Tumor necrosis factor (TNF) is identified as a pro-inflammatory cytokine critical to the pathology of liver disease. In the carbohydrate metabolism, TNF has been demonstrated to impede the insulin signaling pathway, thereby precipitating glucose intolerance and insulin resistance. In lipid metabolism, TNF upregulates genes implicated in fatty acid synthesis, resulting in increased lipid accumulation within the liver. In amino acid metabolism, TNF has shown to promote the gene expression for amino acid catabolism, leading to decreased protein synthesis. Additionally, TNF stimulates the production of other chemokines and inflammatory cytokines that can further exacerbate liver injury. Overall, TNF is crucial in developing liver diseases by disrupting various metabolic pathways in the liver, causing insulin resistance, lipid accumulation, and decreased protein synthesis. This review summarizes the present understanding of TNF's role in the regulation of carbohydrate, lipid and amino acid metabolism in liver disease together with its potential therapeutic implications.

Preoperative use of biologics has been inconsistently reported to be associated with increased frequency of infectious and surgical anastomotic complications in inflammatory bowel disease patients. We aimed to evaluate the rates of 30-day postoperative morbidity and mortality in Crohn's disease patients exposed preoperatively to biologics. Data were collected from the NSQIP (National Surgical Quality Improvement Program). Crohn's disease patients undergoing open or laparoscopic ileocolectomy were identified using corresponding ICD 10 and CPT Codes from the NSQIP Participant Use Data File (PUF) for 2021. Patients were divided based on the preoperative use of biologics (group 1) and (group 2) for whom no biologics were used. A total of 910 patients (female n = 473; 52%, mean age of 42.3 ± 16.1) were included. The group 1 patients were significantly younger (40.30 years ± 15.33) than group 2 (43.58 years ± 16.8, p = 0.002) and had significantly slightly higher ASA III and IV scores (97.4% vs. 97.2%, p = 0.004). On the other hand, group 2 had a significantly higher prevalence of hypertension (20.2% vs. 12.8%, p = 0.003) and chronic obstructive pulmonary disease (2.6% vs. 0%, p = 0.001). No significant difference in remaining preoperative variables, surgical approach (laparoscopic vs. open), and comorbidities were found between the two groups. Only a significant prevalence of deep vein thrombosis and thromboembolism was found in patients exposed to biologics (1.1% vs. 0%, p = 0.027). Crohn's disease patients undergoing ileocolectomy and exposed preoperatively to biologics did not show a significant increase in 30-day postoperative morbidity and mortality. The outcomes did not support the concept that biological agents increase septic complications.

Crohn's disease (CD) is a chronic inflammatory bowel disease leading to symptoms such as abdominal pain, diarrhea, weight loss, fatigue, and complications such as strictures and fistulas. Ustekinumab (CNTO 1275) and briakinumab (ABT-874) are monoclonal antibodies that target the standard p40 subunit of the cytokines interleukin-12 and interleukin-23 (IL-12/23p40), which are involved in the pathogenesis of CD. Briakinumab has been withdrawn for the treatment of CD, making ustekinumab the only available antibody against the p40 subunit of interleukin-12 and interleukin-23 approved for this purpose.

To assess the benefits and harms of anti-IL-12/23p40 antibodies for induction of remission in CD, as compared to no treatment, placebo, other drug treatment, or varying dosing schedules.

We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and MEDLINE (from inception to 2 February 2024) and Embase (from inception until 12 August 2022). We also searched ClinicalTrials.gov, WHO ICTRP, references, and conference abstracts to identify additional studies.

We included randomized controlled trials (RCTs) of at least four weeks' duration in which monoclonal antibodies against IL-12/23p40 were compared to placebo, no treatment, or another active comparator in people with active CD. We also included trials examining different doses of antibodies against IL-12/23p40.

Two review authors independently screened studies for inclusion and extracted data. We assessed the methodological quality of the included studies using Cochrane's RoB 2 tool. The primary outcome was failure to induce clinical remission by week 8, or 6 to 12 as available. Secondary outcomes included failure to induce clinical improvement (clinical response), induction of endoscopic remission, quality of life, and adverse events, serious adverse events, and withdrawals due to adverse events. We calculated the risk ratio (RR) or risk difference (RD) and 95% confidence intervals (95% CI) for each outcome unless substantial heterogeneity was detected. We analyzed data on an intention-to-treat basis. We assessed the certainty of the evidence using the GRADE approach.

Eight RCTs involving a total of 3224 participants with CD met the inclusion criteria. All studies were double-blinded. We assessed the risk of bias for most outcomes as either low risk of bias or some concerns. Based on a pooled analysis of three trials, ustekinumab decreased the number of participants failing to achieve clinical remission at eight weeks when compared to placebo. Seventy-four per cent (693/938) of participants in the ustekinumab group and 87% (421/483) of those in the placebo group did not enter clinical remission (RR 0.85, 95% CI 0.81 to 0.89; 3 studies; 1421 participants; high-certainty evidence). Treatment with ustekinumab likely did not lead to more serious adverse events when compared to placebo, with 5% (48/966) and 6% (30/505) of participants affected in the ustekinumab and placebo groups, respectively (RD -0.01, 95% CI -0.03 to 0.01; 3 studies; 1471 participants; moderate-certainty evidence). A single small study in children compared two different induction doses of ustekinumab. The evidence for this outcome is very uncertain due to wide CIs. Eighty-one per cent (17/21) of participants receiving the higher induction dose (9 mg/kg or 390 mg) did not enter clinical remission at eight weeks, compared to 78% (18/23) of participants receiving the lower induction dose of 3 mg/kg or 130 mg (RR 1.03, 95% CI 0.77 to 1.39; 1 study; 44 participants; very low-certainty evidence). Separate safety data for the eight-week time point were not available for this comparison. Based on one trial comparing ustekinumab to adalimumab, the evidence is very uncertain about which is the more beneficial drug. Fifty per cent (95/191) of participants receiving ustekinumab did not enter remission compared to 52% (101/195) of participants receiving adalimumab (RR 0.96, 95% CI 0.79 to 1.17; 1 study; 386 participants; very low-certainty evidence). Separate results on adverse events at eight weeks were not reported for this comparison.

Ustekinumab reduces the risk of people with CD failing to enter clinical remission at eight weeks. It probably does not lead to more serious adverse events when compared to placebo. There were inadequate data to conclude the more effective induction dose of ustekinumab in children. No studies evaluated adverse events at eight weeks for this comparison. There may be little to no difference between ustekinumab and other biologics, such as adalimumab or guselkumab, in inducing clinical remission at week 8, but the evidence is very uncertain, and separate data on adverse events at eight weeks were not available.

This systematic review aims to elucidate the use of corticosteroids in randomized clinical trials (RCTs) evaluating biologics and small molecules for inflammatory bowel disease (IBD). We analyzed corticosteroid use during both the induction and maintenance phases, highlighting areas needing standardization and improvement in clinical research.

