Management of Crohn’s disease in Taiwan: consensus guideline of the Taiwan Society of Inflammatory Bowel Disease updated in 2023

1) Nutrition

Dietary interventions play crucial roles in mediating remission, reducing inflammation, and promoting mucosal healing, which are key aspects of CD management. Exclusive enteral nutrition (EEN) is the primary nutritional therapy for mild-tomoderate CD in pediatric patients, and its efficacy for mediating remission is comparable to corticosteroids [33]. Another innovative dietary approach, CDED plus PEN, has been developed specifically for patients with CD. In a randomized trial, CDED alone and CDED plus PEN were demonstrated to be effective in achieving clinical remission in pediatric patients with CD, without the need of additional medications by week 6, and remission was sustained at week 24 in 80% of the patients [93]. Because malnutrition affects approximately 65%–70% of patients with CD, nutritional support has become increasingly vital in CD management, particularly in patients with weight loss and malnutrition before surgery [1,90].

2) Induction

The oral administration of 5-ASA remains under debate and is generally limited to patients with mild CD or those with ileocolonic involvement. Moreover, 5-ASA can be discontinued for patients undergoing biologic therapy, particularly because no clear benefits of long-term 5-ASA treatment have been observed in approximately one-third of patients with CD [94]. According to a meta-analysis by the ECCO, both 5-ASA and sulfasalazine are well tolerated by patients with mild-to-moderate CD. However, 5-ASA had no significant efficacy for achieving clinical remission (relative risk [RR], 1.28; 95% CI, 0.97–1.69) [95]. Although the efficacy of 5-ASA is under debate, Hart et al. [96] suggested that its early initiation following diagnosis and dosage optimization are linked to a longer duration of 5-ASA therapy. Because of the stringent reimbursement criteria for advanced therapies in Taiwan, the committee recommends the use of oral 5-ASA as an alternative to remission therapy in patients with mild colonic CD. However, if efficacy is suboptimal, treatment escalation is highly recommended.

Systemic corticosteroids such as prednisolone are effective in achieving remission in CD. When 5-ASA is ineffective, clinicians may consider using corticosteroids, including cortisone, prednisone, hydrocortisone, methylprednisolone, beclometasone, and budesonide [97]. However, in a systematic review of 8 trials, budesonide was found to be less effective than conventional steroids (pooled RR, 0.85; 95% CI, 0.75–0.97), although it was associated with a lower risk of corticosteroid-related adverse events [98]. Notably, in cases of more severe ileocecal CD (CDAI > 300), budesonide was inferior to prednisolone for mediating remission (RR, 0.52; 95% CI, 0.28–0.95).

Systemic corticosteroids are effective initial therapies for moderate-to-severe CD [33]. However, their use should be limited. They have limited efficacy for maintaining remission, and prolonged exposure can lead to toxicity issues.

MTX has been demonstrated to be effective in mediating remission for steroid-dependent and steroid-refractory CD, as evidenced by retrospective analysis and randomized controlled trials studies [99,100]. However, its efficacy in the era of newer, more effective biologic therapies remains uncertain. A systematic review conducted in 2020 revealed that MTX monotherapy was not superior to placebo for inducing clinical remission in CD [101]. A more recent systematic review of 163 studies indicated that MTX at a higher parenteral dose of 25 mg/week was more effective for mediating remission in CD compared with lower oral doses [102]. Thiopurines (AZA and 6-MP) were demonstrated to provide no additional benefits compared with placebo for mediating remission. Early initiation of AZA treatment in patients with CD within 8 weeks of diagnosis was not more effective than placebo for achieving corticosteroid-free remission [103]. A 2019 review that reanalyzed 48 meta-analyses of CD yielded conflicting results regarding the effectiveness of AZA or 6-MP in comparison with placebo, with these treatments exerting impact in a small number of patients ( < 1,000). Therefore, larger randomized controlled trials are warranted to confirm these findings [104]. However, due to the time required for thiopurines to take effect (typically 2–3 months), their use as induction therapy alone may not be reasonable.

