Treatment Strategies in Inflammatory Bowel Diseases

Background: The prevalence of inflammatory bowel disease (IBD) is rising globally. In Germany, these conditions affect 0.7% of the population, or approximately 600 000 patients. Treatment strategies have become more diversified as a result of an improved understanding of disease pathogenesis. It remains unclear how the currently available drugs should best be used in each individual patient.

Methods: This review is based on pertinent publications retrieved by a selective search in PubMed, with special attention to phase III and IV trials and to the German and European guidelines on the treatment of IBD.

Results: An improved understanding of the immunological mechanisms of disease underlies the current treatment strategies in patients with IBD. For those with a complex clinical course, monoclonal antibodies against pro-inflammatory cytokines (TNF, IL-12/IL-23, IL-23) and cell adhesion molecules (α4β7) are of established therapeutic value, along with “small molecules” such as JAK inhibitors and sphingosine-1-phosphate receptor modulators. The numerous studies that have been performed, only a few of which have been head-to-head comparison trials, and the (network) meta-analyses that have been published to date do not imply that any single one of these drugs can be considered the universal, primary treatment for all patients with IBD. In this review, we discuss the available substances and certain important differential-therapeutic aspects of the treatment of IBD.

Conclusion: The treatment of a patient with IBD must take his or her prior treatment(s) and comorbidities into account, along with individual patient characteristics and treatment goals. Rational decision-making is required on the basis of the mechanism of action and the side-effect profile of the various drugs that are now available for use.

Crohn’s disease (CD) and ulcerative colitis (UC) are the two main types of inflammatory bowel disease (IBD). CD is characterized by discontinuous zones of transmural inflammation that can arise in any part of the gastrointestinal tract but are mainly found in the ileocecal junction and the colon. UC, on the other hand, is characterized by a continuous zone of inflammation of the rectal mucosa with variable proximal extension; in rare cases, the terminal ileum is affected as well (“backwash ileitis”).

The prevalence of IBD is on the rise around the world. In Europe and North America alone, more than 3.5 million people suffer from IBD (1). Older figures suggest prevalence rates in Germany of 100 to 200 per 100 000 people for CD and 150 per 100,000 people for UC (2). Evaluations of health insurance data from the German federal state of Hesse (an inherently imprecise method) led to an estimated figure of 610 000 persons with IBD in Germany (0.7% of the population); other figures derived from data of the statutory health insurance carriers in Germany reveal a 13% rise in the prevalence of CD and a 29% rise in the prevalence of UC by 2018, compared to 2012 (3). Initial presentations are increasingly seen in persons over age 70. IBD is often thought of as a chronic, progressive disease, with progressive destruction of the intestinal tract and accumulation of various types of damage, yet a study of the Epi-IBD cohort, including persons with a new diagnosis of CD, revealed overall outcomes that were better than expected (4). In 5 years of follow-up, only 22% of patients underwent surgery and 36% were hospitalized for active CD. The disease progressed in 14% of patients with a transition from inflammation without penetration or strictures to a complicating penetration or stricture. Among the western European patients in this cohort, 33% were treated with biologic agents, 66% with immunosuppressants, and 56% with 5-acetylsalicylic acid (ASA) preparations, which are no longer recommended in the guidelines.

The data of patients with UC were analyzed analogously (5). Among these patients, only 23% were hospitalized for active UC; 11% were treated with biologic agents, and 29% with immunosuppressants. Thus, the vast majority of patients with IBD whether CD or UC) have a relatively favorable course. The standard drugs (mesalazine and budesonide or steroids) generally suffice.

IBD is a systemic disease whose manifestations can also include inflammatory reactions in the eyes, skin, and joints. Its symptoms include diarrhea, abdominal pain, blood in the stool, weight loss, and fatigue. It can be complicated by intestinal stenosis and fistulization and it elevates the risk of colorectal cancer. Thus, despite the generally good prognosis of IBD, some patients have complex courses with progressively destructive disease. These patients need optimized anti-inflammatory treatment (6, 7).

