Cyclosporine, tacrolimus, and mycophenolate mofetil in the treatment of inflammatory bowel disease

Gastroenterol Clin N Am 33 (2004) 141–169

Cyclosporine, tacrolimus, and mycophenolate mofetil in the treatment of inflammatory bowel disease Conor G. Loftus, MDa,b, Laurence J. Egan, MDa,b, William J. Sandborn, MDa,b,* a

Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA b Department of Medicine, Mayo Medical School, 200 First Street SW, Rochester, MN 55905, USA

In the past decade, immunosuppressive drugs have come to play an integral role in the treatment of patients with inflammatory bowel disease (IBD) [1]. Patients who fail to respond to corticosteroids, and those who are steroiddependent, are frequently treated with immunosuppressive drugs, such as azathioprine, 6-mercaptopurine, and methotrexate, and biotechnology technology agents, such as infliximab [1]. The delayed onset of action (approximately 3 months) seen with azathioprine, 6-mercaptopurine, and methotrexate has limited their use for the acute treatment of patients with moderate to severely active IBD, but this problem has been at least partially circumvented by the introduction of a rapidly acting agent, infliximab. In patients who fail to respond to the first-line immunosuppressive agents listed previously, consideration may be given to use of the calcineurin inhibitors (cyclosporine and tacrolimus) and mycophenolate mofetil as alternative or adjunctive immunosuppressive therapies for refractory IBD. This article reviews the use of cyclosporine, tacrolimus, and mycophenolate mofetil in patients with IBD, with emphasis on pharmacology, results in controlled clinical trials, and safety, and issues related to dosing and toxicity monitoring. Calcineurin inhibitors Calcineurin inhibitors with proved or possible efficacy in IBD include cyclosporine (Sandimmune), cyclosporine microemulsion formulation * Corresponding author. E-mail address: [email protected] (W.J. Sandborn). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.02.001

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(Neoral, Gengraf), and tacrolimus (FK506, Prograf). Sirolimus (rapamycin, Rapamune) is another calcineurin inhibitor that has been approved for use in the transplantation setting but has not been studied in patients with IBD.

Cyclosporine Clinical pharmacology Cyclosporine is a lipophilic peptide with inhibitory effects on both the cellular and humoral immune systems. Cyclosporine acts to down-regulate the cellular immune response by blocking the production of interleukin-2 by T-helper lymphocytes [2]. At the molecular level, cyclosporine binds with the cyclosporine-binding protein, cyclophilin, forming a cyclosporinecyclophilin complex. This complex then binds to and inhibits calcineurin, a cytoplasmic phosphatase enzyme involved in the activation of T cells [3]. In addition to its direct inhibitory effects on T-cell function, cyclosporine also indirectly inhibits B-cell function, by blocking the production of B-cell activating factors, and interferon-c, by T-helper cells [4]. It is not known which of these cyclosporine-induced effects on cellular and humoral immunity account for any therapeutic action in Crohn’s disease or ulcerative colitis. In the United States, the original commercially available formulations of cyclosporine included a liquid oral preparation (Sandimmune, 100 mg/mL); oral gelatin capsules (Sandimmune, 25, 50, and 100 mg); and an intravenous concentrate (Sandimmune, 50 mg/mL). After an oral dose of the liquid cyclosporine preparation, maximal absorption occurs at approximately 4 hours with bioavailability ranging between 12% and 35% [5,6]. The oral gelatin cyclosporine capsules have an equivalent bioavailability to the oral liquid cyclosporine solution [7]. The absorption of cyclosporine in the small intestine is a function of contact time, which varies in accordance with small bowel length, motility, and mucosal integrity [5,6,8,9]. Crohn’s disease [9] and short-bowel syndrome [10] may impair the absorption of orally administered cyclosporine. Bile is also required for cyclosporine absorption, and biliary diversion may lead to drug malabsorption [11]. As a means of improving the bioavailability of orally administered cyclosporine, and eliminating the need for the presence of bile to allow for maximal absorption, new microemulsion cyclosporine formulations (Neoral, Gengraf) have been approved for use in the United States (see later). In addition, reports have suggested that the coadministration of vitamin E [12], or ursodeoxycholic acid [13], may improve the bioavailability of the standard oral cyclosporine formulation. Oral cyclosporine for autoimmune diseases can be divided into two groups based on the cyclosporine dose: low-dose oral cyclosporine (
5 mg/

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kg/d, based on the Sandimmune formulation) and high-dose oral cyclosporine (>5 mg/kg/d). This classification is based on the finding that oral cyclosporine at doses less than or equal to 5 mg/kg/d has a considerably lower risk of causing biopsy-proved cyclosporine nephropathy [14]. It has been recommended that patients with autoimmune diseases not be treated with oral cyclosporine at doses greater than 5 mg/kg/d to avoid nephrotoxicity and other dose-dependent toxicities [14]. Intravenous cyclosporine at doses of 2 to 4 mg/kg/d are best classified as high dose, being equivalent to oral cyclosporine doses of 8 to 16 mg/kg/d (assuming oral bioavailability of approximately 25%). It is of importance to consider the results of clinical trials of cyclosporine in terms of these drug-dosing categories.

Clinical response in Crohn’s disease Three large, controlled trials of low-dose oral cyclosporine (
5 mg/kg/d) for treatment of chronically active Crohn’s disease and maintenance of medically induced remission failed to show a beneficial treatment effect (Table 1) [15–17]. The Cyclosporin Study Group of Great Britain and Ireland [15] reported on 146 patients with active Crohn’s disease who were randomized to oral cyclosporine (5 mg/kg/d) or placebo. There was no significant difference in the number of patients who achieved remission in the cyclosporine group (26 [36%] of 72) as compared with the placebo group (32 [43%] of 74) at 3 months. In the Canadian Crohn’s Relapse Prevention Trial [16], 305 patients with either active Crohn’s disease or Crohn’s disease in remission (patients stratified according to disease activity) were randomized to oral cyclosporine (mean final dose of 4.8 mg/kg/d) or placebo. After 18 months of treatment, there was no significant difference in the number of patients who achieved or maintained remission in the cyclosporine group (60 [40%] of 151) as compared with the placebo group (74 [48%] of 154). The European Trial of Sandimmune in Crohn’s disease [17] randomized 182 patients with active Crohn’s disease to receive either oral cyclosporine (5 mg/kg/d) or placebo. After 4 months, there was no difference in remission rates between the treatment (35%) and placebo (27%) groups, whereas at 12 months only 20% of patients in both groups remained in clinical remission. One controlled trial of patients with active Crohn’s disease using highdose oral cyclosporine (7.6 mg/kg/d) did report a positive treatment effect [18]. In this study by Brynskov et al [18], 71 patients with active Crohn’s ileitis, ileocolitis, or colitis were randomized to oral cyclosporine (mean final dose 7.6 mg/kg/d) or placebo for 3 months. At follow-up, 59% of patients in the treatment group achieved remission as compared with 32% in the placebo group (P = .03). In patients who entered remission, the treatment effect was seen within 2 weeks. Whereas the therapeutic advantage of cyclosporine was maintained during a 3-month cyclosporine taper, only 11% of patients maintained substantial improvement after cyclosporine was

