Previous Exposure to Advanced Therapies in Acute Severe Ulcerative Colitis: A New Risk Factor for Colectomy?

Inflammatory Bowel Disease Clinical

The efficacy of infliximab has been demonstrated in patients with both acute severe and moderate-severe ulcerative colitis (UC). However, there is a need for 'real-life data' to ensure that conclusions from trial settings are applicable in usual care. We therefore examined the national experience of anti-tumour necrosis factor-α (TNF-α) therapy in UC. Case notes review of patients with UC who had received compassionate access (CA) anti-TNF-α therapy from prospectively maintained inflammatory bowel disease databases of six Australian adult teaching hospitals. Patients either received drug for acute severe UC (ASUC) failing steroids (n = 29) or for medically refractory UC (MRUC) (n = 35). In ASUC, the treating physicians judged that anti-TNF-α therapy was successful in 20/29 patients (69%); in these cases, anti-TNF-α was able to be discontinued (after 1-3 infusions in 19/20 responders) as clinical remission was achieved. Consistent with this perceived benefit, only 7/29 (24%) subsequently underwent colectomy during a median follow up of 12 months (interquartile range (IQR) 5-16). Eight of the 35 patients with MRUC (23%) required colectomy during a median follow up of 28 months (IQR 11-43). The majority of these patients (20/35 or 57%) had anti-TNF-α therapy for ≥4 months, whereas, 27/29 (93%) of ASUC patients had CA for ≤3 months. These data show an excellent overall benefit for anti-TNF-α therapy in both ASUC and MRUC. In particular, only short-duration anti-TNF-α was required in ASUC. These real-life data thus support the clinical trial data and should lead to broader use of this therapy in UC.

Background Response to therapy in acute severe ulcerative colitis (ASUC) is highly variable ranging from steroid response to salvage therapy failure and emergency colectomy. Biomarkers that accurately predict outcomes in ASUC early in the admission may help improve its management. We aimed to ascertain whether peripheral serum cytokine levels on admission correlate with refractoriness to medical therapy. Methods Peripheral blood was collected from 34 subjects, including 29 patients with ASUC on admission (baseline) and 5 healthy controls. All patients with ASUC received intravenous steroids, with those refractory to steroids going on to receive infliximab (IFX) salvage. Eight cytokines were measured at baseline using a multiplexed cytokine assay (Bio-Rad). Clinical response to steroids and/or to the first IFX dose was assessed and used to classify patients based on increasing order of disease refractoriness (steroid-responders, IFX-responders and IFX non-responders). These groups were then evaluated to check for correlations with baseline cytokine levels. Results Our cohort consisted of steroid responders (n=9), IFX responders (n=12) and IFX non-responders (n=8). Median serum IL-6 level was 1.6 pg/mL (IQR:1.6-2.1) in healthy controls compared to 2.7 pg/mL (IQR:1.4-6.3) in ASUC (p=0.3). In patients with ASUC, there was a positive correlation between IL-6 and treatment refractoriness (Spearman’s correlation [rs]=0.56, p=0.002). Compared with steroid responders (1.36 pg/mL), serum IL-6 was significantly higher in both IFX responders and IFX non-responders (3.44 and 5.50 pg/mL, p=0.02 and p=0.009 respectively) (Fig 1). Patients with ASUC had higher serum IL-8 compared to healthy controls (17.8 vs 6.9 pg/mL, p=0.005). There was no correlation between IL-8 levels and ASUC treatment refractoriness (rs=0.22, p=0.3). Similarly, there was no difference in IL-8 levels in ASUC patients when classified by treatment response (Kruskal Wallis, p=0.5). Serum TNF level did not differ between healthy controls and patients with ASUC (19.5 and 22.2pg/mL, p=0.5). TNF levels did not correlate with treatment refractoriness in ASUC (rs=-0.06, p=0.75) and there were no differences between the ASUC response groups (p=0.6). Levels of GM-CSF, IFN-g, IL-2, IL-4 and IL-10 were predominantly below the detection limit of each assay. Conclusion In this ASUC cohort, serum IL-6 level on admission correlated with treatment refractoriness and may help identify patients at higher risk of requiring salvage therapy as well as those at higher risk of failing IFX. Further studies are needed to elucidate the function of IL-6 in ASUC and whether it may represent a potential predictor of outcomes in ASUC.

