To Tumor Necrosis Factor Inhibitors Research Articles

P433 Sex-based differences in response to tumor necrosis factor inhibitor induction therapy for ulcerative colitis: a pooled analysis of individual patient-level clinical trials data

Abstract Background There are increasing data on sex-based differences in IBD epidemiology, phenotype and outcomes. The purpose of this study was to characterize sex-based differences in response to tumor necrosis factor inhibitor (TNFi) therapies in patients with ulcerative colitis (UC). Methods We conducted a pooled analysis of individual-level data from randomized clinical trials (RCTs) on induction therapy with infliximab and golimumab, accessed through the Yale University Open Data Access platform. We analyzed patients in the treatment and placebo arms separately. Using multivariable logistic regression modeling, we compared the primary outcome of clinical remission, and secondary outcomes of clinical response and mucosal healing, according to clinical trial definitions, between male and female patients with UC at week 6 (golimumab) or week 8 (infliximab) of induction therapy. Effect estimates were expressed as adjusted odds ratios (aOR) and 95% confidence intervals (CI). Results We included 1639 patients (696, 42.5% were women, Table) from two trials using infliximab (ACT-1 and 2) and one trial using golimumab (PURSUIT). Male patients were older than female patients in the treatment arm of the overall cohort [mean age (standard deviation) 31.31 (16.53) years and 29.34 (15.19) years, respectively). All other baseline characteristics, such as sex, race, Mayo score at screening, and concomitant systemic corticosteroid and immunomodulator use were comparable. Compared to female patients, male patients were significantly less likely to achieve clinical remission in both treatment and placebo arms (aOR 0.55, 95% CI 0.31, 0.97 and 0.34, 95% CI 0.15, 0.82, respectively, Figure). Compared to female patients, male patients were significantly less likely to achieve mucosal healing and clinical response in the treatment arm (aOR 0.47, 95% CI 0.27, 0.83 and 0.51, 95% CI 0.29, 0.90, respectively), but there was no significant difference in these secondary outcomes by sex in the placebo arm. Conclusion Based on this analysis of pooled data from RCTs, we demonstrate that clinical remission, response and mucosal healing with TNFi induction therapies are less likely in male patients compared to female patients with UC. Clinical remission is also less likely in male patients on placebo. These finding may lead to further research on sex-based differences in treatment outcomes, including mechanistic studies.

P192 Secukinumab provides rapid and sustained improvements in subgroup analyses of joint tenderness and swelling in patients with psoriatic arthritis: 2-year results from the Phase 3 FUTURE 5 study

Abstract Background/Aims We report the 2-year effects of secukinumab on 78 tender joint count (TJC)/76 swollen joint count (SJC) scores in key subgroups of FUTURE 5: patients naive/with prior inadequate response (IR) to tumour necrosis factor inhibitors (TNFis), and patients with/without concomitant methotrexate (MTX) use. Methods 996 patients with active psoriatic arthritis, who received ≤3 prior TNFis and/or concomitant MTX, were randomised to secukinumab 300 or 150 mg with loading dose (LD), 150 mg without LD or placebo. Treatments were given at baseline, Weeks 1-4 and every 4 weeks thereafter. Placebo-treated patients were re-randomised to secukinumab 300/150 mg at Week 16 (non-responders) or 24 (responders). Secukinumab dose could be escalated from 150 to 300 mg from Week 60 and maintained thereafter. ACR20 response and changes in 78 TJC/76 SJC are reported over 2 years in TNFi-naive/IR and with/without concomitant MTX subgroups. Results The primary endpoint, ACR20 response at Week 16, is reported elsewhere. At Week 104, 78.1%, 81.8% and 80.8% of TNFi-naive patients achieved an ACR20 response versus 74.0%, 72.1% and 69.8% of TNFi-IR patients with secukinumab 300, 150 and 150 mg no LD, respectively. At the same timepoint, 76.5%, 80.2% and 78.3% of patients with concomitant MTX achieved an ACR20 response versus 77.6%, 78.6% and 77.6% of patients without concomitant MTX with secukinumab 300, 150 and 150 mg no LD, respectively. At Week 104, mean change from baseline in adjusted 78 TJC/76 SJC scores for TNFi-naive and TNFi-IR patients was -14.1/-8.6 and -19.0/-9.1 for secukinumab 300 mg, -15.7/-9.6 and -19.1/-12.2 for secukinumab 150 mg, and -17.7/-10.9 and -17.9/-9.9 for secukinumab 150 mg no LD, respectively (Table 1). At Week 104, mean change from baseline in adjusted 78 TJC/76 SJC scores for patients with and without concomitant MTX was -15.7/-8.5 and -15.1/-3.4 for secukinumab 300 mg, -16.4/-10.4 and -16.8/-10.1 for secukinumab 150 mg, and -17.0/-10.3 and -18.6/-11.1 for secukinumab 150 mg no LD, respectively. Conclusion Secukinumab provided rapid improvements in TJC and SJC at Week 16, which were sustained through Week 104, irrespective of TNFi history/concomitant MTX use. P192 Table 1:Selected baseline characteristics and 78 TJC and 76 SJC Results at Week 104Selected baseline characteristicsVariableSEC 300 mg (N = 222)SEC 150 mg (N = 220)SEC 150 mgno LD (N = 222)PBO (N = 332)Mean adjusted 78 TJC scoreTotal population19.821.221.821.2Mean adjusted 76 SJC scoreTotal population10.012.111.911.778 TJC and 76 SJC Results at Week 104EndpointSECPBO-SEC300 mg SC(N = 100)150 mg SCa(N = 100)150 mg SCno LDb(N = 222)300 mg SC (N = 153)150 mgc (N = 153)Adjusted 78 TJC (total population)Change from baseline (SD)-15.4 (12.5)-16.6 (14.3)-17.7 (15.3)-17.2 (14.9)-15.2 (13.0)Adjusted 76 SJC (total population)Change from baseline (SD)-8.7 (7.3)-10.3 (10.5)-10.6 (9.6)-10.7 (10.0)-9.6 (9.2)Adjusted 78 TJC (TNF status)TNFi-naiveChange from baseline (SD)-14.1 (11.6)-15.7 (14.1)-17.7 (15.0)-16.6 (13.7)-14.5 (12.6)TNFi-IRChange from baseline (SD)-19.0 (14.3)-19.1 (14.7)-17.9 (16.3)-18.9 (18.1)-17.6 (14.5)Adjusted 76 SJC (TNF status)TNFi-naiveChange from baseline (SD)-8.6 (7.2)-9.6 (9.6)-10.9 (10.1)-10.5 (8.6)-9.2 (7.5)TNFi-IRChange from baseline (SD)-9.1 (7.8)-12.2 (12.8)-9.9 (7.9)-11.0 (13.4)-10.9 (13.4)Adjusted 78 TJC (MTX use)Concomitant MTX useChange from baseline (SD)-15.7 (12.3)-16.4 (14.7)-17.0 (14.0)-17.8 (16.0)-15.8 (14.2)No concomitant MTX useChange from baseline (SD)-15.1 (12.8)-16.8 (13.9)-18.6 (16.8)-16.4 (14.0)-14.7 (12.1)Adjusted 76 SJC (MTX use)Concomitant MTX useChange from baseline (SD)-8.5 (5.9)-10.4 (11.1)-10.3 (8.6)-10.7 (9.6)-8.9 (7.8)No concomitant MTX useChange from baseline (SD)-8.9 (8.7)-10.1 (10.0)-11.1 (10.8)-10.6 (10.6)-10.1 (10.2)aIncludes 76 patients who were uptitrated to SEC 300 mg starting at Week 60;bIncludes 77 patients who were uptitrated to SEC 300 mg starting at Week 60;cIncludes 52 patients who were uptitrated to SEC 300 mg starting at Week 60. Data are reported as observed. N=number of randomised patients; n=number of patients with evaluation. IR, inadequate response; LD, loading dose; MTX, methotrexate; PBO, placebo; PsA, psoriatic arthritis; SD, standard deviation; SEC, secukinumab; SJC, swollen joint count; TJC, tender joint count; TNFi, tumour necrosis factor inhibitor. Disclosure I. McInnes: Grants/research support; AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, UCB. H. Chinoy: Grants/research support; AbbVie, Amgen, Biogen, BMS, Janssen, Lilly, Novartis, UCB. D. Asquith: Corporate appointments; Employee of Novartis. Shareholder/stock ownership; Shareholder of Novartis. A. White: Corporate appointments; Employee of Novartis. Shareholder/stock ownership; Shareholder of Novartis. C. Gaillez: Corporate appointments; Employee of Novartis. Shareholder/stock ownership; Shareholder of Novartis and Bristol Myers Squibb.