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Response (%) Author (ref)

No. of Patients

Low dose Jewell 146 et al [15] Feagan 305 et al [16] Stange 182 et al [17] High dose Brynskov 71 et al [18]

Initial daily dose (mg/kg)

Site of disease

5

SB, IC, C

5

SB, IC, C

5

N.st

5–7.5

SB, IC, C, PA

Corticosteroids (%)

Treatment duration (mo)

Cyclosporine

Placebo

P

77

12

36

43

NS

61

18

40

48

NS

100

3

35

27

NS

34

3

59

32

0.03

Abbreviations: C, colon; IC, ileocolonic; NS, not significant; N.st, not stated; PA, perianal; SB, small bowel.

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Table 1 Controlled trials of oral cyclosporine for active Crohn’s disease

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discontinued [19]. Patients receiving cyclosporine in combination with corticosteroids seemed to have a greater response rate than those receiving cyclosporine alone. Numerous uncontrolled trials of both oral and intravenous cyclosporine for active inflammatory Crohn’s disease have reported promising short-term but not long-term response rates [20–45]. Of 227 patients reported in 26 uncontrolled trials, clinical response was observed in 0% to 100%, with an overall mean response of 64% (145 of 227). In those patients who did respond, the effect of cyclosporine was rapid, with improvement usually occurring within 2 to 3 weeks. The overall mean initial oral cyclosporine dose was 10 mg/kg/day (range 5–15 mg/kg/d). Initiation of cyclosporine by continuous intravenous infusion at a dose of 1 to 4 mg/kg/d may induce more rapid clinical improvement, and this strategy has been advocated by some groups [30,32–39,41,43]. A controlled trial comparing oral with intravenous cyclosporine in patients with Crohn’s disease has not been undertaken. The frequency of long-term clinical improvement after discontinuation of highdose cyclosporine was much lower than the frequency of initial short-term response, with an overall mean long-term improvement of 29% (58 of 200). In many of these studies, maintenance therapy with azathioprine, 6mercaptopurine, or methotrexate was not systematically used. The rates of sustained improvement seem to be substantially greater if cyclosporine is used as a rescue induction therapy that bridges the patient to maintenance therapy with one of the other slower-acting immunosuppressive agents [33,35,38–40]. Although there have been no controlled trials of cyclosporine for fistulizing Crohn’s disease, a number of the uncontrolled trials that included patients with fistulas suggested a positive treatment effect with high-dose cyclosporine [21,23,25,29,30,33,34,36,39,43–45]. Of 53 patients with fistulizing disease (pooled from all of the uncontrolled studies), the initial short-term fistula closure rate ranged from 0% to 100% with an overall mean short-term closure rate of 77% (41 of 53). Long-term fistula closure after discontinuation of cyclosporine treatment was reported in 42% (22 of 53) of patients. Oral cyclosporine doses ranging from 8 to 10 mg/kg/d were reported effective for healing fistulas, with time to fistula closure ranging from 0.5 to 4 weeks. Some centers advocate initial therapy with intravenous cyclosporine, 4 mg/kg/d by continuous infusion for 10 days, followed by oral cyclosporine, 8 mg/kg/ d [30,33,34,36]. The clinical advantage of this approach has not been demonstrated in controlled trials. Controlled trials in Crohn’s disease have shown that low-dose oral cyclosporine (
5 mg/kg/d) was not effective either for treatment of chronically active inflammatory disease or for maintenance of remission. In contrast, one controlled trial of high-dose oral cyclosporine (mean dose 7.6 mg/kg/d), and multiple uncontrolled trials of oral cyclosporine at doses greater than 5 mg/kg/d or 4 mg/kg/d intravenously, suggest that high-dose cyclosporine may be effective for both inflammatory and fistulizing Crohn’s disease.

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Clinical response in ulcerative colitis There have been no controlled trials of either low- or high-dose oral cyclosporine in patients with ulcerative colitis. Four controlled trials of intravenous cyclosporine in patients with severe ulcerative colitis have reported a positive treatment effect (Table 2) [46–49]. Lichtiger et al [46] randomized 20 patients with severe, steroid-refractory ulcerative colitis to treatment with placebo (N = 9) or intravenous cyclosporine, 4 mg/kg/d as a continuous infusion for 14 days (N = 11). Nine of 11 cyclosporine-treated patients (82%) responded compared with none of the placebo-treated patients. Those who responded were continued on oral cyclosporine, 8 mg/ kg/d. At 6 months, 5 (45%) of 11 cyclosporine-treated patients maintained a clinical response. In the second study, 30 patients with severe ulcerative colitis were randomized to monotherapy with a continuous infusion of cyclosporine, 4 mg/kg/d, or methylprednisolone, 40 mg/d [47]. After 8 days, 9 (64%) of 14 patients who received cyclosporine responded compared with 8 (53%) of 15 receiving methylprednisolone. Patients who responded received Table 2 Controlled trials of intravenous cyclosporine for severe ulcerative colitis Author (ref)

Agent Total administered patients (No. patients)

Initial IV daily dose Corticosteroids (mg/kg) (No. patients)

20

Cyclosporine (11)

4

11

Placebo (9)

—

9

Cyclosporine (14a)

4

0

9 (64)

7 (50)

Methylprednisolone (15)

40 (mg/d) 15

8 (53)

3 (20)

Response (No. patients) (%) 14 d

Lichtiger et al [46]

D’Haens et al [47]

Svanoni et al [48]

30

30

Cyclosporine (15)

4

0

Cyclosporine 4 4 + Prednisolone (15) +1 15 (mg/kg/d) Van Assche 70 et al [49]

9 (82) 0 8d

6 mo 5 (45) 0 12 mo

14 d

NA

10 (67)

—

14 (93)

—

8d

3 mo

Cyclosporine (34b)

4

16

28 (82)

23 (68)

Cyclosporine (35)

2

21

29 (83)

26 (74)

Abbreviations: NA, not available; NS, not significant. a One patient was found to have C difficile and was withdrawn on day 2. b One patient was withdrawn after the start of the first infusion because of anaphylactic reaction.

