A man in his 30s with longstanding ileal Crohn's disease was found to have pulmonary sarcoidosis during routine pre-biologic evaluation. Although he had no respiratory symptoms, lung function testing showed mildly reduced diffusion capacity. Radiological imaging demonstrated diffuse pulmonary nodules and mediastinal lymphadenopathy, and transbronchial biopsies confirmed non-necrotising granulomas consistent with sarcoidosis. In the setting of postoperative endoscopic Crohn's recurrence and pulmonary sarcoidosis with mildly reduced diffusion capacity, infliximab was selected to provide dual disease control. Crohn's disease improved endoscopically and histologically, while follow-up CT showed radiological improvement of the pulmonary sarcoidosis. This case highlights the diagnostic complexity of overlapping granulomatous diseases and the potential therapeutic advantage of tumour necrosis factor-alpha inhibition when treatment of both conditions is being considered.

Ulcerative colitis (UC), a primary subtype of inflammatory bowel disease, remains incompletely understood in terms of its molecular etiology. This study aimed to characterize the gene signatures associated with m6A, m7G, m5C, and m1A RNA modifications and explore their potential role in UC pathogenesis. We integrated three GEO datasets and, via LASSO regression, random forest, and SVM-RFE algorithms, identified three core differentially expressed RNA methylation-related genes (DERMGs): upregulated IFIT5 and MSI2 and downregulated NCBP1. These biomarkers showed diagnostic capability in the training cohort, with area under the curve (AUC) values above 0.75. The nomogram incorporating all three markers achieved an AUC of 0.947, with robust performance maintained in both the testing set and an additional external validation cohort. Functional enrichment analysis revealed that IFIT5 and MSI2 expression was positively correlated, whereas NCBP1 expression was inversely correlated with key inflammatory pathways, such as TNFA signaling via NF-κB, the inflammatory response, IL6/JAK/STAT3 signaling, and apoptosis. Immune infiltration assessment revealed that the expression of the core DERMGs was primarily associated with T cell subsets, as further supported by partial correlation analysis controlling for inflammatory burden. In addition, changes in the expression of these genes corresponded with clinical remission after treatment with infliximab or vedolizumab. In vitro experiments confirmed that LPS stimulation upregulated IFIT5 and MSI2 and downregulated NCBP1 in NCM460 and Caco-2 colonic epithelial cells. Collectively, these findings highlight the involvement of RNA methylations in UC pathogenesis and suggest IFIT5, MSI2, and NCBP1 as potential diagnostic and therapeutic targets.

Background: Subcutaneous infliximab (SC-IFX) represents a significant advance for patients with inflammatory bowel disease (IBD) due to the possibility of home self-administration. However, at this time, there are no clear recommendations for implementing model-informed precision dosing (MIPD) in accordance with real-world clinical knowledge. Objective: The aim of the present study is to develop a population pharmacokinetic (PopPK) model for SC-IFX. Methods: A multicenter retrospective observational study was performed in adult patients (both naïve patients and those switched from intravenous administration) diagnosed with IBD. PopPK analysis was performed using NONMEM with a nonlinear mixed-effects model approach. A stepwise covariate modeling approach was implemented to identify anthropometric and clinical factors influencing SC-IFX disposition. The bootstrap method was used for internal model validation. Results: A total of 250 serum concentration samples of IFX, corresponding to 45 patients, were analyzed. A one-compartment model with first-order absorption adequately described the data. The final model included total body weight and suspected immunogenicity as covariates of clearance (CL). Suspected immunogenicity was associated with a 70.0% increase in clearance, while each kg deviation from the median weight (73 kg) modified clearance by 0.888%/kg. Conclusions: A PopPK model for SC-IFX was successfully developed and validated using European real-world data. This exploratory model establishes a foundation for future MIPD applications, offering a structured approach to initiate or transition patients to SC-IFX therapy.