The etiology of IBD is multifactorial, including genetic, microbial, and environmental factors (e.g., smoking, antibiotic use), ultimately resulting in a heightened intestinal immune response. Impaired barrier function in the gastrointestinal tract promotes the translocation of commensal microorganisms (8), which are, in turn, taken up by immune cells of the innate immune system; this leads to excessive production of pro-inflammatory cytokines (e.g., interferon [INF]-γ, tumor necrosis factor [TNF-α]), and interleukins including IL-12 and IL-23). As a result, more immune cells are recruited into the mucosa, and the intestinal inflammation is perpetuated (9). These mechanisms have provided targets for directed therapies that selectively inhibit major signaling pathways of the inflammatory process (Figure). For a detailed description of the immune pathogenesis of IBD, see the eBox.

Figure

The immune pathogenesis of inflammatory bowel disease

eBox

The immune pathogenesis of IBD as a rational basis for new therapeutic approaches

Lifestyle modification and nutritional interventions

Lifestyle changes, particularly relating to diet, are increasingly being used as treatment for IBD, as they accord well with patients’ needs and are safe and easily accessible. In pediatrics, exclusive enteral nutrition (EEN) has been established as the first line of treatment to induce remission in CD (7), after large systematic reviews repeatedly showed its non-inferiority to systemic steroid treatment. The obvious limitations of EEN are the difficulty of adhering to it and its incompatibility with normal social life beyond the short term (11). Concepts have been introduced to circumvent the acceptance problems and to mimic the assumed mechanisms of action, in particular, by avoiding potentially pro-inflammatory food components that can damage to the intestinal mucosa (12) and making use of the modulatory effect on the microbiome to lessen the burden of pro-inflammatory microorganisms (13). One such concept is the Crohn‘s Disease Exclusion Diet (CDED), in which potentially pro-inflammatory foods (gluten, dairy products, animal fats, processed meat, and all highly processed foods) are excluded. This diet combined with 50% PEN (partial enteral nutrition) (CDED + PEN) led to remission at 6 weeks in 70% of participating children and adolescents and meets with greater acceptance among patients than EEN (14). In a pilot study in adults with CD, CDED + PEN and CDED alone yielded clinical remission rates of 68% and 57%, respectively, at six weeks, with 80% still in remission at the end of the 24-week observation period (15). The low FODMAP diet (FODMAP = fermentable oligosaccharides, disaccharides, monosaccharides and polyols), which has been used successfully in the symptomatic treatment of irritable bowel syndrome, with response rates of 50–80%, has also lessened the symptom burden of IBD in clinical studies, but without endoscopically demonstrated reduction of disease activity (16). The details of these diets are shown in Table 1. It should be noted that targeted nutritional therapy for patients with IBD must be closely supervised by a specially trained nutritionist and accompanied by strict medical monitoring and guidance; its risks include macro- and micronutrient deficiencies, nutritional and eating disorders, and psychosocial dysfunction.

Table 1

Nutritional therapy approaches in the treatment of IBD

The current treatment of IBD

The treatments that are now approved for IBD (Table 2) help many patients, yet there remain sizeable subgroups of patients in which they are insufficiently effective or must be discontinued because of adverse side effects. The central goal of treatment for patients with CD and UC is steroid-free remission, because repetitive or long-term steroid treatment can have serious adverse effects, both acute and chronic. The principles of therapeutic decision-making are summarized in the guidelines of the DGVS (7, 17) and the European Crohn‘s Colitis Organization (ECCO) (18, 19). The German guidelines deliberately refrain from assigning ranks or priorities to drugs in such a way as to dictate specific decisions in certain cases. Rather, emphasis is placed on individualized treatment, in consideration of personal treatment goals and in view of the potential complications or contraindications. Nonetheless, in this review, we report the strength of each drug recommendation in the German guidelines, in order to give our readers the broadest possible informational basis for decision-making. These reported strengths reflect the strength of the evidence underlying each recommendation, including the consistency of the study findings, the clinical relevance of the endpoints and their importance to patients, the risk-benefit ratio, patient preferences, and ease of implementation. Recommendation grade A (RG A) corresponds to a strong recommendation, recommendation grade B (RG B) to an otherwise not qualified recommendation, and recommendation grade 0 (RG 0) to an open recommendation (“may be considered/may be omitted”).

