anti-TNF Agents Research Articles

Crohn's disease after surgery: Changes in post-operative management strategies over time and their impact on long-term re-operation rate-A retrospective multicentre real-world study.

Few data are available addressing the impact of post-operative management of Crohn's disease (CD) on long-term clinical course. To assess the evolution of post-operative management strategies over the last 40 years and their impact on the re-operation rate of CD. We included 657 patients with CD who had undergone their first radical ileo-caecal resection between 1980 and 2020. Three cohorts were defined according to year of surgery: cohort 1 (1980-1998; n = 198), cohort 2 (1999-2009; n = 218) and cohort 3 (2010-2020; n = 241). We estimated exposure to immunomodulators and anti-TNFα agents after surgery and rates of re-operation using Kaplan-Meier survival analyses. We used Cox proportional hazards regression to assess the association of clinical variables with time to re-operation. Immunosuppressants, (IMMs) and anti-TNFα exposure within 5 years after surgery increased significantly from cohort 1 to cohort 2 and cohort 3 (IMMs: 1.6%, 38.2% and 28.0%, respectively, p < 0.001; anti-TNFα: 0.0%, 20.7% and 52.0%, respectively, p < 0.001). There was no significant difference across cohorts regarding the cumulative probability of re-operation within 5 and 10 years. Multivariate analysis identified IMMs/anti-TNFα exposure before the first surgery (HR 9.15; 95% CI 2.77-30.21) and post-operatively (HR: 0.24; 95% CI 0.07-0.74) as variables associated with the risk of re-operation. However, these associations had a time-varying effect and become non-significant after 5 and 2 years after surgery, respectively. Despite increased post-operative use of IMMs and anti-TNFα agents in the last two decades, the impact of these strategies on the risk of long-term re-operation rate has been modest.

A Practical guide to selecting and using new Crohn's disease therapies.

This review details the three new agents, including two novel mechanisms of action, approved to treat Crohn's disease in recent years. We review efficacy, safety, prescribing information, and available data on positioning these new therapies. Risankizumab and upadacitinib are novel mechanisms of action approved to treat moderate to severe Crohn's disease. Risankizumab targets the cytokine interleukin-23. Upadacitinib is a selective Janus kinase-1 inhibitor approved for use in individuals who have previously failed or are intolerant to an anti-TNF agent. Subcutaneous infliximab provides a novel method of administering maintenance dosing of a longstanding and efficacious therapy. Risankizumab has shown efficacy in both biologic naïve and biologic experienced populations. The SEQUENCE trial shows superiority of risankizumab over ustekinumab for disease response in patients who have previously failed an anti-tumor necrosis factor agent. Upadacitinib has shown good efficacy in clinical trials even in the setting of a mandated steroid taper during induction. Subcutaneous infliximab maintenance therapy appears noninferior to i.v. infliximab and shows good treatment persistence in real world transitions. Additional data is needed to better understand how to position these therapies.

Ustekinumab or Vedolizumab after Failure of Anti-TNF Agents in Crohn’s Disease: A Review of Comparative Effectiveness Studies

Background: Anti-tumour necrosis factor (TNF) agents are effective in Crohn’s disease (CD), but some patients lose responsiveness and require alternative biologic therapy. Until recently, ustekinumab and vedolizumab were the only other biological agents approved for use in CD. There are no randomised trials which compare the efficacy of these two agents in patients with anti-TNF refractory disease, but several retrospective cohort studies have compared their effectiveness in this setting. Aim: To review the effectiveness of ustekinumab and vedolizumab in anti-TNF refractory patients with CD. Methods: We included studies that compared the effectiveness of ustekinumab and vedolizumab in treating patients with anti-TNF refractory CD. We recorded the sample size, primary and secondary outcome measures and whether the studies employed adjustments for appropriate confounders. Results: Fourteen studies were included with a total sample size of 5651, of whom 2181 (38.6%) were treated with vedolizumab and the rest were treated with ustekinumab (61.4%). Of the fourteen studies included, eight found ustekinumab to be more effective in achieving clinical remission/steroid-free remission in the induction phase or during maintenance therapy (at least 1-year post-treatment) or that treatment persistence rates with ustekinumab were higher than with vedolizumab. Only one study reported vedolizumab to be superior during the maintenance phase in terms of clinical remission or treatment persistence rates. Biochemical outcomes were reported in five studies, two of which showed superiority for ustekinumab at 14 weeks and the other at 52 weeks. Only two studies reported endoscopic and/or radiologic outcomes; of these, one study showed ustekinumab to be significantly better at achieving endoscopic and radiologic responses. Adverse outcomes were broadly comparable, barring a single study which reported a lower hospitalisation rate for severe infection with ustekinumab. Conclusions: Most studies found ustekinumab to be more effective or non-inferior to vedolizumab in treating patients with anti-TNF refractory CD. Although many studies adjusted appropriately for confounders, the possibility of residual confounding remains and further data from prospective studies are warranted to confirm these findings. Further studies are required to compare these two therapies to other emerging therapies, such as Janus-kinase inhibitors.

Next-Generation Anti-TNFα Agents: The Example of Ozoralizumab.

