Anti-IL-17A antibodies are used in rheumatological conditions. While not approved for multiple sclerosis (MS), anti-IL-17As reduce new gadolinium-enhancing lesions. Optimal treatment for those with MS and comorbid rheumatological conditions remains unclear. We report safety and efficacy outcomes for anti-IL-17A treatment with and without concurrent MS disease modifying therapy (DMT). Patients with MS and anti-IL-17A use were identified using electronic medical records. Primary outcomes were severe infections and markers of immunosuppression. Secondary outcomes were MS relapses and new MRI lesions. Six patients (median age: 50.1) without recent MS disease activity had anti-IL-17A monotherapy exposures (17.4 total patient-years); seven (median age: 48.2) had concurrent MS DMT use (8.8 patient-years), including anti-CD20 treatment in three patients. One patient on anti-IL-17A monotherapy had a serious infection. No patients had new or worsening lymphopenia. Four of six patients on anti-IL-17A monotherapy had new MS disease activity. No relapses or new MRI lesions occurred during concurrent MS DMT use. No significant safety concerns were identified with anti-IL-17A and MS DMT combination therapy, although exposure duration was limited. More MS disease activity was seen with anti-IL-17A monotherapy. Dual therapy with an MS DMT may be reasonable for MS patients who require anti-IL-17A treatment.

There is limited evidence on real-world patterns and safety of biologic switch timing in patients with ulcerative colitis (UC)/Crohn's disease (CD). This study investigated biologic therapy switch occurrence in real-world practice and compared the risk of any infection and serious infection between patients with overlapping (OS) vs non-overlapping switches (NOS).

This retrospective observational study identified patients with UC/CD initiating biologic therapy between September 1, 2017, and August 31, 2022, in Optum's de-identified Clinformatics Data Mart Database. Crude incidence rates (IRs) per 1000 person-years (PYs) and timing of switch were assessed. Biologic switch events were categorized as OS (switch to another biologic within ≤5 half-lives after discontinuation of initial biologic) or NOS (switch to another biologic >5 half-lives after discontinuation of initial biologic). Inverse probability of treatment weighted Cox proportional hazards modeling estimated adjusted hazard ratios (aHRs) of any infection and serious infection associated with switch timing.

Among 11,992 adult patients newly initiating a biologic therapy for UC/CD, 1293 patients underwent a biologic switch, 64.2% of which were considered an OS. Adjusted IRs per 1000 PYs, for any infection, were comparable across switching groups. No significant differences in the aHRs of infections were found between OS and NOS (any infection: aHR, 1.40; P = .17; serious infection: aHR, 0.95; P = .93).

OSs were common and not associated with an increased risk of serious infection vs non-overlapping biologics. Shortened washout periods may pose minimal safety risks to patients while improving UC/CD therapy management and improving trial recruitment.

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a chronic inflammation of the gastrointestinal tract with unknown etiology. The cause of IBD is widely considered multifactorial, with prevailing hypotheses suggesting that the microbiome and various environmental factors contribute to inappropriate activation of the mucosal immune system in genetically susceptible individuals. Although the incidence of IBD has stabilized in Western countries, it is rapidly increasing in newly industrialized countries, particularly China, making IBD a global disease. Significant changes in multiple biomarkers before IBD diagnosis during the preclinical phase provide opportunities for earlier diagnosis and intervention. Advances in technology have driven the development of telemonitoring tools, such as home-testing kits for fecal calprotectin, serum cytokines, and therapeutic drug concentrations, as well as wearable devices for testing sweat cytokines and heart rate variability. These tools enable real-time disease activity assessment and timely treatment strategy adjustments. A wide range of novel drugs for IBD, including interleukin-23 inhibitors (mirikizumab, risankizumab, and guselkumab) and small-molecule drugs (etrasimod and upadacitinib), have been introduced in the past few years. Despite these advancements, approximately one-third of patients remain primary non-responders to the initial treatment, and half eventually lose response over time. Precision medicine integrating multi-omics data, advanced combination therapy, and complementary approaches, including stem cell transplantation, psychological therapies, neuromodulation, and gut microbiome modulation therapy, may offer solutions to break through the therapeutic ceiling.

Therapeutic options in inflammatory bowel disease (IBD) have expanded significantly. Patients often experience primary or secondary loss of response to biologics or small molecules therapy. Determining which patients may benefit from combination of two therapies remains a key question.

Combination therapy leverages complementary mechanisms of action, conventionally using tumor necrosis factor antagonists simultaneously with immunosuppressive agents, and more recently using two advanced therapies together. Combination of two advanced therapies has shown promise in two recent randomized trials for improving clinical and endoscopic outcomes while maintaining acceptable safety profiles. Observational studies highlight its potential for refractory disease and complex phenotypes. Guidelines still conservatively recommend monotherapy for IBD patients, even for those at high risk for complications.

Advanced combination therapy (ACT) represents a potential significant advancement in managing IBD, offering treatment options for refractory cases, concomitant immune-mediated diseases and high-risk populations. Nonetheless, further randomized trials and registry data are needed to generate evidence to support broader adoption of this approach. Future research should focus on cost-effectiveness, longer-term treatment strategies and safety to refine its application in clinical practice.

Advanced combination therapy with biologics and small molecules has seen more widespread implementation for inflammatory bowel disease (IBD). However, there is a paucity of data available to guide the successful de-escalation of combination therapy following the achievement of disease remission. Therefore, we pursued this retrospective study to evaluate our center's approach to de-escalation of these patients.

