anti-TNF Research Articles

Tristetraprolin in cardiomyocytes has a protective role in pressure-overloaded hearts

Abstract Background Elevated circulating levels of TNFα, IL-6 and the soluble TNF receptors predict adverse outcomes in patients with heart failure. However, the targeted anti TNF approaches resulted in worsening heart failure or death. The entire scenario of how the expression levels of inflammatory cytokines are maintained in failing hearts must be elucidated to develop novel and effective treatments for heart failure. Although transcriptional control is a determinant of the kinetics of proinflammatory cytokine gene expression, the stability of the mRNA also has a key function in coordinating immune responses. Tristetraprolin (TTP) has been shown to control mRNA decay by associating with the 3’- untranslated region and critical for the decay of the mRNAs for cytokines. The role of TTP in nonimmune cells such as cardiomyocytes remains to be elucidated. Purpose The purpose of this study is to examine the in vivo role of proinflammatory cytokine degradation by TTP in cardiomyocytes during cardiac remodelling under pressure overload. Methods Cardiomyocyte-specific TTP–deficient mice were generated. The mice were subjected to pressure overload by means of transverse aortic constriction (TAC) to induce heart failure. Cardiac remodelling was assessed by echocardiography as well as histological and molecular analyses 4 weeks after operation. Cytokine mRNA levels were examined by quantitative PCR. Results Cardiomyocyte-specific TTP–deficient mice showed no cardiac phenotypes under baseline conditions. However, the mice exhibited severe systolic dysfunction, indicated by left ventricular fractional shortening, after 4 weeks of pressure overload by means of TAC compared with control littermates (fractional shortening, control littermates 35.8% versus cardiomyocyte-specific TTP-deficient mice 19.9%, p = 0.000). In addition, those hearts showed increases in collagen deposition and the mRNA levels of Col1a2 and Nppb (1.4 times (p = 0.023), 1.5 times (p = 0.033), and 2.0 times (p = 0.020), respectively) compared to corresponding control hearts. Four weeks after TAC, the Il6 mRNA level was upregulated 2.7 times (p = 0.000), but not other cytokine mRNAs, including Tnfα, in cardiomyocyte-specific TTP–deficient hearts compared to controls. Conclusions The degradation of cytokine mRNA by TTP in cardiomyocytes plays a protective role in failing hearts and the TTP–mediated pathway in cardiomyocytes might be a therapeutic target to treat patients with heart failure.

Abstract 15430: Dramatic Reduction in Lipoprotein(a) With Immunosuppressant, Anti-Inflammatory, and Antimicrobial Therapy in a Patient With Multiple Inflammatory Diseases

Background: Lipoprotein(a) (Lp(a)) is a potent, causative risk factor for ASCVD. Patients with inflammatory and autoimmune diseases are also at increased ASCVD risk. There is a complex, incompletely understood relationship between inflammation and Lp(a), including observations that IL-6 induces LPA gene expression. We present a unique case of dramatic Lp(a) lowering occurring with a combination of immunosuppressing, anti-inflammatory, and antimicrobial therapies. Case: A 50-year-old Black woman was referred to Lipid Clinic for Lp(a) of 138 mg/dL. Medical history included Crohn’s disease, total colectomy and end ileostomy, seronegative inflammatory polyarthropathy with psoriatic arthritis, and reactive neutrophilic dermatosis with suspected bowel-associated dermatitis-arthritis syndrome (BADAS). CT coronary calcium score was 0 Agatston units, but plaque was visible in her right coronary artery below the threshold for quantification. With rosuvastatin 5mg daily (which can increase Lp(a)), she experienced a ~25% reduction in LDL-C (baseline 102 mg/dL). She was not treated with niacin or PCSK9 inhibitors. Over the course of ~2.5 years, as the patient experienced BADAS flares she received extensive immunosuppressing, anti-inflammatory, and antimicrobial treatment including adalimumab (TNF-alpha inhibitor), sulfasalazine, dapsone, and doxycycline, and her Lp(a) decreased from 138 mg/dL to a low of 48 mg/dL (65% reduction) (Figure). Conclusion: Previous studies have shown that certain immunosuppressing therapies may lower Lp(a), and in this unique case we observed a dramatic reduction in Lp(a) during treatment with a complex regimen of immunosuppressing, anti-inflammatory, and antimicrobial therapies in a patient experiencing frequent flares of inflammatory diseases. The relationship between Lp(a), systemic inflammation, and the potential effects of anti-inflammatory and immunosuppressive therapies on Lp(a) deserves further study.

