Abstract
Background and Aims
Options for medical management of patients with acute severe colitis [ASC] failing intravenous (i.v.) steroids are limited and include rescue therapy with either infliximab or ciclosporin. In patients failing infliximab, second-line rescue therapy with ciclosporin is an alternative. The aim of this study was to investigate the efficacy and safety of ciclosporin in patients with steroid-refractory ASC failing first-line rescue therapy with infliximab.
Methods
This is a retrospective, tertiary centre study undertaken from 2010 to 2017. Included were patients hospitalized for ASC and treated with i.v. ciclosporin after failing i.v. steroids and infliximab within the previous 2 months. Time to colectomy, clinical response, and occurrence of adverse events were analysed.
Results
Forty patients with steroid-resistant ASC were included. Patients were followed for a median of 13 months (interquartile range [IQR] 5–32 months). Colectomy-free survival was 65%, 59.4%, and 41.8% at 1 month, 3 months and 1 year, respectively. Sixty percent of patients [24/40] achieved clinical remission at a median of 2 weeks [IQR 1–3 weeks]. Infliximab levels before ciclosporin infusion were available for 26 patients [median level 17.5 mg/mL, IQR 8–34 mg/mL] and were not associated with adverse events. Sixteen patients [40%] experienced adverse events after ciclosporin treatment, but none resulted in drug discontinuation.
Conclusions
In patients with i.v. steroid–refractory ASC who failed infliximab therapy, second-line rescue therapy with ciclosporin was shown to be effective and safe. This is the largest patient cohort to receive ciclosporin as second-line rescue therapy for ASC. We believe that ciclosporin may be offered to selected patients prior to referral for colectomy.
Keywords: Ulcerative colitis, ciclosporin, infliximab, anti-TNF
1. Introduction
Ulcerative colitis [UC] is a chronic inflammatory disease affecting the colon. The severity of the disease can vary and is defined by several clinical, biochemical, and endoscopic parameters. Isolated inflammation of the colon can also be a manifestation of Crohn’s disease [CD], affecting about one-third of patients, and is associated with a less progressive disease course.1 Acute severe colitis [ASC], defined by Truelove and Witts over 50 years ago,2 will affect up to 25% of patients with UC.3 Of these, up to 33% fail intravenous [i.v.] steroids, which have been the mainstay of conventional, first-line therapy in this setting.4
The options for medical management of ASC failing i.v. steroids are limited, and include either calcineurin inhibitors, such as ciclosporin and tacrolimus, or infliximab [IFX]. The use of ciclosporin as rescue therapy for patients who have failed i.v. corticosteroids has become well established since its first description in 1990.5 Later, two randomized, controlled trials showed the efficacy and safety of this treatment regimen, with short-term response rates between 64% and 82%.6,7 Data regarding the efficacy of tacrolimus in the setting of patients with ASC failing i.v. corticosteroids is less robust. However, two small randomized controlled studies did show efficacy in such a setting.8,9 The introduction of IFX has provided an alternative effective therapeutic option for patients with ASC failing i.v. corticosteroids.10 The efficacy and safety of IFX in this setting is considered equivalent to that of ciclosporin, following two randomized studies demonstrating short-term response rates with avoidance of colectomy in 80–85% of patients for both drugs.11,12 In the past several years, IFX has become the predominant agent used in such cases. Secondary to its increased use in ASC, patients failing IFX in such a setting are becoming more prevalent.13
In patients who fail IFX rescue therapy, colectomy is usually recommended. A second-line rescue therapy [sequential] with ciclosporin after IFX failure is potentially an alternative. However, safety concerns and scarce evidence have limited its use in such a setting. Current guidelines recommend colectomy following failure of one rescue treatment,4,14 stating safety concerns and lack of data in regards to sequential medical rescue therapy.
The aim of this study was to investigate the efficacy and safety of ciclosporin in patients with steroid-refractory severe colitis failing first-line rescue therapy with IFX.
