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Review
Ability of different rescue therapies to save the bowel in acute, severe, steroid-refractory ulcerative colitis Expert Rev. Gastroenterol. Hepatol. 8(6), 695–702 (2014)
Klaudia Farkas, Tama´s Molna´r and Zolta´n Szepes* First Department of Medicine, University of Szeged, 8-10 Koranyi fasor, Szeged, H6720, Hungary *Author for correspondence: [email protected]
To date, corticosteroids have been the primary therapies for acute, severe ulcerative colitis (UC). Patients not responding to intravenous steroids assessed at 3–5 days of the treatment are candidates for second-line rescue therapy. Cyclosporine (CsA), tacrolimus and infliximab (IFX) are also effective therapeutic options in acute, severe UC. In this review we summarized the results of the published studies examining and comparing the efficacy of CsA, tacrolimus and IFX as rescue therapies, and assessing the outcome of switching the drugs in case of therapeutic failure. KEYWORDS: acute ulcerative colitis • cyclosporine • infliximab • rescue therapy • tacrolimus
Acute severe ulcerative colitis (UC) is a potentially emergency condition that requires close cooperation between gastroenterologists and surgeons. Intravenous corticosteroids remain the first-line treatment in acute severe UC. Hospitalized patients who fail to respond to 3–5 days intensive treatment with steroids most frequently in a dose of 1 mg/bwkg daily should be considered as candidates for rescue treatment [1]. The calcineurin inhibitors cyclosporine (CsA) and tacrolimus that selectively inhibit T-cell-mediated IL-2 production and the monoclonal antibody blocking TNF-a infliximab (IFX) are potential therapeutic choices to save the bowel [1–3]. Although the short-term response rates of CsA are about 70–80%, it is also well known that a high number of the initial responders relapse and about 50% of them will undergo colectomy in the following 3–7 years [4,5]. In the case of tacrolimus, remission is achieved in 50–70% of the patients, while long-term colectomy-free survival varies between 50 and 62%. After inducing remission with tacrolimus and CsA, immunosuppression is usually maintained with the use of azathioprine or 6-mercaptopurine. IFX has been established as an effective therapeutic option in acute steroid-refractory UC. First, a randomized controlled trial by Jarnerot et al. found a single IFX infusion to be
informahealthcare.com
10.1586/17474124.2014.909726
an effective and safe rescue therapy in patients experiencing an acute severe or moderately severe attack of UC not responding to conventional treatment [3]. The efficacy of IFX in moderateto-severe UC had also been demonstrated in a large population of the active ulcerative colitis trial (ACT) 1 and 2 studies [6]. This review aims to summarize the results of the published studies examining and comparing the short- and long-term results of CsA, tacrolimus and IFX as rescue therapies and assess the outcome of switching the drugs in case of therapeutic failure. Cyclosporine
Intravenous (i.v.) CsA proved to be an effective rescue therapy for severe attacks of UC. In the first randomized, double-blind, controlled trial by Lichtiger et al., 9 of 11 patients (82%) treated with CsA 4 mg/kg had a response within a mean of 7 days and avoided early colectomy, as compared with 0 of 9 patients who received placebo [2]. Short-term efficacy of cyclosporine therapy as an i.v. steroidreplacement drug was also confirmed by the study by D’Haens et al. [7]. They investigated the effects of i.v. CsA 4 mg/kg/day as single i.v. therapy (without glucocorticosteroids) for severe UC and compared these with the response to glucocorticosteroids 40 mg/day.