P196 Secukinumab provides sustained improvements in subgroup analyses of joint tenderness and swelling in patients with psoriatic arthritis: 5year results from the Phase3 FUTURE 2 study

Abstract Background/Aims We report the 5-year efficacy of secukinumab, an anti-interleukin17A inhibitor with long-term efficacy and tolerability in patients with psoriatic arthritis (PsA), on reduction of 78 tender joint count (TJC)/76 swollen joint count (SJC) scores in key subgroups of FUTURE 2: patients naive/with a prior inadequate response (IR) to tumour necrosis factor inhibitors (TNFis), and patients with/without concomitant methotrexate (MTX) use. Methods 397 patients with active PsA, who received ≤3 prior TNFis and/or concomitant MTX, were randomised to secukinumab (300, 150, 75 mg) or placebo at baseline, Weeks 1-4, and every 4 weeks thereafter. Placebo-treated patients were rerandomised to secukinumab 300 or 150 mg at Week 16 (nonresponders) or 24 (responders). Secukinumab dose could be escalated from 150 to 300 mg or from 75 to 150/300 mg following physician’s assessment from Week 128 and maintained thereafter. ACR20 response and changes in 78 TJC/76 SJC are reported over 5 years for secukinumab 300 and 150 mg (approved PsA doses) in TNFi-naive/IR and with/without concomitant MTX subgroups. Results The primary endpoint, ACR20 response at Week 24, is reported elsewhere. In the secukinumab 300 and 150 mg arms, 79.6% and 77.1% of TNFinaive patients achieved an ACR20 response versus 56.3% and 66.7% of TNFi-IR patients at Week 260. At the same timepoint, 62.5% and 73.5% of patients with concomitant MTX use achieved an ACR20 response versus 84.8% and 75.0% of patients without concomitant MTX use in the secukinumab 300 and 150 mg arms, respectively. At Week 260, mean change from baseline in adjusted 78 TJC/76 SJC scores for TNFi-naive and TNFi-IR patients was −13.1/−9.5 and −12.0/−8.9 for secukinumab 300 mg and −15.3/−8.8 and −14.4/−7.9 for secukinumab 150 mg, respectively (Table 1). At Week 260, mean change from baseline in adjusted 78 TJC/76 SJC scores for patients with and without concomitant MTX was −11.2/−8.9 and −14.4/−9.7 for secukinumab 300 mg and −14.7/−9.5 and −15.4/−7.5 for secukinumab 150 mg, respectively. P196 Table 1:Selected baseline characteristics and 78 TJC and 76 SJC results at Week 24 and Week 260Selected baseline characteristicsVariableSEC 300 mg SC(N = 100)SEC 150 mg SC (N = 100)PBO (N = 98)Mean adjusted 78 TJC scoreTotal population20.224.123.4Mean adjusted 76 SJC scoreTotal population11.211.912.178 TJC and 76 SJC results at Week 24 and Week 260EndpointWeek 24Week 260SEC300 mg SC (N = 100)SEC150 mg SC (N = 100)PBO-SEC300 mg SC (N = 45)PBO-SEC150 mg (N = 43)SEC300 mg SC (N = 100)SEC150 mg SCa (N = 100)PBO-SEC 300 mg SC (N = 45)PBO-SEC 150 mgb (N = 43)Adjusted 78 TJC (total population)Change from baseline (SD)−10.4 (10.8)−12.1 (16.5)−10.6 (14.1)−9.7 (13.6)−12.8 (10.7)−15.1 (15.9)−14.5 (15.4)−12.5 (10.6)Adjusted 76 SJC (total population)Change from baseline (SD)−7.2 (5.8)−6.3 (7.7)−9.7 (9.5)−9.6 (10.7)−9.3 (6.1)−8.5 (7.9)−9.5 (8.1)−8.3 (6.3)Adjusted 78 TJC (TNF status)TNFi-naiveChange from baseline (SD)−10.7 (10.8)−13.0 (16.6)−3.5 (13.9)−8.0 (10.7)−13.1 (11.1)−15.3 (16.7)−14.8 (16.0)−11.5 (10.2)TNFi-IRChange from baseline (SD)−9.8 (10.9)−10.3 (16.4)−11.0 (11.4)−13.4 (19.5)−12.0 (9.6)−14.4 (14.0)−14.0 (15.1)−15.7 (12.0)Adjusted 76 SJC (TNF status)TNFi-naiveChange from baseline (SD)−6.9 (4.8)−6.7 (8.2)−10.5 (11.0)−6.8 (6.2)−9.5 (5.7)−8.8 (8.8)−9.4 (9.0)−8.4 (6.9)TNFi-IRChange from baseline (SD)−7.8 (7.4)−5.7 (6.5)−7.8 (5.0)−15.6 (16.3)−8.9 (7.4)−7.9 (5.1)−9.6 (6.1)−7.9 (4.6)Adjusted 78 TJC (MTX use)Concomitant MTX useChange from baseline (SD)−10.3 (8.7)−10.6 (16.7)−8.7 (13.1)−7.6 (14.3)−11.2 (9.1)−14.7 (14.5)−12.7 (12.5)−11.4 (11.4)No concomitant MTX useChange from baseline (SD)−10.5 (12.3)−13.3 (16.4)−15.2 (16.8)−14.2 (12.0)−14.4 (12.0)−15.4 (17.5)−16.8 (18.6)−14.1 (9.6)Adjusted 76 SJC (MTX use)Concomitant MTX useChange from baseline (SD)−6.9 (6.1)−6.0 (8.5)−8.9 (8.6)−8.8 (9.7)−8.9 (6.0)−9.5 (9.1)−8.6 (5.3)−9.4 (7.2)No concomitant MTX useChange from baseline (SD)−7.4 (5.7)−6.6 (6.9)−11.6 (12.4)−11.2 (13.8)−9.7 (6.2)−7.5 (6.5)−10.6 (10.7)−6.6 (4.6)aSEC 150 mg arm includes 42 patients who were uptitrated to SEC 300 mg from Week 128.bPBO-SEC 150 mg arm includes 19 patients who were uptitrated to SEC 300 mg from Week 128. Data are reported as observed.N=number of randomised patients; n=number of patients with evaluation. IR, inadequate response; MTX, methotrexate; PBO, placebo; PsA, psoriatic arthritis; SC, subcutaneous; SD, standard deviation; SEC, secukinumab; SJC, swollen joint count; TJC, tender joint count; TNFi, tumour necrosis factor inhibitor. Conclusion Analysis of 78 TJC/76 SJC scores demonstrated that treatment with secukinumab significantly reduced joint tenderness and swelling at Week 24, which were sustained over 5 years, irrespective of TNFi history/concomitant MTX use. Disclosure I. McInnes: Grants/research support; Research grants, consultation fees, or speaker honoraria: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer and UCB. H. Chinoy: Grants/research support; Research grants, travel grants, consultancy or speaker honoraria: AbbVie, Amgen, Biogen, BMS, Janssen, Lilly, Novartis and UCB. D. Asquith: Shareholder/stock ownership; Employee of Novartis. Shareholder of Novartis. A. White: Shareholder/stock ownership; Employee of Novartis. Shareholder of Novartis. C. Gaillez: Shareholder/stock ownership; Employee of Novartis. Shareholder of Novartis and Bristol Myers Squibb.

