Abstract: Pouchitis is the most frequent long-term complication of Ileal Pouch-Anal Anastomosies (IPAA) surgery for Ulcerative Colitis (UC) which is a nonspecific inflammation of the ileal reservoir. Its clinical frequency varies depending on the definition and the follow up but is approximately 50% after a decade. Antibiotics and probiotics are currently the most widely accepted treatment in pouchitis patients. Objective of this study was to meta-analyze efficacy of probiotics and antibiotics in the management of pouchitis. All databases specially Pubmed, Web of Science, Scopus, Cochrane and Google Scholar were searched between 1965 and December 2009 and relevant controlled clinical trials were extracted, reviewed and validated according to the study protocol. The outcome of interest was defined by a Pouchitis Disease Activity Index (PDAI)<7. Thirteen clinical trials were included in the meta-analysis. Pooling of the results from eight trials yielded a Relative Risk (RR) of 5.33 with a 95% CI of 2.12-13.35 and a significant RR (p = 0.0004) in all kind of probiotics treatment group in comparison with the placebo group. Summary RR for clinical improvement in six trials was 14.17 with a 95% CI of 1.19-168.93 (p = 0.036) in efficacy of VSL#3 (all doses) comparing to placebo and slightly more effective for VSL#3 (6 g day-1) comparing to placebo with RR of 20.35 with a 95% CI of 6.16-67.22 (p<0.0001). Efficacy of antibiotics comparing to placebo showed a summary RR of 2.68 with a 95% CI of 0.4-17.99 and p = 0.3107 for clinical improvement in three trials. The summary RR for efficacy of ciprofloxacin comparing to metronidazole was 0.68 with a 95% CI of 0.44-1.06 (p = 0.8913). In conclusion, alongside the benefit of probiotics and antibiotics in the management of pouchitis, effects of probiotics and antibiotics on pouchitis vary according to different mixtures of microorganisms strains in probiotics and different spectrums of antibiotics.
INTRODUCTION
Pouchitis is the most frequent long-term complication of Ileal Pouch-Anal Anastomosies (IPAA) surgery for Ulcerative Colitis (UC) which is a nonspecific inflammation of the ileal reservoir. Its clinical frequency varies depending on the definition and the follow up but is approximately 50% after a decade (Ruseler-van Embden et al., 1994; Stochi and Pemberton, 2001).
Although, the exact etiology of pouchitis remains largely unknown, some studies have identified that reduced counts of lactobacilli and bifidobacteria within the pouch and subsequent dysregulation of inflammatory response may contribute to the development of this syndrome (Gosselink et al., 2004a; Ohge et al., 2005).
The Pouchitis Disease Activity Index (PDAI) was proposed by Sandborn et al. (1994) as a tool for objective and reproducible scoring of signs and symptoms of pouchitis in diagnosis of disease. According to PDAI, active pouchitis is defined as a score ≥ 7 and remission is defined as a score <7.
Therapeutic approaches include several pharmacological agents that seem helpful for the treatment of pouchitis. Given the association, antibiotics and probiotics are currently the most widely accepted treatment in pouchitis patients (Elahi et al., 2009; Rahimi et al., 2006, 2007a).
Acute or chronic types of pouchitis can usually be treated effectively with antibiotics, making these agents the mainstay of treatment (Elahi et al., 2009). Clinical experiences have demonstrated that most patients with pouchitis respond to antibiotic therapy, most often with metronidazole or ciprofloxacin. Metronidazole has been the most commonly used drug and the majority of patients show an initial response at a dose of 750-1500 mg day1. Moreover, ciprofloxacin may have better efficacy and less toxicity compared with metronidazole in treatment of acute pouchitis (Madden et al., 1994; Sandborn, 1994; Shen et al., 2001). While the majority of patients with pouchitis respond to a two-week treatment course with a single antibiotic, some may have refractory disease, requiring combination antibiotic therapy (Mimura et al., 2002). However, relatively few randomized controlled antibiotic trials have been performed.
