Patient Years Research Articles

The impact of certolizumab pegol treatment on the incidence of anterior uveitis flares in patients with axial spondyloarthritis: 48-week interim results from C-VIEW

BackgroundAcute anterior uveitis (AAU) is the most common extra-articular manifestation in patients with axial spondyloarthritis (axSpA). C-VIEW investigates the impact of the Fc-free TNF inhibitor certolizumab pegol (CZP) on AAU...

Malignancy Rates in Brodalumab Clinical Studies for Psoriasis.

BackgroundBrodalumab is a fully human anti–interleukin-17 receptor A monoclonal antibody efficacious for the treatment of adults with moderate-to-severe plaque psoriasis.ObjectiveThis study summarizes malignancy rates in psoriasis clinical studies of brodalumab.MethodsData were pooled from one phase II study and three large, multicenter, phase III randomized studies of brodalumab for the treatment of psoriasis, including two studies with randomization to brodalumab, ustekinumab, or placebo. Data from the 52-week (brodalumab and ustekinumab) and long-term (brodalumab) pools were summarized as exposure-adjusted or follow-up time-adjusted event rates per 100 patient-years (PY).ResultsExposure-adjusted event rates per 100 PY at 52 weeks were lower with brodalumab (n = 4019; 3446 total PY of exposure) than with ustekinumab (n = 613; 495 total PY of exposure), including adjudicated malignancies (0.9 vs 2.6) and Surveillance, Epidemiology, and End Results (SEER)-adjudicated malignancies (0.3 vs 0.4). The exposure-adjusted event rate of adjudicated malignancies in the brodalumab group remained stable in the long-term analysis (0.9 [82 events]).ConclusionsRates of malignancy among brodalumab-treated patients with psoriasis were generally low.Trial registryClinicalTrials.gov identifier NCT00975637; NCT01101100; NCT01708590 (AMAGINE-1); NCT01708603 (AMAGINE-2); NCT01708629 (AMAGINE-3).Electronic supplementary materialThe online version of this article (10.1007/s40257-020-00512-4) contains supplementary material, which is available to authorized users.

Incidence, risk factors and re-exacerbation rate of severe asthma exacerbations in a multinational, multidatabase pediatric cohort study.

BackgroundThere are sparse real‐world data on severe asthma exacerbations (SAE) in children. This multinational cohort study assessed the incidence of and risk factors for SAE and the incidence of asthma‐related rehospitalization in children with asthma.MethodsAsthma patients 5‐17 years old with ≥1 year of follow‐up were identified in six European electronic databases from the Netherlands, Italy, the UK, Denmark and Spain in 2008‐2013. Asthma was defined as ≥1 asthma‐specific disease code within 3 months of prescriptions/dispensing of asthma medication. Severe asthma was defined as high‐dosed inhaled corticosteroids plus a second controller. SAE was defined by systemic corticosteroids, emergency department visit and/or hospitalization all for reason of asthma. Risk factors for SAE were estimated by Poisson regression analyses.ResultsThe cohort consisted of 212 060 paediatric asthma patients contributing to 678 625 patient‐years (PY). SAE rates ranged between 17 and 198/1000 PY and were higher in severe asthma and highest in severe asthma patients with a history of exacerbations. Prior SAE (incidence rate ratio 3‐45) and younger age increased the SAE risk in all countries, whereas obesity, atopy and GERD were a risk factor in some but not all countries. Rehospitalization rates were up to 79% within 1 year.ConclusionsIn a real‐world setting, SAE rates were highest in children with severe asthma with a history of exacerbations. Many severe asthma patients were rehospitalized within 1 year. Asthma management focusing on prevention of SAE is important to reduce the burden of asthma.

The risk of treated anxiety and treated depression among patients with psoriasis and psoriatic arthritis treated with apremilast compared to biologics, DMARDs and corticosteroids: a cohort study in the United States MarketScan database.

Anxiety and depression are common among psoriasis and psoriatic arthritis (PsA) patients, but rates may differ by treatment. To quantify the risk of incident treated anxiety, depression and mixed anxiety+depression in users of apremilast compared with users of other treatments for psoriasis and PsA. We conducted two separate cohort studies of psoriasis and PsA patients treated with apremilast, tumour necrosis factor inhibitor biologics, interleukin-17, -23 or -12/23 inhibitor biologics, conventional DMARDs or systemic corticosteroids in the United States MarketScan database. Cohort entry was date of first study drug after 21 March 2014. We identified cases who had a depression and/or anxiety diagnosis with a prescription for antidepressant/antianxiety medication within 30days of the diagnosis code. We calculated incidence rates (IRs) and incidence rate ratios with 95% confidence intervals (CIs) for treated anxiety, treated depression and treated anxiety+depression per 1000 patient-years (PY) among patients. Among the psoriasis cohort, IRs for each outcome were similar between exposure categories and highest among users of systemic corticosteroids alone. IRs (95% CI) for apremilast alone were 9.2 (6.6-12.5), 4.6 (2.8-7.1) and 4.6 (2.8-7.1) per 1000 PY for treated anxiety, treated depression and treated anxiety+depression, respectively. In the PsA cohort, the rate of anxiety was highest among users of apremilast alone; rates of depression and anxiety+depression were similar for apremilast compared with other PsA treatments. IRs for each outcome were also high for users of corticosteroids in both the psoriasis and PsA cohorts. Among patients with psoriasis, users of apremilast had similar rates of anxiety and depression as users of other non-corticosteroid systemic psoriasis treatments. Among PsA patients, users of apremilast had similar rates of depression and anxiety+depression compared with users of other systemic non-corticosteroid PsA drugs; however, the rate of anxiety was slightly higher.

