Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. Randomized trial of tofacitinib in active ulcerative colitis: analysis of efficacy based on patient-reported outcomes Tofacitinib, an oral Janus kinase inhibitor, as monotherapy or with background methotrexate, in Japanese patients with rheumatoid arthritis: an open-label, long-term extension study Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Systematic Assessment of Factors Influencing Preferences of Crohn's Disease Patients in Selecting an Anti‐Tumor Necrosis Factor Agent (CHOOSE TNF TRIAL) Efficacy of Vedolizumab Induction and Maintenance Therapy in Patients With Ulcerative Colitis, Regardless of Prior Exposure to Tumor Necrosis Factor Antagonists Vedolizumab as induction and maintenance therapy for ulcerative colitis. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis.
BACKGROUND Ulcerative colitis is a chronic inflammatory disease of the colon for which current treatments are not universally effective . One additional treatment may be tofacitinib ( CP-690,550 ) , an oral inhibitor of Janus kinases 1 , 2 , and 3 with in vitro functional specificity for kinases 1 and 3 over kinase 2 , which is expected to block signaling involving gamma chain-containing cytokines including interleukins 2 , 4 , 7 , 9 , 15 , and 21 . These cytokines are integral to lymphocyte activation , function , and proliferation . METHODS In a double-blind , placebo-controlled , phase 2 trial , we evaluated the efficacy of tofacitinib in 194 adults with moderately to severely active ulcerative colitis . Patients were r and omly assigned to receive tofacitinib at a dose of 0.5 mg , 3 mg , 10 mg , or 15 mg or placebo twice daily for 8 weeks . The primary outcome was a clinical response at 8 weeks , defined as an absolute decrease from baseline in the score on the Mayo scoring system for assessment of ulcerative colitis activity ( possible score , 0 to 12 , with higher scores indicating more severe disease ) of 3 or more and a relative decrease from baseline of 30 % or more with an accompanying decrease in the rectal bleeding subscore of 1 point or more or an absolute rectal bleeding subscore of 0 or 1 . RESULTS The primary outcome , clinical response at 8 weeks , occurred in 32 % , 48 % , 61 % , and 78 % of patients receiving tofacitinib at a dose of 0.5 mg ( P=0.39 ) , 3 mg ( P=0.55 ) , 10 mg ( P=0.10 ) , and 15 mg ( P<0.001 ) , respectively , as compared with 42 % of patients receiving placebo . Clinical remission ( defined as a Mayo score ≤2 , with no subscore > 1 ) at 8 weeks occurred in 13 % , 33 % , 48 % , and 41 % of patients receiving tofacitinib at a dose of 0.5 mg ( P=0.76 ) , 3 mg ( P=0.01 ) , 10 mg ( P<0.001 ) , and 15 mg ( P<0.001 ) , respectively , as compared with 10 % of patients receiving placebo . There was a dose-dependent increase in both low-density and high-density lipoprotein cholesterol . Three patients treated with tofacitinib had an absolute neutrophil count of less than 1500 . CONCLUSIONS Patients with moderately to severely active ulcerative colitis treated with tofacitinib were more likely to have clinical response and remission than those receiving placebo . ( Funded by Pfizer ; Clinical Trials.gov number , NCT00787202 . ) Background Tofacitinib , a novel , oral Janus kinase inhibitor , demonstrated a dose-dependent efficacy for induction of clinical response and remission in patients with active ulcerative colitis ( UC ) . The objective of the current study was to determine the effect of tofacitinib on patient-reported outcomes ( PROs ) . Methods Eligible patients ( ≥18 years of age ) with a diagnosis of active UC ( total Mayo score of 6 - 12 points and moderately-to-severely active disease on sigmoidoscopy ) were r and omized in a 2:2:2:3:3 ratio to receive oral tofacitinib 0.5 mg , 3 mg , 10 mg , or 15 mg , or placebo twice daily ( BID ) for 8 weeks . PROs were assessed by the Inflammatory Bowel Disease Question naire ( IBDQ ) and the Inflammatory Bowel Disease Patient-Reported Treatment Impact ( IBD PRTI ) survey . Results At Week 8 , mean IBDQ total scores had improved relative to baseline across all five treatment groups ( baseline range 123.2 - 134.5 ; Week 8 range 149.6 - 175.4 ) . Improvement from baseline was significantly greater ( P = 0.001 ) for tofacitinib 15 mg BID versus placebo . For tofacitinib 15 mg BID , most patients reported satisfaction or extreme satisfaction , definite preference for tofacitinib , and definite willingness to use tofacitinib again on the IBD PRTI at week 8 . Patients achieving