Biologic therapy involving anti-tumor necrosis factor-α (anti-TNFα) agents has fundamentally changed the management of patients with immune-mediated inflammatory diseases, including rheumatoid arthritis, thus benefiting many patients. Nevertheless, the inability of some patients to achieve low disease activity or clinical remission remains a major concern. To address such concerns, next-generation anti-TNFα agents that differ from the immunoglobulin G-format anti-TNFα agents that have been used to date are being developed using antibody-engineering technology. Their unique design employing novel molecular characteristics affords several advantages, such as early improvement of clinical symptoms, optimization of drug bioavailability, enhancement of tissue penetration, and a reduction in side effects. This holds promise for a new paradigm shift in biologic therapy via the use of next-generation anti-TNFα agents. Ozoralizumab, a next-generation anti-TNFα agent that was recently approved in Japan, comprises a variable region heavy-chain format. It has a completely different structure from conventional therapeutic antibodies, such as a small molecular size, an albumin-binding module, and a unique format that produces an avidity effect. Ozoralizumab exhibited rapid biodistribution into joints, provided attenuation of Fcγ receptor-mediated inflammatory responses, and had a high binding affinity to TNFα in non-clinical studies. In clinical trials, ozoralizumab yielded an early improvement in clinical symptoms, a sustained efficacy for up to 52 weeks, and an acceptable tolerability in patients with rheumatoid arthritis. This review focuses on the results of pre-clinical and clinical trials for ozoralizumab and outlines the progress in next-generation antibody development.

Comparing the Effects of Anti-TNF Agent and Ustekinumab on Small Bowel Inflammation in Crohn’s Disease: Inverse Probability Weighting With Stabilized Weights of Propensity Scores

Abstract Background Endoscopic mucosal healing serves as a critical predictor for achieving long-term remission in Crohn’s disease treatment. Recent data indicate that the effectiveness of healing varies based on the location of gastrointestinal inflammation. Additionally, reports suggest that antitumor necrosis factor-α (anti-TNF-α) agents exhibit reduced efficacy in treating small intestinal inflammation compared to colorectal inflammation. Conversely, limited research exists regarding the impact of the anti-IL12/23 agent ustekinumab (UST) on small intestinal inflammation. This study aimed to compare the effects of anti-TNF-α agents and UST on small intestinal inflammation using propensity score analysis. Methods This retrospective observational study involved 70 patients with Crohn’s disease who had inflammation in the small intestine and had initiated treatment with either anti-TNF agents or UST between March 2015 and August 2021. Endoscopic findings were evaluated before treatment commencement and at 1–2 years post-treatment initiation. The propensity score was employed to compare the efficacy of TNF agents and UST on small bowel inflammation. Results Ustekinumab exhibited greater improvement in the small intestinal endoscopy score than anti-TNF-α antibodies according to the propensity score analysis (inverse probability weighting; P = .0448). However, no significant disparity was observed in the overall improvement of endoscopic scores between UST and anti-TNF-α antibodies (P = .5938). Conclusions This study suggests that UST might be more effective than anti-TNF-α agents in treating small intestinal inflammation in Crohn’s disease.

An in vitro analysis of the interaction between infliximab and granulocyte–monocyte apheresis

ObjectivePrimary non-response and secondary loss of response to anti-TNF agents are common in inflammatory bowel disease. Increasing drug concentrations are correlated to better clinical response and remission rates. Combination of granulocyte–monocyte apheresis (GMA) with anti-tumor necrosis factor (TNF) agents could be an option in these patients. The objective of our study was to perform an in vitro assay to determine if the GMA device can lead to infliximab (IFX) adsorption. Patients and methodsA blood sample was obtained from a healthy control. It was incubated with three concentrations of IFX (3, 6, and 9μg/ml) at room temperature for 10min. At that time, 1ml was collected to determine the IFX concentration. Then, 10ml of each drug concentration was incubated with 5ml of cellulose acetate (CA) beads from the GMA device at 200rpm for 1h at 37°C to simulate physiological human conditions. A second sample of each concentration was collected and IFX levels were determined. ResultsNo statistically significant differences were observed in the IFX levels in the blood samples before and after incubation with the CA beads (p=0.41) and after repeated measurements (p=0.31). Mean change was 3.8μg/ml. ConclusionsThe in vitro combination of GMA and IFX did not change the circulating levels of IFX at the three concentrations tested, suggesting that there is no interaction between the drug and the apheresis device in vitro and that they might be safely combined with each other.

The role of immune checkpoint inhibitors in the development and treatment of infectious processes

The incidence and prevalence of oncological diseases, which are in second place in terms of the frequency of causes of death, is steadily increasing among the population of the Russian Federation. Advances in translational medicine, including immunotherapy, have revolutionized cancer treatment strategies. A special breakthrough has been achieved in two areas of immunotherapy that have modernized cancer treatment: chimeric T-cell receptors and antibodies known as immune checkpoint inhibitors (ICTs) blocking cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein-1 (PD-1) and ligand programmed cell death receptor (PD-L1). ICTs enhance the adaptive immune response of the tumor and can cause adverse effects as a result of hyperactivation of T cells, which often leads to the emergence of an opportunistic infection. In addition, immunosuppressive drugs, which are often prescribed to mitigate the side effects associated with ICT, are also a risk factor for infection. The purpose of the review is to analyze the literature on possible relationships between ICT inhibitors and the risk of infection, as well as to consider the possible benefits of ICT inhibitors as a treatment for various types of infections, including viral, parasitic and fungal, as well as sepsis. Although ICT inhibitors have demonstrated the ability to significantly prolong the life expectancy of patients with advanced cancer, they often lead to adverse events, which often requires treatment with immunosuppressive drugs, including corticosteroids, anti-TNF and other biological agents. The overall effect of ICT inhibitors on human infections remains poorly understood. Further research is needed to understand the basic mechanisms of the immunological effects of ICT inhibitors on various types of infections, which in some cases may be beneficial.