Infliximab is an effective salvage therapy in acute severe ulcerative colitis; however, the optimal dosing strategy is unknown. We performed a systematic review and meta-analysis to examine the impact of infliximab dosage and intensification on colectomy-free survival in acute severe ulcerative colitis. Studies reporting outcomes of hospitalized steroid-refractory acute severe ulcerative colitis treated with infliximab salvage were identified. Infliximab use was categorized by dose, dose number, and schedule. The primary outcome was colectomy-free survival at 3 months. Pooled proportions and odds ratios with 95% confidence intervals were reported. Forty-one cohorts (n = 2158 cases) were included. Overall colectomy-free survival with infliximab salvage was 79.7% (95% confidence interval [CI], 75.48% to 83.6%) at 3 months and 69.8% (95% CI, 65.7% to 73.7%) at 12 months. Colectomy-free survival at 3 months was superior with 5-mg/kg multiple (≥2) doses compared with single-dose induction (odds ratio [OR], 4.24; 95% CI, 2.44 to 7.36; P < 0.001). However, dose intensification with either high-dose or accelerated strategies was not significantly different to 5-mg/kg standard induction at 3 months (OR, 0.70; 95% CI, 0.39 to 1.27; P = 0.24) despite being utilized in patients with a significantly higher mean C-reactive protein and lower albumin levels. In acute severe ulcerative colitis, multiple 5-mg/kg infliximab doses are superior to single-dose salvage. Dose-intensified induction outcomes were not significantly different compared to standard induction and were more often used in patients with increased disease severity, which may have confounded the results. This meta-analysis highlights the marked variability in the management of infliximab salvage therapy and the need for further studies to determine the optimal dose strategy.

Anti-tumour necrosis factor (TNF) agents are used as induction and maintenance therapy in ulcerative colitis (UC) refractory to standard therapy and as rescue therapy in acute severe UC (ASUC). To determine long-term outcomes including colectomy rates, predictors of maintenance of response and remission, risk of serious adverse events by reviewing 12-year clinical experience from a single centre in Australia. Seventy-one patients with moderate-severe UC (Mayo score ≥6) (n = 52) and ASUC (n = 19) treated with anti-TNF agents were included. Primary end-points were colectomy at 12 weeks and colectomy-free survival at last follow up. Secondary endpoints included clinical response (decrease in Mayo score of ≥3) and remission (Mayo score ≤2). Colectomy at 12 weeks was 1%, and colectomy-free survival was 69%. Using full Mayo score, at 3 months, 32/37 (87%) refractory and 9/12 (75%) ASUC patients responded to anti-TNF therapy; 19/37 (51%) refractory and 8/12 (67%) ASUC patients were in remission. Long-term response rates (mean follow up 37.4 months) were 24/44 (55%) and 11/15 (73%) in refractory and ASUC groups respectively. Long-term remission rates were 43% in refractory and 60% in ASUC patients. Twenty two of 71 (31%) underwent colectomy (mean time 50.4 months). Clinical non-response at 3 months was a predictor of colectomy (hazard ratio = 9.346; P = 0.001). ASUC predicted long-term maintenance of response (odds ratio 19.4; P = 0.013) and remission (odds ratio 6.13; P = 0.037). Two of 71 patients had serious infections. Anti-TNF therapy is effective in both refractory and ASUC. We argue that early anti-TNF therapy may improve outcome in UC.

Infliximab rescue therapy is effective in patients with corticosteroid refractory acute severe ulcerative colitis, but predictors of response remain poorly understood. We aimed to identify predictors of colectomy in this high-risk patient population. Patients hospitalized with acute severe ulcerative colitis who received infliximab after failing intravenous corticosteroid therapy between July 2012 and June 2017 were retrospectively identified. Stepwise regression with backward elimination was used to identify predictors of colectomy at 90days and 1year. Ninety-day and 1-year colectomy rates were compared between the patients who received 5mg/kg and 10mg/kg IFX rescue dose. Sixty-three patients met the eligibility criteria. Twenty-nine patients received 5mg/kg, and 34 received 10mg/kg infliximab dose. Serum albumin on admission (OR 0.10; p = 0.04) and band neutrophil percentage at the time of infliximab administration (OR 1.21; p = 0.02) were independent predictors of 90-day colectomy. A combination of serum albumin ≤ 2.5g/dl and band neutrophil count ≥ 13% had a 100% positive predictive value for 90-day colectomy. Unadjusted 90-day and 1-year colectomy rates were similar in the 5mg/kg and 10mg/kg infliximab groups. After adjusting for confounding factors, 10mg/kg infliximab dose was potentially protective for 90-day (OR 0.07; p = 0.06) but not for 1-year colectomy (OR 0.19; p = 0.16). Bandemia and low serum albumin are independent predictors of failure of infliximab rescue therapy in acute severe ulcerative colitis. Serum albumin ≤ 2.5g/dl and band neutrophil count ≥ 13% had a 100% positive predictive value for 90-day colectomy.

