Anti-tumor Necrosis Factor Alpha Agents Research Articles

Outcomes of Intravenous Tocilizumab Treatment for Refractory Pars Planitis

ABSTRACT Purpose To evaluate outcomes of intravenous (IV) tocilizumab (TCZ) in patients with pars planitis refractory to conventional immunomodulatory therapy and anti-tumor necrosis factor (TNF) alpha agents. Methods Medical records of eight patients diagnosed with pars planitis and treated with monthly 4 or 8 mg/kg IV TCZ were reviewed. The primary objective was to initiate and sustain remission continuously for three consecutive months. Secondary outcome measures were changes in best corrected visual acuity (BCVA), degree of anterior chamber (AC) inflammation, vitreous cell, vitreous haze, presence of vitreous or pars plana exudates, peripheral vasculitis, fluorescein angiography (FA) score and central subfieldthickness (CST) on macular optical coherence tomography (OCT). Results Fourteen eyes of eight patients were treated with IV TCZ. Seven patients were women. The average age was 31.35 ± 16.42 years. In 6 (75%) out of 8 patients, IV TCZ, either as monotherapy or in combination with another conventional immunomodulatory agent, induced and sustained remission. The average FA score reduced from 11.15 ± 3.52 at the baseline visit to 6.50 ± 2.12 at the one-year follow-up visit (p-value < 0.05). None of the patients experienced any side effects of IV TCZ. Conclusion IV Tocilizumab (TCZ) may represent an effective and safe treatment option for patients diagnosed with pars planitis resistant to conventional immunomodulatory therapy and anti-TNF alpha agents.

Therapeutic sequencing in inflammatory bowel disease: Determining the optimal position of vedolizumab for long-term Crohn's disease control using real-world evidence.

Several biologics are available for the treatment of moderate to severe Crohn's disease, but data to optimize their use are scarce. Vedolizumab (VDZ) is a gut-selective anti-lymphocyte trafficking monoclonal antibody that was approved in 2014 for the treatment of moderate to severe Crohn's disease. Based on real-world evidence, a model was developed to examine the effect of VDZ's position in the treatment sequence on clinical outcomes. The aim of this study was to develop a model using real-world data to investigate how the positioning of VDZ in a sequence of biologic therapies for CD affects clinical effectiveness outcomes of quality-adjusted life-years (QALYS), patient-reported disease activity, and surgery rates. A semi-Markov sequential model was developed to identify the optimal position of VDZ in a treatment sequence that included corticosteroids (CS), two biologics, and best supportive care (BSC). Using real-world data, three sequences were compared: VDZ as first (position), second, and last biologic (with anti-tumor necrosis factor alpha agents adalimumab (ADA) and infliximab (IFX) and the anti-interleukin-12 and -23 agent ustekinumab (UST) as alternative biologic treatments). Published real-world evidence informed model inputs. Vedolizumab sequences were compared and ranked based on QALYS, patient-reported outcomes from Crohn's disease activity index scores, or proportion of patients undergoing surgery by the 10-year time horizon for model simulation. Sensitivity analyses were used to evaluate the impact of model input uncertainty. Vedolizumab as the first biologic was the optimal position for this treatment according to all criteria, including yielding the highest QALYs (5.09) versus VDZ in second (4.97) and third (4.96) biologic sequence positions in sequences containing CS, anti-TNFα (aggregated data), UST, and BSC; 1780/2000 (89%) probabilistic simulations. In sequences containing ADA, VDZ, and UST biologics, ADA and VDZ in the first-line biologic position yielded QALYs of 5.09 versus 5.07, respectively. Adalimumab as the first biologic was best for clinical remission. This simulation model using real-world evidence indicates that positioning VDZ or ADA as the first biologic is likely to lead to improved long-term patient outcomes when compared to administering these treatments later or starting with IFX monotherapy.

Stratified Patient Profiling for Vedolizumab Effectiveness in Crohn's Disease: Identifying Optimal Subgroups for Enhanced Treatment Response in the EVOLVE Study.

This analysis evaluated the relative performance of vedolizumab and anti-tumor necrosis factor alpha (anti-TNFα) agents in subpopulations of biologic therapy-naive patients with Crohn's disease (CD) and assessed whether patients in whom vedolizumab would have a larger treatment effect vs anti-TNFα agents could be identified. Data were from EVOLVE, a real-world, multicountry, retrospective cohort study of patients with inflammatory bowel disease who initiated first-line biologic treatment with vedolizumab (n = 195) or anti-TNFα agents (n = 245). Prediction models for time to clinical remission were developed in vedolizumab- and anti-TNFα-treated patients and used to estimate effect scores, a metric of predicted comparative efficacy, for each patient. Patients were ranked by effect scores and potential subpopulations were investigated. Simplified rules to identify these subpopulations were also developed using classification tree analysis. Among all patients, median time to clinical remission was 7.8months (vedolizumab) and 11.1months (anti-TNFα) (P < 0.05). Among patients in the top 40% of the effect score distribution, the median time to clinical remission was 4.8months (vedolizumab) vs 18.1months (anti-TNFα) (adjusted hazard ratio 2.0, 95% confidence interval 1.3-2.9). A simplified rule for identifying a subpopulation more likely to benefit from vedolizumab was based on having an ongoing CD exacerbation, no prior emergency visits, and non-stricturing disease. Subpopulations of biologic-naive patients with CD in whom vedolizumab appeared to have a larger effect relative to anti-TNFα agents for the outcome of clinical remission were identified. Validation of the identified subpopulations and simplified rules are warranted to confirm these findings. NCT03710486. Graphical Abstract available for this article.

