying CT- and TT-genotypes （ P ＜0.05）. After 24 weeks treatment， the reductions in DAS28‑CRP， ESR and CRP were significantly greater in CC‑genotype patients than in CT‑ and TT‑genotype patients （ P ＜0.05）， and the 24‑week DAS28‑CRP was significantly lower in the CC‑genotype patients than in CT‑ and TT‑genotype patients （ P ＜0.05）. The MIR499 rs3746444 GG-genotype showed significantly higher ACR20， ACR50 and ACR70 response rates （91.46%， 73.17%， 52.44%） than those carrying AG‑ and AA‑genotypes （ P ＜0.05）. After 24 weeks of treatment， the reductions in DAS28‑CRP， ESR and CRP were significantly greater in GG‑genotype patients than in AG- and AA-genotype patients and the 24‑weeks DAS28‑CRP was significantly lower in the GG‑genotype patients than in AG- and AA-genotype patients （ P ＜0.05）. Among the nine combined‑genotyps， the CC+GG genotype yielded the best treatment response. The MIR149 rs2292832 CC and MIR499 rs3746444 GG genotypes were independent predictors of clinical remission （ P ＜0.01）， whereas baseline DAS28‑CRP ≥ 6.5 served as a negative predictor of clinical remission （ P ＜0.05）.CONCLUSIONS Gene polymorphisms of MIR149 rs2292832 and MIR499 rs3746444 significantly influence the therapeutic effect of tofacitinib combined with iguratimod in patients with moderate-to-severe RA. Patients carrying CC and GG genotypes achieve better treatment responses.

BACKGROUND:Porous gradient hydroxyapatite/zirconia composite, which can adhere to a variety of cel s, such as osteoblasts, bone marrow mesenchymal stem cel s and chondrocytes, can induce and promote fracture healing or replace bone defects. OBJECTIVE:To review the development and application of porous gradient hydroxyapatite/zirconia composite in bone tissue engineering. METHODS:Articles related to porous gradient hydroxyapatite/zirconia composite in bone tissue engineering were retrieved in CNKI and PubMed databases (1971-01/2014-12). The key words were“porous bioceramic, bone tissue engineering, bone morphogenetic protein-2, induced pluripotent stem cel s”in Chinese and English, respectively. A total of 54 articles based on inclusion criteria and exclusion criteria were obtained for the review. RESULTS AND CONCLUSION:Porous gradient hydroxyapatite/zirconia composite can provide a scaffold to induce natural y forming bone growing to fil the three-dimensional pores, thus realizing the perfect integration of tissue-engineered bone material and host-bone tissue. As zirconia functions as an enhancer of hydroxyapatite, high-quality artificial bone materials, which have elastic modulus, fracture toughness and structure similar to human bone, can be prepared by adjusting the proportion and porosity of materials. Additional y, the new hydroxyapatite/zirconia foamed ceramics as tissue-engineered bone carrying bone morphogenetic protein-2/chitosan gel sustained release system and bone marrow mesenchymal stem cel s derived from induced pluripotent stem cel s wil be expected to increase bone formation and bone fusion rates significantly in the future.