Besides antibiotic therapy, probiotics are being researched as a prevention of pouchitis episodes. When the inflammation reduced or eliminated, the problem of maintaining remission remains. In recent years a series of placebo controlled randomized clinical trials have been conducted demonstrating that the modification of bacteria flora using probiotic bacteria preparation may be highly effective (Elahi et al., 2008; Furrie et al., 2005; Kruis et al., 1997; Pochapin, 2000; Rahimi et al., 2008a,b; Sen et al., 2002). They comprise a variety of bacterial species including Lactobacilli, Bifidiobacteria and streptococci as well as non pathogenic Esherichia coli (Gionchetti et al., 2003). Although, the mechanism of action of probiotics has not been fully elucidated, clinical and preclinical studies have shown that probiotics have anti-inflammatory effects (Gionchetti et al., 2003; Gionchetti et al., 2000; Mimura et al., 2004). Most randomized control trial, on the use of probiotics are limited by small sample sizes, making it possible that a true positive effect of therapy has not been detected because of low power. There is no comparative meta-analysis on the efficacy of probiotics and antibiotics for management of pouchitis. Meta-analysis technique is a statistical procedure for combining data from multiple studies and is necessary because only summary statistics are available in the literature to assess the magnitude and the benefits from use of antibiotics or probiotics in management of pouchitis. Our previous meta-analysis showed effectiveness of antibiotics and probiotics in IBD and Irritable Bowel Syndrome (IBS) (Nikfar et al., 2008; Rahimi et al., 2006, 2007a, 2008a, b; Rezaie et al., 2010). In our last meta-analysis, we found that use of antibiotics in pouchitis is beneficial. In the present work, the effect of both probiotics and antibiotics in patients who had undergone IPAA is reviewed and meta-analyzed.
Data sources and meta-analysis: The search terms clinical trials, antibiotics, probiotics, pouchitis and IPAA were searched in all relevant databases especially Pubmed, Web of Science, Scopus, Cochrane and Google Scholar for studies reported use of probiotics or antibiotics in treatment of IPAA from 1965 up to December 2009. A total of 892 results were examined. Primary outcomes included clinical improvement and remission in IPAA by use of probiotics and antibiotics. The definition was varied from study to study; therefore, PDAI score ≥ 7 was defined as an endpoint to harmonize studies. After primary search, data which were duplicate, reviews, case study, or low quality studies were excluded.
Assessment of trial quality: The methodological quality of included trials was assessed using the Jadad score, which judges of the descriptions of randomization, blinding and dropouts (withdrawals) in the trials (Table 1). This is summarized as follow: a: whether randomized or not (yes = 1 point, No = 0); b: whether randomization was described appropriately or not (yes = 1 point, No = 0); c: double blind (yes = 1 point, No = 0); d: was the double blinding described appropriately (yes = 1 point, No = 0); e: whether withdrawals and dropouts described or not (yes = 1 point, No = 0). The quality scale ranges from 0 to 5 points with a low quality report of score 2 or less and a high quality report of score at least 3 (Jadad, 1998).
Statistical analysis: Data from selected studies were extracted in the form of 2x2 tables. Included studies were weighted and pooled. The data were analyzed using Statsdirect software version 2.7.7. Relative risk (RR) and 95% confidence intervals (95% CI) were calculated using the Mantel-Haenszel and Der Simonian-Laird method. The Cochran Q test was used to test heterogeneity. The event rate in the experimental (intervention) group against the event rate in the control group was calculated using L'Abbe plot as an aid to explore the heterogeneity of effect estimates. Funnel plot analysis was used as publication bias indicator.
| Table 1: | Jadad quality score of randomized, controlled trials included in the meta-analysis |
RESULTS
We reviewed total of 892 abstract and titles were found and reviewed in first step (Fig. 1), of which, 864 were excluded on the basis of title and abstract irrelevancy or duplication. Therefore, 28 studies were scrutinized in full text, of which, 13 were considered eligible and met inclusion criteria for systematic review of probiotics and antibiotics for pouchitis and included in this analysis. Of excluded studies, one was case report, 9 were open study and were not randomized properly, one was pilot study and the other 4 has no placebo control in their treatment or they used mezalasine as concomitant therapy.
