To STRIDE or not to STRIDE: a critique of "treat to target" in Crohn´s disease.

INTRODUCTION: The STRIDE consensus suggested to focus on mucosal healing, based on biomarkers and endoscopy, in addition to clinical endpoints as treatment target. This narrative review provides a critique of this concept in Crohn´s disease. AREAS COVERED: We analyze and discuss the limitations of endpoints as targets, their currently limited achievability, and the controversial evidence relating to 'treat to target.' The relevant publications in Pubmed were identified in a literature review with the key word 'Crohn´s disease.' EXPERT OPINION: All targets and endpoints have their limitations, and, even if reached, not all have unequivocally been shown to improve prognosis. The major deficiency of STRIDE is not only the lack of validation and agreement upon endpoints but little evidence of their achievability in a sizable proportion of patients by dose or timing adjustments or switching the medication. Above all, the concept should be based on clear evidence that patients indeed benefit from appropriate escalation of treatment and relevant controlled studies in this regard have been controversial. Until the STRIDE approach is proven to be superior to standard treatment focusing on clinical well-being, the field should remain reluctant and expect more convincing evidence before new targets are approved.

Prioritization in inflammatory bowel disease therapy.

INTRODUCTION: Most guidelines for IBD still recommend step-by-step therapy with initially classic drugs such aminosalicylates (in ulcerative colitis) or steroids but avoid prioritizing certain biological drugs and JAK inhibitors in the complicated course. This review provides an aid to pending therapy decisions. AREAS COVERED: In this review, we analyze the evidence for Crohn's disease as well as ulcerative colitis in order to optimize and 'personalize' the choice of therapy, especially in difficult cases. The relevant publications in Pubmed were identified in a continuous literature review with the key words 'Crohn´s disease' and 'ulcerative colitis.' EXPERT OPINION: Based on this complex data set following standard therapies steroid-refractory Crohn´s disease should preferentially be treated with combined infliximab plus azathioprine or risankizumab, in second line after their failure with ustekinumab or 7adalimumab. In steroid-refractory ulcerative colitis infliximab plus azathioprine or upadacitinib should be preferred in first line, filgotinib, tofacitinib or ustekinumab in second line. A steroid-dependent course in both diseases requires azathioprine or vedolizumab, in second line infliximab or Janus kinase inhibitors. The conclusions drawn from these complex data may be helpful for individual decision making in daily clinical practice.

Comment on Depoorter, L.; Vandenplas, Y. Probiotics in Pediatrics. A Review and Practical Guide. Nutrients 2021, 13, 2176.

We read the review by Depoorter et al. [...].

Twenty-five years of biologicals in IBD: What´s all the hype about?

Twenty-five years ago the field was revolutionized by the introduction of infliximab as the first hybrid anti-TNF-antibody. Subsequently, other humanized anti-TNFs were developed and marketed, followed by antibodies to new targets including integrins (vedolizumab) and interleukin 12/23 (ustekinumab). All these so-called biologicals were shown in registrational trials to induce remission superior to placebo but consistently were effective in only a minority of patients. Even though in most trials only the responders were selected to continue on the respective medication for maintenance, many experienced a secondary loss of response and only a minority of usually <25% of the initial cohort achieved long-term (1 year) remission. In 'real life studies', the outcome was somewhat better, probably due to proper selection of patients and open, mostly retrospective study designs. A clear benefit of biologicals is apparent in otherwise treatment refractory patients, in extraintestinal manifestations and in Crohn´s disease (CD) with fistulizing complications. Biologicals achieve mucosal healing (MH) more often than corticosteroids or thiopurines, and MH is associated with improved prognosis. However, this does not justify escalating treatment until MH is reached since controlled trials proving this point of 'treat to target' are lacking both in ulcerative colitis and CD. Surgical rates have decreased with increasing use of biologicals, but disease progression has not been proven to improve. With the exception of opportunistic infections, serious adverse events are rare. In conclusion, biologicals have changed the scene considerably and expanded our armamentarium, but there is also a marketing hype fostering expectations without evidence.

Steroid-refractory ulcerative colitis: a critical review of national and international guideline recommendations.

Es gibt zahlreiche nationale und internationale Leitlinien zu chronisch entzündlichen Darmerkrankungen, die auf vergleichbarer Evidenz sowie ähnlichen Prozeduren beruhen und daher homogen sein sollten. In dieser kritischen Übersicht wurden die Leitlinienempfehlungen aus Europa (ECCO), Deutschland, Großbritannien, Kanada, den USA und Japan zur Therapie der steroidrefraktären Colitis ulcerosa verglichen. Die meisten Leitlinien unterschieden zwischen moderater/schwerer (ambulanter) und schwerer/fulminanter Colitis in der Klinik. Die Empfehlungen zur ersten Kategorie weisen gravierende Unterschiede auf, während zur Behandlung des stationären Patienten weitgehende Übereinstimmung herrscht. Verschiedene Erklärungen für die Inkonsistenzen werden diskutiert.