2014 Informa UK Ltd
ISSN 1747-4124
695
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Review
´ r & Szepes Farkas, Molna
Of the 30 patients included in the study, 53% who received methylprednisolone had a response to therapy versus 64% receiving CsA. At 12 months, 7 of 9 patients (78%) initially controlled with CsA maintained their remission versus 3 of 8 (37%) initially treated with methylprednisolone. The i.v. starting dose of 4 mg/kg CsA is usually recommended in UC patients refractory to corticosteroids, although a lower dose regimen of 2 mg/kg also proved to be as effective as 4 mg/kg/day in only one study by Van Assche et al. [8]. Shortterm colectomy rates proved to be 13.1 and 8.6% at the dose regimens of 4 and 2 mg/kg, respectively, in this study. According to the European Crohn’s and Colitis Organisation guideline, suitable target levels of CsA in responders on oral medication are whole-blood trough levels of 150–250 ng/ml. The 2-h post-dose peak levels give the best estimate of drug exposure and an appropriate target appears to be 700 ng/ml [9]. Long-term colectomy rates vary between 60 and 88% among patients in whom CsA initially induced remission [4]. 83% of the patients with a severe attack of UC in the Moskovitz’s study showed initial response to CsA, while the long-term colectomy-free remission rate proved to be 63 and 48% at years 1 and 3. In the study by Mocciaro et al., the colectomy rate was 48% at 1 year in 35 UC patients treated with CsA [10]. Colectomy-free survival rates varied between 61 and 77% at 1 year, 43 and 57.7% at 3 years and 48.4 and 54% at 5 years in other studies [11–17]. In our retrospective study, colectomy-free survival was 53.4% during the 4.2-year followup period and significantly increased in the case of a longer duration of CsA therapy. If patients were treated for a year, the probability to avoid colectomy proved to be 66% [18]. After 7 years, colectomy frequencies of 58% [5], 65% [19] and 88% [4] were reported. Tacrolimus
Oral tacrolimus, approved for the prophylaxis of kidney and liver transplant rejection, has been shown to be effective in patients with severe UC refractory to conventional therapy; however, these studies were usually small, single-center observational trials. The largest study by Fellermann et al. reported 38 patients with refractory UC or indeterminate colitis who were treated with oral tacrolimus. Eighteen of 38 patients improved within 14 days. The overall colectomy rate was 34% over 16 months [20]. In the study by Hogenauer et al., 6 of the 9 (67%) patients with active, moderate/severe steroid-refractory UC were in complete remission after 12 weeks of tacrolimus therapy, and 1 (11%) patient underwent colectomy. The colectomy-free survival rate was 67% after a mean follow-up of 21 months [21]. In the first randomized controlled trial of tacrolimus in steroid-refractory UC by Ogata et al. in 2006, two tacrolimus arms with low (5–10 ng/ml) and high (10–15 ng/ml) trough levels were compared with a placebo group. At the end of 2 weeks of treatment, clinical response was observed in 68 and 38% of the patients of the high and low trough groups, respectively, and in 10% of the placebo group [22]. 696
According to the European Crohn’s and Colitis Organisation guidelines, tacrolimus is more effective when given at a dose that achieves a trough concentration of 10–15 ng/ml. The initial oral dose in steroid-refractory patients with active UC is 0.05–0.1 mg/kg/day, which is increased according to the trough level after 24 h [7]. The retrospective single-center study by Baumgart et al. found that tacrolimus was more effective in UC and colonic Crohn’s disease, suggesting the importance of colonic involvement in the therapeutic effect [23]. In a phase III, double-blind, placebo-controlled trial of tacrolimus by Ogata et al., the data of 62 patients with steroid-refractory moderate-to-severe UC were evaluated. The clinical response rate was 50% in the tacrolimus group and 13.3% in the placebo group at week 2 [24]. Although the short-term results of tacrolimus are questionable due to the quality of the studies, data on the long-term outcome of patients on tacrolimus are more obscure. Longterm prognosis was evaluated in only three studies: in the study by Fellermann et al. [20] the colectomy-free rate was 50% in 24 months; in the study by Baumgart et al. [23] the colectomyfree survival rate was 56.5% at 43.8 months; and the study by Yamamoto et al. [25] showed a 62% colectomy-free rate in patients who were clinical responders to tacrolimus during a 65-month follow-up period. These results should be treated with caution because the number of patients enrolled in the trials was small, the majority of the studies were retrospective and in most of the studies disease activity scores were retrospectively calculated. Infliximab
A randomized controlled trial by Jarnerot et al. was the first that found single IFX infusion to be effective in moderate-tosevere steroid-refractory UC [3]. At 90 days, colectomies had been performed on 7 of 24 IFX-treated patients and 14 of 21 placebo patients (p = 0.017). In 2005, Rutgeerts et al. published two large-scale randomized controlled trials (ACT 1 and ACT 2) that showed the efficacy of IFX to that of a placebo for the induction of clinical and endoscopic remission in the cases of moderate-to-severe UC [6]. Long-term benefit of IFX in severe steroid-refractory UC may be still questionable. In the paper by Gustavsson et al., which was the long-term extension of the Jarnerot’s study, the benefit of rescue therapy with IFX in steroidrefractory acute UC was shown to remain after 3 years. 50% of the patients receiving IFX versus 76% receiving placebo had colectomy after a 3-year follow-up in this study [26]. In the study by Kohn et al., 15% of the enrolled patients with severe UC treated with IFX underwent colectomy within 2 months. After a median time of 23 months, 82.9% of the patients avoided late colectomy [27]. A retrospective study of 30 patients conducted at Oxford revealed that 53% of the patients required colectomy and only 17% achieved steroid-free remission after a median follow-up of 13 months [28]. Expert Rev. Gastroenterol. Hepatol. 8(6), (2014)
Ability of different rescue therapies to save the bowel in acute, severe, steroid-refractory UC
Review
Table 1. Summary of trials examining the efficacy of cyclosporine, tacrolimus and infliximab in acute severe ulcerative colitis.
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nanyang Technological University on 04/26/15 For personal use only.