Long-term safety and efficacy of sarilumab over 5 years in patients with rheumatoid arthritis refractory to TNF inhibitors.

The objective of this study was to evaluate the long-term safety and efficacy of sarilumab over 5 years in patients with RA refractory to TNF inhibitors (TNFis). Patients in the 24-week randomized controlled trial (RCT) TARGET (NCT01709578) who received double-blind placebo or sarilumab 150 or 200 mg every 2 weeks (q2w), plus conventional synthetic DMARDs (csDMARDs), were eligible to receive open-label sarilumab 200 mg q2w plus csDMARDs in the open-label extension (OLE), EXTEND (NCT01146652). OLE dose reduction to 150 mg q2w was permitted per investigators' judgement or protocol-mandated safety concerns. Safety and efficacy were assessed through treatment-emergent adverse events (AEs), laboratory abnormalities and clinical DASs. All statistics are descriptive. Of 546 patients, 454 (83%) were treated with sarilumab in the OLE. The cumulative observation period was 1654.8 patient-years (PY; n = 521); 268 patients (51%) had ≥4 years' exposure. Incidence rates per 100 PY of AEs, and AEs leading to discontinuation, infection and serious infection were 160.4, 8.1, 57.8 and 3.9, respectively. Neutropenia was the most common AE (15.3 per 100 PY). An absolute neutrophil count of <1000 cells/mm3 (Grade 3/4 neutropenia) was observed in 74 patients (14.2%) and normalized on treatment in 48. Clinical efficacy was sustained through 5 years' follow-up. Efficacy was similar for patients with 1 and >1 TNFi failure, and similar for patients who either remained on 200 mg or reduced to 150 mg. In patients with RA refractory to TNFi, sarilumab's long-term term safety profile was consistent with previous clinical studies and post-marketing reports. Efficacy was sustained over 5 years. TARGET, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01709578, NCT01709578; EXTEND, ClinicalTrials.gov, https://www.clinicaltrials.gov/ct2/show/NCT01146652, NCT01146652.

Comparative efficacy and safety of secukinumab, ixekizumab, and tofacitinib in patients with active psoriatic arthritis showing insufficient response to tumor necrosis factor inhibitors

Objective This study aimed to determine the relative effectiveness and safety of secukinumab, ixekizumab, and tofacitinib in patients with psoriatic arthritis (PsA) showing insufficient responses to tumor necrosis factor (TNF) inhibitors. Materials and methods A Bayesian network meta-analysis was conducted using direct and indirect data from five randomized controlled trials that examined the efficacy and safety of secukinumab 150 mg or 300 mg every 4 weeks, subcutaneously injected ixekizumab 80 mg every 2 weeks (Q2W) or every 4 weeks (Q4W), and tofacitinib 5 mg or 10 mg twice orally in active PsA patients responding insufficiently to TNF inhibitors. Results Six RCTs, including 1,279 patients, fulfilled the inclusion criteria. Secukinumab 300 mg, listed at the top left of the league table diagonal, was associated with the most favorable American College of Rheumatology 20 (ACR20) response rate. Contrastingly, the placebo, listed at the bottom right of the league table diagonal, showed the least favorable results. The ixekizumab 80 mg Q2W or Q4W, secukinumab 150 mg, and tofacitinib 5 or 10 mg groups exhibited significantly higher ACR20 responses than the placebo group. The surface under the cumulative ranking curve (SUCRA)-based ranking probability suggested that secukinumab 300 mg was most likely the best treatment to achieve the ACR20 response rate, followed by ixekizumab 80 mg Q2W, secukinumab 150 mg, ixekizumab 80 mg Q4W, tofacitinib 5 and 10 mg, and the placebo. Conclusion Secukinumab, ixekizumab, and tofacitinib were effective in PsA patients with inadequate response to TNF inhibitors, without serious adverse event risks.

Depression and anxiety symptoms at TNF inhibitor initiation are associated with impaired treatment response in axial spondyloarthritis.

ObjectivesDepression and anxiety are associated with more severe disease in cross-sectional studies of axial spondyloarthritis (axSpA). We examined the association between baseline symptoms of depression or anxiety and response to TNF inhibitors (TNFi) in axSpA.MethodsBiologic naïve participants from a national axSpA register completed the Hospital Anxiety and Depression Scale (HADS) before initiating TNFi. Symptoms of anxiety and depression were each categorized as moderate–severe (≥11), mild (8–10) and ‘none’ (≤7), and compared against change in disease indices [BASDAI and AS Disease Activity Score (ASDAS)] over time and time to treatment discontinuation using marginal structural models. Inverse-probability weights balanced baseline age, gender, BMI, deprivation, education and baseline values of respective disease indices.ResultsOf the 742 participants (67% male, mean age 45 years), 176 (24%) had moderate–severe and 26% mild depression; 295 (40%) had moderate–severe and 23% mild anxiety. Baseline disease activity was higher in higher HADS symptom categories for both depression and anxiety. Participants with moderate–severe depression had significantly poorer response compared with those with ‘none’ throughout follow-up. At 6 months, the difference was approximately 2.2 BASDAI and 0.8 ASDAS units after balancing their baseline values. Equivalent comparisons for anxiety were 1.7 BASDAI and 0.7 ASDAS units. Treatment discontinuation was 1.59-fold higher (hazard ratio 95% CI: 1.12, 2.26) in participants with moderate–severe anxiety compared with ‘none’.ConclusionsSymptoms of depression and anxiety at TNFi initiation are associated with poorer treatment outcomes. Targeted interventions to optimize mental health have potential to substantially improve treatment response and persistence.