IBD patients undergoing de-escalation of combination biologic therapy from May 2017 to March 2023 with a follow-up visit were included. The need for re-escalation, steroid therapy, and hospitalization at follow-up was compared between the de-escalation method, adherence, patient demographics, disease characteristics, and measures of disease activity.

Fifty IBD patients underwent de-escalation, with a median age of 35.7 years. All 50 patients had a follow-up visit within a median of 168 (111) days. Patients were divided into two groups with 12 (24%) patients requiring re-escalation of therapy and 38 (76%) able to maintain or further de-escalate. Of those that required re-escalation, 3 (25%) required the use of systemic steroids and none required hospitalization for IBD. Non-adherence to the de-escalation plan significantly correlated with the need for re-escalation (P < .001).

Patient adherence and the number of prior failed biologic therapies were identified as potential risk factors for re-escalation. The type of agent being de-escalated (biologic or Janus kinase inhibitors [JAKi] did not correlate with the need for re-escalation).

The combination of different biological and targeted synthetic DMARDs (i.e., combotherapy) has recently emerged in the management of immune-mediated inflammatory diseases (IMID). However, real-life data across specialities and prognostic factors related to combotherapy are lacking.

Multicenter observational study conducted using the Clinical Data Warehouse from Paris Hospitals' Public Assistance including IMID patients under combotherapy, and a matched monotherapy control group. The primary endpoint was the occurrence of serious adverse events (SAE), defined by severe infections, major cardiovascular events, neoplasia and mortality (all-cause).

From 42,071 subjects having an IMID, 131 combotherapy lines were identified among 125 patients (median age of 36 years, 58 % females) between 2017 and 2022. The most frequent IMIDs were inflammatory bowel disease (48.8 %), connective tissue diseases (23.2 %), inflammatory myopathies (14.4 %) and vasculitis (11.2 %). After a median follow-up of 15 months [IQR 19], 30 (24 %) patients presented severe infections, 5 (4 %) neoplasia, 4 (3.2 %) venous thromboembolism, 3 (2.4 %) acute coronary syndromes and 7 (5.6 %) deaths. The 1-year cumulative incidence of SAE and severe infections were 29 % (95 %CI 21-38), and 24 % (95 %CI 16-32), respectively. The survival, incidence of SAE and severe infections were not statistically different from combotherapy patients compared to monotherapy controls (n=251) after adjustment for confounders. In multivariate analyses, we found abatacept + JAKi (HR 6.81, 95 %CI 1.88-24.68), anti-IL-1-based (HR 4.82, 95 %CI 1.17-19.89) and anti-CD20-based (HR 4.03, 95 %CI 1.22-13.31) combotherapies to be independently associated with an increased risk of SAE.

The overall risk of SAE under combotherapy does not seem greatly increased compared to monotherapy, but certain combinations warrant caution. The combotherapy composition seems predictive of safety outcomes.

Vascular cell adhesion molecule (VCAM)-1 has garnered significant research attention due to its potential as a disease biomarker and drug target across several inflammatory pathologies-including atherosclerosis, asthma, rheumatoid arthritis, and inflammatory bowel disease (IBD). The VCAM-1 protein has also been noted for its functional involvement in cancer metastasis and drug resistance to conventional chemotherapeutics. Although the anti-inflammatory and anti-cancer facets of VCAM-1 antagonisation have been examined separately, there is yet to be a review that explicitly addresses the functional interrelationship between these mechanisms. Furthermore, the pleiotropic mechanisms of anti-VCAM-1 therapies may present a useful paradigm for designing drug candidates with synergistic anti-inflammatory and anti-tumorigenic effects. The pathological overlap between inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CRC) serves as the quintessential disease model to observe this therapeutic duality. This review thereby details the adhesive mechanisms of VCAM-1 in colorectal disease-specifically, driving immune cell infiltration during IBD and tumour cell metastasis in CRC-and posits the potential of this receptor as a common drug target for both diseases. To explore this hypothesis, the current progress of novel VCAM-1-directed drug candidates in experimental models of IBD and CRC is also discussed.

Refractory inflammatory bowel disease (IBD) remains challenging despite the availability of various biologics. Advanced combination therapy (ACT) with biologics and Upadacitinib (UPA), a rapid-onset oral selective Janus kinase inhibitor, has shown promise in managing refractory IBD. However, its use in Asia has not been explored. This study aims to fill that gap by providing data from Taiwan.

This retrospective study included refractory IBD patients who received ACT with biologics and UPA, followed up at the Chang Gung Inflammatory Bowel Disease Center from July 2020 to August 2024. Patients were assessed for clinical response and remission at weeks 4, 12, and 24. Safety profiles were monitored throughout the follow-up period to evaluate the risk of adverse events.

Sixteen refractory IBD patients were enrolled. The median disease duration was 4.5 years [IQR 2.25-9.50]. The most common regimen was Ustekinumab plus UPA (63%). Clinical response rates at weeks 4, 12, and 24 were 88%, 83%, and 100%, respectively, while remission rates were 31%, 50%, and 80%. One patient (6.25%) experienced a minor adverse event (acne), with no major events like herpes zoster reactivation or major cardiac complications.

This is the first study in Asia to demonstrate that UPA-based ACT is both effective and safe in treating refractory IBD. However, the limitations of this retrospective, single-center study with a relatively small sample size highlight the need for future larger-scale, multi-center prospective studies to confirm these findings, identify predictors of treatment response, and evaluate long-term outcomes.