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the same medication orally in combination with azathioprine. At 12 months, seven (78%) of nine patients initially controlled with cyclosporine maintained remission compared with three (37%) of eight treated with methylprednisolone. In the third study, 30 patients with severe steroid-refractory ulcerative colitis were randomized to monotherapy with intravenous cyclosporine, 4 mg/ kg/d (steroids were discontinued), or intravenous cyclosporine in combination with continued prednisolone, 1 mg/kg/d [48]. After 14 days, 10 (67%) of 15 patients in the cyclosporine-monotherapy group compared with 14 (93%) of 15 in the combination-therapy group had complete remission. Most recently, a Belgian study randomized 70 patients with severe ulcerative colitis to receive 2 or 4 mg/kg/d of intravenous cyclosporine [49]. After 8 days, 29 (83%) of 35 patients in the 2 mg/kg group and 28 (82%) of 34 in the 4 mg/kg group had responded to treatment. There have been numerous uncontrolled trials of both oral and intravenous cyclosporine in patients with severe ulcerative colitis, the results of which are similar to those from the controlled trials [25,26,30,35,40,41,43,50–84]. These patients had severe ulcerative colitis, had failed standard therapy, and were candidates for colectomy. Of 604 patients studied in 42 trials, the overall mean response (avoidance of colectomy) was 70% (422 of 604). The overall mean initial oral cyclosporine dose was 10 mg/kg/day (range 4–15 mg/kg/d). Cyclosporine by continuous intravenous infusion, at a mean dose of 4 mg/kg/d (range 1–7 mg/kg/d), was the preferred initial route of administration at 27 centers [30,41,43,54,55, 59–62,64–71,73–82,85]. Treatment effect with cyclosporine was rapid, with improvement usually occurring within 1 to 2 weeks. The overall mean longterm response after discontinuation of cyclosporine was 39% (237 of 604). In many of these studies, maintenance therapy with azathioprine or 6mercaptopurine was not systematically used. The rates of long-term improvement seem to be substantially greater if cyclosporine is used as a rescue induction therapy, which bridges the patient to maintenance therapy with one of the other slower-acting immunosuppressive agents [47,65–67,70,71,75,77,80,84]. There has been one controlled trial reporting the use of cyclosporine enemas in patients with refractory left-sided ulcerative colitis [86]. In that study, 40 patients were randomized to receive cyclosporine enemas, 350 mg/d, or placebo for 4 weeks. At completion of the study, there was no difference in the number of patients who responded in the cyclosporine enema group (8 [40%] of 20) as compared with the placebo group (9 [45%] of 20). This negative controlled trial refutes the results from four small uncontrolled trials in 36 patients treated with cyclosporine enemas that suggested that topical cyclosporine therapy might be of benefit [87–90]. In summary, controlled trials suggest that high-dose cyclosporine (2–4 mg/kg/d intravenously) is effective for severe ulcerative colitis. Intravenous cyclosporine at a dose of 2 mg/kg/d seems to be as effective as 4 mg/kg/d, and this intermediate dose may be preferable because of the potential for

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greater toxicity associated with the higher dose (see later). Low-dose cyclosporine has not been evaluated in ulcerative colitis, either for treatment of active disease or for maintenance of remission. Cyclosporine enemas are not effective in patients with refractory left-sided ulcerative colitis. Blood concentrations: monitoring and correlation with clinical response Trough concentrations of cyclosporine can be measured in whole blood, serum, or plasma by a variety of methods including high-pressure liquid chromatography (HPLC), radioimmunoassay (RIA), and fluorescence polarization immunoassay [5,6,91]. In contrast to polyclonal RIA and fluorescence polarization immunoassay, monoclonal RIA, fluorescence polarization immunoassay, and HPLC are specific for parent cyclosporine. The therapeutic window for these assays used in solid organ transplantation is approximately 150 to 300 ng/mL. In patients with autoimmune diseases, the trough whole blood concentrations of cyclosporine (HPLC or monoclonal RIA) that occur with low-dose therapy range from 100 to 250 ng/mL, whereas trough cyclosporine concentrations for high-dose cyclosporine therapy range 251 to 400 ng/mL. It is not entirely clear what whole blood concentrations of cyclosporine are necessary to produce clinical improvement in patients with IBD. In the negative controlled trial of oral cyclosporine for Crohn’s disease (mean final dose 4.8 mg/kg/d) reported by Feagan et al [16], the mean whole blood concentration was 182 ng/mL (monoclonal RIA, target concentration 200 ng/ mL). Similarly, in the negative controlled trial of oral cyclosporine for Crohn’s disease (5 mg/kg/d) reported by Jewell and Lennard-Jones [15], the final median whole blood concentration was 129 ng/mL (monoclonal RIA, therapeutic range 90–270 ng/mL). In contrast, the positive controlled trial of oral cyclosporine for Crohn’s disease (mean final dose 7.6 mg/kg/d) reported by Brynskov et al [18] reported a trend toward higher whole blood concentrations in patients who responded, 471 ng/mL in responders versus 309 ng/mL in nonresponders (polyclonal RIA, therapeutic range 400–800 ng/ mL). In the two fully published controlled trials of intravenous cyclosporine for severe ulcerative colitis, whole blood cyclosporine concentrations did not correlate with clinical response [46,47]. In the study by Lichtiger et al [46], the mean whole blood cyclosporine concentration was 482 ng/mL in responders versus 484 ng/mL in nonresponders (monoclonal RIA, therapeutic range 100– 400 ng/mL). Similarly, in the study by D’Haens et al [47], the mean whole blood cyclosporine concentration was 361 ng/mL in responders versus 385 ng/ mL in nonresponders (monoclonal fluorescence polarization immunoassay). From these five controlled studies [15,16,18,46,47], there does not seem to be a clear correlation between whole blood cyclosporine concentrations and clinical response in patients with IBD. What is clear, however, is that in studies showing a positive treatment effect [18,46,47], high-dose cyclosporine was used (>5 mg/kg/d orally or 4 mg/kg/d intravenously) with high whole

