Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Infliximab in combination with methotrexate in active ankylosing spondylitis: a clinical and imaging study Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. Efficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a double-blind randomised placebo-controlled Phase 3 study Safety and efficacy of golimumab in Chinese patients with active ankylosing spondylitis: 1-year results of a multicentre, randomized, double-blind, placebo-controlled phase III trial. Safety and Efficacy of Golimumab Administered Intravenously in Adults with Ankylosing Spondylitis: Results through Week 28 of the GO-ALIVE Study Secukinumab and Sustained Improvement in Signs and Symptoms of Patients With Active Ankylosing Spondylitis Through Two Years: Results From a Phase III Study Efficacy and safety of adalimumab in Chinese adults with active ankylosing spondylitis: results of a randomised, controlled trial Ankylosing spondylitis assessment group preliminary definition of short-term improvement in ankylosing spondylitis. Risankizumab, an IL-23 inhibitor, for ankylosing spondylitis: results of a randomised, double-blind, placebo-controlled, proof-of-concept, dose-finding phase 2 study Three Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Studies Evaluating the Efficacy and Safety of Ustekinumab in Axial Spondyloarthritis Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active ankylosing spondylitis (TORTUGA): results from a randomised, placebo-controlled, phase 2 trial Double-blind placebo-controlled trial of etanercept in the prevention of work disability in ankylosing spondylitis
Objectives To compare efficacy and safety of various doses of tofacitinib , an oral Janus kinase inhibitor , with placebo in patients with active ankylosing spondylitis ( AS , radiographic axial spondyloarthritis ) . Methods In this 16-week ( 12-week treatment , 4-week washout ) , phase II , multicentre , dose-ranging trial , adult patients with active AS were r and omised ( N=51 , 52 , 52 , 52 , respectively ) to placebo or tofacitinib 2 , 5 or 10 mg twice daily . The primary efficacy endpoint was Assessment of SpondyloArthritis International Society 20 % improvement ( ASAS20 ) response rate at week 12 . Secondary endpoints included objective measures of disease activity , patient-reported outcomes and MRI of sacroiliac joints and spine . Safety was monitored . Results Emax model analysis of the primary endpoint predicted a tofacitinib 10 mg twice daily ASAS20 response rate of 67.4 % , 27.3 % higher than placebo . Supportive normal approximation analysis demonstrated tofacitinib 5 mg twice daily ASAS20 response rate significantly higher than placebo ( 80.8 % vs 41.2 % ; p<0.001 ) ; tofacitinib 2 and 10 mg twice daily demonstrated greater response rate than placebo ( 51.9 % and 55.8 % , respectively ; not significant ) . Secondary endpoints generally demonstrated greater improvements with tofacitinib 5 and 10 mg twice daily than placebo . Objective ( including MRI ) endpoints demonstrated clear dose response . Adverse events were similar across treatment groups with no unexpected safety findings . Dose-dependent laboratory outcome changes returned close to baseline by week 16 . Conclusions Tofacitinib 5 and 10 mg twice daily demonstrated greater clinical efficacy versus placebo in reducing signs , symptoms and objective endpoints of active AS in adult patients with a similar 12-week safety profile as reported in other indications . Trial registration number NCT01786668 OBJECTIVE The signs and symptoms of ankylosing spondylitis ( AS ) respond inadequately to nonsteroidal antiinflammatory drugs , corticosteroids , and disease-modifying antirheumatic drugs in quite a number of patients . Tumor necrosis factor inhibitors have demonstrated success in reducing AS disease activity in a limited number of clinical trials . The objective of this multicenter , r and omized , placebo-controlled study was to evaluate the efficacy and safety of infliximab in patients with AS . METHODS Patients were r and omly assigned to receive infusions of placebo or 5 mg/kg infliximab at weeks 0 , 2 , 6 , 12 , and 18 . Efficacy was assessed using the ASsessment in Ankylosing Spondylitis ( ASAS ) International Working Group