finally someone is pointing this out……
It's Time to Change Tack in IBD Treatment
Marcel A. Behr, MD, MSc, Ildiko Mehes, JD, Charles N. Bernstein
To appear in: Gastroenterology
Accepted Date: 11 June 2024
Introduction
Contemporary reviews on the pathogenesis of IBDs (most commonly Crohn's disease (CD) and ulcerative colitis (UC)) consistently invoke the etiologic triad of genetics, the environment, and the immune system (Figure 1). Yet the current treatment paradigm for IBDs exclusively seeks to dampen or modulate what is presumed to be an excessive or aberrant immune response. Despite mounting recognition that environmental factors (microbes, diet and/or other exposures associated with a Western lifestyle) are critical contributors to both the etiology and the maintenance of disease [4,5], current guideline-based therapies are primarily immunomodulatory. We call these immune-directed therapies (small molecules and biologics). Modifications of environmental factors, by antibiotics, dietary changes, and fecal microbiota transplant (FMT), have proven successful in other gastrointestinal diseases, such as enteric fever, celiac disease, and Clostridium difficile colitis, respectively. In contrast, the development of IBD therapies along these lines has been slow to emerge. We ask: what has impeded the evolution of these therapies? More specifically: are environmental modifications ineffective, or are they merely perceived as ineffective?
While there remains a dearth of head-to-head studies directly comparing any IBD therapies, we argue that environmental modifications may have potential to be efficacious as standalone or, alternatively, adjuncts to current treatments. Yet they remain understudied and undervalued. We suggest that environmental modifications are understudied because of practical limitations: lesser funding driven by limited financial incentives results in fewer studies with smaller sample sizes, absence of blinding and/or lack of placebo controls. We argue that environmental modifications are also undervalued because of dogma; the benefits of immune-directed therapies have overshadowed environmental modifiers and evoked a perception that the latter are not effective. This perception is driven in part by legitimate criticism of the variability of study designs and endpoints, the inability to compare patient populations, or low quality studies. But, we argue for a reappraisal of how clinicians and decision-makers interpret the results: with intellectual curiosity and a willingness of build on existing data. To a patient, every therapy's potential efficacy should be measured by an equivalent yardstick. As detailed below, combination antibiotics may provide a benefit in moderate to severe CD, at least in the first two years, though antibiotics have no proven benefit over the long term. Exclusive Enteral Nutrition (EEN) in CD and FMT in UC have shown promising results for uncomplicated, newly diagnosed, and mild or moderate disease.
There are, however, limited financial incentives to develop a body of high-quality evidence and standardized protocols that would enable clinicians to utilize them. Indeed, in some Western countries, it may be easier to access expensive immune-directed therapies than high-quality personalized dietary support, even though expensive immune-directed therapies are hard to access in other areas of the world. We also argue that the perception that environmental modifications are ineffective is an impediment to innovation. After more than two decades of biologics, we have learned what works for some individuals (symptomatic relief, mucosal healing) and what is not happening for most (durable remission, cure), despite a plethora of recently approved anti-cytokine, anti-integrin, Janus kinase inhibitor, and sphingosine 1-phosphate (SIP) receptor medications. The therapeutic ceiling for patients to both feel better and resolve bowel inflammation remains stubbornly low and surgery remains a mainstay of treatment (40% CD, 10% UC at 10 years in the modern era).