We selected placebo-controlled phase 3 RCTs involving adults with moderate to severe IBD. These studies included detailed reports on corticosteroid use during induction and maintenance phases, with clinical remission and/or corticosteroid-free clinical remission (CSF-CR) as primary endpoints.

Initially, 324 studies were identified and refined to 26 RCTs after screening. Analysis revealed variability in corticosteroid administration. Over time, corticosteroid use showed a decreasing trend (Spearman ρ = -0.42, P = .045). Studies allowing higher corticosteroid doses (up to 40 mg/day of prednisone or equivalent) reported a higher proportion of corticosteroid users (51.8%, range: 42.9%-61%) compared to those excluding patients on doses >20 mg/day (37.5%, range: 31.6%-51.8%; P = .007) or >30 mg/day (41.1%, range: 29.6%-53.7%; P = .023). Trials with mandatory tapering protocols showed a narrower gap between overall clinical remission and CSF-CR rates, with an average difference of 6% in the group without mandatory tapering and 1.2% in the group with forced tapering (T-test P = .038; Cohen's d ≈ 1.1).

This review highlights the variability in corticosteroid use across RCTs and its impact on evaluating new IBD therapies. Standardizing tapering protocols and defining CSF-CR are essential for accurate outcomes.

An alternative to lifelong antiretroviral therapy (ART) is needed to achieve durable control of HIV-1. Here, we show that adeno-associated virus (AAV) delivery of two rhesus macaque antibodies to the simian immunodeficiency virus (SIV) envelope glycoprotein (Env) with potent neutralization and antibody-dependent cellular cytotoxicity can prevent viral rebound in macaques infected with barcoded SIVmac239M after discontinuing suppressive ART. After AAV administration, sustained antibody expression with minimal antidrug antibody responses was achieved in all but one animal. After ART withdrawal, SIV replication rebounded within 2 weeks in all control animals but remained <15 copies per milliliter in plasma for more than a year in four of the eight animals that received AAV vectors encoding Env-specific antibodies. Viral sequences from animals that rebounded with delayed kinetics exhibited restricted clonal diversity and antibody escape mutations in Env. Thus, sustained expression of antibodies with potent antiviral activity can afford durable, ART-free containment of pathogenic SIV infection.

Immunogenicity of biologic agents for inflammatory bowel disease (IBD) is a critical issue, especially for tumor necrosis factor (TNF) inhibitors, where anti-drug antibodies (ADAs) significantly impact drug clearance, efficacy, and safety. Studies have demonstrated that non-TNF biologics tend to have lower susceptibility to immunogenicity, potentially offering advantages, especially in long-term management. Understanding these differences is important for optimizing IBD treatment outcomes.

This review examines immunogenicity associated with different classes and individual biologic agents used in IBD; including TNF inhibitors and biologics targeting integrins and interleukins. We discuss key factors influencing ADAs formation, including drug structure, route of administration, and patient-specific factors. The literature reviewed includes recent clinical studies and long-term trials focusing on strategies to reduce immunogenicity such as therapeutic drug monitoring (TDM) and advanced combination.

While newer biologics demonstrate lower immunogenicity compared to anti-TNF agents, challenges remain in management to overcome existing ADAs responses while advances in genetic profiling, point-of-care TDM, and combination therapies offer promising pathways to reduce immunogenicity and enhance treatment durability. Continued research and innovation in biologic delivery methods, such as oral and subcutaneous formulations, will be critical in the next decade to further mitigate immunogenic risks and improve patient outcomes.

To provide a comprehensive overview of peripheral spondyloarthritis (pSpA), focusing specifically on its occurrence and management in patients with inflammatory bowel disease (IBD).

An exhaustive literature search was conducted in PubMed, Embase, Cochrane Database of Systematic Reviews, and Google Scholar to identify relevant studies on pSpA in IBD patients. Titles, abstracts, and full-text articles were screened for relevance. Data on study design, patient characteristics, diagnostic criteria, main findings, and conclusions were extracted from selected articles. Study quality was assessed using appropriate checklists. Information was synthesized narratively to summarize current understanding.

pSpA is the most common extraintestinal manifestation of IBD, with a median prevalence of 16%. It worsens quality of life and requires collaboration between gastroenterologists and rheumatologists for optimal diagnosis and treatment. Several "red flags" guide appropriate specialist referral of IBD patients with suspected pSpA. Once the diagnosis is confirmed, the choice of therapy depends on IBD phenotype and patterns of articular/axial involvement. Anti-tumor necrosis factor (TNF) drugs are first-line biologics, with interleukin (IL)-12/23 and IL-23 inhibitors as alternatives for anti-TNF failure. Small molecules like apremilast and Janus kinase inhibitors also have utility. Recommended treatment algorithms exist, but more randomized controlled trials are needed.

Early identification of pSpA is crucial in IBD patients to enable timely intervention, prevent structural damage, and minimize disability. A multidisciplinary, holistic approach addressing musculoskeletal and extra-musculoskeletal manifestations is key to optimal patient outcomes.

Psoriasis, a common chronic inflammatory skin disorder, encompasses various subtypes, including guttate, pustular, erythrodermic, and the most common type, plaque psoriasis. Irrespective of the subtype, psoriasis can manifest with multisystemic presentations, including psoriatic arthritis, metabolic disorders, cardiovascular disease, malignancies, chronic kidney disease (CKD), psychiatric illness, and inflammatory bowel disease (IBD). Many comorbidities and concomitant conditions must be considered when selecting the most appropriate therapy for a patient (Kaushik et al., 2019 and Monks et al., 2021) . Ongoing clinical trials and the development of new therapeutic targets contribute to the continuous improvement of available treatment options. Given the dynamic landscape of therapies, particularly when managing complex patients with multiple comorbidities, dermatologists are constantly challenged with the task of adeptly tailoring treatments to each psoriasis patient. This article systematically reviews the current evidence, presenting it as an updated Psoriasis Decision Tree to assist physicians in selecting tailored treatment options.

Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, is a group of chronic, immune-mediated disorders of the gastrointestinal tract that present substantial clinical challenges owing to their complex pathophysiology and tendency to relapse. A treat-to-target approach is recommended, involving iterative treatment adjustments to achieve clinical response, reduce inflammatory markers and achieve long-term goals such as mucosal healing. Lifelong medication is often necessary to manage the disease, maintain remission and prevent complications. The therapeutic landscape for IBD has evolved substantially; however, a ceiling on therapeutic efficacy remains and surgery is sometimes required (owing to uncontrolled disease activity or complications). Effective IBD management involves comprehensive care, including medication adherence and a collaborative clinician-patient relationship. This Review discusses current therapeutic options for IBD, detailing mechanisms of action, efficacy, safety profiles and guidelines for use of each drug class. We also explore emerging therapies and the role of surgery. Additionally, the importance of a multidisciplinary team and personalized care in managing IBD is emphasized, advocating for patient empowerment and involvement in treatment decisions. By synthesizing current knowledge and emerging trends, this Review aims to equip healthcare professionals with a thorough understanding of therapeutic options for IBD, enhancing informed, evidence-based decisions in clinical practice.

