Role of conventional therapies in the era of biological treatment in Crohn’s disease

Outstanding progress regarding the pathophysiology of Crohn's disease (CD) has led to the development of innovative therapeutic concepts. Numerous controlled trials have been performed in CD. This review concentrates on the results of randomized,placebo-controlled trials,and meta-analyses when available,that provide the highest degree of evidence. Current guidelines on the management of CD recommend a step-up approach to treatment involving the addition of more powerful therapies as the severity of disease and refractoriness to therapy increase. The advent of biological drugs has opened new therapeutic horizons for treating CD,modifying the treatment goals. However,the large majority of patients with CD will be managed through conventional therapy,even if they are a prelude to biological therapy.

Navigating new horizons in inflammatory bowel disease:Integrative approaches and innovations

This editorial offers an updated synthesis of the major advancements in the management and treatment of inflammatory bowel disease(IBD),as documented in the World Journal of Gastroenterology between 2023 and early 2024.This editorial explores substantial developments across key research areas,such as intestinal microecology,computational drug discovery,dual biologic therapy,telemedicine,and the integration of lifestyle changes into patient care.Furthermore,the discussion of emerging topics,including bowel preparation in colonoscopy,the impact of the coronavirus disease 2019 pandemic,and the intersection between IBD and mental health,reflects a shift toward a more holistic approach to IBD research.By integrating these diverse areas of research,this editorial seeks to promote a holistic and multidisciplinary approach to IBD treatment,combining emerging technologies,personalized medicine,and conventional therapies to improve patient outcomes.

Rare extraintestinal manifestations of ulcerative colitis treated with dual biologic therapy:A case report

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

Biological therapy for ulcerative colitis:An update

Of the diverse biological agents used for patients with ulcerative colitis, the anti-tumor necrosis factor-α agents infliximab and adalimumab have been used in large-scale clinical trials and are currently widely used in the treatment of inflammatory bowel disease patients. Recent studies have indicated that golimumab, oral tofacitinib and vedolizumab reportedly achieved good clinical response and remission rates in ulcerative colitis patients. Thus, we believe that the detailed investigation of various studies on clinical trials may provide important information for the selection of appropriate biological agents, and therefore, we have extensively reviewed such trials in the present study.

Frequency and prognostic role of mucosal healing in patients with Crohn's disease and ulcerative colitis after one-year of biological therapy

AIM: To assess the endoscopic activity before and after a one-year period of biological therapy and to evaluate the frequency of relapses and need for retreatment after stopping the biologicals in patients with Crohn’s disease (CD) and ulcerative colitis (UC).

Improving cancer therapy by combining cell biological, physical, and molecular targeting strategies

Successful cancer therapy depends on selective killing of tumor cells while sparing normal cells. Selectivity can be achieved through treatment strategies that target tumor cells. A recent report from the Li laboratory （1） describes an elegant strategy to selectively kill tumor cells by combining several targeting strategies based on cell biological, physical, and molecular （genetic） properties of tumor and normal cells that enhances tumor cell killing in vitro and in an in vivo tumor xenograft model. The idea of using a multiplex targeting approach is reminiscent of strategies in which several antibiotics are used to treat bacterial infections while minimizing the chance that rare antibiotic-resistant mutants will arise within a population.

Access to biologicals in Crohn's disease in ten European countries

AIM To analyze access(availability, affordability and acceptability) to biologicals for Crohn's disease(CD) in ten European countries and to explore the associations between these dimensions, the uptake of biologicals and economic development.METHODS A questionnaire-based survey combined with desk research was carried out in May 2016. Gastroenterologists from the Czech Republic, France, Germany, Hungary, Latvia, Poland, Romania, Slovakia, Spain and Sweden were invited to participate and provide data on the availability of biologicals/biosimilars, reimbursement criteria, clinical practice and prices, and use of biologicals. An availability score was developed to evaluate the restrictiveness of eligibility and administrative criteria applied in the countries. Affordability was defined as the annual cost of treatment as a share of gross domestic product(GDP) per capita. Correlations with the uptake of biologicals, dimensions of access and GDP per capita were calculated.RESULTS At the time of the survey, infliximab and adalimumab were reimbursed in all ten countries, and vedolizumab was reimbursed in five countries(France, Germany, Latvia, Slovakia, Sweden). Reimbursement criteria were the least strict in Sweden and Germany, and the strictest in Hungary, Poland and Slovakia. Between countries, the annual cost of different biological treatments differed 1.6-3.3-fold. Treatments were the most affordable in Sweden(13%-37% of the GDP per capita) and the least affordable in the Central and Eastern European countries, especially in Hungary(87%-124%) and Romania(141%-277%). Biosimilars made treatments more affordable by driving down the annual costs. The number of patients with CD on biologicals per 100000 population was strongly correlated with GDP per capita(0.91), although substantial differences were found in the uptake among countries with similar economic development. Correlation between the number of patients with CD on biologicals per 100000 population and the availability and affordability was also strong(-0.75,-0.69 respectively). CONCLUSION Substantial inequalities in access to biologicals were largely associated with GDP. To explain differences in access among countries with similar development needs further research on acceptance.