An atypical presentation of axial spondyloarthritis with severe acute low back pain: A case report

Axial spondyloarthritis (axSpA) represents a chronic inflammatory condition primarily impacting axial joints, characterized by sacroiliitis and spondylitis. In axSpA patients, low back pain (LBP) typically assumes a chronic and inflammatory nature, where diagnostic delays can precipitate disability. However, atypical axSpA presentations pose challenges for early diagnosis and management. In the current study, we detail the case of a 39-year-old male presenting with acute, severe LBP and bilateral sacroiliitis. Initial treatment with non-steroidal anti-inflammatory drugs (NSAIDs), the standard first-line therapy, was discontinued due to severe gastrointestinal bleeding. Following a bone biopsy that excluded alternative etiologies, axSpA was confirmed based on diagnostic criteria. Elevated inflammatory markers, contraindications to NSAIDs, and magnetic resonance imaging findings prompted the initiation of anti-tumor necrosis factor (TNF) therapy. Remarkably, a marked improvement was observed in less than six weeks post anti-TNF therapy commencement. This case underscores the significance of recognizing atypical axSpA presentations and underscores the potential for swift and robust responses to anti-TNF agents. Optimal patient outcomes hinge upon effective disease pattern recognition and treatment selection.

Urinary prostanoids are elevated by anti-TNF and anti-IL6 receptor disease-modifying antirheumatic drugs but are not predictive of response to treatment in early rheumatoid arthritis

BackgroundDisease-modifying antirheumatic drugs (DMARDs) are widely used for treating rheumatoid arthritis (RA). However, there are no established biomarkers to predict a patient’s response to these therapies. Prostanoids, encompassing prostaglandins, prostacyclins, and thromboxanes, are potent lipid mediators implicated in RA progression. Nevertheless, the influence of DMARDs on prostanoid biosynthesis in RA patients remains poorly understood. This study aims to assess the impact of various DMARDs on urinary prostanoids levels and to explore whether urinary prostanoid profiles correlate with disease activity or response to therapy.MethodsThis study included 152 Swedish female patients with early RA, all rheumatoid factor (RF) positive, enrolled in the NORD-STAR trial (registration number: NCT01491815). Participants were randomized into four therapeutic regimes: methotrexate (MTX) combined with (i) prednisolone (arm ACT), (ii) TNF-α blocker certolizumab pegol (arm CZP), (iii) CTLA-4Ig abatacept (arm ABA), or (iv) IL-6R blocker tocilizumab (arm TCZ). Urine samples, collected before start of treatment and at 24 weeks post-treatment, were analyzed for tetranor-prostaglandin E metabolite (tPGEM), tetranor-prostaglandin D metabolite (tPGDM), 2,3-dinor thromboxane B2 (TXBM), 2,3-dinor-6-keto prostaglandin F1a (PGIM), leukotriene E4 (LTE4) and 12-hydroxyeicosatetraenoic acid (12-HETE) using liquid chromatography–mass spectrometry (LC–MS). Generalized estimating equation (GEE) models were used to analyze the change in urinary eicosanoids and their correlations to clinical outcomes.ResultsPatients receiving MTX combined with CZP or TCZ exhibited significant elevations in urinary tPGEM and TXBM levels after 24 weeks of treatment. Other eicosanoids did not show significant alterations in response to any treatment. Baseline urinary eicosanoid levels did not correlate with baseline clinical disease activity index (CDAI) levels, nor with changes in CDAI from baseline to week 24. Their levels were also similar between patients who achieved CDAI remission and those with active disease at week 24.ConclusionsTreatment with anti-TNF or anti-IL6R agents in early RA patients leads to an increased systemic production of proinflammatory and prothrombotic prostanoids. However, urinary eicosanoid levels do not appear to be predictive of the response to DMARDs therapy.

Efficacy and safety of proactive drug monitoring in inflammatory bowel disease treated with anti-TNF agents: A systematic review and meta-analysis.

A systematic review and a meta-analysis of the literature was conducted to assess efficacy and safety of proactive therapeutic drug monitoring (TDM) versus conventional management during maintenance treatment with anti-tumour necrosis factor (anti-TNFα) in patients with inflammatory bowel disease (IBD). A search was conducted up to January 2022 (MEDLINE, EMBASE, and the Cochrane Library). The primary outcome was the ability to maintain clinical remission at 12 months. The certainty of evidence was determined using the GRADE approach. Nine studies were identified: one systematic review, six randomised clinical trials, and two cohort studies. No superior efficacy of proactive TDM [relative risk 1.16; 95% confidence interval (CI): 0.98-1.37, n=528; I2=55%] was shown. Proactive TDM could improve the durability of anti-TNFα treatment [odds ratio (OR) 0.12; 95%CI: 0.05-0.27; n=390; I2=45%), prevent acute infusion reactions (OR 0.21; 95%CI: 0.05-0.82; n=390; I2=0%), decrease adverse events (OR 0.38; 95%CI: 0.15-0.98; n=390; I2=14%), and reduce the probability of surgery, at lower economical expenditure. The analysed evidence did not confirm the superiority of proactive TDM of anti-TNFα treatment over conventional management in patients with IBD, so proactive TDM should not currently be recommended.