criteria , the Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) , night pain , patient 's global assessment , the Bath Ankylosing Spondylitis Functional Index ( BASFI ) , the Bath Ankylosing Spondylitis Metrology Index ( BASMI ) , chest expansion , the M and er enthesis index , the total swollen joint index , the C-reactive protein level , and the Short Form 36 ( SF-36 ) health survey question naire . The primary end point in this study was the proportion of patients with a 20 % improvement response according to the ASAS International Working Group criteria ( ASAS20 responders ) at week 24 . RESULTS Of the 357 patients screened , 201 were assigned to receive 5 mg/kg infliximab and 78 were assigned to receive placebo . After 24 weeks , 61.2 % of patients in the infliximab group were ASAS20 responders compared with 19.2 % of patients in the placebo group ( P < 0.001 ) . Clinical benefit was observed in patients receiving infliximab as early as week 2 and was maintained over the 24-week study period . Patients receiving infliximab also showed significant improvements in the BASDAI , BASFI , BASMI , chest expansion , and physical component summary score of the SF-36 . Adverse events were reported by 82.2 % of patients receiving infliximab and by 72.0 % of patients receiving placebo ; however , most adverse events in both treatment groups were mild or moderate in severity . CONCLUSION Infliximab was well tolerated and effective in a large cohort of patients with AS during a 24-week study period Objective : To examine the efficacy and safety of infliximab combined with methotrexate compared with methotrexate alone in the treatment of ankylosing spondylitis ( AS ) using MRI and DXA to monitor its impact on bone . Methods : In this single centre study 42 subjects with active AS were treated with methotrexate and were r and omly assigned , in a ratio of 2:1 , to receive five infusions of either 5 mg/kg infliximab or placebo over 30 weeks . The primary outcome was improvement in disease activity as shown by the BASDAI at week 30 . MRI was used to assess the effect of treatments on sacroiliac and spinal enthesitis/osteitis and DXA to monitor bone mineral density . Results : Both therapeutic agents were well tolerated with no dropouts due to adverse events . A significantly greater improvement in mean BASDAI score was seen in the infliximab arm at week 10 ( p = 0.017 ) than in the placebo arm , but this was not maintained by week 30 ( p = 0.195 ) , 8 weeks after the last infusion , at which stage disease flares were reported by some subjects . MRI showed that the mean number of lesions resolving for each subject from week 0 to week 30 was significantly greater in the combination group than in the methotrexate monotherapy group ( p = 0.016 ) . Conclusions : Infliximab in combination with methotrexate was a safe and efficacious treatment in AS over 6 months and was associated with significant regression in enthesitis/osteitis as determined by MRI . However , disease flares were reported 8 weeks after the last infusion , indicating that addition of methotrexate failed to extend the infliximab dosing interval BACKGROUND There are few effective treatments for ankylosing spondylitis , which causes substantial morbidity . Because of the central role of tumor necrosis factor alpha in the spondyloarthritides , we performed a r and omized , double-blind , placebo-controlled trial of etanercept , a recombinant human tumor necrosis factor receptor (p75):Fc fusion protein , in patients with ankylosing spondylitis . METHODS Forty patients with active , inflammatory ankylosing spondylitis were r and omly assigned to receive twice-weekly subcutaneous injections of etanercept ( 25 mg ) or placebo for four months . The primary end point was a composite of improvements in measures of morning stiffness , spinal pain , functioning , the patient 's global assessment of disease activity , and joint swelling . Patients were allowed to continue taking nonsteroidal antiinflammatory drugs , oral corticosteriods ( < or = 10 mg per day ) , and disease-modifying antirheumatic drugs at stable doses during the trial . RESULTS Treatment with etanercept result ed in significant and sustained improvement . At four months , 80 percent of the patients