Several controlled trials have demonstrated the efficacy of biologics for mediating remission in patients with active CD. Anti-TNFα agents, including infliximab, adalimumab, and certolizumab pegol (the last is not approved for CD treatment by the European Union and Taiwan Food and Drug Administration), have been used for both inducing and maintaining remission in CD [95]. In a clinical trial of 108 patients in 1995, 33% of the patients receiving infliximab achieved remission at 4 weeks compared with only 4% of the patients in the placebo group (P=0.005) [105]. Similarly, in the CLASSIC-I trial, 36% of the patients who were naïve to anti-TNFα therapy achieved remission at 4 weeks following adalimumab administration compared with 12% in the placebo group (P=0.001) [106]. Although thiopurines have been used to maintain the remission of steroid-dependent CD, recent clinical trials have suggested that AZA may be inferior to infliximab [107]. For instance, in the SONIC trial, combination therapy with AZA and infliximab exhibited superiority over AZA or infliximab monotherapy for achieving clinical remission (56.8% vs. 30% and 44.4%, P<0.001 compared with AZA alone and P=0.02 compared with infliximab alone) [108]. Anti-TNFα agents are also considered a primary treatment option for pediatric patients with CD having active perianal fistulizing disease [109]. Ustekinumab, a monoclonal antibody targeting the p40 subunit of interleukin (IL)-12 and -23, was demonstrated to exhibit efficacy in inducing remission in CD. In clinical trials, IV ustekinumab provided higher rates of clinical response and remission among patients refractory to TNF antagonists (UNITI-1 trial) or conventional therapy (UNITI-2 trial) compared with placebo. At week 6, patients receiving IV ustekinumab at a dose of 130 mg or 6 mg/kg exhibited significantly higher response rates compared with patients in the placebo group (UNITI-1: 34.3% and 33.7% with ustekinumab vs. 21.5% with placebo, P≤0.003; UNITI-2: 51.7% and 55.5% with ustekinumab vs. 28.7% with placebo, P<0.001) [110]. Vedolizumab, a humanized IgG1 monoclonal antibody targeting α4β7 integrin, demonstrated effectiveness in patients with moderate-to-severe active CD [111]. In the GEMINI 2 clinical trial, patients with CD who were treated with vedolizumab achieved a clinical remission rate of 14.5% compared with 6.8% in those receiving placebo at week 6 after 2 doses administered at week 0 and 2 (P=0.02).

Recently, both risankizumab and upadacitinib have demonstrated efficacy for moderate-to-severe active CD. Risankizumab, an inhibitor of the p19 subunit of IL-23, has demonstrated effectiveness and safety as CD treatment in 2 clinical trials: ADVANCE involving patients with CD who had failed to respond to biologics or conventional treatment and MOTIVATE involving patients with CD who had failed to respond to biologic treatment. These trials revealed higher rates of remission at week 12 among patients receiving 600 mg (ADVANCE: 45%; MOTIVATE: 42%) and 1,200 mg (ADVANCE: 42%; MOTIVATE: 40%) of risankizumab compared with those in the placebo group (ADVANCE: 25%; MOTIVATE: 19%), with statistically significant differences [112]. Promising results have also been found for upadacitinib, an oral inhibitor of JAK1, in 2 recent phase 3 clinical trials: U-EXCEL and U-EXCEED. U-EXCEL enrolled patients with CD who had previously failed to respond to conventional or biologic therapies, and U-EXCEED enrolled patients with a history of biologic treatment failure. Treatment with 45 mg of upadacitinib for 12 weeks demonstrated superior induction of clinical remission, as measured using the CDAI, in both trials (U-EXCEL: 49.5% vs. 29.1%; U-EXCEED: 38.9% vs. 21.1% compared with placebo, P<0.001 for all comparisons) [113].

The concept of “early” biological treatment for CD lacked a clear definition until the “Paris Definition” was established through a consensus by IBD experts. According to this definition, early CD is defined by disease duration of < 18 months [114]. Early treatment encompasses early top-down or accelerated step-up therapy for moderate-to-severe CD and the early introduction of biologics within a short disease duration, typically less than 1 or 2 years [115]. Evidence from trials such as REACT [116] and CALM [117] suggests that early intervention or a treat-to-target approach may improve outcomes.