Study (year)
Patients (n)
Short-term response (%)
Long-term colectomy-free remission (%) At 1 year
At 3 years
At 5 years
Follow-up (years)
Ref.
Cyclosporine Lichtiger et al. (1994)
20
82
–
–
–
Unknown
[2]
D’Haens et al. (2001)
29
64
78
–
–
1
[7]
Van Assche et al. (2003)
73
86.9 (4 mg/kg) versus 91.4 (2 mg/kg)
–
–
–
Unknown
[8]
Moskovitz et al. (2006)
142
83
63
48
–
7
[4]
Mocciaro et al. (2012)
65
71.5
52
43
–
3
[10]
Kobayashi et al. (2010)
72
73.6
–
–
–
Unknown
[12]
Cheifetz et al. (2011)
71
85
61
–
54
5
[13]
Fellermann et al. (2002)
38
47.4
–
–
–
2
[20]
Baumgart et al. (2006)
23
96
–
–
–
Unknown
[23]
Ogata et al. (2012)
62
50
–
–
–
Unknown
[24]
Jarnerot et al. (2005)
45
71
–
–
–
>6 months
[5]
Kohn et al. (2007)
83
85
~70
–
–
23 months
[27]
Rutgeerts et al. (ACT 1-2005)
364
69.4 (5 mg/kg) and 61.5 (10 mg/kg)
~45.5
–
–
13.5 months
[6]
Rutgeerts et al. (ACT 2-2005)
364
64.5 (5 mg/kg) and 69.2 (10 mg/kg)
–
–
–
7.5 months
[6]
Tacrolimus
Infliximab
ACT: Active ulcerative colitis trial.
TABLE 1 summarizes the trials examining the efficacy of CsA, tacrolimus and IFX in acute severe UC.
Comparison between tacrolimus versus CsA
No head-to-head comparison between CsA and tacrolimus in acute severe UC has been published. However, in patients with liver, kidney and bone marrow transplantation tacrolimus appeared to be superior to CsA in improving graft survival and in preventing acute rejection after transplantation [29]. However, these results came from a completely different patient population and naturally it is impossible to extrapolate it to the UC. Comparison between CsA & IFX
The parallel, open-label, randomized, controlled trial by the Groupe d’Etudes Therapeutiques des Affections Inflammatoires Digestives was the first that directly compared the efficacy of CsA and IFX in acute severe UC not responding to intravenous steroid therapy for at least 5 days [30]. CsA and IFX were randomly given to 58 and 57 patients. Treatment failure (defined as the presence of any of the six following criteria: absence of clinical response at day 7; relapse between day 7 and 98 (defined as a Lichtiger score informahealthcare.com
increase of at least 3 points from the previous value that lasts for at least three consecutive days and leads to treatment modification); absence of steroid-free remission at day 98 (defined as a Mayo disease activity index score £2 with an endoscopic subscore £1); a severe adverse event leading to treatment interruption; colectomy and death) was noticed in 60% of the patients given CsA compared with 54% given IFX. No difference was observed in the rate of colectomy between the groups. The clinical activity decreased faster in patients who received IFX versus CsA; this difference was significant on days 3 and 4. The median time to clinical response was 5 days in the CsA group and 4 days in the IFX group. In a retrospective review of inpatients with steroid-refractory UC, the outcomes of 19 patients receiving CsA and 19 receiving IFX were examined [31]. At 3 months, the colectomy rate was 63% for CsA compared to 21% for IFX (p = 0.0094). By 12 months, the rate was 68 and 37% for CsA and IFX (p = 0.06). In this study, CsA was used in a dose of 2 mg/kg and more patients received concomitant immunosuppressive drugs at the time of salvage therapy in the IFX-treated group. An Italian single-center trial conducted in 21 patients found no difference in 30-day remission rates achieved with IFX versus CsA, although IFX was associated with more 697
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Review
´ r & Szepes Farkas, Molna
infectious complications than CsA [32]. Sjo¨berg et al. [14] found that a single IFX infusion was more effective in preventing early and late colectomy than CsA (93 vs 67% at 3 months and 77 vs 57% at 12 months). In this study, the first attack of the disease was significantly more common in IFX-treated patients and patients in the CsA group had more severe disease activity. In the prospective study by Croft et al., the clinical outcomes of 83 CsA- or IFXtreated patients with steroid-refractory acute severe UC were compared. CsA was given to 45 and IFX to 38 patients. Of those patients who received ‡72 h of CsA 2–4 mg/kg, 56% avoided colectomy, while 84% of those administered one dose of IFX 5 mg/kg (p = 0.006) avoided colectomy. At 3 months, the colectomy-free rate was 53% for CsA versus 76% for IFX (p = 0.04) and 42 versus 65% at 12 months (p = 0.04) [33]. A meta-analysis published by Chang et al., including the data of 321 patients, demonstrated that the rates of colectomy at 3 and 12 months, adverse drug reactions and postoperative complications are equivalent when using IFX or CsA as rescue therapy in acute severe UC [34]. The currently ongoing trial CONSTRUCT (COmparison of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis) that aims to determine the clinical and cost effectiveness of IFX and CsA in acute severe steroid-resistant UC may provide an adequate comparison between the two rescue therapies [35]. Switching between calcineurin inhibitors & IFX