Table 2

Efficacy and side effect spectrum of advanced therapeutic agents for inflammatory bowel disease

Ulcerative colitis

Aminosalicylates (5-ASA) are the cornerstone of conventional drug treatment for uncomplicated UC. Many patients can be successfully treated with them over the long term. The optimal form of application depends on the pattern of involvement; it should generally include treatment per rectum (≥ 1 g/d), as this yields high local concentrations of the drug. While isolated proctitis can be treated with suppositories alone (RG A), foams and enemas are suitable for proctosigmoiditis, as they enable more proximal application of the active substance. Additional oral 5-ASA therapy (once per day) at a sufficiently high dosage above 3 g/d, in granule or pellet form, is standard treatment for left-sided colitis and pancolitis (RG A).

If there is an insufficient response to induction therapy with 5-ASA, systemic steroid bolus therapy is indicated at an initial dose of 0.5–1 mg/kg bw/d prednisolone equivalent, regardless of the pattern of involvement (RG A). It is important to aim for a steady dose taper leading to discontinuation within 10–12 weeks; repeated steroid treatments (e.g., twice a year) should be avoided, and a need for them indicates rather that more complex therapies should be initiated. For mild to moderate disease activity, budesonide MMX (9 mg/d) can be used as an alternative, particularly in left-sided colitis (RG B), with fewer systemic side effects. Once remission has been achieved (RG A), 5-ASA monotherapy with steroids should be continued for at least two years (RC B) and can be used over the long term (RC B) to prevent colon cancer. In maintenance therapy, the oral 5-ASA dose can be reduced, although a dose of ≥ 2 g/d has been shown to be more effective in maintaining remission. In the event of a steroid-refractory or steroid-dependent course (i.e., absence of response to steroids or inability to get off steroids), further treatment can be with TNF antibodies (adalimumab, golimumab, infliximab; the last is preferably combined with a thiopurine), mirikizumab, ustekinumab or vedolizumab, calcineurin inhibitors (ciclosporin, tacrolimus [off-label]), JAK inhibitors (filgotinib, tofacitinib, upadacitinib [not yet included in the guideline, because only recently approved (20)]), or the sphingosine-1-phosphate receptor (S1P) modulator ozanimod (EG B). With the exception of calcineurin inhibitors, all of these drugs are also suitable for maintaining remission (EG B). Etrasimod is expected to be approved as an S1P modulator (21) for the treatment of UC in late 2023.

A special situation arises for azathioprine/6-mercaptopurine. This immunosuppressant can be used as monotherapy to maintain remission in patients with UC and steroid-dependent disease course, possibly enabling the discontinuation of steroids.

In fulminant, steroid-refractory acute, severe UC, only infliximab or ciclosporin (or tacrolimus) are recommended in the guidelines. In such cases, proctocolectomy must be considered at an early stage in interdisciplinary discussion with a surgeon who has experience in the treatment of IBD.

Crohn’s disease

In contrast to UC, 5-ASA preparations have no proven value in CD (RG 0) (7, 18). They are not recommended for induction therapy or for maintenance of remission, yet they are nevertheless often used. The standard treatment for mild ileocecal or right-sided colonic involvement is budesonide (9 mg/d) (RG A). In cases of high inflammatory activity and extensive small bowel involvement, systemic steroid bolus treatment is necessary at an initial dose of 1 mg/kg bw with a maximum of 75 mg prednisolone equivalent/day (RG A). Just as in UC, the repetitive use of steroids should be avoided (RG A); in case of frequent relapses, newer drugs should be used to maintain remission. For steroid-dependent or steroid-refractory courses, anti-TNF antibodies (infliximab and adalimumab), ustekinumab, and vedolizumab are available; all of these drugs can also be used to maintain remission (RG B). Extensive small bowel involvement may also be a reason for early use of these drugs (RG 0). The JAK inhibitor upadacitinib and the interleukin-23 antibody risankizumab have only recently been approved and have not yet found their way into the guidelines. Upadacitinib may have therapeutic potential for patients in which various biologic agents have lost their efficacy (22); however, its potential side effects must be considered, particularly in patients at high risk.

The drug of first choice for fistulizing Crohn’s disease is infliximab, as this is the only drug whose use is supported by the findings of a prospective, randomized trial in which the primary endpoint was fistula closure (RG B) (23). Combining infliximab with a thiopurine should always be considered in a young patient, as the combination enhances the therapeutic effect and helps prevent the development of neutralizing autoantibodies against infliximab, which is otherwise very frequent; these benefits, must be weighed against the risk of lymphoma after prolonged treatment, which must be mentioned when discussing this potential combined treatment with the patient. For isolated ileocecal involvement without response to steroids, the so-called LIR!C study has convincingly shown that surgical ileocecal resection is at least as effective as treatment with infliximab, and this is why a recommendation for early elective ileocecal resection in this situation has been included in the German CD guideline. Smoking cessation is especially important for maintaining remission in patients with CD who smoke (EG A), as it halves the recurrence rate.

