Systematic Review: Sequential Rescue Therapy in Severe Ulcerative Colitis: Do the Benefits Outweigh the Risks?

CLINICAL REVIEW ARTICLE

Systematic Review: Sequential Rescue Therapy in Severe Ulcerative Colitis: Do the Benefits Outweigh the Risks? Neeraj Narula, MD,* ,† Michael Fine, MD,* Jean-Frederic Colombel, MD, PhD,† John K. Marshall, MD, MSc,* and Walter Reinisch, MD, PhD*

Background: The options for medical management of acute severe steroid-refractory ulcerative colitis (UC) are limited. Recent guidelines recommend against use of sequential rescue therapy in the setting of failed medical management with initial salvage therapy. A systematic review was conducted to assess outcomes of sequential rescue therapy with infliximab (IFX) and calcineurin inhibitors like cyclosporine (CsA) or tacrolimus (Tac) in patients with steroid-refractory UC.

Methods: A literature search identified studies that investigated treatment with IFX and CsA or Tac in acute severe UC. Outcomes of interest included short-term symptomatic response to treatment, rates of remission, adverse drug reactions, serious infections, mortality, and colectomy at 3 and 12 months. Results: Overall, ten studies with 314 participants were eligible for inclusion. After sequential treatment, patients achieved short-term treatment response in 62.4% (95% confidence interval [CI], 57.0%–67.8%) of cases and remission in 38.9% (95% CI, 33.5%–44.3%). Colectomy rates were 28.3% (95% CI, 21.7%–34.5%) 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%). Conclusions: The risk of sequential therapy in steroid-refractory UC seems lower than initially reported. Caution must be exercised however because of very low-quality evidence. In contrast to recent guidelines, the current analysis does not support a decision for or against use of sequential rescue therapy, which should only be performed at specialized referral centers familiar with the use of calcineurin inhibition. (Inflamm Bowel Dis 2015;21:1683–1694) Key Words: ulcerative colitis, infliximab, cyclosporine, anti–TNF-a, ciclosporin, tacrolimus

A

cute severe ulcerative colitis (UC) will affect up to 25% of patients with UC.1 Of these, up to 30% fail intravenous steroids and may undergo colectomy.2 Medical rescue therapies for steroid-refractory patients can help avoid colectomy and improve long-term outcomes. Calcineurin inhibitors such as cyclosporine (CsA) and tacrolimus (Tac) can be used for steroid-refractory severe UC. Short-term response rates to intravenous CsA range between 64%

and 82% in controlled studies.3,4 Controlled trials of oral Tac targeting trough levels of 10 to 15 ng/mL have shown 2-week response rates of 50% to 68%.5,6 No controlled comparison of these 2 therapies in acute severe UC has been reported. As a result, either can be considered a reasonable treatment option when opting for calcineurin inhibitor therapy for steroid-refractory severe UC.7 Infliximab (IFX) is another recommended option for salvage therapy in steroid-refractory severe UC. IFX is a tumor

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.ibdjournal.org). Received for publication December 10, 2014; Accepted January 22, 2015. From the *Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada; and †Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai Hospital, New York, New York. W. Reinisch has served as a speaker, a consultant, and/or an advisory board member for Abbott Laboratories, AbbVie, Aesca, Amgen, AM-Pharma, Aptalis, Astellas, AstraZeneca, Avaxia, BioClinica, Biogen Idec, Bristol-Myers Squibb, Cellerix, Chemo-Centryx, Celgene, Centocor, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Galapagos, Genentech, Grünenthal, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, Millennium, Mitsubishi Tanabe Pharma Corporation, MSD, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Robarts Clinical Trials, Schering-Plough, Setpoint Medical, Shire, Takeda, Therakos, TiGenix, UCB, Vifor, Yakult, Zyngenia, and 4SC. J-F. Colombel has served as a consultant, an advisory board member, or a speaker for AbbVie, Amgen, BristolMyers Squibb, Celltrion, Ferring, Genentech, Giuliani SPA, Merck & Co., Mitsubishi, Nestle Nutrition Science Partners Ltd., Pfizer Inc., Prometheus Laboratories, Receptos, Takeda/Millennium Pharmaceuticals Inc., UCB Pharma, Vertex, and Dr. August Wolff GmbH & Co. J. K. Marshall has served as a consultant, an advisory board member, or a speaker for AbbVie, Aptalis, AstraZeneca, Celltrion, Cubist, Ferring, Forest, Janssen, Optimer, Procter & Gamble, Shire, Takeda, and Warner Chilcott. The remaining authors have no conflicts of interest to disclose. Reprints: Neeraj Narula, MD, Icahn School of Medicine at Mount Sinai, Division of Gastroenterology, Department of Medicine, One Gustave L. Levy Place, Box 1069, New York, NY 10029 (e-mail: [email protected]). Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000350 Published online 1 April 2015.