Modifying the immune response-the current IBD treatment paradigm
The evidence for immune-directed therapies is largely derived from randomized responder studies (Figure 2). Depending on the agent, and whether the patient was naive to advanced IBD therapies, the percent responders (a) has been on the order of 25-80%. Of the responders, 30-60% were in clinical remission at the end of one year (b). The product of these two proportions has been called the 'net remission' (c = a x b). In two papers by Kayal and colleagues, the net clinical remission at approximately one year has been estimated at 7-35% for CD and 10-45% for UC 7,8. Of note, in UC studies that used a treat-through design (ACT-1, ULTRA-2), the net remission was 34.6% and 22.0%, within the same range 9,10. In these trials, a percent of individuals responded to placebo or maintained remission on placebo after an initial response. Accounting for the difference in maintenance of remission between treatment and placebo, the absolute effect of immune-directed therapies after one year is lower than the net remission (d). This absolute effect can be estimated as 10-20% (10.3%, ACCENT 1; 20.3%, CHARM; 18.4%, GEMINI 1 - detailed calculations in supplementary file) 11-13 with a similar absolute effect in treat-through studies (18.1%, ACT-1; 8.8%, ULTRA-2). These results show that there is currently a 'therapeutic ceiling' for immune-based agents in CD and UC, and this ceiling is below 50% for clinical remission, and lower for other important therapeutic goals described in the STRIDE-II consensus statement. While biologic therapies and oral small molecules have revolutionized the treatment of IBD, and enhanced the quality of life for many, a durable response cannot be assured. Every busy IBD clinic has patients who have failed one to four or more advanced therapies, still in search of an effective solution, and patients who cycle through available therapies with shorter-term or incomplete benefit. Newer immune-directed therapies continue to emerge and have recently been approved or are expected to be approved over the next several years. But none are paradigm-changing, that is, shown to work in the vast majority by chance, or identified by a specific biomarker to work in a subset of patients IS. Data from new clinical trials look promising to deliver new agents that will optimistically allow half of the users to respond and half of the responders to achieve the important goals of clinical and endoscopic remission. There is weak evidence that advanced therapies introduced after the TN inhibitors can close fistulas one of the most debilitating Crohn's disease complications. While great progress has been made with immune-directed therapy in the last two or more decades, it seems that the ceiling has been met, despite many efforts to optimize available drugs. Pharmaceutical and investigator-led studies have begun evaluating biologic agents in combination with other biologic agents or newer advanced small molecules to attempt to break this efficacy ceiling. However, the evidence so far is still largely observational such that efficacy and safety remain in question'. While these advances may help practitioners treat refractory IBD patients, these advanced combination therapies are unlikely to be utilized to treat most patients due to concerns over safety and cost. The goal therefore remains for practitioners and patients to decide which immune mechanism(s) fit best in what clinical scenario and help eventually provide each patient the right drugs) at the right time. We argue that head-to-head trials targeting immune loci versus environmental modification versus the combination would also advance our suite of choices (Table 1) 17,18. A change of approach is needed.
Modifying the environment-changing the IBD treatment paradigm
Trials of environmental factors differ in important ways from immune-directed drug RCTs: they typically include smaller numbers of patients, they often recruit patients with mild to moderate disease activity, patient characteristics such as disease duration or other meaningful variables may be missing, and endpoints may not include objective outcomes such as fecal calprotectin or endoscopic outcomes. We do not advocate for direct comparability. While trials of environmental modifications more consistently use a treat-through study design, few are long term or provide data over the impact of these therapies over two years or longer. Rather than identify primary responders and then randomize this subset, treat-through studies randomize all subjects at the outset, then monitor outcomes over the pre-defined time interval. In addition, it is noteworthy that trials of environment modifications have challenges and limitations separate and apart from those of large pharmaceutical RCTs which have been canvassed in more detail elsewhere. For example, some studies lack a placebo arm, and repeated FMT treatments and dietary compliance can be challenging. It is also difficult to administer identical interventions when it comes to FMT or diet in different jurisdictions worldwide whereas immune drug therapy production is standardized and generally uniform. However, drug studies also involve some lesser degree of nonadherence and are constrained by limitations, such as not being reflective of real-world IBD patient populations.
Notwithstanding these limitations, in CD, two environmental modifiers (antibiotics, EEN) have shown therapeutic promise. In a study of induction with high dose prednisone with a tapering regimen plus combination antibiotics (clarithromycin, rifabutin and clofazimine) or prednisone regimen plus placebo in moderate to severe CD (median CD Activity Index = 286), a signal of increased remission in the antibiotic group was evident both at 16 weeks and at 52 weeks on an intention to treat basis (absolute differences of 16.1% and 18.6%, both p < 0.05, but less than the hypothesized 40% difference) 22. The authors concluded that there was no sustained benefit of antibiotics because their statistical analysis tested whether the groups diverged after 16 weeks, rather than testing whether clinical remission at 52 weeks differed between antibiotics (40.2%) and placebo (21.6%) 22,23. EEN has been shown to be effective at inducing clinical remission and mucosal healing, all with a favorable safety profile [24,26,27]. Pediatric gastroenterologists commonly use EEN as first-line therapy to induce remission in CD 26, and in some countries, like Japan, EEN is also recommended as first-line treatment in adult CD[27]. A recent AGA Clinical Practice Update recommends EEN as "an effective therapy for induction of clinical remission and endoscopic response in CD with stronger evidence in children than adults. It also notes that EEN may be used as a "steroid-sparing bridge" and in malnourished patients before surgery to reduce post-operative complications. Yet EEN remains rarely considered for adults with CD in many Western countries, either because the evidence, as noted, is more limited in adults, or because rates of non-compliance in adults are higher than in children, or both. Despite the under-utilization of EEN, in recent years, there has been "growing recognition of the role of diet in the care of patients with IBD, as both an etiopathogenic risk factor and, more recently, as a disease-modifying modality", with newer dietary therapies emerging, including the Crohn's Disease Exclusion Diet, CD-TREAT, the Specific Carbohydrate Diet, the Mediterranean Diet, and the IBD-AID, among others. These dietary therapies have attempted to reproduce or maintain the efficacy of EEN, or avoid flares of disease, achieving a net remission of up to 63% at 24 weeks, albeit with marked variability across studies [25,28]. Because EEN studies cannot have a complete liquid diet placebo, the absolute effect can only be estimated indirectly. A study of pooled placebo responses in CD showed that 4-12% of placebo recipients were in remission after an average follow up of 14 weeks; placebo response rates did not vary according to severity of disease but the maintenance of remission on placebo was higher in milder diseases (see supplementary file for calculations)[29].
