Real-world Study Of Efficacy And Adverse Events Of Tofacitinib In The Treatment Of Rheumatoid Arthritis

Rheumatoid arthritis(RA)is a chronic progressive systemic autoimmune disease,which is characterized by symmetrical synovitis and bone erosion mainly in small joints and can involve the lungs,cardiovascular system,nervous system,kidney,and other organs.According to the 2010 Rheumatoid Arthritis Classification Criteria issued by the American College of Rheumatology and the European League Against Rheumatism,RA is diagnosed.The commonly used clinical evaluation indicators of RA include disease activity score for 28-joint count based on the erythrocyte sedimentation rate(DAS28-ESR)and health assessment questionnaire-disability index(HAQ-DI),American college of rheumatology 20% improvement(ACR20)response rate.In the progression of RA,cytokines such as interleukin-6(IL-6),IL-12 and interferon(IFN)play important roles in promoting inflammation.The key downstream signaling pathways of these cytokines are Janus kinase(JAK)-signal transducers and activators of transcription(STAT).In addition to mediating the pro-inflammatory effect of cytokines,JAK-STAT also regulates functions of T cell differentiation by mediating IL-2,IL-4,and IL-10,and promotes the development of the hematopoietic system by mediating IL-3,IL-5,granulocyte-macrophage colony-stimulating factor(GM-CSF),and mediates IFN antiviral ability,and many other functions.When the JAK-STAT signaling pathway is activated,it can form a cascade amplification effect to promote the progression of RA through the cytokine signaling network.At present,the strategy of early diagnosis,early treatment,treatment to target,and close monitoring for RA patients is emphasized.In the clinical treatment of RA,the main purpose of treatment is to reduce disease activity and relieve symptoms,prevent the further development of the disease,preserve or restore the physiological function as much as possible,and improve the quality of life of RA patients.The drugs used in the treatment of RA mainly include non-steroidal anti-inflammatory drugs(NSAIDs),glucocorticoids(GC),and disease-modifying anti-rheumatic drugs(DMARDs).Methotrexate(MTX)is the first-line drug for the treatment of RA,which exerts immunosuppressive effects by inhibiting dihydrofolate reductase.Due to the slow onset or insufficient efficacy of MTX,it is often necessary to combine with other drugs to achieve the purpose of rapid improvement in RA.In combination therapy,although GC and leflunomide can rapidly control the disease activity,they are accompanied by high risk of adverse events,such as leukocyte suppression,osteoporosis,and central obesity.Biological agents are not suitable for long-term use because of their high price.In recent years,tofacitinib,an oral small molecule,has emerged as a promising treatment for RA and has been increasingly recommended as monotherapy or combination therapy for RA.Tofacitinib is an oral small-molecule JAK inhibitor that belongs to targeted synthesis disease-modifying anti-rheumatic drugs(ts DMARDs),and inhibits the function of a large number of cytokines.As a non-selective JAK inhibitor,tofacitinib can inhibit all members of the JAK family,including JAK1,JAK2,JAK3,and tyrosine protein kinase 2(TYK2).By competitively inhibiting JAK phosphorylation,tofacitinib can inhibit the pro-inflammatory effect of inflammatory cytokines,regulate the proliferation and differentiation of immune cells,and regulate the development of hematopoietic system.In the treatment of RA,tofacitinib can reduce joint swelling,inhibit bone and joint destruction,reduce the time of morning stiffness,and improve the quality of life.Tofacitinib has a rapid onset and significant effect compared with MTX and can achieve significant effect within 1 month of treatment,tofacitinib also has advantages over non-inferior efficacy and price compared with tumor necrosis factor(TNF)inhibitors,tofacitinib alone or in combination with MTX can also achieve stable therapeutic effects in stable RA patients.Due to the inhibitory effect of tofacitinib on a variety of cytokines,it is inevitable to produce corresponding adverse reactions in clinical treatment,such as infection caused by immune insufficiency,decrease in blood cell level caused by hematopoietic system suppression,gastrointestinal tract involvement.However,the adverse reactions of tofacitinib in the treatment of RA still need to be carefully monitored and accumulated,and there is still a lack of sufficient evidence to use tofacitinib as a part of the first-line treatment.The application of tofacitinib in a wider range of populations still needs to be continuously observed,to improve the status of tofacitinib in the treatment