Cumulative immunosuppressive effects are a major concern if potent immunosuppressive agents are used sequentially. It is also important to decide the order of the therapies because of the different pharmacokinetic characteristics of the drugs. Since IFX levels can be detected in the serum for at least 8 weeks following treatment, the use of tacrolimus or CsA as first-line drugs in steroid-refractory UC may be practical because of their short half-life [36]. Considering the shift between tacrolimus and IFX, little data are available on the efficacy of either drug after the failure of the other. Herrlinger et al. evaluated the efficacy of IFX salvage therapy in patients with refractory UC failing to respond to tacrolimus. Twenty-four patients with tacrolimus-refractory active disease were treated with IFX 5 mg/kg at weeks 0, 2 and 6 and every 8 weeks thereafter, if tolerated [37]. 25% achieved remission following IFX infusion and 17% had an initial response only, but underwent proctocolectomy later because of loss of response or development of a delayed hypersensitivity reaction. Fourteen (58%) patients completely failed to respond, with 10 undergoing colectomy. They concluded that IFX offers a therapeutic option as rescue therapy in about a quarter of patients with active UC after failing to respond to tacrolimus. In a retrospective, observational, single-center study of 12 consecutively enrolled patients with UC refractory to tacrolimus who received IFX therapy (single infusion in the majority of the patients), 50% of the UC patients achieved clinical remission within 30 days. Colectomyfree survival was 58.3% at 41.4 months [38]. No randomized trials assessing the efficacy of tacrolimus after IFX therapy are available. 698
Only a few studies examined the outcomes of CsA and IFX treatment after the failure of the other drug in severe steroidrefractory UC. Ten patients received IFX after CsA failed and 9 patients received CsA after IFX failed in the study by Maser et al. Four patients (40%) in the IFX-salvage group achieved remission, as did 3 (33%) in the CsA-salvage group. Severe adverse events included one patient who developed sepsis and died after receiving IFX salvage [39]. Chaparro et al. examined the efficacy and safety of IFX after CsA failure in patients with steroid-refractory UC in a retrospective review. Of the 35 patients who received the third IFX infusion, 60% achieved remission and 37% achieved partial response. 30% underwent colectomy. The rate of adverse events was 23%, most commonly infections (8.4%). A 40-year-old man in whom CsA failed died of nosocomial pneumonia after the first IFX infusion. According to their results, two-third of corticosteroid- refractory UC patients on IFX therapy might avoid colectomy after failure of CsA [40]. In the retrospective study by Leblanc et al., patients with corticosteroid-refractory UC were reviewed and treated successively by either CsA after IFX failed or IFX after CsA failed. Sixty-five patients who failed to respond to CsA were treated with IFX and 21 patients who failed to respond to IFX received CsA. Of the 65 patients, 24 did not respond to CsA and 41 responded but relapsed under CsA and 6 relapsed immediately after discontinuation. Of the 21 patients, 9 did not respond to IFX and 12 responded but lost response. A total of 20 adverse events in 19 patients were observed after the second-line rescue therapy started, including one death in a patient who developed pulmonary embolism 1 day after surgery [41]. Side effects of rescue therapies