In UC, a net remission of 25% after one year was achieved with FMT treatment compared to none in the control groups. While a complete review of the literature on antibiotics, dietary therapies and FMT is beyond the scope of this commentary and is presented elsewhere, these results provide signals of a favourable absolute effect. Importantly, negative studies exist for all three of antibiotics, dietary modifications and FMT; we argue that this does not negate their potential but rather that more research is required to understand what exactly needs to be modified, when and how.
To summarize, unlike the prevailing wisdom that biologics are very effective and environmental modifications are minimally effective, three environmental modifications have shown signals of efficacy, in CD and in UC. This difference in how we interpret efficacy could be termed 'efficacy relativism', where efficacy is valued differently depending on the therapeutic approach. Our plea is to build on the current evidence using environmental modification as a lone or as a combined therapy.
Patients and their caregivers want safe and effective therapies (and cures) that are accessible, no matter the mechanism of action. They are not uniform in their treatment goals and desires and experience substantial disease heterogeneity, to which current standards of care should adapt. For some, immune-directed therapies work exceptionally well. And for some, dietary therapies and FMT are not appealing options. But for others, environmental modification as monotherapy or adjunct therapy with immune-directed medications is appealing, if it may limit immunosuppression and or improve their quality of life. An unmet need remains for patients who do not experience optimal outcomes from immune-directed therapies alone.
The challenge is twofold: (1) not knowing which medication may work; and (2) not knowing how long a therapy may work. While not downplaying the clear benefits of biologics or newer small molecules, the nuanced patient and clinician perspective is that current treatments have sadly not been a panacea for many or even most patients suffering from IBDs. Considerable suffering and poor quality of life, often in the prime years of adolescence and early adulthood, persist. Data presented to patients as clinical response or remission rates in responders, overstates their benefit, as has been argued by Kayal and colleagues [7,8]. Going beyond the net remission, the absolute effect of treatment, as compared to not taking the treatment, is a fraction, of a fraction, of a fraction (percent responders × percent in remission placebo/treatment ratio). One option that is gaining momentum is the idea of combining existing drugs. Patients (and their families and physicians) want better, something that can work alone or in addition to biologics and small molecules, based on the established triad of IBD etiology. Examples of these approaches are available in the literature, including in studies in Japan (diet + biologics) and Australia (FMT + biologics) (Table 1)[16,30]. The observation that environmental modifications can work is not a definitive pronouncement of their efficacy. Rather, this is a critical conceptual datapoint, upon which one can iteratively understand how they may work, then develop better treatments. Considering the epidemiological data highlighting the significance of environmental factors in the development of IBDs, alongside clinical trial findings demonstrating the feasibility of intervening, it seems logical that some form of environmental modification would be a core component of IBD treatment.
What is needed?
More research is needed on exogenous triggers of disease and disease exacerbation, including potential antigens and biomarkers. This requires funding directed at this aspect of the triad. Funding agencies must support creative and thoughtful environmental mechanistic and interventional studies, to guide both prevention of disease and better treatments. Charity-based funding and national scientific funding agencies should have grant competitions for environmental pathogenetic mechanisms and interventions and leave the optimization of immune therapies to pharma. Most importantly, a global collaborative effort among all stakeholders is urgently needed to develop a clear research roadmap to guide the prevention, treatment and ultimately cure of these enigmatic and challenging diseases.
