What is left when anti-tumour necrosis factor therapy in inflammatory bowel diseases fails?

The inflammatory bowel diseases (IBDs) are chronic incurable conditions that primarily present in young patients. Being incurable, the IBDs may be part of the patient’s life for many years and these conditions require therapies that will be effective over the long-term. Surgery in Crohn’s disease does not cure the disease with endoscopic recurrent in up to 70% of patients 1 year post resection. This means that, the patient will require many years of medications and the goal of the treating physician is to induce and maintain long-term remission without side effects. The development of the anti-tumour necrosis factor alpha (TNFα) agents has been a magnificent clinical advance in IBD, but they are not always effective, with loss of response overtime and, at times, discontinuation is required secondary to side effects. So what options are available if of the anti-TNFα agents can no longer be used? This review aims to provide other options for the physician, to remind them of the older established medications like azathioprine/6-mercaptopurine and methotrexate, the less established medications like mycophenolate mofetil and tacrolimus as well as newer therapeutic options like the anti-integins, which block the trafficking of leukocytes into the intestinal mucosa. The location of the intestinal inflammation must also be considered, as topical therapeutic agents may also be worthwhile to consider in the long-term management of the more challenging IBD patient. The more options that are available the more likely the patient will be able to have tailored therapy to treat their disease and a better long-term outcome.

Roles of G protein-coupled receptors in inflammatory bowel disease

Inflammatory bowel disease(IBD)is a complex disease with multiple pathogenic factors.Although the pathogenesis of IBD is still unclear,a current hypothesis suggests that genetic susceptibility,environmental factors,a dysfunctional immune system,the microbiome,and the interactions of these factors substantially contribute to the occurrence and development of IBD.Although existing and emerging drugs have been proven to be effective in treating IBD,none can cure IBD permanently.G protein-coupled receptors(GPCRs)are critical signaling molecules implicated in the immune response,cell proliferation,inflammation regulation and intestinal barrier maintenance.Breakthroughs in the understanding of the structures and functions of GPCRs have provided a driving force for exploring the roles of GPCRs in the pathogenesis of diseases,thereby leading to the development of GPCR-targeted medication.To date,a number of GPCRs have been shown to be associated with IBD,significantly advancing the drug discovery process for IBD.The associations between GPCRs and disease activity,disease severity,and disease phenotypes have also paved new avenues for the precise management of patients with IBD.In this review,we mainly focus on the roles of the most studied proton-sensing GPCRs,cannabinoid receptors,and estrogen-related GPCRs in the pathogenesis of IBD and their potential clinical values in IBD and some other diseases.

Use of mycophenolate mofetil in inflammatory bowel disease

AIM:To assess the efficacy and safety of mycophenolate mofetil(MMF)prospectively in inflammatory bowel disease(IBD)patients intolerant or refractory to conventional medical therapy.METHODS:Crohn's disease(CD)or ulcerative colitis/ IBD unclassified(UC/IBDU)patients intolerant or refractory to conventional medical therapy received MMF(500-2000 mg bid).Clinical response was assessed by the Harvey Bradshaw index(HBI)or colitis activity index(CAI)after 2,6 and 12 mo of therapy,as were steroid usage and adverse effects.RESULTS:Fourteen patients(9 CD/5 UC/IBDU;8M/6F;mean age 50.4 years,range 28-67 years)were treated and prospectively assessed for their response to oral MMF.Of the 11 patients who were not in remission on commencing MMF,7/11(63.6%)achieved remission by 8 wk.All 3 patients in remission on commencing MMF maintained their remission.Ten patients were still on MMF at 6 mo with 9/14(64.3%)in remission,while of 12 patients followed for 12 mo,8 were in remission without dose escalation(66.7%).Three patients were withdrawn from the MMF due to drug intolerance.There were no serious adverse events attributed due to the medication.CONCLUSION:MMF demonstrated efficacy in the management of difficult IBD.MMF appeared safe,well tolerated and efficacious for both short and long-term therapy,without the need for dose escalation.Further evaluation of MMF comparing it to conventional immunosuppressants is required.