Patients with CD with poor clinical prognostic factors or high-risk indicators, such as perianal disease, upper gastrointestinal involvement, steroid use at diagnosis, ileocolonic disease, smoking, deep ulcers, and extensive ulcer distribution, may benefit from the early initiation of biologic treatment for mitigating adverse events and complications [95,118]. A recent systemic review and meta-analysis of 16 trials involving 6,168 CD patients revealed a higher remission rate in patients with shorter disease durations [119]. Evidence from meta-analyses, prospective clinical trials, and real-world data support that the early initiation of biologic therapy improves clinical outcomes in adult and pediatric CD patients [115,120]. Moreover, the early use of biologics is evidence to reduce healthcare costs [121]. “Top-down” therapy for CD was firstly proposed by D’Haens et al. in 2008 [122], compared an infliximab plus immunosuppression group (without steroids) and a conventional treatment group (conventional step-up with steroids). The trial demonstrated “top-down” therapy with the combination of infliximab with immunosuppression was more effective than conventional step-up management for induction of remission and reduction of corticosteroid use in patients who had been recently diagnosed with CD [122]. A recent multicenter PROFILE study in a CD cohort with all patients had been treated with steroids before the enrollment [123]. Since all subjects had been treated with corticosteroid, the “top-down” and “accelerated step-up” group actually reflect the “accelerated step-up” and “conventional step-up” group according to the definition of D’Haens et al. in 2008 [122,123]. The PROFILE study demonstrated the benefit of “accelerated step-up” over “conventional step-up” in CD subjects, and the intervention by biologic should be initiated at the appropriate time (early stage of CD) through strict monitoring [123].

3) Maintenance

During the maintenance phase of CD treatment, immunosuppressives or biologics (either alone or in combination) are used to sustain remission, and they need to be tailored to meet personal needs. Steroids are ineffective for maintaining remission and can contribute to steroid dependence while increasing the risk of drug-related adverse events. A clinical trial demonstrated that patients with CD who received 6-MP or MTX achieved significantly higher remission maintenance rates than those who received 5-ASA (P<0.001) [124]. Notably, the median time to respond to AZA treatment is 4.5 months, with some patients requiring up to 6 months to show a response [125], rendering therapeutic drug monitoring (TDM) within this period potentially unreliable. A systematic review of 5 clinical trials evaluating MTX and other interventions or placebo for CD remission maintenance concluded that intramuscular MTX at a dose of 15 mg per week is more effective than placebo [126]. Thus, thiopurines such as AZA, 6-MP, and MTX are effective in maintaining CD remission.

In the past decades, advanced therapies have gained prominence and are increasingly being used for maintenance therapy for CD patients. The first-line advanced therapy for CD remission maintenance is anti-TNFα agents. Numerous reviews and meta-analyses have consistently confirmed the efficacy of anti-TNFα agents, including infliximab, adalimumab, and certolizumab, as maintenance treatment [127,128]. In the GEMINI 2 study, patients who received vedolizumab were more likely to achieve clinical remission at 52 weeks than those who received placebo, the remission rates were 39.0% and 36.4% for patients receiving vedolizumab every 8 weeks and 4 weeks, respectively, compared with 21.6% in patients in the placebo group (P<0.001 and P=0.004) [111]. Moreover, in the long-term extension study (GEMINI LTS), patients who received vedolizumab every 4 weeks and followed up for up to 152 weeks exhibited a clinical remission rate of 74% [129]. Additionally, in the VISIBLE 2 trial, patients receiving subcutaneous vedolizumab as maintenance treatment following IV induction therapy exhibited significant clinical remission compared with those receiving placebo (48% for vedolizumab vs. 34.3% for placebo, P=0.008) at week 52 [130].

In the IM-UNITI trial, ustekinumab ensured the maintenance of clinical remission in patients who exhibited a clinical response at week 8 after receiving IV ustekinumab induction treatment [110,131]. At week 44, the remission rates were 53.1% and 48.8% for patients receiving injections every 8 weeks and every 12 weeks, respectively, compared with 35.9% in patients in the placebo group (P = 0.005 and P = 0.04, respectively). During the long-term follow-up period of up to 5 years, the remission rates were 54.9% and 45.2% for patients receiving injections every 8 weeks and every 12 weeks, respectively [132]. The effectiveness of risankizumab was demonstrated in the FORTIFY trial; patients who exhibited a clinical response to IV risankizumab in the ADVANCE or MOTIVATE induction studies were enrolled into a maintenance study and received subcutaneous risankizumab or placebo. The CDAI clinical remission rates were 55% and 52% for patients receiving 180 and 360 mg of risankizumab, respectively, compared with 41% for those receiving a placebo (P=0.003 for 180 mg and P=0.005 for 360 mg compared with placebo). Subcutaneous risankizumab was demonstrated to be effective in maintaining remission [133]. As the treat-to-target concept becomes increasingly implemented for disease monitoring and with a growing emphasis on the tight control of IBD activity, TDM for biologics is a crucial aspect of precision medicine. Reactive TDM algorithms have been proposed, and emerging evidence supports the clinical application of a proactive TDM strategy for prolonging the effectiveness of biologics and improving clinical outcomes, particularly in pediatric patients [134].

