Immunosuppression After Liver Transplantation for Primary Sclerosing Cholangitis Influences Activity of Inflammatory Bowel Disease

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2013;11:517–523

Immunosuppression After Liver Transplantation for Primary Sclerosing Cholangitis Influences Activity of Inflammatory Bowel Disease KRISTIN KAASEN JØRGENSEN,*,‡,§ LINA LINDSTRÖM,储 MILADA CVANCAROVA,¶ TOM H. KARLSEN,*,‡,# MARIA CASTEDAL,** STYRBJÖRN FRIMAN,** ERIK SCHRUMPF,*,‡,§ AKSEL FOSS,§,‡‡ HELENA ISONIEMI,§§ ARNO NORDIN,§§ KATHRINE HOLTE,储 储 ALLAN RASMUSSEN,储 储 ANNIKA BERGQUIST,储 MORTEN H. VATN,*,§,¶¶ and KIRSTEN MURI BOBERG*,‡ *Section for Gastroenterology, ‡Norwegian PSC Research Centre, ‡‡Section for Transplantation Surgery, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; §Institute of Clinical Medicine, ¶Department of Biostatistics, University of Oslo, Norway; 储Department of Gastroenterology and Hepatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; #Division of Gastroenterology, Institute of Medicine, University of Bergen, Bergen, Norway; **The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden; §§Transplantation and Liver Surgery Clinic, Helsinki University Hospital, Helsinki, Finland; 储 储Department of Surgical Gastroenterology and Liver Transplantation, Rigshospitalet University of Copenhagen, Copenhagen, Denmark; and ¶¶EpiGen Institute, Campus Ahus, Akershus University Hospital, Lorenskog, Norway

BACKGROUND & AIMS:

Previous studies have shown conflicting results regarding the course of inflammatory bowel disease (IBD) after liver transplantation in patients with primary sclerosing cholangitis (PSC). We studied the progression of IBD in patients with PSC who have undergone liver transplantation. We also studied risk factors, including medical therapy, that could influence on IBD disease activity.

METHODS:

In a longitudinal multicenter study, we analyzed data from the Nordic Liver Transplant Group on 439 patients with PSC who underwent liver transplantation from November 1984 through December 2006; 353 had IBD at the time of transplantation. We compared IBD activity before and after liver transplantation. Two hundred eighteen patients who had an intact colon and had undergone pretransplant and post-transplant colonoscopies were characterized further.

RESULTS:

Macroscopic colonic inflammation was more frequent after liver transplantation than before liver transplantation (153 vs 124 patients; P < .001). The degree of inflammation decreased in 37 patients (17%), was unchanged in 93 patients (43%), and increased in 88 patients (40%) (P < .001). The rate of relapse after transplantation was higher than that before transplantation (P < .001), and overall clinical IBD activity also increased (P < .001). Young age at diagnosis of IBD and dual treatment with tacrolimus and mycophenolate mofetil were significant risk factors for increased IBD activity after transplantation, whereas combination treatment with cyclosporin A and azathioprine had protective effects.

CONCLUSIONS:

Immunosuppression affects IBD activity after liver transplantation in patients with PSC; a shift from present standard maintenance treatment of tacrolimus and mycophenolate mofetil to cyclosporin A and azathioprine should be considered for these patients.

Keywords: Crohn’s Disease; Colitis; Disease Progression; Therapy.

See editorial on page 524.

P

rimary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease that eventually leads to cirrhosis and liver failure. PSC is a major cause of liver transplantation (Ltx) in the Nordic countries, constituting approximately 17% of all indications.1 It is strongly associated with inflammatory bowel disease (IBD), with a prevalence of IBD among PSC patients in Northern Europe in the range of 70% to 84%.2– 4 IBD in PSC seems to differ phenotypically from IBD without concurrent liver disease in several aspects. The frequency of pancolitis, rectal sparing,

and backwash ileitis is higher,5,6 and the clinical course of colitis is milder.6,7 Nevertheless, the risk of colorectal neoplasia is increased beyond the risk seen in IBD alone,8,9 with an even further increase after Ltx.10,11

Abbreviations used in this paper: CI, confidence interval; CMV, cytomegalovirus; CsA, cyclosporin A; IBD, inflammatory bowel disease; Ltx, liver transplantation; MMF, mycophenolate mofetil; PSC, primary sclerosing cholangitis. © 2013 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2012.12.027

