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Tuberculosis (TB) is a common complication associated with treatment with tumour necrosis factor (TNF) antagonists and Janus kinase (JAK) inhibitors. However, there is uncertainty about the risk of TB relapse in patients with TB and comorbidities requiring treatment with these agents. To assess the risk of TB relapse in patients (re-)started on TNF antagonists or JAK inhibitors. Systematic review. PubMed and Cochrane Library databases until 11 December 2023. Randomized control trials, prospective and retrospective cohort studies, case reports and case series. Patients with current or previous TB who were (re-)started on TNF antagonists or JAK inhibitors. (Re-)introduction of TNF antagonists and JAK inhibitors. All studies meeting entry criteria were included regardless of quality. Categorical data are presented as frequencies and percentages. For non-normally distributed aggregated data, we calculated the pooled weighted median with 95% CI. For individual patient data, the median and interquartile range (IQR) were calculated. Of 5018 articles screened for eligibility, 67 publications reporting on 368 TB patients who (re-)initiated treatment with TNF antagonists for underlying diseases were included. The median age was 42.5 years (95% CI: 40.4–42.5) and the proportion of female patients was 36.6% (n = 74) of patients whose sex was reported. A total of 14 patients (3.8%, 95% CI: 2.1–6.3%) developed TB relapse after a median of 8.5 months (interquartile range, 6.8–14.8 months) following (re-)initiation of anti-TNF treatment. Furthermore, among 251 articles screened for eligibility, 11 reports on TB patients who were (re-)started on JAK inhibitors for underlying diseases were identified. The median age was 62 years (interquartile range, 48.5–68.5 years) and 45.5% (n = 5) were female. Only one patient (9.1%; 95% CI: 0.2–41.3%) had TB reactivation 10 months after starting treatment with ruxolitinib. In addition, 94 patients who were treated with TNF antagonists and two patients temporarily treated with JAK inhibitors for the prevention or treatment of paradoxical reactions were analysed. None of the publications reported microbiological failure or worsening of TB-related symptoms. (Re-)initiation of TNF antagonists and JAK inhibitors may be relatively safe in patients with current or previous TB and the need for further treatment of underlying diseases. [ABSTRACT FROM AUTHOR]

Many patients with inflammatory bowel disease (IBD) experience a loss of effectiveness to biologic therapy (i.e., anti-TNF therapy, etc.). Therefore, in addition to the adverse effects of the treatment, these patients also face failure to achieve and maintain remission. Immunogenicity, the process of production of antibodies to biological agents, is fundamental to the evolution of loss of response to treatment in IBD patients. The presence of these antibodies in patients is linked to decreased serum drug levels and inhibited biological activity. However, immunogenicity rates exhibit significant variability across inflammatory disease states, immunoassay formats, and time periods. In this review, we aimed to elucidate the immunogenicity and immune mechanisms of antibody formation to biologics, the loss of therapy response, clinical results of biological treatment for IBD from systematic reviews and meta-analyses, as well as to summarize the most recent strategies for overcoming immunogenicity and approaches for managing treatment failure in IBD. [ABSTRACT FROM AUTHOR]

Background: Immunosuppression is a major risk factor for the development of visceral leishmaniasis (VL). The number of patients receiving immunosuppressant drugs such as TNF antagonist (anti-TNF) and methotrexate (MTX) is increasing. In these patients, VL is more severe, their response to treatment poorer, and they are at higher risk of relapse, a consequence (largely) of the poor and inappropriate immune response they develop. Objectives: To examine the effect of immunosuppressive treatment on the host immune response and thus gain insight into the reduced efficacy of pentavalent antimonials in these patients. Experiments were performed using BALB/c mice immunosuppressed with anti-TNF or MTX, infected with Leishmania infantum promastigotes, and then treated with Glucantime® at clinical doses. Results: Immunosuppression with both agents impeded parasite elimination from the spleen and bone marrow. Low pro-inflammatory cytokine production by CD4+ and CD8+ T cells was detected, along with an increase in PD-1 and IL-10 expression by B and T cells in the immunosuppressed groups after treatment. Conclusion: The immunosuppressed mice were unable to develop specific cellular immunity to the parasite, perhaps explaining the greater risk of VL relapse seen in pharmacologically immunosuppressed human patients. [ABSTRACT FROM AUTHOR]

BackgroundImmunosuppression is a major risk factor for the development of visceral leishmaniasis (VL). The number of patients receiving immunosuppressant drugs such as TNF antagonist (anti-TNF) and methotrexate (MTX) is increasing. In these patients, VL is more severe, their response to treatment poorer, and they are at higher risk of relapse, a consequence (largely) of the poor and inappropriate immune response they develop.ObjectivesTo examine the effect of immunosuppressive treatment on the host immune response and thus gain insight into the reduced efficacy of pentavalent antimonials in these patients. Experiments were performed using BALB/c mice immunosuppressed with anti-TNF or MTX, infected with Leishmania infantum promastigotes, and then treated with Glucantime® at clinical doses.ResultsImmunosuppression with both agents impeded parasite elimination from the spleen and bone marrow. Low pro-inflammatory cytokine production by CD4+ and CD8+ T cells was detected, along with an increase in PD-1 and IL-10 expression by B and T cells in the immunosuppressed groups after treatment.ConclusionThe immunosuppressed mice were unable to develop specific cellular immunity to the parasite, perhaps explaining the greater risk of VL relapse seen in pharmacologically immunosuppressed human patients.