The relative utility of various drugs in the first-line treatment of IBD

In addition to the classic anti-inflammatory drugs (mesalazine, steroids) and immunosuppressants (mainly thiopurines and methotrexate), six further classes of drugs are now available for the first-line treatment of IBD: namely, antibodies against TNF-α, α4β7 integrins, IL-12/23 and IL-23, and small molecules. Briefly put, these drugs have been approved for use in the event of the inefficacy or intolerability of treatment with conventional drugs or biological agents. This immediately raises the question which patients stand to benefit most from which drug.

The selection of an active drug or substance class should be based on the findings of clinical trials and on patient-specific factors. Results from randomized, controlled clinical trials (RCTs; these are often approval studies) with homogeneous patient groups that are characterized in detail yield valid data in relation to well-defined criteria of inclusion and exclusion. Nonetheless, patients in clinical practice can differ from patients in RCTs in many ways, and observational studies from clinical practice are thus important as well. Head-to-head (H2H) trials are the best way to compare one substance against another. In recent years, for example, such trials have demonstrated the superior clinical efficacy of the α4β7 integrin inhibitor vedolizumab compared to the TNF-alpha inhibitor adalimumab in the treatment of UC (clinical remission, 31.3 % versus 22.5 % at 52 weeks) (24), and the comparable efficacy of the IL12/IL23 antibody ustekinumab and adalimumab in CD (clinical remission, 64.9 % versus 61.0 % at 52 weeks) (25). Further H2H trials will be reported in the years ahead (e.g., risankizumab [IL23-AK] or mirikizumab [IL23-AK] versus ustekinumab [IL12/23-AK] in CD, or brazikumab [IL23 receptor-AK] versus vedolizumab, or else tofacitinib versus cyclosporine A, in UC). As only a limited number of direct comparisons can be made, indirect comparisons of clinical trials in (network) meta-analyses are important as well, but these must be interpreted cautiously, as important differences (e.g., between patient populations and prior treatments) cannot be fully compensated for, even with complex statistical procedures such as propensity scores.

According to a recent network meta-analysis, infliximab followed by risankizumab and upadacitinib appears to be most effective in inducing remission in complex CD. For maintaining remission, upadacitinib followed by adalimumab and infliximab was rated as the most effective treatment (26). Again according to network meta-analyses, upadacitinib appears to be the most effective drug for inducing clinical remission in UC, but also had the most adverse effects. Vedolizumab has the most favorable side effect profile, while ozanimod has the worst (27). The Red Hand Letter issued on March 17, 2023 with the joint participation of the European Medicines Agency (EMA) and the German Federal Institute for Drugs and Medical Devices (BfArM) contains the recommendation that JAK inhibitors should only be used as reserve drugs, and not as first- or second-line treatment, in patients at high risk (i.e., patients who are aged 65 and above, have an increased risk of severe cardiovascular disease, are current or long-term previous smokers, or have an increased risk of cancer). In other patients, however, side effects were rarely seen. The use of these drugs in selected patients after a risk assessment seems reasonable (28, 29).

