Real-world efficacy and safety of tofacitinib treatment in Asian patients with ulcerative colitis

BACKGROUND Real-world data on tofacitinib(TOF)covering a period of more than 1 year for a sufficient number of Asian patients with ulcerative colitis(UC)are scarce.AIM To investigate the long-term efficacy and safety of TOF treatment for UC,including clinical issues.METHODS We performed a retrospective single-center observational analysis of 111 UC patients administered TOF at Hyogo Medical University as a tertiary inflammatory bowel disease center.All consecutive UC patients who received TOF between May 2018 and February 2020 were enrolled.Patients were followed up until August 2020.The primary outcome was the clinical response rate at week 8.Secondary outcomes included clinical remission at week 8,cumulative persistence rate of TOF administration,colectomy-free survival,relapse after tapering of TOF and predictors of clinical response at week 8 and week 48.RESULTS The clinical response and remission rates were 66.3%and 50.5%at week 8,and 47.1%and 43.5%at week 48,respectively.The overall cumulative clinical remission rate was 61.7%at week 48 and history of anti-tumor necrosis factor-alpha(TNF-α)agents use had no influence(P=0.25).The cumulative TOF persistence rate at week 48 was significantly lower in patients without clinical remission than in those with remission at week 8(30.9%vs 88.1%;P<0.001).Baseline partial Mayo Score was significantly lower in responders vs non-responders at week 8(odds ratio:0.61,95%confidence interval:0.45-0.82,P=0.001).Relapse occurred in 45.7%of patients after TOF tapering,and 85.7%of patients responded within 4 wk after re-increase.All 6 patients with herpes zoster(HZ)developed the infection after achieving remission by TOF.CONCLUSION TOF was more effective in UC patients with mild activity at baseline and its efficacy was not affected by previous treatment with anti-TNF-αagents.Most relapsed patients responded again after re-increase of TOF and nearly half relapsed after tapering off TOF.Special attention is needed for tapering and HZ.

Tofacitinib for ulcerative colitis: A promising treatment option

A single center retrospective clinical study revealed the efficacy and safety of tofa-citinib in the treatment of ulcerative colitis(UC).This study has clinical reference value but also has some limitations.Previous studies,including this clinical trial,have shown that tofacitinib could be a promising treatment option for UC,but further clinical research is required to prove this point.

Real-world clinical efficacy of tofacitinib in moderate-to-severe ulcerative colitis

Tofacitinib is an oral small-molecule Janus kinase(JAK)inhibitor that preferentially inhibits JAK1 and JAK3.Its efficacy in inducing and maintaining remission in ulcerative colitis(UC)as well as its safety profile has been demonstrated in multicenter,randomized,double-blind,placebo-controlled trials.Additionally,real-world studies evaluating the effectiveness and adverse effects of tofacitinib have been conducted,affirming its clinical efficacy in moderate-to-severe UC.

Janus激酶抑制药tofacitinib

Janus激酶活化的信号传导及转录激活因子（Janus-activatedkinaseSingaltransducersandactiva—torsoftranscription，JAK—STAT）是近年来新发现的一条与细胞因子密切相关的细胞内信号传导通路，参与细胞的增殖、分化、凋亡以及免疫调节等许多重要的生物学过程。Janus激酶是一种非受体型酪氨酸蛋白激酶。有4个家族成员，分别是JAKl、JAK2、TYK2和JAK3。前3者广泛存在于各种组织和细胞中，而JAK3仅存在于骨髓和淋巴系统。

Efficacy and safety of tofacitinib for treatment of rheumatoid arthritis

Tofacitinib is the first in a new class of nonbiologic disease-modifying antirheumatic drugs(DMARDs), a targeted, synthetic DMARD, approved for the treatment of rheumatoid arthritis(RA) as monotherapy or in combination with methotrexate or other non-biologic DMARD. Tofacitinib, an orally administered Janus kinase(JAK) inhibitor, decreases T-cell activation, pro-inflammatory cytokine production, and cytokine signaling by inhibiting binding of type Ⅰcytokine receptors family and γ-chain cytokines to paired JAK1/JAK3 receptors. The net effect of tofacitinb's mechanism of action is decreased synovial inflammation and structural joint damage in RA patients. To date, six phase 3 trials have been conducted to evaluate the safety and efficacy of tofacitinib under the oral rheumatoid arthritis triaL s(ORAL) series. This review describes the pharmacology of the novel agent, tofacitinib, and details the safety and efficacy data of the ORAL trials.