Comparative effectiveness and safety of non-tumour necrosis factor biologics and Janus kinase inhibitors in patients with active rheumatoid arthritis showing insufficient response to tumour necrosis factor inhibitors: A Bayesian network meta-analysis of randomized controlled trials.

Both biologic and Janus kinase (JAK) inhibitor therapies have demonstrated substantial effectiveness in placebo-controlled studies in patients with active rheumatoid arthritis (RA) showing inadequate responses to tumour necrosis factor (TNF) inhibitors. The purpose of this study was to determine the relative effectiveness and safety of non-TNF biologics and JAK inhibitors in patients with RA showing insufficient response to TNF inhibitors. A Bayesian network meta-analysis incorporating direct and indirect data from randomized controlled trials (RCTs) was used to investigate the effectiveness and safety of non-TNF biologics (abatacept, rituximab, tocilizumab, salirumab and sirukumab) and JAK inhibitors (tofacitinib, baricitinib, upadacitinib and filgotinib) in patients with RA showing insufficient response to TNF inhibitors. Nine RCTs, evaluating 3577 patients for 12weeks fulfilled the inclusion requirements. JAK inhibitors and non-TNF biologics achieved a significant American College of Rheumatology 20% (ACR20) responserelative to the placebo. The ranking probability based on the surface under the cumulative ranking curve (SUCRA)showed that JAK inhibitor treatment was most likely to achieve the highest ACR20 response rate, followed by non-TNF biologics and placebo. The ACR50 rate displayed similar patterns as the ACR20 response rate, but non-TNF biologics have a higher value than JAK inhibitors based on the ACR70 response rate. Adverse events did not reach statistical significance nor did serious adverse events when looking at safety over 12weeks. The confidence intervals overlap, and there is no clinical significance to these safety data, even compared with placebo. Both non-TNF biologics and JAK inhibitors have similar effects in patients with active RA that are refractory to anti-TNF treatment, and there were no differences with regard to safety among the treatments.

Cycling of tumor necrosis factor inhibitors versus switching to different mechanism of action therapy in rheumatoid arthritis patients with inadequate response to tumor necrosis factor inhibitors: a Bayesian network meta-analysis.

Introduction:For patients with rheumatoid arthritis (RA) with an inadequate response to tumor necrosis factor inhibitors (TNFi), main options include cycling onto a different TNFi or switching to a biologic/targeted synthetic disease-modifying antirheumatic drug with a different mechanism of action (MOA). This network meta-analysis (NMA) assessed comparative clinical efficacy of cycling versus switching.Methods:We conducted a literature search in MEDLINE, Embase, and Cochrane Library. Outcomes included proportion of patients with 20%, 50%, or 70% response to American College of Rheumatology criteria (ACR20/ACR50/ACR70 response), Disease Activity Score in 28 joints (DAS28) score below 2.6 or between 2.6 and 3.2, mean change in DAS28 score, mean reduction in and proportion of patients achieving a clinically meaningful reduction (⩾0.22) in Health Assessment Questionnaire score, number of serious adverse events (AEs), and withdrawals for any reason/due to AEs/lack of treatment efficacy. To account for the wide range of study populations and designs, we developed three models to conduct the NMA: fixed-effect, random-effects, and hierarchical Bayesian. PROSPERO ID: CRD42019122993.Results:We identified nine randomized controlled trials and 16 observational studies. The fixed-effect model suggested a 0.99 probability that switch was the better strategy for increasing odds of a clinically meaningful improvement in ACR50 [odds ratio (OR): 1.35 (95% credible interval (CI): 0.96–1.81)]. The fixed-effect model also suggested that switch was associated with lower rates of withdrawal for any reasons [OR: 0.53 (95% CI: 0.40–0.68)]. The random-effects and hierarchical Bayesian models suggested additional uncertainty as they considered more variability than the fixed-effect model.Discussion:Results suggest that switching to a drug with a different MOA is more effective and associated with lower rates of withdrawal than cycling to a different TNFi after failure of first-line TNFi. Further trials that directly compare cycling with switching are warranted to better assess comparative efficacy.Plain language summary Assessment of the effectiveness of different drug treatment strategies in patients with rheumatoid arthritis: an analysis of the published literature Rheumatoid arthritis (RA) is a chronic disease in which inflammation affects joints along with the entire body; this may cause significant pain, joint damage, physical disability, a decreased quality of life, and an increased risk of death.Tumor necrosis factor inhibitors (TNFis) are a common choice as first-line drugs to treat RA. Although they are effective in many patients, therapy with a TNFi is not successful within the first year of treatment in approximately one-third of patients due to either a lack of efficacy or safety issues.When TNFi therapy is unsuccessful, the options are to “cycle” to another TNFi or to “switch” to another drug with a different mechanism of action (MOA). Further studies are needed to help doctors decide the best treatment strategy for their patients when treatment with an initial TNFi fails.This study analyzed 25 published studies in which patients were either “cycled” to another TNFi or “switched” to a drug with a different MOA after unsuccessful treatment with an initial TNFi.The results showed that “switching” to a drug with a different MOA was a better treatment strategy than “cycling” to another TNFi; “switching” increased the chance of clinically meaningful improvement in disease status and lowered the chance of having to stop treatment for any reason.

Comorbidity and response to TNF inhibitors in axial spondyloarthritis: longitudinal analysis of the BSRBR-AS.

ObjectiveComorbidities influence disease assessment in axial spondyloarthritis (axSpA), but their association with response to TNF inhibitors (TNFi) is unclear. We examined associations between comorbidity history at TNFi initiation and: (i) change in disease indices over time; (ii) binary response definitions; and (iii) time to treatment discontinuation.MethodsWe studied participants starting their first TNFi from a national axSpA register. Comorbidity categories were created from 14 physician-diagnosed conditions and compared against: change in disease indices over time using linear mixed effects models; BASDAI50/2 (50% or 2-unit reduction) and BASDAI < 4 at 6 months using logistic models; and time to treatment discontinuation using Cox models. Models were adjusted for age, gender, BMI, deprivation and education.ResultsIn total, 994 were eligible for analysis (68% male, mean age 45 years); 21% had one comorbidity and 11% had ≥2. Baseline disease severity was higher in those with comorbidities across all indices, but absolute improvement over time was comparable for BASDAI and spinal pain. Participants with ≥2 comorbidities had smaller absolute improvement in BASFI and quality of life. This group also had numerically reduced odds of achieving BASDAI50/2 [odds ratio (OR) 0.81; 95% CI: 0.45, 1.45] and BASDAI < 4 (OR 0.57; 95% CI: 0.32, 1.04). Treatment discontinuation was increased in those with two comorbidities [hazard ratio (HR) 1.32; 95% CI: 0.88, 2.00] and ≥3 comorbidities (HR 2.18; 95% CI: 1.20, 3.93) compared with none.ConclusionsParticipants with multiple comorbidities had poorer treatment outcomes, particularly increased treatment discontinuation and poorer improvements in function and quality of life. These results inform clinicians and educate patients about response to the first TNFi given comorbidity burden.

