Evidence-based Translational Study Of JAK Inhibitors In The Treatment Of Rheumatoid Arthritis

Objective: Janus kinases inhibitors(JAKi)are a new type of targeted therapy drugs.At present,six drugs(Filgotinib,Decernotinib,Peficitinib,Upadacitinib,Baricitinib,Tofacitinib)have been developed or are being developed for the treatment of rheumatoid arthritis(RA).In this study,directly Meta analysis and network Meta analysis were used to comprehensively evaluate the effectiveness and safety of these six drugs in the treatment of active RA,and at the same time compare and rank the relative efficacy of the six drugs.Methods: Through searching eight major databases(Pub Med,Embase,Cochrane Library,Web of science,China Biomedical Literature Database,Wanfang Database,China Knowledge Network,VIP Chinese Database),comprehensively collection of JAK inhibition Randomized controlled trial of drugs(Filgotinib,Decernotinib,Peficitinib,Upadacitinib,Baricitinib,Tofacitinib)in the treatment of RA.Two reviewers evaluated the quality of the literature,and extracted data.The statistical method uses Stata12.0 software for directly Meta analysis of data,and ADDIS software for network Meta analysis.Results:(1)Filgotinib: The study included three RCTs,including 916 patients.Meta-analysis results showed that RA patients in Filgotinib 100 mg or Filgotinib 200 mg group were better than placebo in terms of ACR20,ACR50,ACR70,DAS28(CRP)remission rate,HAQ-DI,SJC66,TJC68 and other efficacy indicators,the difference was statistically significant.(P < 0.005).In Filgotinib 200 mg group,SDAI and CDAI were found to be better than the placebo group,and the difference was statistically significant(P< 0.005).In terms of safety,at 12 weeks,hemoglobin,serum creatinine,and decreased neutrophil count were increased in Filgotinib 200 mg group,but the relevant indicators returned to normal within 24 weeks.There was no significant difference in the incidence of liver damage,infection,malignancy,AE,SAE and other safety indicators between the two doses of Filgotinib compared with placebo(P>0.05).(2)Decernotinib: The study included three RCTs,including 492 patients.The results of directly meta-analysis showed that RA patients in Decernotinib 100mg/200mg/300 mg qd and 50mg/100mg/150 mg bid groups were better than placebo in terms of ACR20,ACR50,ACR70,DAS28(CRP)remission rate,HAQ-DI,the difference is statistically significant(P<0.05),Decernotinib 100mg/200 mg qd and 100 mg bid group ACR20,ACR50,ACR70,DAS28(CRP)remission rate,HAQ-DI is better than placebo group,effect lasts until 24 weeks.Laboratory indicators found elevated liver transaminase and decreased neutrophil count,AE and other safety indicators were not significantly different from placebo(P<0.05).The results of the network meta-analysis showed that Decernotinib was better than the other five JAKi in terms of ACR response rate and DAS28(CRP)remission rate.(3)Pefictinib: The study included five RCTs,including 1401 patients.The results showed that RA patients in Peficitinib 100 mg or Peficitinib 150 mg group were better than the placebo group in ACR20,ACR50,ACR 70,DAS28(CRP)remission rate,SDAI,and CDAI.In terms of safety,both doses can cause elevated liver transaminase,hemoglobin,serum creatinine,and decrease in neutrophil count,but will not cause serious clinical consequences.The incidence of safety indicators such as AE and SAE is compared with placebo,the difference was not statistically significant(P<0.05).(4)Upadacitinib: The study included four RCTs,including 3109 patients.At 12 weeks,the results showed that the efficacy indicators of Upadacitinib15 mg and 30 mg were better than the placebo group in ACR20,ACR50,ACR70,DAS28(CRP)remission rate,CDAI and SDAI,and the difference was statistica-lly significant(P < 0.005).In terms of safety,the incidence of shingles,AE,and SAE has increased,and the incidence of other adverse reactions such as liverdamage,infection,malignancy,and cardiovascular events has no signific-ant difference compared with placebo.(5)Baricitinib: The study included six RCTs,including 2854 patients.Meta-analysis results showed that RA patients in the Baricitinib 2mg and 4mg groups were better than the placebo group in ACR20,ACR50,ACR70,DAS28(CRP)remission rates,CDAI,HAQ-DI,and TJC68,and the difference was statistically significant(P < 0.005).The efficacy of SDAI and SJC66 in the Baricitinib4 mg group was better than that of placebo.In terms of safety,abnor-mal laboratory indicators include liver transaminase,increased serum creatini-ne,and decreased neutrophil count.The incidence of AE and other safety indi-cators was similar to that of placebo,and the difference was not statistically si-gnificant(P>0.05).(6)Tofacitinib:The study included seven RCTs,including 2125 patients.The results showed that RA patients in Tofacitinib 5mg and 10 mg groups were better than the placebo group in terms of ACR20,ACR50,ACR70,DAS28(CRP)remission rate,HAQ-DI,SJC66 and other efficacy indicators,and the difference was statistically significant(P < 0.05).Only in tofacitinib 10 mg group,TJC68 was found to be more effective than placebo.Laboratory examination found that serum cholesterol increased and neutrophil count decreased,liver transaminase,hemoglobin,serum creatinine did not increase significantly,and the incidence of AE,SAE and other safety indicators was not significantly different from placebo(P>0.05).Conclusion: Filgotinib,Decernotinib,Peficitinib,Upadacitinib,Baricitinib,Tofacitinib can be used as a single or combined to improve the clinical sympto-ms and signs of patients with active RA.The drug has a rapidly onset,continu-ous effectiveness and reliable safety.Decernotinib can improve the ACR respo-se rate the remission rate of DAS28(CRP)and DAS28(CRP)are the best among the six drugs.Decernotinib 300 mg was found to be higher than that of the other five JAKi in the adverse reaction rate.