CROHNS-00945; No of Pages 8 Journal of Crohn's and Colitis (2014) xx, xxx–xxx
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Mycophenolate mofetil therapy in the management of inflammatory bowel disease — A retrospective case series and review Matthew R. Smith ⁎, Sheldon C. Cooper Gastroenterology Department, The Dudley Group NHS Foundation Trust, Dudley DY1 2HQ, UK
Received 20 November 2013; received in revised form 14 January 2014; accepted 16 January 2014 KEYWORDS Mycophenolate mofetil; Inflammatory bowel disease; Crohn's disease; Ulcerative colitis
Abstract Background and aims: The role of mycophenolate mofetil (MMF) as an immunomodulatory drug in managing inflammatory bowel disease (IBD) is yet to be fully defined. We reviewed our experience of MMF in treating patients with IBD. Methods: Retrospective analysis was performed on all patients treated with MMF for inflammatory bowel disease between 2003 and 2011. Remission was assessed by reviewing clinical, endoscopic and laboratory indices. Results: We identified 36 patients, 23 male (64%), median age 46 years (range 19–75). Nineteen patients had Crohn's disease, 16 with ulcerative colitis (UC), and one with indeterminate colitis. 33 patients (92%) had previously received azathioprine; 32 of whom discontinued this due to side-effects. 26 patients (72%) were concurrently taking oral corticosteroids. Median length of MMF treatment observed was 21.5 months (IQR 9.7–31.6). At 8 weeks, 29 patients (81%) had either achieved or maintained remission. After 6 months, 19 of 33 patients (58%) were in sustained steroid-free remission. At the end of the observation period, 29 patients (81%) remained on MMF. 13 patients (36% of original treatment group; UC/IBDU 8, Crohn's 5) maintained steroid free remission. Median time in remission was 21.4 months (IQR 11.0–30.0). Drug side-effects were experienced by 7 patients (19%), managed by dose reduction in 5 patients, with discontinuation in 2 (6%). Conclusions: Mycophenolate mofetil may represent a promising treatment for inducing and maintaining remission in IBD patients intolerant of thiopurines. It may be of more value and relevance in ulcerative colitis, since less alternative proven therapies are available. © 2014 Published by Elsevier B.V. on behalf of European Crohn's and Colitis Organisation.
⁎ Corresponding author at: c/o Dr SC Cooper's secretary, Gastroenterology Department, The Dudley Group NHS Foundation Trust, Dudley DY1 2HQ, UK. Tel.: + 44 1384456111. E-mail address: [email protected] (M.R. Smith). 1873-9946/$ - see front matter © 2014 Published by Elsevier B.V. on behalf of European Crohn's and Colitis Organisation. http://dx.doi.org/10.1016/j.crohns.2014.01.014 Please cite this article as: Smith MR, Cooper SC, Mycophenolate mofetil therapy in the management of inflammatory bowel disease — A retrospective case series and review, J Crohns Colitis (2014), http://dx.doi.org/10.1016/j.crohns.2014.01.014
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M.R. Smith, S.C. Cooper
1. Introduction Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract. Corticosteroids are commonly used in the initial management of active IBD. However up to half of patients become dependent on or refractory to steroid therapy, and many develop side effects after prolonged exposure.1 Alternative immunomodulatory drugs are frequently prescribed for longer term management. The thiopurines azathioprine and 6-mercaptopurine have been found to be effective in maintaining remission in both Crohn's disease and ulcerative colitis (UC).2–5 However concordance with azathioprine therapy is often limited by side effects, with approximately 25% of patients unable to continue therapy due to adverse side effects.6 Methotrexate (MTX) offers alternative immunomodulatory therapeutic options in Crohn's disease before considering anti-tumour necrosis factor alpha (anti-TNFα agents). In UC there are limited alternatives to the thiopurines, with MTX less commonly used. Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid, is now an established efficacious immunosuppressant used in solid organ transplantation and has been employed in various autoimmune disorders such as psoriasis, ANCA-positive vasculitis and lupus nephritis.7–10 Mycophenolic acid is a non-competitive, reversible inhibitor of inositol monophosphate dehydrogenase, a key enzyme required for de novo synthesis of guanosine nucleotides.11 These are necessary substrates for DNA and RNA synthesis. B and T lymphocytes depend solely on de novo nucleotide synthesis, unlike other cell types (e.g. neutrophils) that can recycle nucleotides via a salvage pathway and therefore the action of MMF is thought to suppress proliferation of this specific cell group. The use of MMF in patients with IBD has been previously reported, especially in those who are steroid dependent, refractory, or intolerant of more conventional therapies. However aside from 2 small randomised comparative studies with azathioprine, this work has been retrospective and hampered by small patient numbers leading to inconsistent outcomes.12–23 Furthermore the reported rates of side effects necessitating discontinuation of therapy have been significant. We report our experience with the use of MMF in our department for predominantly thiopurine-intolerant patients with IBD.
2. Materials and methods
Table 1 Patient demographics, distribution of disease and previous/current therapies. CD, Crohn's disease; UC/IBDU, ulcerative colitis/inflammatory bowel disease unspecified. Patient demographics (n = 36) Age (years) Gender (male: female) Disease subtype CD UC Indeterminate Distribution of disease UC/IBDU (n = 17) Proctitis Left sided Pancolitis CD (n = 19) a Small bowel Colonic Perianal Previous surgery Previous treatments Azathioprine 6-Mercaptopurine Methotrexate Infliximab Concurrent treatments Corticosteroids 5-Aminosalicylates
46.5 (range 19–75) 23: 13 (1.8:1) 19 (53%) 16 (44%) 1 (3%)
1 9 7 10 11 2 5 33 (92%) 7 (19%) 2 (6%) 3 (8%) 26 (72%) 18 (50%)
a 3 patients with CD had multiple sites of disease, (2 sites in 2 patients, 3 sites in 1 patient).
use, including efficacy and tolerance. Due to the retrospective nature of this study we did not have disease activity indices to assess treatment response. Azathioprine failure was defined as a lack of clinical response at a dose of 2.0–2.5 mg/kg body weight, as distinguished from intolerance/adverse effects. Remission was defined by the responsible clinician using a combination of clinical, laboratory and endoscopic indices. We defined treatment success of MMF as steroid-free clinical remission. In line with other previous retrospective studies12 we evaluated initial response in terms of achieving/ maintaining remission at 8 weeks, and then steroid-free remission at 6 months and at the end of time on the database. Failure of MMF was defined as either escalation in medical treatment including the need for surgery, or
2.1. Subjects All patients who had received MMF for IBD at our institution from 2003 to 2011 were identified from a prospectively collected database. Clinical case notes were reviewed, excluding those with less than a six month period of follow-up data. Patients were grouped using the Vienna classification24 as those with Crohn's Disease (CD) or ulcerative colitis/IBD unclassified (UC/IBDU).
2.2. Data collection The following data were collected: demographic data, diagnosis, disease extent (Vienna classification for CD24 and colonic extent for UC) and details of other immunomodulator
Table 2 Side-effects experienced on mycophenolate mofetil therapy (present in 7 patients). Side effect
No. of patients
Nausea Diarrhoea Tremor Rash Leg cramps Insomnia Joint aches Pruritic rash
3a 2 1a 1a 1a 1 1 1a
a
Side effects in those intolerant of and stopping MMF (n = 2).