It's Time to Change Tack in IBD Treatment
Marcel A. Behr, MD, MSc, Ildiko Mehes, JD, Charles N. Bernstein
To appear in: Gastroenterology
Accepted Date: 11 June 2024
Introduction
Contemporary reviews on the pathogenesis of IBDs (most commonly Crohn's disease (CD) and ulcerative colitis (UC)) consistently invoke the etiologic triad of genetics, the environment, and the immune system (Figure 1). Yet the current treatment paradigm for IBDs exclusively seeks to dampen or modulate what is presumed to be an excessive or aberrant immune response. Despite mounting recognition that environmental factors (microbes, diet and/or other exposures associated with a Western lifestyle) are critical contributors to both the etiology and the maintenance of disease [4,5], current guideline-based therapies are primarily immunomodulatory. We call these immune-directed therapies (small molecules and biologics). Modifications of environmental factors, by antibiotics, dietary changes, and fecal microbiota transplant (FMT), have proven successful in other gastrointestinal diseases, such as enteric fever, celiac disease, and Clostridium difficile colitis, respectively. In contrast, the development of IBD therapies along these lines has been slow to emerge. We ask: what has impeded the evolution of these therapies? More specifically: are environmental modifications ineffective, or are they merely perceived as ineffective?
While there remains a dearth of head-to-head studies directly comparing any IBD therapies, we argue that environmental modifications may have potential to be efficacious as standalone or, alternatively, adjuncts to current treatments. Yet they remain understudied and undervalued. We suggest that environmental modifications are understudied because of practical limitations: lesser funding driven by limited financial incentives results in fewer studies with smaller sample sizes, absence of blinding and/or lack of placebo controls. We argue that environmental modifications are also undervalued because of dogma; the benefits of immune-directed therapies have overshadowed environmental modifiers and evoked a perception that the latter are not effective. This perception is driven in part by legitimate criticism of the variability of study designs and endpoints, the inability to compare patient populations, or low quality studies. But, we argue for a reappraisal of how clinicians and decision-makers interpret the results: with intellectual curiosity and a willingness of build on existing data. To a patient, every therapy's potential efficacy should be measured by an equivalent yardstick. As detailed below, combination antibiotics may provide a benefit in moderate to severe CD, at least in the first two years, though antibiotics have no proven benefit over the long term. Exclusive Enteral Nutrition (EEN) in CD and FMT in UC have shown promising results for uncomplicated, newly diagnosed, and mild or moderate disease.
There are, however, limited financial incentives to develop a body of high-quality evidence and standardized protocols that would enable clinicians to utilize them. Indeed, in some Western countries, it may be easier to access expensive immune-directed therapies than high-quality personalized dietary support, even though expensive immune-directed therapies are hard to access in other areas of the world. We also argue that the perception that environmental modifications are ineffective is an impediment to innovation. After more than two decades of biologics, we have learned what works for some individuals (symptomatic relief, mucosal healing) and what is not happening for most (durable remission, cure), despite a plethora of recently approved anti-cytokine, anti-integrin, Janus kinase inhibitor, and sphingosine 1-phosphate (SIP) receptor medications. The therapeutic ceiling for patients to both feel better and resolve bowel inflammation remains stubbornly low and surgery remains a mainstay of treatment (40% CD, 10% UC at 10 years in the modern era).