endoscopic remission ( Mayo endoscopy score of 0 ) had significantly higher IBDQ scores and favorable PRTI scores than those not achieving endoscopic remission . Conclusions Short-term treatment with tofacitinib BID was associated with dose-dependent improvement in health-related quality of life and patient preferences for tofacitinib . The results complement previously reported efficacy and safety data for the Phase II study . ( NCT 00787202 , November 6 , 2008 ) Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis . Here , tofacitinib safety and efficacy data from a long-term extension study in Japanese patients are presented . Methods Study A3921041 was a multi-centre , open-label , long-term extension study that included Japanese patients who had participated in a prior Phase 2 or Phase 3 study of tofacitinib as monotherapy or with background methotrexate .  Patients received tofacitinib 5 mg twice daily ( BID ) or tofacitinib 10 mg BID . Dose adjustment of tofacitinib during treatment period , and concomitant usage of disease-modifying antirheumatic drugs including methotrexate after week 12 were permitted . Primary endpoints were adverse events , laboratory parameters and vital signs . Secondary efficacy endpoints included American College of Rheumatology (ACR)20/50/70 response rates , Disease Activity Score (DAS)28 - 4(erythrocyte sedimentation rate (ESR))<2.6 response rate ( DAS-defined remission ) and Health Assessment Question naire-Disability Index ( HAQ-DI ) score . Safety and efficacy data were assessed throughout the study . Results A total of 486 patients were recruited and treated ( 1439.9 patient-years of exposure ) . 308 patients completed the study .  Median ( range ) duration of treatment in this extension study was 1185 ( 5–2016 ) days . 476 patients ( 97.9 % ) experienced adverse events ; the majority of which ( 97.8 % ) were of mild or moderate severity . The two most common treatment-emergent adverse events were nasopharyngitis ( n = 293 , 60.3 % ) and herpes zoster ( n = 94 , 19.3 % ) . For all tofacitinib-treated patients , the incidence rate ( patients with events per 100 patient-years ) was 10.7 for serious adverse events , 3.3 for serious infections , 7.4 for herpes zoster ( serious and non-serious ) and 1.2 for malignancies ( excluding non-melanoma skin cancer ) . Mean changes from baseline ( start of the index study ) in laboratory parameters were consistent with those seen in previously reported studies of tofacitinib . ACR20/50/70 response rates , DAS-defined remission rates and HAQ-DI scores were sustained through to study completion . Conclusions Tofacitinib ( with or without background methotrexate ) demonstrated a stable safety profile and sustained efficacy in Japanese patients with active rheumatoid arthritis . The risk of herpes zoster appears to be higher in Japanese patients treated with tofacitinib than in the global population .Trial registration Clinical trials.gov NCT00661661 . Registered 7 February 2008 BACKGROUND & AIMS The comparative efficacy and safety of infliximab and azathioprine therapy alone or in combination for ulcerative colitis ( UC ) have not been evaluated previously . METHODS This r and omized , double-blind trial evaluated the efficacy and safety of 16 weeks of treatment with infliximab monotherapy , azathioprine monotherapy , or the 2 drugs combined in  tumor necrosis factor-a antagonist-naive adults with moderate to severe UC . Patients were assigned r and omly to receive intravenous infusions of infliximab 5 mg/kg at weeks 0 , 2 , 6 , and 14 plus daily oral placebo capsules ; oral azathioprine 2.5 mg/kg daily plus placebo infusions on the infliximab schedule ; or combination therapy with the 2 drugs .  Corticosteroid-free clinical remission ( primary end point , week 16 ) was evaluated at weeks 8 and 16 . The study was terminated before the enrollment target was reached . RESULTS A total of 239 patients were included in efficacy analyses . Baseline characteristics were similar between treatment groups . Corticosteroid-free remission at week 16 was achieved by 39.7 % ( 31 of 78 ) of patients receiving infliximab/azathioprine , compared with 22.1 % ( 17 of 77 ) receiving infliximab alone(P = .017 ) and 23.7 % ( 18 of 76 ) receiving azathioprine alone(P = .032 ) . Mucosal healing at week 16 occurred in 62.8 % ( 49 of 78 ) of patients receiving infliximab/azathioprine , compared with 54.6 % ( 42 of 77 ) receiving infliximab ( P = .295 ) and 36.8 % ( 28 of 76 ) receiving azathioprine ( P = .001 ) . Serious infections occurred