A271 EFFECT OF ANTI-TNF AGENTS ON DNA METHYLATION IN PERIPHERAL BLOOD OF PATIENTS WITH INFLAMMATORY BOWEL DISEASE

Abstract Background Despite the success and ongoing use of tumor necrosis factor inhibitors (TNFi) in the treatment of inflammatory bowel disease (IBD), there are no predictors of response to therapy. While much research has gone into understanding genetic risks for IBD, less work has been done exploring epigenetic associations with treatment. Hence, we wondered whether epigenetic changes were associated with failure of TNFi in IBD. Aims Describe the association of TNFi response with DNA methylation in patients with IBD. Methods Participants ≥18 years with IBD (N=169) were selected from the Inflammation, Microbiome, and Alimentation: Gastro-Intestinal and Neuropsychiatric Effects (IMAGINE) Strategy for Patient Oriented Research (SPOR) Network. At enrollment participants completed a questionnaire that included their disease diagnosis, therapy, smoking history, and disease activity using the validated IBD Symptom Inventory (IBDSI). Patients provided whole blood samples that were processed for and run on Illumina DNA methylation arrays. Results The 169 patients were in three treatment groups: TNFi naïve (N=98, never exposed to an anti-TNF agent), TNFi responder (N=32, inactive disease on anti-TNF agent), and TNFi nonresponder (N=39, active disease not on any biologic at time of enrollment). The mean symptom score (SIBDSI) was different across the three groups (pampersand:003C0.001): TNFi nonresponders having a higher SIBDSI (24 ± 6.1) than the TNFi naïve (9.1 ± 5.5) or responder (8.3 ± 4.3) treatment groups. Relative proportions of leukocyte populations were estimated using DNA methylation. CD4 and CD8 T cell and B cell counts were higher (pampersand:003C0.05) in the nonresponders and responders versus TNFi naïve group. Neutrophil counts were lower (pampersand:003C0.05) in the TNFi nonresponders and responders compared to the TNFi naïve group (Figure 1). There was a trend towards increased epigenetic estimates of age acceleration (pampersand:003E0.05) in nonresponders versus responders and TNFi naïve patients, likely driven by disease activity (data not shown). Epigenome-wide analysis of the three groups revealed 16 CpGs for responder versus naïve (e.g. CDK5 regulatory subunit-associated protein 1-like 1 (CDKAL1), and two CpGs for nonresponders versus responders (Table 1). This includes a CpG for guanine nucleotide-binding protein subunit gamma-2 (GNG2) that was shared between the two comparisons. Conclusions Exposure to TNFi is associated with changes in peripheral leukocyte populations independent of response to treatment, indicating a TNFi effect. This implies that anti-TNF treatment is having some effect on patients even if there is clinical nonresponse. Differentially expressed CpGs implicates possible markers of response to treatment, particularly CDKAL1, a gene that has been associated with TNFi response in psoriasis. Funding Agencies Guts and Roses Charity

A221 AZATHIOPRINE DOSING THRESHOLD IN ANTI-TNF COMBINATION THERAPY FOR MINIMIZING IMMUNOGENICITY AND OPTIMIZING TREATMENT EFFICACY FOR PATIENTS WITH INFLAMMATORY BOWEL DISEASE. A RETROSPECTIVE COHORT STUDY

Abstract Background Reported rates of anti-drug antibody (ADA) formation to tumor necrosis factor-a antagonists (anti-TNF) range from 20-75%. One way to reduce the risk of ADA formation is to combine a second immune-suppressing agent such as azathioprine (AZA) with the anti-TNF agent, known as combination therapy. However, it is unknown if the risk of combination therapy, including the additive risk of AZA and anti-TNF side effects, could be reduced by exposing individuals with inflammatory bowel disease (IBD) to the lowest dose of azathioprine while still maintaining the beneficial effect of ADA prevention. Aims To identify the minimum dose of AZA needed to prevent ADA formation to anti-TNF agents in individuals with IBD receiving combination therapy. We also assessed the occurrence of adverse drug events, treatment loss of response, treatment discontinuation and the need for treatment dose escalation. Methods A retrospective cohort study is ongoing in adult participants with IBDreceiving either infliximab or adalimumab in combination with AZA. Patients are divided based on their AZA dosage (low dose group, AZA ampersand:003C2mg/kg/day versus standard dose group, AZA 2mg/kg/day). All participants will be followed for 1 year and observed for the occurrence of ADA formation, adverse drug events, treatment loss of response, treatment discontinuation and the need for treatment dose escalation. Results To date, 48 participants are currently included (low dose, n=29; standard dose, n=19). 42 are on Infliximab and 6 are on Adalimumab. The occurrence of ADA was 17.4% in the low dose group and 20% in the standard dose group (pampersand:003E0.99). More participants lost response to treatment and discontinued anti-TNF therapy in the standard dose group (n=7/19, 36.8%) versus the low-dose group (n=8/29, 27.6%, p=0.54). More participants in the low-dose group received anti-TNF dose escalation (n= 20/29,68.9%) compared to the standard dose group (n=6/19, 31.6%, p=0.017). Adverse events, to Anti-TNF was seen in (n=3/19, 15.7%) in the standard dose group, in comparison to (n=4/29, 13.79%, pampersand:003E0.99) in the low dose group. Adverse events to AZA were surprisingly higher in the low dose group (n=14/29, 48.3%) while in the standard dose, it was (n=5/19, 26.3%, p=0.14). Conclusions The preliminary result of the study suggests that there is no significant difference in anti-drug antibody formation between standard and low doses of azathioprine in combination with anti-TNF therapy, in addition, data showed significant lower rates of Anti-TNF discontinuation and loss of response to treatment in low Azathioprine dose group. Completion of the study will help further define if low-dose AZA can be used for ADA prevention in anti-TNF combination therapy without compromising important clinical outcomes. Funding Agencies None