Inflamm Bowel Dis Volume 21, Number 7, July 2015

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Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc. Unauthorized reproduction of this article is prohibited.


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necrosis factor alpha (TNF-a) antagonist with demonstrated benefit in moderate-to-severe ambulatory UC based on the ACT 1 and ACT 2 trials, where induction response rates of 61% to 69% were observed.8 However, its role in acute severe UC is more controversial with conflicting results seen in early placebocontrolled trials.9,10 The results of a large prospective randomized trial suggested similar rates of treatment failure for both IFX and CsA.11 However, a recent meta-analysis reported superior response rates and lower rates of colectomy at 12 months with IFX compared with CsA in steroid-refractory severe UC.12 There were some limitations in this analysis including the paucity of randomized controlled data in this field. As a result, either IFX or calcineurin inhibition with CsA or Tac remains an option for first-line rescue therapy after steroid failure for severe UC.7 Current guidelines for managing steroid-refractory severe UC advocate colectomy if no response to salvage therapy is seen within 4 to 7 days.7,13 Second-line salvage therapy, after failure of intravenous steroids and a rescue agent, is generally not recommended because it is felt that its risks may exceed its benefits.7,13 This is largely based on initial reports of unacceptably high rates of serious infection and death after sequential therapy with CsA and IFX.14,15 Subsequently, more centers have reported their experiences with sequential rescue therapy. As a result, we undertook a systematic review to identify observational studies and clinical trials that used IFX and CsA or Tac as sequential rescue agents in steroid-refractory acute severe UC.

METHODS Study Selection A systematic literature search was conducted to identify studies that investigated treatment with both calcineurin inhibitors and IFX in acute severe UC. We identified sources from the MEDLINE, Embase, and PubMed databases from 1950 to May 2014. There were no language restrictions. Keywords used were “infliximab or anti-TNF,” “UC or colitis,” and “cyclosporine or cyclosporine A or ciclosporin or ciclosporin A or tacrolimus or FK506.” The reference lists of any studies meeting inclusion criteria were reviewed manually to identify additional relevant publications.

Inclusion/Exclusion Criteria For inclusion in the review, studies were required to meet the following criteria: (1) observational design (prospective or retrospective cohort or case–control) or interventional design (randomized or nonrandomized), (2) subjects with acute severe UC who had failed a course of intravenous or oral steroids before treatment with a rescue therapy, (3) subjects treated initially with either IFX or a calcineurin inhibitor as rescue therapy, (4) subjects were subsequently treated with IFX or a calcineurin inhibitor during the same presentation of acute UC after failure of initial rescue therapy, loss of response to initial rescue therapy, or adverse events attributed to initial rescue therapy, and (5) less

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than 3 months lapsed between time of cessation of 1 rescue therapy and commencement of the second salvage therapy. Some studies did not report failure of a rescue therapy in previous UC flares or report whether patients were naive to previous treatment with rescue therapy but were not excluded for that reason. Where studies did not provide sufficient information, authors were contacted to obtain additional data.

Outcomes of Interest The primary outcome was the short-term symptomatic response to therapy. Secondary outcomes included the rates of remission, colectomy at 3 and 12 months, adverse drug events, serious infections, and mortality during the observational period. Table 1 reports inclusion criteria and definitions of treatment response and remission for each study included in the metaanalysis.

Data Extraction and Quality Assessment Data extraction was performed independently by 2 investigators (N.N. and M.F.) with discrepancies resolved by consensus in consultation with the senior authors (J.K.M., J-F.C., and W.R.). We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to determine the quality of evidence. GRADE uses several domains, including design, consistency, precision, directness, and publication bias, to rate the quality of evidence as high, moderate, low, or very low. These ratings represent an assessment of the likelihood that further research would lead to changes in the estimate of effect.24

Analysis The incidence of each item of interest was calculated from the pooled patients’ data. For each specified item, only those articles that met inclusion criteria and presented detailed information on the items of interest were used. Where applicable, 95% confidence intervals (CIs) are provided. Analyses were performed with GraphPad Prism (version 5.03; GraphPad Software, San Diego, CA).

