Exabis Library

Eductational objectives:
To give an overview of pulmonary dysfunction / diseases which can occur in IBD patients.

Summary:
Subclinical pulmonary dysfunction occurs in up to 60% of IBD patients. The exact mechanism is unknown, but it has been suggested that the bowel inflammation may shift from the bowel to the lung perhaps because they are embryologically related and immunologically connected.
Respiratory diseases in IBD patients may fall under 4 categories:
1) Tracheobronchial involvement:  (tracheo)bronchitis, bronchiectasis, and bronchiolitis; fistulas in Crohn's disease
2) Interstitial lung disease with diverse radiological presentations as nodules, cavities, interstitial pneumonitis
3) Pleuritis, pneumothorax, pulmonary embolism
4) Drug-related pathology: as reported for 5-ASA agents, azathioprine and methotrexate. The widespread use of anti-TNF agents has lead to increased reports of pulmonary infections (tuberculosis and others), and possibly metastatic tumors. Diffuse alveolar damage after infliximab infusion has also been described.
 

Some examples of applying GRADE on clinical questions will be provided, based on our experience with the ECCO Ulcerative Colitis guidelines.

Th17 cells and their main secreting cytokine interleukin-17A (IL-17) are considered as the main pathogenic factors in inflammatory bowel diseases (IBDs). However, anti-IL-17 neutralizing antibodies, a theoretically curative medication for IBDs, paradoxically aggravated intestinal inflammation. The mechanisms by which it mediates the protective and pathologic effects of IL-17 remain unclear in the intestinal epithelium.

The intestinal epithelial responses induced by IL-17 was evaluated using the human small intestinal organoid (enteroid) model.

Organoid-forming efficiency, cell viability and proliferation of enteroids were decreased in proportion to the concentration of IL-17, which did not differ between the enteroids derived from controls and patients with Crohn’s disease. Bulk RNA-sequencing revealed the enrichment of secretion signaling in IL17-treated enteroids. Among its components, PIGR was up-regulated significantly as the concentration of IL-17 increased, resulting in IgA transcytosis and protective role against pathogens. The IL-17-induced cytotoxicity was predominantly mediated by pyroptosis with activation of CASP1 and cleavage of GSDMD. Single-cell RNA- sequencing identified pyroptosis occurred actively in intestinal stem cells (ISCs) and enterocytes. Anti-IL-17 antibody, izekizumab, completely restored IL-17-induced cytotoxicity, but suppressed mucin secretion and IgA transcytosis. CASP1 inhibitor, Ac-YVAD-cmk, restores cytotoxicity induced by IL-17, without impairing its beneficial effects.

IL-17 induces pyroptosis of ISCs and enterocytes, as well as mucin secretion and PIGR-induced IgA transcytosis. Paradoxical gastrointestinal effects of IL-17 neutralizing antibodies may be associated with inhibition of mucin secretion and IgA transcytosis. The inhibition of pyroptosis using the CASP1 inhibitor prevents the cytotoxicity induced by IL-17 without compromising its beneficial effects.