2. Materials and methods
2.1. Patients
Adult colitis patients [UC or isolated Crohn’s colitis; Montreal classification E2, E3, or L3] admitted to the University of Chicago inflammatory bowel disease [IBD] inpatient service between January 2010 and March 2018 for management of ASC refractory to i.v. steroids were included in the study. All patients had received i.v. ciclosporin after receiving IFX within the previous 8 weeks. Patients diagnosed with active small bowel CD, those who had a follow-up of <3 months after discharge, and those who had previously been treated with ciclosporin were excluded. All patients but two underwent flexible sigmoidoscopy, with biopsies taken from the recto-sigmoid colon. Hematoxylin–eosin [H&E] and immunohistochemistry staining were done to rule out Cytomegalovirus infection of the colon.
2.2. Medications
All patients had failed at least 3 days of i.v. corticosteroids [methylprednisolone 20 mg twice daily or higher]. Infliximab was given as a single infusion or several infusions of 5–10 mg/kg. Ciclosporin was given as a continuous infusion at an initial dose of 2–4 mg/kg per day, aiming for serum trough levels of 300–400 ng/mL. In case of response [decrease in bowel movement frequency by 50% with absence of hematochezia], a switch to oral formulation was performed, using a total daily dose equivalent to twice the 24-h intravenous dose. The decision to proceed with ciclosporin instead of standard of care [colectomy] was done according to the attending physician’s discretion. Pneumocystis jirovecii chemoprophylaxis with trimetoprim–sulphametoxazol was routinely administered to all patients receiving ciclosporin.
2.3. Data collection
For all patients, demographic, clinical, laboratory, radiographic, and endoscopic data were attained by a comprehensive review of their electronic medical records. All patients included had clinical follow-up of at least 3 months. The primary end point was colectomy-free survival. Secondary end points included clinical, steroid-free, and endoscopic remission. Clinical remission was defined as absence of blood in the stools and <3 stools per day with absence of abdominal pain. Endoscopic remission [if available] was defined as a Mayo endoscopic subscore of 0 or 1. In addition, all adverse events were described and considered secondary end points. These included surgical complications for the patients who underwent colectomy following infliximab-cyclosporine sequential therapy. The study was approved by the institutional ethics review board [IRB17-0816].
2.4. Statistical analysis
Data was analysed using standard statistical analysis. Data is presented as median with interquartile range [IQR] in the case of non-parametric data and as mean with standard deviation in the case of parametric data. Student’s t-test was used to compare continuous variables. Non-parametric distributed data was analysed using the Mann–Whitney U test or Fisher’s exact test. Correlations were analysed using Spearman’s rank correlation coefficient. Kaplan–Meier curves were generated for time-to-event data, i.e. time from ciclosporin infusion until colectomy. Cox regression models were fitted to examine the effects of the covariates albumin, CRP, and haemoglobin.
3. Results
3.1. Patients
A total of 40 patients [60% males; 10% isolated Crohn’s colitis] were treated with ciclosporin after failing steroids and IFX for severe colitis. The majority of patients had extensive disease [63%]; the median disease duration was 27 months [IQR 7–80]. Ninety percent of the patients fulfilled the Truelove and Witts criteria for ASC, and their endoscopic appearance was considered to be severe. The patients’ characteristics are shown in Table 1. Patients were followed for a median time of 13 months [IQR 5–32]. In all 40 patients, stopping IFX and switching to ciclosporin was due to ineffectiveness of the former therapy. In 30 patients [75%], ciclosporin was initiated following primary non-response to infliximab, which was administered as rescue therapy to patients with ASC failing corticosteroids. Ten patients developed ASC not responding to corticosteroids while on maintenance therapy with infliximab. We did not find a significant difference between the survival curves of these two groups [Log-rank test, p = 0.27]. All patients received adequate dosing of infliximab within 6 weeks of the first ciclosporin infusion and were deemed non-responders prior to commencing ciclosporin therapy. Infliximab levels immediately prior to initiation of ciclosporin treatment were available in 65% [n = 26] of patients in the cohort.
Table 1.