Antagonism of Adherent Invasive E. coli LF82 With Human α-defensin 5 in the Follicle-associated Epithelium of Patients With Ileal Crohn's Disease.

BACKGROUND: The first visible signs of Crohn's disease (CD) are microscopic erosions over the follicle-associated epithelium (FAE). The aim of the study was to investigate the effects of human α-defensin 5 (HD5) on adherent-invasive Escherichia coli LF82 translocation and HD5 secretion after LF82 exposure in an in vitro model of human FAE and in human FAE ex vivo. METHODS: An in vitro FAE-model was set up by the coculture of Raji B cells and Caco-2-cl1 cells. Ileal FAE from patients with CD and controls were mounted in Ussing chambers. The effect of HD5 on LF82 translocation was studied by LF82 exposure to the cells or tissues with or without incubation with HD5. The HD5 secretion was measured in human FAE exposed to LF82 or Salmonella typhimurium. The HD5 levels were evaluated by immunofluorescence, immunoblotting, and ELISA. RESULTS: There was an increased LF82 translocation across the FAE-model compared with Caco-2-cl1 (P < 0.05). Incubation of cell/tissues with HD5 before LF82 exposure reduced bacterial passage in both models. Human FAE showed increased LF82 translocation in CD compared with controls and attenuated passage after incubation with sublethal HD5 in both CD and controls (P < 0.05). LF82 exposure resulted in a lower HD5 secretion in CD FAE compared with controls (P < 0.05), whereas Salmonella exposure caused equal secretion on CD and controls. There were significantly lower HD5 levels in CD tissues compared with controls. CONCLUSIONS: Sublethal HD5 reduces the ability of LF82 to translocate through FAE. The HD5 is secreted less in CD in response to LF82, despite a normal response to Salmonella. This further implicates the integrated role of antimicrobial factors and barrier function in CD pathogenesis.

Genetic risk factors predict disease progression in Crohn's disease patients of the Swiss inflammatory bowel disease cohort.

BACKGROUND: Crohn's disease (CD) may progress from an inflammatory to a stricturing or penetrating disease phenotype. The aim of our study was to identify single nucleotide polymorphisms (SNPs) that predict disease progression in patients of the Swiss IBD Cohort Study (SIBDCS). METHODS: We applied a multi-state Markov model for progression behavior of CD with three behavioral states according to the Montreal classification. The model considered transition from B1 to B2/B3 or from B2 to B3 stage. Model dynamics were summarized with transition intensities by including the effect of SNPs and calculating transition intensities for each SNP. RESULTS: We included 1276 CD patients [669 (52.4%) B1, 248 (19.4%) B2, 359 (28.1%) B3 patients] with a median follow-up of 6.8 (interquartile range = 3.6-9.1; range 0-11.6) years. Probability for a B1 patient to develop a stenosis (B1 to B2, q = 0.033) was twice as much as compared to developing a penetrating complication (B3) during the disease course. In contrast, the probability of entering B3 stage was similar regardless of whether antecedent stricture was present (B2 to B3, q = 0.016) or not (B1 to B3, q = 0.016). We identified SNPs within the gene loci encoding ZMIZ1, LOC105373831 and KSR1 as carrying the highest risk for progression to B3, while the presence of SNPs within gene loci TNFSF15 and CEBPB-PTPN1 protected from progression to B2 or B3. CONCLUSION: We identified new genetic risk factors that can predict disease course in CD patients. A closer understanding on the functional impact of these genetic variations might improve our treatment options finally to prevent disease progression in CD patients.

Fragmentation of Human Neutrophil α-Defensin 4 to Combat Multidrug Resistant Bacteria.

The occurrence and spread of multidrug-resistant bacteria is a prominent health concern. To curb this urgent threat, new innovative strategies pursuing novel antimicrobial agents are of the utmost importance. Here, we unleashed the antimicrobial activity of human neutrophil peptide-4 (HNP-4) by tryptic digestion. We identified a single 11 amino acid long fragment (HNP-41 - 11) with remarkable antimicrobial potential, exceeding that of the full length peptide on both mass and molar levels. Importantly, HNP-41 - 11 was equally bactericidal against multidrug-resistant and non-resistant strains; a potency that was further enhanced by N- and C-terminus modifications (acetylation and amidation, respectively). These observations, combined with negligible cytotoxicity not exceeding that of the full length peptide, presents proteolytic digestion of innate host-defense-peptides as a novel strategy to overcome the current health crisis related to antibiotic-resistant bacteria.