Please cite this article as: Smith MR, Cooper SC, Mycophenolate mofetil therapy in the management of inflammatory bowel disease — A retrospective case series and review, J Crohns Colitis (2014), http://dx.doi.org/10.1016/j.crohns.2014.01.014
MMF management in IBD
3
Table 3 End of study outcomes categorised by disease state. Percentages represent proportion of original group. Anti-TNFα, anti-tumour necrosis factor-alpha; CD, Crohn's disease; UC/IBDU, ulcerative colitis/inflammatory bowel disease unspecified. N/A — not applicable. End of observation outcomes
CD (n = 19)
UC/IBDU (n = 17)
Steroid free remission Remission with a steroid-treated flare Remission with long term steroids Remission with anti-TNFα then steroids Remission with long term anti-TNFα therapy Surgery Refractory to drug therapy Other
5 (26%) 1 2 1 7 (37%) 2 1 N/A
8 (47%) 1 2 N/A N/A 3 1 2a
a
1 patient on 5-ASA only, 1 patient restarted on 6-MP.
Table 4 Comparison of patient disease and treatment variables between those defined as succeeding with MMF treatment and failing. MMF, mycophenolate mofetil; CD, Crohn's disease; UC/IBDU, ulcerative colitis/inflammatory bowel disease unspecified; anti-TNFα, anti-tumour necrosis factor-alpha.
Median age (range) Male CD (n = 19) Small Bowel Colonic Perianal involvement also UC/IBDU (n = 17) Proctitis Left sided Pancolitis Previous small bowel CD surgery Previous treatment with anti-TNFα therapy Clinical status at start of MMF therapy Acute flare Steroid dependent Remission needing long term control
MMF success (n = 13)
%
MMF failure (n = 23)
%
49 (20–74) 8
62
45 (16–75) 15
65
3 2 1
60 40 20
7 8 1
50 57 7
1 4 3 3 1
13 50 38 60 8
0 5 4 2 2
0 56 44 14 9
7 3 3
54 23 23
13 6 4
57 26 17
cessation of MMF due to adverse effects. In particular any steroid use after withdrawal of initial tapering regimen (or inability to withdraw steroids at 6 months or thereafter) was classified as treatment failure. In addition we recorded the time to MMF treatment failure, defined as above, to allow for Kaplan Meier analysis of outcome and comparison by disease subgroup (Crohn's, UC/IBDU).
2.3. Statistical analysis Data were analysed with SPSS 19.0.0 (IBM, USA). All values are expressed as means and standard deviations or as medians and interquartile ranges (IQRs) or ranges as appropriate. Kaplan– Meier survival analysis was used with log-rank testing for difference between Crohn's and UC/IBDU groups respectively. P b 0.05 was considered statistically significant.
2.4. Ethical statement This study had appropriate ethics committee approval.
Figure 1 Kaplan–Meier plot showing clinical remission with mycophenolate mofetil, comparing patients with Crohn's disease and UC/IBDU. Log rank p = 0.425.
Please cite this article as: Smith MR, Cooper SC, Mycophenolate mofetil therapy in the management of inflammatory bowel disease — A retrospective case series and review, J Crohns Colitis (2014), http://dx.doi.org/10.1016/j.crohns.2014.01.014
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Study
Design
Number Number MMF receiving CD: UC dose MMF
Prior AZA Criteria for AZA intolerance success + trialled vs failure follow up time
Fickert 1998 Austria Neurath 1999 Germany
Prospective open
6
CD only 2 g/day
83%
Prospective randomised uncontrolled vs AZA
35
CD only 15 mg/ kg
0
N/A
Fellermann 2000 Germany Orth 2000 Germany
Prospective uncontrolled
24
11: 13
0
N/A
Prospective randomised uncontrolled vs AZA
12
UC only 20 mg/ kg
0
N/A
Hassard 2000 USA
Retrospective 11
CD only 1–3 g/ day
100%
Miehsler 2001 Vienna
Retrospective 15 (2 × matched AZA controls)
CD only 25– 35 mg/ kg
100%
2 g/day
Efficacy– Steroid Intolerant Limitations remission free? of MMF at time (stopped) point
Treatment for 100% No 6/12–CDAI at 6/12 improved CDAI Remission on 5 mg 80% at 6/ No prednisolone at 12 1,2,3,6/12 (CDAI)
17%
Small case series
6%
b 5 mg/day prednisolone at 6/12 Ability to taper steroids at 1,3,6,12/12
42% 3/12 Yes 4% 6/12
8%
Not intention to treat analysis; Not clear if extra courses steroids needed to maintain remission Not steroid free
92% vs No 67% 6/12 88% vs 100% 1 yr
17%
6:5
HBI at 8/52; ability to taper steroids
36%
15:0
Remission at 12/ 12 (not steroid free)
27% HBI No response at 8/52; 9% steroid free 60% 1 yr No
Steroid courses during study to achieve remission (only 38% steroid free at 1 year) Retrospective study
20%
Retrospective study
Notes
80% remission at 6/12 in severe cases (CDAI N 300), 100% moderate. Quicker onset of remission than AZA. Defined as failure if given further steroid courses.
Only 2 remained on MMF N 1 year.
MMF 2× flares vs AZA and used more steroids. 80% pts had a flare during study period.
M.R. Smith, S.C. Cooper
Please cite this article as: Smith MR, Cooper SC, Mycophenolate mofetil therapy in the management of inflammatory bowel disease — A retrospective case series and review, J Crohns Colitis (2014), http://dx.doi.org/10.1016/j.crohns.2014.01.014
Table 5 Summary of published studies using mycophenolate mofetil in the management of inflammatory bowel disease. MMF, mycophenolate mofetil; AZA, azathioprine; MTX, methotrexate; CD, Crohn's disease; UC/IBDU, ulcerative colitis/inflammatory bowel disease unspecified; anti-TNFα, anti-tumour necrosis factor alpha; CDAI, Crohn's disease activity index; HBI, Harvey–Bradshaw index.