Emerging role of dual biologic therapy for the treatment of inflammatory bowel disease

Biologic agents have now been used in the management of inflammatory bowel disease(IBD)for many years where experience,expertise and confidence in their use has developed over time.In the United Kingdom,there are well established guidelines and recommendations for both single agent biologic treatments,and with combination therapy of a biologic agent with a small molecule agent in maintenance therapy.In recent times,there has been increasing interest and experience using dual biologic therapy(DBT)in IBD,primarily in difficult to treat and refractory cases with high disease burden.However,published data on use,experience and safety profiles is limited and large-scale studies remain low in number in this developing area.We therefore aim to present a summary and review of the available published data in this area to help us better understand the emerging role of DBT in IBD.

Metastatic colorectal cancer-past,progress and future

The clinical management of metastatic （stage IV） colorectal cancer （CRC） is a common challenge faced by surgeons and physicians. The last decade has seen exciting developments in the management of CRC, with significant improvements in prognosis for patients diagnosed with stage IV disease. Treatment options have expanded from 5-fluorouracil alone to a range of pharmaceutical and interventional therapies, improving survival, and providing a cure in selected cases. Enhanced understanding of the biologic pathways most important in colorectal carcinogenesis has led to a new generation of drugs showing promise in advanced disease. It is hoped that in the near future the treatment paradigm of metastatic CRC will be analogous to that of a chronic illness, rather than a rapidly terminal condition. This overview discusses the epidemiology of advanced CRC and currently available therapeutic options including medical, surgical, ablative and novel modalities in the management of metastatic colorectal cancer.

Recombination Mutant Human Tumor Necrosis Factor Combined with Chemotherapy in the Treatment of Advanced Cancer

Objective: Past studies showed that tumor necrosis factor (TNF) assisted anti-tumor treatment and intensified the sensitivity of chemotherapy. However its clinical application has been curbed because of its low purity, high dosage, and strong toxicity. The objective of present study is to evaluate the therapeutic effects and adverse reactions of recombinant mutant human tumor necrosis factor (rmhTNF) combined with chemotherapy in patients with advanced malignant tumor. Methods: 105 patients with advanced malignant tumor were randomly divided into trial group, 69 patients, and control group, 36 patients. rmhTNF was injected intramuscularly to the trial group at a dose of 4×106 U/m2, from the 1st to 7th days, the 11th to 17th days combined with chemotherapy course. The chemotherapy plan was as follows: CAP for patients with the NSCLC; FAM for patients with gastric cancer; FC for patients with colorectal cancer. One treatment cycle lasted for 21 days and two cycles were scheduled. The control group was given only the same chemotherapy as the trial group. Results: In the trial group there was 1 CR case and 12 PR cases, and the response rate was 13/69 (18.84%); in the control group 1 PR case, the response rate 1/36 (2.78%). The response rate in the trial group was significantly higher than that in the control group (P=0.022). The response rate for NSCLC in the trial group was 8/17 (47.06%), and 1/6 (16.67%) in the control group. The response rates for gastric cancer and colorectal cancer in the trial groups also were higher than those in the control groups. After the treatment the KPS was 89.00±9.92 in the trial group, and 84.17±8.84 in the control group, with a significant difference between the two groups (P=0.028). The adverse reactions of rmhTNF injection included: pain in the injection area, chill, hardening and swelling and redness in the injection area, fever, ostealgia and myosalgia, and cold-like symptoms. All these adverse reactions were mild and bearable. Conclusion: The administration of rmhTNF in combination with general chemotherapy is an effective and secure means in treating advanced malignant tumor.