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Because some of the immunosuppressive drugs that are administered after Ltx also are used as treatment for refractory IBD, one might anticipate that the clinical course of pre-existing IBD in PSC should improve after Ltx. Previous studies, however, have shown conflicting results. Some studies have depicted a mainly unchanged or improved course of IBD in PSC after Ltx,12–14 whereas others have found disease deterioration in a majority of patients.15–17 We hypothesized that the variable outcome of IBD activity after Ltx might be influenced by the immunosuppressive regimens or by other factors related to the transplantation.16 –18 In a multicenter study within the Nordic Liver Transplant Group we aimed to describe the natural history of IBD in PSC patients undergoing Ltx by comparing the clinical course of IBD before and after Ltx by a longitudinal follow-up evaluation of the patients. We also aimed to identify potential risk factors associated with altered activity of IBD after Ltx.

Patients and Methods Patients The Nordic Liver Transplant Registry1 was used to identify a total of 461 PSC patients who underwent Ltx from November 1984 through December 2006. Twenty-two patients (5%) were excluded because the diagnosis of PSC could not be confirmed by histology or they were lost to follow-up evaluation. Among the remaining 439 patients, 122 (28%) underwent Ltx in Gothenburg, Sweden; 95 (22%) underwent Ltx in Oslo, Norway; 93 (21%) underwent Ltx in Stockholm/Uppsala, Sweden; 83 (19%) underwent Ltx in Helsinki, Finland; and 46 (10%) underwent Ltx in Copenhagen, Denmark. PSC was diagnosed according to accepted criteria, with typical findings of bile duct irregularities on cholangiography.19 The diagnosis of IBD was based on conventional clinical, endoscopic, and histopathologic criteria.3 All patients were followed up regularly at the transplant centers. The medical records were reviewed by experienced physicians at each transplant center. Data regarding the activity of IBD before and after transplantation were retrieved according to a common protocol. When necessary, the patients’ medical charts were obtained from the referring hospitals.

Macroscopic Findings at Endoscopy The macroscopic inflammatory findings at colonoscopy were recorded at the last colonoscopy before Ltx, the first after Ltx, and at the examination closest in time to the last clinical follow-up evaluation. The colonoscopies both before and after Ltx were performed as part of the general follow-up evaluation of PSC-IBD patients, independently of the time of transplantation. The inflammation was graded as normal, mild, moderate, or severe.20 Of the 2 endoscopies after Ltx, the one with the most severe inflammation was selected for comparison with the pre-Ltx investigation. The diagnosis of de novo IBD was based on macroscopic and microscopic findings at endoscopy after Ltx and required normal macroscopic and microscopic findings before Ltx.

Inflammatory Bowel Disease Relapses The frequency of IBD relapses during the last 3 years before and the first 3 years after Ltx were recorded. Patients with a history of IBD less than 2 years before Ltx and/or less than 2 years of follow-up evaluation after Ltx were excluded for this

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purpose. The definition of relapse was based on a modification of the relapse criteria in 2 previous studies.21,22 A relapse was considered present if one or more of the following events were recorded: (1) an increase in IBD-related symptoms leading to a consultation by a specialist, (2) initiation or increase in dose of anti-inflammatory medication for IBD, (3) increase in stool frequency related to IBD, (4) macroscopic fecal blood related to IBD, (5) verified IBD-related inflammatory findings at endoscopy, and (6) colectomy owing to high IBD disease activity.

Inflammatory Bowel Disease Activity Curves Based on the investigators’ general impression of all factors related to IBD activity, the total course of IBD in each patient was recorded from diagnosis of IBD until Ltx and from Ltx to the last clinical follow-up or colectomy, according to 5 disparate predefined IBD activity curves, based on a modification of previously reported disease course patterns (Figure 1).23

Medication We obtained detailed records of the medical therapy for PSC and IBD and of the immunosuppressive therapy after Ltx. Because a majority of the transplanted patients used drugs that have a potential effect on IBD activity, we wanted to study the effect of such medication on the IBD activity after Ltx. The use of a specific drug was defined as a minimum of 3 months’ medication during the first 6 months after transplantation. Acute cellular rejections treated with steroids, antithymocyte globulin, or muromonab-CD3, and treated cytomegalovirus (CMV) infections during the first 6 months after Ltx were recorded. We also recorded the recipients’ HLA status. The study was approved by the ethical committees in the respective countries.

