Scherl, Ellen

Abstract Background Inflammatory bowel disease (IBD)–associated peripheral spondyloarthritis (pSpA) decreases quality of life and remains poorly understood. Given the prevalence of this condition and its negative impact, it is surprising that evidence-based disease definitions and diagnostic strategies are lacking. This systematic review summarizes available data to facilitate development and validation of diagnostics, patient-reported outcomes, and imaging indices specific to this condition. Methods A literature search was conducted. Consensus or classification criteria, case series, cross-sectional studies, cohort studies, and randomized controlled trials related to diagnosis were included. Results A total of 44 studies reporting data on approximately 1500 patients with pSpA were eligible for analysis. Data quality across studies was only graded as fair to good. Due to large heterogeneity, meta-analysis was not possible. The majority of studies incorporated patient-reported outcomes and a physical examination. A total of 13 studies proposed or validated screening tools, consensus, classification, or consensus criteria. A total of 28 studies assessed the role of laboratory tests, none of which were considered sufficiently accurate for use in diagnosis. A total of 17 studies assessed the role of imaging, with the available literature insufficient to fully endorse any imaging modality as a robust diagnostic tool. Conclusions This review highlights existing inconsistency and lack of a clear diagnostic approach for IBD-associated pSpA. Given the absence of an evidence-based approach, a combination of existing criteria and physician assessment should be utilized. To address this issue comprehensively, our future efforts will be directed toward pursuit of a multidisciplinary approach aimed at standardizing evaluation and diagnosis of IBD-associated pSpA.

INTRODUCTION: We evaluated the real-world effectiveness and safety of ustekinumab (UST) in patients with Crohn's disease (CD). METHODS: This study used a retrospective, multicenter, multinational consortium of UST-treated CD patients. Data included patient demographics, disease phenotype, disease activity, treatment history, and concomitant medications. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions were assessed using time-to-event analysis, and clinical predictors were assessed by using multivariate Cox proportional hazard analyses. Serious infections and adverse events were defined as those requiring hospitalization or treatment discontinuation. RESULTS: A total of 1,113 patients (51.8% female, 90% prior antitumor necrosis factor exposure) were included, with a median follow-up of 386 days. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions at 12 months were 40%, 32%, 39%, and 30%, respectively. Biologic-naive patients achieved significantly higher rates of clinical and endoscopic remissions at 63% and 55%, respectively. On multivariable analyses, prior antitumor necrosis factor (hazard ratio, 0.72; 95% confidence interval, 0.49–0.99) and vedolizumab exposure (hazard ratio, 0.65; 95% confidence interval, 0.48–0.88) were independently associated with lower likelihoods of achieving endoscopic remission. In patients who experienced loss of remission, 77 of 102 (75%) underwent dose optimization, and 44 of 77 (57%) achieved clinical response. An additional 152 of 681 patients (22.3%) were dose-optimized because of primary nonresponse incomplete response to UST, of whom 40.1% (61 of 152) responded. Serious infections occurred in 3.4% of patients while other noninfectious adverse events (lymphoma [n = 1], arthralgia [n = 6], rash [n = 6], headache [n = 3], hepatitis [n = 3], hair loss [n = 3], neuropathy [n = 1], and vasculitis [n = 1]) occurred in 2.4% of patients. DISCUSSION: UST represents a safe and effective treatment option for CD, with 40% of patients from a highly refractory cohort achieving clinical remission by 12 months. The greatest treatment effect of UST was seen in biologic-naive patients, and dose escalation may recapture clinical response.