Inflammatory Bowel Diseases (IBDs) such as Crohn's disease and ulcerative colitis are characterized by uncontrolled activation of intestinal immune cells in a genetically susceptible host. Due to the progressive and destructive nature of the inflammatory process in IBD, complications such as fibrosis, stenosis or cancer are frequently observed, which highlights the need for effective anti-inflammatory therapy. Studies have identified altered trafficking of immune cells and pathogenic immune cell circuits as crucial drivers of mucosal inflammation and tissue destruction in IBD. From a drug survival point of view, therapeutic choice result of the right association between efficacy, tolerance and acceptability of each treatment and according to reimbursement rules. [ABSTRACT FROM AUTHOR]

Many patients with inflammatory bowel disease (IBD) experience a loss of effectiveness to biologic therapy (i.e., anti-TNF therapy, etc.). Therefore, in addition to the adverse effects of the treatment, these patients also face failure to achieve and maintain remission. Immunogenicity, the process of production of antibodies to biological agents, is fundamental to the evolution of loss of response to treatment in IBD patients. The presence of these antibodies in patients is linked to decreased serum drug levels and inhibited biological activity. However, immunogenicity rates exhibit significant variability across inflammatory disease states, immunoassay formats, and time periods. In this review, we aimed to elucidate the immunogenicity and immune mechanisms of antibody formation to biologics, the loss of therapy response, clinical results of biological treatment for IBD from systematic reviews and meta-analyses, as well as to summarize the most recent strategies for overcoming immunogenicity and approaches for managing treatment failure in IBD.

CD4+ T-cell activation through recognition of Human Leukocyte Antigen II (HLAII)-presented peptides is a key step in the development of unwanted immune response against biotherapeutics, such as the generation of anti-drug antibodies (ADA). Therefore, the identification of HLAII-presented peptides derived from biotherapeutics is a crucial part of immunogenicity risk assessment and mitigation strategies during drug development. To date, numerous CD4+ T-cell epitopes have been identified by HLAII immunopeptidomics in antibody-based biotherapeutics using either their native or aggregated form. Antibody-target immune complexes have been detected in patients with ADA and are thought to play a role in ADA development by enhancing the presentation of CD4+ T-cell epitopes at the surface of antigen presenting cells (APCs). The aim of this study was to investigate the effect of biotherapeutic antibody-target immune complexes on the HLAII peptide presentation of biotherapeutics in human primary monocyte-derived dendritic cells (DCs). The trimeric tumor necrosis factor (TNF) and its biotherapeutic antagonists infliximab (INFL), adalimumab (ADAL), and a single armed Fab' were used as a model system. The HLAII immunopeptidome of DCs loaded with antagonists or their immune complexes with TNF was analyzed by trapped ion mobility time-of-flight mass spectrometry (timsTOF MS) leading to the identification of ~ 12,000 unique HLAII-associated peptides per preparation. Anti-TNF sequences were detected at a median of 0.3% of the total immunopeptidome, against a majority background of peptides from endogenous and media-derived proteins. TNF antagonist presentation spanned the variable and constant regions in a widespread manner in both light and heavy chains, consistent with previously discovered HLAII peptides. This investigation extends the collection of observed HLAII peptides from anti-TNF biotherapeutics to include sequences that at least partially span the complementary determining regions (CDRs), such as the LCDR1 for both INFL and ADAL. Although antagonist presentation varied significantly across donors, peptides from both bivalent antagonists INFL-and ADAL were more highly presented relative to the Fab'. While TNF immune complexes did not alter overall HLAII presentation, a moderate increase in presentation of a subset of peptide clusters was observed in the case of INFL-TNF, which included HCDR2, HCDR3 and LCDR2 sequences. [ABSTRACT FROM AUTHOR]

CD4+ T-cell activation through recognition of Human Leukocyte Antigen II (HLAII)-presented peptides is a key step in the development of unwanted immune response against biotherapeutics, such as the generation of anti-drug antibodies (ADA). Therefore, the identification of HLAII-presented peptides derived from biotherapeutics is a crucial part of immunogenicity risk assessment and mitigation strategies during drug development. To date, numerous CD4+ T-cell epitopes have been identified by HLAII immunopeptidomics in antibody-based biotherapeutics using either their native or aggregated form. Antibody-target immune complexes have been detected in patients with ADA and are thought to play a role in ADA development by enhancing the presentation of CD4+ T-cell epitopes at the surface of antigen presenting cells (APCs). The aim of this study was to investigate the effect of biotherapeutic antibody-target immune complexes on the HLAII peptide presentation of biotherapeutics in human primary monocyte-derived dendritic cells (DCs). The trimeric tumor necrosis factor (TNF) and its biotherapeutic antagonists infliximab (INFL), adalimumab (ADAL), and a single armed Fab’ were used as a model system. The HLAII immunopeptidome of DCs loaded with antagonists or their immune complexes with TNF was analyzed by trapped ion mobility time-of-flight mass spectrometry (timsTOF MS) leading to the identification of ~ 12,000 unique HLAII-associated peptides per preparation. Anti-TNF sequences were detected at a median of 0.3% of the total immunopeptidome, against a majority background of peptides from endogenous and media-derived proteins. TNF antagonist presentation spanned the variable and constant regions in a widespread manner in both light and heavy chains, consistent with previously discovered HLAII peptides. This investigation extends the collection of observed HLAII peptides from anti-TNF biotherapeutics to include sequences that at least partially span the complementary determining regions (CDRs), such as the LCDR1 for both INFL and ADAL. Although antagonist presentation varied significantly across donors, peptides from both bivalent antagonists INFL and ADAL were more highly presented relative to the Fab’. While TNF immune complexes did not alter overall HLAII presentation, a moderate increase in presentation of a subset of peptide clusters was observed in the case of INFL-TNF, which included HCDR2, HCDR3 and LCDR2 sequences.

PurposeThis study is aimed to assess the efficacy of adalimumab in alleviating peripheral vascular leakage in pediatric chronic anterior uveitis patients, along with its ability to improve best-corrected visual acuity (BCVA) and inflammation parameters, its efficacy in reducing topical glucocorticosteroids (GCs) and systemic immunomodulatory therapy (IMT), and its safety profile.MethodsA self-controlled study of pediatric chronic anterior uveitis patients who presented with peripheral retinal vascular leakage on ultra-widefield fluorescein fundus angiography and underwent adalimumab treatment was conducted. The primary outcome was the extent of retinal vascular leakage at the 3- and 6-month follow-up visits. Secondary outcomes included BCVA, inflammation parameters (fresh keratic precipitates, anterior chamber cell, and vitreous cell grades), frequency of topical glucocorticosteroid eye drops, IMT load, and adverse effects at the 3- and 6-month follow-up visits.ResultsTwenty patients with a mean age of 9.30 ± 3.26 years old were included. The mean follow-up period was 9.0 ± 3.0 months, with all patients followed up for at least 6 months. At the 3- and 6-month follow-ups, the peripheral vascular leakage score decreased significantly (2.87, 95% CI (2.14, 3.60), p < 0.001 for 3 months, 2.75, 95% CI (1.76, 3.73), p < 0.001 for 6 months). Alongside BCVA (p = 0.013 for 3 months, p = 0.005 for 6 months) was improved significantly, inflammatory parameters represented by fresh keratic precipitates, anterior chamber cell, and vitreous cell grades were improved significantly (p < 0.001, p < 0.001, for all parameters) and topical GC usage was significantly reduced (p < 0.001, p < 0.001) at 3 and 6 months. There was also a statistically significant reduction in systemic IMT load at 6 months (p < 0.001). Adverse events in the observation period included local redness around the injection site and mild upper respiratory symptoms.ConclusionAdalimumab could effectively alleviate peripheral vascular leakage in pediatric patients with chronic anterior uveitis. It could also be helpful in improving BCVA and inflammation parameters and decreasing topical glucocorticosteroid eye drops and systemic IMT. Adalimumab is generally safe for pediatric uveitis.

