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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.

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.

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.