This article comments on the letter by Lowell et al, which addresses the next generation of combination therapy for inflammatory bowel disease (IBD). As the understanding of the pathogenesis of IBD continues to improve, treatment strategies are evolving rapidly. The letter examines the current status and future directions of combination therapy for IBD, focusing on approaches that combine biologics with immunomodulators and the emerging dual-biologic therapy (DBT). The traditional combination of biologics and immunomodulators has demonstrated preliminary efficacy by enhancing the effects of biologics through immunomodulation. However, concerns regarding long-term safety warrant careful evaluation. Recent trials, including DUET-Crohn's disease and DUET-ulcerative colitis, have shown promising potential for the broader adoption of DBT. Nevertheless, comprehensive data on efficacy and safety, as well as the effective integration of supportive treatments, remain essential to establish new paradigms for the next generation of IBD care.

Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic and complex autoimmune conditions. Despite the advancements in biologics and small molecules, the therapeutic ceiling persists, posing significant treatment challenges and contributing to the concept of difficult-to-treat IBD. Dual-targeted therapy (DTT), combining two biologic agents or biologics with small molecules, has emerged as a novel approach to address this unmet need by targeting multiple inflammatory pathways simultaneously. Evidence suggests that DTT holds promise in improving clinical and endoscopic outcomes, especially in patients with refractory disease or extraintestinal manifestations. Safety data, while consistent with monotherapy profiles, highlight the importance of vigilant monitoring for infections and other adverse events. Continued research and high-quality trials are crucial to defining optimal DTT regimens and broadening its clinical applicability. This review explores the efficacy and safety of DTT in IBD, reporting data from clinical trials, systematic reviews, and real-world studies.

A growing number of patients with Crohn's disease and ulcerative colitis have disease that is refractory to multiple advanced therapies, have undergone multiple surgeries, and require further treatment options. For this reason, there has been increasing use of multiple simultaneous advanced targeted therapies. Although the knowledge on combined advanced targeted therapy (CATT) in inflammatory bowel disease (IBD) has been largely limited to observational data and early-phase randomized controlled trials, combination of therapies is commonplace in many other diseases. This review discusses conceptual frameworks of CATT in IBD, provides context of combined therapies in other diseases, provides current evidence for CATT in IBD, and projects future applications and positioning of CATT using existing, novel, and orthogonal mechanisms of action. CATT aims to address the need to overcome low efficacy rates and frequent loss of response of current individual therapies. Both treatment exposure and disease duration are major determinants of response to therapy. Identification of safe and effective CATT may impact positioning of this strategy to apply to a broader IBD population.

Background/Objectives: Despite the increasing number of available medications, a significant proportion of IBD patients fail to achieve the current therapeutic targets. Uncontrolled IBD has a significant impact on patients' quality of life and on overall costs for the healthcare system. Given the complex pathophysiology of IBD, Combined Advanced Targeted Therapy (CATT), involving the combination of biologics/small molecules, appears to have biological plausibility and is gaining increasing interest. The aim of this narrative review is to provide the current evidence regarding CATT in IBD and propose future developments in this field. Methods: Relevant literature evidence was searched with pertinent MeSH terms in the most important database. Results: Available evidence of CATT in IBD provides encouraging results in terms of efficacy and effectiveness, with an acceptable safety profile. CATT may represent a therapeutic solution for patients with "difficult-to-treat" IBD or with concomitant immune-mediated inflammatory diseases. However, current data are restricted by an overall low level of evidence and by the short follow-up. Conclusions: There are no data concluding the superiority of one combination therapy over another. Various therapeutic schemes could be applied in the near future. Further studies are needed to provide recommendations and integrate this therapeutic strategy into everyday clinical practice.

Inflammatory bowel diseases (IBDs), primarily encompassing ulcerative colitis and Crohn's disease, represent a challenging spectrum of disorders with a multifaceted pathogenesis. Despite the array of available treatments, a demand for novel therapeutic options persists to achieve remission in a broader patient population. Research findings indicate that relying solely on a single biologic drug may limit future treatment choices, prompting consideration for a more suitable shift from step-up to top-down strategies in certain cases. In the backdrop of advancing drug development, reimagining the application of existing therapies presents a promising avenue. Among these innovative approaches is combination therapy. This review explores the outcomes of recent randomized clinical trials, systematic reviews, and case studies, focusing on dual biologic therapy. It underscores the effectiveness, safety, and tolerability of combining two biologic drugs in IBD, providing insights into a potentially impactful treatment strategy.

Despite advancements in the therapeutic armamentarium for Crohn's disease (CD), biologic and small molecule monotherapies are associated with sub-optimal response and remission rates. Utilizing dual biologic therapy (DBT) holds the potential to increase efficacy in the treatment of refractory or partially responsive CD. Evidence pertaining to this strategy remains limited.

We retrospectively examined refractory CD patients treated with a combination of ustekinumab and vedolizumab. Outcomes to DBT at week (wk) 52 were compared to monotherapy. The primary outcome constituted corticosteroid-free remission. Secondary outcomes included adverse events, infections, hospitalizations, surgeries, treatment persistence, and disease clearance.