Introduction: Cardiac sarcoidosis (CS) is a life-threatening disease in which clear recommendations are lacking. We report a case series of CS successfully treated by tumor necrosis factor (TNF)α antagonists.Methods: We conducted a single-center retrospective study of our patients with CS treated by TNFα antagonists.Results: Four cases (4/84, 4.7%) were found in our database. Mean age was 40 years (range 34–53 years), and all were Caucasian men. Mean follow-up was 54.75 months (range 25–115 months). All patients received corticosteroid therapy (CT) and immunosuppressive therapy (IT). TNFα antagonists (infliximab or adalimumab) were started after the first or second CS relapse under CT and IT. One patient experienced relapse under TNFα antagonists (isolated decreased left ventricular ejection) and responded to a shorter interval of TNFα antagonist infusion. CT was discontinued in three patients treated with TNFα antagonists without relapse or major cardiac events during follow-up. No serious adverse event occurred in our case series, possibly due to dose sparing and frequent arrest of CT.Conclusion: TNFα antagonists were effective in refractory and/or relapsing CS treated by corticosteroids and/or immunosuppressive agents, without serious adverse events, and should be considered earlier in CS treatment scheme.

Purpose: To assess the value of MRI obtained before and after treatment in detecting mucosal healing in patients with ileal Crohn’s disease (CD) treated with anti-TNF drugs. Methods: In this IRB approved retrospective study, 24 patients (M/F 11/13, age 34.0 ± 12.5 years, age range 19–55 years) with ileal CD who underwent anti-TNF treatment, with pre- and post-treatment MRI (mean delay between MRIs 92 ± 57 weeks) were included. All patients underwent routine MR enterography (MRE), which included diffusion-weighted imaging (DWI). Two readers evaluated qualitative features (wall thickness, presence of edema and length of involvement) in consensus and one reader measured the following quantitative variables: relative contrast enhancement (RCE) and apparent diffusion coefficient (ADC) to derive the MaRIA and Clermont scores at baseline, post-treatment and their changes (ΔMaRIA, ΔClermont). Ileocolonoscopy results were used as the reference standard. Data was evaluated using Mann-Whitney U test and receiver operating characteristics analysis to assess the utility of the measures for the detection of mucosal healing. Results: Twenty-four ileal segments were assessed in 24 patients. Nine patients showed mucosal healing while 15 had no mucosal healing on post-treatment endoscopy. Pre-treatment Clermont score and wall thickness and post-treatment MaRIA and Clermont scores, wall thickness, edema, length of involvement as well as ΔMaRIA and ΔClermont were all significantly different in patients with and without mucosal healing (p-range: 0.001-0.041) while MaRIA pre-treatment and ADC pre- and post-treatment were not. Pre-treatment Clermont score as well as post-treatment MaRIA and Clermont scores, wall thickness and ΔMaRIA were all significantly predictive of detection of mucosal healing (AUC 0.813-0.912; p = 0.003-0.024) after anti-TNF treatment. Conclusion: Pre-treatment Clermont score as well as post-treatment MaRIA and Clermont scores, wall thickness and ΔMaRIA are significantly predictive of response to anti-TNF drugs in ileal Crohn’s disease. These results need to be verified in a larger study.

Abstract Background Patient registry data serves an increasing role in drug safety and comparative effectiveness research, but registry databases often do not contain confounder information measured at the same time that treatments begin. This study evaluated a set of approaches for estimating confounder values at treatment initiation using actual data from a rheumatoid arthritis (RA) registry to examine the risk of infection associated with different biologic DMARDs (bDMARDs). Methods We examined the risk of infection associated with starting a TNF inhibitor (TNFi) versus any of the other non-TNFi bDMARDs. Different confounder assessment approaches were tested. All approaches were tested in Cox proportional hazard regression models that used a propensity score (PS). The confounder of interest was the disease activity score (DAS28-CRP). The confounder assessment approaches utilized different temporal relationships between the DAS28-CRP measurement and the start of the treatments of interest. Results We included 219 subjects with RA with 269 initiations of either a TNFi or a different bDMARD or both. Among this group, 305 infections were reported and confirmed through chart review. The hazard ratio (HR) for the risk of infection associated with use of a non-TNFi bDMARD ranged from 1.17 to 3.03 using 13 different approaches; only the approach with the highest HR produced results significantly different than one, but this approach included the fewest subjects and infections. Conclusions The relative risk of infection for TNFi and other non-TNFi bDMARDs was similar using various approaches regarding which DAS28-CRP score should be used as the baseline measure in adjusted analyses.