Interventions and targets aimed at improving quality in inflammatory bowel disease ambulatory care

Over the past decade,there has been increasing focus on improving the quality of healthcare delivered to patients with chronic diseases,including inflammatory bowel disease.Inflammatory bowel disease is a complex,chronic condition with associated morbidity,health care costs,and reductions in quality of life.The condition is managed primarily in the outpatient setting.The delivery of high quality of care is suboptimal in several ambulatory inflammatory bowel disease domains including objective assessments of disease activity,the use of steroid-sparing agents,screening prior to anti-tumor necrosis factor therapy,and monitoring thiopurine therapy.This review outlines these gaps in performance and provides potential initiatives aimed at improvement including reimbursement programs,quality improvement frameworks,collaborative efforts in quality improvement,and the use of healthcare information technology.

Preventing infective complications in inflammatory bowel disease

Over the past decade there has been a dramatic change in the treatment of patients with Crohn’s disease and ulcerative colitis, which comprise the inflammatory bowel diseases (IBD). This is due to the increasing use of immunosuppressives and in particular the biological agents, which are being used earlier in the course of disease, and for longer durations, as these therapies result in better clinical outcomes for patients. This, however, has the potential to increase the risk of opportunistic and serious infections in these patients, most of which are preventable. Much like the risk for potential malignancy resulting from the use of these therapies long-term, a balance needs to be struck between medication use to control the disease with minimization of the risk of an opportunistic infection. This outcome is achieved by the physician’s tailored use of justified therapies, and the patients’ education and actions to minimize infection risk. The purpose of this review is to explore the evidence and guidelines available to all physicians managing patients with IBD using immunomodulating agents and to aid in the prevention of opportunistic infections.

Quality of care delivered to hospitalized inflammatory bowel disease patients

Hospitalized patients with inflammatory bowel disease(IBD)are at high risk for morbidity,mortality,and health care utilization costs.While the literature on trends in hospitalization rates for this disease is conflicting,there does appear to be significant variation in the delivery of care to this complex group,which may be a marker of suboptimal quality of care.There is a need for improvement in identifying patients at risk for hospitalization in an effort to reduce admissions.Moreover,appropriate screening for a number of hospital acquired complications such as venous thromboembolism and Clostridium difficile infection is suboptimal.This review discusses areas of inpatient care for IBD patients that are in need of improvement and outlines a number of potential quality improvement initiatives such as payfor-performance models,quality improvement frameworks,and healthcare information technology.

Artificial intelligence assisted assessment of endoscopic disease activity in inflammatory bowel disease

Assessment of endoscopic disease activity can be difficult in patients with inflammatory bowel disease(IBD)[comprises Crohn's disease(CD)and ulcerative colitis(UC)].Endoscopic assessment is currently the foundation of disease evaluation and the grading is pivotal for the initiation of certain treatments.Yet,disharmony is found among experts;even when reassessed by the same expert.Some studies have demonstrated that the evaluation is no better than flipping a coin.In UC,the greatest achieved consensus between physicians when assessing endoscopic disease activity only reached a Kappa value of 0.77(or 77%agreement adjustment for chance/accident).This is unsatisfactory when dealing with patients at risk of surgery or disease progression without proper care.Lately,across all medical specialities,computer assistance has become increasingly interesting.Especially after the emanation of machine learning–colloquially referred to as artificial intelligence(AI).Compared to other data analysis methods,the strengths of AI lie in its capability to derive complex models from a relatively small dataset and its ability to learn and optimise its predictions from new inputs.It is therefore evident that with such a model,one hopes to be able to remove inconsistency among humans and standardise the results across educational levels,nationalities and resources.This has manifested in a handful of studies where AI is mainly applied to capsule endoscopy in CD and colonoscopy in UC.However,due to its recent place in IBD,there is a great inconsistency between the results,as well as the reporting of the same.In this opinion review,we will explore and evaluate the method and results of the published studies utilising AI within IBD(with examples),and discuss the future possibilities AI can offer within IBD.

Small bowel MRI enteroclysis or follow through:Which is optimal?

