Deepak, Parakkal

Data indicate that earlier initiation of anti-tumor necrosis factor alpha (anti-TNF-α) biologic medicines may prevent progression to irreversible bowel damage and improve outcomes for patients with inflammatory bowel disease (IBD), particularly Crohn’s disease. However, the high cost of such therapies may restrict access and prevent timely treatment of IBD. Biosimilar anti-TNF-α medicines may represent a valuable opportunity for cost savings and optimized patient outcomes by improving access to advanced therapies and allowing earlier anti-TNF-α treatment initiation. Biosimilar anti-TNF-α medicines have been shown to offer consistent therapeutic outcomes to their reference medicines, yet despite entering the IBD treatment armamentarium over 10 years ago, their implementation in clinical practice remains suboptimal. Factors limiting the ‘real’ use of biosimilar anti-TNF-α medicines may include an ongoing lack of understanding and acceptance of biosimilars by both healthcare professionals (HCPs) and patients, as well as systemic factors such as formulary decisions outside of the control of the prescriber. In this review, an expert panel of gastroenterologists discusses HCP-level considerations to improve biosimilar anti-TNF-α utilization in IBD in order to support early anti-TNF-α initiation and maximize patient outcomes.

Abstract Background There is limited data on the clinical effectiveness of upadacitinib (UPA), an oral selective inhibitor of Janus kinase 1 (JAKi), in patients with perianal Crohn's disease (pCD). The objective of this study was to evaluate the real-world effectiveness of UPA in pCD. Methods This retrospective analysis utilized data on adults (>17 years) who initiated UPA at 45 mg/day for active pCD across 10 centers in the United States and Canada. Standardized data extraction and entry protocols were followed. The primary outcome was clinical response, defined as a ≥3-point reduction in Perianal Disease Activity Index (PDAI) between baseline and follow-up. Secondary outcomes included normalization of CRP (<5 mg/L) or hsCRP (<1 mg/L), clinical remission (PDAI ≤4), and rates of hospitalization, antibiotic use, corticosteroid initiation, and new pCD-related surgeries. Fistula healing on MRI pelvis fistula protocol was defined as an absence of T2-weighted hyperintensity and post-contrast enhancement on T1-weighted images. Predictive analyses used Cox proportional hazards models to evaluate baseline factors influencing time to PDAI remission, including BMI, CRP, albumin, PDAI, pCD disease duration, Montreal location and prior biologic exposure (<2 vs 2+). Results A total of 81 patients were treated with UPA for pCD (median age 35 years and 54.3% male). Most had ileocolonic disease (65.4%), with 54% presenting with complex fistulas. Of these, 92.6% had prior anti-TNF exposure, and 91 (88.9%) had prior exposure to 2+ biologics (Table 1). During a median follow-up of 4 months, clinical response (PDAI) was achieved in 17.3%. Improvement was observed in pain and restriction of activities (27.2%), restriction of sexual activity (13.6%), reduction in number of fistulas (11.1%), degree of induration (11.1%), and discharge (35.8%). Median CRP reduction was 21.05% [IQR: 0.00–74.53], and 21.0% achieved a ≥50% reduction in CRP. MRI healing was limited to 17.7% (6/34). Proctitis decreased from 23.5% at baseline to 7.4% at follow-up. During follow-up, hospitalizations occurred in 9.9%, 14.8% required antibiotics, 8.6% underwent examination under anesthesia in 8.6%, seton placement in 6.2%, and abscess drainage in 6.2%. Patients with ileocolonic disease showed the highest remission (54%) and response (15%) rates, while MRI healing was limited across all Montreal locations (7.4%). Lower baseline CRP (p < 0.05) and PDAI scores (p < 0.01) predicted shorter time to remission. Number of prior biologic exposures (p =0.2) and Montreal location (p = 0.7) were not predictive of time to PDAI remission (Figure 1). Conclusion UPA in a real-world cohort is effective in the management of treatment-refractory pCD. Randomized trials are needed to confirm these observations.