The quality of eligible studies was assessed by Jadad score. Seven out of 13 studies received Jadad score ≥ 4. Four studies received Jaded score 3 and other two studies had score of 2 and 1, respectively (Gosselink et al., 2004a; Shen et al., 2001).
The included trials covered 128 patients for probiotic arm, 62 for antibiotic arm and 213 patients for placebo. Among included patients, 172 were women (42.7%) and 231 were men (57.3%). Patients characteristics, type and dosage forms, duration of treatment and outcomes for each study are shown in Table 2-7.
Efficacy of all types of probiotics comparing to placebo: The summary RR for clinical improvement in eight trials (Gionchetti et al., 2000, 2002, 2003; Gosselink et al., 2004b; Kuhbacher et al., 2006; Kuisma et al., 2003; Mimura et al., 2004; Shen et al., 2005) was 5.33 with a 95% CI of 2.12-13.35 and a significant RR (p = 0.0004, Fig. 2a). The Cochrane Q test for heterogeneity indicated that the studies are heterogeneous (p<0.0001, Fig. 2b) and could not be combined, thus the random effects for individual
and summary of RR was applied. Regression of normalized effect vs. precision for all included studies for clinical improvement among all types of probiotics vs. placebo therapy was 1.797054 (95% CI = 0.608753 to 2.985355, p = 0.0101) and Kendall’s test on standardized effect vs. variance indicated tau b = 0.777778, p = 0.012 (Fig. 2c).
Efficacy of VSL#3 (all doses) comparing to placebo: Summary RR for clinical improvement in six trials (Gionchetti et al., 2000, 2002, 2003; Kuhbacher et al., 2006; Mimura et al., 2004; Shen et al., 2005) was 14.17 with a 95% CI of 1-19-168.93 and a significant RR (p = 0.036, Fig. 3a). The Cochrane Q test for heterogeneity indicated that the studies are heterogeneous (p<0.0001, Fig. 3b) and could not be combined, thus the random effects for individual and summary of RR was applied. Regression of normalized effect vs. precision for all included studies for clinical improvement among VSL#3 (all doses) vs. placebo therapy was 2.532234 (95% CI = 1.931703 to 3.132765, p = 0.0003) and Kendall’s test on standardized effect vs. variance indicated tau b = 0.857143, p = 0.0323 (Fig. 3c).
| Fig. 1: | Algorithm of the study selection and inclusion in meta-analysis |
| Table 2: | Outcomes of clinical trials on probiotic |
| RCT: Randomized clinical trial; OL: Open label; AEs: Adverse effects | |
| Table 3: | Patient's characteristic of trials on probiotics |
| CFU (Colony Forming Unit): A measure of viable bacterial or fungal numbers | |
| Table 4: | Patients' characteristics of trials on antibiotics |
| Table 5: | Outcomes of trials on antibiotic |
| RCT: Randomized clinical trial; OL: Open label; AEs: Adverse effect | |
| Table 6: | Patients characteristics of studies comparing ciprofloxacin and metronidazole |
| Table 7: | Outcomes of studies comparison ciprofloxacin with metronidazole |
| RCT: Randomized clinical trial; OL: Open label; AEs: Adverse effect | |
Efficacy of VSL#3 (6 g day1) comparing to placebo: Summary RR for clinical improvement in four trials (Gionchetti et al., 2000; Kuhbacher et al., 2006; Mimura et al., 2004; Shen et al., 2005) was 20.35 with a 95% CI of 6.16-67.22 and a significant RR (p<0.0001, Fig. 4a). The Cochrane Q test for heterogeneity indicated that the studies are not heterogeneous (p = 0.8303, Fig. 4b) and could be combined, thus the fixed effects for individual and summary of RR was applied. Regression of normalized effect vs. precision for all included studies for clinical improvement among VSL#3 (6 g day1) vs. placebo therapy was 1.784746 (95% CI = -4.965545 to 8.535037, p = 0.3732) and Kendall’s test on standardized effect vs. variance indicated tau = 1, p = 0.0833 (Fig. 4c).