Background: Immunosuppression is a major risk factor for the development of visceral leishmaniasis (VL). The number of patients receiving immunosuppressant drugs such as TNF antagonist (anti-TNF) and methotrexate (MTX) is increasing. In these patients, VL is more severe, their response to treatment poorer, and they are at higher risk of relapse, a consequence (largely) of the poor and inappropriate immune response they develop., Objectives: To examine the effect of immunosuppressive treatment on the host immune response and thus gain insight into the reduced efficacy of pentavalent antimonials in these patients. Experiments were performed using BALB/c mice immunosuppressed with anti-TNF or MTX, infected with Leishmania infantum promastigotes, and then treated with Glucantime ® at clinical doses., Results: Immunosuppression with both agents impeded parasite elimination from the spleen and bone marrow. Low pro-inflammatory cytokine production by CD4 + and CD8 + T cells was detected, along with an increase in PD-1 and IL-10 expression by B and T cells in the immunosuppressed groups after treatment., Conclusion: The immunosuppressed mice were unable to develop specific cellular immunity to the parasite, perhaps explaining the greater risk of VL relapse seen in pharmacologically immunosuppressed human patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Bernardo, Solana, Sánchez, Torres, Reyes-Cruz, Carrillo and Moreno.)

Patients treated with the TNF antagonist adalimumab develop anti-therapeutic antibodies (ATA), the prevalence of which varies depending on the assay used. Most assays are compromised due to the presence of adalimumab in the clinical samples. Our objective was to develop an antibody assay, applicable for clinical testing, which overcomes the limitation of therapeutic interference and to further determine the relationship between ATA development, adalimumab levels and disease activity in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS). Use of an electrochemiluminescence platform permitted development of fit-for-purpose immunoassays. Serum samples from patients, taken prior to and at 12 and 24 weeks of treatment, were retrospectively analysed for levels of adalimumab and ATA. Overall, the antibody prevalence was 43.6% at 12 weeks and 41% at 24 weeks of treatment. Disruption of immune complexes by acid dissociation, a strategy often adopted for this purpose, only marginally increased the antibody prevalence to 48.7% and 46% at 12 and 24 weeks respectively. We found that antibody formation was associated with decreasing levels of circulating adalimumab, but no direct effect on disease activity was evident as assessed using DAS28 for RA patients and BASDAI for PsA and AS patients. However, a negative correlation of free adalimumab trough levels with disease activity scores was observed. Data showed that adalimumab levels can serve as an indicator of ATA development which can then be confirmed by ATA testing. Monitoring of both therapeutic and antibodies should be considered during adalimumab therapy to allow clinicians to personalise treatments for maximal therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Introduction The off-label use of TNF antagonists in refractory sarcoidosis is increasingly reported but data on their efficacy and safety are still insufficient. Objective To report on efficacy and safety of TNF antagonists in severe and refractory sarcoidosis. Methods Examination of retrospective demographic, clinical, therapeutic, and adverse event data on 132 sarcoidosis patients (58% women; mean (min–max) age = 45.5 (14–78) years) given TNF antagonists (mainly infliximab, 91%) and investigation of response-linked factors. Results The overall clinical response (complete and partial) rate was 64%. TNF-antagonist efficacy (i.e., significant decrease of the ePOST score) was noted in cases with neurologic, heart, skin, and upper respiratory tract involvements. No significant difference in efficacy was found between anti-TNF used alone and TNF with immunosuppressant. The use of anti-TNF allowed reducing prednisone dosage at end of follow-up ( p < 0.001). Adverse events were observed in 52% of the patients; they included infections (36%) and allergic reactions (8%) and required treatment interruption in 31 cases (23%). When TNF antagonists were interrupted, 13 patients experienced relapses within 14 months on average (median follow-up: 20.5 months). Conclusion TNF antagonists were efficacious in about two-thirds of patients with severe/refractory sarcoidosis but their use led to a high rate of adverse events. [ABSTRACT FROM AUTHOR]

Patients treated with the TNF antagonist adalimumab develop anti-therapeutic antibodies (ATA), the prevalence of which varies depending on the assay used. Most assays are compromised due to the presence of adalimumab in the clinical samples. Our objective was to develop an antibody assay, applicable for clinical testing, which overcomes the limitation of therapeutic interference and to further determine the relationship between ATA development, adalimumab levels and disease activity in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS). Use of an electrochemiluminescence platform permitted development of fit-for-purpose immunoassays. Serum samples from patients, taken prior to and at 12 and 24 weeks of treatment, were retrospectively analysed for levels of adalimumab and ATA. Overall, the antibody prevalence was 43.6% at 12 weeks and 41% at 24 weeks of treatment. Disruption of immune complexes by acid dissociation, a strategy often adopted for this purpose, only marginally increased the antibody prevalence to 48.7% and 46% at 12 and 24 weeks respectively. We found that antibody formation was associated with decreasing levels of circulating adalimumab, but no direct effect on disease activity was evident as assessed using DAS28 for RA patients and BASDAI for PsA and AS patients. However, a negative correlation of free adalimumab trough levels with disease activity scores was observed. Data showed that adalimumab levels can serve as an indicator of ATA development which can then be confirmed by ATA testing. Monitoring of both therapeutic and antibodies should be considered during adalimumab therapy to allow clinicians to personalise treatments for maximal therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Background: Observational studies have described racial differences in inflammatory bowel disease (IBD) genetics, clinical manifestations, and outcomes. Whether race impacts response to biologics in IBD is unclear. We conducted a post hoc analysis of phase 2 and 3 randomized clinical trials in ulcerative colitis to evaluate the effect of race on response to golimumab., Methods: We analyzed pooled individual-level data from induction and maintenance trials of golimumab through the Yale Open Data Access Project. The primary outcome was clinical response. Secondary outcomes were clinical remission and endoscopic healing. Multivariable logistic regression was performed comparing White vs racial minority groups (Asian, Black, or other race), adjusting for potential confounders., Results: There were 1006 participants in the induction (18% racial minority) and 783 participants in the maintenance (17% racial minority) trials. Compared with White participants, participants from racial minority groups had significantly lower clinical response (adjusted odds ratio [aOR], 0.43; 95% confidence interval [CI], 0.28-0.66), clinical remission (aOR, 0.41; 95% CI, 0.22-0.77), and endoscopic healing (aOR, 0.48; 95% CI, 0.31-0.74) at week 6. Participants from racial minority groups also had significantly lower clinical remission (aOR, 0.46; 95% CI, 0.28-0.74) and endoscopic healing (aOR, 0.63; 95% CI, 0.41-0.96) at week 30. There were no racial differences in placebo response rates., Conclusions: Ulcerative colitis participants from racial minority groups were less likely to achieve clinical response, clinical remission, and endoscopic healing with golimumab compared with White participants in induction and maintenance trials. Further studies are needed to understand the impact of race on therapeutic response in IBD., (© The Author(s) 2022. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background & Aims: Little is known about the efficacy of golimumab, a fully human monoclonal antibody to tumor necrosis factor (TNF) −α, for treatment of ulcerative colitis (UC). We evaluated subcutaneous golimumab induction therapy in TNF−α antagonist-naïve patients with moderate-to-severe UC despite conventional treatment. Methods: We integrated double-blind phase 2 dose-finding and phase 3 dose-confirmation trials in a study of 1064 adults with UC (Mayo score: 6−12; endoscopic subscore ≥2; 774 patients in phase 3). Patients were randomly assigned to groups given golimumab doses of 100 mg and then 50 mg (phase 2 only), 200 mg and then 100 mg, or 400 mg and then 200 mg, 2 weeks apart. The phase 3 primary end point was week-6 clinical response. Secondary end points included week-6 clinical remission, mucosal healing, and Inflammatory Bowel Disease Questionnaire (IBDQ) score change. Results: In phase 2, median changes from baseline in the Mayo score were −1.0, −3.0, −2.0, and −3.0, in the groups given placebo, 100 mg/50 mg, 200/100 mg, and 400/200 mg golimumab, respectively. In phase 3, rates of clinical response at week 6 were 51.0% and 54.9% among patients given 200 mg/100 mg and 400 mg/200 mg golimumab, respectively, vs 30.3% among those given placebo (both, P ≤ .0001). Rates of clinical remission and mucosal healing and mean changes in IBDQ scores were significantly greater in both golimumab groups vs the placebo group (P ≤ .0014, all comparisons). Rates of serious adverse events were 6.1% and 3.0%, and rates of serious infection were 1.8% and 0.5%, in the placebo and golimumab groups, respectively. One patient in the 400 mg/200 mg group died as a result of surgical complications of an ischiorectal abscess. Conclusions: Treatment with subcutaneous golimumab induces clinical response, remission, and mucosal healing, and increases quality of life in larger percentages of patients with active UC than placebo. ClinicalTrials.gov Number: NCT00487539. [Copyright &y& Elsevier]