All of these trials included large groups of patients, but were not based on individual characteristics and needs, which are of great importance for the selection of a drug. The list in Table 3 provides guidance for the selection of an individualized treatment. For example, the rapidity of response to treatment with JAK inhibitors in CD and UC may be an important reason to use these drugs. A history of severe infections, particularly in older patients, limits the use of TNF antibodies (30). As for postoperative maintenance of remission in CD, the best efficacy data are currently available for anti-TNF antibodies. Extraintestinal manifestations of IBD can be treated with anti-TNF antibodies, but also with JAK inhibitors and (depending on the extraintestinal manifestation [EIM]) with IL-12/IL-23 antibodies. Specific EIM should always be considered as well; the indications for it are highly specific. Vedolizumab and IL-12/IL-23 antibodies have favorable safety profiles, e.g. with regard to complicating infections, and can thus be given preferentially to patients with the corresponding pre-existing conditions and risk factors. Infections have been found to be less common with ustekinumab as well, but this drug is not without undesirable side effects (31). Latent tuberculosis must be ruled out before the initiation of treatment with any of these drugs except ozanimod. Before TNF antibodies are given, patients must be tested for a hepatitis B infection. Integrin and IL-12/IL-23 antibodies can presumably be used relatively safely in patients with pre-existing cardiovascular disease or an increased tumor risk. TNF antibodies are contraindicated in patients with NYHA stage III/IV heart failure. JAK inhibitors should also only be used in exceptional cases in patients with cardiovascular risk factors, and ozanimod should not be given to patients with arrhythmias or a history of a cardiovascular event in the last six months. Moderate to severe renal insufficiency requires a dose reduction of JAK inhibitors; no studies are available for biologic agents or ozanimod in this situation, and decisions must be made case by cases, as needed. For women desiring to become pregnant, TNF antibodies are again the preferred choice, being supported by the fullest safety data for use during pregnancy and breastfeeding. Experience with the use of vedolizumab or ustekinumab in pregnancy is still limited. To date, however, no unfavorable courses of pregnancy have been reported. It is thus recommended that these drugs can be continued during pregnancy up to delivery, while JAK inhibitors and S1P modulators must not be used.

Table 3

Aspects to be considered in determining the optimal individualized treatment

Along with providing the well-established types of nutritional therapy, pediatric gastroenterologists face the additional challenges presented by the child or adolescent patient, such as the goal of age-appropriate growth and development. Moreover, the use of suitable new drugs in this age group must often be off label because of a lack of data or delays in approval (32).

It would also be very important to be able to predict the individual treatment response with the aid of objective criteria. Many different approaches for this purpose (imaging, serological, histological, immunological, genetic, microbiological) have already been developed in the past. These include a scoring system for predicting the response to vedolizumab in CD (33), molecular imaging with labeled antibodies to predict the response to TNF-AK (34), and the prediction of the development of anti- infliximab antibodies in the presence of the HLADQA1*05 genotype (35). None of these predictive methods have yet been used in the clinical setting.

Perspectives

In the future, precision medicine (PM) will involve individually selected treatment and individual prediction of the treatment response. PM will need to be based on advanced bioinformatic tools, such as systems biology, that integrate all components of the disease process into a network-medicine approach. The ultimate goal is to be able to treat patients with IBD with highly specific, customized PM drugs (36). Current studies are also addressing the safety and efficacy of combinations of two biologic agents; this is a potentially promising approach utilizing combined effects at more than one point in the inflammatory cascade. Until these prospects have been realized, the difficult choice of treatment for patients with IBD will still have to be based on the critical evaluation of study findings, the physician’s personal experience, and, above all, the individual characteristics and needs of the patient.

Conflict of interest statement
AS has received funding from the German Research Foundation, the Thüringer Aufbaubank, the GBA Innovation Fund, Abbvie, Celltrion, and Takeda and lecture honoraria from Abbvie, Bristol-Myers Squibb, Celltrion, CLS Behring, De Prom, Falk Foundation, Ferring, Janssen, Kompetenznetz Darmerkrankungen, MedUpdate, MSD, Recordati-Pharma, sobi rare strength, Takeda and Tillots Pharma AG. He has also served as a paid consultant for Abbvie, Amgen, Bristol-Myers Squibb, Consal, Galapagos, Gilead, Janssen, Lilly, MSD, Repha GmbH, Roche, Pfizer, Pharmacosmos GmbH, Takeda Pharma and Tillots Pharma AG.

RA has received funding from AbbVie, Amgen, Astra Zeneca, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Cellgene, Celltrion Healthcare, Falk Foundation, Ferring, Galapagos, Gilead, InDex Pharmaceuticals, Janssen-Cilag, Kliniksa Pharmaceuticals, Lilly, MSD Sharp & Dohme, Roche Pharma, Samsung Bioepsis, Takeda Pharma, Tillotts Pharma, and Viatris. He also has received research funding from the DFG for TRR241 (IBDome) and SFB1181 (C02).

PCG has received lecture honoraria from Abbvie, Falk Foundation, Pfizer, Janssen-Cilag, and Takeda Pharma and has served as a paid consultant for Abbvie, Janssen-Cilag, and Takeda Pharma.