| Fig. 2a: | Individual and pooled relative risk for the outcome of clinical improvement in the studies considering all types of probiotics vs. placebo therapy |
| Fig. 2b: | Heterogeneity indicators for the outcome of clinical improvement in the studies considering all types of probiotics vs. placebo therapy |
| Fig. 2c: | Publication bias indicators for the outcome of clinical improvement in the studies considering all types of probiotics vs. placebo therapy |
| Fig. 3a: | Individual and pooled relative risk for the outcome of clinical improvement in the studies considering VSL#3 (all doses) vs. placebo therapy |
| Fig. 3b: | Heterogeneity indicators for the outcome of clinical improvement in the studies considering VSL#3 (all doses) vs. placebo therapy |
| Fig. 3c: | Publication bias indicators for the outcome of clinical improvement in the studies considering VSL#3 (all doses) vs. placebo therapy |
| Fig. 4a: | Individual and pooled relative risk for the outcome of clinical improvement in the studies considering VSL#3 (6 g day1) vs. placebo therapy |
| Fig. 4b: | Heterogeneity indicators for the outcome of clinical improvement in the studies considering VSL#3 (6 g day1) vs. placebo therapy |
| Fig. 4c: | Publication bias indicators for the outcome of clinical improvement in the studies considering VSL#3 (6 g day1) vs. placebo therapy |
| Fig. 5a: | Individual and pooled relative risk for the outcome of clinical improvement in the studies considering antibiotics vs. placebo therapy |
| Fig. 5b: | Heterogeneity indicators for the outcome of clinical improvement in the studies considering antibiotics vs. placebo therapy |
Efficacy of antibiotics comparing to placebo: Summary RR for clinical improvement in three trials (Isaacs et al., 2007; Madden et al., 1994; Sambuelli et al., 2002) was 2.68 with a 95% CI of 0.4-17.99 and a non significant RR (p = 0.3107, Fig. 5a). The Cochrane Q test for heterogeneity indicated that the studies are heterogeneous (p = 0.0269, Fig. 5b) and could not be combined, thus the random effects for individual and summary of RR was applied. Regression of normalized effect vs. precision for all included studies for clinical improvement among antibiotics vs. placebo therapy could not be calculated because of too few strata.
Efficacy of ciprofloxacin comparing to metronidazole: The summary RR for clinical improvement in two trials (Gosselink et al., 2004a; Shen et al., 2001) was 0.68 with a 95% CI of 0.44-1.06 and a non significant RR (p = 0.8913, Fig. 6a). The Cochrane Q test for heterogeneity indicated that the studies are not heterogeneous (p = 0.0269, Fig. 6b) and could be combined but because of few included studies, the random effects for individual and summary of RR was applied.
| Fig. 6a: | Individual and pooled relative risk for the outcome of clinical improvement in the studies considering ciprofloxacin vs. metronidazole therapy |
| Fig. 6b: | Heterogeneity indicators for the outcome of clinical improvement in the studies considering ciprofloxacin vs. metronidazole therapy |
Regression of normalized effect vs. precision for all included studies for clinical improvement among antibiotics vs. placebo therapy could not be calculated because of too few strata.
DISCUSSION
The results of this study indicate that antibiotics are not significantly more effective than placebo in management of pouchitis whereas high dose of probiotics are significantly efficient. Among antibiotics tested, ciprofloxacin was better than metronidazole while among probiotics, VSL#3, 6 g day1 was more efficient than lactobacillus or even VSL#3, 3 g day1 in maintenance of remission in pouchitis.