The use of CsA rescue therapies is usually limited by its side effect profile. The short-term side effects include hypertension, hypercholesterolemia, tremor, nausea/vomiting, renal insufficiency, headaches, anaphylaxis, infection, paresthesia and seizures [42]. In our recently published study, side effects occurred in 72.2% of the patients during CsA therapy. The most frequent side effects were hypertension (15.2%), tremor (13.8%), hypertrichosis (9.7%), myalgia and muscle cramping (11.1 and 4.2%, respectively) and numbness of legs (5.5%). Nephrotoxicity or hepatotoxicity occurred in 8.3% of the patients. Increased serum cholesterol and triglyceride levels were detected in 47.2 and 19.4% of the patients, respectively. The most frequent major side effects resulting in discontinuation of CsA were adverse muscle reactions (47.6%) and hypertension (38.1%), followed by gastrointestinal side effects including liver enzyme abnormalities (23.8%) and skin side effects [43]. Due to these common side effects, many patients cannot tolerate CsA therapy. CsA is contraindicated in patients who are severely hypocholesterolemic (serum cholesterol
Review
Ability of different rescue therapies to save the bowel in acute, severe, steroid-refractory ulcerative colitis Expert Rev. Gastroenterol. Hepatol. 8(6), 695–702 (2014)
Klaudia Farkas, Tama´s Molna´r and Zolta´n Szepes* First Department of Medicine, University of Szeged, 8-10 Koranyi fasor, Szeged, H6720, Hungary *Author for correspondence: [email protected]
To date, corticosteroids have been the primary therapies for acute, severe ulcerative colitis (UC). Patients not responding to intravenous steroids assessed at 3–5 days of the treatment are candidates for second-line rescue therapy. Cyclosporine (CsA), tacrolimus and infliximab (IFX) are also effective therapeutic options in acute, severe UC. In this review we summarized the results of the published studies examining and comparing the efficacy of CsA, tacrolimus and IFX as rescue therapies, and assessing the outcome of switching the drugs in case of therapeutic failure. KEYWORDS: acute ulcerative colitis • cyclosporine • infliximab • rescue therapy • tacrolimus
Acute severe ulcerative colitis (UC) is a potentially emergency condition that requires close cooperation between gastroenterologists and surgeons. Intravenous corticosteroids remain the first-line treatment in acute severe UC. Hospitalized patients who fail to respond to 3–5 days intensive treatment with steroids most frequently in a dose of 1 mg/bwkg daily should be considered as candidates for rescue treatment [1]. The calcineurin inhibitors cyclosporine (CsA) and tacrolimus that selectively inhibit T-cell-mediated IL-2 production and the monoclonal antibody blocking TNF-a infliximab (IFX) are potential therapeutic choices to save the bowel [1–3]. Although the short-term response rates of CsA are about 70–80%, it is also well known that a high number of the initial responders relapse and about 50% of them will undergo colectomy in the following 3–7 years [4,5]. In the case of tacrolimus, remission is achieved in 50–70% of the patients, while long-term colectomy-free survival varies between 50 and 62%. After inducing remission with tacrolimus and CsA, immunosuppression is usually maintained with the use of azathioprine or 6-mercaptopurine. IFX has been established as an effective therapeutic option in acute steroid-refractory UC. First, a randomized controlled trial by Jarnerot et al. found a single IFX infusion to be
informahealthcare.com
10.1586/17474124.2014.909726
an effective and safe rescue therapy in patients experiencing an acute severe or moderately severe attack of UC not responding to conventional treatment [3]. The efficacy of IFX in moderateto-severe UC had also been demonstrated in a large population of the active ulcerative colitis trial (ACT) 1 and 2 studies [6]. This review aims to summarize the results of the published studies examining and comparing the short- and long-term results of CsA, tacrolimus and IFX as rescue therapies and assess the outcome of switching the drugs in case of therapeutic failure. Cyclosporine
Intravenous (i.v.) CsA proved to be an effective rescue therapy for severe attacks of UC. In the first randomized, double-blind, controlled trial by Lichtiger et al., 9 of 11 patients (82%) treated with CsA 4 mg/kg had a response within a mean of 7 days and avoided early colectomy, as compared with 0 of 9 patients who received placebo [2]. Short-term efficacy of cyclosporine therapy as an i.v. steroidreplacement drug was also confirmed by the study by D’Haens et al. [7]. They investigated the effects of i.v. CsA 4 mg/kg/day as single i.v. therapy (without glucocorticosteroids) for severe UC and compared these with the response to glucocorticosteroids 40 mg/day.
2014 Informa UK Ltd
ISSN 1747-4124
695
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nanyang Technological University on 04/26/15 For personal use only.