Background/Objectives: Mucosal healing (MH) is a key therapeutic target in inflammatory bowel disease (IBD) associated with sustained remission, reduced hospitalisation, and improved outcomes. Its assessment relies on endoscopic evaluation, which is invasive, costly, and not always feasible. Therapeutic drug monitoring (TDM) of infliximab (IFX) and evaluation of available biomarkers may provide non-invasive tools for predicting treatment response. This study investigated the association between IFX pharmacokinetics, routinely available blood biomarkers and MH to identify potential surrogates for predicting treatment outcomes. Methods: A monocentric, retrospective, real-world study was conducted, and pharmacokinetic analysis was performed in NONMEM version 7.5, applying a model with priors to estimate individual pharmacokinetic parameters. Endoscopic findings were collected, and patients were categorised according to achievement of MH. Univariate and multivariable logistic regression analyses were performed to evaluate the predictive value of tested variables, and receiver operating characteristic (ROC) curve analysis was performed to assess discriminative performance. Results: All evaluated variables demonstrated statistically significant associations with MH (p < 0.05). IFX clearance showed a strong inverse relationship with the probability of achieving MH. Leukocyte count exhibited particularly good discriminative ability, with an area under the ROC curve of 74.04% and an odds ratio of 0.78, highlighting its potential clinical utility. Multivariable logistic regression identified a model including IFX clearance and platelet count (PLT) as the most promising predictors of MH. Significant differences between patient subgroups indicated the association of higher PLT and modestly increased IFX clearance with a lower probability of MH. Conclusions: IFX clearance represents a promising surrogate marker for MH. TDM-derived parameters coupled with routinely available biomarkers may improve treatment response assessment. Combining pharmacokinetic and biomarker-based approaches could reduce reliance on repeated endoscopies while facilitating more effective IBD monitoring in clinical practice.

Perianal fistulizing Crohn's disease (pfCD) represents one of the most challenging manifestations. Optimal management requires a multidisciplinary approach combining surgical drainage, appropriate imaging, and advanced medical therapies. While infliximab remains the first-line medical therapy, primary non-response or secondary loss of response occurs in many patients, which highlights the need for effective alternative treatments. This narrative review summarizes the current evidence regarding medical therapies beyond infliximab, including biologics, small molecules, and emerging therapeutic strategies. A literature search of PubMed, Embase, and Scopus was conducted up to February 2026 to identify studies evaluating medical treatments of pfCD. Current evidence suggests that ustekinumab and upadacitinib remain effective following anti-TNF failure, while vedolizumab demonstrates limited efficacy. Evidence supporting IL-23 inhibitors, including risankizumab and guselkumab, is limited but rapidly evolving, with ongoing prospective trials expected to clarify their role. Novel approaches such as advanced dual-targeted therapy, subcutaneous infliximab optimization, hyperbaric oxygen therapy, and exclusive enteral nutrition have also shown encouraging preliminary results in selected patients. However, most available data derive from post hoc analyses, retrospective cohorts, or small prospective studies, with considerable heterogeneity in outcome definitions and limited incorporation of standardized radiological endpoints. Future adequately powered randomized controlled trials using harmonized clinical and magnetic resonance imaging -based outcomes are essential to establish optimal treatment sequencing and improve long-term fistula healing. Until then, individualized multidisciplinary management remains fundamental to optimizing outcomes in patients with pfCD.

