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Pre-operative immunomodulator use in patients with Inflammatory Bowel Disease
and risk of post-operative complications: a systematic review of observational
studies.
Short title: Immunomodulators and postoperative complications in IBD.
Venkataraman Subramanian1
Richard CG Pollok1
Jin-Yong Kang1
Devinder Kumar2
1Department of Gastroenterology and 2Colorectal Surgery, St George’s Hospital NHS
Trust, Blackshaw Road, London SW17 0QT, United Kingdom.
Address for correspondence
Venkataraman Subramanian
Department of Gastroenterology
Knightsbridge Wing
St George’s Hospital
London SW 17 0QT
Phone: 07910504017, Fax 0208-725-3520
Email: vsubrama@sgul.ac.uk
Key words: immunomodulators, inflammatory bowel disease, postoperative
complications
Abstract
Background: Patients with inflammatory bowel disease (IBD) are frequently treated with
immunomodulators and the possibility of increased post-operative complications in such
patients has been raised. Aim: The purpose of this systematic review was to determine if
the use of immunomodulators affect the risk of postoperative complications following
abdominal surgery in patients with IBD. Methods: We searched electronic databases
(Pubmed, Embase, Ingenta, Zetoc and Ovid) and hand searched citations from the
reference lists in all the articles identified. Studies were included if they evaluated
postoperative complications and defined exposure to individual immunomodulators in the
patient groups.
Results: All 11 studies that met the inclusion criteria were observational studies and of
these two were reported only in abstract form. Five studies reported risks associated with
use of azathioprine, 5 with cyclosporine and 3 with infliximab. None showed an
increased risk of either total or infectious complications associated with
immunomodulator use. However one study published as an abstract, suggested, in a sub-
group analysis, an increased rate of anastamotic complications and rate of re-operation
associated with azathioprine use.
Conclusions: Available evidence does not suggest an increased rate of postoperative
complications associated with immunomodulator use. However the studies reviewed have
small samples sizes, with disparate or no control groups and differing outcome measures
and length of follow up. Larger, multi-centric, controlled studies with well-defined
outcome measures are needed to definitively resolve this issue.
Introduction
Ulcerative colitis (UC) and Crohn’s disease (CD) are complex disorders, collectively
termed as inflammatory bowel disease (IBD). There are wide variations in clinical
practice in the treatment of these diseases, but immunomodulators are commonly used.1
Azathioprine, 6-mercaptopurine, methotrexate, cyclosporin, and infliximab are effective
in many patients with IBD. Despite optimal medical therapy, about two thirds of patients
with CD and one third of patients with UC will eventually require surgery for disease
control.2,3,4 Factors which increase the risk of postoperative complications include
preoperative sepsis,6,7 such as abdominal abscess or systemic infection as well as impaired
nutritional status8 and intestinal obstruction.9
Abdominal surgery for patients with IBD is not without risk. Post-operative complication
rates are higher in patients with CD than in non-inflammatory controls.10,11,12 Among
patients with CD undergoing surgery, between 6% and 45% patients have post-operative
complications13,14 and mortality figures range between 0.5% and 5.5%.15,16 Among
patients with UC undergoing ileal pouch anal anastamosis (IPAA), post-operative
complications are estimated to be around 19-58%, but decreases with the experience of
the surgeon.17,18,19 The commoner early postoperative complications include abdominal
wound infection, anastamotic leakage, pelvic sepsis and small bowel obstruction. Late
complications include anastamotic leak with pelvic sepsis or fistula, anastamotic stricture
and with IPAA pouchitis and pouch dysfunction.20
Post-operative infections increase length of hospital stay, costs, mortality and
morbididty.21 Patients receiving azathioprine or 6-mercaptopurine for IBD have been
reported to be at increased risk of bacterial fungal and protozoal infections, probably
because of bone marrow suppression and leucopenia.22,23 Newer immunomodulators like
infliximab are also known to increase risk of reactivation of tuberculosis and other
opportunistic infections as well as sepsis.24
Although the use of immunomodulators is a major advance in the treatment of IBD, the
safety of these agents in the post-operative setting is a cause for concern. Some clinicians
advocate stopping immunomodulators prior to surgery while others delay surgery for this
reason, in the belief that use of these drugs increases the risk of infectious complications
in the post-operative period. The aim of this systematic review is to examine available
evidence to help guide therapy of patients with IBD over the peri-operative period.