in 2 patients ( 1 patient receiving infliximab , and 1 patient receiving azathioprine ) . CONCLUSIONS Anti – tumor necrosis factor-a – naive patients with moderate to severe UC treated with infliximab plus azathioprine were more likely to achieve corticosteroid-free remission at 16 weeks than those receiving either monotherapy . Combination therapy led to significantly better mucosal healing than azathioprine monotherapy . Clinical Trials.gov number , NCT00537316 Background : Infliximab ( IFX ) , adalimumab ( ADA ) , and certolizumab pegol ( CZP ) have similar efficacy in induction and maintenance of clinical remission in Crohn 's disease ( CD ) . Given the comparable nature of these drugs , patient preferences may influence the choice of the product . We aim ed to identify factors that may contribute to CD patients ' decision in selecting one anti‐tumor necrosis factor ( TNF ) agent over the others . Methods : A prospect i ve survey was performed among anti‐TNF‐naïve CD patients . Prior to completion of a question naire , patients were provided with a written description of the three anti‐TNF agents , focusing on indications , mode of administration , side effects , and scientific evidence of efficacy and safety for each drug . Results : One hundred patients ( 47 females , mean age 45 ± 16 years , range 19–81 ) with an ileal , colonic , or ileocolonic ( 33 % , 40 % , and 27 % , respectively ) disease location completed the question naire . Based on the information provided , 36 % of patients preferred ADA , 28 % CZP , and 25 % IFX , whereas 11 % were undecided . The patients ' decision in selecting a specific anti‐TNF drug was influenced by the following factors : ease of use ( 69 % ) , time required for therapy ( 34 % ) , time interval between application of the drug ( 31 % ) , scientific evidence for efficacy ( 19 % ) , and fear of syringes ( 10 % ) . Conclusions : The majority of patients preferred anti‐TNF medications that were administered by subcutaneous injection rather than by intravenous infusion . Ease of use and time required for therapy were two major factors influencing the patients ' selection of a specific anti‐TNF drug . Patients ' individual preferences should be taken into account when prescribing anti‐TNF drugs . ( Inflamm Bowel Dis 2012 BACKGROUND & AIMS : The efficacy and safety of vedolizumab , a humanized immunoglobulin G1 monoclonal antibody against the integrin & agr;4&bgr;7 , were demonstrated in multicenter , phase 3 , r and omized , placebo‐controlled trials in patients with moderately to severely active ulcerative colitis ( UC ) or Crohn 's disease . We analyzed data from 1 of these trials to determine the effects of vedolizumab therapy in patients with UC , based on past exposure to anti – tumor necrosis factor‐&agr ; ( TNF ) antagonists . METHODS : We performed a post hoc analysis of data from the GEMINI 1 study , collected from 464 patients who received vedolizumab or placebo but had not received a previous TNF antagonist ( naive to TNF antagonists ) and 367 patients with an inadequate response , loss of response , or intolerance to TNF antagonists ( failure of TNF antagonists ) . Predefined outcomes of GEMINI 1 were evaluated in these sub population s. RESULTS : At Week 6 , there were greater absolute differences in efficacy  between vedolizumab and placebo in patients naive to TNF antagonists than patients with failure of TNF antagonists , although the risk ratios ( RRs ) for efficacy were similar for each group . Week 6 rates of response  to vedolizumab and placebo were 53.1 % and 26.3 % , respectively , among patients naive to TNF antagonists ( absolute difference , 26.4 % ; 95 % confidence interval [ CI ] , 12.4–40.4 ; RR , 2.0 ; 95 % CI , 1.3–3.0 ) ; these rates were 39.0 % and 20.6 % , respectively , in patients with failure of TNF antagonists ( absolute difference , 18.1 % ; 95 % CI , 2.8–33.5 ; RR , 1.9 ; 95 % CI , 1.1–3.2 ) . During maintenance therapy , the absolute differences were similar but the RR for efficacy was higher for patients with failure of TNF antagonists than for patients naive to TNF antagonists , for most outcomes . Week 52 rates of remission  with vedolizumab and placebo were 46.9 % and 19.0 % , respectively , in patients naive to TNF antagonists ( absolute difference , 28.0 % ; 95 % CI , 14.9–41.1 ; RR , 2.5 ; 95 % CI , 1.5–4.0 ) and 36.1 % and 5.3 % , respectively , in patients with failure of TNF antagonists ( absolute difference , 29.5 % ; 95 % CI , 12.8–46.1 ; RR , 6.6 ; 95 % CI , 1.7–26.5 ) . No differences in adverse