Review
´ r & Szepes Farkas, Molna
Of the 30 patients included in the study, 53% who received methylprednisolone had a response to therapy versus 64% receiving CsA. At 12 months, 7 of 9 patients (78%) initially controlled with CsA maintained their remission versus 3 of 8 (37%) initially treated with methylprednisolone. The i.v. starting dose of 4 mg/kg CsA is usually recommended in UC patients refractory to corticosteroids, although a lower dose regimen of 2 mg/kg also proved to be as effective as 4 mg/kg/day in only one study by Van Assche et al. [8]. Shortterm colectomy rates proved to be 13.1 and 8.6% at the dose regimens of 4 and 2 mg/kg, respectively, in this study. According to the European Crohn’s and Colitis Organisation guideline, suitable target levels of CsA in responders on oral medication are whole-blood trough levels of 150–250 ng/ml. The 2-h post-dose peak levels give the best estimate of drug exposure and an appropriate target appears to be 700 ng/ml [9]. Long-term colectomy rates vary between 60 and 88% among patients in whom CsA initially induced remission [4]. 83% of the patients with a severe attack of UC in the Moskovitz’s study showed initial response to CsA, while the long-term colectomy-free remission rate proved to be 63 and 48% at years 1 and 3. In the study by Mocciaro et al., the colectomy rate was 48% at 1 year in 35 UC patients treated with CsA [10]. Colectomy-free survival rates varied between 61 and 77% at 1 year, 43 and 57.7% at 3 years and 48.4 and 54% at 5 years in other studies [11–17]. In our retrospective study, colectomy-free survival was 53.4% during the 4.2-year followup period and significantly increased in the case of a longer duration of CsA therapy. If patients were treated for a year, the probability to avoid colectomy proved to be 66% [18]. After 7 years, colectomy frequencies of 58% [5], 65% [19] and 88% [4] were reported. Tacrolimus
Oral tacrolimus, approved for the prophylaxis of kidney and liver transplant rejection, has been shown to be effective in patients with severe UC refractory to conventional therapy; however, these studies were usually small, single-center observational trials. The largest study by Fellermann et al. reported 38 patients with refractory UC or indeterminate colitis who were treated with oral tacrolimus. Eighteen of 38 patients improved within 14 days. The overall colectomy rate was 34% over 16 months [20]. In the study by Hogenauer et al., 6 of the 9 (67%) patients with active, moderate/severe steroid-refractory UC were in complete remission after 12 weeks of tacrolimus therapy, and 1 (11%) patient underwent colectomy. The colectomy-free survival rate was 67% after a mean follow-up of 21 months [21]. In the first randomized controlled trial of tacrolimus in steroid-refractory UC by Ogata et al. in 2006, two tacrolimus arms with low (5–10 ng/ml) and high (10–15 ng/ml) trough levels were compared with a placebo group. At the end of 2 weeks of treatment, clinical response was observed in 68 and 38% of the patients of the high and low trough groups, respectively, and in 10% of the placebo group [22]. 696
According to the European Crohn’s and Colitis Organisation guidelines, tacrolimus is more effective when given at a dose that achieves a trough concentration of 10–15 ng/ml. The initial oral dose in steroid-refractory patients with active UC is 0.05–0.1 mg/kg/day, which is increased according to the trough level after 24 h [7]. The retrospective single-center study by Baumgart et al. found that tacrolimus was more effective in UC and colonic Crohn’s disease, suggesting the importance of colonic involvement in the therapeutic effect [23]. In a phase III, double-blind, placebo-controlled trial of tacrolimus by Ogata et al., the data of 62 patients with steroid-refractory moderate-to-severe UC were evaluated. The clinical response rate was 50% in the tacrolimus group and 13.3% in the placebo group at week 2 [24]. Although the short-term results of tacrolimus are questionable due to the quality of the studies, data on the long-term outcome of patients on tacrolimus are more obscure. Longterm prognosis was evaluated in only three studies: in the study by Fellermann et al. [20] the colectomy-free rate was 50% in 24 months; in the study by Baumgart et al. [23] the colectomyfree survival rate was 56.5% at 43.8 months; and the study by Yamamoto et al. [25] showed a 62% colectomy-free rate in patients who were clinical responders to tacrolimus during a 65-month follow-up period. These results should be treated with caution because the number of patients enrolled in the trials was small, the majority of the studies were retrospective and in most of the studies disease activity scores were retrospectively calculated. Infliximab
A randomized controlled trial by Jarnerot et al. was the first that found single IFX infusion to be effective in moderate-tosevere steroid-refractory UC [3]. At 90 days, colectomies had been performed on 7 of 24 IFX-treated patients and 14 of 21 placebo patients (p = 0.017). In 2005, Rutgeerts et al. published two large-scale randomized controlled trials (ACT 1 and ACT 2) that showed the efficacy of IFX to that of a placebo for the induction of clinical and endoscopic remission in the cases of moderate-to-severe UC [6]. Long-term benefit of IFX in severe steroid-refractory UC may be still questionable. In the paper by Gustavsson et al., which was the long-term extension of the Jarnerot’s study, the benefit of rescue therapy with IFX in steroidrefractory acute UC was shown to remain after 3 years. 50% of the patients receiving IFX versus 76% receiving placebo had colectomy after a 3-year follow-up in this study [26]. In the study by Kohn et al., 15% of the enrolled patients with severe UC treated with IFX underwent colectomy within 2 months. After a median time of 23 months, 82.9% of the patients avoided late colectomy [27]. A retrospective study of 30 patients conducted at Oxford revealed that 53% of the patients required colectomy and only 17% achieved steroid-free remission after a median follow-up of 13 months [28]. Expert Rev. Gastroenterol. Hepatol. 8(6), (2014)
Ability of different rescue therapies to save the bowel in acute, severe, steroid-refractory UC
Review
Table 1. Summary of trials examining the efficacy of cyclosporine, tacrolimus and infliximab in acute severe ulcerative colitis.