Abstract Background Entry criteria and outcome measures of Crohn’s disease (CD) clinical trials have evolved. Patients are now required to have active inflammation on screening endoscopy, with some studies requiring moderate-severe SES-CD scores. Recent trials have endoscopic response as a co-primary endpoint and endoscopic remission (ER) and deep remission (DR) as major secondary endpoints. Pivotal CD maintenance studies typically examine only responders to induction. The SEAVUE study required ≥1 ulceration of any size (SES-CD≥3) at baseline and had a treat-through design. To examine the results in the context of these trial design characteristics, we evaluated endoscopic outcomes at wk52 in the subgroup of pts with moderate-severe baseline SES-CD scores in SEAVUE, as well as those who were in clinical response after induction. Methods Biologic-naïve pts failing or intolerant to conventional therapy with CDAI≥220/≤450 and SES-CD≥3 were eligible. Pts were randomized, 1:1 to UST (~6mg/kg IV at wk0 then, 90mg SC q8w) or ADA (SC, 160mg at wk0, 80mg at wk2, then, 40mg q2w). Endoscopic outcomes were evaluated in all pts and the subgroup with moderate-severe endoscopic disease (baseline SES-CD≥6 for ileocolonic or colonic disease or SES-CD≥4 for isolated ileal disease). Endoscopic response was a ≥50% reduction from baseline in SES-CD, SES-CD≤3, or SES-CD=0 for pts with baseline SES-CD=3. ER was SES-CD≤3 or, 0 in pts with baseline SES-CD=3. DR was CDAI<150 and ER. Results Endoscopic outcomes for the subgroup with moderate-severe endoscopic disease were similar to those of the full cohort of pts. In UST-treated pts, endoscopic response was achieved at wk52 in, 41.9% in the full cohort and, 43.1% in the moderate-severe subgroup (Table, 1). In ADA-treated pts, endoscopic responses were, 36.9% and, 35.4%, respectively. For pts who were in clinical response after induction (Table, 1), endoscopic response rates were, 48.2% in the full cohort and, 49.5% in the moderate-severe subgroup for UST and, 44.8% and, 43.1%, respectively, for ADA. ER and DR rates were generally similar between the full cohort and the moderate-severe subgroup (Table, 2; eg, ERs were UST, 28.5% and ADA, 30.7% in full cohort; UST, 27.1% and, 27.8% ADA in subgroup). ER and DR rates were, 3%-7% higher in induction responders compared with the full cohort. Of note, even among wk16 nonresponders, some pts attained endoscopic outcomes at wk52 (eg, endoscopic responses in wk16 nonresponders were UST, 21.4% and ADA 13.3%). Conclusion In SEAVUE, both the UST and ADA treatment groups achieved high endoscopic response, ER, and DR rates at wk52. Results in pts with moderate-severe endoscopic disease were similar to those of the full cohort, but clinical responders after induction had higher rates than the full cohort.

Abstract Background We studied the efficacy and safety of ustekinumab (UST) vs adalimumab (ADA) through 1 year in biologic-naïve patients (pts) with moderate-to-severe Crohn’s disease. Methods SEAVUE was a multicenter, randomized, blinded, parallel-group, active-controlled study in adults with CD Activity Index (CDAI) scores ≥220/≤450. Biologic-naïve pts failing/intolerant to conventional therapy with any size ulcer on baseline (BL) ileocolonoscopy were eligible. Pts were randomized 1:1 to UST (⁓6mg/kg IV at BL then 90mg SC every 8 weeks [Ws]) or ADA (160/80mg SC at BL/W2, then 40mg SC every 2 Ws) per US-approved regimens (no dose modifications). Primary endpoint was clinical remission at W52 (CDAI <150). Major secondary endpoints were corticosteroid-free remission, clinical response (≥100-point CDAI decrease from BL), remission in pt-reported CDAI components (PRO-2 symptom remission: abdominal pain mean daily score ≤1 and stool frequency mean daily score ≤3), and endoscopic remission (SES-CD score ≤3/0 for pts with BL score=3) at W52 and clinical remission at W16. Results 386 pts were randomized to UST or ADA. BL demographics and disease characteristics were balanced between groups and indicative of pts with early, moderate-to-severe CD (median CD duration, 2.58 years; CDAI, 289.5; SES-CD, 8.0). At W52, 65% of UST-treated and 61% of ADA-treated pts achieved clinical remission (Δ=4.0%; 95% CI, -5.5%, 13.5%; p=0.417). Major secondary endpoints, including endoscopic remission, were similar between groups (Table 1), as were remission rates at assessment points through W52. Some other secondary endpoints showed numerical (not statistical) differences between UST and ADA (Table 1). Key safety events are summarized in Table 2. Among UST-treated and ADA-treated pts, 34.0% and 40.5% had infections, 2.6% and 7.2% had serious adverse events (AEs) of worsening CD, and 6.3% and 11.3% had AEs that led to discontinuation (DC) of study drug, respectively. One ADA-treated pt had active pulmonary TB. Injection-site reactions associated with active treatment occurred in 1.0% of UST-treated and 10.3% of ADA-treated pts. Overall, 15.2% of UST-treated and 23.6% of ADA-treated pts DC before W52. Reasons for DC were primarily lack of efficacy (UST, 2.1% vs ADA, 5.1%), AEs (UST, 5.7% vs ADA, 10.7%), and withdrawal of consent (UST, 5.8% vs ADA, 5.1%). Time to treatment DC was longer with UST vs ADA (post hoc analysis). Conclusion Both UST and ADA were highly effective in this population of biologic-naïve pts. Rates of clinical remission at W52 were not statistically significantly different between treatment groups. DC rates were numerically lower for UST. Safety results were consistent with prior experience for both treatments.