Differences between men and women with nonradiographic axial spondyloarthritis: clinical characteristics and treatment effectiveness in a real-life prospective cohort

BackgroundSex differences with regard to clinical manifestations and response to tumor necrosis factor inhibitors (TNFi) have been delineated for the radiographic form of axial spondyloarthritis (axSpA). More limited evidence for a differential effectiveness of treatment in genders exists for the nonradiographic disease state (nr-axSpA). The aim of the study was to compare demographics, clinical parameters, and response to TNFi in women versus men with nr-axSpA.MethodsWe compared disease characteristics of 264 women and 231 men with nr-axSpA at inclusion in the prospective Swiss Clinical Quality Management Cohort. Response to a first TNFi was assessed in 85 women and 78 men without diagnosed co-morbid fibromyalgia. The primary outcome was the proportion of patients achieving the 40% improvement in the Assessment of SpondyloArthritis international Society criteria (ASAS40) at 1 year. Additional response outcomes were evaluated as secondary outcomes. Patients having discontinued TNFi were considered non-responders. Logistic regression analyses were adjusted for baseline differences, which might potentially mediate the effect of sex on treatment response.ResultsCompared to men, women had a longer diagnostic delay, a higher level of perceived disease activity, and more enthesitis and were in a lower percentage HLA-B27 positive. An ASAS40 response was achieved by 17% of women and 38% of men (OR 0.34; 95% CI 0.12, 0.93; p = 0.02). A significantly lower response rate in women was confirmed in the adjusted analysis (OR 0.19; 95% CI 0.05, 0.62; p = 0.009) as well as for the other outcomes assessed.ConclusionDespite only few sex differences in patient characteristics in nr-axSpA, response rates to TNFi are significantly lower in women than in men.

Distinct Single Cell Gene Expression in Peripheral Blood Monocytes Correlates With Tumor Necrosis Factor Inhibitor Treatment Response Groups Defined by Type I Interferon in Rheumatoid Arthritis.

Previously, we demonstrated in test and validation cohorts that type I IFN (T1IFN) activity can predict non-response to tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA). In this study, we examine the biology of non-classical and classical monocytes from RA patients defined by their pre-biologic treatment T1IFN activity. We compared single cell gene expression in purified classical (CL, n = 342) and non-classical (NC, n = 359) monocytes. In our previous work, RA patients who had either high IFNβ/α activity (>1.3) or undetectable T1IFN were likely to have EULAR non-response to TNFi. In this study comparisons were made among patients grouped according to their pre-biologic treatment T1IFN activity as clinically relevant: “T1IFN undetectable (T1IFN ND) or IFNβ/α >1.3” (n = 9) and “T1IFN detectable but IFNβ/α ≤ 1.3” (n = 6). In addition, comparisons were made among patients grouped according to their T1IFN activity itself: “T1IFN ND,” “T1IFN detected and IFNβ/α ≤ 1.3,” and “IFNβ/α >1.3.” Major differences in gene expression were apparent in principal component and unsupervised cluster analyses. CL monocytes from the T1IFN ND or IFNβ/α >1.3 group were unlikely to express JAK1 and IFI27 (p < 0.0001 and p 0.0005, respectively). In NC monocytes from the same group, expression of IFNAR1, IRF1, TNFA, TLR4 (p ≤ 0.0001 for each) and others was enriched. Interestingly, JAK1 expression was absent in CL and NC monocytes from nine patients. This pattern most strongly associated with the IFNβ/α>1.3 group. Differences in gene expression in monocytes among the groups suggest differential IFN pathway activation in RA patients who are either likely to respond or to have no response to TNFi. Additional transcripts enriched in NC cells of those in the T1IFN ND and IFNβ/α >1.3 groups included MYD88, CD86, IRF1, and IL8. This work could suggest key pathways active in biologically defined groups of patients, and potential therapeutic strategies for those patients unlikely to respond to TNFi.

OP0014 COMPARISON OF ANTERIOR UVEITIS OCCURRENCE DURING TREATMENT WITH SECUKINUMAB, ADALIMUMAB, INFLIXIMAB AND ETANERCEPT IN SPONDYLOARTHRITIS