Quality of life in patients with gastroenteropancreatic tumours: A systematic literature review

BACKGROUND Gastroenteropancreatic neuroendocrine tumours(GEP-NETs)are slow-growing cancers that arise from diffuse endocrine cells in the gastrointestinal tract(GINETs)or the pancreas(P-NETs).They are relatively uncommon,accounting for 2%of all gastrointestinal malignancies.The usual treatment options in advanced GEP-NET patients with metastatic disease include chemotherapy,biological therapies,and peptide receptor radionuclide therapy.Understanding the impact of treatment on GEP-NET patients is paramount given the nature of the disease.Health-related quality of life(HRQoL)is increasingly important as a concept reflecting the patients’perspective in conjunction with the disease presentation,severity and treatment.AIM To conduct a systematic literature review to identify literature reporting HRQoL data in patients with GEP-NETs between January 1985 and November 2019.METHODS The PRISMA guiding principles were applied.MEDLINE,Embase and the Cochrane library were searched.Data extracted from the publications included type of study,patient population data(mid-gut/hind-gut/GI-NET/P-NET),sample size,intervention/comparators,HRQoL instruments,average and data spread of overall and sub-scores,and follow-up time for data collection.RESULTS Forty-three publications met the inclusion criteria.The heterogeneous nature of the different study populations was evident;the percentage of female participants ranged between 30%-60%,whilst average age ranged from 53.8 to 67.0 years.Eight studies investigated GI-NET patients only,six studies focused exclusively on P-NET patients and the remaining studies involved both patient populations or did not report the location of the primary tumour.The most commonly used instrument was the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30(n=28)with consistent results across studies;the GI-NET-specific module Quality of Life Questionnaire-GINET21 was used in six of these studies.A number of randomised trials demonstrated no HRQoL changes between active treatment and placebo arms.The Phase III NETTER-1 study provides the best data available for advanced GEP-NET patients;it shows that peptide receptor radionuclide therapy can significantly improve GEP-NET patients’HRQoL.CONCLUSION HRQoL instruments offer a means to monitor patients’general disease condition,disease progression and their physical and mental well-being.Instruments including the commonly used European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and GINET21 lack,however,validation and a defined minimal clinical important difference specifically for GINET and P-NET patients.

Management of inflammatory bowel disease with Clostridium difficile infection

To address the management of Clostridium difficile (C. difficile) infection (CDI) in the setting of suspected inflammatory bowel disease (IBD)-flare. METHODSA systematic search of the Ovid MEDLINE and EMBASE databases by independent reviewers identified 70 articles including a total of 932141 IBD patients or IBD-related hospitalizations. RESULTSIn those with IBD, CDI is associated with increased morbidity, including subsequent escalation in IBD medical therapy, urgent colectomy and increased hospitalization, as well as excess mortality. Vancomycin-containing regimens are effective first-line therapies for CDI in IBD inpatients. No prospective data exists with regards to the safety or efficacy of initiating or maintaining corticosteroid, immunomodulator, or biologic therapy to treat IBD in the setting of CDI. Corticosteroid use is a risk factor for the development of CDI, while immunomodulators and biologics are not. CONCLUSIONStrong recommendations regarding when to initiate IBD specific therapy in those with CDI are precluded by a lack of evidence. However, based on expert opinion and observational data, initiation or resumption of immunosuppressive therapy after 48-72 h of targeted antibiotic treatment for CDI may be considered.

Innovative therapeutics for inflammatory bowel disease

Inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the gastrointestinal tract, which clinically present as one of two disorders, Crohn's disease or ulcerative colitis. Mainstays of drug treatments for IBD include aminosalicylates, corticosteroids and immunosuppressants such as azathioprine, methotrexate and cyclosporin. Advances in basic research of the pathophysiological process in IBD have been applied to generate a variety of new therapeutics targeting at different levels of the inflammatory processes. New therapies are classified as: (1) Anti-TNFα antibodies; (2) Recombinant cytokines; (3) Selective adhesion blockade; (4) Growth factors; (5) Innate immunostimulation; (6) Nucleic acid based therapies; (7) Gene therapy; (8) Autologous bone-marrow transplantation; (9) Helminths and (10) Extracorporeal immunomodulation. All treatments have the potential to provide more effective and safe treatment for IBD.

Risk of hepatitis B virus reactivation in patients with autoimmune diseases undergoing non-tumor necrosis factor-targeted biologics

Hepatitis B virus reactivation(HBVr)can occur in patients treated with immunosuppressive medications.Risk stratification for HBVr based on hepatitis B virus(HBV)serology and viral load is an important strategy to determine appropriate HBV monitoring and antiviral prophylaxis use.Recent advances in the understanding of pathophysiology of autoimmune diseases have led the development of cytokine-targeted therapies.Tumor necrosis factor(TNF)-αinhibitors have been widely used for patients with inflammatory bowel disease,psoriasis,and rheumatic diseases.Further,the clinical benefits of interleukin(IL)-12/23,IL-17,or Janus kinases inhibitors have been demonstrated in these patients.It is well known that TNF-αinhibitor use can lead to HBVr,however,the risk of HBVr in patients undergoing non-TNF-targeted biologics have not been fully understood.In this review,we discuss the risk of HBVr in patients treated with non-TNF-targeted biologics,and immunological mechanisms of these medications causing HBVr.