Crohn's disease (CD) causes gastrointestinal symptoms (i.e., diarrhea and abdominal pain), systemic symptoms (i.e., fatigue, anemia, weight loss, and fever), and perianal fistulas that produce anal pain. Because of the frequent occurrence of diarrhea and ulcers in the rectum, CD is often exacerbated by perianal abscesses and/or fistulas. Perianal fistulizing CD (PFCD) has an unknown etiology and recurring symptoms such as pain and discharge, which seriously affects the patient's quality of life (QOL). In the past, radical surgery was performed for PFCD, but due to the risk of anal sphincter impairment, conservative therapy using antibiotics and immunosuppressive medications is currently the first treatment option. PFCD management has greatly improved with the use of biologics such as the antitumor necrosis factor alpha (TNF-α) antibodies infliximab and adalimumab. In this review, the results of the administration of anti-TNF-α (certolizumab pegol), anti-interleukin-12/23 (ustekinumab), and anti-α4β7 integrin antibodies (vedolizumab) were evaluated. Our investigation showed that these medications may be effective for maintenance therapy to prevent the recurrence of anal fistulas. In addition to biologics, molecular target drugs and even regenerative medicine using mesenchymal stem cells have been introduced to further expand the treatment options for consideration by medical personnel. We herein discuss the management of PFCD by focusing on studies conducted in the United States and Europe where researchers used recommended guidelines and consensus statements to evaluate the efficacy of each medication and published their findings in peer-reviewed journals.

In contrast to previous network meta-analysis using classical frequentist methods, we evaluated the efficacy and safety of six frequently-used biologics through a Bayesian method.

Web of Science, Scopus, CENTRAL, ClinicalTrials.gov and ICTRP were searched to collect randomized controlled trials (RCTs) in adults with moderate-to-severe Crohn's disease, comparing Infliximab, Adalimumab, Certolizumab pegol, Ustekinumab, Risankizumab, or Vedolizumab, relative to placebo or an active comparator for induction of clinical response (two different definitions) and maintenance of clinical remission. A random-effects model was performed with rankings according to the surface under cumulative ranking curve (SUCRA) probability. Finally, we completed sensitivity and consistency analyses, and evaluated the certainty of evidence through GRADE working group guidance.

We identified 22 and 20 RCTs for induction and maintenance therapy, respectively. Infliximab combined with azathioprine was most effective for inducing clinical response in TNF (tumor necrosis factor) antagonist-naïve patients. For TNF antagonist-experienced patients, Ustekinumab (SUCRA 86.19) and Risankizumab (SUCRA 62.56) have the largest SUCRA in induction of clinical response. Risankizumab has the lowest risk of adverse events (SUCRA 84.81), serious adverse events (SUCRA 94.23), and serious infections (SUCRA 79.73) in induction therapy. Adalimumab and the 10 mg/kg regimen of Infliximab rank highest for maintaining clinical remission.

This analysis suggests that Infliximab in combination with azathioprine may be preferred biologic agents for induction therapy in TNF antagonist-naïve patients. For TNF antagonist-experienced patients, Ustekinumab and Risankizumab may be preferred biologic agents for induction therapy. Risankizumab potentially has the lowest safety risk worth exploring in induction therapy. Adalimumab and the 10 mg/kg regimen of Infliximab have maintenance efficacy benefits for responders to induction therapy.

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=458609, Identifier CRD42023458609.

This article discusses the literature review article by Pacheco et al published in July 2024; the authors provided good reviews of perianal Crohn's disease (CD), and challenges faced by clinicians in the management. CD, characterized by its chronic and relapsing nature, is an idiopathic condition that can involve any segment of the gastrointestinal tract. Perianal disease impacts up to 40% of patients with CD, with perianal fistulas constituting up to 80% of perianal lesions. Perianal CD can be highly incapacitating and profoundly diminish the overall well-being of patients. The management focuses on controlling the perianal sepsis and treating luminal CD. Biologics are crucial to the treatment approach, and results have been encouraging. The surgery focuses on controlling the sepsis, with more definitive treatments being fistula surgery, fecal diversion, and proctectomy as the last resort. This manuscript briefly describes the burden of CD, the challenges posed by perianal CD, and the role of different treatment modalities from colorectal surgeon's perspective.

Treatment options for the medical management of inflammatory bowel disease (IBD) have expanded substantially over the past decade. Multiple classes of advanced therapies, including both monoclonal antibodies and novel oral small molecules, are now available for the treatment of moderately-to-severely active Crohn's disease and ulcerative colitis, highlighted by the approvals of the first IL23p19 antagonists, selective Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators. These advances have been accompanied by the identification of novel targets and the rapid growth in both the number and size of IBD clinical trials. Over a dozen landmark randomized controlled trials (RCTs) have been completed in the past 5 years, including the first head-to-head biologic trials, the first combination biologic studies, and multiple phase III registrational trials of novel compounds with new co-primary and composite end points that will change the treatment landscape for years to come. Importantly, the methodology of RCTs in IBD has evolved substantially, with new trial designs, evaluation of unique patient populations, and different types of efficacy and safety end points being key innovations. In this Review, we provide a comprehensive evaluation of how modern RCTs of IBD medical therapies have evolved and the implications for their appraisal that will help guide the application of these data to clinical practice.

Randomised placebo-controlled trials for the induction of inflammatory bowel disease (IBD) remission involve potential harms to those receiving placebo. Whether these harms are also apparent with placebo during maintenance of remission trials in IBD is unclear. We aimed to examine the potential harms associated with receiving placebo in trials of licensed biologics and small molecules for maintenance of remission of ulcerative colitis and luminal Crohn's disease in a meta-analysis.

We performed a systematic review and meta-analysis. We searched several medical literature databases including MEDLINE (from Jan 1, 1946, to May 31, 2024), Embase and Embase Classic (Jan 1, 1947, to May 31, 2024), and the Cochrane Central Register of Controlled Trials from database inception to May 31, 2024, for randomised placebo-controlled trials of licensed biologics and small molecules for maintenance of remission in adults with IBD reporting data on adverse events over a period of 20 weeks or more. There were no language restrictions or prespecified exclusion criteria. We extracted summary data and pooled data using a random-effects model for any treatment-emergent adverse event, drug-related adverse event, infection, worsening of IBD activity, withdrawal due to adverse events, serious adverse events, serious infection, serious worsening of IBD activity, or venous thromboembolic events, reporting relative risks (RRs) for placebo versus active drug with 95% CIs for each outcomes. The protocol for this meta-analysis was registered with PROSPERO (CRD42024542624).