AIM： TO determine if a nasojejunal tube （NJT） is required for optimal examination of enteroclysis and if patients can be examined only in the supine position. METHODS： Data were collected from all patients undergoing small bowel （SB） magnetic resonance imaging （MRI） examination over a 32-mo period. Patients either underwent a magnetic resonance （MR） follow-through （MRFT） or a MR enteroclysis （MRE） in the supine position. The quality of proximal and distal SB distension as well as the presence of motion artefact and image quality were assessed by 2 radiologists. RESULTS： One hundred and fourteen MR studies were undertaken （MRFT-49, MRE-65） in 108 patients in the supine position only. Image artefact was more frequent in MRE than in MRFT （29.2% vs 18.4%）, but was not statistically significant （P = 0.30）. Adequate distension of the distal SB was obtained in 97.8% of MRFT examinations and in 95.4% of MRE examinations, respectively. Proximal SB distension was, however, less frequently optimal in MRFT than in MRE （P = 0.0036）, particularly in patients over the age of 50 years （P = 0.0099）. Image quality was good in all examinations. CONCLUSION： All patients could be successfully iraaged in the supine position. MRE and MRFT are equivalent for distal SB distension and artefact effects. Proximal SB distension is frequently less optimal in MRFT than in MRE. MRE is, therefore, the preferred MR examination method of the SB.

Novel topical therapies for distal colitis

Distal colitis(DC) can be effectively treated with topical 5ASA agents.Suppositories target the rectum while enemas can reliably reach the splenic flexure.Used in combination with oral 5ASAs,the control of the inflammation is even more effective.Unfortunately,resistant DC does occur and can be extremely challenging to manage.In these patients,the use of steroids,immunosuppressants and the anti-tumor necrosis factor α agents are often required.These,however,can be associated with systemic side effects and are not always effective.The investigation of new topical therapeutic agents is thus required as they are rarely associated with significant blood drug levels and side effects are infrequent.Some of the agents that have been proposed for use in resistant distal colitis include butyrate,cyclosporine and nicotine enemas as well as tacrolimus suppositories and tacrolimus,ecabet sodium,arsenic,lidocaine,rebamipide and Ridogrel enemas.Some of these agents have demonstrated impressive results but the majority of the agents have only been assessed in small open-labelled patient cohorts.Further work is thus required with the investigation of promising agents in the context of randomized double-blinded placebo controlled trials.This review aims to highlight those potentially effective therapies in the management of resistant distal colitis and to promote interest in furthering their investigation.

Vedolizumab for ulcerative colitis: Real world outcomes from a multicenter observational cohort of Australia and Oxford

BACKGROUND Vedolizumab(VDZ),a humanised monoclonal antibody that selectively inhibits alpha4-beta7 integrins is approved for use in adult moderate to severe ulcerative colitis(UC)patients.AIM To assess the efficacy and safety of VDZ in the real-world management of UC in a large multicenter cohort involving two countries and to identify predictors of achieving remission.METHODS A retrospective review of Australian and Oxford,United Kingdom data for UC patients.Clinical response at 3 mo,endoscopic remission at 6 mo and clinical remission at 3,6 and 12 mo were assessed.Cox regression models and Kaplan Meier curves were performed to assess the time to remission,time to failure and the covariates influencing them.Safety outcomes were recorded.RESULTS Three hundred and three UC patients from 14 centres in Australia and United Kingdom,[60%n=182,anti-TNF naïve]were included.The clinical response was 79%at 3 mo with more Australian patients achieving clinical response compared to Oxford(83%vs 70%P=0.01).Clinical remission for all patients was 56%,62%and 60%at 3,6 and 12 mo respectively.Anti-TNF naive patients were more likely to achieve remission than exposed patients at all the time points(3 mo 66%vs 40%P<0.001,6 mo 73%vs 46%P<0.001,12 mo 66%vs 51%P=0.03).More Australian patients achieved endoscopic remission at 6 mo compared to Oxford(69%vs 43%P=0.01).On multi-variate analysis,anti-TNF naïve patients were 1.8(95%CI:1.3-2.3)times more likely to achieve remission than anti-TNF exposed(P<0.001).32 patients(11%)had colectomy by 12 mo.CONCLUSION VDZ was safe and effective with 60%of UC patients achieving clinical remission at 12 mo and prior anti-TNF exposure influenced this outcome.