events were observed among groups . CONCLUSIONS : Vedolizumab demonstrated significantly greater efficacy as induction and maintenance therapy for UC than placebo in patients naive to TNF antagonists and patients with TNF antagonist failure . There were numerically greater treatment differences at Week 6 among patients receiving vedolizumab who were naive to TNF antagonists than patients with TNF antagonist failure . Clinical Trials.gov no : NCT00783718 BACKGROUND Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis . METHODS We conducted two integrated r and omized , double-blind , placebo-controlled trials of vedolizumab in patients with active disease . In the trial of induction therapy , 374 patients ( cohort 1 ) received  vedolizumab  ( at a dose of 300 mg ) or placebo intravenously at weeks 0 and 2 , and 521 patients ( cohort 2 ) received open-label  vedolizumab at weeks 0 and 2 , with disease evaluation at week 6 . In the trial of maintenance therapy , patients in either cohort who had a response to vedolizumab at week 6 were r and omly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks . A response was defined as a reduction in the Mayo Clinic score ( range , 0 to 12 , with higher scores indicating more active disease ) of at least 3 points and a decrease of at least 30 % from baseline , with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1 . RESULTS Response rates at week 6 were 47.1 % and 25.5 % among patients in the vedolizumab group and placebo group , respectively ( difference with adjustment for stratification factors , 21.7 percentage points ; 95 % confidence interval [ CI ] , 11.6 to 31.7 ; P<0.001 ) . At week 52 , 41.8 % of patients who continued to receive vedolizumab every 8 weeks and 44.8 % of patients who continued to receive vedolizumab every 4 weeks were in clinical remission ( Mayo Clinic score ≤2 and no subscore > 1 ) , as compared with 15.9 % of patients who switched to placebo ( adjusted difference , 26.1 percentage points for vedolizumab every 8 weeks vs. placebo [ 95 % CI , 14.9 to 37.2 ; P<0.001 ] and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo [ 95 % CI , 17.9 to 40.4 ; P<0.001 ] ) . The frequency of adverse events was similar in the vedolizumab and placebo groups . CONCLUSIONS Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis . ( Funded by Millennium Pharmaceuticals ; GEMINI 1 Clinical Trials.gov number , NCT00783718 . ) # # # 1.1 Introduction Ulcerative colitis is a lifelong disease arising from an interaction between genetic and environmental factors , observed predominantly in the developed countries of the world . The precise aetiology is unknown and therefore medical therapy to cure the disease is not yet available . Within Europe there is a North – South gradient , but the incidence appears to have increased in Southern and Eastern countries in recent years.1,2 Patients may live with a considerable symptom burden despite medical treatment ( 66 % describe interference with work and 73 % with leisure activities3 ) in the hope that the aetiology of ulcerative colitis will shortly be revealed and a cure emerge . Although this is conceivable in the next decade , clinicians have to advise patients on the basis of information available today . Despite r and omised trials there will always be many questions that can only be answered by the exercise of judgement and opinion . This leads to differences in practice between clinicians , which may be brought into sharp relief by differences in emphasis between countries . This Consensus endeavours to address these differences . The Consensus is not meant to supersede the guidelines of different countries ( such as those from the UK,4 or Germany,5 ) which reach broadly the same conclusions since they are , after all , based on the same evidence . Rather , the aim of the Consensus is to promote a European perspective on the management of ulcerative colitis ( UC ) and its dilemmas . Since the development of guidelines is an expensive and time-consuming process , it may help to avoid duplication of effort in the future . A European Consensus is also considered important because an increasing number of therapeutic trials recruit from Central and Eastern European countries where practice guidelines have yet to be published . This document up date s the previous European Consensus on the diagnosis and management of UC , and
Background The aim of the study was to assess the efficacy and safety of tofacitinib and its impact on quality of life in patients with moderate-to-severe ulcerative colitis .