In the maintenance trial of upadacitinib (U-ENDURE), a higher percentage of patients receiving either 15 mg (37.3%) or 30 mg (47.6%) of upadacitinib achieved clinical remission compared with those receiving placebo (15.1%). Additionally, a higher percentage of patients receiving either 15 mg (27.6%) or 30 mg of upadacitinib (40.1%) demonstrated an endoscopic response compared with those receiving compared with those receiving placebo (7.3%; P<0.001 for all comparisons) [113].

In the SONIC trial, the combination therapy of infliximab and thiopurine was more effective than monotherapy with either infliximab or thiopurine. At week 26, the rate of steroid-free clinical remission was 56.8% in the combination group compared with 44.4% in the infliximab alone group (P=0.02) and 30% in the AZA alone group (P<0.001) [108]. In the DIAMOND trial, adalimumab monotherapy and combination therapy exhibited comparable efficacy at week 26, with clinical remission rates of 68.1% and 71.8%, respectively (P=0.63). However, the combination group exhibited greater endoscopic improvement at week 26 (84.2% vs. 63.8%, P=0.019).

The AGA technical review for the medical management of moderate-to-severe CD [135] suggested that combination therapy with adalimumab and thiopurines may be superior to adalimumab monotherapy for mediating and sustaining remission. However, this conclusion has very low certainty of evidence due to the risk of bias in the DIAMOND trial (open-label study and a very high rate of discontinuation due to treatment intolerance). The advantages of the combination of vedolizumab or ustekinumab with thiopurines or MTX over biologic monotherapy for remission induction and maintenance remain uncertain. This uncertainty is attributed to the lower immunogenicity relative to anti-TNFα therapies.

The considerable financial burden and potential adverse effects of therapy prompt patients in remission to consider drug de-escalation to reduce treatment intensity [136]. Because of the chronic nature of CD, the timing and approach to discontinuing combination therapy or monotherapy are of paramount importance. In a questionnaire survey, patients and physicians in the United States and Europe were found to tend to discontinue immunomodulatory more often than anti-TNFα or biologic therapy, which was driven by concerns regarding cancer risk from long-term radiation exposure and adverse effects [137]. Despite this, the standard practice still involves the continued administration of anti-TNFα therapy. However, for select patients with a low risk of recurrence, discontinuing anti-TNFα might be considered to mitigate costs and minimize side effects [138]. A meta-analysis of 27 studies that evaluated the relapse rate after the cessation of anti-TNFα therapy for CD revealed an overall risk of 44% for CD relapse (95% CI, 36%–51%; I²= 79%; 912 patients) [139]. Furthermore, another study revealed that 67% of patients with IBD who discontinued anti-TNFα therapy remained in clinical remission over the 12-month follow-up, 85% of whom exhibited sustained endoscopic remission [140]. Discontinuation of immunomodulators as monotherapy for CD led to relapse rates of approximately 30% within 2 years and 50%–75% within 5 years [141]. In a Taiwanese observational study involving 54 patients with CD, 59% experienced relapse within a year after discontinuing adalimumab treatment [142]. Additionally, in the VIOLET study in Taiwan, the relapse rates were 36.7% and 64.3% in patients with CD and 42.9% and 52.4% in patients with UC at 6 and 12 months after vedolizumab discontinuation, respectively [143].

In general, the discontinuation of advanced therapy is associated with a risk of relapse, indicating the importance of careful consideration before making such decisions. Unless due to reimbursement issues in Taiwan or other economic factors, determining de-escalation based on noneconomic factors should involve shared decision-making between patients and healthcare providers. Additionally, close monitoring after the de-escalation is strongly recommended for the prompt identification of any signs of disease relapse.