Sixteen of 21 active refractory CD patients (76%) on DBT achieved disease remission at wk 52. Mucosal healing was observed in 38% (n = 6), biochemical remission in 25% (n = 4), and both clinical and biochemical remission in 38% (n = 6). Of these patients, 50% (n = 8) achieved corticosteroid-free remission. Three patients (37.5%) with corticosteroid-free remission achieved complete disease clearance. Paired median fecal calprotectin decreased from 508 to 118 µg/g (P < .0001). Paired C-reactive protein median decreased from 1.04 to 0.50 mg/dL (P < .0001). Median Harvey Bradshaw Index score reduced from 7 to 2 (P = .003). Endoscopic healing was achieved with a paired simple endoscopic score for CD decrease from 6 to 3 (P = .013). Corticosteroid dependency reduced from 17 to 8 patients discontinuing altogether. Patients still requiring corticosteroids experienced a decrease in average daily dose from 9 to 6 mg (P = .045). At wk 52, 5 patients (24%) did not meet the criteria for remission with 4 requiring CD-related surgical intervention. Mean CD-related hospitalizations reduced from 2.95 ± 2.33 to 0.52 ± 1.12 (P < .001) and surgeries from 1.76 ± 1.3 to 0.14 ± 0.4 (P < .001). Three infections with 1 requiring hospitalization and 1 report of headache were noted. Two patients discontinued DBT.

Dual biologic therapy with ustekinumab and vedolizumab is a safe and effective strategy to induce disease remission in refractory CD. Large-scale studies are necessary to validate findings in a prospective setting.

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), often results in significant morbidity among patients with moderate to severe forms. While biologics and small molecules are effective in inducing remission, many patients experience refractory disease or extraintestinal manifestations. This study assesses the safety and efficacy of dual-targeted therapy in IBD patients treated at the Inflammatory Bowel Disease Center.

This retrospective cohort study examined 79 patients with UC or CD who received dual-targeted therapy at the University from October 2018 to August 2023. Data collected included demographics, disease characteristics, previous treatments, and clinical outcomes. Primary outcomes were endoscopic, radiographic, and patient-reported clinical improvements, with secondary outcomes focusing on safety profiles.

Among the 79 patients (42 UC, 37 CD), 97 dual-targeted therapy cases were analyzed, primarily involving a biologic combined with a JAK inhibitor (90.7%). The median therapy duration was 39.1 weeks. Endoscopic improvement occurred in 69% of matched samples, with significant differences between pre- and postdual-targeted therapy Mayo scores for UC (P = .002) and Simple Endoscopic Score for CD (SES-CD) scores for CD (P = .018). The median pre- and postdual-targeted therapy Mayo scores across matched samples were 3 (range 1-3) and 1 (range 0-3), respectively, and for SES-CD scores were 12 (range 0-36) and 4 (range 0-20), respectively. Clinical improvement was reported by 73.2% of patients, with notable reductions in ESR (median 19 [range 2-124] mm/h to 9 [range 0-116] mm/h, P = .006), CRP (median 8.0 [range 0.2-78.5] mg/L to 3.0 [range 0.2-68.2] mg/L, P < .001), and albumin levels (4.0 [range 2.2-4.9] mg/dL to 4.2 [range 3.4-5.2], P < .001). Non-obesity was associated with both more endoscopic improvement (P = .002) and clinical improvement (P = .007). Adverse events occurred in 37 cases, predominantly upper respiratory tract infections and dermatologic issues, with no thromboembolic events reported.

Dual-targeted therapy demonstrated efficacy in improving clinical and endoscopic outcomes in patients with severe, refractory IBD and exhibited an acceptable safety profile. Despite the promising results, further research is needed to confirm these findings and determine optimal therapy combinations.

Advanced combination treatment (ACT), defined as a combination of at least 2 biologic agents, a biologic agent and an oral small molecule, 2 oral small molecules drug with different mechanisms of action is a proposed strategy to improve outcomes in patients with immune-mediated inflammatory disease (IMID). We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing ACT with monotherapy in patients with select IMIDs.

Through a systematic literature search, we identified 10 RCTs (n = 1154) comparing ACT with single agent therapy (monotherapy). The primary outcome was induction of clinical remission. Secondary outcomes were adverse events, serious adverse events, infections, and serious infections. We performed random-effects meta-analysis and used GRADE to appraise certainty of evidence.

Eight out of 10 trials investigated an anti-TNF-α drug (e.g., etanercept, infliximab, golimumab, certolizumab) combined with another biologic (e.g anti-IL-23, anti-integrin, anti-IL-1) or an oral small molecule. There was no significant difference in the likelihood of achieving clinical remission with ACT vs. monotherapy in patients with rheumatoid arthritis (n = 7 RCTs) (RR, 1.75 [95 % CI 0.60-5.13]; moderate heterogeneity (I2 = 33 %)] and systemic lupus erythematosus (n = 1) (RR, 1.20 [0.53-2.72]) (GRADE; low certainty evidence). Patients with rheumatoid arthritis in the ACT arm were more likely to experience adverse events (RR, 1.07 [1.01-1.12]) compared to monotherapy. ACT led to higher rates of induction of clinical remission in patients with IBD (n = 2 RCTs) (RR, 1.68 [1.15-2.46]) with minimal heterogeneity (I2 = 15 %) (GRADE; low certainty evidence), and no differences in the likelihood of adverse events (RR 0.92 [0.80-1.05]). There were no differences in the risk of infections or serious infections in patients treated with ACT or monotherapy with rheumatological disease or IBD.

ACT did not offer clinical benefit in patients with rheumatological IMIDs and resulted in higher rate adverse events in rheumatoid arthritis. ACT may offer clinical benefit without a clear safety signal in patients with IBD, but further trials are warranted. The variability in ACT regimens across studies limits the generalizability of these findings.

Several new treatments including small molecules and biologics have been approved for the treatment of inflammatory bowel diseases in recent years. Clinicians and patients now have a wide variety of therapeutic options to choose from and these novel therapies provide several advantages including oral administration, lower immunogenicity, better selectivity and arguably better safety profiles. An increase in treatment options has increased the complexity of decision-making. Both patients and clinicians have had to become rapidly familiar with efficacy of new medications balanced against a range of pre-initiation requirements, dosing schedules and adverse event profiles.