Materials and Methods
Study Search Protocol
We searched Pubmed (1966-August 2005), Embase (1974-August 2005), Ingenta (1988-
August 2005), Zetoc (1982-August2005) and Ovid (1958-August 2005). Multiple search
strategies were used to find articles that would assess the risk of using immunomodulator
medication on post-operative complications in patients with IBD having abdominal
surgery. Keywords used were (Azathioprine or 6-MP or 6-mercaptopurine or cyclosporin
or infliximab or methotrexate or immunosuppress$) and (surgical complications) and
(Crohn’s disease or ulcerative colitis or inflammatory bowel disease). Other search
strategies included as keywords each immunomodulator and (postoperative or surgical
complications) and (Crohn’s disease or ulcerative colitis or inflammatory bowel disease).
Additionally a final search was performed using the keywords IBD and surgical risk. A
comprehensive review of the reference lists of all articles selected from the Pubmed
search was also performed. For each study we collected information on year of
publication, journal, type of study, duration of study, number of patients with IBD
studied, duration of follow up post-operatively and complication rates in patients treated
with immunomodulator therapy and those not treated with the drug.
Study selection
Studies were included if they met the following criteria:
1. Evaluated patients who had been treated with individual immunomodulator drugs
pre-operatively without withdrawing the drug in the immediate pre-operative
period.
2. Reported complication rates either as infective complications which at the
minimum included wound infection, sepsis, peritonitis, abdominal abscess,
peritonitis or as total complications which also included intestinal obstruction,
thromboembolism and gastrointestinal haemorrhage.
Statistics:
If odds ratio for risk of complications associated with immunomodulator therapy was not
reported by the study, this was calculated from the data given using Epi Info (version
3.2.2 CDC Atlanta).
Results
The initial Pubmed search yielded 196 articles of which 182 were excluded on the basis
of the title. Another 6 were excluded following review of the abstracts. Alternative
keyword searches in Pubmed resulted in identification of one additional article. .
Searches using the Ovid database resulted in identification of one additional study
published in abstract form. The Embase, Ingenta and Zetoc searches did not yield any
additional articles. A comprehensive review of the reference lists of all the articles
selected from the previous searches resulted in selection of one additional study
published in abstract form. A total of 11 studies were finally included.25-35
Azathioprine or 6-mercaptopurine
The effect of azathioprine and 6-mercaptopurine on post-operative complication rates in
patients with IBD has been examined in 5 retrospective reports.28,29,31,33,34(Table1)Page
et.al.28 studied 105 patients with IBD of whom 75 were less than 60 years of age and 30
were older than 60 years. Of these patients 10 of 33(30.3%) on azathioprine and 19 of 72
(26.4%) not on azathioprine had post-operative complications, defined as any
unanticipated event that required either a therapeutic intervention or lengthened hospital
stay. Use of azathioprine did not seem to increase the risk of complications. Another
study29 from the Mayo clinic related to 209 patients with UC who underwent IPAA. Of
these 46 were on azathioprine or 6-mercaptopurine and 151 were on corticosteroids but
not other immunomodulators, while the remainder were on cyclosporin or methotrexate.