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blood cyclosporine concentrations (>400 ng/mL), whereas in the studies showing a negative treatment effect [15,16], low-dose cyclosporine was used (
5 mg/kg/d), with lower mean whole blood concentrations (\ 200 ng/mL). It seems that there is a relatively strong correlation between clinical response and whole blood cyclosporine concentrations (HPLC or monoclonal RIA) when indirectly comparing low- versus high-dose cyclosporine therapy. Safety of cyclosporine in inflammatory bowel disease The incidence of adverse events was relatively low in three large, controlled trials of low-dose oral cyclosporine for Crohn’s disease [15–17]. Sandborn [92] summarized the adverse events reported in 27 studies, which included a total of 343 IBD patients, treated with high-dose cyclosporine therapy as follows: paresthesias (26%); hypertrichosis (13%); hypertension (11%); tremor (7%); nausea or vomiting (6%); renal insufficiency (6%); headache (5%); infection (3%); hepatotoxicity (3%); gingival hyperplasia (2%); seizure (1%); and anaphylaxis with intravenous cyclosporine (0.3%). In that summary, the frequency of adverse events was high (0.94 events per patient), but events were generally dose-related and reversed when either cyclosporine was discontinued or the dose was reduced. One of the most significant concerns associated with the long-term (and perhaps short-term) use of high-dose cyclosporine is the potential for permanent nephrotoxicity. Almost all patients undergoing chronic cyclosporine therapy for autoimmune diseases have a 20% reduction in glomerular filtration rate [93,94], without necessarily manifesting a rise in serum creatinine [95]. The decrease in renal function is usually caused by vasoconstriction of the afferent arteriole, reverses within 2 weeks of cyclosporine discontinuation, and was not thought to cause significant histopathologic changes. A recent study of renal biopsy data from 192 patients with autoimmune diseases (without associated renal insufficiency) treated with oral cyclosporine, however, has suggested that histologic evidence of nephropathy may occur in 21% of these patients [14]. Multivariate analysis showed that risk factors for the development of nephropathy included a greater mean oral cyclosporine dose (9.3 mg/kg/ d versus 8 mg/kg/d); greater maximum increase in serum creatinine; and greater patient age. The authors recommended that patients receiving oral cyclosporine for autoimmune diseases should not receive doses of greater than 5 mg/kg/d, and that the cyclosporine dose be adjusted downward if the serum creatinine increased to levels greater than 30% above baseline [14]. Based on this evidence it is possible that as many as 21% of IBD patients treated with high-dose oral and intravenous cyclosporine may have irreversible renal damage despite having normal serum creatinine levels. Infectious complications were not reported in controlled trials of low-dose oral cyclosporine for Crohn’s disease [15,16]. Severe and fatal opportunistic infections have been reported, however, in patients with IBD who had

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received treatment with high-dose cyclosporine therapy (either > 5 mg/kg/ d orally or 4 mg/kg/d intravenously) [33,61,68,69,74,78,92,96–101]. Opportunistic infections occurred more frequently in patients who received concomitant corticosteroids or azathioprine–6-mercaptopurine. Infections that have been reported in this setting include Pneumocystis carinii pneumonia (three cases, one fatality) [68,69,96]; Staphylococcus aureus sepsis (three cases, one fatality) [74,78,81]; invasive aspergillosis (two cases, one fatality) [97,100]; cytomegalovirus infection [98,99]; herpes esophagitis [61]; a carotid artery mycotic aneurysm requiring surgical resection [33]; and a case of Nocardia asteroides lung abscess [101]. The fact that such infections were not seen in patients receiving low-dose cyclosporine in combination with corticosteroids suggests that the combination of high-dose cyclosporine with corticosteroids ( azathioprine–6-mercaptopurine) increases the risk of opportunistic complications. Hepatotoxicity has been relatively uncommon in the setting of cyclosporine treatment in IBD. Up to 20% of renal transplant patients on cyclosporine have developed hepatotoxicity, with a predominantly cholestatic picture [102]. Cyclosporine may act to inhibit the excretion of bile acids into bile [103]. The potential for hepatotoxicity seems to be higher in cyclosporine-treated IBD patients who are also receiving total parenteral nutrition [104–106]. This observation has led to at least one group recommending that total parenteral nutrition not be used to support patients requiring cyclosporine for control of autoimmune disease [104]. Although paresthesia was a relatively common adverse event in the Sandborn [92] review (26% of patients), serious neurologic sequelae in IBD patients receiving cyclosporine are much less common. The most frequently reported serious adverse neurologic event is grand mal seizure [46,107,108]. The risk of seizures seems to be higher in patients with a total serum cholesterol level of less than 120 mg/dL [109], and it is recommended that these patients not be treated with cyclosporine [110]. There have also been case reports of reversible cortical blindness [107], and optic neuropathy in association with external ophthalmoplegia [111], in patients receiving cyclosporine for IBD. Although malignant lymphoma may be slightly more common in patients with autoimmune diseases treated with cyclosporine (approximately 0.3%) [112,113], lymphoma has not been reported in IBD patients treated with cyclosporine. In addition, although patients with ulcerative colitis are at increased risk of colonic cancer, there have been no reports to suggest that cyclosporine therapy adds to this risk. Dosing and toxicity monitoring Controlled trials have shown that low-dose oral cyclosporine (
5 mg/kg/ d) is ineffective in Crohn’s disease [15–17], and low-dose cyclosporine is not recommended in patients with IBD. High-dose cyclosporine may be

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initiated either orally, at a dose of 8 to 10 mg/kg/d, or intravenously at a dose of 2 to 4 mg/kg/d. Although it remains unclear as to whether initial highdose oral or intravenous cyclosporine is more effective, intravenous therapy has been favored historically in the severely ill, hospitalized patient, and in Crohn’s disease patients with extensive small bowel disease. Patients receiving cyclosporine by continuous intravenous infusion should have whole blood cyclosporine levels and electrolytes checked every 1 to 2 days, aiming for target drug concentrations in the 251 to 350 ng/mL range (HPLC or monoclonal RIA) [110]. When these patients are converted to the oral cyclosporine formulation on discharge from hospital, it is recommended that trough levels and electrolytes be checked weekly for the first month, biweekly for the second month, and monthly thereafter [114]. Total serum cholesterol should be measured at baseline, and cyclosporine should not be initiated if the cholesterol is less than 120 mg/dL. The cyclosporine dose should be adjusted to maintain a serum creatinine level that is no more than 30% above the baseline value. Total duration of cyclosporine therapy should not exceed 4 to 6 months (because of the risk of irreversible nephrotoxicity), remission being maintained thereafter with an alternate immunosuppressive drug.