Clinical and demographic characteristics of ASC patients treated with ciclosporin
| Patient characteristics | |
|---|---|
| Male | 24 [60%] |
| Age (median [IQR]) [years] | 25.7 [20.6–33.8] |
| Disease duration (median [IQR]) [months] | 27.2 [8–77.4] |
| Disease extent | |
| E1 | 1 [2.5%] |
| E2 | 13 [32.5%] |
| E3 | 24 [60%] |
| Crohn’s colitis | 4 [10%] |
| Acute severe colitis [Truelove’s criteria] | 36 [90%] |
| Mayo endoscopic score at presentation | |
| 0–1 | 0 |
| 2 | 10 [25%] |
| 3 | 28 [70%] |
| No assessment | 2 [5%] |
| Maintenance medication following ciclosporin induction | |
| Azathioprine | 9 |
| Vedolizumab | 11 |
| Infliximab | 2 |
| Tofacitinib | 1 |
| Average interval between drugs (days [range]) | 16.8 [1–46] |
| Infliximab drug level at admission (median [range]) | 17.5 [0–86] µg/mL |
3.2. Response to ciclosporin
Ciclosporin was given at a median time of 13 days after the last IFX infusion [IQR 6–28]. Infliximab levels before ciclosporin infusion were available for 26 out of the 40 patients. The median level was 17.5 μg/mL [IQR 8–34]. Ciclosporin was given as an i.v. induction to all patients. Among the ciclosporin-treated patients, 24 [60%] achieved clinical remission, at a median time of 2 weeks [IQR 1–3]. Those who responded were switched to oral ciclosporin. The drug was bridged to thiopurines [mostly azathioprine] and vedolizumab in 9 and 11 of the responding patients, respectively, with ciclosporin and oral steroids tapered over the course of 6–12 weeks. One patient was transitioned to tofacitinib. Over 60% of patients [25/40] were discharged with an intact colon after induction by ciclosporin. Twenty-four patients underwent total colectomy at a median time of 2 weeks [IQR 1.3–26] after induction with ciclosporin. The colectomy-free survival was 65% at 1 month, 59.4% at 3 months, and 41.8% at 1 year [Figure 1]. Among patients with isolated Crohn’s colitis, two [50%] failed medical treatment with ciclosporin and required colectomy. None of albumin, CRP, or haemoglobin influenced the response to ciclosporin on Cox regression analysis.
Figure 1.
Kaplan–Meier analysis of colectomy-free survival after treatment with ciclosporin
3.3. Adverse events
Sixteen patients [40%] experienced adverse events after treatment with ciclosporin [Table 2]. No events of mortality were recorded during the follow-up period. In addition, none of the adverse events yielded discontinuation of the drug. The most common adverse event was hypertension, in 6 patients [15%]. This was mild in severity [median Mean Arterial Pressure of 105.3 mmHg]. Four patients experienced headaches and one patient had palmar paresthesia, which resolved spontaneously. One patient experienced mild decrease in glomerular filtration rate, appropriate for acute kidney injury Stage 1. Two infectious complications occurred. A single patient was diagnosed with Clostridium difficile infection, which later resolved with antibiotic treatment. One patient was found to have influenza, which resolved with Oseltamivir treatment. Infliximab levels did not differ significantly between patients who experienced adverse events and those who did not [median level of 24 and 15 μl/mL respectively, p = 0.69].
Table 2.