strategy,improve the clinical treatment preference,and promote tofacitinib to be closer to the first-line treatment of RA.In this study,the clinical data of RA patients treated with tofacitinib was collected,and the efficacy of tofacitinib was investigated by evaluating the changes in RA patients’ condition,the adverse events of tofacitinib were investigated by following up,to provide an experimental basis for the clinical treatment and guide the clinical rational use of tofacitinib in the treatment of RA.Objective1.To investigate the efficacy of tofacitinib in the treatment of RA in the real world.2.To investigate the adverse events of tofacitinib in RA patients in the real world.Methods1.Enrollment of study casesFrom January 2020 to October 2022,RA patients taking tofacitinib were enrolled from RA patients attending the Rheumatology and immunology Department of the First Affiliated Hospital of Anhui Medical University and the Second Affiliated Hospital of Anhui Medical University.Meanwhile,patients’ basic information,treatment plan,examination results,and other related data were collected.2.Efficacy evaluation of tofacitinib in the treatment of RAAfter 3 and 6 months of tofacitinib treatment,the overall clinical efficacy of tofacitinib in RA patients was evaluated.DAS28-ESR,HAQ-DI,and ACR were used to evaluate the clinical efficacy.The changes in erythrocyte sedimentation rate(ESR),hypersensitive C-reactive protein(hs-CRP),rheumatoid factor(RF),and anti-cyclic citrullinated peptide antibody(ACPA)in RA patients treated with tofacitinib were compared before and after treatment at 0,3,6,9,12,15 and 18 months.The changes of hemoglobin(HGB),red blood cell count(RBC),mean corpuscular volume(MCV),mean corpuscular hemoglobin(MCH),and mean corpuscular hemoglobin concentration(MCHC)were compared respectively before and after tofacitinib treatment at 0,3,6,9,12,15 and 18 months.3.Flow cytometry was used to detect the changes of Th1,Th2,Th17,and Treg cell subsets in peripheral blood of RA patients before and after tofacitinib treatmentPeripheral blood mononuclear cells(PBMCs)were isolated from peripheral blood of RA patients using human lymphocyte separation medium.PBMCs were labeled with monoclonal antibodies,and the subsets of T helper 1(Th1),T helper 2(Th2),T helper17(Th17),and regulatory T(Treg)cells in peripheral blood of RA patients were detected by flow cytometry(FCM)before and after tofacitinib treatment.4.Observation of adverse events and laboratory indicators of tofacitinib in the treatment of RAAdverse events were observed and recorded during the treatment of RA with tofacitinib by following up.The examination results of RA patients treated taking tofacitinib,such as blood routine,liver and kidney function,and urine routine,were collected,and the examination results were grouped according to before and after treatment or according to the time of treatment at 0,3,6,9,12,15,18 months.Results1.Tofacitinib significantly improved the condition of RA patientsIn this study,RA patients treated with tofacitinib were investigated with complete ACR,HAQ-DI and DAS28-ESR questionnaires at 0,3 and 6 months after treatment.After 3 months of tofacitinib treatment,the ACR20 response rate of RA patients was83.33%,ACR50 response rate was 66.67%,and ACR70 response rate was 29.17%.After 6 months of tofacitinib treatment,the ACR20,ACR50,and ACR70 response rates of RA patients were 91.67%,83.33%,and 62.50%,respectively.HAQ-DI decreased from 1.16 at the beginning of tofacitinib treatment to 0.48 in 3rd month(P<0.0001)and0.27 in 6th month after treatment of tofacitinib(P<0.0001).DAS28-ESR decreased from 4.95(moderate disease activity)at the beginning of treatment to 2.96(low disease activity,P<0.0001)in 3rd month and 2.37(remission,P<0.0001)in 6th month after treatment of tofacitinib.Data from RA patients showed that the levels of ESR and hs-CRP approached normal ranges after 3 months of tofacitinib treatment and remained stable over 18 months.RF decreased initially and then increased during 6-18 months of tofacitinib treatment.ACPA did not change significantly during tofacitinib treatment.During tofacitinib treatment,the incidence of anemia in RA patients continued to decrease from 35.25% to 18.31% in 0-9 months and gradually increased to 22.92% in9-15 months.The HGB concentration increased significantly from the 3rd month(P<0.01),kept an increasing trend during the first 12 months,and then maintained at a high level compared with the base line.The RBC showed a non-significant decrease during the first 9 months,but began to increase significantly at 12 months of treatment(P<0.02)and remained at a high level thereafter compared with base line.The MCV,MCH,and MCHC increased during