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nanyang Technological University on 04/26/15 For personal use only.
Study (year)
Patients (n)
Short-term response (%)
Long-term colectomy-free remission (%) At 1 year
At 3 years
At 5 years
Follow-up (years)
Ref.
Cyclosporine Lichtiger et al. (1994)
20
82
–
–
–
Unknown
[2]
D’Haens et al. (2001)
29
64
78
–
–
1
[7]
Van Assche et al. (2003)
73
86.9 (4 mg/kg) versus 91.4 (2 mg/kg)
–
–
–
Unknown
[8]
Moskovitz et al. (2006)
142
83
63
48
–
7
[4]
Mocciaro et al. (2012)
65
71.5
52
43
–
3
[10]
Kobayashi et al. (2010)
72
73.6
–
–
–
Unknown
[12]
Cheifetz et al. (2011)
71
85
61
–
54
5
[13]
Fellermann et al. (2002)
38
47.4
–
–
–
2
[20]
Baumgart et al. (2006)
23
96
–
–
–
Unknown
[23]
Ogata et al. (2012)
62
50
–
–
–
Unknown
[24]
Jarnerot et al. (2005)
45
71
–
–
–
>6 months
[5]
Kohn et al. (2007)
83
85
~70
–
–
23 months
[27]
Rutgeerts et al. (ACT 1-2005)
364
69.4 (5 mg/kg) and 61.5 (10 mg/kg)
~45.5
–
–
13.5 months
[6]
Rutgeerts et al. (ACT 2-2005)
364
64.5 (5 mg/kg) and 69.2 (10 mg/kg)
–
–
–
7.5 months
[6]
Tacrolimus
Infliximab
ACT: Active ulcerative colitis trial.
TABLE 1 summarizes the trials examining the efficacy of CsA, tacrolimus and IFX in acute severe UC.
Comparison between tacrolimus versus CsA
No head-to-head comparison between CsA and tacrolimus in acute severe UC has been published. However, in patients with liver, kidney and bone marrow transplantation tacrolimus appeared to be superior to CsA in improving graft survival and in preventing acute rejection after transplantation [29]. However, these results came from a completely different patient population and naturally it is impossible to extrapolate it to the UC. Comparison between CsA & IFX
The parallel, open-label, randomized, controlled trial by the Groupe d’Etudes Therapeutiques des Affections Inflammatoires Digestives was the first that directly compared the efficacy of CsA and IFX in acute severe UC not responding to intravenous steroid therapy for at least 5 days [30]. CsA and IFX were randomly given to 58 and 57 patients. Treatment failure (defined as the presence of any of the six following criteria: absence of clinical response at day 7; relapse between day 7 and 98 (defined as a Lichtiger score informahealthcare.com
increase of at least 3 points from the previous value that lasts for at least three consecutive days and leads to treatment modification); absence of steroid-free remission at day 98 (defined as a Mayo disease activity index score £2 with an endoscopic subscore £1); a severe adverse event leading to treatment interruption; colectomy and death) was noticed in 60% of the patients given CsA compared with 54% given IFX. No difference was observed in the rate of colectomy between the groups. The clinical activity decreased faster in patients who received IFX versus CsA; this difference was significant on days 3 and 4. The median time to clinical response was 5 days in the CsA group and 4 days in the IFX group. In a retrospective review of inpatients with steroid-refractory UC, the outcomes of 19 patients receiving CsA and 19 receiving IFX were examined [31]. At 3 months, the colectomy rate was 63% for CsA compared to 21% for IFX (p = 0.0094). By 12 months, the rate was 68 and 37% for CsA and IFX (p = 0.06). In this study, CsA was used in a dose of 2 mg/kg and more patients received concomitant immunosuppressive drugs at the time of salvage therapy in the IFX-treated group. An Italian single-center trial conducted in 21 patients found no difference in 30-day remission rates achieved with IFX versus CsA, although IFX was associated with more 697
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Review
´ r & Szepes Farkas, Molna
infectious complications than CsA [32]. Sjo¨berg et al. [14] found that a single IFX infusion was more effective in preventing early and late colectomy than CsA (93 vs 67% at 3 months and 77 vs 57% at 12 months). In this study, the first attack of the disease was significantly more common in IFX-treated patients and patients in the CsA group had more severe disease activity. In the prospective study by Croft et al., the clinical outcomes of 83 CsA- or IFXtreated patients with steroid-refractory acute severe UC were compared. CsA was given to 45 and IFX to 38 patients. Of those patients who received ‡72 h of CsA 2–4 mg/kg, 56% avoided colectomy, while 84% of those administered one dose of IFX 5 mg/kg (p = 0.006) avoided colectomy. At 3 months, the colectomy-free rate was 53% for CsA versus 76% for IFX (p = 0.04) and 42 versus 65% at 12 months (p = 0.04) [33]. A meta-analysis published by Chang et al., including the data of 321 patients, demonstrated that the rates of colectomy at 3 and 12 months, adverse drug reactions and postoperative complications are equivalent when using IFX or CsA as rescue therapy in acute severe UC [34]. The currently ongoing trial CONSTRUCT (COmparison of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis) that aims to determine the clinical and cost effectiveness of IFX and CsA in acute severe steroid-resistant UC may provide an adequate comparison between the two rescue therapies [35]. Switching between calcineurin inhibitors & IFX