In Silico Screening of Ellagic Acid Derivatives and Their Metabolites as Inhibitors for NF-?b and Tnf?

The aim of this study was to evaluate inhibitory effects of ellagic acid derivatives and their metabolites on tumor necrosis factor ? (TNF?) and nuclear factor-?B (NF-?B). In silico molecular docking was performed. 3-O-methyl-3', 4' -methylenedioxy ellagic acid (MMDEA) and urolithin D were to be potent inhibitors of TNF? among tested molecules. For NF-?B (p50 and p65 subunits), MMDEA was found to be a potent inhibitor comparable with tanshinone IIA, a known NF-?B inhibitor. Ellagic acid derivatives seemed to be more effective than urolithins, their metabolites. All of the ellagic acid derivatives and their metabolites were predicted to have good pharmacokinetical properties according to Lipinski's rule of five. These results suggest that ellagic acid derivatives may potentially down-regulate inflammatory responses..

A Systematic Review and Meta-Analysis of Anti-Rheumatic Drugs and Pneumococcal Vaccine Immunogenicity in Inflammatory Arthritis.

Pneumococcal pneumonia is an important cause of morbidity and mortality amongst patients with inflammatory arthritis. Vaccination is recommended by the National Institute for Health and Care Excellence (NICE) but it remains unclear how vaccine efficacy is impacted by different immunosuppressive agents. Our objective was to compare the chance of a seroconversion following vaccination against pneumococcus in patients with inflammatory arthritis to that in the general population, as well as to compare the chance of seroconversion across different targeted therapies. We searched MEDLINE, Embase and the Cochrane Library databases from inception until 20 June 2023. We included randomized controlled trials and observational studies. Aggregate data were used to undertake a pairwise meta-analysis. Our primary outcome of interest was vaccine seroconversion. We accepted the definition of serological response reported by the authors of each study. Twenty studies were identified in the systematic review (2807 patients) with ten reporting sufficient data to be included in the meta-analysis (1443 patients). The chance of seroconversion in patients receiving targeted therapies, relative to the general population, was 0.61 (95% CI 0.35 to 1.08). The reduced odds of response were skewed strongly by the effects of abatacept and rituximab with no difference between patients on TNF inhibitors (TNFis) or IL-6 inhibition and healthy controls. Within different inflammatory arthritis populations the findings remained consistent, with rituximab having the strongest negative impact on vaccine response. TNF inhibition monotherapy was associated with a greater chance of vaccine response compared with methotrexate (2.25 (95% CI 1.28 to 3.96)). JAK inhibitor (JAKi) studies were few in number and did not present comparable vaccine response endpoints to include in the meta-analysis. The information available does not suggest any significant detrimental effects of JAKi on vaccine response. This updated meta-analysis confirms that, for most patients with inflammatory arthritis, pneumococcal vaccine can be administered with confidence and that it will achieve comparable seroconversion rates to the healthy population. Patients on rituximab were the group least likely to achieve a response and further research is needed to explore the value of multiple-course pneumococcal vaccination schedules in this population.

Selective inhibition of soluble TNF using XPro1595 improves hippocampal pathology to promote improved neurological recovery following traumatic brain injury in mice.