Are we giving biologics too late? The case for early versus late use

Corticosteroids and immunomodulators have been the mainstay therapies for Crohn’s disease. Corticosteroids are highly effective to control symptoms in the short- term, but they are not effective in maintaining remission, they heal the mucosa in a reduced proportion of cases, and long-time exposure is associated with an increased risk of infections and mortality. Immunomodulators, azathioprine and methotrexate, heal the mucosa in a higher proportion of patients that corticosteroids but their onset of action is slow and they benefit less than half of patients with Crohn’s disease. In the last decade, medical therapy for Crohn’s disease has experienced a remarkable change due to the introduction of biologic therapy, and particularly the use of anti-tumour necrosis factor-alpha agents. Infliximab, adalimumab, and certolizumab pegol have demonstrated efficacy for induction and maintenance of remission in active Crohn’s disease. These agents have raised the bar for what is a suitable symptomatic response in Crohn’s disease and modification of the natural history of the disease has become a major goal in the treatment of Crohn’s disease. There are several data in the literature that suggest that early use of biologic therapy and achievement of mucosal healing contribute to disease course modification. However, many questions on early biological therapy for Crohn’s disease remain still unanswered.

Role of the combination of biologics and/or small molecules in the treatment of patients with inflammatory bowel disease

Inflammatory bowel disease(IBD)is a group of chronic diseases that includes ulcerative colitis,Crohn’s disease,and indeterminate colitis.Patients with IBD require prolonged treatment and high utilization of healthcare resources for proper management.The treatment of patients with IBD is focused on achieving therapeutic goals including clinical,biochemical,and endoscopic variables that result in improvement of the quality of life and prevention of disability.Advanced IBD treatment includes tumor necrosis factor inhibitors,integrin antagonist,antagonist of the p40 subunit of interleukin 12/23,and small molecule drugs.However,despite the multiple treatments available,about 40%of patients are refractory to therapy and present with persistent symptoms that have a great impact on their quality of life,with hospitalization and surgery being necessary in many cases.Dual therapy,a strategy sometimes applicable to refractory IBD patients,includes the combination of two biologics or a biologic in combination with a small molecule drug.There are two distinct scenarios in IBD patients in which this approach can be used:(1)Refractory active luminal disease without extraintestinal manifestations;and(2)patients with IBD in remission,but with active extraintestinal manifestations or immune-mediated inflammatory diseases.This review provides a summary of the results(clinical response and remission)of different combinations of advanced drugs in patients with IBD,both in adults and in the pediatric population.In addition,the safety profile of different combinations of dual therapy is analyzed.The use of newer combinations,including recently approved treatments,the application of new biomarkers and artificial intelligence,and clinical trials to establish effectiveness during long-term followup,are needed to establish new strategies for the use of advanced treatments in patients with refractory IBD.

Perianal Crohn's disease: Is there something new?

Perianal lesions are common in patients with Crohn's disease, and display aggressive behavior in some cases. An accurate diagnosis is necessary for the optimal management of perianal lesions. Treatment of perianal Crohn's disease includes medical and/or surgical options. Recent discoveries in the pathogenesis of this disease have led to advances in medical and surgical therapy with good results. Perianal lesions in Crohn's disease remain a challenging aspect for both gastroenterologists and surgeons and lead to a greatly impaired quality of life for all patients affected by this disease. A multidisciplinary approach is mandatory to obtain the best results.

Correlations between skin lesions induced by anti-tumor necrosis factor-α and selected cytokines in Crohn's disease patients