Non-infectious uveitis (NIU) comprises a group of immune-mediated inflammatory diseases of the uvea that frequently affect people of working age. If inflammation is not controlled promptly, it may lead to permanent structural damage and visual loss. Prolonged corticosteroid use increases the risk of adverse effects. Contemporary treatment aims not only to control inflammation, but also to minimise dependence on corticosteroids. This narrative review examines the efficacy, safety, and place of biological and targeted therapies in the treatment of NIU. Adalimumab is the best-studied biological agent for intermediate, posterior, and panuveitis, as well as for uveitis associated with juvenile idiopathic arthritis. Infliximab has an important role in severe Behçet-associated uveitis and occlusive retinal vasculitis. Among the biological therapies with mechanisms of action other than TNF-α inhibition, tocilizumab is the best studied, particularly in refractory uveitic macular oedema. Janus kinase inhibitors (JAK inhibitors) are a rapidly developing class of targeted synthetic disease-modifying antirheumatic drugs (DMARDs). Clinical studies in NIU have shown variable efficacy and indicate their potential as a future therapeutic option. Treatment selection should be individualised and should take into account the anatomical form and severity of uveitis, the presence of systemic disease, macular oedema or occlusive retinal vasculitis, age and comorbidities, and the response to previous therapy. Therapeutic drug monitoring, biomarkers, and quantitative imaging parameters represent promising approaches to treatment personalisation; however, their clinical utility requires validation in prospective studies, and they are not currently part of routine clinical practice in non-infectious uveitis.

Background/Objectives: RELA encodes the p65 subunit of NF-κB and plays a critical role in immune regulation, epithelial protection, and anti-apoptotic signaling. Pathogenic RELA variants cause monogenic immune dysregulation with heterogeneous clinical manifestations. However, genotype-phenotype relationships and optimal treatment strategies remain incompletely defined. Methods: We conducted a comprehensive literature-based analysis of reported individuals with RELA variants and additionally described a family carrying a RELA c.706C>T (p.R236*) variant, including a clinically affected proband and his variant-positive father with isolated vitiligo. Clinical, immunological, genetic, endoscopic, and therapeutic data were extracted and summarized using a module-based phenotypic framework. Exploratory analyses were performed to examine potential genotype-phenotype patterns and reported treatment responses. Results: A total of 72 individuals with RELA variants, including the proband and his variant-positive father from the present family, were analyzed. RELA-associated disease exhibited marked clinical heterogeneity, encompassing mucocutaneous, systemic inflammatory, autoimmune, gastrointestinal, hematologic, allergic/eosinophilic, and infection-related manifestations. Exploratory analyses suggested that truncating or splice-site variants were more frequently observed among individuals with mucocutaneous lesions, whereas missense variants appeared to be more common among those with autoimmune manifestations. Tumor necrosis factor (TNF) inhibitors were among the therapies associated with favorable reported responses. In the present family, the proband presented with early-onset Behçet-like intestinal inflammation and achieved clinical and endoscopic remission after thalidomide and dose-escalated infliximab treatment. Conclusions: This study expands the clinical spectrum of RELA-associated disease and highlights preliminary variant-related clinical patterns that require confirmation in larger independent cohorts. The available treatment experience suggests that TNF blockade may be considered as a therapeutic option in selected patients, although comparative efficacy cannot be established from the available data.

Pediatric-onset ulcerative colitis (UC) is characterized by an aggressive phenotype, with higher rates of pancolitis and more rapid progression to a medically refractory state. After failure of conventional therapies and multiple biologic agents, treatment options are limited and often require surgery. We report the case of a 15-year-old girl with a 5-year history of highly refractory pancolitis-type UC. Previous treatments included mesalazine, salazosulfapyridine, tacrolimus, and three biologic agents (infliximab, vedolizumab, and adalimumab), all of which failed to maintain remission. After ustekinumab initiation, she initially experienced mild improvement but subsequently developed a severe clinical relapse (Pediatric Ulcerative Colitis Activity Index score: 40-50) triggered by Edwardsiella tarda infection. Despite infection resolution and treatment with systemic corticosteroids, her condition remained critical. As adjunctive therapy, intensive granulocyte and monocyte adsorptive apheresis (GMA) was administered twice weekly for 10 sessions, followed by twice monthly for 7 sessions, resulting in rapid symptomatic improvement. Follow-up colonoscopy confirmed complete mucosal healing (Mayo Endoscopic Subscore, 0). Intensive GMA may be a safe and effective adjunct to ustekinumab before its full therapeutic effect is achieved, potentially complementing the anti-inflammatory effects of ustekinumab in refractory pediatric UC and may help avoid colectomy even when multiple drug therapies have failed.