tofacitinib treatment(P<0.05).2.Tofacitinib increased the proportion of Treg cell subsetsThe results of FCM showed that the proportion of Treg cells increased significantly after tofacitinib treatment,and the proportion of Th1,Th2,and Th17 decreased.3.Adverse events during tofacitinib treatmentAdverse events observed in RA patients during tofacitinib treatment included 44 cases of infection(including 1 case of hepatitis B,4 cases of tuberculosis,4 cases of herpes,3 cases of HPV-positive,10 cases of non-COVID-19 pneumonia,10 cases of urinary tract infection),1 case of colon benign polyp and 1 case of grade III cervical epithelial neoplasia,31 cases of respiratory adverse events,49 of gastrointestinal adverse events,12 cases of urinary system adverse events,36 cases of nervous system adverse events,41 cases of of skin adverse events,5 allergic cases(one of which was closely related to tofacitinib),34 cases of anemia,44 cases of abnormal elevation of main indicators of liver function injury,10 cases of oral ulcer,9 cases of edema,and 56 cases of insomnia or fatigue.4.Tofacitinibt differentially affects peripheral blood cells and proteinsThe white blood cell count(WBC),the absolute lymphocyte count(ALC),and the absolute neutrophil count(ANC)continued to decrease within 15 months of treatment with tofacitinib(P<0.05),the absolute monocyte count(AMC)showed a decreasing trend within 18 months of treatment without significant difference(P>0.05),and the platelet(PLT)level decreased significantly at 3 months of treatment and remained stable within 12 months.There was no significant change in the total protein(TP)level within 15 months of treatment with tofacitinib,the albumin(ALB)level increased significantly from 3 months of treatment and remained at a high level during 3-18 months,and the globulin(GLO)level decreased significantly from 3 months of treatment and remained at a low level during 3-18 months.5.Tofacitinib caused mild to moderate liver function injuryThere is no significant increase in the levels of alanine transaminase(ALT),γ-glutamyltransferase(GGT),and alkaline phosphatase(ALP)during the treatment of tofacitinib in RA patients overall.The aspartate transaminase(AST)and total bilirubin(TBIL)remained at a high level throughout the 18 months of treatment(P<0.05),and the ratio of ALT to AST was greater than 1 and increased.During the treatment of tofacitinib,the liver injury of all patients were mild to moderate.6.Tofacitinib mildly impaired renal functionDuring tofacitinib treatment,estimated glomerular filtration rate(e GFR)decreased mildly during the first 9 months and then began to increase,urea(UREA)did not change significantly,but creatinine(CRE)and uric acid(UA)increased significantly.During the treatment of tofacitinib,the liver injury of all patients was mild.7.Adverse events occurred during tofacitinib treatmentThe adverse events observed in RA patients during tofacitinib treatment included44 cases of infection(including 1 case of hepatitis B,4 cases of tuberculosis,4 cases of herpes,3 cases of HPV-positive,10 cases of non-COVID-19 pneumonia,and 10 cases of urinary tract infection).There was 1 case of benign polyp of colon and 1 case of grade 3 epithelioma of cervix,31 cases of respiratory adverse events,49 cases of gastrointestinal adverse reactions,12 cases of adverse reactions in urinary system,36 cases of adverse reactions in nervous system,41 cases of adverse skin reaction,5 cases were allergic(1 of which was closely related to tofacitinib administration),34 cases of anemia,44 cases of abnormal elevation of main indicators of liver function injury,10 cases of oral ulcer,9 cases 10 cases of edema,56 cases with insomnia or fatigue.8.The main reason for discontinuation of tofacitinib due to adverse events is infectionIn this study,a total of 17 RA patients discontinued tofacitinib,15 discontinued due to adverse events,2 discontinued due to preparation for pregnancy.Among the 15 patients who discontinued tofacitinib due to adverse events,11 patients discontinued tofacitinib due to infection(or combined with other adverse events),of whom 5 patients were diagnosed with pulmonary tuberculosis or T-SPOT positive.Conclusions1.In the real world,tofacitinib can significantly improve the condition of RA patients within 3 months,further improve within 6 months,achieve stable efficacy at 18 months,improve anemia,and play a therapeutic role by up-regulating the proportion of Treg cell subset in RA patients.2.Long-term use of tofacitinib can cause adverse events such as mild to moderate liver injury,mild kidney injury,affecting the blood system,infection.3.Mycobacterium tuberculosis infection is the most important reason for tofacitinib infection and discontinuation.