Study Design
Please cite this article as: Smith MR, Cooper SC, Mycophenolate mofetil therapy in the management of inflammatory bowel disease — A retrospective case series and review, J Crohns Colitis (2014), http://dx.doi.org/10.1016/j.crohns.2014.01.014
Number CD: UC
MMF dose
Prior AZA trialled
AZA
intolerance Criteria for vs failure success + follow up time
Efficacy– Steroid Intolerant Limitations remission free? of MMF at time (stopped) point
Notes
12
7: 5
1 g/day
100%
10:2
Improved HBI
3 (25%) at 2 yrs
Retrospective 20
CD only 750 mg– 100% 2 g/day
15:5
HBI b 4; ability to taper steroids
2 developed severe gut ulceration thought secondary to MMF. 55% reported side-effects
Retrospective 20
CD only 2 g/day
95%
12:7
Palaniappan Retrospective 70 2007 Leeds, UK
51: 19
1.5 g/ day mean
96%
37:30
Tan 2009 Australia
Retrospective 14
9:5
1–4 g/ day
93%
McDermott 2011 Dublin
Retrospective 78
35:43
mean 1 g/day
Smith 2014 Dudley, UK
Retrospective 36
19:17
Median 2 g/day
Skelly 2002 Prospective Notts, UK open Hafraoui 2002 France Wenzl 2004 Austria
33%
No strict outcome measures
20% No 10–18/ 12 HBI b 4 + b 10 mg/ 55% 6/12 No day 15% 1 yr prednisolone at 6/ 12 Steroid free 24% at Yes remission end study (mean 28/12)
25%
Retrospective study
25%
Retrospective study
2 of 7 AZA failures responded vs 9 of 12 intolerant of AZA
24%
Retrospective study no fixed time endpoint reported
Response similar in AZA-intolerant and failed groups. UC 32% remission vs Crohn's 22%
14:0
HBI/CDAI; steroid free remission
21%
Retrospective study
100%
Not specified
remission at 12/12, 29% 1 yr, ? 24/12 16% 2 yr
28%
Retrospective study
92%
32:1
Steroid free remission at 6/12
6%
Retrospective study
6/14 of this population had failed anti-TNFα therapy and 3/9 Crohn's had failed MTX. 40% reported side-effects no difference in outcome between AZA failure vs intolerant Better outcomes UC vs Crohn's
71% 8/ 52; 64% 6/12; 57% 1 yr
78% 8/ 52; 53% 6/12
No
Yes
Yes
MMF management in IBD
Number receiving MMF
5
6
M.R. Smith, S.C. Cooper
3. Results A total of 36 patients received MMF for IBD between 2003 and 2011: 23 male (64%), median age 46 years (range 19–75). Disease was classified as Crohn's disease in 19 and UC/IBDU in 17 (UC 16, IBDU 1). Disease distribution and other demographics are shown in Table 1. 33 patients (92%) had previously received azathioprine; the remaining 3 patients were not prescribed due to: low thiopurine s-methyltransferase (TPMT) activity, high TPMT activity, and need for full dose allopurinol for recurrent gout. Thirty-two of the 33 patients (97%) discontinued azathioprine due to side-effects. This consisted of intolerable symptoms in 23 (72%) patients, deranged liver function tests in 7 (22%), pancreatitis in 2 (6%). The remaining case was due to treatment failure. Seven patients had subsequently tried 6-mercaptopurine (6-MP) with symptomatic recurrence. Within the Crohn's subgroup, 2 had received methotrexate and 3 had received infliximab as an acute induction course only. The initial starting dose of MMF was between 500 mg and 2 g daily (median dose 1 g), titrated to a dose of 2 g daily where tolerated (maintenance dose median 2 g, range 1– 2 g). At the time of initiation of MMF, 26 patients (72%) were concurrently taking oral corticosteroids with a median dose of 15 mg prednisolone (range 5–40 mg). 18 (50%) were taking an oral 5-aminosalicylate (5-ASA). On commencement of MMF therapy clinical status was as follows: 20 (56%) had acute symptomatic flare, 9 (25%) were in remission but steroid dependent and 7 (19%) were asymptomatic in remission but requiring a long term maintenance therapy (Crohn's disease).
(ten patients). A further four patients (11%) were in remission but still on tapering steroid therapy.
3.4. Overall end study outcomes The median duration of observed MMF treatment was 21.5 months (IQR 9.7–31.6, range 1.8–104.8 months). At end of follow up 29 patients (81%) remained on MMF. Thirteen achieved and maintained steroid free remission throughout the study period (36% of total), with a median duration of MMF treatment 21.4 months (IQR 11–30, range 6.0–42.0 months). This comprised five patients with Crohn's disease (26%), eight with UC/IBDU (47%). A further 13 patients achieved remission following the additional use of long term or pulsed steroids/anti-TNFα therapy. Five patients (14%) were refractory to medical strategies and underwent surgery. Three patients with UC had total colectomy and two patients with Crohn's disease underwent ileocaecal resection. Table 3 summarises the end of study outcomes categorised by disease state, while Table 4 compares the characteristics of the patients succeeding and failing MMF treatment.
3.5. Kaplan–Meier analysis of disease subgroups Fig. 1 shows length of remission/time to treatment failure on MMF using Kaplan–Meier cumulative analysis. There was a difference between disease subgroup outcomes favouring UC/ IBDU, but this did not reach statistical significance using log rank analysis.
3.1. Tolerance/adverse effects of MMF
4. Discussion
Drug side-effects were experienced by 19% (7 out of 36) of patients, the most common being nausea (3) and diarrhoea (2) (see Table 2). Two patients (one with Crohn's disease and one with UC) stopped MMF due to side-effects (at 56 and 84 days respectively), with the remainder responding to dose reduction. No infective complications were observed, and no patient developed neutropenia whilst taking MMF.
This retrospective study further examines the efficacy of mycophenolate mofetil as an alternative oral immunosuppressant to thiopurines in inflammatory bowel disease management, both CD and UC. After six months of MMF therapy, 53% of our patients had achieved or maintained steroid free remission. After a median follow up of 22 months 36% achieved steroid free remission, with the longest duration of treatment up to 3.5 years. Steroid free remission is a most pragmatic and highly desirable end-point given its clinical relevance, and a strength over many other studies to date (see discussion below). As previously mentioned there have been inconsistent results in the published literature with regard to the efficacy of MMF in IBD, which are summarised in Table 5. There have been no randomized, placebo-controlled trials of MMF in IBD. Original enthusiasm was created following a prospective study randomising 70 Crohn's patients to receive either MMF or azathioprine.14 They found MMF to be as effective as azathioprine in achieving remission at six months. However this study's limitations have been noted due to its non-blind nature, lack of intention to treat analysis and lack of steroid free remission as an endpoint (steroid requirements were not recorded).25 Our current study focuses upon steroid free remission as an end-point. The only other prospective comparative trial (patients with UC) found MMF to be inferior to azathioprine but still effective when examining ability to taper steroids and cumulative steroid dose required at
3.2. Eight-week outcomes Eight weeks after commencement of MMF therapy, 35 (97%) patients remained on MMF, with one patient stopping MMF because of adverse symptoms. Remission was achieved or maintained in 28 patients (78%), 68% of those within the CD subgroup (13) and 88% within the UC/IBDU subgroup (14). In the remaining seven patients (5 Crohn's, 2 UC/IBDU) MMF was ineffective, and they went on to receive additional therapy in the form of infliximab in 6 patients, with one patient receiving steroids and ultimately colectomy.