Colectomy is a risk factor for venous thromboembolism in ulcerative colitis

AIM: To compare venous thromboembolism(VTE) in hospitalized ulcerative colitis(UC) patients who respond to medical management to patients requiring colectomy. METHODS: Population-based surveillance from 1997 to 2009 was used to identify all adults admitted to hospital for a flare of UC and those patients who underwent colectomy. All medical charts were reviewed to confirm the diagnosis and extract clinically relevant information. UC patients were stratified by:(1) responsive to inpatient medical therapy(n = 382);(2) medically refractory requiring emergent colectomy(n = 309); and(3) elective colectomy(n = 329). The primary outcome was the development of VTE during hospitalization or within 6 mo of discharge. Heparin prophylaxis to prevent VTE was assessed. Logistic regression analysis determined the effect of disease course(i.e., responsive to medical therapy, medically refractory, and elective colectomy) on VTE after adjusting for confounders including age, sex, smoking, disease activity, comorbidities, extent of disease, and IBD medications(i.e., corticosteroids, mesalamine, azathioprine, and infliximab). Point estimates were presented as odds ratios(OR) with 95%CI.RESULTS: The prevalence of VTE among patients with UC who responded to medical therapy was 1.3% and only 16% of these patients received heparinprophylaxis. In contrast, VTE was higher among patients who underwent an emergent(8.7%) and elective(4.9%) colectomy, despite greater than 90% of patients receiving postoperative heparin prophylaxis. The most common site of VTE was intra-abdominal(45.8%) followed by lower extremity(19.6%). VTE was diagnosed after discharge from hospital in 16.7% of cases. Elective(adjusted OR = 3.69; 95%CI: 1.30-10.44) and emergent colectomy(adjusted OR = 5.28; 95%CI: 1.93-14.45) were significant risk factors for VTE as compared to medically responsive UC patients. Furthermore, the odds of a VTE significantly increased across time(adjusted OR = 1.10; 95%CI: 1.01-1.20). Age, sex, comorbidities, disease extent, disease activity, smoking, corticosteroids, mesalamine, azathioprine, and infliximab were not independently associated with the development of VTE. CONCLUSION: VTE was associated with colectomy, particularly, among UC patients who failed medical management. VTE prophylaxis may not be sufficient to prevent VTE in patients undergoing colectomy.

Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy

AIM To study the innate immune function in ulcerative colitis(UC) patients who fail to respond to anti-tumor necrosis factor(TNF) therapy.METHODS Effects of anti-TNF therapy, inflammation and medications on innate immune function were assessed by measuring peripheral blood mononuclear cell(PBMC) cytokine expression from 18 inflammatory bowel disease patients pre- and 3 mo post-anti-TNF therapy. Toll-like receptor(TLR) expression and cytokine production post TLR stimulation was assessed in UC "responders"(n = 12) and "non-responders"(n = 12) and compared to healthy controls(n = 12). Erythrocyte sedimentation rate(ESR) and C-reactive protein(CRP) levels were measured in blood to assess disease severity/activity and inflammation. Pro-inflammatory(TNF, IL-1β, IL-6), immuno-regulatory(IL-10), Th1(IL-12, IFNγ) and Th2(IL-9, IL-13, IL-17A) cytokine expression was measured with enzyme-linked immunosorbent assay while TLR cellular composition and intracellular signalling was assessed with FACS.RESULTS Prior to anti-TNF therapy, responders and nonresponders had similar level of disease severity and activity. PBMC's ability to respond to TLR stimulation was not affected by TNF therapy, patient's severity of the disease and inflammation or their medication use. At baseline, non-responders had elevated innate but not adaptive immune responses compared to responders(P < 0.05). Following TLR stimulation, nonresponders had consistently reduced innate cytokine responses to all TLRs compared to healthy controls(P < 0.01) and diminished TNF(P < 0.001) and IL-1β(P < 0.01) production compared to responders. This innate immune dysfunction was associated with reduced number of circulating plasmacytoid dendritic cells(p DCs)(P < 0.01) but increased number of CD4+ regulatory T cells(Tregs)(P = 0.03) as well as intracellular accumulation of IRAK4 in non-responders following TLR-2,-4 and-7 activation(P < 0.001). CONCLUSION Reduced innate immunity in non-responders may explain reduced efficacy to anti-TNF therapy. These serological markers may prove useful in predicting the outcome of costly anti-TNF therapy.