Anastamotic leaks, wound dehiscence, pelvic sepsis, perianal fistulas, abscesses,
anastamotic strictures, small bowel obstruction, other infections, pouch removal and
other complications in the first 30 days post-operatively were no different whether
patients were given immunomodulators or not. The risk of late complications (between 1
and 6 months of follow up) was also unaffected by the use of azathioprine or 6-
mercaptopurine. Aberra et.al.31 reviewed infectious complications including wound
infections, sepsis, pneumonia, peritonitis, abdominal abscess, wound dehiscence, urinary
tract infection and fever of more than 390Cwithout identifiable cause in 159 patients with
IBD (71 UC and 88 CD) undergoing abdominal surgery. There were 56 patients on
corticosteroids alone, 52 on azathioprine or 6mercaptopurine with or without
corticosteroids and 5 patients on no immunosuppressants.. The relative risk of all
infectious complications for use of azathioprine or 6-mercaptopurine was 1.41 (0.76-
2.62). Stratified analysis for weight based dosing of azathioprine or 6-mercaptopurine use
in 49 evaluable patients also showed no difference in risk of infection whether a low dose
(6-mercaptopurine or equivalent azathioprine dose of less than 1.5 mg/kg) or high dose
regimen was used.
Another study from the Mayo clinic33 examined the complication rate in the 30-day
period following surgery among 270 patients who underwent abdominal surgery for
Crohn’s disease, including 64 on azathioprine, 38 on 6-mercaptopurine and 4 on
methotrexate. There was no increase in risk of septic or total complications associated
with azathioprine or 6-mercaptopurine use. Finally a Swedish study34 published in
abstract form suggested that azathioprine or 6-mercaptopurine use for CD was associated
with an increased risk of anastamotic complications and need for further surgical
interventions, but the risk of total complications was unaffected.
Cyclosporin
The effect of cyclosporin use on post-operative outcomes in IBD has been reported in 5
small retrospective series (Table 2).25-28,35 Fleshner et.al.25 included patients who had
failed cyclosporin rescue therapy for severe UC unresponsive to corticosteorids
subsequently going on to subtotal colectomy and Brooke ileostomy. Of 45 patient with
severe UC given cyclosporin, 14 required surgery. Of these 6 patients were on
concomitant 6-mercaptopurine and post-operative complications occurred in 8 (57%). In
a similar study Pinna-Pintor et.al26 reported 25 patients with UC (24 on IV cyclosporin
and 1 on oral cyclosporin), of whom 17 required emergency subtotal colectomy while 8
underwent elective surgery. 9(36%) of these had early post-operative complications (first
30 days). There was no control group in either study. The Oxford group27 compared 19
patients on IV cyclosporin and corticosteroids with 25 patients on IV corticosteroids
alone, all of whom underwent sub-total colectomy and ileostomy. No difference in major
or minor surgical or medical complications was found between the two groups. The high
morbidity rate of 76% in the IV corticosteroids group and 63% in the IV cyclosporin and
corticosteroids group was attributed to accounting for even minor complications like
hypokalemia. A study from the Mayo Clinic28 compared 12 patients with UC, on
cyclosporin or methotrexate (6 patients each) and subsequently undergoing elective IPAA
with 151 patients who were on either corticosteroids or no immunosuppressant prior to
surgery. The majority of patients in this study had only mild to moderate disease and
underwent elective surgery, unlike the other three studies cited earlier. No added risk was
associated with use of either cyclosporin or methotrexate in the post-operative period.
The final study by Poritz et.al11 evaluated 41 patients who received IV cyclosporin for
severe UC. Of these 27 underwent surgery and 12 (44%) had post-operative
complications. (Table2)
Infliximab
There are 3 retrospective studies on post-operative outcomes in patients who had received
pre- operative infliximab.30,32,33 Brzezinski et.al.30 reported in abstract form, post-operative
complications in 35 patients with CD (22 had pre-operative infusions and 13 had
infusions up to one month post-operatively). The controls were matched for age, gender,
concomitant immunosuppression, surgical procedure and surgeon. No differences in
length of hospital stay or post-operative complications were noted between the groups.