3.3. Six-month outcomes At six months 33 patients continued to take MMF. Nineteen patients (53% of the original treatment group) were in steroid-free remission: 47% of those within the CD subgroup (9 patients) and 59% of those within the UC/IBDU subgroup
Please cite this article as: Smith MR, Cooper SC, Mycophenolate mofetil therapy in the management of inflammatory bowel disease — A retrospective case series and review, J Crohns Colitis (2014), http://dx.doi.org/10.1016/j.crohns.2014.01.014
MMF management in IBD specified time-points to 1 year.14 Fellerman et al. revealed contradictory findings in a population of patients with UC and Crohn's disease (azathioprine-naïve), with only 4% achieving remission (defined as b 5 mg/day prednisolone required) at six months.15 These studies examined azathioprine-naïve patients. However more recent retrospective series have examined MMF as a second line agent when azathioprine was either not tolerated (constituting the majority) or ineffective. Again conflicting results have been found, and comparison is difficult due to the differing endpoint definitions with few studies opting for steroid free remission as an endpoint (see Table 5). In addition most of the series have less than 20 cases. In a large retrospective UK case series of 70 patients with IBD, 24% achieved steroid free remission after a mean of 28 months follow up. Outcomes were no different in comparing those who were azathioprine-intolerant versus those with thiopurine failure; response to MMF was slightly better in those patients with UC.16 Mc Dermott et al. in a similar sized cohort found a 29% remission rate at 1 year.17 Similarly they found no statistical difference in outcome between those with prior thiopurine intolerance or failure, or between Crohn's disease and UC. These studies would appear to refute earlier suggestion that a subgroup of patients were resistant to thiopurine and MMF, with their common effecting action as purine synthesis inhibitors.18,23 These two studies suggest MMF was at best of limited value, inducing remission in 24–29% of cases. Other smaller series have generally shown enhanced outcomes in comparison, in predominantly azathioprine-intolerant subjects. Our treatment group also comprised azathioprine-intolerant subjects barring 1 case, thus we were unable to assess azathioprine-resistant patients adequately or comparatively. We did not perform multivariate analysis (due to small sample size) to compare variables associated with treatment success or failure (see Table 4), but the 2 groups appeared broadly similar with no clear indicators predicting treatment outcome. Perhaps most interestingly when subdividing our patient group by disease, this appeared to suggest an enhanced effect in the UC/IBDU group at all assessed time-points, with steroid free remission in 47% of patients versus 26% in the Crohn's group overall. Kaplan–Meier plot of length of remission on MMF demonstrated a difference between disease subgroup outcomes favouring UC/IBDU, but this did not reach statistical significance using log-rank analysis. This superior rate in UC/IBDU observed approaches the quoted longer term remission data for azathioprine with rates of around 50% in placebo controlled trials.2,4 Pragmatically, given methotrexate and anti-TNF-α therapies are more relevant treatment options for Crohn's, an alternative to azathioprine in intolerant patients with UC may be of more utility. MMF could potentially be used for both immunomodulation in a step-up management process in those naïve of anti-TNF alpha medication, and also in the UK for those in whom fulminant/sub-fulminant UC has been brought into remission acutely by anti-TNFα therapy. In the latter, NICE guidance stipulates the use of 3 treatments for induction only, so in those who are unable to take thiopurines subsequent alternative immunomodulation is needed.26 The literature to date has documented a significant side-effect profile for MMF, with diarrhoea in particular being well recognised, reported with a frequency of between 13 and 37% in the renal transplant population.27,28 Indeed in the studies
7 to date MMF was discontinued due to side effects in between 8 and 36% of patients.12–23 However in comparison we found MMF to be well tolerated in our patient group: 19% had side effects but only two patients (6%) discontinued MMF due to side effects, with dose reduction being a useful strategy perhaps not employed in other studies. Furthermore, despite not achieving steroid-free remission MMF was continued in a majority of the patients as a co-immunosuppressant. Importantly there were no serious adverse effects, and no cases of neutropenia. There were limitations to our study, namely its retrospective nature and the small sample size, although still representing the third largest to date. Prescribing and patient monitoring was performed by a number of clinicians, with the attendant inter-observer variability in defining endpoints such as remission and making treatment decisions. Furthermore, endoscopic follow-up was not consistent enough to enable analysis in this report. Finally, analysis of changes in C-reactive protein (CRP) may represent a quantitative end point, however baseline CRP (recorded in 31 of 36 subjects) was commonly normal in the first instance (65%, 20 out of 31), due to steroid use (n = 7) or failing to be a useful inflammatory marker for that subject. In the remaining 11 subjects, a fall in CRP in keeping with clinical response was observed in 73% (n = 8, data not shown). We thus did not use CRP as a guide to response in this study. It is noted that of the 23 patients who stopped azathioprine due to intolerable symptoms alone, only 7 (30%) were (unsuccessfully) tried with 6-mercaptopurine. The published literature suggests that a trial of 6-mercaptopurine can be successful in this setting in 48–73% of patients.29,30 Thus perhaps this strategy could have been attempted first prior to switching to MMF, although its success cannot be assumed. In conclusion, mycophenolate mofetil may represent a promising alternative treatment for inducing and maintaining remission in IBD patients intolerant of or unable to receive thiopurines. It appears well tolerated with a good safety profile in thiopurine-intolerant subjects. It may be of more value and relevance in ulcerative colitis, especially since less alternative proven therapies are available to the clinician.
Authorship statement MS was responsible for acquisition and analysis of data, drafting of manuscript; SCC was responsible for study design, analysis of data and revision of the manuscript. Both authors read and approved the final manuscript.
Conflict of interest No financial relationships with a commercial entity producing health-care related products and/or services relevant to this article.
Acknowledgements We would like to thank Lindsey Wood and Jayne Slater for creating and maintaining the IBD database from which data were extracted.
Please cite this article as: Smith MR, Cooper SC, Mycophenolate mofetil therapy in the management of inflammatory bowel disease — A retrospective case series and review, J Crohns Colitis (2014), http://dx.doi.org/10.1016/j.crohns.2014.01.014
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M.R. Smith, S.C. Cooper
References 1. Munkholm P, Langholz E, Davidsen M, Binder V. Frequency of glucocorticoid resistance and dependency in Crohn's disease. Gut 1994;35:360–2. 2. Prefontaine E, Sutherland LR, Macdonald JK, Cepoiu M. Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev 2009 Jan 21;1 [CD000067. Epub]. 3. Prefontaine E, Macdonald JK, Sutherland LR. Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease. Cochrane Database Syst Rev 2010 Jun 16;6 [CD000545. Epub]. 4. Timmer A, McDonald JW, Tsoulis DJ, Macdonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2012;9. http://dx.doi.org/10. 1002/14651858.CD000478.pub3 [CD000478]. 5. Peyrin-Biroulet L, Lémann M. Review article: remission rates achievable by current therapies for inflammatory bowel disease. Aliment Pharmacol Ther 2011;33(8):870–9. 6. Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut 2002;50:485–9. 7. Moore J, Middleton L, Cockwell P, Adu D, Ball S, Little MA, et al. Calcineurin inhibitor sparing with mycophenolate in kidney transplantation: a systematic review and meta-analysis. Transplantation 2009 Feb 27;87(4):591–605. 8. Waiser J, Budde K, Braasch E, Neumayer HH. Treatment of acute c-ANCA positive vasculitis with mycophenolate mofetil. Am J Kidney Dis 1999;34:e9. 9. Liu V, Mackool BT. Mycophenolate in dermatology. J Dermatol Treat 2003;14:203–11. 10. Bijl M, Horst G, Bootsma H, Limburg PC, Kallenberg CG. Mycophenolate mofetil prevents a clinical relapse in patients with systemic lupus erythematosus at risk. Ann Rheum Dis 2003;62:534–9. 11. Ng SC, Chan FK, Sung JJ. Review article: the role of non-biological drugs in refractory inflammatory bowel disease. Aliment Pharmacol Ther 2011;33(4):417–27. 12. Tan T, Lawrance IC. Use of mycophenolate mofetil in inflammatory bowel disease. World J Gastroenterol 2009;15(13):1594–9. 13. Neurath MF, Wanitschke R, Peters M, Krummenauer F, Meyer zum Büschenfelde KH, Schlaak JF. Randomised trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn's disease. Gut 1999;44:625–8. 14. Orth T, Peters M, Schlaak JF, Krummenauer F, Wanitschke R, Mayet WJ, et al. Mycophenolate mofetil versus azathioprine in patients with chronic active ulcerative colitis: a 12-month pilot study. Am J Gastroenterol 2000;95:1201–7. 15. Fellermann K, Steffen M, Stein J, Raedler A, Hämling J, Ludwig D, et al. Mycophenolate mofetil: lack of efficacy in chronic active inflammatory bowel disease. Aliment Pharmacol Ther 2000;14:171–6.