Abstract Background Upadacitinib (UPA) is an oral selective Janus kinase inhibitor approved for the management of moderate-to-severe Crohn’s disease (CD). One in ten CD patients may need a permanent ostomy (colostomy or ileostomy) during their disease course, and this may impact the efficacy of UPA, given its extended-release formulation. However, there is no data available in this population since patients with an ostomy are excluded from registrational CD trials. This study addresses this gap by comparing the real-world clinical effectiveness of UPA in CD patients with and without ostomy. Methods This retrospective cohort study analyzed data from the TriNetX US Collaborative Network of sixty-eight tertiary institutions, to examine adult (≥18 years) CD patients treated with UPA from May 19th, 2023 (FDA approval date) to October 31st, 2024. Patients were categorized based on presence or absence of an ostomy during the previous 5 years, after exclusion of patients with rheumatologic disease indications for UPA usage. A 1:1 propensity score matching (PSM) was performed to balance cohorts on demographics, baseline comorbidities, and CD severity indicators (CD phenotype, extraintestinal manifestations, concurrent corticosteroid and other biologics usage, hemoglobin, and body weight). Cox proportional hazards model estimated hazard ratios (HRs) in matched cohorts for clinical effectiveness as a composite outcome (corticosteroid use, hospitalizations, emergency room visits) and secondary individual outcomes, at one year post-treatment, with a significance threshold set at p < 0.05. Results The study sample of CD patients on UPA included 170 with and 1,428 without a prior ostomy. There were 144 patients in each cohort after PSM. Baseline characteristics of the cohorts are shown in Figure 1. After PSM (Figure 2), there were no significant differences between patients with CD on UPA, with and without prior ostomy, for composite outcomes (HR 0.93, p = 0.64), corticosteroid use (HR 0.78, p = 0.18), hospitalizations (HR 1.13, p = 0.64), or emergency room visits (HR 0.99, p = 0.97). Additionally, no significant differences were observed in opioid use (HR 0.95, p = 0.76), switch to another advanced therapy (HR 1.62, p = 0.06), or elevated biomarkers, including CRP (>10 mg/L, HR 1.00, p = 0.99) and fecal calprotectin (>150 µg/g, HR 0.85, p = 0.63) at the 1-year follow-up. Conclusion In CD patients, UPA demonstrated similar effectiveness for clinical outcomes of corticosteroid use, hospitalizations, emergency room visits and other secondary outcomes, regardless of their ostomy status.

Abstract Background The SEQUENCE trial, in bio-exposed Crohn's disease (CD) patients, demonstrated non-inferiority for clinical remission at 24 weeks and superiority for endoscopic remission at week 48 for risankizumab (RZB) compared to ustekinumab (UST). However, this comparison has not been adequately explored in bio-naive CD patients. Our study aimed to compare the clinical effectiveness among bio-naive CD patients treated with RZB vs. UST in a real-world setting, using data from a US-based multicenter cohort. Methods This retrospective cohort study utilized data from the TriNetX US Collaborative Network, comprising sixty-eight tertiary institutions, to examine adult (≥18 years) bio-naive CD patients initiated on RZB or UST from June 17th, 2022 (FDA approval date) to October 31st, 2024. Patients with prior advanced therapy usage and those with approved rheumatologic disease indications for RZB/UST were excluded. A 1:1 propensity score matching (PSM) analysis was conducted to balance cohorts on demographics, baseline comorbidities, and indicators of CD severity, including CD phenotype, extraintestinal manifestations, concurrent corticosteroid use, hemoglobin, and body weight. Cox proportional hazards models estimated hazard ratios (HRs) in matched cohorts for one-year post-treatment composite outcomes (need for corticosteroids, hospitalizations, emergency room visits, surgeries) with a priori significance threshold of p < 0.05. Results The study sample included 1,630 bio-naive CD patients treated with RZB and 3,105 with UST. Among patients on UST, 658 (21%) were dosed every four to six weeks, after the first dose. Baseline characteristics of the PSM RZB and UST cohorts are shown in Table 1 with 1,568 patients in each cohort. After PSM (Figure 1), there were no significant differences in composite outcome (HR 1.077, p = 0.170), corticosteroid use (HR 1.099, p = 0.110), CD-related surgery (HR 1.231, p = 0.284), hospitalization (HR 0.947, p = 0.615) or ER visits (HR 1.041, p = 0.687). Additionally, no significant differences were observed in opioid use (HR 1.062, p = 0.366), switch to different advanced therapy (HR 1.097, p = 0.468) or elevated disease biomarkers, including CRP (>10mg/l, HR 1.186 p = 0.101) or fecal calprotectin (>150 µg/g; HR 1.109, p = 0.407) at 1-year follow-up. Conclusion In this real-world experience allowing for drug optimization, no difference was observed in bio naïve patients between UST and RZB as far as clinical remission and progression of CD.

Lay Summary In this prospective, multicenter observational study of highly refractory patients with Crohn’s disease of the pouch, risankizumab achieved the primary outcome of clinical remission in 50% and the more stringent secondary outcome of antibiotic- and steroid-free remission in 30.8% at 12 weeks.