in the etanercept group had a treatment response , as compared with 30 percent of those in the placebo group ( P=0.004 ) . Improvements over base-line values for various measures of disease activity , including morning stiffness , spinal pain , functioning , quality of life , enthesitis , chest expansion , erythrocyte sedimentation rate , and C-reactive protein , were significantly greater in the etanercept group . Longitudinal analysis showed that the treatment response was rapid and did not diminish over time . Etanercept was well tolerated , with no significant differences in rates of adverse events between the two groups . CONCLUSIONS Treatment with etanercept for four months result ed in rapid , significant , and sustained improvement in patients with ankylosing spondylitis Objectives To evaluate the efficacy and safety of certolizumab pegol ( CZP ) after 24 weeks in RAPID-axSpA ( NCT01087762 ) , an ongoing Phase 3 trial in patients with axial spondyloarthritis ( axSpA ) , including patients with ankylosing spondylitis ( AS ) and non-radiographic axSpA ( nr-axSpA ) . Methods Patients with active axSpA were r and omised 1:1:1 to placebo , CZP 200 mg every 2 weeks  ( Q2W ) or  CZP 400 mg every 4 weeks ( Q4W ) . In total 325 patients were r and omised . Primary endpoint was ASAS20 ( Assessment of SpondyloArthritis international Society 20 ) response at week 12 . Secondary outcomes included change from baseline in Bath Ankylosing Spondylitis Functional Index ( BASFI ) , Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) , and Bath Ankylosing Spondylitis Metrology Index ( BASMI ) linear . Results Baseline disease activity was similar between AS and nr-axSpA. At week 12 , ASAS20 response rates were significantly higher in CZP 200 mg Q2W and CZP 400 mg Q4W arms versus placebo ( 57.7 and 63.6 vs 38.3 , p≤0.004 ) . At week 24 , combined CZP arms showed significant ( p<0.001 ) differences in change from baseline versus placebo in BASFI ( −2.28 vs −0.40 ) , BASDAI ( −3.05 vs −1.05 ) , and BASMI ( −0.52 vs −0.07 ) . Improvements were observed as early as week 1 . Similar improvements were reported with CZP versus placebo in both AS and nr-axSpA sub population s. Adverse events were reported in 70.4 % vs 62.6 % , and serious adverse events in 4.7 % vs 4.7 % of All CZP versus  placebo groups . No deaths or malignancies were reported . Conclusions CZP rapidly reduced the signs and symptoms of axSpA , with no new safety signals observed compared to the safety profile of CZP in RA . Similar improvements were observed across CZP dosing regimens , and in AS and nr-axSpA patients OBJECTIVE The aim of this study was to assess the efficacy and safety of golimumab in Chinese patients with active AS . METHODS Two hundred and thirteen patients were r and omized in a 1:1 ratio to receive either s.c . injections of placebo from weeks 0 to 20 followed by golimumab 50 mg from weeks 24 to 48 ( group 1 , n = 105 ) or golimumab 50 mg from weeks 0 to 48 ( group 2 , n = 108 ) , both every 4 weeks . Placebo crossover occurred at week 24 , while early escape was at week 16 . The primary endpoint was an improvement of at least 20 % in the Assessment of SpondyloArthritis international Society ( ASAS20 ) criteria at week 14 . Major secondary endpoints included week 24 ASAS20 response and week 14 change scores for BASFI and BASMI . RESULTS Golimumab treatment elicited significantly better responses than placebo in week 14 ASAS20 response [ 49.1 % ( 53/108 ) vs 24.8 % ( 26/105 ) , respectively , P < 0.001 ] , week 24 ASAS20 response ( 50.0 % vs 22.9 % , P < 0.001 ) and mean improvements in BASFI ( -1.26 vs 0.11 , P < 0.001 ) and BASMI ( -0.42 vs -0.19 , P = 0.021 ) scores at week 14 . Additionally , golimumab treatment led to significant improvements in the mental and physical components of health-related quality of life ( HRQoL ) and sleep problems at week 24 , all of which were further improved through week 52 . During the 16-week placebo-controlled study period , 31.4 % and 30.6 % of patients had adverse events ( AEs ) in groups 1 and 2 , respectively ; similar AE reporting rates were observed through week 24 ( 34.3 % and 32.0 % ) and among the golimumab-treated patients through week 56 ( 41.2 % ) . CONCLUSION Golimumab significantly