16. Palaniappan S, Ford AC, Greer D, Everett SM, Chalmers DM, Axon AT, et al. Mycophenolate mofetil therapy for refractory inflammatory bowel disease. Inflamm Bowel Dis 2007;13:1488–92. 17. McDermott E, Keegan D, Hall B, Mhuruchu EN, Murphy S, Doherty G, et al. Mycophenolate mofetil following intolerance or failure of thiopurine therapy in inflammatory bowel diseases. Aliment Pharmacol Ther 2011;34:1030–46. 18. Hassard PV, Vasiliauskas EA, Kam LY, Targan SR, Abreu MT. Efficacy of mycophenolate mofetil in patients failing 6-mercaptopurine or azathioprine therapy for Crohn's disease. Inflamm Bowel Dis 2000;6:16–20. 19. Miehsler W, Reinisch W, Moser G, Gangl A, Vogelsang H. Is mycophenolate mofetil an effective alternative in azathioprineintolerant patients with chronic active Crohn's disease? Am J Gastroenterol 2001;96:782–7. 20. Fickert P, Hinterleitner TA, Wenzl HH, Aichbichler BW, Petritsch W. Mycophenolate mofetil in patients with Crohn's disease. Am J Gastroenterol 1998;93:2529–32. 21. Hafraoui S, Dewit O, Marteau P, Cosnes J, Colombel JF, Modigliani R, et al. Mycophenolate mofetil in refractory Crohn's disease after failure of treatments by azathioprine or methotrexate. Gastroenterol Clin Biol 2002;26:17–22. 22. Skelly MM, Logan RF, Jenkins D, Mahida YR, Hawkey CJ. Toxicity of mycophenolate mofetil in patients with inflammatory bowel disease. Inflamm Bowel Dis 2002;8:93–7. 23. Wenzl HH, Hinterleitner TA, Aichbichler BW, Fickert P, Petritsch W. Mycophenolate mofetil for Crohn's disease: short-term efficacy and long-term outcome. Aliment Pharmacol Ther 2004;19:427–34. 24. Gasche C, Scholmerich J, Brynskov J, D'Haens G, Hanauer SB, Irvine EJ, et al. A simple classification of Crohn's disease: report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998. Inflamm Bowel Dis 2000;6(1):8–15. 25. Atherton JC. Mycophenolate mofetil for Crohn's disease. Gut 2000 May;46(5):740–1. 26. National Institute for Health and Care Excellence. Crohn's disease: management in adults, children and young people, CG152. London: National Institute for Health and Care Excellence; 2012. 27. Solinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 1995;60:225–32. 28. European Mycophenolate Mofetil Cooperative Study Group. Placebo controlled study of mycophenolate mofetil combined with cyclosporine and corticosteroids for prevention of acute rejection. Lancet 1995;345:1321–5. 29. Lees CW, Maan AK, Hansoti B, Satsangi J, Arnott ID. Tolerability and safety of mercaptopurine in azathioprine-intolerant patients with inflammatory bowel disease. Aliment Pharmacol Ther 2008;27:220–7. 30. Boulton-Jones JR, Pritchard K, Mahmoud AA. The use of 6-mercaptopurine in patients with inflammatory bowel disease after failure of azathioprine therapy. Aliment Pharmacol Ther 2000;14:1561–5.
Please cite this article as: Smith MR, Cooper SC, Mycophenolate mofetil therapy in the management of inflammatory bowel disease — A retrospective case series and review, J Crohns Colitis (2014), http://dx.doi.org/10.1016/j.crohns.2014.01.014
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Mycophenolate mofetil therapy in the management of inflammatory bowel disease — A retrospective case series and review Matthew R. Smith ⁎, Sheldon C. Cooper Gastroenterology Department, The Dudley Group NHS Foundation Trust, Dudley DY1 2HQ, UK
Received 20 November 2013; received in revised form 14 January 2014; accepted 16 January 2014 KEYWORDS Mycophenolate mofetil; Inflammatory bowel disease; Crohn's disease; Ulcerative colitis
Abstract Background and aims: The role of mycophenolate mofetil (MMF) as an immunomodulatory drug in managing inflammatory bowel disease (IBD) is yet to be fully defined. We reviewed our experience of MMF in treating patients with IBD. Methods: Retrospective analysis was performed on all patients treated with MMF for inflammatory bowel disease between 2003 and 2011. Remission was assessed by reviewing clinical, endoscopic and laboratory indices. Results: We identified 36 patients, 23 male (64%), median age 46 years (range 19–75). Nineteen patients had Crohn's disease, 16 with ulcerative colitis (UC), and one with indeterminate colitis. 33 patients (92%) had previously received azathioprine; 32 of whom discontinued this due to side-effects. 26 patients (72%) were concurrently taking oral corticosteroids. Median length of MMF treatment observed was 21.5 months (IQR 9.7–31.6). At 8 weeks, 29 patients (81%) had either achieved or maintained remission. After 6 months, 19 of 33 patients (58%) were in sustained steroid-free remission. At the end of the observation period, 29 patients (81%) remained on MMF. 13 patients (36% of original treatment group; UC/IBDU 8, Crohn's 5) maintained steroid free remission. Median time in remission was 21.4 months (IQR 11.0–30.0). Drug side-effects were experienced by 7 patients (19%), managed by dose reduction in 5 patients, with discontinuation in 2 (6%). Conclusions: Mycophenolate mofetil may represent a promising treatment for inducing and maintaining remission in IBD patients intolerant of thiopurines. It may be of more value and relevance in ulcerative colitis, since less alternative proven therapies are available. © 2014 Published by Elsevier B.V. on behalf of European Crohn's and Colitis Organisation.
⁎ Corresponding author at: c/o Dr SC Cooper's secretary, Gastroenterology Department, The Dudley Group NHS Foundation Trust, Dudley DY1 2HQ, UK. Tel.: + 44 1384456111. E-mail address: [email protected] (M.R. Smith). 1873-9946/$ - see front matter © 2014 Published by Elsevier B.V. on behalf of European Crohn's and Colitis Organisation. http://dx.doi.org/10.1016/j.crohns.2014.01.014 Please cite this article as: Smith MR, Cooper SC, Mycophenolate mofetil therapy in the management of inflammatory bowel disease — A retrospective case series and review, J Crohns Colitis (2014), http://dx.doi.org/10.1016/j.crohns.2014.01.014
2
M.R. Smith, S.C. Cooper
1. Introduction Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract. Corticosteroids are commonly used in the initial management of active IBD. However up to half of patients become dependent on or refractory to steroid therapy, and many develop side effects after prolonged exposure.1 Alternative immunomodulatory drugs are frequently prescribed for longer term management. The thiopurines azathioprine and 6-mercaptopurine have been found to be effective in maintaining remission in both Crohn's disease and ulcerative colitis (UC).2–5 However concordance with azathioprine therapy is often limited by side effects, with approximately 25% of patients unable to continue therapy due to adverse side effects.6 Methotrexate (MTX) offers alternative immunomodulatory therapeutic options in Crohn's disease before considering anti-tumour necrosis factor alpha (anti-TNFα agents). In UC there are limited alternatives to the thiopurines, with MTX less commonly used. Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid, is now an established efficacious immunosuppressant used in solid organ transplantation and has been employed in various autoimmune disorders such as psoriasis, ANCA-positive vasculitis and lupus nephritis.7–10 Mycophenolic acid is a non-competitive, reversible inhibitor of inositol monophosphate dehydrogenase, a key enzyme required for de novo synthesis of guanosine nucleotides.11 These are necessary substrates for DNA and RNA synthesis. B and T lymphocytes depend solely on de novo nucleotide synthesis, unlike other cell types (e.g. neutrophils) that can recycle nucleotides via a salvage pathway and therefore the action of MMF is thought to suppress proliferation of this specific cell group. The use of MMF in patients with IBD has been previously reported, especially in those who are steroid dependent, refractory, or intolerant of more conventional therapies. However aside from 2 small randomised comparative studies with azathioprine, this work has been retrospective and hampered by small patient numbers leading to inconsistent outcomes.12–23 Furthermore the reported rates of side effects necessitating discontinuation of therapy have been significant. We report our experience with the use of MMF in our department for predominantly thiopurine-intolerant patients with IBD.