Real-world efficacy and safety of tofacitinib treatment in Asian patients with ulcerative colitis.

Real-world data on tofacitinib (TOF) covering a period of more than 1 year for a sufficient number of Asian patients with ulcerative colitis (UC) are scarce. To investigate the long-term efficacy and safety of TOF treatment for UC, including clinical issues. We performed a retrospective single-center observational analysis of 111 UC patients administered TOF at Hyogo Medical University as a tertiary inflammatory bowel disease center. All consecutive UC patients who received TOF between May 2018 and February 2020 were enrolled. Patients were followed up until August 2020. The primary outcome was the clinical response rate at week 8. Secondary outcomes included clinical remission at week 8, cumulative persistence rate of TOF administration, colectomy-free survival, relapse after tapering of TOF and predictors of clinical response at week 8 and week 48. The clinical response and remission rates were 66.3% and 50.5% at week 8, and 47.1% and 43.5% at week 48, respectively. The overall cumulative clinical remission rate was 61.7% at week 48 and history of anti-tumor necrosis factor-alpha (TNF-α) agents use had no influence (P = 0.25). The cumulative TOF persistence rate at week 48 was significantly lower in patients without clinical remission than in those with remission at week 8 (30.9% vs 88.1%; P < 0.001). Baseline partial Mayo Score was significantly lower in responders vs non-responders at week 8 (odds ratio: 0.61, 95% confidence interval: 0.45-0.82, P = 0.001). Relapse occurred in 45.7% of patients after TOF tapering, and 85.7% of patients responded within 4 wk after re-increase. All 6 patients with herpes zoster (HZ) developed the infection after achieving remission by TOF. TOF was more effective in UC patients with mild activity at baseline and its efficacy was not affected by previous treatment with anti-TNF-α agents. Most relapsed patients responded again after re-increase of TOF and nearly half relapsed after tapering off TOF. Special attention is needed for tapering and HZ.

Safety profile and side effects of infliximab and adalimumab in inflammatory bowel disease at a referral center in northeastern Brazil

Introduction: Anti-tumor necrosis factor-alpha agents (Anti-TNF-alpha) are an effective treatment option in patients with moderate and severe inflammatory bowel disease (IBD). Objectives: To evaluate safety profile of infliximab (IFX) and adalilumab (ADA) in IBD patients over a 10-year period at a referral center in Northeastern Brazil. Methodology: The medical records of 123 patients, of whom 104 (84.5%) had Crohn’s disease and 19 (15.4%) had ulcerative colitis, were reviewed for side effects associated with the use of IFX (n=83) and ADA (n=40). Results: Thirty-one patients (25%) experienced side effects (IFX n=21; ADA n=10) (p=0.971), 15 (48%) of which were severe (IFX n=10; ADA n=5) (p=0.942). Acute reactions occurred in 9 patients (7.3%), infections in 13 (10%), malignancies in 3 (2,4%), psoriasis in 4 (3,2%), in addition to 3 deaths (2,4%). Conclusion: The frequency of side effects was similar for IFX and ADA. Both drugs are safe in the treatment of IBD, but careful screening and monitoring are necessary to identify and follow patients at risk of severe side effects.

Safety profile and side effects of infliximab and adalimumab in inflammatory bowel disease at a referral center in northeastern Brazil

Introduction: Anti-tumor necrosis factor-alpha agents (Anti-TNF-alpha) are an effective treatment option in patients with moderate and severe inflammatory bowel disease (IBD). Objectives: To evaluate safety profile of infliximab (IFX) and adalilumab (ADA) in IBD patients over a 10-year period at a referral center in Northeastern Brazil. Methodology: The medical records of 123 patients, of whom 104 (84.5%) had Crohn’s disease and 19 (15.4%) had ulcerative colitis, were reviewed for side effects associated with the use of IFX (n=83) and ADA (n=40). Results: Thirty-one patients (25%) experienced side effects (IFX n=21; ADA n=10) (p=0.971), 15 (48%) of which were severe (IFX n=10; ADA n=5) (p=0.942). Acute reactions occurred in 9 patients (7.3%), infections in 13 (10%), malignancies in 3 (2,4%), psoriasis in 4 (3,2%), in addition to 3 deaths (2,4%). Conclusion: The frequency of side effects was similar for IFX and ADA. Both drugs are safe in the treatment of IBD, but careful screening and monitoring are necessary to identify and follow patients at risk of severe side effects.