Recurrent herpes zoster in a rheumatoid arthritis patient treated with tofacitinib: A case report and review of the literature

BACKGROUND Tofacitinib is an oral Janus kinase(JAK)inhibitor that is currently approved by the United States Food and Drug Administration for the treatment of rheumatoid arthritis(RA).Varicella zoster virus reactivation leading to herpes zoster(HZ)is an adverse effect of this drug;however,recurrent HZ at the same site is a rare clinical condition.CASE SUMMARY A 70-year-old female RA patient had undergone 1-year of tofacitinib treatment(10 mg daily).About 1 mo after initiation of oral tofacitinib,she developed blisters on the left flank and abdomen and was diagnosed with HZ;antiviral therapy with acyclovir was resolutory.However,5 d prior to presentation at our hospital,erythema and blisters with severe pain recurred at the same site.Small clustered blisters and bullous were visible on the left lumbar abdomen and perineum,with a pain score of 8(visual analogue scale).Antiviral,nutritional supplement,analgesic and other treatments led to healing but over an atypically long period(approximately 26 d,vs approximately 1 wk).HZ is a common and serious adverse reaction of JAK inhibitors,but it rarely recurs.Our patient’s experience of HZ recurrence at the same site,with a wider affected area,more severe pain and longer healing period,is inconsistent with previous reports.CONCLUSION Same-anatomical site HZ recurrence may occur during oral tofacitinib treatment,with more severe clinical manifestations than in the initial occurrence.

Refractory case of ulcerative colitis with idiopathic thrombocytopenic purpura successfully treated by Janus kinase inhibitor tofacitinib:A case report

BACKGROUND Concomitant ulcerative colitis (UC) and idiopathic thrombocytopenic purpura(ITP) is a rare phenomenon. The management of UC with ITP can be challenging,since a decreased platelet count augments UC.CASE SUMMARY A 24-year-old man with UC and steroid-resistant ITP experienced UC flare.Although continuous infusion of cyclosporine was initiated, UC did not improve.The administration of tofacitinib subsequently led to the induction of remission.The patient has maintained remission of UC and ITP for over one year ontofacitinib treatment. Whole transcriptomic sequencing was performed forinflamed rectal mucosae obtained before and after the initiation of Janus kinase(JAK) inhibitor, suggesting that distinct molecular signatures seemed to beregulated by JAK inhibitors and other conventional therapies including tumornecrosis factor lockers.CONCLUSION Tofacitinib should be considered in refractory cases of UC with ITP.

Immediate-release tofacitinib reduces insulin resistance in nondiabetic active rheumatoid arthritis patients:A single-center retrospective study

BACKGROUND An increased risk of insulin resistance(IR)has been identified in rheumatoid arthritis(RA),a chronic inflammatory disorder with elevated levels of pathogenic cytokines.Biologics targeting proinflammatory cytokines can control the disease and improve insulin sensitivity in RA.Although Janus kinase(JAK)signaling can regulate cytokine receptors and participate in RA pathogenesis,it remains to be elucidated whether there is a reduction of IR in such patients under JAK inhibitor(JAKi)therapy.AIM To study the effect of JAKi treatment on the reduction of IR in RA patients with active disease.METHODS A retrospective study was carried out from April 1,2017 to March 31,2021 in a population of non-diabetic patients with active RA who were undergoing tofacitinib(TOF)therapy with 5 mg twice-daily immediate-release formulation.RESULTS Fifty-six RA patients,aged 30 years to 75 years(mean±SD:52.3±11.1)with disease activity score 28 values ranging from 4.54 to 7.37(5.82±0.74),were classified into high-IR(>2.0)and low-IR(≤2.0)groups based on their baseline homeostatic model assessment(HOMA)-IR levels.They had no previous exposure to JAKi,and received TOF therapy for no less than 6 mo.In 30 patients who were naïve to biologics,after a 24-week therapeutic period,the high-IR group showed reduced HOMA-IR levels (3.331 ± 1.036 vs 2.292 ± 0.707, P < 0.001). In another 26patients who were exposed to tumor necrosis factor-α or interleukin-6 blockers, the high-IR group,despite having achieved a decrease but with lower magnitude than in naïve patients, showedreduced HOMA-IR levels (2.924 ± 0.790 vs 2.545 ± 1.080, P = 0.018).CONCLUSIONIn this retrospective study, reduced IR was achieved in non-diabetic active RA patients following24 wk of TOF therapy.