A252 DRUG DISCONTINUATION AND PERSISTENT SYMPTOMS AMONG THE USERS OF BIOSIMILAR AND LEGACY ANTI-TNF DRUGS IN A REAL-WORLD CANADIAN IBD COHORT

Abstract Background Biosimilars and their reference originator drugs are increasingly used for inducing and maintaining remission in Inflammatory Bowel Diseases (IBD). Persistent symptoms, such as fatigue and joint pain, have been reported among individuals with IBD in remission. However, there is limited data on the persistence of symptoms among long-term users of biological therapy. Aims We report on drug discontinuation and persistent symptoms among a multicentre cohort of IBD patients 12 months after initiating anti-TNF originators or biosimilars. Methods We enrolled and followed individuals with IBD (ampersand:003E18 years) who initiated therapy with infliximab or adalimumab, bio-originators/biosimilars, between January 2019 and March 2023. We determined the rate of discontinuation of therapy, persistent symptoms, and quality of life (QoL) after 12 months. Difference in effect estimates (proportions and means) between the two groups (originators versus biosimilars) was determined. Results 181 individuals with IBD (CD = 58%, female = 46%, Caucasian = 85%) were enrolled. 62% were biologic-naïve at initiation. Of the 119 participants who completed a 12-month follow-up visit, about 19% (n = 34) discontinued drug use (all were infliximab users). Insufficient disease control was the most common reason for drug discontinuation (18.2%, n = 33). There was a significant reduction in the number of corticosteroid users at follow-up in both originator (rate ratio: 0.33, 95% confidence interval (CI): 0.16-0.49) and biosimilar users (rate ratio: 0.22, 95% CI: 0.14-0.30). With our limited power, we were unable to detect significant reductions in ER visits and hospitalizations in the first year after initiation of anti-TNF agents compared to that in the preceding year. The severity of pain/discomfort anywhere and the frequency of fatigue and anxiety/depression was not significantly reduced at 12 months in either of the groups. The percentage of those reporting moderate/severe abdominal pain was reduced among biosimilar users (46% to 20%; rate ratio of 0.26, 95% CI: 0.15-0.38), and originator users (28% to 13%, rate ratio 0.16, 95% CI: -0.02, 0.33). The proportion of those reporting rectal urgency at least some of the time was also reduced among both originators (30% at baseline to 9% at follow-up) and biosimilar users (33% to 17%). There was a significant improvement in QoL scores among both originator users (mean difference (MD) 13.0, 95% CI: 6.00-22.0) and biosimilar users (MD 10.0, 95% CI: 6.00-14.0) on the SIBDQ. This improvement was replicated on the EQ-5D only among biosimilar users. Conclusions Our study results suggest that even though the use of anti-TNF drugs leads to improvement in QoL, there may be no reduction in some symptoms, such as fatigue, anxiety, depression. Funding Agencies CIHR

Real-world effectiveness of a single conventional disease-modifying anti-rheumatic drug (cDMARD) plus an anti-TNF agent versus multiple cDMARDs in rheumatoid arthritis: a prospective observational study.

The objective of this prospective, observational multicenter study (NCT03264703) was to compare the effectiveness of single conventional disease-modifying anti-rheumatic drug (cDMARD) plus anti-tumor necrosis factor (TNF) therapy versus multiple cDMARD treatments in patients with moderate-to-severe rheumatoid arthritis (RA) following cDMARD failure in the real-world setting in South Korea. At the treating physicians' discretion, patients received single cDMARD plus anti-TNF therapy or multiple cDMARDs. Changes from baseline in disease activity score 28-joint count with erythrocyte sedimentation rate (DAS28-ESR), corticosteroid use, and Korean Health Assessment Questionnaire (KHAQ-20) scores were evaluated at 3, 6, and 12 months. Of 207 enrollees, the final analysis included 45 of 73 cDMARD plus anti-TNF and 91 of 134 multiple-cDMARD recipients. There were no significant between-group differences (BGDs) in ANCOVA-adjusted changes from baseline in DAS28-ESR at 3, 6 (primary endpoint), and 12 months (BGDs -0.18, -0.38, and -0.03, respectively). More cDMARD plus anti-TNF than multiple-cDMARD recipients achieved a >50% reduction from baseline in corticosteroid dosage at 12 months (35.7% vs 14.6%; p=0.007). Changes from baseline in KHAQ-20 scores at 3, 6, and 12 months were significantly better with cDMARD plus anti-TNF therapy than with multiple cDMARDs (BGD -0.18, -0.19, and -0.19 points, respectively; all p≤0.024). In the real-world setting, relative to multiple cDMARDs, single cDMARD plus anti-TNF therapy significantly improved quality-of-life scores and reduced corticosteroid use, with no significant BGD in disease activity, in RA patients in whom previous cDMARD therapy had failed.