Our search identified 10 826 citations, of which 45 trials including 16 562 patients (10 319 [62·3%] receiving active drug and 6243 [37·7%] placebo) were eligible. The risks of any treatment-emergent adverse event (7297/9546 [76·4%] patients on active drug vs 4415/5850 [75·5%] on placebo; RR 1·01, 95% CI 0·99-1·04; I2 =47%), serious infection (260/10 242 [2·5%] vs 155/6149 [2·5%]; 0·97, 0·79-1·19; I2 =0%), or venous thromboembolic event (12/4729 [0·3%] vs 9/2691 [0·3%]; 0·72, 0·31-1·66; I2 =0%) were not significantly lower with active drug than placebo. The risks of any infection (3208/8038 [39·9%] vs 1713/4809 [35·6%]; 1·14, 1·05-1·23; I2 =60%) or any drug-related adverse event (1094/2997 [36·5%] vs 609/1950 [31·2%]; 1·24, 1·02-1·50; I2 =75%) were higher with active drug than placebo. However, the risks of any worsening of IBD activity (1038/8090 [12·8%] vs 1181/5191 [22·8%]; 0·58, 0·52-0·64; I2 =40%), any withdrawal due to adverse events (610/10 282 [5·9%] vs 561/6207 [9·0%]; 0·71, 0·60-0·84; I2 =43%), any serious adverse events (1066/10 292 [10·4%] vs 742/6198 [12·0%]; 0·85, 0·77-0·94; I2 =17%), or any serious worsening of IBD activity (101/5707 [1·8%] vs 143/3640 [3·9%]; 0·55, 0·42-0·71; I2 =0%) were lower with active drug than placebo. 21 randomised controlled trials were judged as low risk of bias across all domains.

In maintenance of remission trials in IBD, placebo was associated with some clinically significant potential harms. Patients should be counselled about these before participating in clinical trials and consideration given to alternative designs to test novel drugs in IBD.

None.

Patients with inflammatory bowel disease (IBD) receiving infliximab (IFX) commonly experience immunogenic loss of response (LOR) by formation of anti-drug antibodies (ADAs). An immunomodulator (IMM) used in combination with initial IFX induction is known to reduce ADA development and improve clinical outcomes. We aimed to assess the impact of reactively adding an IMM to patients on IFX monotherapy.

We conducted a retrospective cohort study and systematic review with meta-analysis of patients with IBD demonstrating immunologic LOR, with or without clinical LOR, that had an IMM (azathioprine, 6-mercaptopurine, or methotrexate) reactively added (reactive combination therapy; rCT) to combat elevated ADAs and raise IFX level. Data were extracted for pooled effect size estimation using random-effects models, and ADA and IFX trough levels were compared pre- and post-IMM initiation.

We identified 6 patients who received rCT due to rising ADA titers and low IFX levels. Median ADA titer decreased from 506 ng/mL (interquartile range (IQR) [416-750]) to 76.5 ng/mL (IQR [25.8-232]), an 85% decrease (p = 0.031). Median IFX trough increased from 0.4 µg/mL (IQR [0.4-0.48]) to 8.25 µg/mL (IQR [3.7-9.6]), a 20.6-fold increase (p = 0.038). Meta-analysis pooled effect size of 7 studies with 89 patients showed an 87% ADA titer reduction [95% confidence interval (CI) = 72-94%], 6.7-fold increased IFX trough (95% CI = 2.4-18.7), and 76% clinical remission rescue rate (95% CI = 59-93%).

These results suggest rCT is a valid rescue strategy in patients with immunogenic LOR to IFX to reduce ADA titers, restore therapeutic IFX levels, and recapture clinical remission of IBD.

Spondyloarthritis (SpA) is a term to describe a group of chronic inflammatory rheumatic diseases, which have common pathophysiological, genetic, and clinical features. Under the umbrella term SpA, two main groups are subsumed: axial SpA (radiographic axSpA and non-radiographic axSpA) and peripheral SpA (with the leading representative being psoriatic arthritis (PsA) but also arthritis associated with inflammatory bowel disease (IBD), reactive arthritis, and undifferentiated pSpA). The key clinical symptom in axSpA is chronic back pain, typically with inflammatory characteristics, which starts in early adulthood, while the leading clinical manifestations of peripheral SpA (pSpA) are arthritis, enthesitis, and/or dactylitis. Furthermore, extra-musculoskeletal manifestations (EMMs) (acute anterior uveitis, psoriasis, and IBD) can accompany axial or peripheral symptoms. All these factors need to be taken into account when making treatment decisions in SpA patients. Despite the major advances in the treatment landscape over the past two decades with the introduction of biological disease-modifying anti-rheumatic drugs (bDMARDs) and most recently targeted synthetic DMARDs (tsDMARDs), a relevant proportion of patients still does not achieve the desired state of remission (=absence of disease activity). With this implementation of new treatment modalities, clinicians now have more choices to make in the treatment algorithms. However, despite generalized treatment recommendations, all factors need to be carefully considered when deciding on the optimal treatment strategy for an individual patient in clinical practice, aiming at an important first step towards personalized treatment strategies in SpA. In this narrative review, we focus on the efficacy of approved and emerging treatment options in axSpA and PsA as the main representative of pSpA and discuss their selective effect on the different manifestations associated with SpA to provide guidance on drivers of treatment decisions in specific situations.

Perianal fistulizing Crohn's disease (CD) represents a severe phenotype of CD that is associated with significant morbidity and reduction in quality of life. Perianal fistulizing CD is caused by a complex interplay of genetic predisposition, immune dysregulation, gut dysbiosis, and various unknown physiological and mechanical factors. A multidisciplinary approach is hence required for optimal management . A detailed anatomical description and classification of perianal fistula, including comprehensive clinical, endoscopic, and radiological diagnostic workup, is an important prerequisite to treatment. For simple perianal fistulas, use of antibiotics and immunomodulators, with or without fistulotomy, are appropriate measures. The medical management of complex perianal fistula, on the other hand, requires adequate control of infection before initiation of therapy with immunomodulators. In active complex perianal fistula, anti-tumor necrosis factors remain the most accepted therapy, with concomitant use of antibiotics or immunomodulators enhancing the efficacy. For patients refractory to anti-tumor necrosis factors, treatment with anti-integrins, anti-interleukins, and small molecules is being evaluated. Mesenchymal stem cells, hyperbaric oxygen therapy, and exclusive enteral nutrition have also been investigated as adjunct therapies. Despite the expansion of the medical armamentarium, a large proportion of the patients require surgical interventions. In this review, we provide an up-to-date overview of the pathophysiology, clinical presentation, diagnosis, and medical management of perianal fistulizing CD. A brief overview of the surgical management of perianal fistulizing CD is also provided.

Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is a chronic condition characterized by relapsing and remitting inflammation of the gastrointestinal tract. The pathogenesis involves a complex interplay of genetic, environmental, and immune factors. Treatment paradigms have evolved significantly over the past few decades, with the introduction of biologics, particularly anti-TNF (tumor necrosis factor) agents, marking a significant advancement. Anti-TNF therapies, including infliximab, adalimumab, golimumab, and certolizumab pegol, have efficacy in inducing and maintaining remission, promoting mucosal healing, and improving the quality of life in moderate to severe IBD patients. The early and appropriate use of these agents can mitigate disease progression and reduce the dependency on corticosteroids, enhancing long-term patient outcomes. Nevertheless, these therapies are expensive and are associated with potential adverse effects, including increased risk of infections and malignancies. This review discusses the mechanisms, clinical efficacy, safety profiles, and therapeutic positioning of anti-TNF agents in IBD management, integrating current Korean treatment guidelines.