Statistical Analyses Data were described with proportions for categoric variables and median with range for continuous variables. Crude associations between categoric variables were assessed with the chi-square test or the Fisher exact test, when appropriate. For comparison of dependent observations such as the frequency of colonic inflammation before and after Ltx, the McNemar test was used. Cumulative risk of de novo IBD-free survival and patient survival after Ltx were calculated using the Kaplan–Meier method, and survival times were compared with the log-rank test. The different outcomes in IBD activity after Ltx were presented as percentages with 95% confidence intervals (CI) where CIs were constructed using a normal distribution approximation. The severity of IBD activity before and after Ltx in each patient and the rate of relapse before and after Ltx were compared using the Wilcoxon signed-rank test for paired data. The cumulative risks of colectomy caused by refractory IBD before and after Ltx were estimated using competing risk regression analysis,24,25 where colectomy for refractory IBD defined the main event of interest and colectomy owing to other reasons and death were the competing events. The effect of medication and other factors on the course of IBD after Ltx was studied using Cox proportional hazards models stratified by the different transplant centers. P values of .05 or less were considered statistically significant. All statistical analyses were performed with SPSS version 18 (IBM Corp,

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Figure 1. Five predefined curves depicting the course of IBD from diagnosis of IBD until Ltx (pre Ltx), and from Ltx until last follow-up evaluation (post Ltx). Recordings were based on the investigators’ impression of the overall course of IBD in each patient. In the pre Ltx evaluation, the end of the curves represents disease activity at Ltx. In the post Ltx evaluation, the end of the curves represents disease activity at last clinical follow-up. *Including 20 colectomies.

Summers, NY) and Stata version 11 (Stata Corp, College Station, TX). All authors revised the manuscript and approved the final version.

Results Study Population Of the 439 PSC patients undergoing Ltx, 353 (80%) had a diagnosis of IBD at the time of transplantation. The type of IBD and other demographic data are depicted in Table 1. Eleven

Table 1. Demographics and Clinical Features of PSC Patients Undergoing Ltx

Feature

IBD at the time All patients of Ltx (n ⫽ 439) (n ⫽ 353)

Male sex, n (%) 308 (70) Age at diagnosis of PSC 36 (6–70) Age at diagnosis of IBD — Age at Ltx 44.5 (11–73) Type of IBD, n (%) UC — CD — IBD-u — Duration of PSC at Ltx 6.5 (0–37) Duration of IBD at Ltx — Follow-up period after 5 (0–21) Ltx ⬎1 Ltx, n (%) 63 (14)

De novo IBD (n ⫽ 11)

259 (73) 35 (6–67) 25 (3–71) 44 (11–73)

6 (55) 37 (26–58) 52 (41–66) 43 (38–61)

306 (87) 32 (9) 15 (4) 7 (0–37) 15 (0–50) 5 (0–20)

10 (91) 1 (9) 0 5 (0.3–13) — 7 (1–12)

48 (14)

1 (9)

CD, Crohn’s disease; IBD-u, IBD unclassified; UC, ulcerative colitis. NOTE. Results are shown as years in median (range) unless otherwise specified.

patients developed de novo IBD with a median onset of 31 months (range, 12–140 mo) after the transplantation (Table 1). By the time of the study end, 113 (26%) patients had died. Of the 270 PSC-IBD patients with an intact colon at Ltx, the patients with fewer than 6 months of follow-up evaluation after Ltx (n ⫽ 23) and those who lacked a colonoscopy (7 pre-Ltx, 20 post-Ltx, 2 both) were excluded, leaving a study group of 218 cases. Half of the 22 patients with a missing colonoscopy after Ltx had a follow-up period of less than 22 months, and by that time had not yet undergone a surveillance colonoscopy. The pre-Ltx colonoscopy had been performed within 3 years (median, 5 mo; range, 0–36 mo) before Ltx in 199 (91%) patients. After Ltx, a total of 371 colonoscopies were assessed (mean, 1.7 examinations per patient).

Macroscopic Colonic Inflammation Macroscopic colonic inflammation was present in 124 patients (57%; 93 mild, 27 moderate, and 4 severe) before and in 153 patients (70%; 92 mild, 35 moderate, and 26 severe, leading to colectomy in 20 cases) after Ltx (P ⬍ .001) (Figure 2). When comparing the macroscopic inflammatory findings in each patient before and after Ltx, the activity of IBD decreased in 37 patients (17%) (95% CI, 15%–20%), remained unchanged in 93 patients (43%; 95% CI, 36%–50%), and increased in 88 patients (40%; 95% CI, 33%– 47%) (P ⬍ .001) (Figure 2). When comparing the use and discontinuity of azathioprine and aminosalicylates before and after Ltx, no definite pattern was found regarding activity of IBD after Ltx. There was no difference in post-Ltx survival between the groups with and without IBD deterioration after Ltx (P ⫽ .46).