Summary of adverse events
| Event | Number of patients | Management |
|---|---|---|
| Hypertension | 6 | Medical therapy for 2 patients |
| Headache | 4 | Symptomatic |
| Liver function test elevation [<× 3 Upper limit of normal ] | 2 | Follow-up |
| Infection | 7 | |
| Wound infection | 4 | i.v. antibiotics |
| Clostridium difficile | 1 | Oral vancomycin |
| Influenza | 1 | Oseltamivir |
| Intra-abdominal abscess | 1 | Per-cutaneous drainage |
| Venous thromboembolism | 3 | Anti-coagulation |
| Tremor | 1 | Follow-up |
| Paranaesthesia | 1 | Follow-up |
| Seizures | 1 | Anti-convulsive therapy |
| Kidney injury | 1 | Follow-up |
3.4. Postoperative complications in patients who underwent colectomy
Ten out of the 24 patients who underwent colectomy had at least one post-operative complication. Of those, four were wound infections, and one was an intra-abdominal abscess. There were three cases of venous thromboembolism, all occurring after surgery. One patient was not treated with prophylactic anticoagulation for 36 h before diagnosis; the second case was of portal vein thrombosis involving a patient with an abdominal abscess; the third patient had extensive thrombosis involving the internal iliac and portal veins and was eventually diagnosed with anti-phospholipid syndrome. One patient had two episodes of seizures post-operatively. Both occurred while he was off ciclosporin for more than 5 days. The patient had received the drug for less than 48 h, with a peak drug level of 128 ng/mL.
4. Discussion
Patients with severe ulcerative colitis who are failing high-dose corticosteroids and rescue therapy with IFX are a very severely affected subgroup of patients in whom second-line salvage therapy with ciclosporin might be their only chance at avoiding colectomy, an outcome that is desirable in most patients.15 It is also important to recognize that urgent colectomy is associated with adverse outcomes. A recent multicentre observational study of patients with steroid-refractory acute severe ulcerative colitis requiring colectomy in Spain showed an overall mortality rate of 6.3%. The main causes of death were infections and post-operative complications.16 A systematic review revealed that the overall morbidity after colectomy is 50.8%, including high rates of infections.17 Indeed, after failing first-line medical salvage therapy, the relative risks of surgery might be greater than a second attempt at medical rescue therapy. However, available data are limited for sequential therapy with ciclosporin after IFX failure, mainly due to physicians’ concerns regarding the safety and efficacy of such therapy. This scenario is especially relevant because IFX has become the usual first-line drug in the management of inpatients with ASC failing i.v. steroids. Although the benefit of IFX has been shown to be efficacious in treating ASC, a considerable number of patients do not respond to the drug. Several mechanisms have been suggested to explain this, including development of neutralizing anti-drug antibodies18 and faecal loss of the drug.19 Potentially, both mechanisms are not applicable to ciclosporin due to the fact that this is not a protein-based drug. Accordingly, second-line salvage therapy with ciclosporin for patients failing medical rescue with IFX is of significant importance.
The safety of combination therapy with anti-TNF and ciclosporin has been evaluated in other diseases. Several authors have reported on overlapping treatment between anti-TNF and ciclosporin in psoriasis and psoriatic arthritis.20–22 Another study used combination therapy with IFX and ciclosporin in patients with rheumatoid arthritis.23 No serious adverse events or infectious complications were reported in any of these series.
Several trials have looked at sequential rescue medical therapy in patients with ASC. However, the great majority of patients in these reported studies24–28 were treated with IFX following ciclosporin failure. Currently, the more common but understudied clinical scenario is that of the patient who has failed IFX rescue therapy and may now be eligible to receive ciclosporin as a second-line rescue therapy versus colectomy.
Indeed, one meta-analysis29 found there has been only two trials, involving 30 patients treated with ciclosporin following IFX failure. Another meta-analysis30 reported on a study of 7 patients28 from a Spanish cohort. Therefore, a total of 37 patients pooled from three different studies24,26,28 were treated with ciclosporin after IFX failure. In this cohort, the pooled 3-month colectomy rate was 30% at 3 months and 57% at 12 months. However, adverse events were reported in 33% of patients, with serious infections reported in 13.3% of patients. The median interval between the last IFX infusion and ciclosporin initiation was 20 days, and there was no data on IFX drug levels prior to ciclosporin initiation. The data regarding sequential rescue therapy using tacrolimus after IFX failure is even more scarce. Only one study included patients treated with tacrolimus in such a scenario, and there were only 12 patients in that group.31
In our retrospective series from a single tertiary referral centre with extensive experience in the management of patients with acute severe colitis, we used colectomy-free survival as a primary end point, because this event is unambiguous in a retrospective series. Clinical remission rate, a more stringent end point was also reported. The 3 months and 12 months colectomy-free survival rates were 51.4% and 41.8%, respectively, and clinical remission was achieved in 60% of the patients, in a median time of 2 weeks. It is worth noting that our criteria for clinical remission were stringent, requiring normal bowel frequency and no rectal bleeding, as defined by the STRIDE consensus statement.32
In our study, colectomy-free survival rates were lower than in previous prospective trials of ciclosporin use for patients with acute severe colitis.6,11,12 However, in these studies, ciclosporin was given as the first drug after corticosteroid failure, and our cohort probably represents an even more refractory subgroup of patients, because they had already failed both i.v. steroids and medical salvage therapy with IFX prior to receiving ciclosporin.