The options for medical management of acute severe steroid-refractory ulcerative colitis (UC) are limited. Recent guidelines caution against use of sequential rescue therapy in the setting of failed medical management with an initial salvage therapy. A systematic review was conducted to assess the outcomes of sequential rescue therapy with infliximab (IFX) and calcineurin inhibitors like cyclosporine (CsA) or tacrolimus (Tac) in patients with steroid refractory UC. A literature search identified studies that investigated treatment with IFX and CsA or Tac in acute severe UC. The primary outcome was short term symptomatic response to treatment. Secondary outcomes included adverse drug reactions, serious infections, mortality, rates of remission, and colectomy at 3 months and 12 months. Response rates with 95% confidence intervals (CI) are reported. Overall, 10 studies with 314 participants were eligible for inclusion. After sequential treatment patients achieved short-term treatment response in 62.4% (95% CI, 57.0%–67.8%) of cases and remission in 38.9% (95% CI, 33.5%–44.3%). Colectomy was required in 28.3% (95% CI, 21.7%–34.5%) of patients at 3 months and 42.3% (95% CI 36.0–48.6) at 12 months. Adverse events were encountered by 23.0% (95% CI, 17.7%–28.3%) of patients, including serious infections in 6.7% (95% CI, 3.6%–9.8%) and mortality in 1% (95% CI, 0%–2.1%). Our data summarizing experience from observational studies suggest that the risk-benefit ratio of sequential rescue therapy in acute severe UC seems acceptable. In the setting of failure of corticosteroids and an initial rescue therapy for acute severe UC, consideration can be given to use of another salvage agent based on patient preferences and the safety of this experience from observational data. The sequence of IFX followed by calcineurin inhibitors, or vice versa, have similar treatment outcomes and adverse events. Precautions to minimize the risk of adverse events, including early assessment of treatment response, use of serum drug levels to guide initiation of therapy, and early weaning of concurrent corticosteroids is recommended.

Background Steroid exposure has been associated with poorer outcomes following colectomy in acute severe ulcerative colitis. Current treatment algorithms suggest three days of high dose intravenous steroid before the decision to commence rescue therapy. We aimed to look at medium-term outcomes in acute severe ulcerative colitis and their predictors including steroid exposure prior to admission. Methods A retrospective case note and electronic record review were conducted at a tertiary inflammatory bowel disease referral centre of admissions for acute severe ulcerative colitis meeting Truelove and Witts criteria from 2013 to 2019. Identified admissions were categorised as: not on steroid prior to admission or on steroid for less than one week prior to admission, on steroid for over one week prior to admission, and on steroid for over one month prior to admission. Data were analysed using Chi-squared test and Fisher’s exact test as appropriate. Results In total, 109 admissions were identified for acute severe ulcerative colitis meeting Truelove and Witts criteria over 2013 to 2019. Rescue therapy was significantly more likely in patients with over one week of steroid exposure prior to admission (76.0% vs. 28.5%, p = 0.0001). Prior steroid exposure was not associated with failure of medical rescue therapy (p = 0.42). Patients with steroid exposure for at least one week prior to admission trended towards increased likelihood to undergo colectomy during admission (32.0% vs. 16.6%, p = 0.0.09) and were significantly more likely to undergo colectomy within one year of admission (44.0% vs. 21.4%, p = 0.028). Excluding patients with a first presentation of inflammatory bowel disease showed that patients with steroid exposure for at least one week prior to admission trended towards significance to undergo colectomy during admission (32.0% vs. 13.2%, p = 0.05) and were significantly more likely to undergo colectomy within one year of admission (44.0% vs. 20.7%, p = 0.036). Readmissions within one year of acute severe ulcerative colitis admission were not significantly different (40.0% vs. 29.7%, p = 0.33). Conclusion Prolonged steroid exposure prior to admission was associated with an increased likelihood of rescue therapy but was not predictive of response to medical rescue therapy. Colectomy rates at one year were significantly higher with over one week of steroid exposure prior to admission. Consideration should be given to early commencement of rescue therapy in those with prolonged steroid exposure prior to admission.