RESULTS Search Results The literature search identified 958 citations, of which 937 were excluded on review of the title and abstract (Fig. 1). A further 11 studies were excluded after careful review of the full text; 8 provided insufficient information regarding the patients who underwent sequential therapy25–32; one did not provide details regarding the time frame between rescue therapies33; one examined switching to IFX in CsA responders34; and one excluded those who underwent sequential rescue therapy.35 For some studies where only partial information for our outcomes of interest was disclosed, the authors were contacted and asked to provide the relevant information. Tsukamoto et al22 clarified the time frame between rescue treatments that permitted inclusion in the pooled analysis. Minami et al and Ordas et al also provided further detail beyond what was

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Sequential Rescue Therapy in Severe UC

TABLE 1. Definitions Within Studies and Notable Disparities First Author

Year

Inclusion Eligibility for Sequential Rescue Therapy

Definition of Treatment Response and Remission

Notable Exemptions for Meta-analysis Inclusion

Trials that used cyclosporine in sequential therapy Chaparro16 2012 Patients eligible if failed cyclosporine for a corticosteroid- Remission was defined as a normal refractory UC flare and if infliximab therapy was number of bowel movements, started within 1 mo of the failure of cyclosporine absence of rectal bleeding, and a Lichtiger score of less than 4. Partial response was defined as a Lichtiger score of 4–10 Patients who switched to infliximab due to adverse events with cyclosporine and patients who had previously taken cyclosporine or infliximab were excluded 2011 Patients eligible if corticosteroid-refractory moderate– Leblanc15 Remission was defined as absence severe UC flare and successively treated with IFX and of blood in stools, ,3 stools per CsA, and if IFX therapy was started within 1 mo of the day, and no abdominal pain. failure of CsA, or CsA was started within 2 mo of Response is symptom failed IFX improvement that allows for deferral of colectomy, including those who achieve remission Patients were eligible for a second rescue therapy after failure of the first. Patients had to have received a minimum of 1 IFX dose of 5 mg/kg or CsA continuously for 2 d before judged failure 2013 All sequential treatments were given within an interval of Remission was normalization Data provided in abstract for Ordas17 3 mo for failure of symptomatic improvement to a first of symptoms (no diarrhea and no colectomy and adverse rescue therapy hematochezia) with events also included normalization of CRP if patients who received only available. Response was patients mono-rescue therapy, and who had symptomatic authors did not have data improvement allowing avoidance available for those who of colectomy but did not meet underwent sequential criteria for remission rescue therapy only 2008 Patients eligible if steroid-refractory UC and treated Remission was a normal number of Maser14 successively with IFX and CsA or vice versa. Patients bowel movements, absence of had to receive salvage rescue agent within 4 wk of rectal bleeding, and discontinuing the first agent. Salvage therapy included a discontinuation of steroids a minimum of 1 dose of IFX or 1 wk of intravenous within 3 mo. The Lichtiger score CsA. There was a minimum of 24 h between was 3 or less. Response was administration of the sequential rescue therapies defined as a Lichtiger score of 4– 10 2009 Patients initially failed 1 mg$kg21$d21 prednisolone Remission was symptomatic Manosa18 or equivalent. IFX was started at a median of 19 d improvement and discontinuation (range, 5–30 d) after CsA discontinuation; 12/16 of steroids. Response was patients started within the first week of CsA symptomatic improvement that discontinuation allowed avoidance of colectomy Trials that used tacrolimus in sequential therapy Yamamoto19 2009 Patients who were given rescue therapy with IFX were Clinical remission defined as administered concurrently with Tac or within 4 wk of MTWSI score of 4 or less. Tac discontinuation Relapse was MTWSI score of 5 or higher and requirement of additional medical therapy or surgery

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TABLE 1 (Continued) First Author Herrlinger20

Takeuchi21

Tsukamoto22

Minami23

Year

Inclusion Eligibility for Sequential Rescue Therapy

Definition of Treatment Response and Remission

Notable Exemptions for Meta-analysis Inclusion

2010 All patients had severe UC with Lichtiger score .10 at Remission was defined as Lichtiger enrollment. All had failed steroid treatment and had score ,4 and response was score primary or secondary failure to Tac or experienced ,10 adverse events on Tac. Tac was stopped for at least 1 wk before initiation of IFX (1 patient continued Tac with IFX). Patients had negative Tac level before IFX start 2013 Patients with steroid-refractory UC who failed to respond Efficacy was assessed by applying to IFX induction therapy were treated with Tac. Two Mayo DAI. DAI equal or smaller wk lapsed between last dose of IFX and Tac start than 2 meant remission, while at least a 30% decrease in the DAI score was defined as response to therapy 2013 All patients had steroid-refractory or dependent UC (use Remission was partial Mayo score of .40 mg/d for 2 wk without improvement), of 1 or less. Response was with minimum Mayo score of 3, and primary or decrease in partial Mayo score of secondary loss of response to Tac. Authors provided at least 3 points and 30% from details on time between Tac and IFX administration: baseline range of 1–7 d (10 patients had 1 d between treatments) 2014 Severe steroid-refractory UC patients treated with Tac or Response was decreased in MTWSI IFX. Reason for sequential therapy was failure of .3 from baseline. Response was initial rescue therapy to induce remission. Ten to 42 MTWSI score ,5 d lapsed after IFX failure before start of Tac. For Tac failure, IFX was started concurrently in 8 patients and after Tac cessation of 7–11 d in 2 patients