Iron:An emerging factor in colorectal carcinogenesis

The carcinogenic potential of iron in colorectal cancer(CRC) is not fully understood.Iron is able to undergo reduction and oxidation,making it important in many physiological processes.This inherent redox property of iron,however,also renders it toxic when it is present in excess.Iron-mediated generation of reactive oxygen species via the Fenton reaction,if uncontrolled,may lead to cell damage as a result of lipid peroxidation and oxidative DNA and protein damage.This may promote carcinogenesis through increased genomic instability,chromosomal rearrangements as well as mutations of proto-oncogenes and tumour suppressor genes. Carcinogenesis is also affected by inflammation which is exacerbated by iron.Population studies indicate an association between high dietary iron intake and CRC risk.In this editorial,we examine the link betweeniron-induced oxidative stress and inflammation on the pathogenesis of CRC.

Presence of phthalates in gastrointestinal medications: Is there a hidden danger?

Pharmaceutical companies that produce gastrointestinal(GI)medications often utilize phthalates for their ability to localize medication release.Commonly prescribed GI medications that may utilize phthalates are 5-Aminosalicylates,proton pump inhibitors,and pancreatic enzymes.Our understanding of the cumulative health effects of phthalates from medications remains unclear,and there is increasing evidence that phthalates are not harmless.Experimental studies in animals have shown that phthalates,specifically dibutyl phthalate and Di-(2-ethyl-hexyl)phthalate,have the potential to alter and/or inhibit reproductive biology and in utero development.Despite the lack of definitive human data,many cohort and cross-sectional studies demonstrate concerning associations between phthalates and poor health status,specifically developmental problems.Longitudinal studies and studies with larger sample sizes are required to determine whether phthalates actually cause negative health consequences.It is also important that physicians regularly review and discuss with patients the medicinal ingredients in their medications and supplements,specifically in pregnant woman with inflammatory bowel disease.

Stevens-Johnson syndrome complicating adalimumab therapy in Crohn's disease

The anti-tumor necrosis factor(TNF)αmedications demonstrate efficacy in the induction of remission and its maintenance in numerous chronic inflammatory conditions.With the increasing number of patients receiving anti-TNFαagents,however,less common adverse reactions will occur.Cutaneous eruptions complicating treatment with an anti-TNFαagent are not uncommon,occurring in around 20%of patients. Adalimumab,a fully humanized antibody against TNFα, may be expected to cause minimal immune-mediated skin reactions compared to the chimeric monoclonal antibody,infliximab.We,however,report a case of Stevens-Johnson syndrome that required hospitalization and cessation of adalimumab in a patient with Crohn’ s disease(CD).In this case report,a 29-year-old male with colonic and perianal CD with associated erythema nodosum and large joint arthropathy developed severe mucositis,peripheral rash and desquamation,fevers and respiratory symptoms concomitant with a second dose of 40 mg adalimumab after a 2 mo break from adalimumab therapy.Skin biopsies of the abdominal wall confirmed erythema multiforme and the patient was on no other drugs and infective etiologies were excluded.The patient responded rapidly to IV hydrocortisone and was able to be commenced on infliximab without recurrence of the Stevens-Johnson syndrome.Desquamating skin reactions have now been described in three of the TNFαantagonists(infliximab,etanercept and adalimumab).These reactions can be serious and prescribers need to be aware of the potential mucocutaneous side effects of these agents,especially as Stevens-Johnson syndrome is associated with significant morbidity and mortality.

COVID-19,a far cry from the influenza

The outbreak of COVID-19 caused by SARS-CoV-2 was declared by the WHO to have reached the global pandemic level on 11 March 2020.As of 26 April 2020,more than 2900000 COVID-19 infection cases have been confirmed in more than 200 countries with at least 200000 reported deaths.1 Global reinforcement comprehensive interventions have been implemented to stop the pandemic.Unfortunately,since COVID-19 developed in December 2019.