2. Materials and methods
Table 1 Patient demographics, distribution of disease and previous/current therapies. CD, Crohn's disease; UC/IBDU, ulcerative colitis/inflammatory bowel disease unspecified. Patient demographics (n = 36) Age (years) Gender (male: female) Disease subtype CD UC Indeterminate Distribution of disease UC/IBDU (n = 17) Proctitis Left sided Pancolitis CD (n = 19) a Small bowel Colonic Perianal Previous surgery Previous treatments Azathioprine 6-Mercaptopurine Methotrexate Infliximab Concurrent treatments Corticosteroids 5-Aminosalicylates
46.5 (range 19–75) 23: 13 (1.8:1) 19 (53%) 16 (44%) 1 (3%)
1 9 7 10 11 2 5 33 (92%) 7 (19%) 2 (6%) 3 (8%) 26 (72%) 18 (50%)
a 3 patients with CD had multiple sites of disease, (2 sites in 2 patients, 3 sites in 1 patient).
use, including efficacy and tolerance. Due to the retrospective nature of this study we did not have disease activity indices to assess treatment response. Azathioprine failure was defined as a lack of clinical response at a dose of 2.0–2.5 mg/kg body weight, as distinguished from intolerance/adverse effects. Remission was defined by the responsible clinician using a combination of clinical, laboratory and endoscopic indices. We defined treatment success of MMF as steroid-free clinical remission. In line with other previous retrospective studies12 we evaluated initial response in terms of achieving/ maintaining remission at 8 weeks, and then steroid-free remission at 6 months and at the end of time on the database. Failure of MMF was defined as either escalation in medical treatment including the need for surgery, or
2.1. Subjects All patients who had received MMF for IBD at our institution from 2003 to 2011 were identified from a prospectively collected database. Clinical case notes were reviewed, excluding those with less than a six month period of follow-up data. Patients were grouped using the Vienna classification24 as those with Crohn's Disease (CD) or ulcerative colitis/IBD unclassified (UC/IBDU).
2.2. Data collection The following data were collected: demographic data, diagnosis, disease extent (Vienna classification for CD24 and colonic extent for UC) and details of other immunomodulator
Table 2 Side-effects experienced on mycophenolate mofetil therapy (present in 7 patients). Side effect
No. of patients
Nausea Diarrhoea Tremor Rash Leg cramps Insomnia Joint aches Pruritic rash
3a 2 1a 1a 1a 1 1 1a
a
Side effects in those intolerant of and stopping MMF (n = 2).
Please cite this article as: Smith MR, Cooper SC, Mycophenolate mofetil therapy in the management of inflammatory bowel disease — A retrospective case series and review, J Crohns Colitis (2014), http://dx.doi.org/10.1016/j.crohns.2014.01.014
MMF management in IBD
3
Table 3 End of study outcomes categorised by disease state. Percentages represent proportion of original group. Anti-TNFα, anti-tumour necrosis factor-alpha; CD, Crohn's disease; UC/IBDU, ulcerative colitis/inflammatory bowel disease unspecified. N/A — not applicable. End of observation outcomes
CD (n = 19)
UC/IBDU (n = 17)
Steroid free remission Remission with a steroid-treated flare Remission with long term steroids Remission with anti-TNFα then steroids Remission with long term anti-TNFα therapy Surgery Refractory to drug therapy Other
5 (26%) 1 2 1 7 (37%) 2 1 N/A
8 (47%) 1 2 N/A N/A 3 1 2a
a
1 patient on 5-ASA only, 1 patient restarted on 6-MP.
Table 4 Comparison of patient disease and treatment variables between those defined as succeeding with MMF treatment and failing. MMF, mycophenolate mofetil; CD, Crohn's disease; UC/IBDU, ulcerative colitis/inflammatory bowel disease unspecified; anti-TNFα, anti-tumour necrosis factor-alpha.
Median age (range) Male CD (n = 19) Small Bowel Colonic Perianal involvement also UC/IBDU (n = 17) Proctitis Left sided Pancolitis Previous small bowel CD surgery Previous treatment with anti-TNFα therapy Clinical status at start of MMF therapy Acute flare Steroid dependent Remission needing long term control
MMF success (n = 13)
%
MMF failure (n = 23)
%
49 (20–74) 8
62
45 (16–75) 15
65
3 2 1
60 40 20
7 8 1
50 57 7
1 4 3 3 1
13 50 38 60 8
0 5 4 2 2
0 56 44 14 9
7 3 3
54 23 23
13 6 4
57 26 17
cessation of MMF due to adverse effects. In particular any steroid use after withdrawal of initial tapering regimen (or inability to withdraw steroids at 6 months or thereafter) was classified as treatment failure. In addition we recorded the time to MMF treatment failure, defined as above, to allow for Kaplan Meier analysis of outcome and comparison by disease subgroup (Crohn's, UC/IBDU).
2.3. Statistical analysis Data were analysed with SPSS 19.0.0 (IBM, USA). All values are expressed as means and standard deviations or as medians and interquartile ranges (IQRs) or ranges as appropriate. Kaplan– Meier survival analysis was used with log-rank testing for difference between Crohn's and UC/IBDU groups respectively. P b 0.05 was considered statistically significant.
2.4. Ethical statement This study had appropriate ethics committee approval.
Figure 1 Kaplan–Meier plot showing clinical remission with mycophenolate mofetil, comparing patients with Crohn's disease and UC/IBDU. Log rank p = 0.425.
Please cite this article as: Smith MR, Cooper SC, Mycophenolate mofetil therapy in the management of inflammatory bowel disease — A retrospective case series and review, J Crohns Colitis (2014), http://dx.doi.org/10.1016/j.crohns.2014.01.014
4
Study
Design
Number Number MMF receiving CD: UC dose MMF
Prior AZA Criteria for AZA intolerance success + trialled vs failure follow up time
Fickert 1998 Austria Neurath 1999 Germany
Prospective open
6
CD only 2 g/day
83%
Prospective randomised uncontrolled vs AZA
35
CD only 15 mg/ kg
0
N/A
Fellermann 2000 Germany Orth 2000 Germany
Prospective uncontrolled
24
11: 13
0
N/A
Prospective randomised uncontrolled vs AZA
12
UC only 20 mg/ kg
0
N/A
Hassard 2000 USA
Retrospective 11
CD only 1–3 g/ day
100%
Miehsler 2001 Vienna
Retrospective 15 (2 × matched AZA controls)
CD only 25– 35 mg/ kg
100%
2 g/day
Efficacy– Steroid Intolerant Limitations remission free? of MMF at time (stopped) point
Treatment for 100% No 6/12–CDAI at 6/12 improved CDAI Remission on 5 mg 80% at 6/ No prednisolone at 12 1,2,3,6/12 (CDAI)
17%
Small case series
6%
b 5 mg/day prednisolone at 6/12 Ability to taper steroids at 1,3,6,12/12
42% 3/12 Yes 4% 6/12
8%
Not intention to treat analysis; Not clear if extra courses steroids needed to maintain remission Not steroid free
92% vs No 67% 6/12 88% vs 100% 1 yr
17%
6:5
HBI at 8/52; ability to taper steroids
36%
15:0
Remission at 12/ 12 (not steroid free)
27% HBI No response at 8/52; 9% steroid free 60% 1 yr No
Steroid courses during study to achieve remission (only 38% steroid free at 1 year) Retrospective study
20%
Retrospective study
Notes
80% remission at 6/12 in severe cases (CDAI N 300), 100% moderate. Quicker onset of remission than AZA. Defined as failure if given further steroid courses.