Modifying the immune response-the current IBD treatment paradigm
The evidence for immune-directed therapies is largely derived from randomized responder studies (Figure 2). Depending on the agent, and whether the patient was naive to advanced IBD therapies, the percent responders (a) has been on the order of 25-80%. Of the responders, 30-60% were in clinical remission at the end of one year (b). The product of these two proportions has been called the 'net remission' (c = a x b). In two papers by Kayal and colleagues, the net clinical remission at approximately one year has been estimated at 7-35% for CD and 10-45% for UC 7,8. Of note, in UC studies that used a treat-through design (ACT-1, ULTRA-2), the net remission was 34.6% and 22.0%, within the same range 9,10. In these trials, a percent of individuals responded to placebo or maintained remission on placebo after an initial response. Accounting for the difference in maintenance of remission between treatment and placebo, the absolute effect of immune-directed therapies after one year is lower than the net remission (d). This absolute effect can be estimated as 10-20% (10.3%, ACCENT 1; 20.3%, CHARM; 18.4%, GEMINI 1 - detailed calculations in supplementary file) 11-13 with a similar absolute effect in treat-through studies (18.1%, ACT-1; 8.8%, ULTRA-2). These results show that there is currently a 'therapeutic ceiling' for immune-based agents in CD and UC, and this ceiling is below 50% for clinical remission, and lower for other important therapeutic goals described in the STRIDE-II consensus statement. While biologic therapies and oral small molecules have revolutionized the treatment of IBD, and enhanced the quality of life for many, a durable response cannot be assured. Every busy IBD clinic has patients who have failed one to four or more advanced therapies, still in search of an effective solution, and patients who cycle through available therapies with shorter-term or incomplete benefit. Newer immune-directed therapies continue to emerge and have recently been approved or are expected to be approved over the next several years. But none are paradigm-changing, that is, shown to work in the vast majority by chance, or identified by a specific biomarker to work in a subset of patients IS. Data from new clinical trials look promising to deliver new agents that will optimistically allow half of the users to respond and half of the responders to achieve the important goals of clinical and endoscopic remission. There is weak evidence that advanced therapies introduced after the TN inhibitors can close fistulas one of the most debilitating Crohn's disease complications. While great progress has been made with immune-directed therapy in the last two or more decades, it seems that the ceiling has been met, despite many efforts to optimize available drugs. Pharmaceutical and investigator-led studies have begun evaluating biologic agents in combination with other biologic agents or newer advanced small molecules to attempt to break this efficacy ceiling. However, the evidence so far is still largely observational such that efficacy and safety remain in question'. While these advances may help practitioners treat refractory IBD patients, these advanced combination therapies are unlikely to be utilized to treat most patients due to concerns over safety and cost. The goal therefore remains for practitioners and patients to decide which immune mechanism(s) fit best in what clinical scenario and help eventually provide each patient the right drugs) at the right time. We argue that head-to-head trials targeting immune loci versus environmental modification versus the combination would also advance our suite of choices (Table 1) 17,18. A change of approach is needed.
Modifying the environment-changing the IBD treatment paradigm
Trials of environmental factors differ in important ways from immune-directed drug RCTs: they typically include smaller numbers of patients, they often recruit patients with mild to moderate disease activity, patient characteristics such as disease duration or other meaningful variables may be missing, and endpoints may not include objective outcomes such as fecal calprotectin or endoscopic outcomes. We do not advocate for direct comparability. While trials of environmental modifications more consistently use a treat-through study design, few are long term or provide data over the impact of these therapies over two years or longer. Rather than identify primary responders and then randomize this subset, treat-through studies randomize all subjects at the outset, then monitor outcomes over the pre-defined time interval. In addition, it is noteworthy that trials of environment modifications have challenges and limitations separate and apart from those of large pharmaceutical RCTs which have been canvassed in more detail elsewhere. For example, some studies lack a placebo arm, and repeated FMT treatments and dietary compliance can be challenging. It is also difficult to administer identical interventions when it comes to FMT or diet in different jurisdictions worldwide whereas immune drug therapy production is standardized and generally uniform. However, drug studies also involve some lesser degree of nonadherence and are constrained by limitations, such as not being reflective of real-world IBD patient populations.
Notwithstanding these limitations, in CD, two environmental modifiers (antibiotics, EEN) have shown therapeutic promise. In a study of induction with high dose prednisone with a tapering regimen plus combination antibiotics (clarithromycin, rifabutin and clofazimine) or prednisone regimen plus placebo in moderate to severe CD (median CD Activity Index = 286), a signal of increased remission in the antibiotic group was evident both at 16 weeks and at 52 weeks on an intention to treat basis (absolute differences of 16.1% and 18.6%, both p < 0.05, but less than the hypothesized 40% difference) 22. The authors concluded that there was no sustained benefit of antibiotics because their statistical analysis tested whether the groups diverged after 16 weeks, rather than testing whether clinical remission at 52 weeks differed between antibiotics (40.2%) and placebo (21.6%) 22,23. EEN has been shown to be effective at inducing clinical remission and mucosal healing, all with a favorable safety profile [24,26,27]. Pediatric gastroenterologists commonly use EEN as first-line therapy to induce remission in CD 26, and in some countries, like Japan, EEN is also recommended as first-line treatment in adult CD[27]. A recent AGA Clinical Practice Update recommends EEN as "an effective therapy for induction of clinical remission and endoscopic response in CD with stronger evidence in children than adults. It also notes that EEN may be used as a "steroid-sparing bridge" and in malnourished patients before surgery to reduce post-operative complications. Yet EEN remains rarely considered for adults with CD in many Western countries, either because the evidence, as noted, is more limited in adults, or because rates of non-compliance in adults are higher than in children, or both. Despite the under-utilization of EEN, in recent years, there has been "growing recognition of the role of diet in the care of patients with IBD, as both an etiopathogenic risk factor and, more recently, as a disease-modifying modality", with newer dietary therapies emerging, including the Crohn's Disease Exclusion Diet, CD-TREAT, the Specific Carbohydrate Diet, the Mediterranean Diet, and the IBD-AID, among others. These dietary therapies have attempted to reproduce or maintain the efficacy of EEN, or avoid flares of disease, achieving a net remission of up to 63% at 24 weeks, albeit with marked variability across studies [25,28]. Because EEN studies cannot have a complete liquid diet placebo, the absolute effect can only be estimated indirectly. A study of pooled placebo responses in CD showed that 4-12% of placebo recipients were in remission after an average follow up of 14 weeks; placebo response rates did not vary according to severity of disease but the maintenance of remission on placebo was higher in milder diseases (see supplementary file for calculations)[29].