To provide a simple guide to practising clinicians on recently approved and emerging therapies and address key challenges around treatment strategies such as optimal sequencing and timing of treatment.

We comprehensively searched the published literature and major conference abstracts to identify phase III placebo-controlled and active comparator trials for Crohn's disease and ulcerative colitis.

Data for recently approved therapies including selective Janus kinase inhibitors, sphingosine-1 receptor modulators and p19 interleukin (IL)-23 inhibitors have demonstrated improved patient outcomes in both Crohn's disease and ulcerative colitis. Further comparative head-to-head studies have improved our understanding of when and how to optimally use newer therapies, specifically for IL-23 inhibitors. Data for emerging treatment options and novel treatment strategies such as early effective treatment, combinations of treatments and implications for sequencing are continuing to transform IBD care continually.

Recently approved novel therapies have expanded the range of medical options available to treat IBD. However, further data from long-term extension studies, real-world studies and head-to-head trials are warranted to better inform the long-term safety and optimal sequencing of treatments for patients living with IBD.

Current therapeutic strategies for inflammatory bowel disease (IBD) have reached a plateau in the rates of response and/or remission achieved with a single therapeutic agent. Consequently, the advanced combination therapy (ACT) strategy has emerged as a novel treatment concept for IBD. ACT involves the use of two different targeted therapies, whether biologic or small molecules, with the primary goal of overcoming the therapeutic plateau. Real-world evidence is accumulating among patients undergoing ACT, especially those dealing with concurrent IBD and extraintestinal manifestations or grappling with medically refractory IBD. The recently conducted VEGA study, a randomized clinical trial, has provided crucial insights by demonstrating that the short-term combination of dual biological agents can lead to superior disease control compared to single agents in patients diagnosed with ulcerative colitis (UC). This suggests that ACT holds promise as a therapeutic option to enhance disease control effectively. However, there is still limited evidence of ACT in UC patients who have proven refractory to biologic therapy and patients with Crohn's disease. This review aims to discuss whether ACT represents the optimal approach for overcoming the therapeutic ceiling in IBD.

Ulcerative colitis (UC) is an idiopathic, chronic inflammatory bowel disease (IBD) most often located in the rectum, but may involve the entire colon. Extra intestinal manifestations (EIMs) occur with varying frequency depending on the affected organ. The most common ones are musculoskeletal EIMs, affecting up to 33%-40% of IBD patients. These include, among others, inflammatory back pain, tendinitis, plantar fasciitis and arthritis. Only a few case reports in literature discuss Achilles tendinitis.

This report describes a patient with UC and Achilles tendinitis in whom after many unsuccessful attempts of treatment with sulfasalazine, mesalazine, glucocorticosteroids, infliximab and tofacitinib, a complete UC remission and resolution of Achilles tendinitis were achieved with the use of dual biologic therapy (DBT)-ustekinumab and adalimumab (ADA).

This case mentions rare EIMs of UC and suggests that DBT may be an alternative for patient with ulcerative colitis and EIMs.

Inflammatory bowel disease (IBD) is entering a potentially new era of combined therapeutics. Triantafillidis et al provide an insightful review of the current state of combination therapy, with a focus on the use of a combined biologic and immunomodulator, as well as emerging data on the future potential of dual-biologic therapy (DBT). While current evidence for DBT is limited, encouraging safety profiles and ongoing trials suggest a brighter future for this approach. The importance of controlled trials should be stressed in establishing new treatment paradigms. Ongoing prospective randomized trials of DBT and perhaps future combinations of biologics and small molecule therapies will hopefully guide the next generation of IBD care.

Although biologics have revolutionized the treatment of Crohn's disease (CD), an efficacy ceiling has been reached. Combining biologic therapies may improve remission rates.

EXPLORER, a phase 4, single-arm, open-label study, evaluated triple combination therapy with vedolizumab (300 mg on day 1, weeks 2 and 6, and then every 8 weeks), adalimumab (160 mg on day 2, 80 mg at week 2, then 40 mg every 2 weeks), and methotrexate (15 mg weekly) in biologic-naïve patients with newly diagnosed, moderate- to high-risk CD. Endoscopic remission at week 26 (primary end point; Simple Endoscopic Score for CD ≤2), clinical remission at weeks 10 and 26 (secondary end point; Crohn's Disease Activity Index <150), and incidences of adverse events and serious adverse events were evaluated.

Among 55 enrolled patients, the mean CD duration was 0.4 years, the mean baseline Simple Endoscopic Score for CD was 12.6, and the mean baseline Crohn's Disease Activity Index was 265.5. At week 26, 19 patients (34.5%) were in endoscopic remission. At weeks 10 and 26, 34 (61.8%) and 30 patients (54.5%), respectively, were in clinical remission. Post hoc Bayesian analysis showed that the probabilities that triple combination therapy produced a higher endoscopic remission rate (33.5%; 95% credible interval, 22.4-45.7) than placebo (14%), vedolizumab monotherapy (27%), or adalimumab monotherapy (30%) were 99.9% or higher, 86.3%, and 71.4%, respectively. Six patients had serious adverse events.

Combination therapy resulted in endoscopic and clinical remission at week 26 in 34.5% and 54.5% of patients, respectively, with no safety signal related to the treatment regimen. This supports further evaluation of combination therapy in CD.

gov number: NCT02764762.