Tofacitinib for the treatment of ulcerative colitis: A review of the literature

Ulcerative colitis (UC) is a chronic immune-mediated inflammatory condition affecting the colon. Recently, tofacitinib, an oral small molecule that is an inhibitor of the Janus kinase signal transduction pathway, was proven efficacious for inducing and maintaining remission in adult patients with moderate to severe UC in three global Phase III studies. The purpose of this review is to summarize existing data on the efficacy, safety, and quality of life issues related to use tofacitinib as well as highlight recent real-world experience with this drug among patients with UC.

Precautions before starting tofacitinib in persons with rheumatoid arthritis

Tofacitinib is an immunosuppressive and disease-modifying therapy in rheumatoid arthritis.It may result in many infections flaring up.It is important to take precautions of all kinds(cardiovascular,malignancy,infections etc.)before starting tofacitinib.In this article,we have highlighted important steps where we need to take precautions before starting tofacitinib.

Glucocorticoids combined with tofacitinib in the treatment of Castleman’s disease:A case report

BACKGROUND Castleman’s disease(CD),also known as vascular follicular lymphadenopathy is a rare proliferative disease of lymphoid tissue of unknown etiology that is clinically classified as unicentric CD(UCD) or multicentric CD(MCD) depending on lymph node involvement.At present,idiopathic MCD(iMCD) is treated with interleukin-6 inhibitors,but some patients have poor clinical outcomes.This paper reports on a case of iMCD that achieved a good therapeutic effect after treatment with glucocorticoids combined with tofacitinib.The relevant data are summarized and reported below.CASE SUMMARY This paper reports on a case of MCD in a 49-year-old female with persistent peritoneal effusion as the first manifestation and combined with multiple lymphadenopathies.Lymph node biopsy showed Castleman’s disease-like changes.The ascites subsided after treatment with glucocorticoids and tofacitinib,indicating that the treatment was effective.CONCLUSION The combination of glucocorticoids with tofacitinib is an effective regimen for the treatment of CD.

Tofacitinib的合成

4-氯-7H-吡咯并[2,3-d]嘧啶(2)经保护、取代、脱保护得到N-[(3R,4R)-1-苄基-4-甲基哌啶-3-基]-N-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(7),7脱苄基后无需分离,直接与氰乙酸乙酯缩合得到抗类风湿性关节炎药tofacitinib,总收率约57%(以2计),纯度99.4%。

Efficacy and Safety of Tofacitinib in Chinese Patients with Rheumatoid Arthritis

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis(RA). This study assessed the efficacy and safety of tofacitinib in Chinese patients with RA enrolled in Phase 3 and long?term extension(LTE) studies.Methods: ORAL Sync was a 1?year, randomized, placebo?controlled, Phase 3 trial. Patients received tofacitinib 5 or 10 mg twice daily(BID) or placebo advanced to tofacitinib 5 or 10 mg BID at 3 or 6 months. All patients remained on ≥1 background conventional synthetic disease?modifying antirheumatic drug. ORAL Sequel is an open?label LTE study(data?cut: March 2015; data collection and analyses were ongoing, and study database was not locked at the time of analysis; study was closed in 2017). Efficacy outcomes: American College of Rheumatology(ACR) 20/50/70 response rates and Disease Activity Score in 28 joints using erythrocyte sedimentation rate(DAS28?4 [ESR]). Patient? and physician?reported outcomes: Health Assessment Questionnaire?Disability Index(HAQ?DI), Patient and Physician Global Assessment of Arthritis, and pain(visual analog scale). Safety was assessed throughout.Results: ORAL Sync included 218 patients; 192 were subsequently enrolled into ORAL Sequel. In ORAL Sync, more patients achieved ACR20(tofacitinib 5 mg BID, 67.4%; 10 mg BID, 70.6%; placebo, 34.1%) and DAS28?4(ESR) <2.6(tofacitinib 5 mg BID, 7.1%;10 mg BID, 13.1%; placebo, 2.3%) with tofacitinib versus placebo at Month 6. Mean changes from baseline in HAQ?DI were greater with tofacitinib versus placebo at Month 6. In ORAL Sequel, efficacy was consistent to Month 48. Incidence rates for adverse events of special interest in tofacitinib?treated patients were similar to the global population.Conclusions: Tofacitinib significantly reduced signs/symptoms and improved physical function and quality of life in Chinese patients with moderate?to?severely active RA up to Month 48. The safety profile was consistent with the global population.Clinical Trial Identifier: NCT00856544 and NCT00413699.