Infliximab is an effective option in patients with ulcerative colitis previously exposed to full subcutaneous anti-TNF agent: Results from a real-world multicenter study

BackgroundData on infliximab efficacy in bio-exposed patients with ulcerative colitis (UC) are limited. AimsTo evaluate infliximab effectiveness and its predictors in UC patients with prior exposure to subcutaneous (SC) anti-TNF agent. MethodsIn this multicenter retrospective study (8 centers), we included all consecutive UC patients with prior exposure to subcutaneous anti-TNF, starting infliximab for symptomatic UC, excluding acute severe colitis. Corticosteroid-free clinical remission (CFREM) was assessed at week 14 (W14) and W52 while endoscopic improvement (CFREM + endoscopic Mayo score≤1) was evaluated at W14. ResultsOverall, 104 patients were included (pancolitis=54.8%, primary failure to subcutaneous anti-TNF=57.4%, concomitant immunosuppressant=53.8%, median partial Mayo score at baseline=7[5–8]). The rate of CFREM was 33.6% (35/104) at W14 and 40.4% (42/104) at W52. At W14, endoscopic improvement was achieved in 29.8%(31/104). In multivariable analysis, concomitant immunosuppressant was associated with higher rate of CFREM at W14(OR=2.83[1.06–7.54], p = 0.037) and W52(OR=2.68[1.16–6.22];p = 0.021), while primary failure to a previous subcutaneous anti-TNF agent led to lower rate of CFREM at W14 (OR=0.37[0.14–0.98], p = 0.046). After a median follow-up of 20.9 months[11.7–33.7]), 50.0%(52/104) patients had discontinued infliximab. ConclusionInfliximab is an effective option in UC patients previously exposed to prior subcutaneous anti-TNF agent and should be used with concomitant immunosuppressant.

Biological Agents in the Treatment of Crohn's Disease: A Propensity Score-Matched Analysis From the Prospective Persistence Australian National IBD Cohort (PANIC3) Study.

Comparative effectiveness research provides data on the relative benefits and risks between treatments. In Crohn's disease (CD), however, there are few head-to-head studies comparing advanced therapies and none with long-term follow-up. Real-world effectiveness, defined by treatment persistence, obtained from prospective population-based patient cohorts, may help determine the best sequencing and positioning of biological agents. We analyzed the prospectively collected population-based Australian national Pharmaceutical Benefits Scheme dispensing data registry (2005-2019) for CD. There is no mandated biological agent prescribing order, and all citizens and permanent residents are eligible for treatment irrespective of insurance status. Propensity score matching was performed to reduce selection bias. There were 2,029 lines of therapy in 1,446 patients (median age 43 years, interquartile range 34-58, 44% male patients) over the 15-year period with 5,618 patient-years of follow-up. Per line of therapy, 915/2,029 (45.1%) patients used adalimumab, 722/2,029 (35.6%) used infliximab, 155/2,029 (7.6%) used vedolizumab, and 237/2,029 (11.7%) used ustekinumab. When used in biological agent-naive patients, there was no difference in persistence between any agent ( P > 0.05). Used after first line in biological agent-experienced CD, ustekinumab had significantly better persistence than non-ustekinumab biological agents ( P = 0.0018), vs anti-tumor necrosis factor (TNF) alpha therapy ( P = 0.006) or vedolizumab ( P < 0.001). Ustekinumab persistence was unaffected by prior biological agent exposure ( P = 0.51). After anti-TNF use, ustekinumab had superior persistence to an alternative anti-TNF agent ( P = 0.033) and to vedolizumab ( P = 0.026). Using a propensity score-matched analysis adjusted for age, immunomodulator use, and bio-exposed status, ustekinumab had superior persistence to anti-TNF ( P = 0.01). Multivariate predictors of worse persistence were the use of a non-ustekinumab biological agent (adjusted hazard ratio 2.10, P < 0.001), and bio-experienced status (adjusted hazard ratio 1.23, P < 0.001). This large national prospective database with nonhierarchical prescribing of biological agents did not identify superior persistence of any agent in bio-naive CD. However, for patients with bio-experienced CD, persistence was greater with ustekinumab.