Crohn's disease (CD) is a chronic, relapsing immune mediated disease, which is one of the two major types of inflammatory bowel disease (IBD). Fistulizing CD poses a significant clinical challenge for physicians. Effective management of CD requires a multidisciplinary approach, involving a gastroenterologist and a GI surgeon while tailoring treatment to each patient's unique risk factors, clinical representations, and preferences.

This comprehensive review explores the intricacies of fistulizing CD including its manifestations, types, impact on quality of life, management strategies, and novel therapies under investigation.

Antibiotics are often used as first-line therapy to treat symptoms. Biologics that selectively target TNF-α, such infliximab (IFX), have shown high efficacy in randomized controlled trials. However, more than 50% of patients lose response to IFX, prompting them to explore alternative strategies. Current options include adalimumab and certolizumab pegol combination therapies, as well as small-molecule drugs targeting Janus kinases such as Upadacitinib. Furthermore, a promising treatment for complex fistulas is mesenchymal stem cells such as Darvadstrocel (Alofisel), an allogeneic stem cell-based therapy. However, surgical interventions are necessary for complex cases or intra-abdominal complications. Setons and LIFT procedures are the most common surgical options.

The perianal disease affects up to one-third of individuals with Crohn's disease (CD), causing disabling symptoms and significant impairment in quality of life, particularly for those with perianal fistulising CD (PFCD). The collaborative effort between gastroenterologists and surgeons is essential for addressing PFCD to achieve fistula closure and promote luminal healing. Limited fistula healing rates with conventional therapies have prompted the emergence of new biological agents, endoscopic procedures and surgical techniques that show promising results. Among these, mesenchymal stem cells injection is a particularly hopeful therapy. In addition to the burden of fistulas, individuals with perianal CD may face an increased risk of developing anal cancer. This underscores the importance of surveillance programmes and timely interventions to prevent late diagnoses and poor outcomes. Currently, there is no established formal anal screening programme. In this review, we provide an overview of the current state of the art in managing PFCD, including novel medical, endoscopic and surgical approaches. The discussion also focuses on the relevance of establishing an anal cancer screening programme in CD, intending to propose a risk-based surveillance algorithm. The validation of this surveillance programme would be a significant step forward in improving patient care and outcomes.

Rapidity of effect of advanced therapies for patients with Crohn's disease (CD) can be an essential decision parameter; however, comparative evaluation is lacking. We aimed to compare early response for advanced CD therapies in a network meta-analysis (NMA).

We searched systematically MEDLINE, Embase, and CENTRAL up to 19 February 2024, for randomised controlled trials. The co-primary outcomes were induction of clinical remission (Crohn's Disease Activity Index (CDAI) ≤150) and clinical response (≥100-point reduction in CDAI) within the first 6 weeks of treatment. We incorporated any assessment within this time point in a Bayesian random-effects NMA following PRISMA-NMA guidance (PROSPERO ID: CRD42022368509).

Twenty-five studies, comprising 7414 patients, were included. Infliximab combined with azathioprine or monotherapy ranked highest for induction of clinical remission within 6 weeks and was significantly superior to certolizumab, ustekinumab, guselkumab, vedolizumab, and upadacitinib. However, superiority over risankizumab 600 mg and adalimumab 160/80 mg was non-significant. Accordingly, infliximab in combination with azathioprine and guselkumab 600 mg ranked highest in the corresponding analysis of clinical response with no statistical significance demonstrated. Among bio-exposed patients, none of whom received infliximab, upadacitinib, and risankizumab induced the highest clinical responses. On the other hand, vedolizumab, certolizumab, and ustekinumab ranked lowest across the analyses.

We found infliximab to be ranked highest and superior to all other agents but risankizumab and adalimumab, demonstrating the highest probability of early induction of remission. Upadacitinib and risankizumab induced the highest clinical responses in bio-exposed patients. However, infliximab was not investigated in this population.

Inflammatory bowel disease remains a difficult disease to effectively treat, especially fistulizing Crohn's disease. Perianal fistulas in the setting of Crohn's disease remain an area of unmet need with significant morbidity in this patient population. Up to one third of Crohn's patients will have perianal fistulizing disease and current medical and surgical interventions are of limited efficacy. Thus, most patients experience significant morbidity, narcotic use, and loss of employment and end up with multiple surgical interventions. Mesenchymal stem cells (MSCs) have shown efficacy in phase 3 clinical trials, but considerable infrastructure challenges make MSCs limited with regard to scalability in clinical practice. Extracellular vesicles, being derived from MSCs and capturing the secretome functionality of MSCs, offer similar physiological utility regarding mechanism, while also providing an off the shelf regenerative medicine product that could be widely used in daily clinical practice.

An alternative to lifelong antiretroviral therapy (ART) is needed to achieve durable control of HIV-1. Here we show that adeno-associated virus (AAV)-delivery of two rhesus macaque antibodies to the SIV envelope glycoprotein (Env) with potent neutralization and antibody-dependent cellular cytotoxicity can prevent viral rebound in macaques infected with barcoded SIVmac239M after discontinuing suppressive ART. Following AAV administration, sustained antibody expression with minimal anti-drug antibody responses was achieved in all but one animal. After ART withdrawal, SIV replication rebounded within two weeks in all of the control animals but remained below the threshold of detection in plasma (<15 copies/mL) for more than a year in four of the eight animals that received AAV vectors encoding Env-specific antibodies. Viral sequences from animals with delayed rebound exhibited restricted barcode diversity and antibody escape. Thus, sustained expression of antibodies with potent antiviral activity can afford durable, ART-free containment of pathogenic SIV infection.

The expanding options in advanced therapies for ulcerative colitis (UC) and Crohn's disease (CD) present challenges in treatment selection. Persistence analysis assesses drug durability in real-world settings, acting as a surrogate marker for medication efficacy and tolerance. Unlike traditional comparative studies, persistence analysis provides insights extending beyond the initial year of treatment.

To provide real-world evidence on treatment effectiveness, tolerability and preferences of physicians and patients regarding various advanced therapies for IBD.

We conducted a systematic review of observational studies up to March 2023 assessing advanced therapies' persistence in UC and CD. Advanced therapies under examination included infliximab, adalimumab, vedolizumab, ustekinumab, golimumab, certolizumab and tofacitinib. We pooled the persistence of each agent and conducted a meta-analysis to compare the persistence of newer agents with traditional TNF inhibitors (TNFi)-specifically infliximab and adalimumab.