Cyclosporine microemulsion formulation Clinical pharmacology To improve the bioavailability of orally administered cyclosporine (bioavailability 12% to 35%), microemulsion formulations of cyclosporine (Neoral, Gengraf) were developed [115]. The microemulsion formulations contain polyethylene glycol, caster oil, medium-chain triglycerides, and lowmolecular-weight glycols. The bioavailability of the microemulsion formulations, relative to the standard oral formulation, is increased significantly (145% to 239% increase) [115,116]. In patients receiving the microemulsion formulation, there is less interindividual and intraindividual variation in cyclosporine pharmacokinetics [117], improved absorption in the setting of small bowel disease [118], and decreased dependence on bile for absorption [119]. As with standard oral cyclosporine, bioavailability of oral liquid microemulsion cyclosporine is equal to a gelatin capsule of microemulsion cyclosporine [120]. In addition, the microemulsion formulation has been shown to be therapeutically equivalent to the standard oral cyclosporine formulation in transplant patients [121]. Clinical response in inflammatory bowel disease Three uncontrolled studies have evaluated one oral microemulsion cyclosporine formulation (Neoral) in patients with IBD [83,122,123]. In the

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first study, Actis et al [83] compared oral microemulsion cyclosporine with a historical cohort treated with a combination of intravenous followed by standard oral cyclosporine in patients with severe steroid-refractory ulcerative colitis. Forty patients received intravenous cyclosporine (2 mg/kg/d), with an initial response rate of 65% (26 of 40). The responders subsequently received standard oral cyclosporine (6–8 mg/kg/d) for a 6-month maintenance period, during which the sustained response rate fell to 37.5% (15 of 40). Fourteen patients were treated with oral microemulsion cyclosporine (4.6 mg/kg/d) for a period of 3 months, with an initial response rate of 100%. At 6 months, the sustained response rate in the microemulsion group had dropped to 50% (six patients failing during the 3-month treatment period, and one patient failing after discontinuation of treatment). Azathioprine was used (in combination with cyclosporine) in 38% (10 of 26) of responders to intravenous therapy, and in 42% (6 of 14) of responders to microemulsion therapy. The mean whole blood cyclosporine concentrations (monoclonal RIA or monoclonal PFIA) were 216 ng/mL and 211 ng/mL in the standard cyclosporine and microemulsion cyclosporine groups, respectively. Seven (17.5%) of 40 patients who received intravenous cyclosporine experienced severe adverse events, with discontinuation of therapy in three (two patients who developed severe cholestasis [104], and one fatality caused by pulmonary embolism). No major toxicity or need for discontinuation of therapy occurred in the patients receiving microemulsion cyclosporine. The second study evaluated whether or not oral microemulsion cyclosporine allows for rapid corticosteroid tapering in patients with steroid-dependent chronic active ulcerative colitis [122]. Microemulsion cyclosporine was administered to nine patients (5 mg/kg/d), with an initial short-term response rate of 89% (eight of nine) and a long-term response rate at 3 months of 56% (five of nine). At the beginning of cyclosporine treatment, the median 1-month cumulative corticosteroid dose was 750 mg (range 375–1050 mg), compared with a median 1-month cumulative dose of 225 mg during the third month of cyclosporine therapy (range 0–570 mg). Seven patients reached whole blood cyclosporine levels in the range of 200 ng/mL (monoclonal assay, otherwise unspecified). No major toxicity related to microemulsion cyclosporine was observed. The authors concluded that the microemulsion formulation may be useful in weaning patients with chronic active ulcerative colitis from corticosteroids. In the third study, Navazo et al [123] reported on 11 patients treated with oral microemulsion cyclosporine (10 patients with steroid-refractory ulcerative colitis and 1 patient with steroid-refractory indeterminate colitis). The dose was 7 to 7.5 mg/kg/d of microemulsion cyclosporine, with an initial short-term response rate of 82% (9 of 11) and a long-term response of 55% (6 of 11). The six patients manifesting a long-term response were all treated with azathioprine–6-mercaptopurine. Target whole blood cyclosporine levels in this study were 250 to 350 ng/mL (monoclonal RIA). No major toxicity related to microemulsion cyclosporine was observed.

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Although randomized controlled trials are needed to assess definitively the efficacy and safety of microemulsion cyclosporine compared with standard intravenous and oral cyclosporine, these results suggest that microemulsion cyclosporine may be as effective as standard intravenous or oral cyclosporine in severe ulcerative colitis with potentially less toxicity. Tacrolimus Clinical pharmacology Tacrolimus is a macrolide antibiotic with immunomodulatory properties similar to cyclosporine [124]. Tacrolimus has relatively low oral bioavailability ranging from 21% to 27%, but there is less interpatient variability than there is with standard oral cyclosporine (Sandimmune) [125–127]. The low bioavailability of tacrolimus is likely caused in part by its poor aqueous solubility, and the fact that as a macrolide antibiotic it likely has a promotility effect. Tacrolimus, however, is not dependent on bile or mucosal integrity for absorption [128–130]. These pharmacologic differences suggest a possible advantage of treatment with oral tacrolimus over standard oral cyclosporine, particularly in patients with small bowel Crohn’s disease. In the United States, commercially available formulations of tacrolimus include an oral capsule (0.5, 1, or 5 mg) and an intravenous concentrate (5 mg/mL). Tacrolimus is usually dosed 0.1 to 0.2 mg/kg/d orally and 0.01 to 0.02 mg/kg/d intravenously. Clinical response The only randomized, controlled trial of tacrolimus in IBD patients has recently been reported by Sandborn et al [131] (Table 3). Forty-eight patients with Crohn’s disease and draining perianal or enterocutaneous fistulas were randomized to treatment with oral tacrolimus, 0.2 mg/kg/d, or placebo for 10 weeks. The primary outcome measure was fistula improvement, as defined by closure of greater than or equal to 50% of draining fistulas and maintenance of closure for at least 4 weeks. A secondary outcome measure was fistula remission, as defined by closure of all fistulas and maintenance of closure for at least 4 weeks. The rate of fistula improvement was significantly greater in patients treated with tacrolimus (9 [43%] of 21) compared with placebo (2 [8%] of 25) (P = .01). The rates of fistula remission were similar in patients treated with tacrolimus (2 [10%] of 21) compared with placebo (2 [8%] of 25) (P = 1). Clinical improvement was not seen in the small subgroup of patients with abdominal fistulas. Sixty-three percent of patients had previously been treated with infliximab, and 56% to 62% were receiving concomitant therapy with azathioprine or 6-mercaptopurine. The most significant adverse event in patients treated with tacrolimus was nephrotoxicity, with 38% (8 of 21) of treated patients having an increase of serum creatinine from baseline of greater than 30%. No patients developed serious infections, sepsis, or opportunistic infections. The initial tacrolimus dose of 0.2 mg/kg/d resulted