Tissue markers may predict treatment response to antitumor necrosis factor-α agents in children with Crohn's disease.

Patients with moderate-severe Crohn's disease (CD) who are treated with antitumor necrosis factor alpha (TNF-α) agents may be subjected to primary nonresponse or partial response. We aimed to identify tissue markers that may predict response to these agents. Pediatric patients (6-18 years) with either ileal or ileo-colonic CD who were treated with anti-TNF-α were stratified into three different groups based on their overall response to therapy at the end of induction including clinical and laboratory parameters (group 1-full responders [FR], group 2-partial responders [PR], group 3-nonresponders [NR]). Seven tissue markers (fibronectin, interleukin [IL]-23R, IL-23, TNF-α, collagen-III, IL-13R, and hypoxia-inducible factors [HIF]-1α) were evaluated. Immunofluorescence (IF) analyses were performed on biopsies from the terminal ileum, which were retrieved up to 6 months before treatment initiation. Twenty-six CD patients (16 [61.5%] males; age 13.9 ± 2.9 years), including 8 (30.8%) with ileal disease and 18 (69.2%) with ileo-colonic disease, were enrolled. Terminal ileum biopsies from nine patients from group 1, nine from group 2, and eight from group 3 were evaluated. Three antibodies were found to be significantly different between NR and FR groups; Collagen III and fibronectin stains were significantly more prominent in NR patients, while TNF-α stain was significantly more pronounced in FR, p < 0.05 for each. PR could not have been predicted with neither of markers. Decreased tissue IF intensity of fibronectin and collagen III and increased intensity of TNF-α may predict response to anti-TNF-α treatment.

P468 Relevance of anti-drug antibodies in context of supra-therapeutic anti-TNF concentrations

Abstract Background The low serum concentration of anti-tumor necrosis factor-alpha (anti-TNFα) agents and the presence of anti-drug antibodies are related to poor therapeutic outcomes in inflammatory bowel disease (IBD). We aimed to evaluate the prognosis of patients having both antidrug antibodies and supratherapeutic drug concentrations. Methods IBD patients on maintenance infliximab (IFX) or adalimumab (ADA) therapy were prospectively recruited. Serum drug concentrations and antidrug antibodies were measured (Anser, Prometheus). The drug concentrations were classified as subtherapeutic (IFX: &amp;lt;3 µg/mL; ADA: &amp;lt;5 µg/mL), therapeutic (IFX: 3-8 µg/mL; ADA 5-10 µg/mL), and supratherapeutic (IFX &amp;gt; 8 µg/mL; ADA &amp;gt; 10 µg/mL) concentrations regardless of the timing of blood sample collection. We analysed the relationship between i) drug concentrations and ii) the presence and absence of anti-drug antibodies with use of systemic corticosteroids and anti-TNF discontinuation. Results Of 172 patients (122 CD [70.9%], 44 UC [25.6%], 3 IBD-U [1.7%], and 3 IBD-pouch [1.7%]), the median age was 32.3 years (range, 24.8-42.5), and the median duration of IBD was 9.7 years (range 5.3-15.6). IFX and ADA were used in 81 (47.1%) and 91 (52.9%) patients, respectively, and concurrent usage of immunomodulators and systemic corticosteroids was observed in 39 (22.7%) and 23 (13.4%) patients, respectively. Supratherapeutic, therapeutic, and subtherapeutic concentrations were observed in 74 (43.0%), 32 (18.6%), and 66 (38.4%), respectively. The patients with antidrug antibodies (n = 79, 45.9%) showed a higher frequency of having subtherapeutic drug concentrations (68.4% vs 12.9%, P &amp;lt; 0.001) compared to those without antibodies, and the presence of antibodies was an independent predictor of discontinuation of anti-TNFα agents (hazard ratio 3.50, 95% confidence interval 1.88-6.51, P &amp;lt; 0.001, Fig. 1A). In subgroup analysis, patients with antidrug antibodies and supratherapeutic drug concentration exhibited a tendency to have improved drug persistence compared to those with subtherapeutic drug concentration, albeit insignificantly (P = 0.099, Fig. 1B). However, the persistence in this group was still poorer than that observed in patients without antibodies (P = 0.003). Finally, neither anti-TNFα concentrations nor the presence of antidrug antibodies were associated with the need for additional systemic corticosteroid use within 6 months. Conclusion The presence of antidrug antibodies can predict the discontinuation of anti-TNFα agents despite supratherapeutic drug levels. While supratherapeutic drug concentration may improve the treatment persistence of anti-TNFα agents in patients with anti-drug antibodies, it does not last as long as in those without antibodies.