reduced clinical symptoms/signs and improved physical function , range of motion and HRQoL in Chinese patients with active AS without unexpected safety concerns . TRIAL REGISTRATION Clinical Trials.gov , NCT01248793 Objective . To evaluate the safety and efficacy of intravenous golimumab ( GOL ) in patients with active ankylosing spondylitis ( AS ) . Methods . In a phase III , r and omized , double-blind , placebo (PBO)-controlled trial , 208 patients were r and omized ( 1:1 ) to intravenous ( IV ) infusions of GOL 2 mg/kg ( n = 105 ) at weeks 0 , 4 , 12 , and every 8 weeks , or PBO ( n = 103 ) at weeks 0 , 4 , and 12 , with crossover to GOL at Week 16 . The primary endpoint was ≥ 20 % improvement from baseline in the Assessment of Spondyloarthritis International Society Criteria ( ASAS20 ) at Week 16 . Secondary endpoints included ASAS40 , ≥ 50 % improvement in the Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI50 ) , and change in the Bath Ankylosing Spondylitis Functional Index ( BASFI ) at Week 16 . Safety was monitored through Week 28 . Results . Significantly greater proportions of GOL-treated patients had ASAS20 response at Week 2 ( 37.1 % vs 19.4 % ; p = 0.005 ) and at Week 16 ( 73.3 % vs 26.2 % ; p < 0.001 ) . At Week 16 , 41.0 % of those receiving GOL achieved BASDAI50 compared with 14.6 % of those taking PBO ( p < 0.001 ) , and the GOL group had greater mean improvement in BASFI ( −2.4 vs −0.5 ; p < 0.001 ) . Through Week 16 , 23.3 % of patients in the PBO group and 32.4 % of patients in the GOL group had ≥ 1 adverse event ( AE ) ; infections being the commonest type of AE . Through Week 28 , two GOL-treated patients had a serious AE . Conclusion . GOL 2 mg/kg administered IV at weeks 0 , 4 , and every 8 weeks significantly reduced the signs and symptoms of AS in adults . AE were consistent with other antitumor necrosis factor therapies , with no new safety signals ( Clinical trials.gov : NCT02186873 ) Secukinumab improved the signs and symptoms of ankylosing spondylitis ( AS )  over 52 weeks in the phase III MEASURE 2 study . Here , we report longer‐term ( 104 weeks ) efficacy and safety results Background and objectives Efficacy of adalimumab for ankylosing spondylitis ( AS ) has been established for Western population s but not in the Chinese population . This study is the first to evaluate the efficacy and safety of adalimumab in Chinese patients with AS . Methods Chinese adults with active AS who had an inadequate response or were intolerant to ≥1 non-steroidal anti-inflammatory drugs were r and omised to  adalimumab 40 mg ( N=229 )  or matching placebo ( N=115 ) subcutaneously every other week ( EOW ) for 12 weeks , followed by a 12-week open-label adalimumab 40 mg EOW phase . The primary efficacy endpoint was the percentage of patients meeting the Assessment in Spondyloarthritis International Society ( ASAS20 ) response criteria at week 12 . The recently developed AS Disease Activity Score ( ASDAS ) , as well as efficacy measures of spinal mobility , disease activity , physical function and quality of life were evaluated . Results At week 12 , adalimumab treatment result ed in a significantly greater percentage of ASAS20 responders than placebo ( 67.2 % versus 30.4 % , respectively ; p<0.001 ) . Differences in ASAS20 were observed as early as week 2 ( 42.8 % vs 6.1 % , respectively ; p<0.001 ) . The percentages of patients achieving ASAS40 , ASAS 5/6 and ASDAS inactive disease were significantly greater with adalimumab than placebo at week 12 ( all p<0.001 ) . Tuberculosis was reported in one patient . No cases of malignancy , lymphoma , demyelinating disease or lupus-like syndrome were reported during the study . Conclusions Adalimumab significantly reduced the signs and symptoms , improved physical function and quality of life of Chinese patients with active AS , and was generally safe and well tolerated in this population OBJECTIVE To develop criteria for symptomatic improvement in patients with ankylosing spondylitis ( AS ) , using outcome domain data from placebo-controlled clinical trials of nonsteroidal antiinflammatory drugs ( NSAIDs ) . METHODS Patient data from 5 short-term , r and omized , controlled trials were used to assess equivalence , reliability , and responsiveness