SAFETY OF ANTI-TUMOR NECROSIS FACTOR AGENTS COMPARED TO USTEKINUMAB AND VEDOLIZUMAB IN ELDERLY PATIENTS WITH ULCERATIVE COLITIS

Abstract BACKGROUND Common first-line treatments for ulcerative colitis (UC) currently include anti-tumor necrosis factor (anti-TNF) agents, ustekinumab (interleukin-12/interleukin-23 receptor antagonist), and vedolizumab (integrin antagonist). However, there are safety concerns when prescribing biologic therapies to elderly patients. While these medications have all demonstrated general efficacy and safety in UC, this study aims to examine the long-term comparative safety of anti-TNF agents with vedolizumab and ustekinumab in elderly patients with UC. METHODS The Research Network on TriNetX database was accessed on September 26, 2023, to identify patients at least 65 old who were diagnosed with UC: the first cohort included patients prescribed anti-TNF agents (included adalimumab, certolizumab pegol, golimumab, and infliximab) and the second cohort included patients prescribed either vedolizumab or ustekinumab. Primary outcomes included mortality, corticosteroid use, subsequent colectomy, colon cancer, infections, and all-cause hospitalizations within 10 years after matching for age, sex, and race. All analyses were performed in real-time using built-in statistical algorithms on TriNetX. RESULTS After matching cohorts, 1,075 elderly patients with UC patients were included in each cohort as shown in table 1. Patients who were prescribed anti-TNF therapy had a significantly increased 10-year risk of mortality (10.7%) compared to patients on either vedolizumab or ustekinumab therapy (5.77%) (OR 1.96, 95% CI [1.42, 2.7], p &amp;lt;0.0001). Corticosteroid use was higher in the anti-TNF cohort (40.6% vs 34.9%, p= 0.007). There were no significant differences between the two cohorts when comparing the need for colectomy (3.26% vs 2.23%, p = 0.15) or colorectal cancer occurrence (1.67% vs 2.05%, p=0.52) within 10 years. However, the anti-TNF cohort had a higher risk of all-cause hospitalization (32.5 % vs 22%, p=&amp;lt;0.0001), respiratory tract infections (18.4% vs 14.5%, p=0.015), and urinary tract infections (10.4% vs 7%, p=0.005). CONCLUSION In elderly patients with UC, ustekinumab or vedolizumab are safer treatment options compared to anti-TNF therapy. Table 1 Demographics and Comparative 10-year Outcomes of Elderly Patients with UC.

LOWER MORTALITY RISK WITH COMBINATION THERAPY WITH ANTI-TNF THERAPY AND THRIOPURINE COMPARED TO THIOPURINE ALONE IN ELDERLY PATIENTS WITH UC

Abstract INTRODUCTION Despite increasing incidence rates of ulcerative colitis (UC) in the elderly, efficacy and safety data for medical management in this cohort is lacking due to underrepresentation in clinical trials and registries. Selection of medical therapy is often complex, taking into consideration a multitude of factors, including real and perceived risks of infection and malignancy. In the past, immunomodulators, such as thiopurines, were commonly used as monotherapy for maintenance, offering the added advantages of affordability and oral administration. Indeed, there are elderly patients who have been maintained for decades on thiopurine monotherapy. Further, thiopurines can be used in combination with anti-TNF therapy for improved efficacy and reduced immunogenicity compared to monotherapy with either agent in ulcerative colitis (UC). Whether the use of combination therapy imposes an additive risk compared to thiopurine monotherapy is still unclear. This study aimed to investigate outcomes of thiopurine monotherapy versus combination therapy with anti-TNF agents in elderly patients (age ≥65 years) with UC. METHODS The TriNetX Research Network was accessed on October 15th, 2023, to compare outcomes in elderly patients 65 years or older with UC who are receiving thiopurine monotherapy and patients who are receiving combination therapy with an anti-TNF (adalimumab, certolizumab pegol, golimumab, or infliximab). The outcomes examined were 1-year rate of corticosteroid and colectomy as well as 10-year rate of mortality, colon cancer, skin cancer, and respiratory and urinary tract infections. Statistical risk analysis was performed using the TriNetX analytical platform. RESULTS A total of 2,597 patients (2,245 thiopurines monotherapy and 352 AZA plus anti-TNF combination therapy) were included in the study (Table 1). Among the monotherapy and combination therapy cohorts, mean age was 71 years old and approximately 56% male. Ten-year mortality was higher in the thiopurine monotherapy group (OR 1.67, p=0.002). The combination therapy cohort had higher rates of steroid use (32.4% vs. 24.3%, p=0.001) and colectomy at 1 year compared to the monotherapy cohort (4.5% vs. 1.2%, p&amp;lt;0.001). There was no significant difference in 10-year risk of colon cancer (OR 1.05, p=0.88), skin cancer (OR 1.51, p=0.06), incidence of respiratory (OR 1.48, p=0.07) and urinary tract infections (OR 1.18, p=0.23). CONCLUSION The study findings highlight the risks of thiopurine use in patients over the age of 65 given the significantly higher 10-year mortality risk in thiopurine monotherapy-treated patients. The results also suggest that combination therapy with thiopurine and anti-TNF therapies - despite utilization in patients with more active disease indicators - is not associated with an additive risk in terms of infection and mortality in elderly patients. Table 1 Characteristics and Outcomes of Elderly Patients with UC either on Thiopurine Monotherapy or Combination Therapy with anti-TNF agents

HERMANSKY-PUDLAK SYNDROME-ASSOCIATED INFLAMMATORY BOWEL DISEASE: A SYSTEMATIC REVIEW ON CLINICAL MANIFESTATIONS AND INVESTIGATIONS INTO OPTIMAL MANAGEMENT