Maternal and Neonatal Outcomes in Vedolizumab and Ustekinumab Exposed Pregnancies: Results from the PIANO registry.

Pregnancy outcomes in inflammatory bowel disease (IBD) patients with quiescent disease are similar to the general population. Data from the Pregnancy Inflammatory bowel disease And Neonatal Outcomes (PIANO) registry have demonstrated the safety of anti-tumor necrosis factor alpha (TNFs) agents and thiopurines in pregnancy. The objective of this study was to provide information from the PIANO registry on maternal and fetal outcomes in patients exposed to the newer biologics ustekinumab (UST) and vedolizumab (VDZ). In this multicenter prospective observational study, we included pregnant women with singleton pregnancies and a diagnosis of IBD. Questionnaires were administered to women at study intake, each subsequent trimester, delivery, and at 4, 9, and 12 months after birth. Bivariate analyses were utilized to determine the independent effects of specific drug classes on outcomes. The exposure cohorts were VDZ, UST, anti-TNFs, immunomodulators, and combination with anti-TNFs and immunomodulators. All were compared to no exposure and to biologics/immunomodulators. There were 1669 completed pregnancies with 1610 live births. Maternal mean age was 32.1 (SD 4.6) years at delivery with 66 VDZ and 47 UST exposed. Women on UST were more likely to have Crohn's disease. There was no increased risk of spontaneous abortion, small for gestational age, low birth weight, neonatal intensive care unit stay, congenital malformations, or intrauterine growth restriction with in utero VDZ or UST exposure. The rate of preterm birth was lower (0.0%) for UST-exposed as compared to other groups including VDZ (13.8%), anti-TNF (8.2%), combination therapy (14.2%), immunomodulator (12.3%), and unexposed (9.7%)(p = 0.03). Rates of serious infections at birth, 4 months, and within the first 12 months of life were comparable among all groups. Nonserious infections were lower at 12 months in UST exposed pregnancies. There was no increased risk signal for placental complications in the VDZ cohort. UST infant concentrations at birth were increased whereas VDZ concentrations were overall decreased compared to maternal serum drug concentration. This analysis of UST and VDZ exposure during pregnancy suggests no increase in complications compared to TNFs, immunomodulators and combination TNFs/immunomodulators. No signal was found for increased placental events with either therapy. Continuation of UST and VDZ throughout pregnancy is recommended.

Efficacy of Combined Initial Treatment of Methotrexate with Infliximab in Pediatric Crohn's Disease: A Pilot Study.

The combination of antitumor necrosis factor-alpha (TNF-α) agents with immunomodulators (IMMs) is a common treatment for pediatric Crohn's disease (CD). Although methotrexate (MTX) can be a first-line medication as an IMM, most clinicians in real-life practice, especially in South Korea, are more familiar with thiopurines. This study aimed to compare the efficacy and immunogenicity of MTX and azathioprine (AZA) as concurrent therapies for pediatric CD. In this pilot study, 29 newly diagnosed pediatric patients with moderate-to-severe CD were randomized to receive either MTX (n = 15) (15 mg/body surface area (BSA) per week) or oral AZA (n = 14) (0.5 mg/kg per day) in combination with Infliximab (IFX). The primary outcomes were the proportion of patients in endoscopic, biochemical, and transmural remission after 14 and 54 weeks of IFX therapy. The trough levels (TLs) of IFX and anti-drug antibody (ADA) levels were also compared. Among the 29 patients, there were no significant differences in the biochemical (p = 1.0 at week 14, p = 0.45 at week 54), endoscopic (p = 0.968 at week 14, p = 0.05 at week 54), or transmural (p = 0.103 at week 54) remission rates between the two medications during the concurrent therapy. Additionally, the trends in the IFX trough and ADA levels over time during the treatments were similar for both medications, with no significant differences (p = 0.686, p = 0.389, respectively). The MTX showed comparable efficacy to the AZA in pediatric CD patients with moderate-to-severe disease. This effectively maintained adequate IFX levels and reduced ADA production. Therefore, although additional large-scale clinical trials are needed, this study demonstrated that either MTX or AZA can be selected as IMMs in the concurrent treatment of pediatric CD, depending on individual medical institutions' circumstances.

Black Inflammatory Bowel Disease Patients Have Lower Response to Antitumor Necrosis Factor Agents Compared With White Patients.

Most studies on the safety and efficacy of antitumor necrosis factor alpha (anti-TNF) agents in the treatment of inflammatory bowel disease have included few Black patients. We aimed to evaluate the therapeutic response rate in Black IBD patients compared with White patients. We conducted a retrospective review of IBD patients who were treated with anti-TNF agents and assessed those with therapeutic drug levels for clinical, endoscopic, and radiologic response to anti-TNF treatment. We identified 118 patients who met the inclusion criteria. Black IBD patients had significantly higher prevalence of endoscopic and radiologic active disease compared with White patients (62% and 34%, respectively; P = .023), despite similar proportions reaching therapeutic titers (67% and 55%, respectively; P = .20). Moreover, Black patients had significantly higher rate of IBD-related hospitalizations than White patients (30% vs 13%, respectively; P = .025) while on anti-TNF agents. Black IBD patients on anti-TNF agents had a significantly higher prevalence of active disease and more IBD-related hospitalizations than White patients.