Only 2 remained on MMF N 1 year.
MMF 2× flares vs AZA and used more steroids. 80% pts had a flare during study period.
M.R. Smith, S.C. Cooper
Please cite this article as: Smith MR, Cooper SC, Mycophenolate mofetil therapy in the management of inflammatory bowel disease — A retrospective case series and review, J Crohns Colitis (2014), http://dx.doi.org/10.1016/j.crohns.2014.01.014
Table 5 Summary of published studies using mycophenolate mofetil in the management of inflammatory bowel disease. MMF, mycophenolate mofetil; AZA, azathioprine; MTX, methotrexate; CD, Crohn's disease; UC/IBDU, ulcerative colitis/inflammatory bowel disease unspecified; anti-TNFα, anti-tumour necrosis factor alpha; CDAI, Crohn's disease activity index; HBI, Harvey–Bradshaw index.
Study Design
Please cite this article as: Smith MR, Cooper SC, Mycophenolate mofetil therapy in the management of inflammatory bowel disease — A retrospective case series and review, J Crohns Colitis (2014), http://dx.doi.org/10.1016/j.crohns.2014.01.014
Number CD: UC
MMF dose
Prior AZA trialled
AZA
intolerance Criteria for vs failure success + follow up time
Efficacy– Steroid Intolerant Limitations remission free? of MMF at time (stopped) point
Notes
12
7: 5
1 g/day
100%
10:2
Improved HBI
3 (25%) at 2 yrs
Retrospective 20
CD only 750 mg– 100% 2 g/day
15:5
HBI b 4; ability to taper steroids
2 developed severe gut ulceration thought secondary to MMF. 55% reported side-effects
Retrospective 20
CD only 2 g/day
95%
12:7
Palaniappan Retrospective 70 2007 Leeds, UK
51: 19
1.5 g/ day mean
96%
37:30
Tan 2009 Australia
Retrospective 14
9:5
1–4 g/ day
93%
McDermott 2011 Dublin
Retrospective 78
35:43
mean 1 g/day
Smith 2014 Dudley, UK
Retrospective 36
19:17
Median 2 g/day
Skelly 2002 Prospective Notts, UK open Hafraoui 2002 France Wenzl 2004 Austria
33%
No strict outcome measures
20% No 10–18/ 12 HBI b 4 + b 10 mg/ 55% 6/12 No day 15% 1 yr prednisolone at 6/ 12 Steroid free 24% at Yes remission end study (mean 28/12)
25%
Retrospective study
25%
Retrospective study
2 of 7 AZA failures responded vs 9 of 12 intolerant of AZA
24%
Retrospective study no fixed time endpoint reported
Response similar in AZA-intolerant and failed groups. UC 32% remission vs Crohn's 22%
14:0
HBI/CDAI; steroid free remission
21%
Retrospective study
100%
Not specified
remission at 12/12, 29% 1 yr, ? 24/12 16% 2 yr
28%
Retrospective study
92%
32:1
Steroid free remission at 6/12
6%
Retrospective study
6/14 of this population had failed anti-TNFα therapy and 3/9 Crohn's had failed MTX. 40% reported side-effects no difference in outcome between AZA failure vs intolerant Better outcomes UC vs Crohn's
71% 8/ 52; 64% 6/12; 57% 1 yr
78% 8/ 52; 53% 6/12
No
Yes
Yes
MMF management in IBD
Number receiving MMF
5
6
M.R. Smith, S.C. Cooper
3. Results A total of 36 patients received MMF for IBD between 2003 and 2011: 23 male (64%), median age 46 years (range 19–75). Disease was classified as Crohn's disease in 19 and UC/IBDU in 17 (UC 16, IBDU 1). Disease distribution and other demographics are shown in Table 1. 33 patients (92%) had previously received azathioprine; the remaining 3 patients were not prescribed due to: low thiopurine s-methyltransferase (TPMT) activity, high TPMT activity, and need for full dose allopurinol for recurrent gout. Thirty-two of the 33 patients (97%) discontinued azathioprine due to side-effects. This consisted of intolerable symptoms in 23 (72%) patients, deranged liver function tests in 7 (22%), pancreatitis in 2 (6%). The remaining case was due to treatment failure. Seven patients had subsequently tried 6-mercaptopurine (6-MP) with symptomatic recurrence. Within the Crohn's subgroup, 2 had received methotrexate and 3 had received infliximab as an acute induction course only. The initial starting dose of MMF was between 500 mg and 2 g daily (median dose 1 g), titrated to a dose of 2 g daily where tolerated (maintenance dose median 2 g, range 1– 2 g). At the time of initiation of MMF, 26 patients (72%) were concurrently taking oral corticosteroids with a median dose of 15 mg prednisolone (range 5–40 mg). 18 (50%) were taking an oral 5-aminosalicylate (5-ASA). On commencement of MMF therapy clinical status was as follows: 20 (56%) had acute symptomatic flare, 9 (25%) were in remission but steroid dependent and 7 (19%) were asymptomatic in remission but requiring a long term maintenance therapy (Crohn's disease).
(ten patients). A further four patients (11%) were in remission but still on tapering steroid therapy.
3.4. Overall end study outcomes The median duration of observed MMF treatment was 21.5 months (IQR 9.7–31.6, range 1.8–104.8 months). At end of follow up 29 patients (81%) remained on MMF. Thirteen achieved and maintained steroid free remission throughout the study period (36% of total), with a median duration of MMF treatment 21.4 months (IQR 11–30, range 6.0–42.0 months). This comprised five patients with Crohn's disease (26%), eight with UC/IBDU (47%). A further 13 patients achieved remission following the additional use of long term or pulsed steroids/anti-TNFα therapy. Five patients (14%) were refractory to medical strategies and underwent surgery. Three patients with UC had total colectomy and two patients with Crohn's disease underwent ileocaecal resection. Table 3 summarises the end of study outcomes categorised by disease state, while Table 4 compares the characteristics of the patients succeeding and failing MMF treatment.
3.5. Kaplan–Meier analysis of disease subgroups Fig. 1 shows length of remission/time to treatment failure on MMF using Kaplan–Meier cumulative analysis. There was a difference between disease subgroup outcomes favouring UC/ IBDU, but this did not reach statistical significance using log rank analysis.
3.1. Tolerance/adverse effects of MMF
4. Discussion
Drug side-effects were experienced by 19% (7 out of 36) of patients, the most common being nausea (3) and diarrhoea (2) (see Table 2). Two patients (one with Crohn's disease and one with UC) stopped MMF due to side-effects (at 56 and 84 days respectively), with the remainder responding to dose reduction. No infective complications were observed, and no patient developed neutropenia whilst taking MMF.