4) Other Treatment Considerations

For some patients with CD, surgical intervention is a primary treatment option. A randomized controlled, multicenter, open-label trial (LIR!C Trial) investigated laparoscopic ileocecal resection for CD affecting the terminal ileum ( < 40 cm of diseased bowel) in patients who did not respond to conventional therapy. The study revealed that laparoscopic ileocecal resection is cost-effective and leads to quality of life improvement. This approach is a viable alternative to infliximab therapy for ileocecal CD [144,145].

In 2018, the ECCO and the European Society of Coloproctology jointly released consensus guidelines regarding the surgical management of CD [146]. The guidelines outline a systematic approach to treating severe CD, addressing various clinical scenarios that necessitate emergency surgery, such as perforation, peritonitis, and massive hemorrhage, which occur in approximately 6%–16% of patients with CD. To ensure appropriate management, patients with severe active disease should be regularly monitored for clinical signs and should undergo blood tests and assessments of signs of systemic toxicity. Given the complexity of the disease, a single preoperative assessment for severe active CD may not suffice for determining the appropriate surgical intervention. Conducting repeated evaluations with a radiologist interpreting preoperative images and performing thorough examinations of postoperative specimens with the assistance of a pathologist are essential Additionally, perioperative nutrition support can contribute to improved surgical outcomes [90,91,147]. Adopting a multidisciplinary approach involving gastroenterologists, a colorectal surgeon, and other relevant specialists is crucial for enhancing the outcomes of patients with CD.

1) Pregnant and Breastfeeding Women

Preconception consultation is a crucial step for all women of reproductive age with CD. The most effective and safest methods of birth control are long-acting and reversible (e.g., a hormonal or nonhormonal intrauterine device or a contraceptive implant). Having a comprehensive understanding of the impact of CD on pregnancy and planning for pregnancy is crucial, not only during pregnancy but also shortly after CD diagnosis. This knowledge helps women with CD make informed decisions about family planning [3]. According to findings from the PIANO registry, the use of corticosteroids during pregnancy is associated with an increased risk of various adverse oucomes, including preterm birth, small-for-gestational-age infants, low birth weight, intrauterine growth restriction, and neonatal intensive care unit admission [194]. Moreover, corticosteroid use during the second or third trimester is associated with a higher risk of serious infections in infants before the age of 1 year. This indicates the importance of managing CD disease activity before and during pregnancy by using steroidsparing therapies [194].

Flare-ups in pregnant women should be managed in adherence to current treatment guidelines applicable to nonpregnant patients, including 5-ASA, corticosteroids, immunomodulators, and biologic agents [195]. For pregnant women with active disease, thiopurine monotherapy or the combination of thiopurine and biologics can be continued throughout pregnancy, with the monitoring of serum anti-TNFα levels to guide treatment decisions. Concerns about fetal exposure to biologics exist; however, the discontinuation of biologics may increase the risk of relapse in pregnant women [195]. Notably, the findings from the PIANO registry revealed that the discontinuation of biologics in the third trimester was not associated with higher relapse rates at 4, 9, and 12 months postpartum [196]. The decision to discontinue biologics should be based on individual needs and should be thoroughly discussed with patients [195]. If a medication is discontinued before the third trimester, it should be resumed promptly after childbirth [195]. In previous studies on rheumatic diseases, MTX has been reported to have embryotoxic potential and is associated with a high risk of miscarriage [197]. Because MTX is contraindicated in pregnancy, both women and men are advised to discontinue MTX use 3 months before attempting to conceive as well as to avoid its use during pregnancy and breastfeeding [197]. Similarly, cyclosporin, metronidazole, and ciprofloxacin are also not recommended for breastfeeding mothers [198]. However, mesalamine, 5-ASA agents, and biologics are generally well tolerated during breastfeeding and can be safely continued [199,200]. Animal reproduction studies have suggested that upadacitinib may pose risks to fetal development. Therefore, women of reproductive age are advised to use effective contraception during upadacitinib therapy and for 4 weeks after its completion. Whether upadacitinib is present in breast milk remains unknown. Due to the potential for serious adverse reactions in breastfeeding infants, breastfeeding is not recommended during upadacitinib treatment and for 6 days after the last upadacitinib dose [201].

The ECCO guidelines on reproductive medicine and pregnancy recommend delaying live vaccination, including rotavirus vaccination, for at least 6 months in infants following the maternal use of biologic therapy during pregnancy [202]. A previous study revealed that infants who developed fatal disseminated BCG infection after vaccination had detectable levels of infliximab for up to 1 year after antenatal exposure [195]. The European Medicines Agency recommends avoiding live-attenuated vaccines during the first year of life in infants exposed to infliximab. Furthermore, the AGA guidelines suggest refraining from administering live vaccines within the first 6 months of age if the mother was exposed to any biologic therapy other than certolizumab during the third trimester of pregnancy [203].