Diagnosis and monitoring of Crohn’s disease (CD) incorporates laboratory parameters and both endoscopic and radiological assessments. Cross-sectional imaging (computed tomography and magnetic resonance enterography [CTE/MRE]), has shown high diagnostic accuracy for detecting small bowel and colonic CD, and provides complementary findings to ileocolonoscopy. Quantitative measurements wall thickness, contrast enhancement, T2 hyperintensity, and direct identification of ulcerative lesions have demonstrated correlation with ileoscopic and histological findings of inflammation. Wall thickening and on MRE correlate with histological findings of inflammation. Following medical treatment, radiological remission [or transmural normalization] by MRE or CTE parallels endoscopic healing with an estimated accuracy of 90%. Additional studies have also shown that the radiological response of inflamed bowel segments to medical therapy is associated with improved long-term outcomes, including reductions in future hospitalization rates or requirement for surgery. Furthermore, cross-sectional abnormalities may exist even in the presence of normal endoscopic examination of the terminal ileum, and even in the absence of histological findings of active inflammation. In these circumstances, patients with normal endoscopy and histology but with persistent cross-sectional imaging alterations face a worse prognosis in terms of relapse, surgery requirements and hospitalizations. Therefore, cross-sectional imaging should be integrated in the definition of complete remission in association with endoscopy and histology.
In a different setting, CT and MRE has demonstrated a high diagnostic accuracy to detect strictures and penetrating complications such as fistulas and abscesses and have a high impact on patient management. Beyond the standard definition of stricture by CTE or MRE, another relevant aspect is the identification and quantification of fibrosis by imaging biomarkers. The proportion of patients developing intestinal strictures increases over the years after a diagnosis of CD and represents the main cause of damage progression and surgery in that group of patients. Different strategies based on MRE have been studied with the aim to detect and quantify the degree of fibrosis deposition, including diffusion-weighted imaging (DWI), magnetization transfer and delayed enhancement. However, recent data from a multicentric study suggests that only DWI shows a good correlation with the fibrosis in the bowel but also with inflammation. Thus, the contribution of additional imaging biomarkers such as the amount of creeping fat or modern stiffness quantification by MR elastography deserves further attention.

Ozanimod, a sphingosine 1-phosphate (S1P) receptor modulator selectively targeting S1P₁ and S1P₅, is approved in the US for the treatment of moderately to severely active ulcerative colitis (UC). In the pivotal phase 3 True North randomised controlled trial in moderate-to-severe UC, significantly more patients (pts) achieved clinical response and remission with ozanimod vs placebo (PBO) at week (wk) 10 of the induction period. Here, we report the rapidity of ozanimod-induced symptomatic response and remission in pts from True North (NCT02435992).

In True North, pts were randomised to once-daily ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or PBO (Cohort 1) or received open-label ozanimod (Cohort 2) during induction. This analysis evaluated symptomatic response (defined as ≥1 point and ≥30% decrease from baseline in adapted partial Mayo score and ≥1 point decrease from baseline in rectal bleeding score [RBS] or absolute RBS ≤1) and symptomatic remission (defined as RBS of 0 and stool frequency score [SFS] ≤1 point and ≥1 point decrease from baseline at each study visit from wk 2 through 10.

During induction, 645 pts were randomised to ozanimod (n=429) or PBO (n=216) in Cohort 1, and 367 pts received open-label ozanimod in Cohort 2. Baseline demographics and clinical characteristics were well balanced across groups. Differences in symptomatic response were observed between ozanimod and PBO recipients in Cohort 1 as early as 2 wk after ozanimod initiation (1 wk post-titration) for the overall population (36.1% vs 26.4%; difference: 9.6% [95% CI, 2.1–17.0]; Figure 1) and tumour necrosis factor inhibitor (TNFi)-naïve pts (38.5%, n=301 vs 29.1%, n=151; difference: 9.4% [95% CI, 0.2–18.5]), and as early as 4 wk for TNFi-exposed pts (42.2%, n=128 vs 27.7%, n=65; difference: 15.8% [95% CI, 1.8–29.8]). Differences in symptomatic remission were observed between ozanimod and PBO recipients in Cohort 1 as early as 5 wk after ozanimod initiation (4 wk post-titration) for the overall population (26.3% vs 16.7%; difference: 8.6% [95% CI, 1.8–15.4] Figure 2), as early as 4 wk for TNFi-naïve pts (27.2% vs 17.9%; difference: 9.4% [95% CI, 1.5–17.4]), and as early as 8 wk for TNFi-exposed pts (22.7% vs 12.3%; difference: 11.7% [95% CI, 1.3–22.1]). Rates of symptomatic response and remission in pts receiving open-label ozanimod (Cohort 2) were similar to those in pts receiving randomised ozanimod (Cohort 1).