JS has received funding from AbbVie, Bristol-Myers Squibb, Falk Foundation, Janssen, MSD, Pfizer, and Shire.

JdL has received research funding and honoraria from Abbvie, Takeda, and Falk Foundation.

CS has received funding from Abbvie, Amgen, Berlin Chemie, Biogen, Bristol-Myers Squibb, CED Service, Celltrion, Ewopharma, Dr. Falk, Galapagos, Janssen-Cilag, med update, Merckle, MSD Sharp & Dohme, Norgine, Novartis, Olympus, Pentax, Pfizer, Shire, Shield Therapeutics, and Takeda.

Manuscript dates received on 21 November 2022, revised version accepted on 17 May 2023.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
Prof. Dr. med. Andreas Stallmach
Klinik für Innere Medizin IV, Universitätsklinikum Jena
Am Klinikum 1, D-07747 Jena, Germany

Cite this as:
Stallmach A, Atreya R, Grunert PC, Stallhofer J, de Laffolie J, Schmidt C: Treatment strategies in inflammatory bowel diseases. Dtsch Arztebl Int 2023; 120: 768–78. DOI: 10.3238/arztebl.m2023.0142

►Supplementary Material

eReferences, eBox:
www.aerzteblatt-international.de/m2023.0142

References

1. Ng SC, Shi HY, Hamidi N, et al.: Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 2018; 390: 2769–78

2. Manthey CF, Reher D, Huber S: Was ist gesichert in der Therapie chronisch-entzündlicher Darmerkrankungen. Internist 2021; 62: 1269–79

3. Holstiege J, Klimke K, Akmatov MK, Kohring C, Dammertz L, Bätzing J: Bundesweite Verordnungstrends biologischer Arzneimittel bei häufigen Autoimmunerkrankungen, 2012 bis 2018. Versorgungsatlas 2021; Bericht Nr. 21/03.

4. Burisch J, Kiudelis G, Kupcinskas L, et al.: Natural disease course of Crohn‘s disease during the first 5 years after diagnosis in a European population-based inception cohort: an Epi-IBD study. Gut 2019; 68: 423–33

5. Burisch J, Katsanos KH, Christodoulou DK, et al.: Natural disease course of ulcerative colitis during the first five years of follow-up in a European population-based inception cohort-an epi-IBD study. J Crohns Colitis 2019; 13: 198–208

6. Kucharzik T, Koletzko S, Kannengiesser K, Dignass A: Ulcerative colitis—diagnostic and therapeutic algorithms. Dtsch Arzteblatt Int 2020; 117: 564–74

7. Sturm A, R. Atreya R, Bettenworth D, et al.: Aktualisierte S3-Leitlinie „Diagnostik und Therapie des Morbus Crohn“ der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS). Z Gastroenterol 2022; 60: 332–418

8. Kempski J, Huber S: Das Darmmikrobiom in der Pathogenese und Therapie chronisch-entzündlicher Darmerkrankungen. Inn Med (Heidelb) 2022; 63: 1022–7

9. Neurath MF: Targeting immune cell circuits and trafficking in inflammatory bowel disease. Nat Immunol 2019; 20: 970–9

10. Coskun M, Vermeire S, Nielsen OH: Novel targeted therapies for inflammatory bowel disease. Trends Pharmacol Sci 2017; 38: 127–42

11. Lawley M, Wu JW, Navas-Lopez VM, et al.: Global variation in use of enteral nutrition for pediatric Crohn disease. J Pediatr Gastroenterol Nutr 2018; 67: e22–e9

12. Gkikas K, Logan M, Nichols B, et al.: Dietary triggers of gut inflammation following exclusive enteral nutrition in children with Crohn‘s disease: a pilot study. BMC Gastroenterol 2021; 21: 454

13. Plitt T, Faith JJ: Seminars in immunology special issue: nutrition, microbiota and immunity. The unexplored microbes in health and disease. Semin Immunol 2023; 66: 101735

14. Levine A, Wine E, Assa A, et al.: Crohn‘s disease exclusion diet plus partial enteral nutrition induces sustained remission in a randomized controlled trial. Gastroenterology 2019; 157: 440–50 e8