P358 Long-term clinical outcomes of intestinal Behçet’s disease: a 30-year cohort study at a tertiary hospital in South Korea

Abstract Background Long-term clinical data on intestinal Behçet’s disease (BD) are scarce because of the rarity of this disease, and many issues remain unresolved due to the difficulty in performing a well-designed clinical trial or epidemiologic study. We aimed to investigate the long-term clinical outcomes of patients with intestinal BD with a 30-year cohort study at a tertiary hospital in South Korea, a hospital with the largest number of patients with intestinal BD worldwide. Additionally, we aimed to identify factors that could predict various clinical outcomes, including anti-tumor necrosis factor-alpha (anti-TNF-α) agent use, intestinal surgery, hospitalization, and emergency room visits. Methods A cohort of 780 patients with intestinal BD between 1997 and 2021 was investigated to determine the long-term clinical outcomes and prognostic factors at the inflammatory bowel disease Clinic of Severance Hospital, Seoul, Korea. Results During the median follow-up period of 12.7 ± 7.2 years, 5-aminosalicylic acids, corticosteroids, immunomodulators, and anti-tumor necrosis factor-alpha (TNF-α) agents were required in 94.9%, 67.2%, 43.8%, and 14.6% of the patients, respectively. The cumulative rates of anti-TNF-α use were 3.7%, 7.5%, 8.5%, 12.1%, 17.6%, and 24.0%, and that of abdominal surgery were 5.7%, 10.9%, 12.6%, 16.5%, 21.6%, and 28.3%, at 1, 3, 5, 10, 20, and 30 years, respectively, after the initial diagnosis of intestinal BD. The cumulative rates of hospitalization were 11.8%, 21.9%, 27.9%, 38.8%, 54.4%, and 74.8% and that of emergency room visits were 10.0%, 19.8%, 22.7%, 31.6%, 50.0%, and 65.0% at 1, 3, 5, 10, 20, 30 years. Older age at primary diagnosis, previous appendectomy history, higher disease activity index for intestinal Behçet’s disease score, systemic BD, multiple intestinal ulcers, deep intestinal ulcers, higher C-reactive protein, lower hemoglobin, and lower albumin levels were associated with poor prognosis. Married status, higher body mass index, oral ulceration, and arthritis were negatively associated with a poor prognosis. Conclusion The data on the long-term clinical outcomes of intestinal BD and their prognostic factors could guide physicians for adequate patient monitoring and optimizing individualized treatments.

Free antibodies-to-infliximab are biomarker for predicting the effect of dose intensification in pediatric Crohn's disease patients with secondary loss of response.

Immunogenicity to antitumor necrosis factor alpha agents, such as infliximab (IFX), may lead to therapeutic failure. This study evaluated the relationship between free and total antibodies-to-infliximab (ATIs), trough levels (TLs) of IFX, and the response to dose intensification. We performed a prospective, observational study including pediatric patients with Crohn's disease (CD) receiving IFX maintenance therapy without dose intensification. We compared clinical and laboratory outcomes according to the presence of free and total ATIs. Factors associated with response to IFX dose intensification were investigated by analyzing IFX TLs and free and total ATIs. Of the 98 patients, 9 patients had detectable free ATIs and 38 patients had total ATIs. Patients with free ATIs had significantly lower TLs (0.7 versus 5.1 µg/mL, p < 0.001) than patients without free ATIs. However, there was no difference in the IFX TLs according to the presence of total ATIs (p = 0.2523). Analysis of the 38 samples with total ATIs showed that response to dose intensification was significantly lower in patients with free ATIs than those without free ATIs (22.2% versus 65.5%, p < 0.001). In addition, free ATIs were the only factor with poor response to dose intensification [odds ratio (OR): 14.15, 95% confidence interval (CI): 1.31-151.97, p = 0.0140]. According to the receiver operating characteristic analysis, the optimal cutoff level indicating non-response to IFX dose intensification was 30.0 AU/mL for free ATIs concentration (area under curve, 0.792; 95% CI: 0.590-0.942; sensitivity, 60.0%; specificity, 96.7%; p = 0.0241). Free ATIs, but not total ATIs, have a negative impact on the course of CD. Free ATIs are potential reliable biomarker for predicting the effect of dose intensification in patients with loss of response to IFX. Future studies based on serial and proactive therapeutic drug monitoring are required in the future.