CRP, C-reactive protein; DAI, Disease Activity Index; IFX, infliximab; MTWSI, Modified Truelove and Witts Severity Index.

available in their abstracts, which was included in this pooled analysis.17,23 Some authors did not respond to our inquiry or could not provide further details beyond their abstracts and as such were excluded from our pooled analysis.25–27,30,33 Overall, 10 studies with 314 participants were eligible for pooled analysis.14–23 Treatment response, remission, and mortality rates were reported in all of the studies. Data on adverse events were reported in 8 studies, serious infection rate in 9 studies, 12-month colectomy rate in 8 studies, and 3-month colectomy rate in 5 studies.

Characteristics of Included Studies Characteristics of studies included are outlined in Tables 1 and 2. One study used a prospective design,21 and the remaining studies were retrospective cohort. Most of the studies used a multiple-dose regimen of IFX for induction. In studies assessing sequential experience with CsA, the intravenous formulation was used for induction. The dosing and target level of CsA was variable among studies, with a range between 20018 and 400 ng/mL,14 reported. Further details are provided in Table 2. Tac was administered orally in all of the studies eligible for inclusion, with a target trough level ranging from 519 to 15 ng/mL.21–23 A large portion of patients in all of the studies were on

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concomitant steroids and/or thiopurines during the sequential rescue therapy, except for Yamamoto et al19 and Takeuchi et al21 where patients were largely weaned off steroids and thiopurines before commencement of a sequential rescue therapy. The duration and technique used for steroid tapering in these studies were not specified.

Sequential Therapy with Cyclosporine Five studies reported therapeutic response and included 230 subjects who received IFX after CsA or vice versa (Table 3). Among 193 patients who failed CsA and then received IFX, 129 (66.8%; 95% CI, 60.2%–73.4%) achieved a therapeutic response and 80 (41.5%; 95% CI, 34.6%–48.4%) achieved remission. The colectomy rate was 29.7% at 3 months (41/138; 95% CI, 22.1%– 37.3%) and 42.8% at 12 months (59/138; 95% CI, 34.5%– 51.1%). Adverse events were noted in 21.7% of patients (31/ 138; 95% CI, 14.8%–28.6%), including serious infections in 8.7% (12/138; 95% CI, 4.0%–13.4%) and death in 1.6% (3/ 193; 95% CI, 0%–3.4%). The median interval between stopping CsA and starting IFX ranged from 2 to 19 days. There were 37 patients who failed IFX and then started CsA. Treatment response was achieved in 59.5% (22/37; 95%





FIGURE 1. PRISMA diagram detailing search results.

CI, 43.7%–75.3%), and remission was attained in 18.9% (7/37; 95% CI, 6.2%–31.5%) of patients. Colectomy was required in 30.0% (9/30; 95% CI, 13.6%–46.4%) by 3 months and 56.7% (17/30; 95% CI, 39.0%–74.4%) by 12 months. Adverse events were encountered by 33.3% (10/30; 95% CI, 16.4%–50.2%), including serious infections in 13.3% (4/30; 95% CI, 1.1%–25.4%). No deaths were reported. The median interval between cessation of IFX and start of CsA ranged from 19 to 21 days.

Sequential Therapy with Tacrolimus Five studies reported 84 subjects who received IFX and Tac in sequence. Among 59 patients who failed Tac and then commenced IFX, 50.8% (30/59; 95% CI, 38.0%–63.6%) showed therapeutic response and 40.7% (24/59; 95% CI, 28.2%–53.2%) achieved remission. The colectomy rate was 8.3% (1/12; 95% CI, 0%–23.9%) at 3 months and 43.5% (20/46; 95% CI, 29.2%– 57.8%) at 12 months. Adverse events were reported in 12/49 (24.5%; 95% CI, 12.5%–36.5%), including serious infections in 1/49 (1.7%; 95% CI, 0%–5%). No deaths were reported. The median interval between failure of Tac and initiation of IFX ranged from 1 day to 4 weeks. It is worthwhile to mention that 2 studies added IFX but continued Tac despite failure of Tac therapy.19,23 Twenty-five patients were reported who failed IFX and then began Tac. Treatment response was achieved in 15/25 (60%; 95% CI, 40.8%–79.2%), and remission was attained in 11/25 (44%; 95% CI, 24.5%–63.5%). Colectomy was

necessary in 5/25 (20%; 95% CI, 4.3%–35.7%) by 12 months. Adverse events occurred in 3/25 (13.6%; 95% CI, 0%–27.0%) without any serious infections or deaths. The median interval between stopping IFX and commencing Tac was 2 weeks.