Early cardiovascular structural and functional abnormalities as a guide to future morbid events.

Our aim was to evaluate the predictive value of a battery of 10 non-invasive tests of cardiovascular structural and functional health on the future risk of cardiovascular morbid events. A total of 1900 asymptomatic adults concerned about their risk for cardiovascular disease underwent non-invasive assessment with 10 tests of vascular and cardiac structure and function. A disease score (DS) was calculated for each individual based on these 10 tests. Follow-up (mean 9.2 years) for cardiovascular morbidity and mortality was available for 1442 individuals (mean age 53.2 years, 48.2% women). Those in the lowest DS tertile (0-2) experienced 0.16 cardiovascular events per 100 patient-years (PY), those in the middle tertile (3-5) experienced 0.86 events per 100 PY, and those in the highest tertile (6+) experienced 1.3 events per 100 PY (p < .001). Sensitivity analysis, assuming a neutral effect of DS on projected events in subjects not followed, did not alter statistical significance. Risk assessment using the Framingham risk score (FRS) also predicted morbid events but the two methods differed in identifying individuals at high risk. The net reclassification index was improved by 0.11 (p = 0.01) when DS was added to FRS. Assessing the biological disease process in the arteries and heart of asymptomatic adults provides a guide to the risk of a future cardiovascular morbid event. Larger and longer studies are needed to determine whether risk factor algorithms, the severity of the biological process or some combination is the optimal method for identifying individuals in need of intervention to delay morbid events.

Abstract WMP47: Poor Risk Factor Control and Lower Levels of Physical Activity Predict Incident Major Cardiovascular Events in Patients With Symptomatic Vertebrobasilar Disease: A Post-Hoc Analysis of the SAMMPRIS Trial

Background: Symptomatic vertebrobasilar (VB) atherosclerotic disease is associated with a high risk of recurrent stroke despite optimal medical therapy. Objective: In this study, we aim to examine the prognosis and associations between risk factors and recurrent major cardiovascular events (MACE) in patients with symptomatic VB stenosis randomized in the medical arm of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) study. Methods: Data from subjects in the medical arm of the SAMMPRIS trial with an infarct in the territory of vertebral or basilar arteries (n= 73) were analyzed. The primary outcome was MACE: defined as stroke, myocardial infarction, or other cardiovascular death during follow up. Mean risk factor values were compared between subjects who met the primary outcome at 2 years versus those who did not, using T-tests and χ2 tests. Results: Among 73 patients with VB stenosis randomized to medical treatment, 18 patients (24.6%) had recurrent MACE over a mean follow up of 2.8 years. This was significantly less than the rate of MACE in those with VB enrolled in the WASID trial (9.7 per 100-patient years vs. 20.9 per 100-patient years, p&lt;0.01). Predictors of MACE at 2 years were increased triglyceride level (adjusted OR per 50 units increase in triglyceride 1.94, 95% CI 1.15-3.28) and increased HbA1c level (adjusted OR per 1 unit increase in HbA1c 2.07, 95% CI 0.97-4.45), and lower physical activity status measured by PACE (out of target defined by PACE ≤ 4: moderate activity &lt; 5 days per week or intense activity &lt; 3 days per week) (2.5 ± 1.0 vs. 3.3 ± 1.8, p = 0.028) (Table). Conclusions: In patients with symptomatic VB disease, improvement of medical treatment over time led to a reduction in cardiovascular event rates but this risk remains elevated as nearly 1 in 5 patients had MACE within 2 years. Further risk factor optimization and lifestyle changes are needed to reduce the rates of MACE in this patient population.