2) Pediatric Patients

Meta-analyses have increasingly supported EEN as the first-line induction regimen for children with active mild-to-moderate CD [204,205]. A cross-sectional survey of 85% of specialist IBD centers in the United Kingdom revealed that polymeric feeds were used as the first-line therapy in every center, and EEN was typically recommended for 6 weeks by 70% of these centers [206]. EEN offers numerous benefits to patients, including higher remission rates (up to 80%), avoidance of steroids, correction of malnutrition and micronutrient deficiencies, and promotion of adequate growth and improved quality of life. However, EEN has some disadvantages such as low palatability, a high risk of early withdrawal, high costs related to elemental diets, and potential adverse effects (mostly diarrhea and vomiting) [207]. The CDED, which combines a whole-food diet with PEN, was reported to be as effective as EEN for inducing remission at week 6, with superior tolerability (97.5% compared with 73.6% for EEN; P=0.002). Additionally, by week 12, a higher percentage of children treated with CDED plus PEN (75.6%) achieved corticosteroid-free remission compared with those treated with EEN alone (45.1%) and PEN alone (P=0.01; OR, 3.77; 95% CI, 1.34–10.59) [208].

Currently, the approved treatments for mediating remission in pediatric IBD patients include corticosteroids, EEN, CDED plus PEN, MTX, and anti-TNFα agents [209]. Corticosteroids are considered the first-line therapy for mediating remission in pediatric patients with moderate-to-severe active CD, but they are not typically used as maintenance therapy. A meta-analysis that compared the efficacy of EEN and corticosteroids did not reveal a significant difference in remission induction (OR, 1.35; 95% CI, 0.90–2.10; P=0.14). However, EEN was found to be superior to corticosteroids for achieving short-term improvement in mucosal inflammation and the reduction of PCDAI [210]. Immunomodulators are often included in the regimen for maintaining remission. The monitoring of growth curves is recommended.

3) Cancer Patients

Immunosuppressive treatment is associated with reduced rates of new or recurrent cancer in patients with IBD who have experienced significant inflammation for 3 or more years [211]. The use of biologics or anti-TNFα is not associated with cancer occurrence in patients with CD [212-215]. In patients with a history of cancer, including gastrointestinal, dermatologic, hematologic, and solid tumors, the risk of subsequent cancer did not differ between groups treated with vedolizumab or ustekinumab and groups without exposure to immunosuppressive agents [212]. Similarly, in patients with a prior nondigestive malignancy, the risk of incident cancer did not vary between groups with vedolizumab treatment and anti-TNFα therapy [213]. However, caution should be exercised when considering thiopurine and anti-TNFα therapy for patients with a history of NMSC [216-218]. The prolonged use of thiopurine (adjusted OR, 4.27; 95% CI, 3.08–5.92) or the persistent use of anti-TNFα therapy (adjusted OR, 2.18; 95% CI, 1.07–4.46) in patients with IBD is associated with a higher risk of NMSC development and recurrence [217]. Notably, evidence regarding the increased incidence of non-Hodgkin’s lymphoma resulting from thiopurine or anti-TNFα treatment has primarily been obtained in Caucasian populations, with limited data available for Asian populations. Therefore, the impact of differences in ethnicity should be considered in the assessment of incidence rates of malignancies in the future [219]. Comprehensive support from gastroenterologists and oncologists is crucial for managing patients with IBD having a history of cancer, and healthcare providers must be aware of the potential impact of immunosuppressants on cancer risk [216].

4) Elderly Populations

In contrast to patients diagnosed as having IBD at a younger age, those with onset in older age exhibit distinct disease characteristics, clinical presentations, natural history, and baseline immunosenescence [220]. Elderly patients with CD commonly present with rectal bleeding, whereas symptoms such as abdominal pain, fever, and weight loss are less prevalent in elderly patients than in younger patients who often have more involvement of the ileum [221]. Current evidence suggests that elderly patients are at a higher risk of adverse events due to the prolonged use of corticosteroids than younger adults [221]. Thiopurines should be prescribed for elderly patients with caution due to concerns regarding potential drug interactions, an elevated risk of lymphoma, NMSC, and serious infection [221]. Additionally, elderly patients with IBD often have a higher burden of comorbidities than younger adults, and effectively managing these comorbid conditions can mitigate the potential risks associated with IBD. Immunomodulatory treatments with a lower overall risk of infection or malignancy, such as anti-integrin, anti-IL-12/-23, or anti-IL-23 antibodies, may be more suitable for elderly patients [222,223].