To provide an overview of the current literature regarding the use of advanced combination therapy (ACT) in patients with inflammatory bowel disease (IBD). Although the treatment of IBD has come a long way, many patients do not respond or will lose response to currently available treatments over time. ACT has been proposed as a model to create sustained remission in difficult-to-treat IBD patient populations. This review discusses the available literature supporting the use of ACT, followed by practical tips for applying this model of treatment to clinical practice.

Both observational and controlled evidence have demonstrated that there may be an increased benefit of ACT in specific IBD patient populations compared to advanced targeted immunomodulator (TIM) monotherapy. Additional data is required to understand how to best use combination TIMs and the long-term risks associated with this strategy.

While the literature has demonstrated the potential for benefit in both Crohn's disease and ulcerative colitis, the use of ACT is currently off-label and long-term controlled data is needed. The successful application of ACT requires careful consideration of both patient and disease profiles as well as close monitoring of treatment response and adverse events.

Inflammatory bowel disease (IBD) is a chronic and relapsing immune-mediated disease of the gastrointestinal tract with a gradually increasing global incidence and prevalence. A prolonged course of IBD leads to a decline in patient quality of life and the creation of a substantial economic burden on society. Owing to the lack of specific diagnostic markers, the diagnosis of IBD still needs a gold standard based on a combination of clinical manifestations, imaging, laboratory, and endoscopic results. Accordingly, the current goals of IBD treatment are to alleviate clinical symptoms and reduce recurrence rates. Therefore, it is imperative to develop a standard set of procedures to diagnose and treat IBD. In this review, we summarize prominent and emerging studies, outline classical and contemporary approaches to diagnosing and managing IBD, and integrate multiple guidelines. Furthermore, we propose the possibility of establishing an early and comprehensive diagnostic workflow and personalized management strategy in the future. We aim to enhance the quality and standardization of diagnostic and treatment procedures for IBD.

The treatment of patients with inflammatory bowel disease (IBD), especially those with severe or refractory disease, represents an important challenge for the clinical gastroenterologist. It seems to be no exaggeration to say that in these patients, not only the scientific background of the gastroenterologist is tested, but also the abundance of "gifts" that he should possess (insight, intuition, determination, ability to take initiative, etc.) for the successful outcome of the treatment. In daily clinical practice, depending on the severity of the attack, IBD is treated with one or a combination of two or more pharmaceutical agents. These combinations include not only the first-line drugs (e.g., mesalazine, corticosteroids, antibiotics, etc) but also second- and third-line drugs (immunosuppressants and biologic agents). It is a fact that despite the significant therapeutic advances there is still a significant percentage of patients who do not satisfactorily respond to the treatment applied. Therefore, a part of these patients are going to surgery. In recent years, several small-size clinical studies, reviews, and case reports have been published combining not only biological agents with other drugs (e.g., immunosuppressants or corticosteroids) but also the combination of two biological agents simultaneously, especially in severe cases. In our opinion, it is at least a strange (and largely unexplained) fact that we often use combinations of drugs in a given patient although studies comparing the simultaneous administration of two or more drugs with monotherapy are very few. As mentioned above, there is a timid tendency in the literature to combine two biological agents in severe cases unresponsive to the applied treatment or patients with severe extraintestinal manifestations. The appropriate dosage, the duration of the administration, the suitable timing for checking the clinical and laboratory outcome, as well as the treatment side-effects, should be the subject of intense clinical research shortly. In this editorial, we attempt to summarize the existing data regarding the already applied combination therapies and to humbly formulate thoughts and suggestions for the future application of the combination treatment of biological agents in a well-defined category of patients. We suggest that the application of biomarkers and artificial intelligence could help in establishing new forms of treatment using the available modern drugs in patients with IBD resistant to treatment.

Current data on dual biologic therapy in children are limited. This multicenter study aimed to evaluate the effectiveness and safety of dual therapy in pediatric patients with inflammatory bowel disease (IBD).

A retrospective study from 14 centers affiliated with the Pediatric IBD Interest and Porto Groups of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. Included were children with IBD who underwent combinations of biologic agents or biologic and small molecule therapy for at least 3 months. Demographic, clinical, laboratory, endoscopic, and imaging data were collected. Adverse events were recorded.

Sixty-two children (35 Crohn's disease, 27 ulcerative colitis; median age 15.5 [interquartile range, 13.1-16.8] years) were included. They had all failed previous biologic therapies, and 47 (76%) failed at least 2 biologic agents. The dual therapy included an anti-tumor necrosis factor agent and vedolizumab in 30 children (48%), anti-tumor necrosis factor and ustekinumab in 21 (34%) children, vedolizumab and ustekinumab in 8 (13%) children, and tofacitinib with a biologic in 3 (5%) children. Clinical remission was observed in 21 (35%), 30 (50%), and 38 (63%) children at 3, 6, and 12 months, respectively. Normalization of C-reactive protein and decrease in fecal calprotectin to <250 µg/g were achieved in 75% and 64%, respectively, at 12 months of follow-up. Twenty-nine (47%) children sustained adverse events, 8 of which were regarded as serious and led to discontinuation of therapy in 6.

Dual biologic therapy may be effective in children with refractory IBD. The potential efficacy should be weighed against the risk of serious adverse events.

To assess the safety of early vs late biologic switch in patients with inflammatory bowel disease.

In this retrospective study, we included patients with inflammatory bowel disease who underwent biologic switch between January 2014 and July 2022 at a tertiary center. The primary outcome was any infection by 6 months.