This retrospective study further examines the efficacy of mycophenolate mofetil as an alternative oral immunosuppressant to thiopurines in inflammatory bowel disease management, both CD and UC. After six months of MMF therapy, 53% of our patients had achieved or maintained steroid free remission. After a median follow up of 22 months 36% achieved steroid free remission, with the longest duration of treatment up to 3.5 years. Steroid free remission is a most pragmatic and highly desirable end-point given its clinical relevance, and a strength over many other studies to date (see discussion below). As previously mentioned there have been inconsistent results in the published literature with regard to the efficacy of MMF in IBD, which are summarised in Table 5. There have been no randomized, placebo-controlled trials of MMF in IBD. Original enthusiasm was created following a prospective study randomising 70 Crohn's patients to receive either MMF or azathioprine.14 They found MMF to be as effective as azathioprine in achieving remission at six months. However this study's limitations have been noted due to its non-blind nature, lack of intention to treat analysis and lack of steroid free remission as an endpoint (steroid requirements were not recorded).25 Our current study focuses upon steroid free remission as an end-point. The only other prospective comparative trial (patients with UC) found MMF to be inferior to azathioprine but still effective when examining ability to taper steroids and cumulative steroid dose required at
3.2. Eight-week outcomes Eight weeks after commencement of MMF therapy, 35 (97%) patients remained on MMF, with one patient stopping MMF because of adverse symptoms. Remission was achieved or maintained in 28 patients (78%), 68% of those within the CD subgroup (13) and 88% within the UC/IBDU subgroup (14). In the remaining seven patients (5 Crohn's, 2 UC/IBDU) MMF was ineffective, and they went on to receive additional therapy in the form of infliximab in 6 patients, with one patient receiving steroids and ultimately colectomy.
3.3. Six-month outcomes At six months 33 patients continued to take MMF. Nineteen patients (53% of the original treatment group) were in steroid-free remission: 47% of those within the CD subgroup (9 patients) and 59% of those within the UC/IBDU subgroup
Please cite this article as: Smith MR, Cooper SC, Mycophenolate mofetil therapy in the management of inflammatory bowel disease — A retrospective case series and review, J Crohns Colitis (2014), http://dx.doi.org/10.1016/j.crohns.2014.01.014
MMF management in IBD specified time-points to 1 year.14 Fellerman et al. revealed contradictory findings in a population of patients with UC and Crohn's disease (azathioprine-naïve), with only 4% achieving remission (defined as b 5 mg/day prednisolone required) at six months.15 These studies examined azathioprine-naïve patients. However more recent retrospective series have examined MMF as a second line agent when azathioprine was either not tolerated (constituting the majority) or ineffective. Again conflicting results have been found, and comparison is difficult due to the differing endpoint definitions with few studies opting for steroid free remission as an endpoint (see Table 5). In addition most of the series have less than 20 cases. In a large retrospective UK case series of 70 patients with IBD, 24% achieved steroid free remission after a mean of 28 months follow up. Outcomes were no different in comparing those who were azathioprine-intolerant versus those with thiopurine failure; response to MMF was slightly better in those patients with UC.16 Mc Dermott et al. in a similar sized cohort found a 29% remission rate at 1 year.17 Similarly they found no statistical difference in outcome between those with prior thiopurine intolerance or failure, or between Crohn's disease and UC. These studies would appear to refute earlier suggestion that a subgroup of patients were resistant to thiopurine and MMF, with their common effecting action as purine synthesis inhibitors.18,23 These two studies suggest MMF was at best of limited value, inducing remission in 24–29% of cases. Other smaller series have generally shown enhanced outcomes in comparison, in predominantly azathioprine-intolerant subjects. Our treatment group also comprised azathioprine-intolerant subjects barring 1 case, thus we were unable to assess azathioprine-resistant patients adequately or comparatively. We did not perform multivariate analysis (due to small sample size) to compare variables associated with treatment success or failure (see Table 4), but the 2 groups appeared broadly similar with no clear indicators predicting treatment outcome. Perhaps most interestingly when subdividing our patient group by disease, this appeared to suggest an enhanced effect in the UC/IBDU group at all assessed time-points, with steroid free remission in 47% of patients versus 26% in the Crohn's group overall. Kaplan–Meier plot of length of remission on MMF demonstrated a difference between disease subgroup outcomes favouring UC/IBDU, but this did not reach statistical significance using log-rank analysis. This superior rate in UC/IBDU observed approaches the quoted longer term remission data for azathioprine with rates of around 50% in placebo controlled trials.2,4 Pragmatically, given methotrexate and anti-TNF-α therapies are more relevant treatment options for Crohn's, an alternative to azathioprine in intolerant patients with UC may be of more utility. MMF could potentially be used for both immunomodulation in a step-up management process in those naïve of anti-TNF alpha medication, and also in the UK for those in whom fulminant/sub-fulminant UC has been brought into remission acutely by anti-TNFα therapy. In the latter, NICE guidance stipulates the use of 3 treatments for induction only, so in those who are unable to take thiopurines subsequent alternative immunomodulation is needed.26 The literature to date has documented a significant side-effect profile for MMF, with diarrhoea in particular being well recognised, reported with a frequency of between 13 and 37% in the renal transplant population.27,28 Indeed in the studies
7 to date MMF was discontinued due to side effects in between 8 and 36% of patients.12–23 However in comparison we found MMF to be well tolerated in our patient group: 19% had side effects but only two patients (6%) discontinued MMF due to side effects, with dose reduction being a useful strategy perhaps not employed in other studies. Furthermore, despite not achieving steroid-free remission MMF was continued in a majority of the patients as a co-immunosuppressant. Importantly there were no serious adverse effects, and no cases of neutropenia. There were limitations to our study, namely its retrospective nature and the small sample size, although still representing the third largest to date. Prescribing and patient monitoring was performed by a number of clinicians, with the attendant inter-observer variability in defining endpoints such as remission and making treatment decisions. Furthermore, endoscopic follow-up was not consistent enough to enable analysis in this report. Finally, analysis of changes in C-reactive protein (CRP) may represent a quantitative end point, however baseline CRP (recorded in 31 of 36 subjects) was commonly normal in the first instance (65%, 20 out of 31), due to steroid use (n = 7) or failing to be a useful inflammatory marker for that subject. In the remaining 11 subjects, a fall in CRP in keeping with clinical response was observed in 73% (n = 8, data not shown). We thus did not use CRP as a guide to response in this study. It is noted that of the 23 patients who stopped azathioprine due to intolerable symptoms alone, only 7 (30%) were (unsuccessfully) tried with 6-mercaptopurine. The published literature suggests that a trial of 6-mercaptopurine can be successful in this setting in 48–73% of patients.29,30 Thus perhaps this strategy could have been attempted first prior to switching to MMF, although its success cannot be assumed. In conclusion, mycophenolate mofetil may represent a promising alternative treatment for inducing and maintaining remission in IBD patients intolerant of or unable to receive thiopurines. It appears well tolerated with a good safety profile in thiopurine-intolerant subjects. It may be of more value and relevance in ulcerative colitis, especially since less alternative proven therapies are available to the clinician.
Authorship statement MS was responsible for acquisition and analysis of data, drafting of manuscript; SCC was responsible for study design, analysis of data and revision of the manuscript. Both authors read and approved the final manuscript.
Conflict of interest No financial relationships with a commercial entity producing health-care related products and/or services relevant to this article.
Acknowledgements We would like to thank Lindsey Wood and Jayne Slater for creating and maintaining the IBD database from which data were extracted.
Please cite this article as: Smith MR, Cooper SC, Mycophenolate mofetil therapy in the management of inflammatory bowel disease — A retrospective case series and review, J Crohns Colitis (2014), http://dx.doi.org/10.1016/j.crohns.2014.01.014
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M.R. Smith, S.C. Cooper
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Please cite this article as: Smith MR, Cooper SC, Mycophenolate mofetil therapy in the management of inflammatory bowel disease — A retrospective case series and review, J Crohns Colitis (2014), http://dx.doi.org/10.1016/j.crohns.2014.01.014