1) Fistulas

Various treatment modalities are available for managing complex perianal fistulas in CD, including advancement flaps, ligation of the inter-sphincteric fistula tract, and fibrin glue, but their efficacy is limited. Complicated ano- and rectogenital fistulas related to CD warrant treatment by experienced multidisciplinary teams [95,245]. Although antibiotics are recommended for controlling perianal sepsis, evidence supporting antibiotic monotherapy for perianal fistula closure is lacking [95]. Patients with concurrent fistulas and abscesses are not recommended to undergo endoscopic balloon dilation due to the potential disruption of nearby fistula tracts or abscesses during the procedure [246]. Because moderate-to-severe fistulizing CD is rare and difficult to treat, an approach involving medical and surgical management should be considered [247]. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) have shown promising results for treating complex perianal fistulas in CD [248]. In a randomized placebo-controlled trial, 52-week treatment with Cx601 had long-term efficacy and safety in patients with CD [249]. Although the treatment options for patients with CD with complex perianal fistulas are limited, darvadstrocel, a novel minimally invasive therapy, is recommended in case of inadequate responses of fistulas to ≥ 1 conventional treatment or biologic therapy [250]. Additionally, the combination of surgical and medical therapy, such as anti-TNFα or immunomodulators, may yield more favorable outcomes for perianal fistula healing in patients with CD than surgery or medical therapy alone [251].

2) Stenosis

Strictures are common complications in CD and result from complex processes involving inflammation and fibrosis. Distinguishing between the levels of active inflammation and the extent of fibrosis within strictures by using current techniques is challenging. Currently, no reliable technique is available for the accurate determination of the extent of intestinal fibrosis in CD [32,252]. Cross-sectional imaging modalities such as IUS, CTE, and MRE are promising tools for the diagnosis of bowel strictures in patients with CD [253].

More than one-third of patients with CD exhibit a unique fibrostenosing phenotype, characterized by the progressive narrowing of the intestinal lumen due to fibrosis [141]. Although no specific treatment exists for fibrotic intestinal strictures, patients with CD are recommended to undergo assessments to determine the extent of the inflammatory component in the stricture [141]. Both cross-sectional imaging studies and biomarkers such as CRP, ESR, and fecal calprotectin can be used to assess the inflammation level [254]. Anti-inflammatory therapies, including corticosteroids; immunosuppressive medications, such as thiopurines and MTX; and biologic agents, may alleviate inflammatory lesions and other related symptoms. However, they cannot directly prevent or reverse substantial intestinal fibrosis and strictures [141]. In a clinical investigation, approximately 39% of patients with CD having stenosis who received anti-TNFα therapy underwent abdominal surgery in the subsequent year, with a surgery incidence rate of 1.8 per 1,000 person-months [255]. In a retrospective study of 262 patients with CD, infliximab (54%) or adalimumab (46%) treatment demonstrated effectiveness in 87% and 73% of patients, respectively, over 6 and 12 months; this finding highlights the advantages of early intervention with medication in terms of treatment success [256]. In a multicenter, prospective, observational study evaluating the efficacy of adalimumab in patients with CD and symptomatic small bowel strictures, almost two-thirds of the patients achieved treatment success by week 24 of adalimumab treatment. Furthermore, more than half of the patients remained surgery-free 4 years after treatment [257]. Moreover, combination therapy with anti-TNFα agents has been demonstrated to be effective in preventing therapeutic failure in patients with CD (HR, 0.17; 95% CI, 0.4–0.71; P=0.015) [258].