15. Yanai H, Levine A, Hirsch A, et al.: The Crohn‘s disease exclusion diet for induction and maintenance of remission in adults with mild-to-moderate Crohn‘s disease (CDED-AD): an open-label, pilot, randomised trial. Lancet Gastroenterol Hepatol 2022; 7: 49–59

16. Peng Z, Yi J, Liu X: A low-FODMAP diet provides benefits for functional gastrointestinal symptoms but not for improving stool consistency and mucosal inflammation in IBD: a systematic review and meta-analysis. Nutrients 2022; 14: 2072

17. Kucharzik T, Dignass A, Atreya A, et al.: Aktualisierte S3-Leitlinie Colitis ulcerosa (Version 6.1). Februar 2023—AWMF-Registriernummer: 021–009. Z Gastroenterol 2023; 61: 1046–134

18. Torres J, Bonovas S, Doherty G, et al.: ECCO guidelines on therapeutics in Crohn‘s disease: medical treatment. J Crohns Colitis 2020; 14: 4–22

19. Spinelli A, Bonovas S, Burisch J, et al.: ECCO guidelines on therapeutics in ulcerative colitis: surgical treatment. J Crohns Colitis 2022; 16: 179–89

20. Danese S, Vermeire S, Zhou W, et al.: Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. Lancet 2022; 399: 2113–28

21. Sandborn WJ, Vermeire S, Peyrin-Biroulet L, et al.: Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies. Lancet 2023; 401: 1159–1171

22. Chugh R, Braga-Neto MB, Fredrick TW, et al.: Multicenter real-world experience of upadacitinib in the treatment of Crohn‘s disease. J Crohns Colitis 2023; 19: 504–12

23. Present DH, Rutgeerts P, Targan S, et al.: Infliximab for the treatment of fistulas in patients with Crohn‘s disease. N Engl J Med 1999; 340: 1398–405

24. Sands BE, Peyrin-Biroulet L, Loftus EV Jr., et al.: Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis. N Engl J Med 2019; 381: 1215–26

25. Sands BE, Irving PM, Hoops T, et al.: Ustekinumab versus adalimumab for induction and maintenance therapy in biologic-naive patients with moderately to severely active Crohn‘s disease: a multicentre, randomised, double-blind, parallel-group, phase 3b trial. Lancet 2022; 399: 2200–11

26. Barberio B, Gracie DJ, Black CJ, Ford AC: Efficacy of biological therapies and small molecules in induction and maintenance of remission in luminal Crohn‘s disease: systematic review and network meta-analysis. Gut 2023; 72: 264–74

27. Lasa JS, Olivera PA, Danese S, Peyrin-Biroulet L: Efficacy and safety of biologics and small molecule drugs for patients with moderate-to-severe ulcerative colitis: a systematic review and network meta-analysis. Lancet Gastroenterol Hepatol 2022; 7: 161–70

28. Ytterberg SR, Bhatt DL, Mikuls TR, et al.: Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med 2022; 386: 316–26

29. Charles-Schoeman C, Buch MH, Dougados M, et al.: Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance. Ann Rheum Dis 2023; 82: 119–29

30. Mucke J, Simon HU, Burmester GR: The safety of antirheumatic drugs. Dtsch Arztebl Int 2022 (Forthcoming): arztebl.m2021.0389

31. Honap S, Meade S, Ibraheim H, Irving PM, Jones MP, Samaan MA: Effectiveness and safety of ustekinumab in inflammatory bowel disease: a systematic review and meta-analysis. Dig Dis Sci 2022; 67: 1018–35

32. Buderus S, Scholz D, Behrens R, et al.: Inflammatory bowel disease in pediatric patients: characteristics of newly diagnosed patients from the CEDATA-GPGE registry. Dtsch Arzteblatt Int 2015; 112: 121–7

33. Dulai PS, Boland BS, Singh S, et al.: Development and validation of a scoring system to predict outcomes of vedolizumab treatment in patients with Crohn‘s disease. Gastroenterology 2018; 155: 687–95.e10

34. Atreya R, Neumann H, Neufert C, et al.: In vivo imaging using fluorescent antibodies to tumor necrosis factor predicts therapeutic response in Crohn‘s disease. Nat Med 2014; 20: 313–8