抗类风湿性关节炎药Tofacitinib

研究表明，多重细胞因子信号通路失调在类风湿性关节炎（RA）的病理生理学过程中发挥重要作用，一系列失控的细胞因子介导的炎症级联反应导致RA相关的多种细胞，包括T细胞、B细胞、单核细胞、巨噬细胞和破骨细胞处于长期激活状态，从而引发持续炎症及关节结构性损伤；

Inflammation responsive tofacitinib loaded albumin nanomedicine for targeted synergistic therapy in ulcerative colitis

Patients with ulcerative colitis(UC)often loss responses over long term usage of conventional therapies.Tofacitinib,a pan-Janus kinases(JAK)inhibitor is approved for moderate to severe UC treatment,while dose-limiting systemic side effects including infections,cancers and lymphoma limit its popularity of clinical application.This study sought to construct an anti-mucosal vascular addressin cell-adhesion molecule-1(anti-MAdCAM-1)antibody modified reactive oxygen species(ROS)responsive human serum albumin-based nanomedicine denoted as THM,to improve the therapeutic efficacy of tofacitinib for UC treatment.THM has the drug releasing properties in response to ROS stimulation.In vitro studies show that THM selectively adhered to the endothelial cells and had obvious anti-inflammatory effect on macrophages.Meanwhile,the nanomedicine can inhibit the phenotypic switching of M1 macrophages and promote M2 polarization to produce anti-inflammatory medicators during wound healing.In addition,in vivo fluorescence imaging verified that THM exhibited enhanced preferential accumulation and extended retention in inflamed colon.Moreover,THM significantly reduced the production of proinflammatory cytokines in the colon and suppressed the homing of T cells to the gut in dextran sodium sulfate induced experimental colitis.This work elucidates that the inflamed colon-targeted delivery of tofacitinib by nanomedicine is promising for UC treatment and sheds light on addressing the unmet medical need.

Continuation,reduction,or withdrawal of tofacitinib in patients with rheumatoid arthritis achieving sustained disease control:a multicenter,open-label,randomized controlled trial

Background:Rheumatoid arthritis(RA),a chronic systemic autoimmune disease,is characterized by synovitis and progressive damage to the bone and cartilage of the joints,leading to disability and reduced quality of life.This study was a randomized clinical trial comparing the outcomes between withdrawal and dose reduction of tofacitinib in patients with RA who achieved sustained disease control.Methods:The study was designed as a multicenter,open-label,randomized controlled trial.Eligible patients who were taking tofacitinib(5 mg twice daily)and had achieved sustained RA remission or low disease activity(disease activity score in 28 joints[DAS28]≤3.2)for at least 3 months were enrolled at six centers in Shanghai,China.Patients were randomly assigned(1:1:1)to one of three treatment groups:continuation of tofacitinib(5 mg twice daily);reduction in tofacitinib dose(5 mg daily);and withdrawal of tofacitinib.Efficacy and safety were assessed up to 6 months.Results:Overall,122 eligible patients were enrolled,with 41 in the continuation group,42 in the dose-reduction group,and 39 in the withdrawal group.After 6 months,the percentage of patients with a DAS28-erythrocyte sedimentation rate(ESR)of<3.2 was significantly lower in the withdrawal group than that in the reduction and continuation groups(20.5%,64.3%,and 95.1%,respectively;P<0.0001 for both comparisons).The average flare-free time was 5.8 months for the continuation group,4.7 months for the dose reduction group,and 2.4 months for the withdrawal group.Conclusion:Withdrawal of tofacitinib in patients with RA with stable disease control resulted in a rapid and significant loss of efficacy,while standard or reduced doses of tofacitinib maintained a favorable state.Trial Registration:Chictr.org,ChiCTR2000039799.