Summary of Sequential Therapy Experience In total, 314 patients underwent sequential therapy with a calcineurin inhibitor and IFX. Most patients responded to third-line rescue therapy (62.4%; 95% CI, 57.0%–67.8%; 196/314), with remission in 38.9% (122/314; 95% CI, 33.5%–44.3%) (Figs. 2 and 3). The overall colectomy rate was 28.3% (51/180; 95% CI, 21.7%–34.5%) at 3 months and 42.3% (101/239; 95% CI, 36.0%–48.6%) at 12 months, as illustrated in Figs. 4 and 5. Adverse events were encountered by 23.0% (55/239; 95% CI, 17.7%–28.3%) of patients, including serious infections in 6.7% (17/252; 95% CI, 3.6%–9.8%) and mortality in 1% (3/314; 95% CI, 0%–2.1%) (Figs. 6–8).

Quality Assessment According to the GRADE system for assessing quality, evidence from observational evidence begins with a “low” rating. We downgraded the rating to “very low” due to the risk of bias in some of the observational studies, mainly due to inclusion of abstracts where the risk of bias was largely unclear. Details are available in Supplemental Digital Content 1, http://links.lww. com/IBD/A776. www.ibdjournal.org |

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TABLE 2. Characteristics of Included Studies and patients First Author

Year

CNI Regimen

Sequence Studied

Trials that used cyclosporine in sequential therapy Chaparro16 2012 IV to achieve therapeutic CsA -. IFX range (target level not specified) 2011 IV 2 or 4 mg/kg/d with CsA -. IFX Leblanc15 switch to oral at double dose if response IFX -. CsA

No. of patients

Thiopurines in 87% of patients

Median: 6 d (range, 0–30 d)

65

Steroids in 83%; AZA/6-MP in 49%; MTX in 5%


21

Steroids in 90%; AZA/6-MP in Median: 19 d (range, 10–35 d) 48%; MTX in 29% 22% of patients receiving IFX on NA concurrent steroids/AZA; 70% of patients receiving CsA on concurrent steroids/AZA NA 7 patients on concomitant Median: 17 d (range, 1–30 d) immunosuppressants

2013 IV to achieve therapeutic CsA -. IFX range (target level not specified)

55

Maser14

2008 IV to achieve trough levels of 300–400 ng/mL

IFX -. CsA CsA -. IFX

7 10

IFX -. CsA

9

2009 IV 4 mg/kg/d with target CsA -. IFX trough level of 200– 400 ng/mL Trials that used tacrolimus in sequential therapy Yamamoto19 2010 Oral at target trough level Tac -. IFX of 5–10 ng/mL

16

6 patients on concomitant immunosuppressants 75% on concurrent thiopurines; 100% on steroids


12

1/12 on concurrent steroids, 7/12 on concurrent Tac, 3/12 on concurrent AZA/Tac

Tac -. IFX

24

10/24 on thiopurines, 4/24 on MTX, 1/24 on concurrent Tac

Patients who were given rescue therapy with IFX were administered concurrently with Tac or within 4 wk of Tac discontinuation 1 wk between Tac cessation and IFX start

Tac -. IFX

13

11/13 on steroids, 3/13 on thiopurines

Range of 1–7 d (10 patients had 1 d between treatments)

IFX-. Tac

22

Nil

2 wk lapsed between last dose of IFX and Tac start

IFX-. Tac

3

Details not provided

10–42 d

Tac -. IFX

10

Manosa18

Tsukamoto22

Takeuchi21

Minami23

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2010 Oral at 0.1 mg/kg, with target trough level of 10 ng/mL 2013 Oral at target trough level of 10–15 ng/mL for 2 wk, then 5–10 ng/mL 2013 Oral to target trough level of 10–15 ng/mL as induction, then 5–10 ng/mL as maintenance 2014 Oral at 0.1 mg/kg, with target trough level of 10–15 ng/mL

Time Lapsed Between Rescue Treatments

47

Ordas17

Herrlinger20

Concomitant Medication


IFX was started concurrently in 8 patients, and after Tac cessation of 7–11 d in 2 patients