Among 63 observational studies, vedolizumab had the highest 1-year persistence in UC (73.8%, 95% CI: 70.0%-77.6%) and ustekinumab in CD (77.5%, 95% CI: 72.9%-82.1%). Compared to TNFi, vedolizumab demonstrated increased persistence with a relative risk (RR) of 1.30 (95% CI: 1.19-1.41) for UC and 1.14 (95% CI: 1.09-1.20) for CD at 1 year, while ustekinumab demonstrated a RR of 1.15 (95% CI: 1.07-1.23) for CD at 1 year. Vedolizumab exhibited sustained increased persistence in UC over 2 years compared to TNFi (RR: 1.33, 95% CI 1.14-1.54).

This meta-analysis highlights the superior persistence of ustekinumab and vedolizumab over TNFi, and offers valuable insights for clinicians navigating the challenging landscape of UC and CD therapeutic choices.

Crohn's disease (CD) is a subtype of chronic and incurable inflammatory bowel disease. It can affect the entire gastrointestinal tract and its etiology is unknown.

The aim of this consensus was to establish the most relevant aspects related to definitions, diagnosis, follow-up, medical treatment, and surgical treatment of Crohn's disease in Mexico.

Mexican specialists in the areas of gastroenterology and inflammatory bowel disease were summoned. The consensus was divided into five modules, with 69 statements. Applying the Delphi panel method, the pre-meeting questions were sent to the participants, to be edited and weighted. At the face-to-face meeting, all the selected articles were shown, underlining their level of clinical evidence; all the statements were discussed, and a final vote was carried out, determining the percentage of agreement for each statement.

The first Mexican consensus on Crohn's disease was produced, in which recommendations for definitions, classifications, diagnostic aspects, follow-up, medical treatment, and surgical treatment were established.

Updated recommendations are provided that focus on definitions, classifications, diagnostic criteria, follow-up, and guidelines for conventional medical treatment, biologic therapy, and small molecule treatment, as well as surgical management.

Inflammatory bowel disease (IBD) is associated with adverse clinical outcomes, including chronic kidney disease and mortality, due in part to chronic inflammation. Little is known about the effects of anti-tumor necrosis factor (TNF) therapy on kidney disease progression and mortality among patients with new-onset IBD.

To examine the association of incident use of TNF inhibitors with subsequent decline in kidney function and risk of all-cause mortality.

This retrospective cohort study used data from the US Department of Veterans Affairs health care system. Participants were US veterans with new-onset IBD enrolled from October 1, 2004, through September 30, 2019. Data were analyzed from December 2022 to February 2024.

Incident use of TNF inhibitors.

The main outcomes were at least 30% decline in estimated glomerular filtration rate (eGFR) and all-cause mortality.

Among 10 689 patients (mean [SD] age, 67.4 [12.3] years; 9999 [93.5%] male) with incident IBD, 3353 (31.4%) had diabetes, the mean (SD) baseline eGFR was 77.2 (19.2) mL/min/1.73 m2, and 1515 (14.2%) were newly initiated on anti-TNF therapy. During a median (IQR) follow-up of 4.1 (1.9-7.0) years, 3367 patients experienced at least 30% decline in eGFR, and over a median (IQR) follow-up of 5.0 (2.5-8.0) years, 2502 patients died. After multivariable adjustments, incident use (vs nonuse) of TNF inhibitors was significantly associated with higher risk of decline in eGFR (adjusted hazard ratio [HR], 1.34 [95% CI, 1.18-1.52]) but was not associated with risk of all-cause mortality (adjusted HR, 1.02 [95% CI, 0.86-1.21]). Similar results were observed in sensitivity analyses.

In this cohort study of US veterans with incident IBD, incident use (vs nonuse) of TNF inhibitors was independently associated with higher risk of progressive eGFR decline but was not associated with risk of all-cause mortality. Further studies are needed to elucidate potentially distinct pathophysiologic contributions of TNF inhibitor use to kidney and nonkidney outcomes in patients with IBD.

Biologics and small molecules have been increasingly applied in Crohn's disease (CD) and ulcerative colitis (UC). But the robustness of their trials has not been evaluated.

We initially collected all the approved biologics or small molecules for CD or UC up to December 1, 2022. Databases were then queried by keywords in chemical name and CD or UC. Randomized controlled trials (RCTs) in the two-arm, 1:1 design were included. Fragility index (FI) and fragility quotient (FQ) were subsequently calculated.

We included twenty-eight RCTs, including nine pivotal trials listed in approval labels, nineteen non-pivotal trials not included in the labels. The median sample size was 99 [IQR, 60-262] and the median number of loss-of-follow-up (LFU) was 14 [IQR, 8-43]. Pivotal trials in the labels had the median FI of 8 [IQR, 4-14, n = 6] that was marginally higher than non-pivotal trials (3 [IQR, 2-4], p = 0.08). The median FQ was 0.0330 [IQR, 0.1220-0.0466] and 0.0310 [IQR, 0.0129-0.0540] for pivotal and non-pivotal trials, respectively (p = 1.0). The sample size and FI were significantly correlated (Spearman correlation coefficient [r] = 0.56, 95 %CI 0.21-0.78, p = 0.003). The number of total events was also significantly correlated with FI (r = 0.53, 95 %CI 0.17-0.77, p = 0.006). Study p-values were significantly associated with FI (p = 0.01): trials with p-values < 0.001 had the highest median FI of 10 [IQR, 6-17]. No factor was found strongly correlated with FQ.

Results from trials assessing administration-approved biologics or small molecules for treating CD or UC were vulnerable to small changes by measuring FI or FQ. Pivotal studies contributing to regulatory approvals exhibited a relatively higher degree of resilience compared to non-pivotal trials.

The therapeutic armamentarium for managing Crohn's disease (CD) has expanded significantly in recent decades. Several biologics with three different mechanisms of action [anti-tumor necrosis factor (TNF)-α, anti-integrin α4β7, and anti-IL 12/23] are currently available to manage CD.

This narrative review aims to summarize the most significant efficacy and safety data on the use of infliximab (IFX), adalimumab (ADA), vedolizumab (VDZ) and ustekinumab (UST) for the treatment of CD obtained from studies conducted in the real world (RW), compared to the results of randomized clinical trials (RCTs).

RW studies reported that biologic agents included in this analysis have higher remission rates and lower adverse event rates than findings from RCTs for treating patients with CD. All biological agents have proven effective and safe in RW studies, even when using biosimilars or switching to subcutaneous administration of the molecules for which they are available. Finally, anti-TNF-α agents, particularly IFX, have a higher rate of adverse events (AEs) than VDZ and UST. Therefore, patients at higher risk of AEs may benefit from other biologics than anti-TNF-α. However, further long-term RW studies are needed to confirm these findings.

The availability of approved therapies for Crohn's disease has significantly increased over the past decade. To choose the appropriate therapy for the patient, ideally head to head studies, and data on positioning could help the provider individualize the decision. Due to the paucity of head-to-head trial data, we turn to network meta-analysis and real-world studies to help guide our treatment choices. Ultimately, the best approach is to consider each patient on an individual basis, taking into consideration the characteristics of their disease, individual risk factors, extra-intestinal manifestations, co-morbid conditions, patient age, cost, and personal preferences. In this review, we summarize the evidence comparing biologic as well as small molecule therapies for the treatment of moderate-to-severe Crohn's disease. We have summarized the evidence in relation to factors such as efficacy, fistulizing disease, pregnancy, infection risk, and co-existing conditions.