To determine the efficacy of XPro1595 to improve pathophysiological and functional outcomes in a mouse model of traumatic brain injury (TBI). Symptoms associated with TBI can be debilitating, and treatment without off-target side effects remains a challenge. This study aimed to investigate the efficacy of selectively inhibiting the soluble form of TNF (solTNF) using the biologic XPro1595 in a mouse model of TBI. Use XPro1595 to determine whether injury-induced solTNF promotes hippocampal inflammation and dendritic plasticity, and associated functional impairments. Mild-to-moderate traumatic brain injury (CCI model) was induced in adult male C57Bl/6J WT and Thy1-YFPH mice, with XPro1595 (10 mg/kg, S.C.) or vehicle being administered in a clinically relevant window (60 minutes post-injury). The animals were assessed for differences in neurological function, and hippocampal tissue was analyzed for inflammation and glial reactivity, as well as neuronal degeneration and plasticity. We report that unilateral CCI over the right parietal cortex in mice promoted deficits in learning and memory, depressive-like behavior, and neuropathic pain. Using immunohistochemical and Western blotting techniques, we observed the cortical injury promoted a set of expected pathophysiology's within the hippocampus consistent with the observed neurological outcomes, including glial reactivity, enhanced neuronal dendritic degeneration (dendritic beading), and reduced synaptic plasticity (spine density and PSD-95 expression) within the DG and CA1 region of the hippocampus, that were prevented in mice treated with XPro1595. Overall, we observed that selectively inhibiting solTNF using XPro1595 improved the pathophysiological and neurological sequelae of brain-injured mice, which provides support for its use in patients with TBI.

Disseminated tuberculosis after anti-TNF alpha treatment: Do not blindly trust the IGRA test

IntroductionInterferon gamma release assay (IGRA) is used to detect latent tuberculosis prior to biological treatments in the context of suspected inflammatory rheumatism. MethodsWe report the case of a 50-year-old woman with negative IGRA test before adalimumab introduction for presumed axial spondyloarthritis. ResultsThe worsening of symptoms under treatment led to further investigations and the diagnostic of disseminated tuberculosis (TB) was later established with miliary and multiple bone locations such as spondylitis and sacroilitis. The patient's history revealed past exposure to tuberculosis. This observation illustrates the limitations of IGRA in such situation due to its variable performance for active TB diagnosis. ConclusionMisdiagnosis is frequent in bone tuberculosis due to non-specific signs. We draw the attention to the importance of a global risk assessment prior to the introduction of biological treatment for suspected chronic inflammatory rheumatism and recall the risk factors for false-negative IGRA. An extended treatment course may be necessary after exposure to anti-TNF-alpha.

Investigation of corticosteroid-NSAID prodrugs for TNF-α and IL6 receptors, their characterization, single crystal XRD and DFT studies: A combined experimental and theoretical approach

In continuation of our research towards the synthesis of steroidal derivatives, we have synthesized corticosteroids-NSAIDs derivatives 3i-3p as potent anti-inflammatory agents. The products obtained have been characterized using elemental analysis, spectroscopic techniques (FT-IR, 1H NMR, 13C NMR, UV–Vis and mass spectrometry) and product 3k has also been characterized with the help of single crystal X-ray crystallography. The inhibition of pro-inflammatory cytokines is a key approach to abate severe inflammation. In this work a series of corticosteroids-NSAIDs derivatives are reported whose activity were performed on RAW264.7 cell line and have been identified as potential TNF alpha and IL6 inhibitors. Our work demonstrates that these corticosteroid derivatives may be useful for the development of anti-inflammatory agents. Among these derivatives, 11,17-dihydroxy-3,20-diketo-pregn-1,4-diene-21-yl-2-(1,8‑diethyl-1,3,4,9-tetrahydropyrano[3,4-β]indol-1-yl)acetate (3j) was identified as the most potent anti-inflammatory agent, which showed significant anti-inflammatory activity by inhibiting the LPS-induced pro-inflammatory mediator TNF-α and IL6 in a dose-dependent manner without any cytotoxicity.