Relapse of Inflammatory Bowel Disease According to our definition, 186 (85%) of 218 study patients were eligible for recording of IBD relapses. A signifi-

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Figure 2. Frequency and severity of IBD activity in PSC patients (n ⫽ 218) before and after Ltx.

cantly higher number of patients had experienced one or more episodes of relapse throughout the first 3 years after compared with the last 3 years before Ltx (77 [41%] vs 53 [28%]; P ⫽ .011). There was a significant increase in the relapse rate (number of relapses/person-year) after as compared with before Ltx (P ⬍ .001) (Figure 3). In 80% of patients with a relapse before Ltx and in 90% of those with a relapse after Ltx, the identification of each relapse was based on the presence at least 2 of the relapsedefining criteria.

Inflammatory Bowel Disease Activity Curves The clinical activity during the total course of IBD before and after Ltx, as assessed by the IBD activity curves, was evaluated in 216 (99%) of 218 patients (Figure 1). A significantly higher number of patients had experienced clinical IBD activity

Figure 3. Number of relapses per person-year during the last 3 years before and the first 3 years after Ltx (n ⫽ 186).

after transplant compared with before transplant (96 [44%] vs 50 [23%]; P ⬍ .001; Figure 1).

Cumulative Risk of Colectomy Owing to Active Disease A total of 127 (35%) patients, all with concomitant IBD, underwent colectomy. Ninety-four colectomies were performed before (52 active disease, 24 neoplasia, 13 both, 5 other causes) and 33 were performed after Ltx (14 active disease, 10 neoplasia, 6 both, 3 other causes). The cumulative risk of colectomy owing to active IBD in the group of PSC-IBD patients still at risk after Ltx (n ⫽ 259; 20 end points) was increased compared with the corresponding risk before Ltx (n ⫽ 353; 65 end points) but without reaching statistical significance (hazard ratio, 1.4; 95% CI, 0.4 –1.2; P ⫽ .22).

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Table 2. Univariate and Multivariate Analyses of Risk Factors for Deteriorated IBDa After Transplant in PSC Patients Variable Male sex Both intrahepatic and extrahepatic distribution of PSC Age ⬍20 y at diagnosis of IBD Tacrolimusb Tacrolimus and MMFb CsAb CsA and azathioprineb Aminosalicylatesb Ursodeoxycholic acidb Steroid-treated rejectionc ATG/OKT3-treated rejectionc Treated CMV infectionc

Variable present, yes/no, n

Univariate HR

95% CI

P value

154/64 170/40

1.5 1.1

0.9–2.3 0.7–2.0

.134 .64

62/156 71/147 65/153 20/198 50/168 83/135 44/171 125/93 30/188 47/171

1.7 1.6 3.5 0.8 0.2 1 0.6 1 0.6 0.9

1.1–2.6 1.0–2.6 2.1–5.8 0.4–1.3 0.1–0.5 0.7–1.7 0.3–1.2 0.7–1.6 0.3–1.0 0.51–1.5

.027 .05 ⬍.001 .265 ⬍.001 .862 .129 .949 .061 .6

Multivariate HR

95% CI

P value

1.8 1.9 3.9

1.1–2.9 0.9–3.7 1.9–7.9

.011 .067 .001

0.4

0.2–0.9

.043

ATG, antithymocyte globulin; HR, hazard ratio; OKT3, muromonab-CD3. aBased on findings of macroscopic colonic inflammation with deterioration of IBD in 88 of 218 patients. bUsed for a minimum of 3 months during the first 6 months after Ltx. cTreatment during the first 6 months after Ltx. Steroid use was not included in the analyses because all patients used this as long-term maintenance treatment. Results are stratified with regard to the different transplant centers.