Role of anti-tumor necrosis factor-alpha agents in treatment of sarcoidosis: A meta-analysis

ImportanceAnti-tumor necrosis factor-alpha agent (anti-TNF-α) is considered an effective third-line therapy for refractory sarcoidosis,studies observing the efficacy of anti-TNF-α agents show conflicting results. ObjectiveWe performed an up-to-date systemic meta-analysis to determine effectiveness and further elucidate the role of anti-TNF-α in the treatment of sarcoidosis. Data sourcesA systematic search was carried out in PubMed/Medline, EMBASE, and Cochrane Library for studies reporting the therapeutic effects of anti-TNF drugs on patients with pulmonary and extra-pulmonary sarcoidosis, published up to April 10, 2022. The study was registered in the international prospective register of systematic reviews (PROSPERO) under ID: CRD42022364614. Study selectionClinical trials written reporting the therapeutic effects of anti-TNF drugs on patients with pulmonary and extra-pulmonary sarcoidosis were included. Data extraction and synthesisStatistical analyses were performed with Comprehensive Meta-Analysis software, and the random-effects model was used. The combined overall treatment success was determined for patients with pulmonary and extrapulmonary sarcoidosis. Main outcomes and measuresOverall treatment success rate wasdefined as no disease progression or improvement in symptoms. ResultsEight clinical trial articles were included in the meta-analysis; four used Infliximab, two Etanercept, one Adalimumab, and one Ustekinumab and Golimumab. The mean age of participants was 48.5 years. The duration of drug therapy ranged from 14 to 45 weeks. We found a combined overall treatment success rate, defined as no disease progression or improvement in symptoms, of 69.9% (95% CI 35.0-90.9, I2: 70%) in the pulmonary sarcoidosis group and 74.5% (95% CI 36.3-93.7, I2: 90%) in the extrapulmonary sarcoidosis group. There was no evidence of publication bias in either group. Conclusion and relevanceTreatment of refractory sarcoidosis with anti-TNF-α agents was effective in both pulmonary and extrapulmonary sarcoidosis, with a slightly higher efficacy seen in extrapulmonary sarcoidosis. Further randomized controlled trials should be conducted to determine the effects of anti-TNF-α agents as a part of the management strategy of sarcoidosis. Patients with pulmonary sarcoidosis should be studied separately from patients with extrapulmonary sarcoidosis to adjust for confounding results.

S99 Upadacitinib in the Treatment of Ulcerative Colitis. Initial Real-World Experience From a Tertiary Care Center

Background: Upadacitinib is a selective Janus kinase inhibitor approved by the FDA in March 2022 for the treatment of patients with moderate to severe ulcerative colitis (UC) who have had an inadequate response or intolerance to anti-tumor necrosis factor alpha agents (TNF-a). Methods: This single center retrospective cohort study included adult patients (age >18 years) with moderate to severe UC who were prescribed upadacitinib at the Mayo Clinic, Rochester, Minnesota. After obtaining institutional review board approval, we searched the electronic medical record to identify patients with UC who had previously failed therapy with Anti-TNF-a and were subsequently treated with Upadacitinib. The primary outcome was clinical response as described by patient reported outcomes. Outcomes were assessed at patients’ most recent follow-up. We also evaluated for adverse events. Results: A total of 23 UC patients received upadacitinib and were included in this analysis. The median age at diagnosis was 31 years, (range 23-54 years) and 11 patients were males. Prior medications included Azathioprine (n=5), Vedolizumab (n=15) Ustekinumab (n=12) and Tofacitinib (n=7). Pre-treatment endoscopic severity was graded as Mayo 2 in 11 and Mayo 3 in 12 cases. The median pretreatment Calprotectin and serum C-reactive protein (CRP) were 920 mcg/g (range 200-3469) and 13 mg/L (range 3-36) respectively. Post treatment information is available for 17 patients (last follow up: September 15, 2022). Median treatment duration was 84 day (16-334 days). Clinical improvement was observed in 12 (70.5%) patients. Amongst the 5 cases that did not respond, 3 cases had primary sclerosing cholangitis, 1 underwent colectomy and colectomy is being considered in 2 cases. There were no adverse effects reported with Upadacitinib use. Conclusion(s): In a single center cohort of 23 patients with UC refractory to anti-TNF-a, upadacitinib use resulted in clinical improvement in 70% of patients with no adverse events. Further long-term data is being collected.