AIM:To investigate the correlation between the appearance of skin lesions and concentration of interleukin(IL)-17A,IL-23 and interferon-γ(IFN-γ)in Crohn’s disease(CD)patients during anti-tumor necrosis factor-α(TNF-α)therapy METHODS:A prospective study included 30 adult patients with CD of Caucasian origin(19 men and 11women;mean age±SD 32.0±8.6 years)during biological therapy with anti-TNF-αantibodies from January2012 to March 2013.Eighteen patients were treated with infliximab,seven with adalimumab and five withcertolizumab.Inclusion criteria were exacerbation of the underlying disease,Crohn’s Disease Activity Index over 300 and the ineffectiveness of previously used non-biological therapies.Patients with a history of psoriasis,atopic dermatitis and other autoimmune skin lesions were excluded from the study.The control group consisted of 12 healthy subjects.A diagnostic survey was carried out,blood tests and careful skin examination were performed,and the serum levels of IL-17,IL-23 and IFN-γwere measured using an enzyme-linked immunosorbent assays technique.Dermatoses that have developed in the course of biological therapy in patients who had no pre-existing skin lesions of similar character were qualified as skin lesions induced by antiTNF-αtherapy.RESULTS:Skin manifestations occurred in 18 of CD patients during the anti-TNF-αtherapy(60%),in the average time of 10.16±3.42 mo following the beginning of the 52-wk treatment cycle.Skin lesions observed in CD patients during biological therapy included psoriasiform lesions(44.4%),and eczema forms lesions(22.2%).In CD patients with drug induced skin lesions significantly higher levels of hemoglobin(13.3±1.5 g/dL vs 10.8±1.9 g/dL,P=0.018)and hematocrit(39.9%±4.5%vs 34.3%±5.4%,P=0.01),as well as a significantly lower level of platelets(268±62×103/μL vs 408±239×103/μL,P=0.046)was observed compared with CD patients without skin manifestations.The concentrations of IL-17A and IL-23in CD patients with skin lesions developed under antiTNF-αtherapy were significantly higher compared to those in patients without lesions(IL-17A:39.01±7.03pg/mL vs 25.71±4.90 pg/mL,P=0.00004;IL-23:408.78±94.13 pg/mL vs 312.15±76.24 pg/mL,P=0.00556).CONCLUSION:Skin lesions in CD patients during bio-logical therapy may result from significantly increased concentrations of IL-17A and IL-23,which are strongly associated with TNF-α/Th1 immune pathways.

How to manage inflammatory bowel disease during the COVID-19 pandemic:A guide for the practicing clinician

Managing inflammatory bowel disease(IBD)during the coronavirus disease 2019(COVID-19)pandemic has been a challenge faced by clinicians and their patients,especially concerning whether to proceed with biologics and immunosuppressive agents in the background of a global outbreak of a highly contagious new coronavirus(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2).The knowledge about the impact of this virus on patients with IBD,although it is still scarce,is rapidly evolving.In particular,concerns surrounding medications’impact for IBD on the risk of acquiring SARS-CoV-2 infection or developing COVID-19,and potentially exacerbate viral replication and the COVID-19 course,are a current thinking of both practicing clinicians and providers caring for patients with IBD.Managing patients with IBD infected with SARS-CoV-2 depends on both the clinical activity of the IBD and the occasional development and severity of COVID-19.In this review,we summarize the current data regarding gastrointestinal involvement by SARS-CoV-2 and pharmacologic and surgical management for IBD concerning this infection,and the COVID-19 impact on both the patient's psychological functioning and endoscopy services,and we concisely summarize the telemedicine roles during the COVID-19 pandemic.

Therapeutic drug monitoring in inflammatory bowel disease:The dawn of reactive monitoring

Inflammatory bowel disease(IBD)is a chronic condition that significantly affects the quality of life of its patients.Biologic drugs have been the mainstay treatment in the management of IBD patients but despite their significant contribution,there remains a proportion of patients that do not respond or lose response to treatment.Therapeutic drug monitoring(TDM)involves measuring levels of serum drug concentrations and anti-drug antibodies.TDM of biologic drugs initially emerged to understand treatment failure in other immune mediated inflammatory diseases.This was then introduced in IBD to rationalize primary non-response or secondary loss of response,given that low serum drug concentrations or the formation of anti-drug antibodies are variably associated with treatment failure.The aim of this narrative review is to provide an overview regarding the current use of TDM in clinical practice and to present the evidence available regarding its use in both proactive and reactive clinical settings in preventing and managing treatment failure.This review also presents the existing evidence regarding the association of various clinical outcomes with specific thresholds of drug concentrations,in everyday practice.A narrative review of published articles and conference abstracts regarding the use of TDM in IBD management,through an electronic search using PubMed and ScienceDirect.TDM has proven to be superior and more cost effective in guiding management of patients with treatment failure compared to empiric dose escalation or change in treatment.Despite a trend towards an association between clinical outcomes and drug concentrations,proactive TDM based strategies have not been shown to achieve clear benefit in long-term outcomes.In the clinical setting,TDM has proven to be useful in managing IBD patients,and its use in the reactive setting,as an additional tool to help manage patients with treatment failure,is being promoted as newer guidelines and consensus groups implement TDM as part of the management plan.