TABLE 2 (Continued)

First Author

Treatment Response (No. of patients)

Remission (No. 3-mo of patients) colectomy

Trials that used cyclosporine in sequential therapy Chaparro16 34 21 Leblanc15 38 16 13 3 Ordas17 38 29 4 1 Maser14 6 4 5 3 Manosa18 13 10 Trials that used tacrolimus in sequential therapy Yamamoto19 6 6 Herrlinger20 10 6 Tsukamoto22 8 6 Takeuchi21 12 8 Minami23 3 3 6 6

12-mo colectomy (No. of patients)

Adverse Events (No. of patients)

Serious Infections (No. of patients)

Mortality (No. of patients)

8 26 7 NA NA 2 2 5

14 35 13 NA NA 4 4 6

11 15 5 NA NA 1 5 3

3 7 2 NA NA 1 2 1

1 1 0 0 0 1 0 0

1 NA NA NA NA NA

5 11 NA 5 0 4

2 8 2 3 NA NA

0 1 0 0 0 0

0 0 0 0 0 0

6-MP, 6-mercaptopurine; AZA, azathioprine; CNI, calcineurin inhibitor; CsA, cyclosporine A; IFX, infliximab; IV, intravenous; MTX, methotrexate; NA, data not available; Tac, tacrolimus.

DISCUSSION The management of steroid-refractory acute severe UC is clinically challenging and requires collaborative care with a team of health professionals including both a gastroenterologist and a colorectal surgeon. Current guidelines advocate that failure of 1 medical rescue therapy should prompt colectomy.7,13 This is mainly due to concern for serious infections and increased mortality in the setting of a second medical rescue therapy. However, our systematic review suggests that the outcomes of sequential rescue therapy may not be as unsafe as previously thought. The pooled experience of sequential therapy in steroid-refractory severe UC suggests an adverse event rate of 23.0%, with serious infections in 6.7% and mortality in 1%. All of the deaths that occurred were in patients who received IFX subsequent to failure of a calcineurin inhibitor. However, there were extenuating or atypical circumstances around 2 of the 3 mortalities reported. One patient had psychomotor retardation and after his colectomy was delayed for legal reasons, he remained on corticosteroids for over 3 months. He eventually underwent colectomy but died 2 days postoperatively because of nosocomial pneumonia.16 Another death was due to pulmonary embolism at day 1 after colectomy. This patient received CsA for 16 days before 2 infusions of IFX and received concomitant steroids and azathioprine.15 Mortality in the setting of sequential rescue therapy for severe UC can reflect both ongoing disease activity and the cumulative

background exposure to conventional therapies such as corticosteroids. Avoidance of colectomy with ileostomy is desirable for most patients. A recent study revealed that patients with UC are willing to accept a 10-year risk of mortality from lymphoma or infection of greater than 5% to avoid an ostomy, regardless of medication efficacy.36 Patients preferred J-pouch surgeries to ostomies and perceive J-pouch surgery as an acceptable option when medical therapy is unable to induce durable remission.36 Given this, the use of sequential rescue therapy may be preferred by many patients, despite the risks of adverse outcomes including death. This systematic review demonstrates a pooled response rate of 62.4% and a remission rate of 38.9%, meaning a large portion of patients who otherwise would have received colectomy can be treated into remission. Where sequential rescue therapy yields a response but not remission, physicians should use this opportunity to wean corticosteroids rapidly and optimize nutritional status before elective colectomy. Outcomes of elective colectomy are significantly better than those of urgent colectomy, with improved morbidity and mortality rates,37,38 as well as more opportunity for one-stage procedures that avoid the need for ostomy.39 Although not measured directly in this systematic review, deferral of urgent colectomy to the elective setting can be associated with significant improvement in patient outcomes and should also be considered a successful outcome of sequential rescue therapy. www.ibdjournal.org |

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1.6 0.0 1.2 0.0 0.0 0.0 1.0 3 0 3 0 0 0 3 8.7 1.7 6.6 13.3 0.0 7.3 6.7 12 1 13 4 0 4 17 21.7 24.5 22.5 33.3 13.6 25.0 23.0 30 12 42 10 3 13 55 42.8 43.5 42.9 56.7 20.0 40.0 42.3

FIGURE 2. Summary of pooled results for treatment response.

CNI, calcineurin inhibitor; CsA, cyclosporine A; IFX, infliximab; NA, data not available; Tac, tacrolimus.