Introduction: Acute severe ulcerative colitis (ASUC) represents a medical emergency associated with high mortality and morbidity. While corticosteroids are the primary treatment, cases that are unresponsive often require rescue therapy with either infliximab or cyclosporine to reduce the rate of colectomy. Janus kinase inhibitors, such as tofacitinib and upadacitinib, are a highly efficacious therapy with rapid induction of clinical response in moderate to severe ulcerative colitis (UC). Limited data are available on its use on ASUC. We present the first case utilizing upadacitinib as sequential medical rescue therapy in ASUC as well as intestinal ultrasound as a useful tool for disease and response monitoring. Case Presentation: A 69-year-old female who presented with corticosteroid-refractory ASUC partially responded to dose-intensified infliximab and finally achieved clinical remission with upadacitinib. This resulted in swift clinical remission and significant improvement in her mucosal inflammation on intestinal ultrasound. Conclusion: This successful intervention not only avoided colectomy but demonstrated sustained clinical and sonographic remission 16 weeks of post-treatment. Upadacitinib, with its rapid action and efficacy, shows promise in ASUC and should be supported by registration trials and real-world studies. Despite successful outcomes in this case, further validation and long-term data are necessary.

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The standard therapy for acute severe ulcerative colitis (ASUC) is intravenous corticosteroids; however, 30% of ulcerative colitis (UC) patients do not recover with corticosteroids alone. Few studies have reported the efficacy and safety of tofacitinib for ASUC with steroid resistance. We report a case series of successful first-line treatment consisting of tofacitinib (20 mg/day) administered to ASUC patients with steroid resistance. Patients diagnosed with ASUC at our institution between October 2018 and February 2020 were retrospectively evaluated. They were administered a high dose of tofacitinib (20 mg) after showing no response to steroid therapy in a dose of 1-1.5 mg/kg/day. Eight patients with ASUC, 4 (50%) men, median age 47.1 (range 19-65) years, were included. Four patients were newly diagnosed, and the median UC duration was 4 (range 0-20) years. Six of the 8 patients were able to avoid colectomy. One patient (patient 2) had no response; however, remission was achieved after switching from tofacitinib to infliximab. One patient (patient 6) with no response to tofacitinib underwent total colectomy. Only one patient (patient 4) experienced an adverse event, local herpes zoster, treated with acyclovir without tofacitinib discontinuation. Clinical remission without serious adverse events can be achieved with high probability and colectomy can be avoided by first administering high-dose tofacitinib to steroid-resistant ASUC patients. Tofacitinib may be one of the first-line treatment options for steroid-resistant ASUC.

Acute severe ulcerative colitis is a high stakes event with significant numbers still requiring emergent colectomy, representing a need to establish alternative medical management options. We report a case series of tofacitinib as rescue therapy in biologic-experienced patients with acute severe ulcerative colitis. Four patients were identified over a 1-year period at our institution who initiated tofacitinib for acute severe ulcerative colitis. All four had previously failed at least two biologics, including infliximab, and were failing high-dose oral prednisone therapy before admission. All patients had Mayo disease activity index of at least 10 at admission. After no significant improvement despite receiving a minimum of 3 days of intravenous methylprednisolone and based on elevated Ho and Travis indices at Day 3, patients were offered rescue tofacitinib for induction of remission, or colectomy. Standard induction of tofacitinib was used [10 mg twice daily], and one patient was escalated to 15 mg twice daily after inadequate response. All patients experienced improvement in objective symptoms and laboratory markers, and were discharged without colectomy on tofacitinib as maintenance therapy and prednisone taper; 30-day and 90-day colectomy rates on tofacitinib maintenance therapy were zero and 90-day readmission rate was also zero. Two of four patients achieved steroid-free remission on maintenance tofacitinib monotherapy based on clinical symptoms and follow-up endoscopy. No major adverse reaction was reported during induction or maintenance therapy. Tofacitinib may be an acceptable rescue agent in biologic-experienced patients with acute severe ulcerative colitis. Tofacitinib may also be safely continued as maintenance therapy once remission has been achieved.