There was no statistically significant difference between patients who had early biologic switch (≤30 days, n = 51) and late switch (>30 days, n = 77) in either infectious or noninfectious adverse events by 6 and 12 months.

Early biologic switch is safe. A prolonged washout period between 2 biologics is unnecessary.

In patients with inflammatory bowel disease (IBD), a combination of dysbiosis, increased intestinal permeability, and insufficient regulatory responses facilitate the development of chronic inflammation, which is driven by a complex interplay between the mucosal immune system and the environment and sustained by immune priming and ongoing cellular recruitment to the gut. The localization of immune cells is mediated by their expression of chemokine receptors and integrins, which bind to chemokines and adhesion molecules, respectively. In this article, we review the mechanisms of action of anti-trafficking therapies for IBD and consider clinical observations in the context of the different mechanisms of action. Furthermore, we discuss the evolution of molecular resistance to anti-cytokines, in which the composition of immune cells in the gut changes in response to treatment, and the potential implications of this for treatment sequencing. Lastly, we discuss the relevance of mechanism of action to combination therapy for IBD.

Inflammatory bowel disease (IBD) is a chronic systemic immune-mediated disorder. The disease is triggered and perpetuated by a complex interplay between genetic predisposition, dysregulated immune responses, and environmental factors. Pediatric IBD is considered to be more aggressive compared with adult-onset IBD, and commonly requires more intensive pharmacological and surgical treatments. Although the use of targeted therapy, such as biologic therapy and small molecule therapy, is on the rise, there are children with IBD who are refractory to all current therapeutic options. For them, a combination of biologic agents or a biologic agent with small molecules as dual-targeted therapy (DTT) may be a possible therapeutic option. The main indications for DTT are high inflammatory burden and refractoriness to standard therapy, extra-intestinal manifestations of IBD, adverse effects of therapy, and co-existing immune-mediated inflammatory disorders. Several combination therapies were described for pediatric refractory IBD. The main ones were anti-tumor necrosis factor (TNF) agents and vedolizumab (VDZ), anti-TNF and ustekinumab (UST), VDZ and UST, and biologic agents with tofacitinib. DTT exhibits high efficacy, with high rates of clinical response and remission as well as biomarker remission. The data on endoscopic and radiologic remission are scarce. Most of the adverse effects reported under DTT were mild; however, the serious ones that had been observed mandate a profoundly cautious approach when considering it. Triple immunosuppressive therapy and combinations of biologics with emergent therapies such as selective Janus kinase inhibitors, sphingosine-1-phosphate receptor modulators, and anti-interleukin-23 agents, are potential future regimens for children with IBD who are refractory to current therapeutic options. This review provides an update of publications on these issues.

The current mainstay treatment modalities for inflammatory bowel disease (IBD) include immunomodulators (methotrexate and thiopurines), biologics (antitumour necrosis factor alpha (TNF-α) being the most commonly used) and other monoclonal antibodies such as the anti-integrins and anti-interleukins (IL-12/23). While ideally treatment should be initiated early in the disease process to avoid relapses and complications, the major recurring issue continues to be primary and secondary loss of response, with often 'diminishing returns' in terms of efficacy for the next line of therapies prescribed for patients with IBD. Additional concerns include the long-term risk factors such as malignancy and susceptibility to infections. Recently, there has been an influx of new and emerging medications entering the market that are showing promising efficacy results in patients with moderate-to-severe disease who have previously failed to respond to multiple drugs. This review will focus on these novel and emerging therapies-in essence, 'horizon scanning'-which includes the antiadhesion agents, cytokine inhibitors, Janus kinase inhibitors, phosphodiesterase inhibitors, sphingosine-1 phosphate receptor modulators and MicroRNA-124 (miR-124) upregulators.

Inflammatory bowel disease (IBD) is a group of chronic multifactorial inflammatory disorders including two major entities: Crohn's disease (CD) and ulcerative colitis (UC). Preliminary evidence suggests that patients with IBD may be at increased risk of developing intestinal and extraintestinal cancers (EICs). Actually, little is known about the association between IBD and EICs, and there is ever-growing concern regarding the safety of immunomodulators and biological therapy, which may represent a risk factor for carcinogenesis.

The aim of this review is to summarize the evidence regarding the association between IBD and EICs, the safety of immunomodulators and biological therapy and the management of immunomodulators and biologic agents in IBD patients with prior or current EICs.

IBD patients have a higher risk of developing different forms of extraintestinal solid organ tumors and hematological malignancies. Immunomodulators and biological therapy may increase the risk of developing some types of EICs and may be consciously used in patients with IBD and current or prior history of malignancy.

Decisions regarding the use of immunomodulators or biological therapies should be made on an individual basis, considering a multidisciplinary approach involving oncologists.

Dual targeted therapy (DTT) has emerged as an attractive therapeutic option for select patients with active inflammatory bowel disease (IBD) who are unable to achieve remission with biologic or small molecule monotherapy. We conducted a systematic review of specific DTT combinations in patients with IBD.

We conducted a systematic search of MEDLINE, EMBASE, Scopus, CINAHL Complete, Web of Science Core Collection, and Cochrane Library to identify articles related to the use of DTT for the treatment of Crohn Disease (CD) or ulcerative colitis (UC) published before February 2021.