Risk Factors for Increased Inflammatory Bowel Disease Activity After Transplant All patients used a small dose of prednisolone (5 mg) as long-term maintenance treatment after Ltx. As an additional immunosuppressive treatment, 142 patients used tacrolimus (71 alone, 65 in combination with mycophenolate mofetil [MMF], and 6 in combination with other compounds) and 74 cyclosporin A (CsA) (20 alone, 50 in combination with azathioprine, and 4 in combination with other compounds) (Table 2). In patients who underwent Ltx before 2000 (n ⫽ 83), the immunosuppressive regimen involved CsA in 63% and tacrolimus in 37% of cases. In patients undergoing liver transplant from 2000 (n ⫽ 135), CsA and tacrolimus were used in 17% and 83% of cases, respectively. Univariate analyses revealed age younger than 20 years at diagnosis of IBD, use of tacrolimus, and dual therapy with tacrolimus and MMF as significant risk factors for worsening of IBD, whereas dual treatment with CsA and azathioprine showed a significant protective effect (Table 2). All significant factors in the univariate analyses except for tacrolimus remained statistically significant in the multivariate analyses (Table 2). Neither use of aminosalicylates, steroid– and antithymocyte globulin/muromonab-CD3–treated rejections, nor treated CMV infections were significant risk factors (Table 2). Exclusion of patients with de novo IBD (n ⫽ 11) did not change the results of the multivariate analyses. After correction for multiple testing according to Bonferroni, no statistically significant association with deteriorated IBD activity after Ltx was detected for HLA-B and DRB1 variants (data not shown). However, a trend toward an increased frequency of the PSC-associated HLA-B*08 allele among patients with deteriorated IBD activity (36.0%) as compared with patients with improved (26.7%) or unchanged (30.6%) activity should be noted.

De Novo Inflammatory Bowel Disease After Ltx, 10 (24%) of the 42 patients using tacrolimus (3 as single treatment, 6 in combination with MMF, and 1 in combination with azathioprine) as opposed to only 1 (3%) of

the 35 patients using CsA developed de novo IBD. The de novo IBD-free survival was decreased significantly in the group of patients receiving tacrolimus vs those who did not (P ⬍ .001).

Discussion This longitudinal study of IBD activity in liver-transplanted PSC patients shows an increase in IBD activity after Ltx with regard to colonic inflammation, number of relapses, overall IBD activity, and risk of colectomy owing to high disease activity, although the latter did not reach statistical significance. Dual immunosuppressive treatment with tacrolimus and MMF was associated with increased IBD activity after transplant, whereas combination treatment with CsA and azathioprine showed a protective effect. The multicenter design, the inclusion of the highest number of patients reported until now, as well as the evaluation of IBD activity before and after Ltx measured with multiple modalities, strengthens the study. We find it unlikely that the observed increase in IBD activity after Ltx can be explained as a natural course of IBD because PSC-IBD is described as typically quiescent in earlier studies.4,7 To evaluate the endoscopic activity of IBD after Ltx, we chose the colonoscopy with the highest degree of macroscopic inflammation to avoid underreporting the disease outcome. This strategy also may be supported by the longitudinal assessment of the clinical IBD activity (Figure 1). However, we cannot exclude the possibility of a somewhat reduced threshold for colonoscopy after Ltx owing to an increased accessibility to health care. Although we recorded both macroscopic and microscopic findings at colonoscopy, we based our analysis on the macroscopic findings because this modality traditionally has been regarded as the main characteristic of IBD activity, and because there were more complete data. Our finding of an increased IBD relapse rate after Ltx is consistent with an earlier study by Ho et al.21 The possibility that other factors such as side effects of post-transplant medications (ie, MMF) and colonic infections (ie, CMV) could mimic IBD symptoms and thereby to some extent interfere with our results was excluded as much as possible by careful assessment