Marchal et.al32 reported on 40 patients who had been treated with infliximab pre-
operatively and compared it to 39 patients who had never received infliximab, but had
surgery in the same period. The groups were comparable for indications for surgery and
concomitant drugs, except that the infliximab group had significantly more patients on
CS. There was no difference between the groups in the frequency of both early (less than
10 days) and late (10 days to 3 months) complications and also the duration of hospital
stay. A study from the Mayo Clinic33 compared 52 patients who had received infliximab
(either 8 weeks before or within 1 week of surgery) with 218 who did not receive
infliximab. No differences in post-operative complications including infectious
complications were noted in the first 30 days after surgery. (Table3) In all 3 studies a
majority of patients on infliximab as well as the control group were on concomitant
steroids or immunomodulators.
Discussion
Peri-operative use of azathioprine along with corticosteroids has been shown to increase
the risk of urinary tract infections compared to patients on cyclosporin and corticosteroids
in patient undergoing renal transplantation.36,37 All the 5 retrospective studies28,29,31,33,34 on
postoperative complication risk associated with azathioprine or 6-mercaptopurine use in
patients with IBD found that the risk is unchanged. Cyclosporin use has been associated
with an increased risk of opportunistic infections and pnuemocystis carinii prophylaxis
has been suggested when it is used in patients with severe UC.38 Most studies looking at
postoperative complications associated with cylosporin use in patients with IBD, did not
include a control group. The complication rates in these studies25,26,35 compares well with
the overall morbidity in patients with UC undergoing emergency subtotal colectomy for
severe UC which ranges from 24-70%.39-43 Patients on cyclosporin not only have severe
disease, but also have surgery performed later than those on corticosteroids alone, which
possible increases their risk of postoperative complications. A larger prospective study or
a multi-centre retrospective database analysis could provide clearer answers. About 12%
of patients with CD on infliximab infusions have an infectious complication attributable
to the drug.24 All 3 retrospective studies30,32,33 on use of infliximab in the pre and peri-
operative period, reported so far showed no differences in postoperative complication
rates between infliximab treated and untreated patients with CD, suggesting that patients
treated with infliximab can undergo abdominal surgery safely.
When comparing postoperative complication among these patients, there are several
confounders that need to be considered. The age of the patient and associated co-
morbidities could influence the outcomes. Page et al.28 reported that elderly (age more
than 60 years) patients with IBD had significantly higher postoperative complication
rates and the length of hospital stay was longer in this group. Operation specific details
like indication for surgery, type of surgery (resection and anastamosis versus
strictureplasty or colonic versus small bowel surgery) and whether surgery performed
was an emergency or elective procedure could also have implications on outcomes. Only
two studies27,32 gave details of the operative procedure between treated and untreated
groups. Page et.al.28 and Abrera et.al.31 reported that indication for surgery was not an
independent risk factor for postoperative complications. Colombel et.al.33 found both the
type of surgery and the indications for surgery were not independent predictors of risk for
postoperative complications. Indication for drug usage, dose and the duration of therapy
are other potential confounders. Abrera et.al.31 compared different drug dosages in the
immunomodulator group and reported that this had no effect on complication rates.
The definition of postoperative complication also varies between different studies.
Operation specific complications like abdominal sepsis, wound dehiscence, anastamotic
leaks and early re-operation rates may be more relevance in this context than electrolyte
disturbances, cardiac complications, urinary tract and respiratory infections. Two
studies29,32 provided data on individual complications and reported no differences in rates
of specific complications between the groups. Mylerid et.al.34 looked at anastamotic
complications and re-operation rates in a subgroup analysis and found that these
complications were significantly associated with immunomodulator use. Future studies
need to address these confounders and also focus on complications specific to the
surgical procedure. The need for this is further highlighted from the study by Tay et.al44
that suggests significantly lower postoperative intra-abdominal septic complications
associated with the use of any immunomodulator drug. This study had been excluded
from the present analysis since all patients treated with immunomodulators were
considered together irrespective of the individual drug used.
In summary the existing observational studies suggest that use of immunomodulators is
not associated with an increased risk of total or infectious post- complications following
surgery for IBD. Most studies are on limited number of patients and often used disparate
control groups with differing definitions on outcomes measured and the time frame of
follow up. Larger, preferably multi-centric, controlled studies with well-defined
standardised criteria are needed to definitively resolve this issue.
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