The Effect of Anti-Tumor Necrosis Factor-Alpha Therapy within 12 Weeks Prior to Surgery on Postoperative Complications in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

The rate of abdominal surgical interventions and associated postoperative complications in inflammatory bowel disease (IBD) patients is still substantially high. There is an ongoing debate as to whether or not patients who undergo treatment with anti-tumor necrosis factor-alpha (TNF-α) agents may have an increased risk for general and surgical postoperative complications. Therefore, a systematic review and meta-analysis was conducted in order to assess the effect of anti-TNF-α treatment within 12 weeks (washout period) prior to abdominal surgery on 30-day postoperative complications in patients with IBD. The results of previously published meta-analyses examining the effect of preoperative anti-TNF-α treatment on postoperative complications reported conflicting findings which is why we specifically focus on the effect of anti-TNF-α treatment within 12 weeks prior to surgery. PubMed, Cochrane, Scopus, Web of Science, World Health Organization Trial Registry, ClinicalTrials.gov and reference lists were searched (June 1995−February 2022) to identify studies, investigating effects of anti-TNF-α treatment prior to abdominal surgery on postoperative complications in IBD patients. Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated and subgroup analyses were performed. In this case, 55 cohort studies (22,714 patients) were included. Overall, postoperative complications (OR, 1.23; 95% CI, 1.04−1.45; p = 0.02), readmission (OR, 1.39; 95% CI, 1.11−1.73; p = 0.004), and intra-abdominal septic complications (OR, 1.89; 95% CI, 1.44−2.49; p < 0.00001) were significantly higher for anti-TNF-α-treated patients. Significantly higher intra-abdominal abscesses and readmission were found for anti-TNF-α-treated CD patients (p = 0.05; p = 0.002). Concomitant treatment with immunosuppressives in <50% of anti-TNF-α-treated patients was associated with significantly lower mortality rates (OR, 0.32; 95% CI, 0.12−0.83; p = 0.02). Anti-TNF-α treatment within 12 weeks prior to surgery is associated with higher short-term postoperative complication rates (general and surgical) for patients with IBD, especially CD.

Long-term clinical outcomes of intestinal Behçet's disease: A 30-year cohort study at a tertiary hospital in South Korea.

We aimed to identify the long-term clinical outcomes of and prognostic factors for intestinal Behçet's disease (BD). A cohort of 780 patients with intestinal BD between 1997 and 2021 was investigated to determine long-term clinical outcomes and prognostic factors at an inflammatory bowel disease clinic at Severance Hospital, Seoul, Korea. During the median follow-up period of 12.7±7.2years, 5-aminosalicylic acids, corticosteroids, immunomodulators, and anti-tumor necrosis factor-alpha (TNF-α) agents were required in 94.9%, 67.2%, 43.8%, and 14.6% of the patients, respectively. The cumulative rates of anti-TNF-α use were 3.7%, 7.5%, 8.5%, 12.1%, 17.6%, and 24.0%, and those for abdominal surgery were 5.7%, 10.9%, 12.6%, 16.5%, 21.6%, and 28.3%, at 1, 3, 5, 10, 20, and 30years, respectively, after initial diagnosis of intestinal BD. The cumulative rates of hospitalization were 11.8%, 21.9%, 27.9%, 38.8%, 54.4%, and 74.8%, and those of emergency room visits were 10.0%, 19.8%, 22.7%, 31.6%, 50.0%, and 65.0% at 1, 3, 5, 10, 20, and 30years. Older age at primary diagnosis, previous appendectomy history, higher disease activity index for intestinal Behçet's disease score, systemic BD, multiple intestinal ulcers, deep intestinal ulcers, higher C-reactive protein, lower hemoglobin, and lower albumin levels were associated with poor prognosis. Married status, higher body mass index, oral ulceration, and arthritis were negatively associated with poor prognosis. Data on the long-term clinical outcomes of intestinal BD and their prognostic factors could guide physicians in patient monitoring and in optimizing individualized treatment.

De-Escalation of Anti-Tumor Necrosis Factor Alpha Agents and Reduction in Adverse Effects: A Systematic Review.

Background: The long-term use of anti-TNF-α agents can lead to adverse effects, such as infections and immune-mediated cutaneous reactions. Whether de-escalation by dose reduction or interval lengthening reduces these adverse effects is uncertain. This systematic review aims to compare the incidence of infections and skin manifestations after anti-TNF-α dose de-escalation with standard dosing. Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception to 14 January 2022. Randomized controlled trials (RCTs) and observational studies comparing anti-TNF-α de-escalation strategies with standard dosing among patients with inflammatory conditions, that report on infections, skin manifestations, or both, were included. The risk of bias was assessed with the revised Cochrane risk-of bias tool (RCTs) or the Newcastle–Ottawa scale (non-RCTs). Results: Fourteen RCTs and six observational studies (or 2706 patients) were included. Eight RCTs had low risk of bias or some concerns. Four non-RCTs were of good methodological quality. The studies described patients with axial spondyloarthritis (8 studies, 780 patients), rheumatoid arthritis (7 studies, 1458 patients), psoriasis (3 studies, 332 patients), or inflammatory bowel disease (2 studies, 136 patients). De-escalation strategies included interval lengthening (12 studies, 1317 patients), dose reduction (6 studies, 1130 patients), or both (2 studies, 259 patients). Overall, the occurrence of infections and skin manifestations did not differ between standard treatment and de-escalation. The disappearance of infections or skin manifestations after de-escalation was only reported in two studies. The majority of studies focused on etanercept and adalimumab. Heterogeneity in reporting of infections and skin manifestations precluded meta-analysis. Conclusion: We found that anti-TNF-α de-escalation does not reduce infections or skin reactions. A de-escalation strategy should not be recommended for the sole purpose of reducing drug-related adverse effects. The meticulous documentation of adverse effects is recommended to further address this question. Registration: PROSPERO CRD42021252977.