Twenty-nine studies were identified comprising 288 patients started on DTT for partially or non-responsive IBD. We identified 14 studies with 113 patients receiving anti-tumor necrosis factor (TNF) and anti-integrin therapies (i.e., vedolizumab and natalizumab), 12 studies with 55 patients receiving vedolizumab and ustekinumab, nine studies with 68 patients receiving vedolizumab and tofacitinib, five studies with 24 patients receiving anti-TNF therapy and tofacitinib, six studies with 18 patients receiving anti-TNF therapy and ustekinumab, and three studies with 13 patients receiving ustekinumab and tofacitinib.

DTT is a promising approach to improve IBD treatment for patients with incomplete responses to targeted monotherapy. Larger prospective clinical studies are needed to confirm these findings as is additional predictive modeling to identify the patient subgroups most likely to require and benefit from this approach.

There is not enough information to position medications for the treatment of Crohn's disease (CD). Therefore, using a network meta-analysis and systematic review, we evaluated the efficacy and safety of combination therapy and infliximab (IFX) monotherapy in CD patients.

We identified randomized controlled trials (RCTs) in CD patients who were given IFX-containing combination therapy versus IFX monotherapy. Induction and maintenance of clinical remission were the efficacy outcomes, while adverse events were the safety outcomes. The surface under cumulative ranking (SUCRA) probabilities was used to assess ranking in the network meta-analysis.

In total, 15 RCTs with 1586 CD patients were included in this study. There was no statistical difference between different combination therapies in induction and maintenance of remission. In terms of inducing clinical remission, IFX + EN (SUCRA: 0.91) ranked highest; in terms of maintaining clinical remission, IFX + AZA (SUCRA: 0.85) ranked highest. There was no treatment that was significantly safer than the others. In terms of any adverse events, serious adverse events, serious infections, and infusion/injection-site reactions, IFX + AZA (SUCRA: 0.36, 0.12, 0.19, and 0.24) was ranked lowest for all risks; while IFX + MTX (SUCRA: 0.34, 0.06, 0.13, 0.08, 0.34, and 0.08) was rated lowest for risk of abdominal pain, arthralgia, headache, nausea, pyrexia, and upper respiratory tract infection.

Indirect comparisons suggested that efficacy and safety of different combination treatments are comparable in CD patients. For maintenance therapies, IFX + AZA was ranked highest for clinical remission and lowest for adverse events. Further head-to-head trials are required.

Advanced therapies for inflammatory bowel disease [IBD] could potentially lead to a state of immunosuppression with an increased risk of opportunistic infections [OIs]. We aimed to provide an update on the incidence of OIs among adult IBD patients in randomized controlled trials [RCTs] of approved biologics and small-molecule drugs [SMDs]. Also, we aimed to describe OI definitions utilized in RCTs, to ultimately propose a standardized definition.

Electronic databases were searched from January 1, 1990, until April 16, 2022. Our primary outcome was incidence rate of overall OIs among IBD patients exposed and unexposed to biologics or SMDs. We also describe specific OIs reported in included trials, as well as definitions of OIs within studies when provided.

Ninety studies were included. The incidence rates of reported OIs were 0.42 and 0.21 per 100 person-years in patients exposed to advanced therapies and placebo, respectively. This was highest for anti-tumour necrosis factors [0.83 per 100 person-years] and Janus kinase inhibitors [0.55 per 100 person-years] and lowest for anti-integrins and ozanimod. On meta-analysis, no increased risk of OIs was observed. None of the studies provided a detailed definition of OIs, or a comprehensive list of infections considered as OIs.

Different mechanisms of action may have specific OI profiles. In the absence of a uniform definition of OIs, these estimates are less reliable. We propose a definition to be used in future studies to help provide standardized reporting. When using this definition, we saw significant differences in incidence rates of OIs across mechanisms of action.

The advent of biologics and small molecules in inflammatory bowel disease (IBD) has marked a significant turning point in the prognosis of IBD, decreasing the rates of corticosteroid dependence, hospitalizations and improving overall quality of life. The introduction of biosimilars has also increased affordability and enhanced access to these otherwise costly targeted therapies. Biologics do not yet represent a complete panacea: A subset of patients do not respond to first-line anti-tumor necrosis factor (TNF)-alpha agents or may subsequently demonstrate a secondary loss of response. Patients who fail to respond to anti-TNF agents typically have a poorer response rate to second-line biologics. It is uncertain which patient would benefit from a different sequencing of biologics or even a combination of biologic agents. The introduction of newer classes of biologics and small molecules may provide alternative therapeutic targets for patients with refractory disease. This review examines the therapeutic ceiling in current treatment strategies of IBD and the potential paradigm shifts in the future.

Spondyloarthritis and inflammatory bowel diseases are chronic immune disorders of the joints and the gut that often coexist in the same patient, increasing the burden of each disorder, worsening patients' quality of life, and influencing therapeutic strategies. Genetic predisposition, environmental triggers, microbiome features, immune cell trafficking, and soluble factors such as cytokines contribute to the pathogenesis of both articular and intestinal inflammation. Most of the molecular targeted biological therapies developed over the last two decades were based on evidence that specific cytokines may be involved in these immune diseases. Despite pro-inflammatory cytokine pathways sharing the pathogenesis of both articular and gut diseases (i.e., tumor necrosis factor and interleukin-23), several other cytokines (i.e., interleukin-17) may be differently involved in the tissue damage process, depending on the specific disease and the organ involved in inflammation, making difficult the identification of a therapeutic plan that is efficacious for both inflammatory manifestations. In this narrative review, we comprehensively summarize the current knowledge on cytokine involvement in spondyloarthritis and inflammatory bowel diseases, underlining similarities and differences among their pathogenetic pathways; finally, we provide an overview of current and potential future treatment strategies to simultaneously target both articular and gut immune disorders.