Efficacy of TNF-Alpha Inhibitors to Control Inflammation and Prevent Secondary Complications in Non-Infectious Uveitis: A Real-Life Experience from Switzerland

ABSTRACT Purpose To evaluate the efficacy of systemic tumor necrosis factor-alpha inhibitors (TNFi) in the treatment of non-infectious uveitis (NIU). Methods This Swiss multicenter retrospective cohort study included patients with NIU requiring TNFi during the period from 2001 to 2018. Risk factors for the occurrence of new complications were identified using Cox regression analysis and hazard ratios (HR). Results Seventy-one patients (126 eyes; mean age 40.6 ± 14.4 years, mean duration of uveitis 46.0 ± 61.8 months) were followed for 40.2 ± 17.3 months after addition of TNFi. Under TNFi, visual acuity improved from 0.2 ± 0.3 to 0.1 ± 0.3 logMAR (p < 0.001). The portion of patients under systemic corticosteroids decreased from 81.7% to 25.4% (p < 0.001), while that for conventional synthetic disease-modifying anti-rheumatic drugs insignificantly decreased from 63.4% to 50.7% (p > 0.05). In 80.2% of eyes, complications were present at baseline with epiretinal gliosis (39.7%), cataract (41.3%) and macular edema (ME; 27.8%) being the most common. New complications under TNFi were encountered in 49.2% of eyes, also including recurrence (5 eyes) or new onset of ME (14 eyes). The need for switching of TNFi was associated with further complications (HR 3.78, p = 0.012). Conclusion Although the efficacy and tolerability of TNFi in a real-life setting are favorable, treatment is often initiated late, i.e., after many eyes have already developed complications. Even with TNFi, new complications, particularly ME, cannot be completely avoided. Further research is needed to assess the impact of earlier initiation of TNFi therapy.

CIAPs control RIPK1 kinase activity-dependent and-independent cell death and tissue inflammation.

Cellular inhibitor of apoptosis proteins (cIAPs) are RING-containing E3 ubiquitin ligases that ubiquitylate receptor-interacting protein kinase 1 (RIPK1) to regulate TNF signalling. Here, we established mice simultaneously expressing enzymatically inactive cIAP1/2 variants, bearing mutations in the RING domains of cIAP1/2 (cIAP1/2 mutant RING, cIAP1/2MutR ). cIap1/2MutR/MutR mice died during embryonic development due to RIPK1-mediated apoptosis. While expression of kinase-inactive RIPK1D138N rescued embryonic development, Ripk1D138N/D138N /cIap1/2MutR/MutR mice developed systemic inflammation and died postweaning. Cells expressing cIAP1/2MutR and RIPK1D138N were still susceptible to TNF-induced apoptosis and necroptosis, implying additional kinase-independent RIPK1 activities in regulating TNF signalling. Although further ablation of Ripk3 did not lead to any phenotypic improvement, Tnfr1 gene knock-out prevented early onset of systemic inflammation and premature mortality, indicating that cIAPs control TNFR1-mediated toxicity independent of RIPK1 and RIPK3. Beyond providing novel molecular insights into TNF-signalling, the mouse model established in this study can serve as a useful tool to further evaluate ongoing therapeutic protocols using inhibitors of TNF, cIAPs and RIPK1.

Advances in the Diagnosis and Treatment of Enthesitis-Related Arthritis.

Enthesitis-related arthritis (ERA) represents 5-30% of all cases of juvenile idiopathic arthritis (JIA) and belongs to the spectrum of the disorders included in the group of juvenile spondyloarthritis. In the last decade, there have been considerable advances in the classification, diagnosis, monitoring, and treatment of ERA. New provisional criteria for ERA have been recently proposed by the Paediatric Rheumatology INternational Trials Organisation, as part of a wider revision of the International League of Associations for Rheumatology criteria for JIA. The increased use of magnetic resonance imaging has shown that a high proportion of patients with ERA present a subclinical axial disease. Diverse instruments can be used to assess the disease activity of ERA. The therapeutic recommendations for ERA are comparable to those applied to other non-systemic JIA categories, unless axial disease and/or enthesitis are present. In such cases, the early use of a TNF-alpha inhibitor is recommended. Novel treatment agents are promising, including IL-17/IL-23 or JAK/STAT pathways blockers.