Objectives: To investigate the clinical characteristics and risk factors of Pneumocystis jirovecii pneumonia (PCP) in rheumatoid arthritis (RA) patients treated with adalimumab. Methods: We conducted a multicenter, retrospective, case–control study to compare RA patients treated with adalimumab with and without PCP. Data from 17 RA patients who were diagnosed with PCP and from 89 RA patients who did not develop PCP during adalimumab treatment were collected. Results: For the PCP patients, the median age was 68 years old, with a median RA disease duration of eight years. The median length of time from the first adalimumab injection to the development of PCP was 12 weeks. At the onset of PCP, the median dosages of prednisolone and methotrexate were 5.0 mg/day and 8.0 mg/week, respectively. The patients with PCP were significantly older ( p < 0.05) and had more structural changes ( p < 0.05) than the patients without PCP. Computed tomography of the chest revealed ground-glass opacity without interlobular septal boundaries in the majority of the patients with PCP. Three PCP patients died. Conclusions: PCP may occur early in the course of adalimumab therapy in patients with RA. Careful monitoring, early diagnosis, and proper management are mandatory to secure a good prognosis for these patients. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy of etanercept in patients with an ankylosing spondylitis hip lesion. Materials and Methods: Between March 2008 and December 2011, this study evaluated 13 patients with hip lesions who were refractory to conventional therapy. The general improvement was evaluated by the Harris hip score, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), ESR, CRP, and complications. Results: The mean Harris hip score changed from 55.6±3.4 to 87.2±4.3(P=0.01). The mean BASDAI/ BASFI decreased from 6.8±1.7/6.8±1.6 before treatment to 4.4±1.8(P=0.02)/4.3±1.1(P=0.02) after treatment. The mean ESR/CRP changed from 48.4±31.5/5.8±5.1 to 20.8±19.7(P=0.06)/3.1±4.2(P=0.03). No complications were encountered. Conclusion: These results suggest that etanercept can induce significant pain improvement in most ankylosing spondylitis hip lesions. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) demyelination in a patient receiving tumour necrosis factor alpha (TNF-α) antagonist therapy in our practice prompted a search of the literature to assess the evidence for a causal relationship between TNF antagonist therapy and demyelination. We summarise clinical data extracted on 65 reported cases of CNS demyelination in patients receiving TNF antagonist therapy and show that the data are consistent with a drug-related aetiology given the temporal relationship between TNF antagonist initiation and symptoms, de-challenge-re-challenge phenomenon and the later age of disease onset compared with sporadic multiple sclerosis. Research on TNF signalling pathways also suggests a plausible causative role of TNF antagonist therapy in demyelination. However to date, controlled trial and pharmacovigilance data do not show an increased risk of demyelination in patients receiving TNF antagonist therapy. These data may be underpowered to exclude such a risk and pooled, collaborative data from multiple registries are warranted. Given the uncertainty in this area, clinicians should adhere to existing clinical guidance advising avoidance of TNF antagonist therapy in patients with a personal or family history of demyelination, and ensure all suitable patients are enrolled in long term safety registries in countries where these are established. [ABSTRACT FROM AUTHOR]

Competing Interests: Competing interests: None.