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of the patient records according to our definition of IBD relapse. The tendency toward a higher risk of colectomy owing to active IBD after Ltx as compared with before Ltx is consistent with the results of Dvorchik et al,15 who used a study design similar to ours. He followed up a group of PSC-IBD patients who underwent Ltx and found a significantly higher cumulative risk of colectomy owing to high IBD activity after Ltx compared with before Ltx using Cox regression analysis. We used competing risk regression analysis, which takes noninformative censoring into account, and this might explain why our results did not reach significant values. We regard both the current and previous findings of an association between tacrolimus and high IBD activity after Ltx16,18 somewhat surprising because tacrolimus represents a well-established IBD treatment.26 Convincing evidence for the efficacy of MMF on IBD activity, however, is lacking.27 We found it difficult to ascertain whether the association with deteriorated IBD activity after Ltx in our study was caused by tacrolimus, MMF, or by synergistic effects in this combination treatment. Regarding the limited number of patients included and the study design, we were not able to fit a statistical model to explore this possible association further. Our observation could support the theory that IBD in PSC represents a unique type of IBD with a unique response to treatment, or, alternatively, that the character of IBD in general changes after Ltx. Both CsA and azathioprine are established IBD treatment options.27 Our finding of an association between combination treatment with CsA and azathioprine and unchanged or decreased IBD activity after Ltx is in accordance with a previous study by Haagsma et al16 who found increased IBD activity-free survival after Ltx in patients using a triple regimen of CsA, azathioprine, and prednisolone. In contrast to our results, some earlier studies found that a majority of PSC patients experienced improved IBD activity after Ltx.12,13,28 These studies were smaller in size and used a different statistical approach without comparing the effect of different immunosuppressive regimens. Interestingly, the vast majority of the patients in these studies received treatment with CsA and azathioprine. We cannot exclude the possibility that the use of different immunosuppressive regimens in different time periods has affected our study results. However, patient follow-up evaluation, the endoscopic and clinical assessments, or other identifiable factors have not changed significantly during the study period. Among the 11 (5%) of 218 patients recorded as ongoing smokers at the time of Ltx, 10 continued to smoke after Ltx (data not shown). This observation makes it unlikely that smoking had any impact on the present results. The frequency and time of onset of de novo IBD after Ltx and the decreased de novo IBD-free survival in patients using tacrolimus vs those who did not are consistent with earlier findings.16,18,29 The observation that 10 of 11 patients who developed de novo IBD received tacrolimus may suggest a role for this compound in the pathogenesis of IBD after transplant. The limited number of patients, however, must be taken into account in the interpretation of these results. Although we found no difference in survival between the groups with and without worsening of IBD after Ltx, the presence of active colitis affects the morbidity of the patients undergoing Ltx. Considering both the known association between

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colonic inflammation and development of neoplasia30 and the high risk of colonic neoplasia after Ltx,10,11 efforts should be put into restricting the IBD activity after transplant. Both tacrolimus and CsA are effective and potent immunosuppressants with broadly similar effects and side effects.31 There is a paucity of randomized investigations of tacrolimus vs CsA. To fully compare the 2 compounds further studies are needed. The limitations of this study were the retrospective design and the multiplicity of endoscopic examiners, with the possibility of a heterogeneous estimation of disease activity. In conclusion, our results show an increase in IBD activity after Ltx in PSC patients. The high number of patients with deterioration of IBD after Ltx illustrates the importance of close follow-up evaluation to optimize IBD treatment. In PSC patients undergoing Ltx, a shift in maintenance treatment from tacrolimus and MMF to CsA and azathioprine may seem beneficial. References 1. Karlsen TH. The Nordic Liver Transplant Registry (NLTR). Annual report 2010. Available at: www.scandiatransplant.org. 2. Wiesner RH, Grambsch PM, Dickson ER, et al. Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis. Hepatology 1989;10:430 – 436. 3. Fausa O, Schrumpf E, Elgjo K. Relationship of inflammatory bowel disease and primary sclerosing cholangitis. Semin Liver Dis 1991;11:31–39. 4. Jørgensen KK, Grzyb K, Lundin KE, et al. Inflammatory bowel disease in patients with primary sclerosing cholangitis: clinical characterization in liver transplanted and nontransplanted patients. Inflamm Bowel Dis 2012;18:536 –545. 5. Loftus EV Jr, Harewood GC, Loftus CG, et al. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut 2005;54:91–96. 6. Joo M, Abreu-e-Lima P, Farraye F, et al. Pathologic features of ulcerative colitis in patients with primary sclerosing cholangitis: a case-control study. Am J Surg Pathol 2009;33:854 – 862. 7. Lundqvist K, Broomé U. Differences in colonic disease activity in patients with ulcerative colitis with and without primary sclerosing cholangitis: a case control study. Dis Colon Rectum 1997;40: 451– 456. 8. Soetikno RM, Lin OS, Heidenreich PA, et al. Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis. Gastrointest Endosc 2002;56:48 –54. 9. Broomé U, Löfberg R, Veress B, et al. Primary sclerosing cholangitis and ulcerative colitis: evidence for increased neoplastic potential. Hepatology 1995;22:1404 –1408. 10. Broomé U, Bergquist A. Primary sclerosing cholangitis, inflammatory bowel disease, and colon cancer. Semin Liver Dis 2006;26: 31– 41. 11. Loftus EV Jr, Aguilar HI, Sandborn WJ, et al. Risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis following orthotopic liver transplantation. Hepatology 1998;27:685– 690. 12. Gavaler JS, Delemos B, Belle SH, et al. Ulcerative colitis disease activity as subjectively assessed by patient-completed questionnaires following orthotopic liver transplantation for sclerosing cholangitis. Dig Dis Sci 1991;36:321–328. 13. Saldeen K, Friman S, Olausson M, et al. Follow-up after liver transplantation for primary sclerosing cholangitis: effects on survival, quality of life, and colitis. Scand J Gastroenterol 1999; 34:535–540. 14. van de Vrie W, de Man RA, van Buuren HR, et al. Inflammatory