Abstract Background and Aims Perianal fistuliing Crohn’s disease [PFCD] is an aggressive phenotype of Crohn’s disease defined by frequent relapses and disabling symptoms. A novel consensus classification system was recently outlined by the TOpCLASS consortium, which seeks to unify disease severity with patient-centred goals but has not yet been validated. We aimed to apply this to a real-world cohort and to identify factors that predict transition between classes over time. Methods We identified all patients with PFCD and at least one baseline and one follow-up pelvic MRI [pMRI]. TOpCLASS classification, disease characteristics, and imaging indices were collected retrospectively at time periods corresponding with respective MRIs. Results We identified 100 patients with PFCD, of whom 96 were assigned TOpCLASS Classes 1–2c at baseline. Most patients [78.1%] started in Class 2b, but changes in classification were observed in 52.1% of all patients. Male sex [72.0%, 46.6%, 40.0%, p = 0.03] and prior perianal surgery [52.0% vs 44.6% vs 40.0%, p = 0.02] were more frequently observed in those with improved class compared to unchanged and worsened class. Baseline pMRI indices were not associated with changes in classification; however, greater improvements in mVAI, MODIFI-CD, and PEMPAC were seen among those who improved. Linear mixed effect modelling identified only male sex [-0.31, 95% CI -0.60 to -0.02] with improvement in class. Conclusion The TOpCLASS classification highlights the dynamic nature of PFCD over time. However, our ability to predict transitions between classes remains limited and requires prospective assessment. Improvement in MRI index scores over time was associated with a transition to lower TOpCLASS classification.

Abstract Background Pivotal trials have shown that ustekinumab is effective in ulcerative colitis (UC). However, the population included in these trials do not represent the cohort of patients treated in the real world. In this study, we aimed to describe the effectiveness and safety of ustekinumab in a clinical cohort of patients with UC. Methods We performed a multicenter retrospective cohort study and included patients with active UC starting ustekinumab. Variables collected included demographics, clinical data, and disease activity (measured using partial Mayo score [PMS] and endoscopic Mayo score) at follow-up. The primary outcomes were cumulative rates of steroid-free clinical and biochemical remission (SFCBR), defined as a PMS <2 while off steroids and a normal C-reactive protein and/or fecal calprotectin. Results A total of 245 patients met inclusion criteria. The median time of follow-up was 33 (interquartile range, 17-53) weeks, and 214 (87.3%) had previous exposure to a biologic and/or tofacitinib. Rates of SFCBR, clinical remission, and endoscopic remission at 6 and 12 months were 12.0% (n = 16 of 139), 29.0% (n = 71 of 175), and 18.0% (n = 7 of 39), and 23.8% (n = 15 of 63), 54.3% (n = 57 of 105), and 31.0% (n = 9 of 29), respectively. Non-Hispanic White race, higher baseline PMS, and the use of concomitant corticosteroids were independently associated with failure to achieve SFCBR. Of the 73 that were dose escalated, 28.4% did not respond, 49.3% experienced a benefit, and 21.6% achieved remission. Conclusions In a population enriched with refractory UC, ustekinumab was well tolerated and induced remission in a significant number of patients. Larger studies with a longer follow-up are warranted.

Abstract Background Extraintestinal manifestations (EIMs) of inflammatory bowel diseases (IBDs) are a common and debilitating feature of disease, occurring in up to 40% of patients with IBD, yet predicting who may develop them is difficult. The goal of our study was to better characterize which patients may be at highest risk of developing not only 1 EIM, but also multiple EIMs, across both diseases. Methods A retrospective study of participants enrolled in the SPARC IBD (Study of Prospective Adult Research Cohort with IBD) registry was performed, and demographic and clinical data were analyzed. A total of 1211 patients with data available on EIMs were included, and differences among variables with vs without EIMs were assessed. Results A total of 329 participants with at least 1 EIM were identified, compared with 882 participants without any EIMs. Crohn’s disease patients and women were more likely to have 2 or more EIMs (P = .005 and P ≤ .001, respectively). Participants with ocular manifestations were likeliest to have at least 2 EIMs (P ≤ .001). Even when diagnosis was controlled for, involvement of the right colon (P = .021) was predictive of IBD-associated arthritis across both diseases in a multivariate generalized linear model. Conclusions This is the first comprehensive large-cohort assessment of how EIMs relate to one another at the individual vs systems levels. Further, our analysis is the first to recognize specific locations of colon involvement associated with EIMs of IBD, regardless of IBD type. These results are important in identifying patients at risk of developing future EIMs and may help with risk stratification when choosing treatments.

INTRODUCTION: There is a paucity of data on the real-world effectiveness of therapies in patients with Crohn's disease of the pouch. METHODS: This was a prospective multicenter study evaluating the primary outcome of remission at 12 months of therapy for Crohn's disease of the pouch. RESULTS: One hundred thirty-four patients were enrolled. Among the 77 patients with symptoms at baseline, 35 (46.7%) achieved remission at 12 months. Of them, 12 (34.3%) changed therapy. There was no significant association between therapy patterns and remission status. DISCUSSION: Approximately 50% with symptoms at enrollment achieved clinical remission at 12 months, most of whom did so without a change in therapy.