Ustekinumab is an effective treatment of Crohn's disease (CD). Of interest to patients is knowing how soon symptoms may improve. We analyzed ustekinumab response dynamics from the ustekinumab CD trials.

Patients with CD received intravenous induction with ustekinumab ∼6 mg/kg (n = 458) or placebo (n = 457). Week 8 ustekinumab responders received subcutaneous ustekinumab 90 mg as the first maintenance dose or as an extended induction dose for nonresponders. Patient-reported symptom changes (stool frequency, abdominal pain, general well-being) within the first 14 days and clinical outcomes through week 44 were evaluated using the CD Activity Index.

After ustekinumab infusion, stool frequency improvement was significantly (P < .05) greater than placebo on day 1 and for all patient-reported symptoms by day 10. In patients with no history of biologic failure or intolerance, cumulative clinical remission rates increased from 23.0% at week 3 to 55.5% at week 16 after the subcutaneous dose at week 8. Corresponding cumulative rates for patients with a history of biologic failure or intolerance increased from 12.9% to 24.1%. Neither change from baseline in CD Activity Index score nor week 8 ustekinumab pharmacokinetics were associated with week 16 response. Among all patients who received subcutaneous ustekinumab 90 mg q8w, up to 66.7% were in clinical response at week 44.

Ustekinumab induction provided symptom relief by day 1 post-infusion. Following ustekinumab infusion and a subcutaneous 90 mg injection, clinical outcomes continued to increase through week 16 and up to week 44. Regardless of week 8 clinical status or ustekinumab pharmacokinetics, patients should receive additional treatment at week 8.

gov numbers, NCT01369329, NCT01369342, and NCT01369355.

The treatment armamentarium for inflammatory bowel disease has expanded rapidly in the past several years with new biologic and small molecule-agents approved for moderate-to-severe ulcerative colitis and Crohn's disease. This has made treatment selection more challenging with limited but evolving guidance as to where to position each medication. In this review, we discuss the efficacy data for each agent approved in the United States by reviewing their phase 3 trial data and other comparative effectiveness studies. In addition, safety considerations and use in special populations are summarized with proposed algorithms for positioning therapies. The aim is to provide a synopsis of high-impact data and aid in outpatient treatment decision-making for patients with inflammatory bowel disease.

Design of randomised controlled trials (RCTs) examining maintenance of clinical remission in inflammatory bowel disease (IBD) varies, with some trials re-randomising patients who have responded to active drug during induction to either active drug or placebo and others treating patients through with active drug or placebo from baseline. Whether this influences therapeutic gain of drug over placebo is unknown.

We searched the literature to January 2023 for maintenance of remission trials of biologics or small molecules versus placebo in IBD. We extracted maintenance of remission rates according to trial design; either trials re-randomising patients or trials treating patients through. We pooled data in a meta-analysis for all patients, and according to type of IBD. We calculated the number needed to treat (NNT), with a 95% confidence interval (CI), to assess therapeutic gain of active drug over placebo according to trial design.

We identified 37 maintenance of remission trials (12,075 patients). Rates of maintenance of clinical remission were higher (41.9% with active drug, versus 20.3% with placebo), and NNT lowest (5; 95% CI 4-6), in trials re-randomising patients compared with those treating through (maintenance of remission rate 30.9% with active drug versus 14.6% with placebo, NNT = 7; 95% CI 5-9). Results were similar when trials were analysed according to IBD type but were more marked in ulcerative colitis RCTs (maintenance of remission rates in re-randomised trials 39.4% with active drug versus 17.8% with placebo, NNT = 5; 95% CI 3-7; treat-through trials 27.3% with active drug versus 11.9% with placebo, NNT = 7; 95% CI 5-11.5).

Trials re-randomising patients had generally higher maintenance of remission rates, lower NNTs, and greater therapeutic gains over placebo.

The selection process for advanced therapies in patients with inflammatory bowel diseases (IBDs) must prioritize safety, especially when considering new biologic agents or oral molecule modulators. In C57BL/6 mice, oral infection with Toxoplasma gondii induces intestinal inflammation through excessive tumor necrosis factor (TNF) production, making TNF neutralization a potential therapeutic intervention. Considering this, the present study aimed to evaluate the therapeutic effects of BmooMP-α-I, a snake venom metalloprotease isolated from Bothrops moojeni, which could promote TNF hydrolysis, in treating T. gondii-induced ileitis. The results showed that C57BL/6 mice orally infected with 50 cysts of T. gondii from the Me49 strain and treated with BmooMP-α-I exhibited prolonged survival and improved morbidity scores. Additionally, the treatment ameliorated both the macroscopic and microscopic aspects of the intestine, reduced macrophage influx, and decreased the production of inflammatory mediators by mesenteric lymph node cells. These findings provide compelling experimental evidence supporting the ability of BmooMP-α-I to alleviate ileal inflammation. Considering that the currently available therapeutic protocols are not completely effective and often result in side effects, the exploration of alternative strategies involving novel therapeutic agents, as demonstrated in this study, has the potential to significantly enhance the quality of life for patients suffering from inflammatory bowel diseases.

Crohn's disease is a complex, relapsing and remitting inflammatory disorder of the gastrointestinal tract with a variable disease course. While the treatment options for Crohn's disease have dramatically increased over the past two decades, predicting individual patient response to treatment remains a challenge. As a result, patients often cycle through multiple different therapies before finding an effective treatment which can lead to disease complications, increased costs, and decreased quality of life. Recently, there has been increased emphasis on personalized medicine in Crohn's disease to identify individual patients who require early advanced therapy to prevent complications of their disease. In this review, we summarize our current approach to management of Crohn's disease by identifying risk factors for severe or disabling disease and tailoring individual treatments to patient-specific goals. Lastly, we outline our knowledge gaps in implementing personalized Crohn's disease treatment and describe the future directions in precision medicine.

Dose escalation of self-injectable biologic therapy for inflammatory bowel diseases may be required to counteract loss of response and/or low drug levels. Payors often require completion of a prior authorization (PA), which is a complex approval pathway before providing coverage. If the initial PA request is denied, clinic staff must complete a time and resource-intensive process to obtain medication approval.

This study measured time from decision to dose escalate to insurance approval and evaluated impact of approval time on disease activity.

This was a single-center retrospective analysis of adult patients with IBD prescribed an escalated dose of biologic therapy at an academic center with an integrated specialty pharmacy team from January to December 2018. Outcomes included time to insurance approval and the association between approval time and follow-up C-reactive protein (CRP) and Short Inflammatory Bowel Disease Questionnaire (SIBDQ) scores. Associations were tested using linear regression analyses.