Safety results of ixekizumab with 1822.2 patient-years of exposure: an integrated analysis of 3 clinical trials in adult patients with psoriatic arthritis

BackgroundThe long-term safety was assessed in patients with psoriatic arthritis who were treated with ixekizumab in three clinical trials (SPIRIT-P1/-P2/-P3).MethodsIntegrated safety data from three trials (controlled and uncontrolled), including two pivotal phase 3, randomized, double-blind clinical trials: SPIRIT-P1 and SPIRIT-P2, were assessed. Safety data were integrated from the all ixekizumab exposure safety population (defined as all patients receiving ≥ 1 dose of ixekizumab). We report exposure-adjusted incidence rates (IRs) per 100 patient-years (PY) at 1-year intervals up to 3 years for adverse events.ResultsTotal exposure to IXE reached 1822.2 PY (1118 patients). The IRs/100 PY for the following treatment discontinuations were as follows: adverse events (5.3); serious infections (1.3); injection-site reactions (12.7); infections (34.2); and deaths (0.3). The IRs for treatment-emergent adverse events decreased or remained stable over time, the most common being upper respiratory tract infection, nasopharyngitis, and injection-site reactions. The IRs for serious adverse events and serious infections remained stable over time, whereas for injection-site reactions and general infections, IRs decreased with longer ixekizumab exposure. Opportunistic infections were limited to oral and esophageal candida and localized herpes zoster. No suicide or self-injury-related behaviors were reported. The IRs/100 PY for safety topics of special interest included inflammatory bowel disease (adjudicated; 0.1), depression (1.6), malignancies (0.7), and major adverse cardiovascular events (0.6).ConclusionsThe findings of this integrated safety analysis in patients with psoriatic arthritis are consistent with the known safety profile of ixekizumab. No unexpected safety signals were observed with ixekizumab treatment in patients with psoriatic arthritis.Trial registrationSPIRIT-P1 (NCT01695239; Registered August 08, 2012), SPIRIT-P2 (NCT02349295; September 23, 2014), and SPIRIT-P3 (NCT02584855; August 04, 2015).

P425 SPOSIB SB2: a Sicilian prospective observational study of patients with inflammatory bowel disease treated with infliximab biosimilar SB2

Abstract Background Few data on Infliximab (IFX) biosimilar SB2 in inflammatory bowel disease (IBD) are available. Methods SPOSIB SB2 is a multicentre, observational, prospective study performed among the cohort of the Sicilian Network for Inflammatory Bowel Disease (SN-IBD). All consecutive patients with Crohn’s disease (CD) or Ulcerative Colitis (UC) starting IFX biosimilar SB2 from the introduction of the drug in Sicily (March 2018) to September 2019 (18 months) were enrolled. Patients were divided into five groups (group A: naive to IFX, naive to anti-TNFs; group B: naive to IFX, previously exposed to other anti-TNFs; group C: switch from IFX originator to SB2; group D: switch from CT-P13 to SB2; group E: multiple switches: from IFX originator to CT-P13 to SB2). The primary end-point was the assessment of safety, in terms of the rate of serious adverse events (SAEs). Secondary end-point was the evaluation of effectiveness, in terms of steroid-free clinical remission and clinical response at 8 weeks and at the end of follow-up, and as treatment persistency. Results 276 patients (median age 39 years; CD 49.3%, UC 50.7%) were included [group A: 127 (46.0%); group B: 65 (23.6%); group C: 17 (6.2%); group D: 43 (15.6%); group E: 24 (8.7%)]. The cumulative number of infusions of SB2 was 1798, the median follow-up was 8 months (IQR: 4–12 months), and the total follow-up time was 182.7 patient-years (PY). Sixty-seven SAEs occurred in 57 patients (20.7%), with an incidence rate of 36.7 per 100 PY, and 26 of them caused the withdrawal of the drug. The incidence rate ratio (IRR) of SAEs was higher among patients in group B compared with group A (57.7 vs. 30.2 per 100 PY; IRr = 1.91; p = 0.026) and group C (57.7 vs. 18.9 per 100 PY; IRr = 2.93; p = 0.045). The effectiveness of IFX biosimilar SB2 after 8 weeks of treatment was evaluated in patients naïve to IFX (group A + B; n = 192): 110 patients (57.3%) had steroid-free remission, 26 patients (13.5%) achieved a partial response, while 56 patients had no response (29.2%). At the end of follow-up, 72 patients (26.1%) interrupted the treatment, without significant differences in treatment persistency estimations between the five groups (log-rank p = 0.15). Conclusion This is the first prospective study on the use of IFX biosimilar SB2 in IBD. Safety and efficacy of SB2 seem to be overall similar to those reported for IFX originator and IFX biosimilar CT-P13. A higher incidence of SAEs was observed among patients naive to IFX and previously exposed to other anti-TNFs.