S3239 Paradoxical Pustular Psoriasis Secondary to TNF Alpha Inhibitor Use in Ulcerative Colitis

S3239 Paradoxical Pustular Psoriasis Secondary to TNF Alpha Inhibitor Use in Ulcerative Colitis

S3207 Induction of Remission in TNF-Alpha Inhibitor Refractory Acute Severe Ulcerative Colitis With Upadacitinib: A Case Report

S3207 Induction of Remission in TNF-Alpha Inhibitor Refractory Acute Severe Ulcerative Colitis With Upadacitinib: A Case Report

P27 A case of unilateral scleritis and biopsy proven retinal vasculitis in an elderly woman with rheumatoid arthritis and previous retinal detachment surgery with silicone oil band

P27 A case of unilateral scleritis and biopsy proven retinal vasculitis in an elderly woman with rheumatoid arthritis and previous retinal detachment surgery with silicone oil band

Therapeutic antibodies in rheumatology

Emil von Behring's serum therapy for diphtheria was the first therapeutic use of antibodies. More than 100 years later, anew era in the treatment of rheumatic diseases began in 1998 with the approval of infliximab, an antibody directed against tumor necrosis factor alpha (TNF alpha). The special feature of antibody therapy is the ability to bind and neutralize antigens in ahighly specific manner. In addition, target cells can be eliminated by activation of the immune system. These properties of the immune system are exploited in rheumatology to eliminate inflammatory cytokines or antibody-producing Blymphocytes. The tolerability is usually good but potential side effects, such as reactivation of tuberculosis with anti-TNF alpha treatment must be considered. Currently, 20different antibodies and fusion proteins have been approved in Germany for the treatment of various inflammatory rheumatic diseases. Biosimilars can contribute to aprice reduction after the patent protection expires. Many additional target antigens are being investigated and further structural innovations (e.g., bispecific antibodies, nanobodies or coupling with small molecules) are being developed.

Uncovering the Role of Epstein-Barr Virus Infection Markers for Remission in Rheumatoid Arthritis.

Epstein-Barr virus (EBV) infection has been shown as a potential risk factor for the development of rheumatoid arthritis (RA). This prospective research aimed to investigate whether EBV infection markers changed during the six-month follow-up period in 133 RA patients (80 newly diagnosed on methotrexate (MTX)-RA-A, and 53 on biologic therapy-RA-B) and whether it was related to a disease outcome. Reduction of disease activity and inflammation was obtained. A significant decline in seroprevalence and titer for anti-VCA-IgM (p = 0.022 and p = 0.026) and anti-EA(D)-IgM (p = 0.022 and p = 0.006) in RA-A, and in seroprevalence and titer of anti-EA(D)-IgG in the RA-B subgroup (p = 0.021 and p = 0.006) were detected after the follow-up. A lower titer of anti-EBNA1-IgG could be considered a significant marker of RA remission in all RA patients regardless of age and gender (OR = 0.99, 95% CI OR = 0.98-0.99, p = 0.038), and also in RA-B patients separately (OR = 0.988, 95% CI OR = 0.98-0.99, p = 0.041). This study supported the basic hypothesis that the immune response to EBV infection is involved in the RA pathogenesis, at the beginning of the disease or during the RA evolution. Moreover, the potential influence of MTX or TNF-alpha inhibitors on the impairment of the host to control EBV infection was indirectly refuted.