Background: Therapy with tumour necrosis factor α (TNF) inhibitors can be associated with paradoxical reactions, namely the de novo development or flaring of conditions that usually respond to these therapeutic agents, such as arthritis, inflammatory bowel disease, sarcoidosis or psoriasis. They are considered a class effect of these drugs, and their incidence ranges from 1 to 5%, with paradoxical psoriasis (psoriasis vulgaris, palmoplantar pustulosis, scalp psoriasis and their combinations) being most frequently reported. Treatment of paradoxical psoriasis often requires withdrawal of the inducing drug and switching to another anti-TNF agent, but often this cannot avoid recurrence or persistence of the rash and/or loss of the therapeutic effect on the underlying condition. Case Report: We report on a 47-year-old woman who developed incapacitating palmoplantar pustulosis and psoriasis vulgaris flare with severe scalp and nail involvement after 5 months of treatment with adalimumab for psoriatic arthritis. Several treatments, including topical corticosteroids, photochemotherapy, ciclosporin, acitretin and etanercept 50 mg twice a day for 1 month, were ineffective or not tolerated. Treatment with ustekinumab 45 mg provided complete resolution of skin lesions with acceptable therapeutic control of the arthritis, with a follow-up duration of 16 months. Conclusion: A review of the reported cases suggests that this may be a therapeutic option in patients who develop paradoxical psoriasis while under treatment for arthritis or Crohn's disease. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To evaluate the safety, efficacy, and effectiveness of TNF antagonists in patients with sarcoidosis. Methods: A descriptive study of a case series registered in BIOBADASER and a systematic review was performed. The search strategy of articles published between 1998 and July 2011 in Medline, Embase, and the Cochrane Library included synonyms of sarcoidosis and synonyms of TNF antagonists. Results: Seven patients treated with infliximab (IFX) and 1 with etanercept (ETN) switched to IFX for inefficacy were registered in BIOBADASER 2.0. In 3, treatment is still ongoing. Reasons for discontinuation were serious adverse events in 2 cases, inefficacy in 2 cases, and complete clinical response in 2 cases. Eight serious adverse events were reported. In the selected 69 of 2262 reports and 1 abstract of the review, 232 patients (89.9%) were treated with IFX and 26 (10.0%) were treated with ETN. In 2 randomized clinical trials, favorable response of the lung disease was reported with IFX. In other randomized clinical trials, no improvement of ocular manifestations was reported with ETN. In the cases series, results were diverse. Mean weighted rates of adverse events, infections, serious infections, and malignancy were 39.9, 22.1, 5.9, and 1.0 per 100 patient-years, respectively. Conclusions: There is insufficient evidence to ensure the efficacy of TNF antagonists in sarcoidosis. Nevertheless, IFX may be effective in selected manifestations of the disease. Before starting treatment of sarcoidosis with IFX, a careful evaluation of the benefit/risk ratio must be considered on an individual basis. [Copyright &y& Elsevier]

Objective. To determine the incidence of and risk factors for non-melanoma skin cancer (NMSC) in a national cohort of veterans with RA.Methods. We examined skin cancer risk in a cohort of 20 648 patients with RA derived from the Department of Veterans’ Affairs (VA) national administrative databases. The cohort was divided into two medication groups: patients treated with non-biologic and TNF-α antagonist DMARDs. We defined skin cancer as the first occurrence of an International Classification of Disease, Version 9, Clinical Modification (ICD-9-CM) code for NMSC after initiation of a DMARD. Outcome risk was described using hazard ratios (HRs) with Cox proportional hazards regression for time-to-event analysis and logistic regression. We performed medical record review to validate the diagnosis of NMSC.Results. Incidence of NMSC was 18.9 and 12.7 per 1000 patient-years in patients on TNF-α antagonists and non-biologic DMARDs, respectively. Patients on TNF-α antagonists had a higher risk of developing NMSC (HR 1.42; 95% CI 1.24, 1.63). Risk factors for NMSC included older age, male gender, NSAID and glucocorticoid use and a history of prior malignancies. There was substantial agreement between ICD-9-CM diagnosis of NMSC and medical record validation (κ = 0.61).Conclusion. TNF-α antagonist therapy in veterans with RA may be associated with an increased risk of NMSC, compared with therapy with non-biologic DMARDs. Rheumatologists should carefully screen patients receiving TNF-α antagonists for pre-cancerous skin lesions and skin cancer. [ABSTRACT FROM PUBLISHER]

ABSTRACT A 38-year-old woman developed clinical, biochemical, radiological and histopathological evidence of cutaneous and pulmonary sarcoidosis 5 months after commencing adalimumab for chronic plaque psoriasis. Signs and symptoms resolved within 3 months of cessation of adalimumab. [ABSTRACT FROM AUTHOR]

Background: New biologic therapies are available for moderate to severe psoriasis. Objective: To determine the most cost-effective sequence of biologic treatments. Methods: Through modeling of the clinical pathway of biologic agents, adalimumab, alefacept, efalizumab, etanercept, and infliximab, the costs and benefits (quality-adjusted life-years [QALYs]) were determined. A decision rule determined the optimal treatment sequence comparing costs and QALYs. Results: While infliximab was found to provide the most incremental QALY and etanercept was found to be the least costly, on balance, the incremental cost-effectiveness ratio of adalimumab was the most favorable (ICER == $$544/QALY). Consequently, the optimal sequence would begin with adalimumab and be followed by etanercept, infliximab, efalizumab, and alefacept, respectively. The limitations of this study are that evidence was based on indirect comparisons of biologic effectiveness, and toxicities were not included in the model. Conclusions: In consideration of cost-effectiveness in prescribing biologics for moderate to severe psoriasis, the optimal sequence would begin with adalimumab. [ABSTRACT FROM AUTHOR]

a measure of healthcare cost containment, the total number of vials of entanercept (25 mg) that can be prescribed for patients with inflammatory arthritis is restricted in Korea. Consequently, attempts to extend the dosing interval while maintaining the efficacy have not been an uncommon clinical practice. The aim of this study was to determine if extended doing interval of etanercept can be effective in patients with ankylosing spondylitis (AS). We performed a retrospective analysis using medical records at a single tertiary hospital. One hundred and nine patients with AS and 79 patients with rheumatoid arthritis (RA) started on etanercept between November 2004 and November 2009 were indentified. Etanercept (25 mg) was started with twice-weekly dosing schedule. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), C-reactive protein (CRP), and etanercept dosing interval for AS patients at 0, 3, 9, 15, 21 months were reviewed. Dosing interval for RA patients was analyzed for comparison. In AS, mean dosing interval was 4.7 ± 2.1 days at 3 months and was increased to 12.1 ± 7.0 days at 21 months. Despite the progressive increase in the dosing interval, the mean BASDAI declined rapidly at 3 months, and continued to decrease over 21 months. Mean CRP declined after 3 months of therapy and remained low thereafter. In RA, mean dosing interval was 4.0 ± 1.2 days at 3 months and 5.1 ± 1.8 days at 21 months. In conclusion, in AS, extended dosing of etanercept can be effective without compromising clinical and laboratory markers of disease activity as measured by BASDAI and CRP, respectively. Tapering of etanercept was less accommodating in RA when compared to AS. [ABSTRACT FROM AUTHOR]