Safety of Ocrelizumab in Multiple Sclerosis: Updated Analysis in Patients with Relapsing and Primary Progressive Multiple Sclerosis

Ongoing safety reporting is crucial to understanding the long-term benefit–risk profile of ocrelizumab (OCR) in patients with multiple sclerosis (MS). The safety and efficacy of OCR have been characterised in one Phase II study in relapsing-remitting MS (NCT00676715), two identical Phase III trials in relapsing MS (RMS; OPERA I/II [NCT01247324]/[NCT01412333]) and the Phase III trial in primary progressive MS (PPMS; ORATORIO [NCT01194570]). Safety outcomes were reported for all patients who received OCR during the controlled treatment and associated OLE periods of the Phase II and Phase III clinical trials, plus the ongoing Phase IIIb trials VELOCE, CHORDS/CASTING, OBOE, ENSEMBLE and associated substudies (OCR all-exposure population). The number of post-marketing patients exposed to OCR is based on estimated total number of vials sold, as well as US claims data. To account for the different exposure lengths, the incidence rate per 100 patient years (PY) is presented. Adverse events (AEs) were classified according to the Medical Dictionary for Regulatory Activities. As of July 2018, 4,501 patients with MS received OCR in clinical trials resulting in 12,559 PY of exposure. Reported rates per 100 PY in the OCR all-exposure population (95% confidence interval) were as follows: AEs, 255 (252–258); serious AEs, 7.52 (7.05–8.02); infections, 77.1 (75.5–78.6); serious infections, 2.01 (1.77–2.27); malignancies, 0.47 (0.36–0.61); and AEs leading to treatment discontinuation, 1.15 (0.97–1.35). As of April 2019, approximately 96,000 patients with MS have initiated OCR globally in the post-marketing setting and the data remain generally consistent with that observed in clinical trials. Updated OCR all-exposure population data using a January 2019 cut-off and selected post-marketing data will be presented. The reported rates of events per 100 PY in the ocrelizumab all-exposure clinical trial population and post-marketing settings continue to be generally consistent with those seen during the controlled treatment period in the RMS and PPMS populations. The rate of AEs leading to treatment discontinuation also remained stable with additional patient exposure. Long-term safety data will continue to be reported on a regular basis.

Real-World Safety of an Implantable Continuous Glucose Sensor Over Multiple Cycles of Use: A Post-Market Registry Study.

Previously, the safety and accuracy of the Eversense continuous glucose monitoring (CGM) system were characterized in three pivotal trials among individuals with type 1 diabetes (T1D) and type 2 diabetes (T2D) with a single 90- or 180-day sensor insertion–removal cycle. The Post-Market Clinical Follow-up (PMCF) registry is a prospective study evaluating the long-term safety and performance of the Eversense CGM system over multiple sensor insertion–removal cycles among adults with T1D and T2D. All patients who had a sensor subcutaneously implanted across 534 participating centers in Europe and South Africa from June 2016 to August 2018 were enrolled. Adverse events (AEs) were recorded at each visit and patients were instructed to inform their clinic if they experienced any AEs between visits. AEs were adjudicated for relatedness to the device, procedure, or drug (dexamethasone acetate). The primary safety endpoint was the rate of related serious adverse events (SAEs) through four sensor insertion–removal cycles. The registry enrolled 3023 patients. As of last follow-up, 5417 sensors had been inserted with a total of 1260 patient-years (PYs) of follow-up: 969 patients had used the system for at least 6 months and 173 patients had used the system for at least 1 year. No related SAEs were reported. The most frequently reported related AEs were sensor location site infection (0.96%; 2.46 events per 100 PYs), inability to remove the sensor upon first attempt (0.76%; 1.90 events per 100 PYs), and adhesive patch location site irritation (0.66%; 1.59 events per 100 PYs). One nonserious allergic reaction to lidocaine was reported, which resolved with administration of an antihistamine. The full intended sensor life was achieved by 91% of 90-day sensors and 75% of 180-day sensors. The PMCF registry provides real-world evidence that the Eversense CGM system is safe over multiple cycles of use.

Long-term surveillance of biologic therapies in systemic-onset juvenile idiopathic arthritis: data from the German BIKER registry.

Using data from the German Biologics JIA Registry (BIKER), long-term safety of biologics for systemic-onset JIA with regard to adverse events of special interest was assessed. Safety assessments were based on adverse event reports after first dose through 90 days after last dose. Rates of adverse event, serious adverse event and 25 predefined adverse events of special interest were analysed. Incidence rates were compared for each biologic against all other biologics combined applying a mixed-effect Poisson model. Of 260 systemic-onset JIA patients in this analysis, 151 patients received etanercept, 109 tocilizumab, 71 anakinra and 51 canakinumab. Patients with etanercept had higher clinical Juvenile Arthritis Disease Activity Score 10 scores, active joint counts and steroid use at therapy start. Serious adverse events were reported with higher frequency in patients receiving canakinumab [20/100 patient years (PY)] and tocilizumab (21/100 PY). Cytopenia and hepatic events occurred with a higher frequency with tocilizumab and canakinumab. Medically important infections were seen more often in patients with IL-6 or IL-1 inhibition. Macrophage activation syndrome occurred in all cohorts with a higher frequency in patients with canakinumab (3.2/100 PY) and tocilizumab (2.5/100 PY) vs anakinra (0.83/100 PY) and etanercept (0.5/100 PY). After adjustment only an elevated risk for infections in anakinra-treated patients remained significant. Three definite malignancies were reported in patients ever exposed to biologics. Two deaths occurred in patients treated with etanercept. Surveillance of pharmacotherapy as provided by BIKER is an import approach especially for patients on long-term treatment. Overall, tolerance was acceptable. Differences between several biologics were noted and should be considered in daily patient care.