of multiple items in the 5 outcome domains for AS treatment : physical function , pain , spinal mobility , patient global assessment , and inflammation . At least one measure per domain was responsive ( st and ardized response mean of > 0.5 ) , except for the spinal mobility domain , which was omitted from the criteria . We developed and tested c and i date improvement criteria in a r and om two-thirds subset from the 3 largest trials and used the remaining one-third for validation . These 3 largest trials included 923 patients ( 631 receiving NSAIDs , 292 in placebo groups ) . We selected the multiple domain definition that best distinguished NSAID treatment from placebo by chi-square test and that had a placebo response rate of < or = 25 % . RESULTS C and i date definitions were changes in single domains and in multiple measure indices , as well as combinations of improvements in multiple domains . Worsening in a domain was defined as a change for the worse of > or = 20 % and a net change for the worse of > or = 10 units on a scale of 0 - 100 . Partial remission ( for comparison purpose s ) was defined as an end-of-trial value of < 20/100 in each of the 4 domains . Among 20 c and i date criteria , change of > or = 20 % and > or = 10 units in each of 3 domains and absence of worsening in the fourth discriminated best in the development subset ( 51 % of patients improved with NSAIDs , 25 % with placebo ; chi2 = 36.4 , P < 0.001 ) . Results were confirmed in the validation subset . Almost all patients satisfying the definition of partial disease remission at the end of the trial had also improved by this criterion . Among all 923 patients , improvement rates using this criterion were 49 % for NSAID-treated patients and 24 % for placebo-treated patients . CONCLUSION Although further validation using data from new trials is still needed , we conclude that we have developed a clinical ly valid , easy-to-use measure of short-term improvement in AS Objectives To evaluate the efficacy and safety of risankizumab , a humanised monoclonal antibody targeting the p19 subunit of interleukin-23 ( IL-23 ) , in patients with active ankylosing spondylitis ( AS ) . Methods A total of 159 patients with biological-naïve AS , with active disease ( Bath Ankylosing Spondylitis Disease Activity Index score of ≥4 ) , were r and omised ( 1:1:1:1 ) to risankizumab ( 18 mg single dose , 90 mg or 180 mg at day 1 and weeks 8 , 16 and 24 ) or placebo over a 24-week blinded period . The primary outcome was a 40 % improvement in Assessment in Spondylo Arthritis International Society ( ASAS40 ) at week 12 . Safety was assessed in patients who received at least one dose of study drug . Results At week 12 , ASAS40 response rates were 25.5 % , 20.5 % and 15.0 % in the 18 mg , 90 mg and 180 mg risankizumab groups , respectively , compared with 17.5 % in the placebo group . The estimated difference in proportion between the 180 mg risankizumab and placebo groups ( primary endpoint ) was –2.5 % ( 95 % CI –21.8 to 17.0 ; p=0.42 ) . Rates of adverse events were similar in all treatment groups . Conclusions Treatment with risankizumab did not meet the study primary endpoint and showed no evidence of clinical ly meaningful improvements compared with placebo in patients with active AS , suggesting that IL-23 may not be a relevant driver of disease pathogenesis and symptoms in AS . Trial registration number NCT02047110 ; Pre- results To evaluate the efficacy and safety of ustekinumab in 3 r and omized , placebo‐controlled studies in patients with axial spondyloarthritis ( SpA ) . Studies 1 and 2 included patients with radiographic axial SpA ( anti – tumor necrosis factor [anti‐TNF]–naive patients and patients with inadequate response or intolerance to anti‐TNF , respectively ) ; study 3 patients had nonradiographic axial BACKGROUND At present , biological disease-modifying anti-rheumatic drugs ( DMARDs ) are the only treatment recommended for patients with ankylosing spondylitis who have not responded to first-line treatment with non-steroidal anti-inflammatory drugs ( NSAIDs ) . The TORTUGA trial investigated the efficacy and safety of filgotinib , an oral selective Janus kinase 1 ( JAK1 ) inhibitor , for the treatment of patients with active