Endoscopic balloon dilation is the first-line therapy for short strictures (typically defined as those ≤ 5 cm) in patients with CD [254]. Strictureplasty and resection are also viable alternative treatment options [141,259]. A systematic review of 33 studies involving a total of 1,463 patients revealed that endoscopic dilation was technically successful in 90% of cases, with a subsequent possibility of re-dilation in 73.5% of cases and surgical intervention in 42.9% of cases within 24 months [259]. Moreover, strictures with a length of ≤ 5 cm were significantly associated with surgery-free outcomes (HR, 2.5; 95% CI, 1.4–4.4) [141]. Two prospective studies involving 95 and 35 patients with CD, respectively, demonstrated that endoscopic balloon dilatation conducted using balloon-assisted enteroscopy yielded technical success rates of > 90% [260,261]. Endoscopic dilation and strictureplasty are contraindicated for stenoses associated with abscesses, phlegmons, fistulas, high-grade dysplasia, and malignancy [141].

Patients with IBD and colonic strictures exhibit a higher risk of neoplasms due to the potential obstruction from strictures for colonoscopy screenings, which may hinder the early detection of colon cancer [262]. When endoscopic treatment is unfeasible or medical therapy fails or is contraindicated, resection is recommended [254]. Early surgical resection is suggested for patients with symptomatic strictures, ileocecal CD without signs of inflammation, or strictures > 5 cm in length [141,259,263]. Timely identification and isolation of localized ileocecal disease in high-risk patients at diagnosis can prevent complications, reduce clinical recurrence rates, and reduce remission durations compared with patients receiving prolonged medical treatment [141]. The rate of emergency surgery was 6.7% within 5 years of diagnosis and 8.8% within 15 years, with the overall risk of surgical recurrence being 35.9% [264]. Strictureplasty is a viable option for cases involving fibrotic strictures [265]. Resection of the affected bowel segment can render postoperative medical therapy more effective, thereby reducing the requirement for biologic therapy among patients with limited ileocecal CD [262,266].

3) Anemia and Micronutrient Deficiency

Patients with CD may present with various types of anemia caused by several conditions, including iron deficiency anemia (IDA), anemia of chronic disease, and micronutrient deficiency-associated anemia. Among these, IDA remains the predominant type in patients with IBD and can be differentiated from anemia of chronic disease based on the ferritin level of < 100 μg/L when CRP levels are elevated [267]. Platelet counts also serve as an indicator of disease severity in patients with CD. A univariate analysis revealed a positive correlation between the CD activity index and platelet count (P<0.001) [268]. In a cohort of 72,026 patients discharged from the index hospitalization for CD, 8.1% presented with IDA, with a prolonged hospital stay (4 days, interquartile range 2–6 days vs. 3 days, interquartile range 2–5 days; P<0.001) compared with those without IDA [269]. In a recent study in Taiwan, the identified risk factors for persistent anemia were low body mass index, corticosteroid usage, thiopurine usage, colectomy, and small bowel resection after IBD diagnosis [270]. Patients with IBD who were anemic exhibited higher rates of hospital admission (P<0.01) and mortality (P<0.01). IDA adversely affects quality of life by causing fatigue; reduced physical performance; dizziness; headaches; dyspnea upon exertion; and pallor of the skin, nails, and conjunctiva [267]. Persistent inflammation in the intestinal mucosa leads to blood loss from the gastrointestinal tract, malabsorption, and iron deficiency [271]. In addition to microcytic anemia caused by IDA, macrocytic anemia caused by vitamin B₁₂ and folate deficiencies is common in patients with CD, and it is associated with hematological and neurological abnormalities and a high risk of thrombosis [272]. Therefore, to treat anemia, appropriate dietary adjustments are recommended to rectify existing deficiencies, and iron and micronutrient supplementation should be provided when necessary.

Micronutrient and electrolyte deficiencies are vital concerns requiring careful monitoring post-surgery in patients with IBD. A study reported that 39.0% of patients with IBD and intestinal Behcet’s disease had deficiencies of micronutrients, with patients with CD constituting 83% of this deficiency group [273]. The prevalence of vitamin B₁₂ deficiency among patients with CD was reported to be 15.6% (95% CI, 9.7%–20%), with 22.2% (95% CI, 16%–28%) exhibiting folic acid deficiency. Notably, in all patients with anemia, resolution occurred following supplementation with vitamin B₁₂ or folic acid [272]. Ileal resection in patients with CD and bowel surgery in patients with IBD pose high risks for micronutrient deficiency, such as impaired absorption of vitamin B₁₂ and folic acid and reduced levels of vitamin D and ferritin. Close monitoring with adequate supplementation is essential to avoiding complications associated with micronutrient deficiencies.