CYP3A4基因位点多态性对托法替布治疗类风湿关节炎临床疗效及药品不良反应的影响

目的探讨CYP3A4*4,CYP3A4*18,CYP3A4*1G基因位点多态性对托法替布治疗类风湿关节炎(RA)临床疗效及药品不良反应(ADR)的影响。方法选取医院风湿免疫科2020年2月至2022年8月收治的RA患者309例作为RA组,予枸橼酸托法替布片,每日2次,每次5 mg,共治疗6个月;选取同期的健康人群165例作为对照组。采用荧光聚合酶链反应(PCR)法检测CYP3A4*4,CYP3A4*18,CYP3A4*1G基因位点多态性;根据美国风湿病学学会(ACR)制订的ACR20标准评价托法替布的临床疗效,以是否符合ACR20标准,将RA患者分为改善组(181例)和未改善组(128例);统计治疗期间RA患者与托法替布相关的ADR,采用Karch和Lasagna评定法判定因果关系,以因果关系是否判定为肯定、很可能和可能,将RA患者分为ADR组(58例)和无ADR组(251例)。结果RA组和对照组患者的CYP3A4*4,CYP3A4*18,CYP3A4*1G基因位点多态性均无显著差异(P>0.05)。改善组和未改善组患者的疾病活动度差异显著(P<0.05),CYP3A4*4,CYP3A4*18,CYP3A4*1G基因位点多态性均无显著差异(P>0.05)。ADR累及系统为实验室检验异常、皮肤系统、消化系统、呼吸系统、血液系统,分别发生27例、11例、7例、5例、3例;ADR严重程度为轻度51例,中度7例。ADR组和无ADR组患者的CYP3A4*1G基因位点多态性差异显著(P<0.05),CYP3A4*4和CYP3A4*18基因位点多态性均无显著差异(P>0.05)。结论CYP3A4*1G基因位点多态性与托法替布治疗RA的ADR有相关性。使用托法替布时,应监测患者的CYP3A4*1G基因位点多态性,必要时调整剂量,保证用药安全。

托法替布片药物利用评价标准建立及应用

目的建立托法替布片药物利用评价标准(DUE),为托法替布片临床合理使用提供参考。方法参考国内外托法替布药品说明书、相关诊疗指南、专家共识及临床研究,建立托法替布片DUE标准,并以此标准回顾性分析某三甲医院2021年1月1日—2023年9月30日托法替布片门诊处方的合理性。结果共纳入1086张托法替布片门诊处方,用药适应证符合率93.6%,用法用量符合率93.6%,4张处方存在潜在的药物相互作用。结论该院托法替布片使用较合理,但在适应证、用法用量、药物相互等方面仍存在一定的问题,应加强干预,确保患者用药安全。

托法替布用于类固醇难治性免疫相关性心肌炎病例分析

免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)是近年来抗肿瘤治疗的重要药物,能为患者带来显著的生存收益。然而ICIs引起的免疫相关性不良反应不容忽视,特别是ICIs相关性心肌炎,发生率低但致死率高。糖皮质激素是目前治疗ICIs相关性心肌炎的首选及核心方案。在激素治疗过程中,如病情加重,可联合吗替麦考酚酯(mycophenolate mofetil,MMF)、他克莫司、英夫利昔单抗等其中1种药物。阿仑单抗和阿巴西普对于糖皮质激素治疗无效的严重心肌炎患者可能有效,但阿巴西普可能促进肿瘤的生长。本文对1例使用特瑞普利单抗联合西妥昔单抗以及伊立替康抗肿瘤方案出现免疫相关性心肌炎,随即采用糖皮质激素联合人免疫球蛋白治疗失败后,加用口服托法替布,心肌损伤生物标志物显著下降的结肠癌患者进行分析讨论,以期为临床类固醇难治性免疫相关性心肌炎提供新的治疗思路。

Game changer:How Janus kinase inhibitors are reshaping the landscape of ulcerative colitis mana

Recent advancements in the treatment landscape of ulcerative colitis(UC)have ushered in a new era of possibilities,particularly with the introduction of Janus kinase(JAK)-signal transducer and activator of transcription inhibitors.These novel agents offer a paradigm shift in UC management by targeting key signaling pathways involved in inflammatory processes.With approved JAK inhibitors(JAKis),such as tofacitinib,filgotinib,and upadacitinib,clinicians now have powerful tools to modulate immune responses and gene expression,potentially revolutionizing the treatment algorithm for UC.Clinical trials have demonstrated the efficacy of JAKis in inducing and maintaining remission,presenting viable options for patients who have failed conventional therapies.Real-world data support the use of JAKis not only as first-line treatments but also in subsequent lines of therapy,particularly in patients with aggressive disease phenotypes or refractory to biologic agents.The rapid onset of action and potency of JAKis have broadened the possibilities in the management strategies of UC,offering timely relief for patients with active disease and facilitating personalized treatment approaches.Despite safety concerns,including cardiovascular risks and infections,ongoing research and post-marketing surveillance will continue to refine our understanding of the risk-benefit profile of JAKis in UC management.