Long-Term Safety of Adalimumab in 29,967 Adult Patients From Global Clinical Trials Across Multiple Indications: An Updated Analysis

IntroductionThe safety profile of adalimumab was previously reported in 23,458 patients across multiple indications. Here we report the long-term safety of adalimumab in adults with plaque psoriasis (Ps), hidradenitis suppurativa (HS), rheumatoid arthritis (RA), ankylosing spondylitis, psoriatic arthritis, non-radiographic axial spondyloarthritis, peripheral spondyloarthritis, Crohn’s disease (CD), ulcerative colitis (UC), and non-infectious uveitis (UV).MethodsSafety data from 77 clinical trials were pooled. Safety assessments included adverse events (AEs) and serious AEs (SAEs) that occurred after the first study dose and within 70 days (5 half-lives) after the last study dose.ResultsA total of 29,967 patients were included, representing 56,916 patient-years (PY) of exposure. The most frequently reported SAE of interest was infection (3.7/100 PY) with highest incidences in CD, RA, UV, and UC (3.5/100 PY–6.9/100 PY); serious infections in Ps (1.8/100 PY) and HS (2.8/100 PY) were lower. The observed number of deaths was below what would be expected in an age- and sex-adjusted population for most adalimumab-treated patients (including Ps). Lack of real-life data and limited long-term data (> 5 years) for most patients are limitations of this analysis.ConclusionThe safety profile of adalimumab was consistent with previous findings and no new safety signals were observed.

Prophylactic Antibiotic Use and Risk of Meningococcal Infections in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Treated with Eculizumab Who Received Meningococcal Vaccination: Results from the International PNH Registry

Prophylactic Antibiotic Use and Risk of Meningococcal Infections in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Treated with Eculizumab Who Received Meningococcal Vaccination: Results from the International PNH Registry

P4668Risk of valvular heart disease in bromocriptine-treated women with hyperprolactinaemic disorders

Abstract Background Systematic echocardiographic screening is currently recommended for patients with hyperprolactinemic disorders treated with dopamine agonists, due to a perceived risk of cardiac valve regurgitation as observed in patients with Parkinson's disease. The dopamine agonist bromocriptine is used frequently in hyperprolactinemia patients, but its relation to cardiac valve disease remain uncertain. Purpose To determine the incidence of valvular heart disease in bromocriptine-treated women with hyperprolactinaemic disorders compared with matched controls from background population. Methods In nationwide Danish registries, we identified patients with hyperprolactinaemic disorders treated with bromocriptine between 1995–2017. Patients were matched 1:5 with population controls based on age and sex using incidence density sampling. We estimated the risk of valvular heart disease defined as admission and/or outpatient clinic visits. Incidence rates, cumulative incidence curve and adjusted cox-proportional hazard models were used to assess outcomes. Results A total of 23883 female bromocriptine users and 119415 controls were included. Median age was 29.9 years (Q1-Q3 26.4–33.8). Both groups had few comorbidities, 218 (0.9%) patients and 787 (0.7%) controls with hypertension, 160 (0.7%) patients and 629 (0.5%) controls with diabetes, 408 (1.7%) patients and 1305 (1.1%) controls were beta-blocker users. During a mean follow-up of 19 years 106 (0.44%) patients and 416 (0.35%) controls were diagnosed with valvular heart disease. Incidence rates were 0.254 per 1000 patient years (PY) in bromocriptine users (95% CI 0.21–0.31) and 0.198 per 1000 PY in the control cohort (95% CI 0.18–0.22). Overall, the cumulative incidence of valvular heart disease was 0.6% (95% CI 0.48–0.73) among patients and 0.5% (95% CI 0.4–0.51) among controls; P=0.03 (figure 1a). In adjusted analysis bromocriptine users still had a significant higher risk of valvular heart disease (hazard ratio=1.32, 95% CI 1.06–1.64, P=0.01). Incidence of valvular heart disease Conclusion The use of bromocriptine in younger and otherwise healthy women with hyperprolactinaemic disorders, were associated with a low absolute risk of cardiac valve disease. Still risk was approximately 30% higher compared with age- and sex matched controls. Our study suggests a low clinical yield of echocardiographic screening in this patient population. Acknowledgement/Funding Internal grant, Copenhagen University Hospital Rigshospitalet

P2873Novel ICD therapy reduction programming in primary and secondary prevention: reduced mortality and ICD-therapies in a real-life cohort