Rates of latent and active tuberculosis in BGC vaccinated, immunosuppressed Crohn's disease patients form Bulgaria before and during anti-tumor necrosis factor therapy.

Although the use of anti-tumor necrosis factor-alpha (anti-TNF-α) agents is highly effective in achieving and maintaining remission in patients with moderate-to-severe IBD, they place the patient at increased risk of developing opportunistic infections, including new cases of tuberculosis infection (TBI) and/or reactivation of latent tuberculosis infection (LTBI). Our study aims to determine the incidence of TBI [active tuberculosis (ATBI) and LTBI] among patients with Crohn's disease (CD) receiving anti-TNF-α therapy. We performed a retrospective analysis of consecutive CD patients undergoing anti-TNF-α (infliximab, adalimumab) treatment for a minimum of 6 months, in the period between June 2010 and December 2019, followed-up at a reference IBD center. All patients were HIV negative, and BCG vaccinated. In all patients, ATBI was excluded and all were tested for LTBI prior to initiating a biological treatment. Before starting the biological treatment, we established LTBI in 11/109 (10.1%): 8/11 (72.7%) patients were TST positive, 2/11 (18.2%) were IGRA positive and TST negative, 1/11 (9.1%) were both IGRA and TST positive. In patients undergoing biological therapy with previous negative screening test for tuberculosis, a total of 16/74 (21.6%) patients were newly diagnosed with LTBI. The median induration (not erythema) diameter of TST is 8 (IQR 5-17) mm. Active pulmonary tuberculosis infection, developed in 3/74 (4.1%) patients. One patient developed ATBI on the background of chemoprophylaxis with INH for LTBI. Specialists should thoroughly analyse all patient clinical data, chest X-ray results, epidemiological and BCG status, as well as perform a LTBI screening before initiating immunosuppressive and/or biological treatment. IBD patients have a higher risk of developing TBI in the first 12 months.

P425 Rates of tuberculosis infection in Crohn’s Disease patients before and during anti-tumor necrosis factor therapy

Abstract Background In the last, 20 years, IBD treatment has made great progress with the implementation of biological drugs. Although the use of anti-tumor necrosis factor-alpha (anti-TNF-α) agents is highly effective in achieving and maintaining remission, 1, anti-TNF-α agents are associated with a, 5-fold increased risk of reactivation of various opportunistic infections, including TBI, 2,3. Our study aims to determine the incidence of TBI (active tuberculosis (ATBI) and latent tuberculosis (LTBI)) among patients with Crohn’s disease (CD) receiving anti-TNF-α therapy. Methods For the period between June, 2010 to December, 2019, we performed a retrospective analysis of a total of, 109 CD patients, screened before the start of biological treatment. Anti-TNF-α therapy was initiated by, 97 patients, 74 of whom were retested for TBI during follow-up. All patients were BCG vaccinated. Results Before starting biological treatment, we etablished LTBI in, 11/109 (10.1%):, 8/11 (72.7%) patients were TST (+) alone, 2/11 (18.2%) were IGRA (+) and TST (-), 1/11 (9.1%) were both IGRA and TST (+). Chest x-ray abnormalities were not detected in all, 11 patients. After prophylaxis with isoniazid (INH), 300 mg / daily for, 9 months, 9/11 (83.3%) patients with LTBI reached treatment with an anti-TNF α agent. Of this group, 7/9 (77.8%) patients were retested for TBI:, 6/7 (85,7%) were TST and IGRA were (-), and one (14,3%) developed active pulmonary tuberculosis. Two patients were lost to follow up. In the follow-up of patients under anti-TNF-α therapy, 74/97 (76.3%) patients were retested for TBI, with median duration of anti-TNF-a therapy was, 24 (IQR, 6–90) months. A total of, 16/74 (21.6%) patients were newly diagnosed with LTBI:, 5/16 (31.3%) had TST conversion alone, 8/16 (50.0%) were TST(+) and IGRA (-), 1/16, 6.3%) were both TST and IGRA (+), 1/16 (6.3%) had IGRA conversion alone, 1/16 (6.3%) were TST (-) and IGRA (+). ATBI developed in, 3/74 (4.1%) patients, one of them on the background of chemoprophylaxis with INH for LTBI. Median duration after the first dose of biologic therapy to detection of TBI was, 12 (IQR, 6–60) months. Conclusion This study instruct the clinician to be specifically vigilant when initiating anti-TNF-α therapy in IBD patients, because reactivation of TBI is a life-threatening complication in immunosuppressed patients.