CsA -. IFX Tac -. IFX all CNI -. IFX IFX -. CsA IFX -. Tac IFX -. all CNI Total outcomes with sequential therapy (all CNI -. IFX, or vice versa)

193 59 252 37 25 62 314

129 30 159 22 15 37 196

66.8 50.8 63.1 59.5 60.0 59.7 62.4

80 24 104 7 11 18 122

41.5 40.7 41.3 18.9 44.0 29.0 38.9

41 1 42 9 NA 9 51

29.7 8.3 28.0 30.0 NA 30.0 28.3

59 20 79 17 5 22 101

% % %

Remission, n Total Treatment Patients Response, n Sequential Treatment Regimen

TABLE 3. Summary of Sequential Therapy Experience

%

3-Month Colectomy, n

%

12-Month Colectomy, n

Adverse Events, n

Serious Infections, n

%

Mortality, n

%

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Of note, urgent colectomy also has adverse outcomes, and these may be worse than those attributed to sequential rescue therapy. A recent meta-analysis concluded that the risk of postoperative mortality after emergent surgery in UC is 5.7% (95% CI, 4.0%–8.1%).37 Another systematic review revealed that the overall morbidity after colectomy is 50.8% (95% CI, 45.9%– 55.7%), including high rates of infectious complications such as septicemia (18%), pneumonia (11.2%), abscess (8.6%), wound infections (12.7%), and urinary tract infection (4.3%).38 There are certain clinical settings where urgent colectomy is the only advisable management option, such as perforation, refractory megacolon, or exsanguinating hemorrhage.40 However in the setting of failed medical management with steroids or salvage therapy, the relative risks of surgery and an alternative rescue therapy should be considered. The decision to proceed to alternative salvage therapies or surgery should be made promptly, however, as it has been shown that postoperative complications tend to correlate with longer time from admission to colectomy.41 Several authors have reported on sequential therapy experiences in psoriasis, with patients transitioning from CsA to

FIGURE 3. Summary of pooled results for treatment remission.





FIGURE 4. Summary of pooled results for 3-month colectomy rate.

FIGURE 6. Summary of pooled results for overall adverse events.

etanercept (a recombinant human soluble TNF receptor fusion antibody) or vice versa. All of these reported experiences include several weeks of overlapping treatment, and no patients are on concomitant systemic corticosteroids.42–44 No serious adverse events or infectious complications were reported in any of these series. Indeed, there may even be a synergistic effect of calcineurin inhibitors with anti–TNF-a therapies. The combination of CsA with anti–TNF-a antibodies was found to reduce interferon gamma production by CD4+ T cells, TNF-a expression from macrophages, and activity of type 1 T helper cells in murine models.45 There is limited experience with concurrent use of calcineurin inhibitors and anti–TNF-a therapies in humans with UC. In the study by Yamamoto et al,19 10 of 12 patients who were given IFX after failure of Tac were continued on concurrent Tac, but the limited sample size does not inform whether those on concurrent Tac were more likely to have therapeutic response than those not using Tac. The combination of calcineurin inhibitors and anti–TNF-a therapies has been explored in some other autoimmune diseases. An open-label study of refractory rheumatoid arthritis patients found that the addition of IFX (3 mg/kg at 0, 2, 6, and every 8 wk thereafter) to patients already on CsA

(2 mg$kg21$d21) and prednisone 5 mg per day led to achievement of the American College of Rheumatology (ACR) 20 response criteria in 80% of patients and reduction in swollen and tender joints in 76%.46 The combination was well tolerated, and in 12 months of follow-up, 2 patients developed upper respiratory tract infections that responded well to oral antibiotics and 2 patients discontinued treatment, one due to hypersensitivity reaction to IFX and the other because of activation of pulmonary tuberculosis.46 Another prospective open-label trial evaluated the role of adalimumab with CsA in patients with severely active psoriatic arthritis. In this trial, 57, 58, and 55 patients were treated with CsA (2.5–3.75 mg$kg21$d21), adalimumab (40 mg every other week), or the combination of both. At 12 months, the ACR 50 response rates were 36%, 69%, and 87%, respectively (P , 0.0001 and P ¼ 0.03 compared with monotherapy arms), with similar adverse events and no serious infections or mortality in any group.47 The serious infectious complications observed in these trials of combination therapy for immune-mediated conditions other than UC are quite low. In UC, our systematic review demonstrates a serious infectious complication rate of 6.7%,

FIGURE 5. Summary of pooled results for 12-month colectomy rate.