Abstract Background Implantable cardioverter defibrillator therapy (ICD), with or without combined cardiac resynchronization therapy, has been demonstrated to reduce mortality and morbidity in patients with heart failure. Nevertheless, ICD therapies are associated with increased mortality and morbidity. It was shown that ICD therapy reduction was associated with reduced event-rates. Aims It was our goal to examine a novel therapy reduction ICD programming in a real-life-cohort that also includes a notable proportion of patients with secondary prevention ICD indication. Methods Our study, based on a real-life register, contained 1013 patients. 609 patients (60%) received ICDs or CRT-Ds for secondary prevention indication. Devices implanted before May 2014 were programmed according to conventional ICD programming (CP), devices implanted since May 2014 have been programmed with a novel programming (NP) (high rate cut-off, longer detection intervals, 4 to 6 ATPs in VT-Zone). The following endpoints were analyzed for time to first event: mortality (247), appropriate therapies (248), appropriate ATPs (172), appropriate shocks (150), inappropriate therapies (102), inappropriate ATPs (49) and shocks (150). Results Middle follow-up time was 25.6 months (IQR 14.0–36.0 months) and cumulative patient years (PY) were 2165.3. According to Kaplan-Meier-analysis, there was a significant reduction in mortality-rate due NP compared to CP (19.2% vs. 30.2%, p=0.001) in the whole study population, as well as in patient subgroups with primary and secondary prevention (each p&lt;0.05). Further, NP was associated with a reduced amount of appropriate (18.8% vs. 49.6%, p&lt;0.001) and inappropriate therapies (5.2% vs. 21.8%, p&lt;0.001). In Cox-regression-model, NP showed a significant reduction in mortality (HR=0.45; p=0.001) alongside history of diabetes (HR=1.35), history of chronic kidney disease (HR=1.76), reduced EF (HR=1.29) and 2nd preventional indication (HR=1.66). Further, NP was associated with a 62% reduction of appropriate and 81% reduction of inappropriate Therapies in multivariate analyses. These results were consistent after stratification for primary and secondary prevention (each p&lt;0.05) both in Kaplan-Meier-analysis and Cox-regression-model. Regarding primary prevention, NP reduced significantly ATPs (2.7 events per 100 PY (= E/100PY) vs 16.0 E/100PY, p&lt;0.001) as well as shocks (3.7 E/100PY vs. 8.6 E/100PY, p&lt;0.05). Further, in secondary prevention NP was linked to a significant reduction of ATPs (11.6 E/100PY vs. 16.5E/100PY, p&lt;0.05) and shocks (7.6 E/100PY vs. 18.0 E/100PY, p=0.001). Conclusion Novel ICD programming reduced mortality and morbidity due to appropriate or inappropriate ICD therapies independent from ICD indication. For the first time a novel ICD programming with high rate cut-off, longer detection intervals and multiple ATPs showed a benefit regarding mortality especially in patients with secondary prevention ICD indication.

697 Safety of Ustekinumab in Inflammatory Bowel Diseases: Integrated Safety Analysis of Results From Phase 2 and 3 Studies in Crohn's Disease and Ulcerative Colitis

INTRODUCTION: Ustekinumab (UST) is a well-established therapy in Crohn's disease (CD) and psoriatic diseases. UST was safe and effective in phase 3 ulcerative colitis (UC) studies. Pivotal studies of UST in CD (UNITI, IMUNITI) and UC (UNIFI) had similar designs, which allows for integrated analysis across both indications. We present an integrated safety analysis of UST in inflammatory bowel disease (IBD). METHODS: Data from 6 phase 2/3 studies were pooled, and safety was evaluated through 1 year of follow-up. In phase 3, pts received a single IV placebo (PBO) or UST (130 mg or ∼6 mg/kg) induction dose followed by SC maintenance doses of PBO or UST (90 mg q8w or q12w). Concomitant immunomodulators (IMM) and corticosteroids were permitted. All pts who received ≥1 dose of UST were included. Safety outcomes through 1 year are presented as the number of pts with events per 100 patient-years (PY) of follow-up. RESULTS: At induction baseline (2370 pts in pooled phase 3 IBD studies), median age was 38.0 years, 46.9% were receiving corticosteroids, 30.8% were receiving IMM, 53.0% had failed biologics, and 37.1% were naïve to biologics. In phase 3 IBD studies, through Wk8 of PBO-controlled induction, the frequency of key safety events was similar between UST and PBO (Table 1). In addition, through 1 year across phase 2/3 IBD studies (Table 2), numbers of pts per 100 PY with key safety events were similar between treatment groups. The most frequently occurring AEs (excluding diseases under study) were arthralgia (PBO 16.93 vs UST 16.56), headache (16.43 vs 16.50), nausea (13.25 vs 11.94), and abdominal pain (14.59 vs 11.54); infections were nasopharyngitis (16.26 vs 18.11) and upper respiratory tract infection (11.40 vs 11.36). For serious infections, the CD-specific event of anal abscess occurred in PBO 2.02 and UST 0.90 pts per 100 PY. When CD-specific events were excluded, overall rates of serious infections were similar between UC and CD. The only malignancy (excluding NMSC) reported in &gt;1 UST-treated patient was prostate cancer; no lymphomas were reported through 1 year. Two pts receiving UST (0.12 per 100 PY; both had UC) died from events that investigators considered to be unrelated to study agent (esophageal varices hemorrhage and acute respiratory failure during thyroid surgery). CONCLUSION: The safety profile of UST in pts with UC and across integrated IBD indications through 1 year was favorable and consistent with the established safety profile in pts with CD and psoriatic disease.