Objectives. To compare the clinical manifestations of spinal disease, peripheral arthritis and enthesitis, and to evaluate the effectiveness of adalimumab in a large cohort of patients with AS in relation to the presence or absence of psoriasis. [ABSTRACT FROM PUBLISHER]

We evaluated the short-term effects of the anti-interleukin-6 (IL-6) receptor antibody tocilizumab (TCZ) in six patients with rheumatoid arthritis (RA) who had been refractory to tumor necrosis factor (TNF) antagonist therapy. All subjects were considered to be secondary nonresponders to TNF antagonists as decided by each physician. The Disease Activity Score of 28 Joints (DAS28) appeared to improve slowly by TCZ compared with TNF antagonist therapy, but significantly decreased at 24 weeks. One patient achieved DAS28 remission [DAS28–erythrocyte sedimentation rate (ESR) <2.60, and 5 of 6 patients showed good or moderate clinical response. The change in the clinical Disease Activity Index was similar to that of the DAS28–ESR. The serum level of matrix metalloproteinase-3 (MMP-3), a marker for synovial overgrowth, also significantly decreased after the treatment (518 ± 567 at baseline, 141 ± 90 ng/ml at 24 weeks, p < 0.05). One patient discontinued TCZ because of tuberculous peritonitis. Although physicians need to watch for infectious adverse events, these data indicate that TCZ is effective for treating RA patients refractory to TNF antagonists. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor (TNF) is a central regulator of chronic inflammatory diseases and plays a major role in the host immune system against tuberculosis (TB). TNF antagonists, infliximab and etanercept are effective in treating chronic inflammatory diseases by inhibiting TNF, but increase the risk of TB as a result of immunosuppression. Previous studies have shown that the risk of TB is greater in patients who received infliximab than in those who received etanercept and several hypotheses on the action mechanisms of the two agents have been presented in order to explain this difference in the risk of TB. As the clinical use of TNF antagonists increase, the incidence rate of TB may increase. Therefore, it is necessary that clinicians considering the use of TNF antagonists pay much attention to the prevention and control of TB and understand the mechanisms of action of the TNF antagonists. This case shows that etanercept treatment can be safely administered during the treatment of TB. In the future, additional studies will be needed to determine the safety of etanercept and the optimal time for the administration of etanercept during the TB treatment. [ABSTRACT FROM AUTHOR]

Adalimumab is a monoclonal antibody that inhibits TNF, an osteogenic cytokine involved in the pathogenesis of chronic, disabling inflammatory diseases. Adalimumab is indicated for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and Crohn's disease. It alleviates the symptoms of these diseases, prevents disease progression in some patients and, in the case of Crohn's disease, induces and maintains remission. Compared with traditional disease-modifying antirheumatic drugs that offer significantly less benefit, adalimumab is much more costly. However, most studies to date demonstrate the cost-effectiveness of adalimumab treatment. Cost-effectiveness data for newer indications of adalimumab, including ankylosing spondylitis and Crohn's disease, are needed. As longer term data for adalimumab become available, the cost-effectiveness data will have greater precision. [ABSTRACT FROM AUTHOR]

Objective. To evaluate the effectiveness and safety of adalimumab in patients with rheumatoid arthritis (RA) who previously discontinued tumour necrosis factor (TNF) antagonists for any reason in clinical practice. [ABSTRACT FROM PUBLISHER]

The HUMIRA® (adalimumab) Pen is a novel, integrated, disposable autoinjection delivery system for the subcutaneous injection of adalimumab. Adalimumab is a biological disease modifier for the treatment of rheumatoid arthritis and other chronic debilitating diseases mediated by tumor necrosis factor. Sustaining long-term efficacy with a biological therapy is influenced by patient adherence to the therapeutic regimen, which is often affected by the route of drug administration. Self-administered injectables offer several advantages over intravenous injections (i.e., portability, convenience and flexible scheduling). In particular, patients with chronic, debilitating diseases may need a self-administered medication available in an easy-to-use and convenient delivery device that minimizes pain and facilitates adherence to therapy. The adalimumab Pen offers these benefits and recent evidence indicates that patients overwhelmingly prefer the adalimumab Pen to the prefilled syringe. [ABSTRACT FROM AUTHOR]

Abstract: Background:: Adalimumab is a therapeutic monoclonal antibody for SC administration by 2 single-use injection devices providing bioequivalent amounts of adalimumab: a ready-to-use, prefilled syringe and an integrated, disposable delivery system, the autoinjection Pen. Although pens have been shown to be preferred over syringes by patients requiring long-term SC administration of medications, there are no data on preference and pain in the use of biologics in patients with chronic inflammatory diseases. Objective:: The aim of this study was to assess injection-site pain, tolerability, and patient preference of 2 delivery systems of adalimumab. Methods:: Patients with rheumatoid arthritis were enrolled in a Phase II, multicenter, open-label, singlearm, sequential trial. Patients self-administered a standard dose of adalimumab 40 mg SC every other week at each of 3 monitored clinical visits: visit 1 (syringe), visits 2 and 3 (Pen). At each visit, patients rated their pain on an 11-point scale (0 = none to 10 = pain as bad as it could be) immediately after injection and 15—30 minutes after injection and provided their impressions of and preferences for each delivery system. Safety events were recorded throughout the study and 70 days after final study dose. Results:: Fifty-two patients were enrolled in the trial and completed all 3 visits (32 women, 20 men; mean [SD] age, 53.8 [12.1] years). Forty (76.9%) patients reported that the Pen was less painful than the syringe, 4 (7.7%) patients found the syringe to be less painful, and 8 (15.4%) patients had no preference. Patients had statistically significant reductions in injection-pain scores from visit 1 to visit 2 and from visit 1 to visit 3. No new safety signals or apparent differences regarding tolerability between the syringe and Pen were observed. In addition, 46 (88.5%) patients preferred the Pen, 3 (5.8%) preferred the syringe, and 3 (5.8%) had no preference. Overall, patients evaluated the Pen as easier to use (94.2%), more convenient (92.3%), requiring less time to inject (82.7%), and safer (88.5%). Conclusions:: Patients experienced less pain self-administering adalimumab via the Pen and preferred it versus the syringe. Further, patients perceived the Pen to be easier to use and more convenient. Both delivery systems were generally well tolerated. [Copyright &y& Elsevier]