An Update Review on the Paneth Cell as Key to Ileal Crohn's Disease.

The Paneth cells reside in the small intestine at the bottom of the crypts of Lieberkühn, intermingled with stem cells, and provide a niche for their neighbors by secreting growth and Wnt-factors as well as different antimicrobial peptides including defensins, lysozyme and others. The most abundant are the human Paneth cell α-defensin 5 and 6 that keep the crypt sterile and control the local microbiome. In ileal Crohn's disease various mechanisms including established genetic risk factors contribute to defects in the production and ordered secretion of these peptides. In addition, life-style risk factors for Crohn's disease like tobacco smoking also impact on Paneth cell function. Taken together, current evidence suggest that defective Paneth cells may play the key role in initiating inflammation in ileal, and maybe ileocecal, Crohn's disease by allowing bacterial attachment and invasion.

Human ß-Defensin 2 Mediated Immune Modulation as Treatment for Experimental Colitis.

Defensins represents an integral part of the innate immune system serving to ward off potential pathogens and to protect the intestinal barrier from microbial encroachment. In addition to their antimicrobial activities, defensins in general, and human ß-defensin 2 (hBD2) in particular, also exhibit immunomodulatory capabilities. In this report, we assessed the therapeutic efficacy of systemically administered recombinant hBD2 to ameliorate intestinal inflammation in three distinct animal models of inflammatory bowel disease; i.e., chemically induced mucosal injury (DSS), loss of mucosal tolerance (TNBS), and T-cell transfer into immunodeficient recipient mice. Treatment efficacy was confirmed in all tested models, where systemically administered hBD2 mitigated inflammation, improved disease activity index, and hindered colitis-induced body weight loss on par with anti-TNF-α and steroids. Treatment of lipopolysaccharide (LPS)-activated human peripheral blood mononuclear cells with rhBD2 confirmed the immunomodulatory capacity in the circulatory compartment. Subsequent analyzes revealed dendritic cells (DCs) as the main target population. Suppression of LPS-induced inflammation was dependent on chemokine receptor 2 (CCR2) expression. Mechanistically, hBD2 engaged with CCR2 on its DC target cell to decrease NF-κB, and increase CREB phosphorylation, hence curbing inflammation. To our knowledge, this is the first study showing in vivo efficacy of a systemically administered defensin in experimental disease.

Infodemiology of Crohn's disease and Ulcerative colitis using Google Trends - an approach to investigate patient needs.

INTRODUCTION: Inflammatory bowel diseases (IBD) highly affect quality of life. The course of disease and success of treatment are variable. These factors result in a high number of psychiatric comorbidities with patients requiring extensive medical consultation or additional psychotherapy. Unfortunately, time is often limited in daily clinical care, which leaves patients not feeling sufficiently informed about their disease. Patients often compensate by searching the internet, with possibly harmful information. We aim to identify information gaps to allow a more complete education of patients. METHODS: We analyzed the internet search behavior using the key words [Morbus Crohn] (CD) and [Colitis ulcerosa] (UC) using Google Trends. In addition, we investigated which websites are the first hits on Google, as those are most likely visited by patients. RESULTS: Symptoms, nutrition and therapy are central topics for persons interested in IBD. The searches concerning symptoms or therapies do not match the actual incidence or prevalence of comorbidities as well as the more commonly used therapies or established nutritional recommendations. We found a distinct impact of well-known personalities on disease related searches. The first suggested websites on google showed great heterogeneity of responsible publishers, often with possible conflict of interests. In line with those observations, quality of website content is highly heterogeneous. CONCLUSION: This study showed a need of information concerning symptoms, nutrition and therapy that should be considered during patient education. Since time in physician patient dialogue is short it may be helpful to further evaluate websites independently in order to give recommendations of websites offering reliable information.

Microbiota and mucosal defense in IBD: an update.

Introduction: Inflammatory bowel diseases (IBD) are on the rise worldwide. This review covers the current concepts of the etiology of Crohn´s disease and ulcerative colitis by focusing on an unbalanced interaction between the intestinal microbiota and the mucosal barrier. Understanding these issues is of paramount importance for the development of targeted therapies aiming at the disease cause.Area covered: Gut microbiota alterations and a dysfunctional intestinal mucosa are associated with IBD. Here we focus on specific defense structures of the mucosal barrier, namely antimicrobial peptides and the mucus layer, which keep the gut microbiota at a distance under healthy conditions and are defective in IBD.Expert commentary: The microbiology of both forms of IBD is different but characterized by a reduced bacterial diversity and richness. Abundance of certain bacterial species is altered, and the compositional changes are related to disease activity. In IBD the mucus layer above the epithelium is contaminated by bacteria and the immune reaction is dominated by the antibacterial response. Human genetics suggest that many of the basic deficiencies in the mucosal response, due to Paneth cell, defensin and mucus defects, are primary. Nutrition may also be important but so far there is no therapy targeting the mucosal barrier.