FIGURE 7. Summary of pooled results for serious infections. www.ibdjournal.org |

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FIGURE 8. Summary of pooled results for mortality.

possibly due to higher rates of concurrent corticosteroid use than in trials of rheumatoid arthritis and psoriatic arthritis. Most of the studies included in this systematic review continued corticosteroids during sequential rescue therapy. However, in the studies by Yamamoto et al and Takeuchi et al, only 1 patient received concomitant corticosteroid therapy during IFX administration.19,21 No patients in these cohorts experienced any infectious complications or death. Use of corticosteroids has been previously linked with serious infections in patients with UC.48,49 Furthermore, separate studies have demonstrated that preoperative CsA or IFX does not seem to increase the risk of postoperative infectious complications.50–52 Thus, when considering the use of sequential rescue therapy, tapering corticosteroids may be essential to lower the risk of serious infectious events. The response rates demonstrated with sequential therapy in our study were similar no matter which agent was used first. The remission rate seen for IFX after failed calcineurin inhibitor therapy was numerically higher, but this difference was not statistically significant (P ¼ 0.0825 using Fisher’s exact test). Maser at al suggested that initial use of calcineurin inhibitors may be reasonable because of a shorter half-life of these agents (CsA: 6 h,53 Tac: 12 h54) compared with IFX (18.5 d55).14 However, our systematic review found that administration of calcineurin inhibitors after failure of IFX was not associated with any mortality, but too few patients underwent this sequence to adequately inform clinicians on the safety of this regimen. One potential technique to help maximize safety outcomes is to check drug levels before commencement of sequential rescue therapy. Non-response to IFX may be due to rapid metabolism or clearance of the drug, with potential loss of drug in stool as a potential explanation.56 Assessment of IFX drug levels and antibodies to confirm the mechanism of non-response can also be useful to minimize toxicity and guide initiation of a calcineurin inhibitor. Rubin et al57 reported their experience with primary non-response to IFX due to formation of antidrug antibodies and rapid clearance of IFX, with initiation of CsA when serum IFX was no longer detectable. A patient with partial response to IFX but with rapid

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clearance leading to negative drug levels with no antidrug antibodies may benefit from an additional booster dose of IFX instead of switching to a calcineurin inhibitor, but the exact protocol and dose for a booster is currently still being studied in prospective studies (ClinicalTrials.gov: NCT01971814). Calcineurin inhibitor drug levels are readily available and similarly can be checked before beginning IFX therapy. Herrlinger et al20 ensured that all patients being considered for sequential rescue treatment had negative Tac levels before start of IFX. Use of therapeutic drug monitoring in randomized controlled trials on outcomes of IFX after failure of calcineurin inhibitors, and vice versa, could help clarify the use of drug levels in this setting. In conclusion, acute severe UC provides challenges for physicians and surgeons who manage these patients. When both corticosteroids and initial rescue therapy fail, a second salvage agent can be considered. The risk of sequential therapy in steroid-refractory UC seems lower than initially reported. However, the evidence is limited as data from prospective controlled trials are missing. The sequence of IFX followed by calcineurin inhibitors, or vice versa, appear to have similar treatment outcomes regarding avoidance of colectomy and risk of adverse events. Sequential rescue therapy should only be performed at specialized referral centers familiar with the use of calcineurin inhibition.7 Early tapering of corticosteroids may help lower the risk of serious infectious complications. The optimal time interval between rescue agents is not clear from this systematic review, but assessing for clearance of initial drug used before initiation of a sequential therapy may help minimize toxicity associated with salvage therapies. Regardless, decisions about response to rescue therapy should be made in a timely manner, as postoperative complications are increased in those who have prolonged medical therapy before colectomy. Certain situations require urgent colectomy, such as refractory megacolon, perforation, or severe hemorrhaging, and use of sequential rescue therapy should be avoided in these cases. More prospective controlled trials could further inform outcomes with sequential rescue therapy compared with urgent colectomy in a setting of failed medical management and determine whether IFX or calcineurin inhibitors should be given first, or administered as combination, in patients with steroid-refractory UC. In the absence of prospective trials, ongoing comprehensive reporting of observational experiences is necessary to continue monitoring the safety of this experience.

ACKNOWLEDGMENTS The study investigators would like to thank Dr. Satoshi Tanida (Nagoya, Japan), Dr. Ingrid Ordas (Barcelona, Spain), and Dr. Hiroshi Nakase (Kyoto, Japan) for providing additional data for use in the meta-analysis. Author contributions: Study concept and design, analysis and interpretation of data, drafting of the article, and statistical analysis, N. Narula; Study concept, design, and supervision and drafting of the article, J. K. Marshall, W. Reinisch; Study design




and drafting of the article, J-F. Colombel; Literature search, acquisition of data, and quality assessment, M. Fine, N. Narula.

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