In UC, a net remission of 25% after one year was achieved with FMT treatment compared to none in the control groups. While a complete review of the literature on antibiotics, dietary therapies and FMT is beyond the scope of this commentary and is presented elsewhere, these results provide signals of a favourable absolute effect. Importantly, negative studies exist for all three of antibiotics, dietary modifications and FMT; we argue that this does not negate their potential but rather that more research is required to understand what exactly needs to be modified, when and how.
To summarize, unlike the prevailing wisdom that biologics are very effective and environmental modifications are minimally effective, three environmental modifications have shown signals of efficacy, in CD and in UC. This difference in how we interpret efficacy could be termed 'efficacy relativism', where efficacy is valued differently depending on the therapeutic approach. Our plea is to build on the current evidence using environmental modification as a lone or as a combined therapy.
Patients and their caregivers want safe and effective therapies (and cures) that are accessible, no matter the mechanism of action. They are not uniform in their treatment goals and desires and experience substantial disease heterogeneity, to which current standards of care should adapt. For some, immune-directed therapies work exceptionally well. And for some, dietary therapies and FMT are not appealing options. But for others, environmental modification as monotherapy or adjunct therapy with immune-directed medications is appealing, if it may limit immunosuppression and or improve their quality of life. An unmet need remains for patients who do not experience optimal outcomes from immune-directed therapies alone.
The challenge is twofold: (1) not knowing which medication may work; and (2) not knowing how long a therapy may work. While not downplaying the clear benefits of biologics or newer small molecules, the nuanced patient and clinician perspective is that current treatments have sadly not been a panacea for many or even most patients suffering from IBDs. Considerable suffering and poor quality of life, often in the prime years of adolescence and early adulthood, persist. Data presented to patients as clinical response or remission rates in responders, overstates their benefit, as has been argued by Kayal and colleagues [7,8]. Going beyond the net remission, the absolute effect of treatment, as compared to not taking the treatment, is a fraction, of a fraction, of a fraction (percent responders × percent in remission placebo/treatment ratio). One option that is gaining momentum is the idea of combining existing drugs. Patients (and their families and physicians) want better, something that can work alone or in addition to biologics and small molecules, based on the established triad of IBD etiology. Examples of these approaches are available in the literature, including in studies in Japan (diet + biologics) and Australia (FMT + biologics) (Table 1)[16,30]. The observation that environmental modifications can work is not a definitive pronouncement of their efficacy. Rather, this is a critical conceptual datapoint, upon which one can iteratively understand how they may work, then develop better treatments. Considering the epidemiological data highlighting the significance of environmental factors in the development of IBDs, alongside clinical trial findings demonstrating the feasibility of intervening, it seems logical that some form of environmental modification would be a core component of IBD treatment.
What is needed?
More research is needed on exogenous triggers of disease and disease exacerbation, including potential antigens and biomarkers. This requires funding directed at this aspect of the triad. Funding agencies must support creative and thoughtful environmental mechanistic and interventional studies, to guide both prevention of disease and better treatments. Charity-based funding and national scientific funding agencies should have grant competitions for environmental pathogenetic mechanisms and interventions and leave the optimization of immune therapies to pharma. Most importantly, a global collaborative effort among all stakeholders is urgently needed to develop a clear research roadmap to guide the prevention, treatment and ultimately cure of these enigmatic and challenging diseases.
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