In the overall population, ozanimod was associated with higher rates of symptomatic response and remission vs PBO as early as 2 and 5 wk, respectively, after treatment initiation. Both clinical endpoints were more rapidly achieved in TNFi-naïve vs TNFi-exposed pts.

Subcutaneous (SC) formulation of vedolizumab (VDZ) is available for Crohn’s disease (CD) and ulcerative colitis (UC). We assessed the efficacy, safety, and pharmacokinetic (PK) profiles of patients with inflammatory bowel diseases (IBD) who switched from intravenous (IV) to SC VDZ treatment in two prospective, real world cohorts.

The primary cohort is an ongoing open-label, real life, prospective single centre cohort study. As a validation cohort, we used the Initiative on Crohn and Colitis (ICC) registry, a prospective, observational, nationwide registry including patients switching from IV to SC VDZ. In both cohorts, patients receiving IV VDZ maintenance for >4 months were offered to switch treatment to SC VDZ, 108 mg every 2 weeks. In the primary cohort, assessment of clinical, biochemical and PK parameters took place at baseline, at approximately 10 weeks following the switch and at the physician’s discretion thereafter. In the ICC cohort, follow up visits were at week 12 and 24. The primary endpoint was the proportion of patients discontinuing SC VDZ at week 24.

In total, 78 (50 CD (64%) and 28 UC (36%)) and 54 patients (29 CD (54%) and 25 UC (46%)) were included in the primary and ICC cohort respectively (table 1). During follow up, 8 (10.3%) of the primary cohort and 6 (11.1%) patients of the ICC cohort stopped VDZ SC during follow-up time till week 24, after a median treatment duration of 18 (IQR=5-19) and 10 (IQR=7-15) weeks, respectively.  Treatment withdrawal was most often caused by adverse events (AE), in total for 8 out of 132 patients (6%) (table 2). Four patients had loss of response to SC VDZ. Three of these patients had biochemical disease activity at initiation of SC therapy. Reported AEs included headache and injection related reactions. The median VDZ concentration increased from 11 ug/mL (IQR=9.4-20) to 28 ug/mL (IQR=24.3-31.2, p<0.0001) and from 20 ug/mL (14.3-26.3) to 34.6 ug/mL (26.8-42.9) (p<0.01), between baseline and visit 1 in the primary and validation cohort, respectively (figure 1).

The present abstract reports real world experience of switching IV to SC VDZ maintenance treatment in IBD patients in two observational Dutch cohorts. VDZ concentrations were significantly higher after the switch to SC VDZ. A switch from IV to SC VDZ appears to be effective and safe. However, a proportion of patients switched back to IV VDZ due to injection related AEs.

Several therapeutic options are now available in ulcerative colitis after anti-TNF failure, but no data compared hitherto tofacitinib and vedolizumab.

We compared the effectiveness of tofacitinib and vedolizumab in UC patients with prior exposure ≥ 1 anti-TNF.

In this multicentre retrospective study, we consecutively included all adult UC patients with partial Mayo score > 2, with ≥ 1 prior anti-TNF agent and started either tofacitinib (10mg b.i.d ± decreased to 5 mg b.i.d from week 8 (W8)) or vedolizumab (300 mg IV at W0-W2-W6 -W14 [± additional W10]) between January 2019 and June 2021.

The primary endpoint was corticosteroid-free clinical remission or CFREM (partial Mayo score ≤ 2) at W16. Secondary endpoints were endoscopic improvement (CFREM + endoscopic Mayo score ≤ 1) and mucosal healing (CFREM + endoscopic and histological remission defined as Nancy index ≤ 1).

All the comparisons were performed using propensity score analyses (inverse probability of treatment weighting) adjusted on gender, smoking, UC duration and extent, number of prior biologics or prior primary failure to biologics, concomitant 5-ASA, steroids or immunosuppressive agents, and disease severity.