Purpose: This study is aimed to assess the efficacy of adalimumab in alleviating peripheral vascular leakage in pediatric chronic anterior uveitis patients, along with its ability to improve best-corrected visual acuity (BCVA) and inflammation parameters, its efficacy in reducing topical glucocorticosteroids (GCs) and systemic immunomodulatory therapy (IMT), and its safety profile., Methods: A self-controlled study of pediatric chronic anterior uveitis patients who presented with peripheral retinal vascular leakage on ultra-widefield fluorescein fundus angiography and underwent adalimumab treatment was conducted. The primary outcome was the extent of retinal vascular leakage at the 3- and 6-month follow-up visits. Secondary outcomes included BCVA, inflammation parameters (fresh keratic precipitates, anterior chamber cell, and vitreous cell grades), frequency of topical glucocorticosteroid eye drops, IMT load, and adverse effects at the 3- and 6-month follow-up visits., Results: Twenty patients with a mean age of 9.30 ± 3.26 years old were included. The mean follow-up period was 9.0 ± 3.0 months, with all patients followed up for at least 6 months. At the 3- and 6-month follow-ups, the peripheral vascular leakage score decreased significantly (2.87, 95% CI (2.14, 3.60) , p < 0.001 for 3 months, 2.75, 95% CI (1.76, 3.73) , p < 0.001 for 6 months). Alongside BCVA ( p = 0.013 for 3 months, p = 0.005 for 6 months) was improved significantly, inflammatory parameters represented by fresh keratic precipitates, anterior chamber cell, and vitreous cell grades were improved significantly ( p < 0.001, p < 0.001, for all parameters) and topical GC usage was significantly reduced ( p < 0.001, p < 0.001) at 3 and 6 months. There was also a statistically significant reduction in systemic IMT load at 6 months ( p < 0.001). Adverse events in the observation period included local redness around the injection site and mild upper respiratory symptoms., Conclusion: Adalimumab could effectively alleviate peripheral vascular leakage in pediatric patients with chronic anterior uveitis. It could also be helpful in improving BCVA and inflammation parameters and decreasing topical glucocorticosteroid eye drops and systemic IMT. Adalimumab is generally safe for pediatric uveitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Song, Zhao, Xiao, Gao, Li and Zhang.)

Soluble TNFRs (tumour necrosis factor receptors) inhibit in-vivo and in-vitro bioactivities of TNF, and thus the secretion of soluble TNFRs could be a physiological principle to attenuate the bioactivities of TNF. Two types of TNFR have been identified and both forms can be released from cells. In this study, soluble TNFRs in seminal plasma from three groups of men were analysed: from men with normal semen quality ( = 32), with reduced semen quality ( = 7) and vasectomized men ( = 3). Sensitive and specific enzyme-linked immunosorbent assays were utilized to detect soluble TNFRs in seminal plasma, based on capture antibodies directed against non-TNF-binding sites of the TNFRs and digoxigenin (DIG)-labelled TNF. The mean ± standard deviation levels of p55 TNFR were 56.4 ± 20, 64.4 ± 17 and 45.4 ± 5 ng/ml in the three groups, respectively. The concentration of p75 TNFR was < 1 ng/ml in all groups. The results suggest an exclusive existence of high amounts of the soluble p55 TNFR in seminal plasma. Seminal plasma from vasectomized men contained p55 TNFR at approximately the same levels as the specimen from the two other groups, indicating that the source of p55 TNFR is not the testis but rather some tissue more distal in the male genital tract, such as the prostate or the seminal vesicles. The soluble p55 TNFR was purified from human seminal plasma, using affinity and gel filtration chromatography. Further characterization of the purified p55 revealed a protein with a molecular weight of −22 kDa, both under reducing and non-reducing conditions. Probably due to the elongated structure of p55 TNFR, the molecule behaved as a larger protein (50 kDa) by gel filtration chromatography. The isolated TNFR inhibited TNF cytotoxicity . [ABSTRACT FROM PUBLISHER]

Background: Nonadherence to biologic therapy in inflammatory bowel disease (IBD) is associated with risk of relapse, immunogenicity, and disease complications. Significant nonadherence prevalence is reported with tumor necrosis factor (TNF) antagonists but the risk of nonadherence with newer biologics with better safety profiles is unknown. This study aimed to investigate if IBD patient-preferences favoring biologic discontinuation vary by biologic class and analyze factors associated with such preferences., Methods: A convenience sample of 200 adults with IBD on biologic therapy treated at an academic outpatient center was surveyed using a 22-point questionnaire. Patient-preference favoring treatment discontinuation between TNF-antagonist and non-TNF-antagonist biologics [vedolizumab (VDZ)/ustekinumab (UST)] was compared using χ  2 test. Risk factors associated with a preference to discontinue biologic therapy were evaluated using univariable and multivariable logistic regression, and Spearman rank correlation analyses., Results: A total of 190 questionnaires were analyzed that contained data on preferences regarding biologic discontinuation (median age 36 years, 62% were females; 63% had Crohn disease; 56% were receiving a TNF antagonist, 31% VDZ, and 14% UST). Overall, 32% patients reported a preference to discontinue biologic treatment with a higher proportion among those receiving a TNF antagonist compared with VDZ/UST (39.6% vs 21.4%; P < 0.01). Current VDZ/UST use was independently associated with a reduced odds of patient-preference favoring biologic discontinuation [adjusted odds ratio: 2.67 (1.42-5.01); P < 0.01]. The most concerning factor to patients was the perceived risk of side effects. Patients on VDZ/UST perceived their therapy to be safer than those receiving a TNF antagonist ( r = 0.2, P = 0.04)., Conclusions: Patient-preference favoring treatment discontinuation is improved with VDZ/UST compared with TNF-antagonist biologic therapy., (© The Author(s) 2020. Published by Oxford University Press on behalf of Crohn's & Colitis Foundation.)