Another important factor is having a strategy for maintenance therapy when embarking on medical salvage therapy with ciclosporin for patients with ASC, especially in patients who have already failed anti-TNF agents. Classically, patients treated with ciclosporin for ASC were bridged to azathioprine. However, recent publications have shown the safety and efficacy of bridging patients treated with ciclosporin for ASC to vedolizumab,33,34 and indeed in our cohort the majority of patients who responded to ciclosporin were bridged to vedolizumab. This was done according to the protocol described before by Christensen et al.33 Patients received the first dose of vedolizumab once remission was achieved with ciclosporin. A ciclosporin taper was started following the completion of vedolizumab loading doses.
One important concern when considering a second-line rescue therapy is safety, especially when potentially combining immunosuppressive therapies. In our cohort of patients, sequential therapy with ciclosporin after IFX was associated with less adverse events than reported in previous publications about sequential rescue therapy.27,28 Likewise, there were fewer post-operative complications in our cohort in comparison with previous studies of colectomy in patients with steroid-refractory UC.14 We are also the first to report on IFX levels prior to ciclosporin initiation, and despite having significant drug levels in the majority of the patients, there was no increased risk of infectious complications regardless of IFX level at ciclosporin initiation. This finding could possibly alleviate some concerns that such patients would be at increased risk of complications and that ciclosporin should only be initiated once IFX levels are undetectable.35
There were several limitations to our study, mainly linked to its retrospective nature. The side effects of both drugs may have been underestimated. It should also be emphasized that the patients were treated by experienced physicians in a large referral centre. Patients ultimately needing surgery were operated on by experienced colorectal surgeons in a centre performing a high volume of colectomies per year. Caution should be exercised when extrapolating these findings to less experienced centres.
Our study represents the largest cohort of patients treated with sequential rescue therapy with ciclosporin after IFX failure, larger than the three previous studies combined. It assessed clinical efficacy and safety as well as IFX levels prior to ciclosporin initiation, and showed acceptable efficacy and no serious adverse events.
In conclusion, in patients with severe steroid-refractory colitis who failed first-line rescue therapy with IFX, sequential rescue therapy with ciclosporin avoided colectomy in a significant number of patients, with an acceptable side effect profile. Ciclosporin is a reasonable option to consider before pursuing the irrevocable decision of colectomy and its variable long-term outcomes. The decision, however, should be made on an individual basis, in an experienced tertiary centre.
Funding
This work received no outside funding.
Conflict of Interest
RW, JEO, KEJ and OVY have no relevant disclosures. AS has received funding from AbbVie, Celltrion, and Takeda. SD has received grant support from Pfizer. JP has received grants from Takeda and Abbvie, and serves as a consultant for Verastem. He was on the advisory board for Pfizer and Janssen. DTR is a consultant and has received grant support from Abbvie, Merck & Co., Janssen, Takeda, and Pfizer. RDC is a consultant at Abbvie, Celgene, Janssen, Pfizer, Takeda, and UCB Pharma. No funding or sponsorship was received for this study or publication of this article.
Author Contributions
RW is this submission’s guarantor. RW, JEO, and DTR conceived and designed the study. RW, JEO, and DTR drafted the manuscript, with critical revisions by RDC, AS, SD, and JP. All authors contributed to the acquisition of the data. RW, JEO, KEJ, and OVY contributed to the analysis and interpretation of data. All authors approved the final version of the manuscript.
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