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bowel disease and liver transplantation for primary sclerosing cholangitis. Eur J Gastroenterol Hepatol 2003;15:657– 663. Dvorchik I, Subotin M, Demetris AJ, et al. Effect of liver transplantation on inflammatory bowel disease in patients with primary sclerosing cholangitis. Hepatology 2002;35:380 – 384. Haagsma EB, Van den Berg AP, Kleibeuker JH, et al. Inflammatory bowel disease after liver transplantation: the effect of different immunosuppressive regimens. Aliment Pharmacol Ther 2003; 18:33– 44. Moncrief KJ, Savu A, Ma MM, et al. The natural history of inflammatory bowel disease and primary sclerosing cholangitis after liver transplantation–a single-centre experience. Can J Gastroenterol 2010;24:40 – 46. Verdonk RC, Dijkstra G, Haagsma EB, et al. Inflammatory bowel disease after liver transplantation: risk factors for recurrence and de novo disease. Am J Transplant 2006;6:1422–1429. Chapman RW, Arborgh BA, Rhodes JM, et al. Primary sclerosing cholangitis: a review of its clinical features, cholangiography, and hepatic histology. Gut 1980;21:870 – 877. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 1987;317:1625– 1629. Ho GT, Seddon AJ, Therapondos G, et al. The clinical course of ulcerative colitis after orthotopic liver transplantation for primary sclerosing cholangitis: further appraisal of immunosuppression post transplantation. Eur J Gastroenterol Hepatol 2005;17: 1379 –1385. Riis L, Vind I, Politi P, et al. Does pregnancy change the disease course? A study in a European cohort of patients with inflammatory bowel disease. Am J Gastroenterol 2006;101:1539 –1545. Henriksen M, Jahnsen J, Lygren I, et al. Ulcerative colitis and clinical course: results of a 5-year population-based follow-up study (the IBSEN study). Inflamm Bowel Dis 2006;12:543– 550. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999;94:496 –509. Pintilie M, Risks C. A practical perspective. Chichester, UK: John Wiley & Sons, 2006.

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26. Ogata H, Matsui T, Nakamura M, et al. A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis. Gut 2006;55:1255–1262. 27. Ng SC, Chan FK, Sung JJ. Review article: the role of non-biological drugs in refractory inflammatory bowel disease. Aliment Pharmacol Ther 2011;33:417– 427. 28. Stephens J, Goldstein R, Crippin J, et al. Effects of orthotopic liver transplantation and immunosuppression on inflammatory bowel disease in primary sclerosing cholangitis patients. Transplant Proc 1993;25:1122–1123. 29. Joshi D, Bjarnason I, Belgaumkar A, et al. The impact of inflammatory bowel disease post-liver transplantation for primary sclerosing cholangitis. Liver Int 2013;33:53– 61. 30. Rutter M, Saunders B, Wilkinson K, et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 2004;126:451– 459. 31. Scott LJ, McKeage K, Keam SJ, et al. Tacrolimus: a further update of its use in the management of organ transplantation. Drugs 2003;63:1247–1297.

Reprint requests Address requests for reprints to: Kristin Kaasen Jørgensen, MD, Section for Gastroenterology, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Box 4950 Nydalen, 0424 Oslo, Norway. e-mail: [email protected]; fax: (47) 23-07-06-70. Acknowledgment The authors thank Kristian Holm at the Norwegian PSC Research Centre (Oslo, Norway) for support with the database, and Per Sangfelt at the University Hospital of Uppsala (Sweden) for the contribution of patient data. Conflicts of interest The authors disclose no conflicts. Funding Supported by grants from the South-Eastern Norway Regional Health Authority and the Swedish Cancer Society.