35. Wilson A, Peel C, Wang Q, Pananos AD, Kim RB: HLADQA1*05 genotype predicts anti-drug antibody formation and loss of response during infliximab therapy for inflammatory bowel disease. Aliment Pharmacol Ther 2020; 51: 356–63

36. Fiocchi C, Dragoni G, Iliopoulos D, et al.: Results of the seventh scientific workshop of ECCO: precision medicine in IBD-what, why, and how. J Crohns Colitis 2021; 15: 1410–30

e1. Kullberg MC, Jankovic D, Feng CG, et al.: IL-23 plays a key role in helicobacter hepaticus-induced T cell-dependent colitis. J Exp Med 2006; 203: 2485–94

e2. Hue S, Ahern P, Buonocore S, et al.: Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J Exp Med 2006; 203: 2473–83

e3. Papp KA, Blauvelt A, Bukhalo M, et al.: Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis. N Engl J Med 2017; 376: 1551–60

e4. Atreya R, Neurath MF: IL-23 blockade in anti-TNF refractory IBD: from mechanisms to clinical reality. J Crohns Colitis 2022; 16: ii54-ii63

e5. Herrera-deGuise C, Serra-Ruiz X, Lastiri E, Borruel N: JAK inhibitors: a new dawn for oral therapies in inflammatory bowel diseases. Front Med 2023; 10: 1089099

e6. Dal Buono A, Gabbiadini R, Alfarone L, et al.: Sphingosine 1-phosphate modulation in inflammatory bowel diseases: keeping lymphocytes out of the intestine. Biomedicines 2022; 10: 1735

e7. Atreya R, Neurath MF: Mechanisms of molecular resistance and predictors of response to biological therapy in inflammatory bowel disease. Lancet Gastroenterol Hepatol 2018; 3: 790–802

e8. Hanauer SB, Feagan BG, Lichtenstein GR, et al.: Maintenance infliximab for Crohn‘s disease: the ACCENT I randomised trial. Lancet 2002; 359: 1541–9

e9. Rutgeerts P, Sandborn WJ, Feagan BG, et al.: Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353: 2462–76

e10. Hanauer, SB, Sandborn WJ, Rutgeerts P, et al.: Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn‘s disease: the CLASSIC-I trial. Gastroenterology 2006; 130: 323–33; quiz 591

e11. Reinisch W, Sandborn WJ, Hommes DW, et al.: Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut 2011; 60: 780–7

e12. Sandborn, WJ, van Assche G, Reinisch W, et al.: Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2012; 142: 257–65. e1–3

e13. Sandborn WJ, Feagan BG, Marano C, et al.: Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2014; 146: 85–95; quiz e14–5

e14. Sandborn WJ, Feagan BG, Rutgeerts P, et al.: Vedolizumab as induction and maintenance therapy for Crohn‘s disease. N Engl J Med 2013; 369: 711–21

e15. Feagan BG, Rutgeerts P, Sands BE, et al.: Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013; 369: 699–710

e16. Feagan BG, Sandborn WJ, Gasink C, et al.: Ustekinumab as induction and maintenance therapy for Crohn‘s disease. N Engl J Med 2016; 375: 1946–60

e17. Sands BE, Sandborn WJ, Panaccione R, et al.: Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2019; 381: 1201–14

e18. D‘Haens G, Panaccione R, Baert F, et al.: Risankizumab as induction therapy for Crohn‘s disease: results from the phase 3 ADVANCE and MOTIVATE induction trials. Lancet 2022; 399: 2015–30

e19. Sandborn WJ, Su C, Sands BE, et al.: Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2017; 376: 1723–36

e20. Feagan BG, Danese S, Loftus EV Jr, et al.: Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial. Lancet 2021; 397: 2372–84

e21. Danese S, Vermeire S, Zhou W, et al.: Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. Lancet 2022; 399: 2113–28

e22. Abbvie: Second phase 3 induction study confirms Upadacitinib (RINVOQ®). Improved clinical and endoscopic outcomes in patients with Crohn‘s Disease https://news.abbvie.com/2022-02-24-Second-Phase-3-Induction-Study-Confirms-Upadacitinib-RINVOQ-R-Improved-Clinical-and-Endoscopic-Outcomes-in-Patients-with-Crohns-Disease (last accessed on 22 October 2023).

e23. Sandborn WJ, Feagan BG, D‘Haens G, et al.: Ozanimod as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2021; 385: 1280–91