Background:Randomized controlled trials indicate that compared to tumor necrosis factor inhibitors (TNFi), secukinumab (SEC) has similar efficacy regarding axial inflammation in spondyloarthritis (SpA), better efficacy regarding cutaneous psoriasis, but is inferior in inflammatory bowel disease (IBD). However, the efficacy of SEC compared to TNFi in anterior uveitis (AU) has not been extensively studied.Objectives:To compare the occurrence of AU in patients with SpA treated with SEC, adalimumab (ADA), infliximab (IFX) or etanercept (ETN), in clinical practice.Methods:Patients with ankylosing spondylitis or undifferentiated SpA starting either SEC, ADA, IFX or ETN, in 2015 through 2017, were identified in the Swedish Rheumatology Quality register, and were linked to the national patient register for identification of AU. AU-flares were defined as the number of visits with an AU diagnosis, separated by a ≥60 days penalty interval, within ophthalmology outpatient care, during the respective bDMARD treatment.Follow-up started at the bDMARD initiation, and ended at the first of Dec 31st2017, death, emigration or discontinuation date of the bDMARD.To assess and accommodate treatment channeling, crude incidence rates for AU-flares were determined (A) for all bDMARD treatment starts, (B) excluding patients with an AU diagnosis during the year prior to the bDMARD start, and (C) in addition, excluding all first line bDMARD treatment starts.Hazard ratios (HR) for time until a first on-treatment AU diagnosis were estimated using Cox regression (ADA=reference), adjusted for sex, age, and any history of AU, and estimating robust confidence intervals to account for the individuals contributing multiple lines of treatment.Results:In total, 2,684 patients (52% women) contributed 3,255 treatment initiations. SEC was less frequently used as first line bDMARD and there was channeling of patients with previous AU, towards treatment with ADA, and away from ETN (Table 1). Further, AU occurred almost exclusively in patients with a pre-treatment history of AU (data not shown).Table 1.AnalysisTreat-ment starts, NPrevious AU1Age at treat-ment start, mean (sd)N Previous bDMARD, medianHR (95% CI) for first AU-diagnosisAU flares, NFollow-up2, yearsA. All treatment starts, N=3255SEC33321%48 (13)22.0 (1.2-3.3)52241ADA87234%44 (12)1Ref175973IFX71421%43 (14)00.9 (0.6-1.4)68677ETN133617%44 (14)00.9 (0.7-1.3)1021290B. Excluding patients with prior AU within 1 year before treatment start, N=2907SEC30413%47 (13)23.1 (1.4-7.3)10212ADA71119%44 (13)1Ref18792IFX63311%43 (14)01.0 (0.4-2.3)8599ETN125912%44 (14)01.8 (1.0-3.4)431204C. Excluding patients with prior AU within 1 year before treatment start and first line bDMARD, N=1288SEC28414%48 (13)22.5 (1.0-6.2)10198ADA37418%45 (13)1Ref11384IFX18512%45 (14)21.3 (0.4-4.0)4166ETN44517%47 (14)11.9 (0.9-4.0)234391) Anterior uveitis between 2001 and treatment start; 2) Total follow-up time for analyses of incidence rate.The incidence rates of AU-flares were higher for SEC and ETN compared to ADA and IFX, in the analyses (B, C) accommodating for channeling, figure 1.Compared to ADA, the adjusted HRs of a first on-treatment AU-diagnosis were also higher for SEC and ETA, Table 1.Conclusion:In clinical practice, SEC and ETN are associated with a higher incidence of AU than ADA and INF, suggesting a poorer protective effect of SEC and ETN against AU. These preliminary results should be interpreted in light of pronounced treatment channeling, which was only partly accommodated for.Disclosure of Interests:Ulf Lindström: None declared, Karin Bengtsson: None declared, Tor Olofsson: None declared, Daniela Di Giuseppe: None declared, Bente Glintborg Grant/research support from: Grants from Pfizer, Biogen and Abbvie, Helena Forsblad-d’Elia Grant/research support from: Unrestricted grant from Novartis., Consultant of: Advisory Board Fees from Sandoz, Novartis, and Abbvie, Lennart T.H. Jacobsson Consultant of: AbbVie, Eli Lilly, Janssen, Novartis and Pfizer, Johan Askling Grant/research support from: JA acts or has acted as PI for agreements between Karolinska Institutet and the following entities, mainly in the context of the ARTIS national safety monitoring programme of immunomodulators in rheumatology: Abbvie, BMS, Eli Lilly, Merck, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB Pharma

P281 52-Week efficacy and safety of ixekizumab in r-axSpA/AS patients naïve to biologic treatments or with prior inadequate response/intolerance to tumor necrosis factor inhibitors

Abstract Background Radiographic axial spondylitis (r-axSpA), or ankylosing spondylitis (AS), is a chronic inflammatory disease of the axial skeleton associated with serious pain, stiffness and limited flexibility, impairing quality of life. Two clinical trials demonstrated efficacy and safety of ixekizumab (IXE), a humanised anti-IL-17 IgG4 antibody, in r-axSpA/AS patients naïve to biologics, or with prior inadequate response/intolerance to tumor necrosis factor inhibitors (TNFi) over 16 weeks. This study assessed the treatment effect over 52 weeks. Additionally, the influence of baseline inflammation, measured by C-reactive protein (CRP) and/or spinal MRI on ASAS40 response at week 16 was investigated. Methods Data from two Phase 3, randomised, double-blind, placebo (PBO)-controlled trials, with patients who fulfilled the Assessment of Spondylo-Arthritis International Society (ASAS) criteria for AS and were either biologic-naïve (COAST-V, NCT02696785) or TNFi-experienced (COAST-W, NCT02696798), were analysed. We compared the proportion of patients achieving ASAS20/40, a 50% improvement of baseline Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) and assessed the change in spinal pain. Missing data was handled by using non-responder imputation for ASAS20/40 and BASDAI50 response rates and modified Baseline Observation Carried Forward (mBOCF) for spinal pain change from baseline. To investigate the influence of baseline inflammation on the efficacy, we examined the ASAS40 response at week 16 by baseline CRP (normal; ≤5 or elevated; &amp;gt;5 mg/L) and/or MRI Spondyloarthritis Research Consortium of Canada (SPARCC) spine score (&amp;lt;2 or ≥ 2) using an integrated COAST-V/W dataset. Results At week 16, significantly more IXE than PBO-treated patients achieved ASAS20/40 and BASDAI50 and a decrease in spinal pain. Decreases in disease activity were maintained through week 52 (Table 1). These outcomes occurred in both biologic-naïve and TNFi-experienced patients. Safety outcomes were consistent with previous IXE studies. At week 16, in the integrated dataset, significantly more IXE than PBO-treated patients achieved ASAS40 response regardless of baseline CRP or MRI spine SPARCC score. Conclusion Through week 52, treatment with IXE resulted in sustained efficacy in biologic-naïve and TNFi-experienced AS patients with no unexpected safety signals. Furthermore, at week 16, IXE demonstrated efficacy (ASAS40) irrespective of baseline CRP levels or spinal MRI score. Disclosures K. Gaffney: Consultancies; Abbvie, Eli Lilly, UCB, Novartis. Member of speakers’ bureau; Eli Lilly, UCB, Novartis. Grants/research support; Abbvie, Pfizer. D. Aletaha: Member of speakers’ bureau; Abbvie, Amgen, Celgene, Eli Lilly, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, Sanofi/Genzyme. Grants/research support; Abbvie, Novartis, Roche. A.J. Bradley: Corporate appointments; Eli Lilly employee. Shareholder/stock ownership; Eli Lilly. M.H. Nassab: Corporate appointments; Eli Lilly employee. S. Liu Leage: Corporate appointments; Eli Lilly employee. R. Micheroli: None.

P263 Should we advocate biologic dose-reduction in patients with AxSpA?