Abstract Hermansky-Pudlak Syndrome (HPS) is a rare autosomal condition resulting from a mutation in 1 of at least 7 different genes leading to the triad of tyrosine-positive oculocutaneous albinism, platelet dysfunction leading to prolonged bleeding time, and ceroid lipofuscin within the reticuloendothelial system. The latter of these can result in systemic derangements including renal failure, pulmonary fibrosis, cardiomyopathy, and a disabling granulomatous colitis. This colitis is a unique type of inflammatory bowel disease (IBD) with complications such as intestinal fistulization, ileitis, enterocolitis and perianal disease. There is data to suggest that HPS colitis is due to the development of classical IBD. However, optimal management remains undetermined. Our systematic review aims to analyze the clinical presentation behind HPS colitis, endoscopic versus histopathological findings, and ultimate treatment plans required for optimal management of this disease among HPS genotypes. A comprehensive literature review was conducted on patients with HPS and its associated colitis manifestations from inception to August 2023. Analyses on patient demographics, clinical presentation, HPS genotype, endoscopic versus histopathological findings, medical versus surgical interventions were thoroughly performed. Six cohort studies on HPS patients with coexisting colitis were identified. A total of 84 patients comprised these studies with mean age 32 +/- 9.65. Racial breakdowns were 68% Puerto Rican, 23% white, 4% Indian, 2% Mexican, 1% Honduran, and 1% African American. 59 patients had the HPS-1 genotype, 8 with HPS-3, 3 with HPS-4, and 1 with HPS-6. The most common presenting symptoms were hematochezia (37%), diarrhea (23%), abdominal pain (16%), and constipation (10%). Endoscopic evaluation showed normal gross findings in 65% of cases and abnormalities in only 35%. However, IBD-associated histopathological positivity was more prevalent with the most common findings being granulomas (33%), macrophages without colitis (19%), macrophages with colitis (15%), and lymphoid aggregates (10%). Medical therapy was initiated in 48 cases with the most common medications being steroids (46%), followed by anti-TNFa agents (40%), and immunomodulators (35%). 28 cases required surgical intervention with the most common operation performed being a (subtotal) colectomy and ileostomy. There were scattered cases of laparoscopic loop ileostomies, total colectomies, and proctocolectomies too. Interestingly, 10 patients received no intervention whatsoever. HPS-associated colitis is a debilitating condition that remarkably resembles IBD. There is no consensus on optimal therapy and many patients ultimately require operative intervention. The HPS-1 gene appears to be highly prevalent in this condition and younger patients are more affected, however more research is needed.

P1002 De novo and drug-induced skin manifestations in Inflammatory Bowel Disease patients: The impact of anti-tumour necrosis factor therapy

Abstract Background Skin disorders in inflammatory bowel disease (IBD) consist of extra-intestinal manifestations (EIM) or drug-induced lesions. This study explores de novo skin lesions and the emergence of immune-mediated skin disorders induced by anti-tumour necrosis factor (anti-TNF) agents. Methods Patients with EIMs, de novo skin lesions, and drug-induced skin eruptions were identified from an IBD patient database on advanced therapies. Data on time intervals from the initiation of IBD treatment to the development of skin disorders, causative agents, and subsequent management were collected. Results In a cohort of 1,773 patients (993 with ulcerative colitis, 746 with Crohn’s disease, and 31 with IBD unclassified), 30% (549) exhibited skin manifestations, with 28% (491 cases) showing de novo skin conditions. Identified skin manifestations included psoriasis/psoriasiform rash (18.3%), eczema (16.3%), seborrheic dermatosis (13.8%), acne (9.8%), actinic keratosis (5.3%), rosacea (4.7%), erythema nodosum (EN, 3.5%), cutaneous Crohn's disease (CCD, 2.6%), folliculitis (1.8%), pyoderma gangrenosum (PG, 1.5%), and others. Of the skin lesions, 31.8% (175) occurred before the IBD diagnosis, with a median duration of 8 years, while 51.9% (286) developed post-diagnosis unrelated to therapies. Biologic therapies improved extraintestinal skin lesions in 19 patients (3.4%). Notably, all 3 EN cases and 4 out of 5 PG cases achieved full resolution with biological treatments, leading to improved IBD activity. Similarly, 9 out of 10 Crohn’s disease patients with CCD showed improved skin conditions following biological treatments Fifty-eight patients (3.3%) experienced drug-induced skin lesions, with a median age at IBD diagnosis of 35 years (ranging from 17 to 67). The majority (91.3%) of cases were attributed to anti-TNF agents, and psoriasiform lesions were the most prevalent (60.3%). The median duration from treatment initiation to the onset of drug-induced skin lesions was 23 months (ranging from 0 to 115 months). Among the affected individuals, 19 using originator anti-TNF agents developed skin lesions, with 13 having psoriatic lesions. In comparison, 34 patients on biosimilar anti-TNF agents developed skin lesions, and 23 of them had psoriatic lesions. The progression of skin lesions led to anti-TNF discontinuation in 33 patients, of whom 25 transitioned to Vedolizumab or Ustekinumab. Resolution occurred in 22 patients. Conclusion Anti-TNF-induced skin lesions, notably psoriasiform lesions, appear to be more prevalent in the biosimilar era among IBD patients, often leading to discontinuation. Nevertheless, resolution is possible through strategic switches to alternative biologic agents.