Tacrolimus Suppositories in Therapy-Resistant Ulcerative Proctitis.

BACKGROUND: Ulcerative proctitis may often be managed with topical salicylates or steroids alone, but in some patients, symptoms are persistent and severe. We analyzed the efficacy of tacrolimus suppositories in patients who had proven refractory to combined topical and systemic treatment. METHODS: In this retrospective analysis, ulcerative colitis activity index (CAI), side effects, co-medication and drug levels were assessed in 43 patients with distal ulcerative colitis who received suppositories containing 2 mg of tacrolimus b.i.d. as add-on medication. RESULTS: A total of 23 patients with ulcerative proctitis presented to follow-up within ≤50 days (mean 27.0 days) after suppositories were started. A decrease in CAI (from 8.0 to 5.5 points) was observed and 52.3% reached clinical remission (CAI ≤4). In total, 43 patients were available for analysis, of whom 9 had inflammation of the sigmoid colon as well. For the entire cohort, the median treatment duration was 76 days; 60% were in remission on the last documented visit. Serum measurements revealed a substantial tacrolimus level with a mean of 5.5 ng/mL. We observed one case of mild reversible acute kidney injury. CONCLUSIONS: In ulcerative proctitis, adding tacrolimus suppositories can be an effective and safe option when topical mesalazine, corticoid formulations and concomitant oral or parenteral medications have failed.

Human Endogenous Retroviruses: Residues of Ancient Times Are Differentially Expressed in Crohn's Disease.

BACKGROUND: Eight percent of the human genome consists of human endogenous retroviruses (HERV). These genetic elements are remnants of ancient retroviral germ-line infections. Altered HERV expression is associated with several chronic inflammatory diseases. A physiological role of the HERV-derived proteins syncytin-1 and -2 has been described for the integrity of the human placental cell layer in terms of maintaining feto-maternal tolerance. The aim of this project was to investigate HERV expression in Crohn's disease (CD) with a further focus on syncytins in the gut. MATERIAL AND METHODS: Seventy-four ileal and colonic tissue samples of CD patients and healthy controls have been investigated for mRNA expression of major HERV groups by a comprehensive microarray screening. The most prominent differences have been validated by qRT-PCR. Immunohistochemistry (IHC), Western Blot (WB) and qRT-PCR were performed for syncytin-1 and -2. RESULTS: HERV microarray screening revealed a distinct expression profile in ileal and colonic tissue, as well as differential expression in CD compared to healthy controls. qRT-PCR validated differential expression of at least 3 HERV-groups in CD. qRT-PCR, IHC and WB showed a tissue-dependent diminished epithelial expression of syncytins in inflamed CD. CONCLUSION: For the first time, HERV expression has been comprehensively studied in the gut. Between CD and healthy controls we could show a tissue dependent differential HERV expression profile. Notably, we could show that syncytin-1 and -2 are expressed in the epithelial layer in ileal and colonic tissue samples, whereas their diminished tissue-dependent expression in inflamed CD might modulate inflammatory processes at the gut barrier.

Proteolytic Degradation of reduced Human Beta Defensin 1 generates a Novel Antibiotic Octapeptide.

Microbial resistance against clinical used antibiotics is on the rise. Accordingly, there is a high demand for new innovative antimicrobial strategies. The host-defense peptide human beta-defensin 1 (hBD-1) is produced continuously by epithelial cells and exhibits compelling antimicrobial activity after reduction of its disulphide bridges. Here we report that proteolysis of reduced hBD-1 by gastrointestinal proteases as well as human duodenal secretions produces an eight-amino acid carboxy-terminal fragment. The generated octapeptide retains antibiotic activity, yet with distinct characteristics differing from the full-length peptide. We modified the octapeptide by stabilizing its termini and by using non-natural D-amino acids. The native and modified peptide variants showed antibiotic activity against pathogenic as well as antibiotic-resistant microorganisms, including E. coli, P. aeruginosa and C. albicans. Moreover, in an in vitro C. albicans infection model the tested peptides demonstrated effective amelioration of C. albicans infection without showing cytotoxity on human cells. In summary, protease degradation of hBD-1 provides a yet unknown mechanism to broaden antimicrobial host defense, which could be used to develop defensin-derived therapeutic applications.