Background Patients with acute severe ulcerative colitis (ASUC) may be refractory to treatment with steroids and anti-tumour necrosis factor agents (anti-TNF). Ciclosporin inhibitors (CNI) have been used effectively as a fast-acting bridge to slower-onset immunomodulators in thiopurine-naive patients; concerns over toxicity limit prolonged use as maintenance. Patients who are azathioprine-exposed or anti-TNF-refractory have limited medical treatment options, often resulting in colectomy. Combination of CNI as induction and slower-acting but potentially safer vedolizumab (VDZ) has recently been used in patients with severe inflammatory bowel disease (IBD). We aim to review the utility in ASUC. Methods A systematic bibliographic review was conducted on PubMed using the keywords ”vedolizumab”, ”calcineurin inhibitors”, ”inflammatory bowel disease”, ”severe ulcerative colitis” within the period 2013 to October 2018. Results There were 2 prospective observational studies (1–2) [N= 30] and 1 retrospective study(3) [N=39]. Patients were refractory to conventional treatment with steroids and/or anti-TNF therapy. CNI (ciclosporin or tacrolimus) was used for induction of remission in majority of cases, or as rescue agent in those failing induction with Vedolizumab [subgroup of 1 study, N=7]. In 2 studies, IV cyclosporine or Tacrolimus was started; a week later, CNI-responsive patients were given VDZ induction/maintenance and CNIs were stopped after 8–12 weeks per protocol. In another study, VDZ was initiated on average 30days after CNI, with average combination CNI+VDZ of 64 days Combination CNI+VDZ showed good short-term efficacy. At 1 year, there was a respectable colectomy-free rate of 75%, comparable to other studies with infliximab/ciclosporin combined with azathioprine. In those receiving steroids at baseline, Steroid-free remission was achieved in 18/36 = 50% at week 14. Serious adverse events (N=7) were attributed to CNIs; there were no deaths. Conclusions Preliminary studies of combination CNI and VDZ in patients with ASUC appear promising. Further prospective trials are needed for the confirmation of the utility and efficacy of this treatment strategy in the management of ASUC

Background Parenteral ciclosporin (CsA) is an effective rescue therapy for acute severe ulcerative colitis (ASUC) and has similar efficacy to infliximab (IFX). Although CsA is cheaper and can facilitate bridging to any IBD therapy, including newer biologics, its use is limited by variable pharmacokinetics and possibility of significant systemic toxicity particularly associated with the intravenous preparation. Despite favourable pharmacokinetics and bioavailability, the use of lipid-emulsified oral CsA in steroid-refractory ASUC is undefined. Methods All patients who received oral CsA (Neoral®) rescue therapy for ASUC at Addenbrooke’s Hospital, Cambridge, UK from Nov 2014 to May 2020 were identified from electronic healthcare records. Baseline data and outcomes were extracted and compared to patients who received IFX rescue therapy. Statistical significance was assessed using non-parametric tests. Survival estimates were computed using the Kaplan-Meier method. Results A total of 37 patients received oral CsA for refractory ASUC. Median time from admission to CsA initiation was 5 days (IQR 4–6 d) and median initial dose was 8 mg/kg/d (IQR 7–8 mg/kg/d). At admission, the median CRP was 26 (IQR 14–95) and Truelove and Witt’s severity criteria met in 21/37 (57%). 70% of patients (26/37) avoided colectomy during the index admission. No parameters were demonstrated to predict need for acute colectomy. Median follow-up after hospital discharge was 3 years (IQR 2-5years). For those who avoided acute colectomy, median duration of therapy was 4 months (IQR 2.5-5months) with bridging to azathioprine (24/26, 92%), vedolizumab (1/26, 4%), or 5-ASA (1/26, 4%). Estimated colectomy-free survival in responders were 84%, 84% and 78% at 12, 24, and 60 months. No parameters were shown to predict colectomy-free survival. Comparable colectomy-free outcomes were obtained for contemporaneous IFX-treated ASUC patients in our hospital. 9 of 26 patients remained biologic-naïve and colectomy-free after a median of 3 years. Estimated colectomy and biologic-free survival were 51%, 47% and 18% at 12, 24, and 60 months. 15 patients experienced adverse events, which were all mild and self-limiting. There were 3 infective complications. No patients required drug cessation and no serious adverse events associated with parenteral CsA occurred. Conclusion In this cohort, oral CsA was a safe, well tolerated and effective rescue therapy for steroid-refractory ASUC. A proportion of patients remain biologic and colectomy-free for up to 5 years. Given the feasibility to bridge to effective maintenance therapies, including newer biologics, oral CsA should be considered as a rescue therapy in ASUC and avoids many of the side effects associated with intravenous CsA.

Tofacitinib Is Safe and Effective When Used in Combination With Infliximab for the Management of Refractory Ulcerative Colitis