Thus, treatment is toward reducing fecal concentrations of bacteria through use of bacteria to alter the relative balance of anaerobes or other bacteria (Sandborn et al., 2000). Results also indicated that studies on all types of probiotics vs. placebo were heterogeneous and could not be combined. Besides, publication bias existed; we could say that this efficacy is relatively significant and homogenous and could be combined for use of VSL#3 especially in dose of 6 g day1. It has been proved that probiotics can directly or indirectly affect endogenous flora and immune system that shifts the balance between aggressive and regulator factors in response to mucosal flora toward suppressive activity (Ulisse et al., 2001). Pronio et al showed that treatment with VSL#3 is associated with expansion of both CD4-CD25 and CD4-LAP-regulatory T cell in filtrating the laminar propria or on the induction of nitric oxide synthesis (Pronio et al., 2008). In an open study in 2007, oral administration of high dose of VSL#3 which is effective in treatment of active pouchitis, was found to be related in increasing of fecal concentration of bifidiobacteria, Lactobacillus and Thermophilus (Gionchetti et al., 2000, 2007; Venturi et al., 1999) or due to increasing cytokine IL-10 and decreasing cytokine IL-1, TNF-α and INF-g (Hart et al., 2004; Ulisse et al., 2001). Considering the effectiveness of immunologic modifiers agents on IBD (Rahimi et al., 2007b, c), some of actions of probiotics especially VSL#3 can be well explained. Among probiotics, only high dose (6 g day) of VSL#3 acted more effectively in patients especially with severe inflammation. In contrast, treatment with L-rhamnosus GG alone didn't results in any clinical improvement of pouch inflammation (Kuisma et al., 2003). L-rhammosus seems to act mainly via its effect on antagonizing pathogens directly through release of antimicrobial compounds or reducing the gut pH by lactic acid production (Langhendries et al., 1995) competing to binding to receptor site with potential pathogens and competing with pathogens (Fujiwara et al., 1997; Kailasapathy and Chin, 2000) for available nutrients and other growth factors (Rolfe, 2000). Thus the idea that action of VSL on regulation of inflammation factors is more responsible for its efficacy is supported.
This meta-analysis also showed that antibiotic therapy in overall is not statistically effective in treatment of pouchitis. In addition, studies of single antibiotic therapy were heterogeneous and could not be combined. It has been demonstrated that metronidazole as a commonly-used antibiotic in the examined trials was not much effective than placebo in terms of endoscopic inflammation changes (Madden et al., 1994). However, comparison of ciprofloxacin with metronidazole was homogenous and indicated that ciprofloxacin which eradicates two kinds of pathogens without disturbing majority of anaerobic bacteria is preferable to metronidazole with greater improvement in symptoms, endoscopic scores and reduction in total of PDAI. Moreover, several studies indicate adverse effect of metronidazole that is estimated about 30% when compared to 0% for ciprofloxacin (Shen et al., 2001). This result was also confirmed by our previous report (Elahi et al., 2009). Combination of ciprofloxacin with rifaximine resulted in significant improvement in clinical symptoms, endoscopic and histological activity (Abdelrazeq et al., 2005). This could propose the idea that combining of different kinds of antibiotic for acute pouchitis is more helpful than single therapy that has also support of other studies even for probiotics (Doherty et al., 2010; Elahi et al., 2008; Van-Gossum et al., 2007).
Although in the recent years, several review articles about usage of antibiotic and probiotic in pouchitis have been reported but global approval cannot be obtained yet because of limitations of various clinical trials and lack of meta-analysis. Considering different effects of probiotics containing different mixtures of microorganisms strains and antibiotics with different broad spectrums on pouchitis, there is still a need for performing studies to evaluate the flora of pouch and some randomized placebo control clinical trials about antibiotic combination therapy and antibiotic-probiotic combination therapy with defined endpoint in both acute and chronic pouchitis with clear patient's characteristics.
ACKNOWLEDGMENT
This study was in part supported by Tehran University of Medical Science.