Insights on in-silico approaches for identifying potential bioactive inhibitors for TNF-α and IL-6 proteins associated with rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic immunocompromised disorder that primarily affects joints thereby leading to synovial inflammation, pain, stiffness, stress, and affecting the quality of life. The present study aimed to determine and identify bioactive compounds that can be developed as potential inhibitors to target human TNF-α and IL-6 proteins associated with RA. The present study also aimed to determine physiochemical properties and toxicity of compounds by ADMET, identify binding pockets via CASTp server, stereochemical quality of protein by PROCHECK, MMGB/SA analysis by fastDRH and molecular dynamics (WebGro). The findings of the present study revealed staurosporine was the most effective compound against TNF-α with the highest binding affinity of −10.8 kcal/mol. Similarly, withanoside L showed the highest binding affinity of −8.2 kcal/mol when docked against IL-6. In the present study, rutin, withanoside II, and withanoside IV did not follow Lipinski’s rule of five whereas staurosporine, somnifericin, and withanolide L followed RO5. In the present study, the top binding pocket of TNF-α had highest area (SA) of 2743.25 Å2 and volume (SA) 4514.06 Å3 whereas IL-6 had highest area (SA) of 63.54 Å2 and volume (SA) of 38.58 Å3 respectively. In this study, Ramachandran plot analysis revealed that 90.2% and 95.2% residues for TNF-α and IL-6 proteins occupied the most favored region. In the present study, TNF-α rutin complex and IL-6 rutin complex showed the highest PB1 score of 13.69 kcal/mol and 12.30 kcal/mol respectively. WebGro server estimated molecular dynamic properties (RMSD, Rg, SASA, RMSF and hydrogen bonds) of the proteins. Bio2Byte tools predicted the biophysical behaviour of the proteins. The findings of the present study revealed that staurosporine and withanolide L could be developed as potential inhibitors of TNF- α and IL-6, however further in-vitro and in-vivo studies are required to validate these results.

E11 The burden of illness perception among patients with juvenile idiopathic arthritis

Abstract Background Juvenile Idiopathic Arthritis (JIA) is a debilitating condition that can negatively impact the life of children [1]. Indeed, because of a prolonged course of active disease, patients may experience several limitations and tend to have their unique perception of their illness. Objectives This study aimed to to investigate the illness perception of patients with JIA. Methods We conducted a cross-sectional study including children with JIA (according to the International League of Associations for Rheumatology (ILAR)), recruited from our rheumatology department. Sociodemographic data and disease characteristics were collected. The patients were invited to answer the Brief Illness Perception Questionnaire (BIPQ) to quantify their perception of the disease and how it affects their life. For the patients under the age of 11 years old, we asked the parents to answer the questionnaire. The BIPQ is a nine-item questionnaire rated using a 0-to10 response scale that assesses cognitive illness representations: consequences, timeline, personal control, treatment control, identity, emotional representations and illness comprehensibility [2]. Result Our study involved 31 patients with an average age of 28.7 [9–45] years and consisted of 12 (38.7%) males and 19 (61.3%) females. The mean age at onset and the duration of the disease were 6.6 years [2–13] and 255.84 [36–444] months, respectively. The distribution of the different forms of JIA was as follows: oligoarticular (n = 6), enthesitis-related arthritis (n = 4), polyarticular with positive rheumatoid factor (RF) (n = 9), polyarticular with negative RF (n = 7) and systemic form (n = 5). Regarding treatment modalities, 13 (41.9%) were on corticosteroids, 21 (67.7%) were treated with Cs-DMARDS and 11 (39.3%) were on anti-TNF alpha. Eleven patients required total hip replacement. The mean PGA was 27.6/100. Only eight patients had moderate to severe disease activity. All the patients responded to the entire BIPQ questionnaire with an average score of 46.48/80 [18–68]. Regarding the first question assessing the impact of the disease on life, our patients responded with an average score of 4.7/10 reflecting a healthy perception of the disease. There was a significant association between how much patients experience their symptoms and the emotional impact of the disease (r = 0.8; P = 0.001). Moreover, patients who had a personal and treatment control, were less prone to be affected by the disease emotionally (r = -0.006; P = 0.9). Conclusion Our work highlighted the importance of assessing illness perception of patients with JIA. This condition should be evaluated from different perspectives in order to implement a personalized management strategy. Ethics This work is ethically approved Key words: Juvenile idiopathic arthritis, illness perception