154

Fistula location (No. of patients)

Concomitant medications (No. of patients)

Agent Administered

No. of patients

Abdo

PA

Both

Cort

A/6-MP

Abx

Initial daily dose (mg/kg/d)

Tacrolimus Placebo P value

21 25

0 3

20 22

1 0

5 4

13 14

13 19

0.2 —

Response (No. of patients) (%) Fistula improvementa

Fistula remissionb

9 (43%) 2 (8%) 0.01

2 (10%) 2 (8%) 1

Abbreviations: A/6-MP, azathioprine/6-mercaptopurine; Abdo, abdominal; Abx, antibiotics; Cort, corticosteroids; PA, perianal. a Closure of 50% of particular fistulas that were draining at baseline, and maintenance of closure for at least 4 wk. b Closure of all fistulas, and maintenance of that closure for at least 4 wk. Sandborn WJ, Present DH, Isaacs KL, et al. Tacrolimus for the treatment of fistulas in patients with Crohn’s disease: a randomized, placebo-controlled trial. Gastroenterology, in press.

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Table 3 Patient response in a controlled trial of tacrolimus for fistulizing Crohn’s disease

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in a mean whole blood tacrolimus concentration at 1 week of 22.5 ng/mL (target 10–20 ng/mL), and 90% (19 of 21) of patients required dose reduction because of either high tacrolimus levels or adverse events. The authors concluded that oral tacrolimus at an initial dose of 0.2 mg/kg/d was efficacious for the treatment of perianal fistulas in patients with Crohn’s disease and that adverse events, which were seen frequently in tacrolimustreated patients, could be managed in most instances with dose reduction. There have been a number of uncontrolled studies reporting positive treatment effects in patients with Crohn’s disease [132–136] and ulcerative colitis [134,136,137]. In the series by Ierardi et al [135], 13 patients with refractory Crohn’s ileitis, ileocolitis, or colitis were treated with tacrolimus, 0.1 to 0.2 mg/kg/d, aiming for target tacrolimus trough levels of 5 to 10 ng/ mL (competitive binding microparticle enzyme immunoassay). Patients in this series did not receive concomitant treatment with either azathioprine or 6-mercaptopurine. The median treatment period was 27.3 months (range, 2– 93 months). Significant clinical improvement was reported in 85% (11 of 13) at 6 months and 69% (9 of 13) at 12 months. Of six patients with fistulizing disease, three had complete fistula closure with one further patient having significant fistula healing without complete closure. Although minor adverse effects (headache, tremor) were reported in 46% (6 of 13) of patients, treatment was discontinued in only one patient because of toxicity (severe tremor). Nephrotoxicity was not reported in this series. Fellermann et al [136] reported on 30 patients (21 ulcerative colitis, 6 Crohn’s disease, 2 indeterminate colitis, and 1 pouchitis) who participated in an open-label trial with tacrolimus. All patients had been refractory to standard therapy. Of 21 patients with severe steroid-refractory ulcerative colitis, 71% (10 of 14) receiving intravenous tacrolimus (0.01–0.02 mg/kg/d) and 71% (five of seven) receiving oral tacrolimus (0.1–0.2 mg/kg/d) achieved rapid remission. Six (75%) of eight patients with either Crohn’s or indeterminate colitis showed initial improvement, but when tacrolimus was discontinued, four of six patients relapsed. The single patient with pouchitis had clinical but not endoscopic improvement. The mean duration of treatment was 8 months. In the pediatric series reported by Bousvaros et al [134], 14 patients (10 ulcerative colitis, 2 Crohn’s colitis, and 2 indeterminate colitis) were treated with oral tacrolimus, 0.1 mg/kg twice daily, to achieve whole blood trough tacrolimus levels of 10 to 15 ng/mL. Nine (69%) of 13 patients responded to treatment within 14 days (one patient withdrew from the study after 48 hours, not specified). The long-term response rate at 1 year was 22% (two of nine) in the ulcerative colitis group and 75% (three of four) in those with Crohn’s or indeterminate colitis. Nephrotoxicity or opportunistic infections were not observed in this series. Both Sandborn [132] and Lowry et al [133] reported positive treatment effects in fistulizing Crohn’s disease treated with oral tacrolimus. Sandborn [132] successfully used oral tacrolimus, 0.15 to 0.29 mg/kg/d, adjusted to