220 patients were included, median age 39, 53% female, and 96% white. Overall median time from decision to dose escalate to insurance approval was 7 days [interquartile range (IQR) 1, 14]. Approval time was delayed when an appeal was required [median of 29 days (IQR 17, 43)]. Patients with a longer time to insurance approval were less likely to have CRP improvement (p = 0.019). Time to insurance approval did not significantly impact follow-up SIBDQ scores.

Patients who had a longer time to insurance approval were less likely to have improvement in CRP, highlighting the negative clinical impact of a complex dose escalation process.

Colonic epithelial repair is a key determinant of health. Repair involves changes in epithelial differentiation, an extensive proliferative response, and upregulation of regeneration-associated "fetal-like" transcripts, including Ly6a (Sca-1), that represent Yap1 and interferon targets. However, little is known about how this regenerative program terminates and how homeostasis is restored during injury and inflammation. Here we show that, after the initial entry into the regenerative state, the subsequent upregulation of tumor necrosis factor (TNF) receptor 2 (R2, TNFR2, Tnfrsf1b) clears the regenerative signaling and restores homeostatic patterns of epithelial differentiation. Targeted deletion of epithelial TNFR2 in vivo and in colonoid cultures revealed persistent expression of Ly6a, hyperproliferation, and reduced secretory differentiation. Moreover, mice lacking epithelial TNFR2 also failed to complete colon ulcer healing, suggesting that partial resolution of regenerative signaling is essential for the completion of the repair process. These results demonstrate how epithelial cells dynamically leverage a colitis-associated cytokine to choreograph repair.

Background: Inflammatory Bowel Disease (IBD) impacts millions worldwide, presenting a major challenge to healthcare providers and patients. The advent of biologic therapies has enhanced the prognosis, but many patients exhibit primary or secondary non-response, underscoring the need for rigorous monitoring and therapy optimization to improve outcomes. Objective: This narrative review seeks to understand the role of therapeutic drug monitoring (TDM) in optimizing treatment for IBD patients, especially for those on combination therapies of biologics and immunomodulators. Methods: A comprehensive synthesis of the current literature was undertaken, focusing on the application, benefits, limitations, and future directions of TDM in patients receiving a combination of biologic therapies and immunomodulators. Results: While biological therapies have improved outcomes, rigorous monitoring and therapy optimization are needed. TDM has emerged as a pivotal strategy, enhancing outcomes cost-effectively while reducing adverse events. While most data pertain to monotherapies, TDM's applicability also extends to combination therapy. Conclusion: TDM plays a crucial role in the treatment optimization of IBD patients on combination therapies. Further research is needed to fully understand its potential and limitations in the broader context of IBD management.

Inflammatory Bowel Diseases had their first peak in incidence in countries in North America, Europe, and Oceania and are currently experiencing a new acceleration in incidence, especially in Latin America and Asia. Despite technological advances, 90 years after the development of the first molecule for the treatment of IBD, we still do not have drugs that promote disease remission in a generalized way. We carried out a narrative review on therapeutic advances in the treatment of IBD, the mechanisms of action, and the challenges facing the therapeutic goals in the treatment of IBD. Salicylates are still used in the treatment of Ulcerative Colitis. Corticosteroids have an indication restricted to the period of therapeutic induction due to frequent adverse events, while technologies with less systemic action have been developed. Most immunomodulators showed a late onset of action, requiring a differentiated initial strategy to control the disease. New therapeutic perspectives emerged with biological therapy, initially with anti-TNF, followed by anti-integrins and anti-interleukins. Despite the different mechanisms of action, there are similarities between the general rates of effectiveness. These similar results were also evidenced in JAK inhibitors and S1p modulators, the last therapeutic classes approved for the treatment of IBD.

Antibody engineering has developed into a wide-reaching field, impacting a multitude of industries, most notably healthcare and diagnostics. The seminal work on developing the first monoclonal antibody four decades ago has witnessed exponential growth in the last 10-15 years, where regulators have approved monoclonal antibodies as therapeutics and for several diagnostic applications, including the remarkable attention it garnered during the pandemic. In recent years, antibodies have become the fastest-growing class of biological drugs approved for the treatment of a wide range of diseases, from cancer to autoimmune conditions. This review discusses the field of therapeutic antibodies as it stands today. It summarizes and outlines the clinical relevance and application of therapeutic antibodies in treating a landscape of diseases in different disciplines of medicine. It discusses the nomenclature, various approaches to antibody therapies, and the evolution of antibody therapeutics. It also discusses the risk profile and adverse immune reactions associated with the antibodies and sheds light on future applications and perspectives in antibody drug discovery.

Perianal Crohn's disease affects 25%-35% of patients with Crohn's disease and has proven to be one of the most difficult complications of the disease to treat. Patients with perianal Crohn's disease have lower health-related quality of life scores typically related to pain and fecal incontinence. In addition, patients with perianal Crohn's disease have higher rates of hospitalizations, surgeries, and overall healthcare costs. A multidisciplinary approach is necessary for the successful management of Crohn's disease with perianal fistula. Medical management is required to treat the underlying immune dysregulation to heal the luminal inflammation and the inflammation within the fistula tracts. Current options for medical therapy include biologics, dual therapy with thiopurines, therapeutic drug monitoring, and a close follow-up. Surgical management is critical to drain abscesses before immunosuppressive therapy and place setons when appropriate. Once the patient's inflammatory burden is well managed, definitive surgical therapies including fistulotomies, advancement flaps, and ligation of intersphincteric fistula tract procedures can be considered. Most recently, the use of stem cell therapy in the treatment of perianal fistula has given new hope to the cure of perianal fistula in Crohn's disease. This review will outline the most current data in the medical and surgical management of perianal Crohn's disease.

Along with the rising prevalence of inflammatory bowel disease (IBD) [Crohn's disease (CD) and ulcerative colitis (UC)], biological therapies need an update/insight.

This review included randomized controlled trials (RCTs) from PubMed database (2000-October 2022) of approved biologics and small molecules with primary outcome analysis on efficacy (clinical response/remission/mucosal healing) and/or adverse events (AEs). Considered for this review under biologics classes are TNF-α inhibitors, leukocyte trafficking inhibitors, and anti IL-12/IL-23; and under small molecules are Janus-kinase inhibitors, and sphingosine-1-phosphate receptor modulators.

In CD, clinical response and remission were better with tofacitinib (61.23%) and infliximab (44.86%), respectively, in the induction phase, and these were better with ustekinumab in the maintenance phase. In UC, the maximum rate of response, remission, and mucosal healing were obtained with infliximab during the induction phase (67.49%, 35.99%, and 60.25%, respectively). During the maintenance phase, response rate was better with ustekinumab, but remission and mucosal healing were better with vedolizumab. The combined percentage of AEs was highest with infliximab (174.45%) and least with ozanimod (23.04%), and most commonly belonged to the 'infection and infestation system organ class (SOC).' These efficacy and safety analyses will help in the optimization of biologic treatment in IBD.