Abstract Background Dose optimisation of biologic drugs is attractive on cost and safety grounds. As in RA, some patients with axSpA who respond well to TNF-inhibitor (TNFi) drugs can reduce the dose and remain symptomatically well. However, there are no clear data to support dose reduction strategies nor to identify those likely, and those unlikely, to respond to lower dose treatment. Methods 71 patients, from 6 UK centres, who fulfilled criteria for AS (modified New York criteria) or AxSpA (ASAS criteria) and who had reduced their dose of TNFi therapy were identified and followed up for 24 months. All were stable responders to TNFi treatment; their responses to treatment fulfilled NICE criteria and were maintained for at least six months by the time of dose reduction. Those who reverted to full-dose treatment and those who did not were identified and data about demographics, disease activity and patients’ approaches to dose reduction were recorded. Results 55 (77.5%) patients remained on lower-dose treatment (REM) and 16 (22.5%) reverted to full-dose (REV). Mean dose reduction for each of the 4 agents was adalimumab 39%, etanercept 39%, golimumab 26%, and infliximab 46%. Overall dose reduction was 39% and 44% for REM and REV patients respectively. Both groups responded equally to treatment by all measures at dose reduction. In this small study, the data suggest that female gender and younger age are associated with reversion and that REV patients scored lower on BASDAI and CRP at the initiation of TNFi treatment. REV patients’ mean BASDAI, BASFI, BASMI scores increased from dose reduction to dose reversion but mean CRP scores decreased from 3.76 to 3.5mg/dl (7.9%). Even at the point of reversion REV patients still met original response criteria. The majority of patients in both groups reached the decision jointly with clinicians. 62 (89.9%) patients were either confident or neither worried nor confident about the decision to reduce the dose. Patients’ approach to dose-reduction was not associated with reversion and neither the duration of disease nor the time to initiation of biologic treatment appeared to associate with the likely success or failure of reduced dose TNFi treatment. Men with high initial CRP levels appear likely to respond well to biologic dose-reduction. The worsening of symptoms but maintenance of low CRP levels raises questions as to the mechanisms underpinning dose-reversion. Conclusion 77.5% patients in this study continued to respond well to a mean 39% reduction in biologic dose for 2 years. In the absence of long-term efficacy data, advocating dose-reduction to stable responders is appropriate. Disclosures L. Van Rossen: Consultancies; Novartis, UCB. Honoraria; Abbvie, Novartis, pfizer, UCB. Grants/research support; EKHUFT, UCB. C. Boyle: Honoraria; Novartis. A. Chan: None. K. Gaffney: Consultancies; Abbvie, UCB, Pfizer, Novartis, Lilly. Honoraria; Abbvie, UCB, Pfizer, Novartis, Lilly. Member of speakers’ bureau; Abbvie, UCB, Pfizer, Novartis, Lilly. Grants/research support; Abbvie, UCB, Pfizer, Novartis, Lilly. A. Gilbert: Other; consultant for Boehringer Ingelheim Germany as a Global Patient Relations manager working in Scleroderma. C. Harris: Honoraria; Novartis, UCB. P. Machado: Consultancies; Abbvie, BMS, Celgene, Janssen, MSD, Novartis, Pfizer, Roche and UCB. Honoraria; Abbvie, BMS, Celgene, Janssen, MSD, Novartis, Pfizer, Roche and UCB. S. Liliana: None. R. Sengupta: Consultancies; Abbvie, Biogen, Celgene, Novartis, UCB. Honoraria; Abbvie, Biogen, Celgene, Novartis, UCB. A. Keat: None.

Guselkumab in patients with active psoriatic arthritis who were biologic-naive or had previously received TNFα inhibitor treatment (DISCOVER-1): a double-blind, randomised, placebo-controlled phase 3 trial

Many patients with psoriatic arthritis have an inadequate response to tumor necrosis factor (TNF) inhibitors. Guselkumab, a specific inhibitor of interleukin-23 (IL-23) via IL-23 p19 subunit binding, significantly improved psoriatic arthritis signs and symptoms with an acceptable safety profile in a phase 2 trial. This multicentre, double-blind, randomised, placebo-controlled, phase 3 trial was done at 86 sites in 13 countries across Asia, Australasia, Europe, and North America and enrolled adults with active psoriatic arthritis (at least three swollen and three tender joints; and C-reactive protein ≥0·3 mg/dL) despite standard therapies. Eligibility criteria included inadequate response to or intolerance of standard treatment, including at least 4 months of apremilast, at least 3 months of non-biologic disease-modifying antirheumatic drugs (DMARDs), or at least 4 weeks of non-steroidal anti-inflammatory drugs for psoriatic arthritis. About 30% of study participants could have previously received one or two TNF inhibitors. Patients were randomly assigned (1:1:1, computer-generated permuted blocks; stratified by baseline DMARD and previous TNF inhibitor use) to subcutaneous guselkumab 100 mg every 4 weeks; guselkumab 100 mg at weeks 0, 4, then every 8 weeks; or matching placebo. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) at week 24 in all patients per assigned treatment group using non-responder imputation. Safety was assessed in all patients per treatment received. This trial is registered at ClinicalTrials.gov, NCT03162796 (active, not recruiting). From Aug 28, 2017, to Aug 17, 2018, we screened 624 patients, of whom 381 were randomly assigned and treated with guselkumab every 4 weeks (n=128), guselkumab every 8 weeks (n=127), or placebo (n=126). 362 patients continued study treatment up to week 24. The primary endpoint was met: ACR20 at week 24 was achieved by significantly greater proportions of patients in the guselkumab every 4 weeks group (76 [59%] of 128 [95% CI 50-68]) and every 8 weeks group (66 [52%] of 127 [43-61]) than in the placebo group (28 [22%] of 126 [15-30]), with percentage differences versus placebo of 37% (95% CI 26-48) for the every 4 weeks group and 30% (19-41) for the every 8 weeks group (both p<0·0001). Serious adverse events up to week 24 occurred in no patients receiving guselkumab every 4 weeks, four (3%) patients receiving guselkumab every 8 weeks, and five (4%) patients receiving placebo. Up to week 24, one patient in the placebo group died from cardiac failure and two had serious infections; no guselkumab-treated patient died or had serious infections. Guselkumab demonstrated a favourable benefit-risk profile and might be an effective treatment option for patients with active psoriatic arthritis. Janssen Research and Development.

Impact of Smoking in Response to Tumor Necrosis Factor Inhibitors in Axial Spondyloarthritis: Methodologic Considerations for Longitudinal Observational Studies

Observational data facilitate examination of treatment-effect heterogeneity, but the risk of bias is substantial. The present study was undertaken to highlight methodologic considerations through an analysis of whether smoking affects response to tumor necrosis factor inhibitors (TNFi) in axial spondyloarthritis (SpA). We used longitudinal data from the British Society for Rheumatology Biologics Register for Ankylosing Spondylitis. Participants fulfilling the Assessment of SpondyloArthritis international Society criteria for axial SpA who started their first TNFi were eligible for analysis. In comparing the impact of smoking status, weighted generalized estimating equations were used to examine changes in several continuous outcome measures, including the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Ankylosing Spondylitis Disease Activity Score (ASDAS). Inverse probability weights were used to account for differences in baseline covariates and excluded participants. We separately assessed response in the first 3 months to account for nonrandom dropout. For 840 participants who started on TNFi, 1,641 assessments from 627 individuals were analyzed (69% male, mean age 46 years). A total of 33% were current smokers and 30% ex-smokers. Ex-smokers and current smokers had worse disease than never smokers at baseline. Accounting for these differences, response did not differ according to smoking status. Compared to never smokers, ex-smokers (β = -0.6, 95% confidence interval [95% CI] -1.4, 0.3) and current smokers (β = -0.4, 95% CI -1.1, 0.4) had a similar response according to the BASDAI and ASDAS (ex-smokers β = -0.1, 95% CI -0.5, 0.3; current smokers β = -0.01, 95% CI -0.4, 0.4) at 3 months. TNFi response did not differ according to baseline smoking status in this UK cohort. Conflicting results from previous studies were likely due to methodologic differences. This analysis highlights potential sources of bias that should be addressed in future studies.