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achieve target trough levels of 10 to 20 ng/mL, in three patients with complicated Crohn’s disease with proximal small bowel involvement or fistulas. Tacrolimus was used as a bridge to maintenance therapy with either methotrexate or azathioprine–6-mercaptopurine. Lowry et al [133] reported on the outcome of 11 patients with perianal Crohn’s disease (one to four perianal fistulas) who were refractory to standard therapy, and were treated with oral tacrolimus, 0.15 to 0.31 mg/kg/d for 5 to 47 weeks. Azathioprine or 6-mercaptopurine was administered concomitantly. Nine (82%) of 11 underwent perianal surgical procedures during tacrolimus therapy. Seven (63%) of 11 patients had complete fistula closure, and a further four patients (36%) had partial fistula healing. Long-term remission was maintained, after discontinuation of tacrolimus, in six of seven patients who achieved complete fistula closure. Four patients developed nephrotoxicity, peak creatinine ranging from 1.6 to 2 mg/dL (see later). Based on the controlled data of Sandborn et al [131] demonstrating that tacrolimus is effective for Crohn’s disease fistulas, and the absence of controlled data regarding the efficacy of cyclosporine for this indication, tacrolimus may be considered, in preference to cyclosporine, for the treatment of Crohn’s disease fistulas in patients who have failed antibiotics, azathioprine or 6-mercaptopurine, and infliximab. Preliminary data suggest that tacrolimus may also be beneficial in the treatment of refractory Crohn’s ileocolitis and ulcerative colitis, but controlled trials are needed to confirm these findings. Safety of tacrolimus in inflammatory bowel disease In the controlled study by Sandborn et al [131], the most commonly reported adverse events among 21 patients receiving tacrolimus were as follows: paresthesia (11 [57%] of 21); headache (10 [48%] of 21); creatinine increase greater than 30% from baseline (8 [38%] of 21); insomnia (6 [29%] of 21); tremor (6 [29%] of 21); nausea or vomiting (6 [29%] of 21); leg cramps (5 [24%] of 21); diarrhea (4 [19%] of 21); and pruritus (4 [19%] of 21). Nephrotoxicity was the most serious adverse event noted, and there were no episodes of sepsis, serious infection, or opportunistic infection. Although adverse events were frequently reported in tacrolimus-treated patients, most of these events were dose-related and were managed successfully with dose reduction (see later). Dosing and toxicity monitoring Tacrolimus in patients with IBD is usually administered at a dose of 0.1 to 0.2 mg/kg/d orally or 0.01 to 0.02 mg/kg/d intravenously. Whole blood tacrolimus concentrations and electrolytes should be measured weekly for the first month, biweekly for the second month, and monthly thereafter. The target range for tacrolimus concentrations is 10 to 20 ng/mL. The tacrolimus dose should be adjusted to maintain a serum creatinine level that is no more than 30% above the baseline value. In the study by Sandborn, a tacrolimus

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dose of 0.2 mg/kg/d led to a mean whole blood tacrolimus concentration of 22.5 ng/mL at week 1. The mean final tacrolimus dose at week 10 was 0.16 mg/ kg/d and the mean final tacrolimus blood concentration was 8.3 ng/mL. These results suggest that an initial tacrolimus dose of 0.2 mg/kg/d, adjusted to a target blood concentration range (10–20 ng/mL) and for toxicity, is the maximal tolerated dose for the treatment of Crohn’s disease. An uncontrolled pilot study of low-dose tacrolimus (2–4 mg/d) reported a beneficial effect despite low blood concentrations (\10 ng/mL) in patients with rheumatoid arthritis [138]. Because many of the adverse events among IBD patients treated with tacrolimus seem to be dose-related, the efficacy of low-dose tacrolimus (0.05–0.15 mg/kg/d) adjusted to lower target blood levels (3–10 ng/ mL) should be determined in patients with Crohn’s disease.

Mycophenolate mofetil (Cellcept) Clinical pharmacology Mycophenolate mofetil is an ester prodrug of mycophenolic acid, the active moiety that gives the drug its immunosuppressive properties [139]. Mycophenolic acid decreases de novo synthesis of guanosine nucleotides by reversible inhibition of inosine monophosphate dehydrogenase. This drug has a directed action against T and B lymphocytes, because they depend on the de novo synthesis of purines for proliferation, whereas other cell types, such as neutrophils and macrophages, can use salvage pathways [139]. Mycophenolic acid can also inhibit growth of intestinal smooth muscle and synthesis of fibronectin [140], and theoretically may be useful in preventing smooth-muscle hyperplasia and stricture formation in patients with Crohn’s disease. Most experience with mycophenolate mofetil has been in the context of cardiac and renal transplantation. It has been compared with either placebo or azathioprine in combination with cyclosporine and steroids in randomized controlled trials in renal-transplant recipients [141–143]. Patients receiving mycophenolate mofetil had significantly fewer biopsy-proved rejection episodes, but there was no difference in graft loss or mortality at 12 months [141–143] or 3 years [142]. Patients receiving 2 g daily had a better safety profile than those receiving 3 g daily [141–143], and the cumulative incidence of combined graft loss and death was reduced with the lower dose. In the United States, commercially available formulations of mycophenolate mofetil include an oral capsule (250 mg) and tablet (500 mg), and powder for solution (200 mg/mL) and suspension (200 mg/mL). Clinical response There have been two randomized trials [144,145] and a number of small, uncontrolled series [146–152] suggesting a possible therapeutic role for

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mycophenolate mofetil in patients with Crohn’s disease and ulcerative colitis (Table 4). In the first randomized trial [144], 70 patients with steroiddependent chronic active Crohn’s disease received either mycophenolate mofetil, 15 mg/kg (approximately 1.5 g/d), or azathioprine, 1.5 mg/kg/d, in combination with prednisone, 50 mg daily, which was tapered to a maintenance dose of 5 mg daily. In patients with moderately active Crohn’s disease (Crohn’s disease activity index 150–300), decline in disease activity with mycophenolate mofetil was similar to that with azathioprine. In patients with highly active disease (Crohn’s disease activity index > 300), however, those treated with mycophenolate mofetil had a significantly greater decrease in Crohn’s disease activity index score after the first month of treatment, compared with those receiving azathioprine (mean Crohn’s disease activity index decline of 265 versus 117 points). The positive results in the subgroup of patients with high disease activity should be interpreted with caution because this was a secondary end point. Only two patients treated with mycophenolate mofetil experienced adverse events (drug rash, vomiting), compared with seven in the azathioprine group [144]. In the second randomized trial [145], 24 patients with active ulcerative colitis were randomly assigned to mycophenolate mofetil, 20 mg/kg (approximately 1.5 g/d), or azathioprine, 2 mg/kg/d, in combination with prednisone, 50 mg daily, which was tapered according to a standard protocol. Remission rates were higher in the azathioprine group, compared with the mycophenolate mofetil group, at 4 weeks (92% versus 67%); 3 months (92% versus 67%); 6 months (83% versus 78%); and 1 year (100% versus 88%). Patients receiving azathioprine experienced no severe adverse events, compared with two severe adverse events among those receiving mycophenolate mofetil (recurrent upper airways infection, bacterial meningitis) [145]. The data from these two small controlled trials suggest that mycophenolate mofetil, in combination with corticosteroids, may be a therapeutic alternative to combination therapy with azathioprine and corticosteroids in patients with active Crohn’s disease or ulcerative colitis [144,145]. In uncontrolled series or reports [146–152] a total of 75 patients (56 Crohn’s disease, 19 ulcerative colitis) with refractory IBD were treated with mycophenolate mofetil with positive [146,147,150,151] and negative [148,149,152] treatment effects reported. Of the 56 Crohn’s disease patients treated with mycophenolate mofetil, the overall response rate was 52% (29 of 56). Four of the series reported treatment of perianal Crohn’s disease [146,147,151,152], with overall improvement in 69% (11 of 16) and complete fistula closure in 44% (7 of 16) [146,151]. Of 19 ulcerative colitis patients treated with mycophenolate mofetil, the overall response rate was 47% (9 of 19). The overall mean dose of mycophenolate mofetil was 2 g daily (range, 1–3 g daily). Adverse events were reported in 20% (15 of 75) of the patients treated in these uncontrolled series (see later) [147–149,151,152].