ankylosing spondylitis . METHODS In this completed , r and omised , double-blind , placebo-controlled , phase 2 trial , we enrolled adult patients from 30 sites in seven countries ( Belgium , Bulgaria , Czech Republic , Estonia , Pol and , Spain , and Ukraine ) . Eligible patients had active ankylosing spondylitis and an inadequate response or intolerance to two or more NSAIDs . Patients were r and omly assigned ( 1:1 ) with an interactive web-based response system to receive filgotinib 200 mg or placebo orally once daily for 12 weeks . R and omisation was stratified by current use of conventional synthetic DMARDs and previous receipt of anti-tumour necrosis factor therapy . The patients , study team , and study sponsor were masked to treatment assignment . The primary endpoint was the change from baseline in ankylosing spondylitis disease activity score ( ASDAS ) at week 12 , which was assessed in the full analysis set ( ie , all r and omised patients who received at least one dose of study drug ) . Safety was assessed according to actual treatment received . This trial is registered with Clinical Trials.gov , number NCT03117270 . FINDINGS Between March 7 , 2017 , and July 2 , 2018 , 263 patients were screened and 116 r and omly assigned to filgotinib ( n=58 ) or placebo ( n=58 ) . 55 ( 95 % ) patients in the filgotinib group and 52 ( 90 % ) in the placebo group completed the study ; three ( 5 % ) patients in the filgotinib group and six ( 10 % ) in the placebo group discontinued treatment . The mean ASDAS change from baseline to week 12 was -1·47 ( SD 1·04 ) in the filgotinib group and -0·57 ( 0·82 ) in the placebo group , with a least squares mean difference between groups of -0·85 ( 95 % CI -1·17 to -0·53 ; p<0·0001 ) . Treatment-emergent adverse events were reported in 18 patients in each group , the most common being nasopharyngitis ( in two patients in the filgotinib group and in four patients in the placebo group ) . Treatment-emergent adverse events led to permanent treatment discontinuation in two patients ( a case of grade 3 pneumonia in the filgotinib group and of high creatine kinase in the placebo group ) . No deaths were reported during the study . INTERPRETATION Filgotinib is efficacious and safe for the treatment of patients with active ankylosing spondylitis who have not responded to first-line pharmacological therapy with NSAIDs . Further investigation of filgotinib for ankylosing spondylitis is warranted . FUNDING Galapagos and Gilead Sciences Objectives Etanercept has been shown to be rapidly effective in suppressing disease activity in ankylosing spondylitis ( AS ) . The aim of this study was to determine whether etanercept improves work instability as measured by the Ankylosing Spondylitis Work Instability Scale ( AS-WIS ) . Method Forty patients with active AS who were in work but were work unstable were recruited . Patients were r and omised to receive 25 mg etanercept or placebo twice weekly for 12 weeks . The primary outcome was change in AS-WIS at week 12 . The AS-WIS is a patient-derived outcome measure which allows stratification of the risk of job loss . Secondary outcomes included clinical outcomes and gait parameters . Results The mean improvement in AS-WIS score at week 12 was 2.75 in the etanercept group and 0.68 in the placebo group ( p=0.125 ) . The risk of job loss decreased for 11 ( 55 % ) of the etanercept group compared with 7 ( 35 % ) in the placebo group . Conversely , the risk of job loss increased in 3 ( 15 % ) of the placebo group compared with 1 ( 5 % ) in the etanercept group . There was no statistically significant difference between treatment groups in change in WIS categories ( Mann – Whitney U test=0.153 , p=0.160 ) . Significant improvement with etanercept was seen at week 12 in clinical outcomes and gait parameters .  Etanercept was well tolerated , with no dropouts due to adverse events . Conclusion This small study confirms the efficacy of etanercept on clinical outcome measures in patients with AS and suggests an effect on work instability which needs to be replicated in a larger controlled study
To compare the relative efficacy of current and investigational biologic and oral small molecule ( OSM ) treatments for active ankylosing spondylitis ( AS ) .