Overall, 400 patients will be included. Among the 200 first patients, 87 and 112 received tofacitinib and vedolizumab, respectively (one missing patient). Except for more pancolitis (54.0% vs 38.4%, p=0.028), less immunosuppressive therapies (4.6% vs 27.7%, p < 0.001), and higher rate of prior exposure ≥ 2 biologics (87.4% vs 37.5%, p < 0.001) in tofacitinib arm, baseline characteristics were similar across the two groups including concomitant 5-ASA (10.3% vs 18.8%) and steroids (23.0% vs 31.2%). Vedolizumab infusion at W10 was performed in 34.3% while 42.5% received tofacitinib 10 mg b.i.d until W16.

CFREM was achieved in 54.2% and 42.5% in tofacitinib and vedolizumab, respectively p=0.089). The rate of CFREM at W16 was 57.4% vs 51.1% (p=0.77) after one biologic, 55.4% vs 41.8% (p=0.61) after 2 biologics, 56.9% vs 6.3% (p=0.007) after at least 3 biologics, and 59.0% vs 33.3% (p=0.17) in the subgroup with partial Mayo score ≥ 6, in tofacitinib and vedolizumab groups, respectively.

Tofacitinib was more effective than vedolizumab to achieve CFREM at W16 in patients with primary failure to at least biologic (71.6% vs 30.8%, p=0.049).

Among 177 patients, endoscopic improvement was higher in patients treated with tofacitinib (33.6 % vs 7.1%, p=0.048). Mucosal healing was observed in 6.4% vs 3.8% in tofacitinib and vedolizumab arms, respectively (p=0.27).

Tofacitinib and vedolizumab are effective after failure to anti-TNF agents. Tofacitinib seems to be more effective in case of primary failure to biologics and multiple therapeutic failure.

Educational objectives

1) Understand the management of rectovaginal fistulas in CD

to discuss the reasons for pouch dysfunction and failure
to explore the results of salvage surgery for the ileooanal pouch

Surgery is highly effective in treating Crohn’s disease, but is not curative, and up to half of the patients would suffer from surgical recurrence, and will require additional surgery. Redo surgery for Crohn’s is challenging, and may include cases who already had multiple surgeries, potentially with intraperitoneal mesh ventral hernia repairs, and imminent short bowel, and this is where sound surgical judgment, combined with superb technical skills are required.

Laparoscopy is a valid option for redo cases. However, even in experienced laparoscopic teams, approximately ¼ to 1/3 of the redo Crohn’s cases are being converted. Convertion should be pre-emptive, before complication occurs, instead of converting because an intraoperative complication has already been occurred.

In redo case, the length of the bowel becomes a prominent issue, and the surgeon should be as bowel preserving as possible on one hand, yet effective to induce remission on the other. Strictureplasty should be considered whenever possible.  Side-to-side isoperistaltic strictureplasty results in 37% surgical recurrence in a mean follow-up of 11 years, 1/3 of them were amenable for a second strictureplasty. In Strictureplasty over the ileocecal valve,  14% required additional surgery.

If strictureplasty is not feasible, and resection is mandatory, the common belief is that a large side-to-side anastomosis is associated with better long-term patency. However, The Kono-S anastomosis, preserving the mesentery, has been recently assessed in the SuPREMe-CD trial. At 18 months follow-up, endoscopic recurrence was found in only 25% of the Kono-S patients, compared to 67% in the conventional anastomosis group. This was translated to a significantly lower rate of surgical recurrence in 2 years. On the other hand, Coffey suggested that radical mesenteric resection was associated with significantly lower rate of surgical recurrence compared to historical control. Redo Crohn’s surgery requires experience and expertise, and should be done by dedicated and experienced IBD surgeons.

1. To understand the challenges of redo surgery for Crohn's disease 
2. To review the use of laparoscopy for redo surgery for Crohn's disease 
3. To discuss bowel length preserving techniques in surgery for Crohn's disease 
4. To discuss the long term results of different types of anastomosis for  surgery for Crohn's disease