Long-term efficacy and safety of tildrakizumab for moderate-to-severe psoriasis: pooled analyses of two randomized phase III clinical trials (reSURFACE 1 and reSURFACE 2) through 148 weeks.

SummaryBackgroundTildrakizumab is a specific anti‐interleukin‐23p19 monoclonal antibody approved for the treatment of plaque psoriasis.ObjectivesTo evaluate the long‐term efficacy and safety of tildrakizumab treatment for patients with moderate‐to‐severe psoriasis for up to 148 weeks.MethodsPooled analysis from two double‐blind, randomized controlled trials: reSURFACE 1 and reSURFACE 2. Efficacy was assessed for responders (≥ 75% improvement in Psoriasis Area and Severity Index; PASI 75) and partial responders (PASI 50–75) to tildrakizumab 100 mg and 200 mg at week 28 who were maintained on the same dose (administered every 12 weeks), and for partial responders or nonresponders (PASI < 50) to etanercept 50 mg at week 28 who, after a 4‐week washout, were switched to tildrakizumab 200 mg (administered at weeks 32 and 36, and every 12 weeks thereafter). Safety was assessed in the all‐patients‐as‐treated population. Three different methods of imputing missing data were used: nonresponder imputation (NRI), multiple imputation and observed cases. The Clinicaltrials.gov numbers are NCT01722331 (reSURFACE 1) and NCT01729754 (reSURFACE 2).ResultsAt week 148 (NRI), 72·6%, 53·8% and 28·9% of tildrakizumab 100‐mg responders and 80·2%, 59·9% and 32·6% of tildrakizumab 200‐mg responders had PASI 75, 90 and 100 responses, respectively. For partial responders to tildrakizumab 100 mg and 200 mg, the proportions of patients achieving PASI 75, 90 and 100 responses were 32·5%, 25·0% and 10·0%; and 47·1%, 27·5% and 12·8%, respectively. For patients who were partial responders or nonresponders to etanercept, the proportions of patients achieving PASI 75, 90 and 100 responses were 66·9%, 43·8% and 14·9% at week 148. Rates of discontinuations due to adverse events [tildrakizumab 100 mg: 1·7 per 100 patient‐years (PYs); tildrakizumab 200 mg: 1·2 per 100 PYs] and exposure‐adjusted rates of serious adverse events (5·9 per 100 PYs; 5·5 per 100 PYs), severe infections (1·1 per 100 PYs; 1·1 per 100 PYs), malignancies (0·6 per 100 PYs; 0·4 per 100 PYs) and major adverse cardiovascular events (0·4 per 100 PYs; 0·5 per 100 PYs) were low.ConclusionsTildrakizumab was well tolerated and efficacy was well maintained in week 28 responders who continued tildrakizumab treatment through 3 years, or improved among etanercept partial responders or nonresponders who switched to tildrakizumab. What's already known about this topic? Tildrakizumab 100 mg and 200 mg are efficacious and well tolerated with short‐term use in the treatment of patients with moderate‐to‐severe plaque psoriasis. What does this study add? High levels of efficacy are maintained for up to 3 years of psoriasis treatment with tildrakizumab.There is a favourable long‐term safety profile with both tildrakizumab 100 mg and 200 mg, with a low incidence of adverse events of special interest through 3 years.

P035 Clostridium difficile infection in ulcerative colitis: Data from the tofacitinib clinical program and an insurance claims database