Table 4 Randomized trials of mycophenolate mofetil in patients with steroid- dependent inflammatory bowel disease No. of Patients

Diagnosis

Treatment (no. of patients)

Initial dose (mg/kg/d)

Corticosteroids (no. of patients)

Response Delta CDAIa CDAI \ 300b CDAI > 300b 0–1 mo 3–6 mo 0–1 mo 3–6 mo

Neurath et al [144]

70

CD

MM (35)

AZA (35) P value

15

2.5

35

35

120

97 0.42

45

12c 0.1

265

117 0.01

3

42c 0.23

Remission (No. patients)d

Orth et al [145]

24

UC

4 wk

3 mo

6 mo

12 mo

MM (12)

20

12

8

8

8

7

AZA (12)

2

12

11

11

11

12

Abbreviations: AZA,azathroprine; CD, Crohn’s disease; MM, mycophenolate mofetil; UC, ulcerative colitis. a Change in Crohn’s disease activity index (CDAI) with treatment at specified time intervals. b Baseline CDAI. c Negative changes indicate decreases in CDAI scores. d Remission as defined by clinical colitis activity index  4 at specified time points.

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Author (ref)

159

160

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Safety of mycophenolate mofetil in inflammatory bowel disease Of the total 169 patients treated with mycophenolate mofetil for IBD [144–152], 9% (16 of 169) discontinued therapy because of adverse events attributed to the medication. These adverse events were nausea and vomiting (4 [25%] of 16); atypical (possibly medication-related) colitis (2 [12.5%] of 16); and one case each of recurrent upper airway infections, bacterial meningitis, migraine, depression, multidermatomal herpes zoster, diffuse maculopapular rash, increased diarrhea, bone marrow suppression, headache, and conjunctivitis or parotitis (1 [6%] of 16). In the two patients who developed atypical colitis (both had ulcerative colitis and one developed life-threatening gastrointestinal bleeding) [152], the histologic features were highly suggestive of a drug etiology. The dose of mycophenolate mofetil in both cases was 1 g daily. The development of colitis in patients treated with mycophenolate mofetil has also been described in a series of four renal-transplant recipients [153]. The patients in that series, however, were receiving high-dose immunosuppression that included mycophenolate mofetil, 3 g daily. The development of colitis in these patients may be caused by enterohepatic cycling of mycophenolic acid resulting in high colonic concentrations of the metabolite [154]. Although this adverse event may occur with lower doses of mycophenolate mofetil [152], it seems more likely to be a dose-dependent phenomenon [153,154]. These data contrast with the paucity of adverse events reported by Neurath et al [144] in 70 patients receiving 1.5 g daily (two patients had adverse events: drug rash and vomiting). When compared with azathioprine, mycophenolate mofetil, 2 to 3 g daily, has also been reported to be associated with a higher incidence of lymphoproliferative disorders after 3 years of follow-up (3% versus 0.6%) [142]. In addition, mycophenolate is teratogenic and should be avoided in pregnancy, whereas azathioprine may be used cautiously in this group.

Dosing and toxicity monitoring In hepatic transplantation, the recommended dose of mycophenolate mofetil is 1 g intravenously twice daily or 1.5 g orally twice daily. Cardiac transplant patients receive 1.5 g either orally or intravenously twice daily. Patients receiving mycophenolate mofetil should have blood counts checked weekly for the first month, and monthly thereafter, monitoring for myelosuppression. In the setting of IBD, the most commonly used dose is 2 g daily orally [144–152]. Although this dosing schedule seems reasonable given the limited published experience, large double-blind placebo-controlled trials are needed to address the outstanding questions regarding efficacy, dosing, and safety of mycophenolate mofetil in patients with IBD. Outside of such studies, this medication should be reserved for patients who are refractory to, or intolerant of, azathioprine–6-mercaptopurine, methotrexate, and infliximab.

Crohn’s disease

Cyclosporine Tacrolimus Mycophenolate mofetil

Ulcerative colitis

Inflammatory induction

Fistulizing induction

Steroid sparing

Maintenance therapy

Steroid refractory

Steroid dependent

Maintenance therapy

+  +/

+ + 

  +/

  

++  

+ +/ +/

  

+, One controlled trial. ++, More than one controlled trial. þ/, uncontrolled data. , no clear indication.

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Table 5 Indications for cyclosporine, tacrolimus and mycophenolate mofetil in patients with inflammatory bowel disease

161

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Summary Controlled trials have shown efficacy for intravenous cyclosporine in patients with severe ulcerative colitis, oral tacrolimus in patients with Crohn’s disease complicated by draining perianal fistulas, and mycophenolate mofetil in patients with active Crohn’s disease. Based on these controlled data, patients with IBD refractory to treatment with corticosteroids, azathioprine or 6-mercaptopurine, methotrexate (Crohn’s disease), and infliximab (Crohn’s disease) may be treated with the second-line immunosuppressive agents cyclosporine, tacrolimus, and mycophenolate mofetil in selected circumstances (Table 5).

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