Cumulative immunosuppressive effects are a major concern if potent immunosuppressive agents are used sequentially. It is also important to decide the order of the therapies because of the different pharmacokinetic characteristics of the drugs. Since IFX levels can be detected in the serum for at least 8 weeks following treatment, the use of tacrolimus or CsA as first-line drugs in steroid-refractory UC may be practical because of their short half-life [36]. Considering the shift between tacrolimus and IFX, little data are available on the efficacy of either drug after the failure of the other. Herrlinger et al. evaluated the efficacy of IFX salvage therapy in patients with refractory UC failing to respond to tacrolimus. Twenty-four patients with tacrolimus-refractory active disease were treated with IFX 5 mg/kg at weeks 0, 2 and 6 and every 8 weeks thereafter, if tolerated [37]. 25% achieved remission following IFX infusion and 17% had an initial response only, but underwent proctocolectomy later because of loss of response or development of a delayed hypersensitivity reaction. Fourteen (58%) patients completely failed to respond, with 10 undergoing colectomy. They concluded that IFX offers a therapeutic option as rescue therapy in about a quarter of patients with active UC after failing to respond to tacrolimus. In a retrospective, observational, single-center study of 12 consecutively enrolled patients with UC refractory to tacrolimus who received IFX therapy (single infusion in the majority of the patients), 50% of the UC patients achieved clinical remission within 30 days. Colectomyfree survival was 58.3% at 41.4 months [38]. No randomized trials assessing the efficacy of tacrolimus after IFX therapy are available. 698
Only a few studies examined the outcomes of CsA and IFX treatment after the failure of the other drug in severe steroidrefractory UC. Ten patients received IFX after CsA failed and 9 patients received CsA after IFX failed in the study by Maser et al. Four patients (40%) in the IFX-salvage group achieved remission, as did 3 (33%) in the CsA-salvage group. Severe adverse events included one patient who developed sepsis and died after receiving IFX salvage [39]. Chaparro et al. examined the efficacy and safety of IFX after CsA failure in patients with steroid-refractory UC in a retrospective review. Of the 35 patients who received the third IFX infusion, 60% achieved remission and 37% achieved partial response. 30% underwent colectomy. The rate of adverse events was 23%, most commonly infections (8.4%). A 40-year-old man in whom CsA failed died of nosocomial pneumonia after the first IFX infusion. According to their results, two-third of corticosteroid- refractory UC patients on IFX therapy might avoid colectomy after failure of CsA [40]. In the retrospective study by Leblanc et al., patients with corticosteroid-refractory UC were reviewed and treated successively by either CsA after IFX failed or IFX after CsA failed. Sixty-five patients who failed to respond to CsA were treated with IFX and 21 patients who failed to respond to IFX received CsA. Of the 65 patients, 24 did not respond to CsA and 41 responded but relapsed under CsA and 6 relapsed immediately after discontinuation. Of the 21 patients, 9 did not respond to IFX and 12 responded but lost response. A total of 20 adverse events in 19 patients were observed after the second-line rescue therapy started, including one death in a patient who developed pulmonary embolism 1 day after surgery [41]. Side effects of rescue therapies
The use of CsA rescue therapies is usually limited by its side effect profile. The short-term side effects include hypertension, hypercholesterolemia, tremor, nausea/vomiting, renal insufficiency, headaches, anaphylaxis, infection, paresthesia and seizures [42]. In our recently published study, side effects occurred in 72.2% of the patients during CsA therapy. The most frequent side effects were hypertension (15.2%), tremor (13.8%), hypertrichosis (9.7%), myalgia and muscle cramping (11.1 and 4.2%, respectively) and numbness of legs (5.5%). Nephrotoxicity or hepatotoxicity occurred in 8.3% of the patients. Increased serum cholesterol and triglyceride levels were detected in 47.2 and 19.4% of the patients, respectively. The most frequent major side effects resulting in discontinuation of CsA were adverse muscle reactions (47.6%) and hypertension (38.1%), followed by gastrointestinal side effects including liver enzyme abnormalities (23.8%) and skin side effects [43]. Due to these common side effects, many patients cannot tolerate CsA therapy. CsA is contraindicated in patients who are severely hypocholesterolemic (serum cholesterol