E42 Severe infectious adverse events in children treated with biological agents

Abstract Background Since the 90’s, biologics, as a novel class of drugs, have revolutionized the therapeutic field of autoimmune and inflammatory diseases in children by providing effective treatment options. Biologics aim to modify targeted pathways to interfere with the immunologic aberration creating the clinical disease, However, alteration of the pathways increase the risk of infection. We report a series of severe infectious adverse events (SIAE) in children treated with biologics. Objectives and Methods This is a retrospective study over a period of 10 years (January 2012-October 2022) conducted in the Department of Pediatric Rheumatology and internal Medicine, A. Harouchi Mother and Child Hospital CHU Ibn Rochd, Casablanca, Morocco. The aim of our study is to assess SIAE in children treated with Results The study included 76 patients on biologics with different diseases dominated by systemic juvenile idiopathic arthritis. Six patients developed SIAE, sex-ratio was 1, four patients received TNF-alpha inhibitors (Infliximab, Adalimumab, Etanercept), 1 on Tocilizumab and 1 on Rituximab. Our 6 patients were on other immunosuppressive agents simultaneously (Corticosteroids, MMF, Azathioprine, Methotrexate). The delay of occurrence of SIAE after the initiation of biologics ranged from 10 days to 7 years. We report 3 cases of Tuberculosis, 2 of which were treated with anti-TNF agents, 1 case of CMV hepatitis, 1 case of Herpes zoster and 1 case of orbital cellulites. Treatment consisted of temporary discontinuation of biologic with specific management of the SIAE by an appropriate anti-infectious agent. The evolution was favorable except one case of death. Discussion and Conclusion Biologics have become an important component of effective management of patients with autoimmune and inflammatory diseases. However, there is an increased risk of SIAE for those patients, especially the risks of Tuberculosis and viral infections, even though systematic screening is performed prior to the start of biotherapy, requiring physician vigilance.

Predictors and optimal management of tumor necrosis factor antagonist nonresponse in inflammatory bowel disease: A literature review.

Tumor necrosis factor-α (TNF-α) antagonists, the first biologics approved for treating patients with inflammatory bowel disease (IBD), are effective for the induction and maintenance of remission and significantly improving prognosis. However, up to one-third of treated patients show primary nonresponse (PNR) to anti-TNF-α therapies, and 23%-50% of IBD patients experience loss of response (LOR) to these biologics during subsequent treatment. There is still no recognized predictor for evaluating the efficacy of anti-TNF drugs. This review summarizes the existing predictors of PNR and LOR to anti-TNF in IBD patients. Most predictors remain controversial, and only previous surgical history, disease manifestations, drug concentrations, antidrug antibodies, serum albumin, some biologic markers, and some genetic markers may be potentially predictive. In addition, we also discuss the next steps of treatment for patients with PNR or LOR to TNF antagonists. Therapeutic drug monitoring plays an important role in treatment selection. Dose escalation, combination therapy, switching to a different anti-TNF drug, or switching to a biologic with a different mechanism of action can be selected based on the concentration of the drug and/or antidrug antibodies.

Shaping the Future of Behçet's Uveitis Management: A Comprehensive Review of Efficacy, Challenges, and Prospects of Biologic Therapies.

Behçet's uveitis (BU), a vision-threatening manifestation of Behçet's disease, poses substantial management challenges due to its chronic, relapsing nature and potential for vision loss. This review explores the role of biologic therapies in the treatment of BU, providing a comprehensive overview of their effectiveness, drawbacks, and future possibilities. Traditionally, management has relied heavily on corticosteroids and conventional immunosuppressants. However, their long-term use is frequently associated with systemic side effects and insufficient control of ocular inflammation. Biologic therapies, particularly TNF-alpha inhibitors like infliximab and adalimumab, have emerged as effective alternatives, offering better disease control and a more favorable safety profile. We critically evaluated these agents, noting their clinical efficacy in reducing inflammatory flares and preserving visual acuity. Despite their benefits, several issues remain. Accessibility, cost, and lack of long-term safety data limit their widespread use. Additionally, individual variability in treatment response necessitates personalized therapeutic strategies. Recent research has shown promise in addressing these challenges, with the emergence of novel biologic agents and personalized medicine approaches. In summary, biologic therapies represent a paradigm shift in BU management, contributing to better patient outcomes. Yet, there are significant challenges to be overcome. As we move forward, continued research, development of novel biologic agents, and a precision medicine approach will shape the future landscape of BU treatment.