NFKB2 polymorphisms associate with the risk of developing rheumatoid arthritis and response to TNF inhibitors: Results from the REPAIR consortium

This study sought to evaluate the association of 28 single nucleotide polymorphisms (SNPs) within NFKB and inflammasome pathway genes with the risk of rheumatoid arthritis (RA) and response to TNF inhibitors (TNFi). We conducted a case-control study in a European population of 1194 RA patients and 1328 healthy controls. The association of potentially interesting markers was validated with data from the DANBIO (695 RA patients and 978 healthy controls) and DREAM (882 RA patients) registries. The meta-analysis of our data with those from the DANBIO registry confirmed that anti-citrullinated protein antibodies (ACPA)-positive subjects carrying the NFKB2rs11574851T allele had a significantly increased risk of developing RA (PMeta_ACPA + = 0.0006) whereas no significant effect was found in ACPA-negative individuals (PMeta_ACPA− = 0.35). An ACPA-stratified haplotype analysis including both cohorts (n = 4210) confirmed that ACPA-positive subjects carrying the NFKB2TT haplotype had an increased risk of RA (OR = 1.39, P = 0.0042) whereas no effect was found in ACPA-negative subjects (OR = 1.04, P = 0.82). The meta-analysis of our data with those from the DANBIO and DREAM registries also revealed a suggestive association of the NFKB2rs1056890 SNP with larger changes in DAS28 (OR = 1.18, P = 0.007). Functional experiments showed that peripheral blood mononuclear cells from carriers of the NFKB2rs1005044C allele (in LD with the rs1056890, r2 = 1.00) showed increased production of IL10 after stimulation with LPS (P = 0.0026). These results provide first evidence of a role of the NFKB2 locus in modulating the risk of RA in an ACPA-dependent manner and suggest its implication in determining the response to TNFi. Additional studies are now warranted to further validate these findings.

PGI4 A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS TO EVALUATE THE EFFICACY AND SAFETY OF TOFACITINIB IN THE TREATMENT OF MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS

To compare the clinical efficacy and safety of tofacitinib, an orally administered small molecule therapy, with approved biologic therapies for the treatment of moderately to severe active ulcerative colitis (UC). A systematic review was conducted to identify randomised controlled trials (RCTs) reporting pre-defined efficacy and safety endpoints for tofacitinib or biological therapies (adalimumab, golimumab, infliximab and vedolizumab). Clinical response and clinical remission after a short-term induction phase (6-10 weeks) and at the end of a longer-term maintenance phase (52-60 weeks) were evaluated using a random effects Bayesian multinomial likelihood model with probit link. Patients with and without prior exposure to TNF inhibitor (TNFi) drugs were considered separately. Sensitivity analyses tested alternatives to the population inclusion criteria (TNFi-failure vs TNFi-exposure) and clinical endpoints (centrally versus locally assessed endoscopic sub-scores). Safety outcomes, including serious infections, were also explored. The network meta-analyses (NMA) adhered to NICE-recommended methods. Searches of Medline, Embase and Cochrane were last performed April 2019. Seventeen RCTs were included in the NMAs. No statistically significant differences between biological therapies and tofacitinib for either TNFi-naïve or TNFi-exposed patients were observed. In TNFi-naïve patients, all therapies were more efficacious than placebo, with infliximab, vedolizumab and tofacitinib ranked best in induction and tofacitinib, vedolizumab and golimumab ranked best in maintenance. In TNFi-exposed patients, only tofacitinib was significantly more efficacious than placebo as induction therapy, and only tofacitinib and vedolizumab were significantly more efficacious as maintenance therapies. Results of the NMA sensitivity analyses were consistent with the base case. There were no significant differences in serious infection rates among therapies. This study provides a contemporary and robust assessment of the relative efficacy and safety of targeted therapies for patients with UC, with specific regard for TNFi-naïve and TNFi-exposed subgroups. These results show that tofacitinib is efficacious in both populations.

858 Reversal of Anti-Drug Antibodies Against Tumor Necrosis Factor Inhibitors With Addition of Immunomodulators: A Systematic Review and Meta-Analysis

INTRODUCTION: The presence of anti-drug antibodies (ADA) to tumor necrosis factor (TNF) inhibitors (infliximab or adalimumab) is one of the reasons for the diminished clinical response in patients with inflammatory bowel disease (IBD). To overcome the loss of response, dose escalation of TNF inhibitors or addition of immunomodulators (methotrexate or thiopurines) is considered before switching to other drugs due to limited therapeutic options. We conducted a systematic review and meta-analysis to assess the overall efficacy of immunomodulators (methotrexate or thiopurines) to reverse the loss of clinical response in IBD patients with TNF inhibitors antibodies. METHODS: We conducted a comprehensive search of multiple electronic databases and conference proceedings including PubMed, EMBASE, Web of Science databases, Google Scholar and manual search of references (from inception through October 2018) to identify studies that reported the clinical response in patients with IBD on TNF inhibitors after the addition of immunomodulators (methotrexate or thiopurines). Clinical response was defined as improvement of symptoms, with either decrease or complete elimination of ADA against TNF inhibitors. The meta-analysis was performed using Der Simonian and Laird random effect model. RESULTS: A total of 4 studies reporting on 72 patients receiving either infliximab (27) or adalimumab (45) were included in our final meta-analysis. 49/72 (68%) patients received either thiopurines (30) or methotrexate (19). Total no of males: females were 32: 40. The mean age and follow up were 37.1 years and 13.5 months respectively. The overall pooled clinical response (Table 1) was 73.86% (95% CI = 47.36-94.38, I2 = 60.77%). Significant heterogeneity was noted in the studies included in our meta-analysis. CONCLUSION: In our limited meta-analysis, addition of immunomodulators to TNF inhibitors were shown to restore the clinical response in 74% of the patients by either decreasing or completely eliminating anti-drug antibody levels. Further long term multicenter studies are needed to further validate these findings

Ixekizumab for treating ankylosing spondylitis.

Axial spondyloarthritis (axSpA) is an umbrella term that includes ankylosing spondylitis and nonradiographic axSpA. Presence or absence of definitive sacroiliitis on radiographs differentiates ankylosing spondylitis (also called radiographic axSpA) from nonradiographic axSpA. There is growing evidence that indicates IL-17 pathway is a key contributor to the pathogenesis of axSpA. Ixekizumab (IXE) is an IL-17A inhibitor (IL-17i) with data to support its use in patients with radiographic axSpA. The pharmacologic properties of IXE were reviewed. Data regarding the use and efficacy of IXE in patients with radiographic axSpA were evaluated. Quality life outcomes and safety profiles of IXE were examined as well. By comparison with other chronic inflammatory arthritides, the number of targeted treatment options for axSpA is currently limited to tumor necrosis factor inhibitor (TNFi) and IL-17i secukinumab. IXE has good evidence of improved outcomes in terms of clinical efficacy, patient reported outcomes and imaging outcomes, with an acceptable safety profile in patients with radiographic axSpA. The current results discussed in this article support use of IXE as a treatment option for TNFi naive as well as in subjects with prior inadequate response to or intolerance to TNFi agents.