BACKGROUND: Patients with inflammatory bowel disease (IBD), particularly ulcerative colitis (UC), have a higher risk of Clostridium difficile infection (CDI) than the general population (1). The incidence of CDI is increasing among patients with IBD, and certain UC treatments may be associated with greater risk (1). We report CDI events in the tofacitinib UC clinical program, and the incidence of CDI among patients receiving other treatments for UC. METHODS: For the tofacitinib UC program, rates of CDI (patients with an adverse event [AE] of CDI, Clostridium difficile colitis, or Clostridium test-positive, plus concomitant oral metronidazole or vancomycin, counted once per cohort) are reported for Induction Cohort (patients from an 8-week Phase [P]2 and two 8-week P3 induction studies; placebo or tofacitinib 10 mg twice daily [BID; NCT00787202; NCT01465763; NCT01458951]); Maintenance Cohort (patients from a 52-week maintenance study; placebo or tofacitinib 5 or 10 mg BID [NCT01458574]); and Overall Cohort (all tofacitinib-treated patients in P2/3 induction and maintenance studies and an ongoing, open-label, long-term extension study [as of December 2016; NCT01470612]). Positive Clostridium difficile test at screening was an exclusion criterion for program entry. Overall Cohort incidence rate (IR) was calculated as number of unique patients with events per 100 patient-years (PY). For contextualization, CDI rates among patients receiving other UC medications were obtained from a retrospective cohort study utilizing data from the Truven MarketScan® Database, an administrative healthcare claims database in the US. Patients with moderately to severely active UC, with either an inpatient or outpatient diagnosis code of CDI, plus a prescription for oral therapy (including metronidazole, vancomycin, and fidaxomicin) within 14 days of CDI diagnosis (observation period: October 1, 2010–September 30, 2015), were included. Truven cohort IRs were calculated as number of patients with events per 100 PY. RESULTS: In the tofacitinib Induction Cohort, CDI occurred in 3 patients (placebo, 1/282 [0.4%]; tofacitinib 10 mg BID, 2/938 [0.2%]). In the Maintenance Cohort, CDI occurred in 3 patients (placebo, 3/198 [1.5%]; tofacitinib 5 or 10 mg BID, 0/394 [0.0%]). In the Overall Cohort of all tofacitinib-treated patients (1,664 PY of follow-up), CDI occurred in 8/1,157 patients (0.7%), with an IR (95% confidence interval [CI]) of 0.48 (0.21, 0.95). Two cases were reported as serious AEs. All were mild (n = 4) or moderate (n = 4) in severity; 6 continued with study treatment, one temporarily discontinued, one permanently discontinued. All CDI cases resolved with treatment. In the Truven Cohort, 160 CDI events occurred during 4,918 PY of follow-up, with an overall CDI IR (95% CI) of 3.25 (2.77, 3.80); of which 116 were CDI-associated hospitalizations (4,936 PY of follow-up). Among patients receiving azathioprine, 6-mercaptopurine, or tumor necrosis factor inhibitors, CDI IRs were 3.23 (2.18, 4.62), 2.31 (1.26, 3.87), and 3.58 (2.95, 4.29), respectively. CONCLUSION(S): In the tofacitinib UC program, CDI rates among patients receiving tofacitinib were similar to or lower than those observed with placebo. The IR among patients receiving tofacitinib was numerically lower than those observed for immunomodulators and tumor necrosis factor inhibitors in the Truven Cohort.

Effect of Gut Involvement in Patients with High Probability of Early Spondyloarthritis: Data from the DESIR Cohort.

Inflammatory bowel disease (IBD) is a well-known extraarticular feature of spondyloarthritis (SpA). The aims of this study were to evaluate factors associated with IBD and incidence over 5 years of followup in the DESIR cohort. DESIR is a prospective observational cohort of patients with recent-onset inflammatory back pain suggestive of axial SpA. All available variables in the database were compared between patients with and without IBD at baseline and 5 years, and occurrence over 5 years of followup, with uni- and then multivariable analysis. At baseline, of 708 patients, 35 had IBD (prevalence 4.94%, CI 95% 3.3-6.5). IBD was associated (multivariable) with history of uveitis, levels of Dickkopf-1, and tumor necrosis factor, but not with phenotypic presentation (peripheral arthritis, enthesitis, dactylitis, uveitis) or baseline serum levels of other cytokines. At 5 years, 480 patients were analyzed, 58 with IBD. IBD was associated (multivariable) with fulfillment of modified New York criteria, sick leave, Bath Ankylosing Spondylitis Disease Activity Index, and smoking. There was no association with magnetic resonance imaging scores, enthesitis, psoriasis, and bone mineral density. Twenty-three incident cases of IBD were recorded: estimated occurrence rate of 0.95/100 (95% CI 0.57-1.35) patient-years (PY). Incidence of IBD is associated (multivariable) with HLA-B27 (OR 0.36, 95% CI 0.22-0.59), fulfillment of modified New York criteria (OR 3.35, 95% CI 1.85-6.08), and familial history of IBD (OR 3.31, 95% CI 1.62-6.77). In early SpA, IBD occurs with an incidence of 1/100 PY, and is associated with poor outcome, familial history of IBD, absence of HLA-B27, and fulfillment of modified New York criteria.

Dr. Kang, et al reply.

To the Editor: We were surprised to read the letter by Berti and colleagues1, commenting on our recent article on the incidence of arterial and venous thrombosis in antineutrophil cytoplasmic antibody–associated vasculitis (AAV)2. They make the unjustified comment that “the incidence estimates for [arterial (ATE) and venous thrombosis events (VTE)] may be inflated” when we give clear and accurate incidence rates. Our incidence of ATE was 2.67/100 patient-years (PY), whereas the 2018 article by Berti, et al 3 reports an incidence of cardiovascular disease as 5.0/100 PY. It would therefore not seem that our incidence estimates were inflated. Our comparison of the characteristics of … Address correspondence to C.D. Pusey, Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK. E-mail: c.pusey{at}imperial.ac.uk