Mesalazine and/or Probiotics for Diverticular Disease
The natural history of diverticular disease remains largely unknown. The lack of any placebo-controlled studies has precluded any meaningful conclusion regarding the appropriate management of this disease. For example, we know that SUDD may recur in up to 35% of cases, and acute diverticulitis may occur in up to 11% of SUDD cases, yet Current Practical Guidelines from the American College of Gastroenterology do not provide any advice regarding treatment for the prevention of recurrence.
Changes in GI microflora are hypothesised to influence the aetiology of diverticular disease. It is hypothesised that microbial imbalance, associated with colonic bacterial overgrowth, may be key for the development of diverticular disease. More recently, it has been hypothesised that chronic inflammation may play a role in the aetiology of diverticular disease. The association between inflammation and diverticular disease was first suggested following detection of both chronic inflammatory infiltrate and increased faecal calprotectin in patients with diverticular disease and acute diverticulitis.
The use of both mesalazine and probiotics was recently proposed for the treatment of SUDD and for the prevention of diverticulitis occurrence. In 2006, we found that both mesalazine and L. casei DG appeared to be effective for the prevention of recurrence of SUDD, but their combined use showed greater promise. This combination was thought to have a synergistic effect, but the small sample size, lack of a placebo group and the open-label enrolment were limiting factors in this early study.
In this way, we chose to replicate this study, using the same mesalazine and probiotic dosage but in a double-blind way and adding a placebo arm.
Recent placebo-controlled trials help further to clarify the conflicting evidence on the role of mesalazine in diverticular disease. For example, Kruis et al. found a trend towards significance in using mesalazine granules 3 g daily rather than placebo on controlling abdominal pain in SUDD; Gaman et al. found mesalazine granules 514.7 ± 30.5 mg daily better than placebo in preventing diverticulitis occurrence, diverticulitis flares and occurrence of surgical treatment; Smith et al. found mesalazine better than placebo in reducing the duration of abdominal pain in SUDD and in reducing the relative quantity of inflammatory genes expression in colonic biopsies. This study found mesalazine to be effective in preventing the recurrence of SUDD, obtaining a significantly higher rate of remission maintenance than placebo.
The rationale for using probiotics in the treatment of diverticular disease is related to the pathogenesis of the disease. Stasis of luminal contents occurs in colonic diverticula, and is probably combined with changes in the spectrum of intestinal microflora. This process may be followed by the occurrence of abnormal metabolites, causing functional changes leading to abdominal symptoms. The action of probiotics includes the production of antimicrobials, competitive metabolic interactions with proinflammatory organisms, and inhibition of adherence and translocations of pathogens. Probiotics may also influence mucosal defence at the levels of immune and epithelial function, such as decreasing several proinflammatory cytokines. This is the first placebo-controlled study assessing the effectiveness and safety of probiotics in preventing the recurrence of SUDD. In this study, we used L. casei as a single probiotic strain. We chose this particular strain as it has previously been shown to colonise the human intestine and resist hydrochloric acid and bile salts, and it appears to persist in the gastrointestinal tract for approximately 2 weeks after discontinuation of treatment. This is an important point, because this persistence permits cyclic administration with adequate patient compliance, without the risk of developing bacterial resistance. Moreover, it seems to be effective against Gram-negative anaerobes. The results obtained confirm this hypothesis: L. casei is significantly better than placebo in maintaining SUDD remission.
The remission rate in group LM is particularly impressive. The combination of mesalazine and probiotics acts against inflammation in two ways: mesalazine down-regulates the inflammatory cascade by inhibition of several proinflammatory factors, whereas L. casei maintains adequate and balanced colonisation of the gastrointestinal tract, inhibiting both colonic bacterial overgrowth and metabolism of pathogens, as well as reducing some proinflammatory cytokines. This approach appears able to maintain an optimal colonic microenvironment, and to keep virtually all patients symptom free.
Regarding secondary endpoints, an interesting finding was that neither the presence of comorbidities nor concomitant therapies (including ASA) were a risk factor for SUDD recurrence. This study confirms recent findings from Etzioni et al. and Humes et al., who did not find any increased risk of diverticulitis recurrence or diverticular perforation in patients with higher Charlson's score or taking ASA. Neither severity nor extent of diverticulosis was a risk factor for SUDD recurrence. This finding differs from that of Hall et al., who found that an involved diverticular segment >5 cm in length was associated with a higher risk of diverticulitis recurrence. This discrepancy may be due to differences in the severity of the disease in the patient populations in the two studies. SUDD is associated with low-grade inflammation, with lower risk of recurrence and complication, whereas diverticulitis is associated with high-grade inflammation, with risk of recurrence and complication related to the severity and the extent of the inflammation. This study showed that acute diverticulitis occurred significantly more frequently in the placebo group than in the active treatment groups. This reinforces the hypothesis that inflammation plays a key role in the pathogenesis of diverticular disease, and that only by controlling inflammation rather than controlling bacteria, we can prevent diverticular disease complications. On the contrary, a recent large trial of mesalazine (MMX 5-ASA) was reported negative in preventing relapses of diverticulitis. However, the study focused on diverticulitis attacks rather than on abdominal symptoms. In this way, the recent DIVA trial evaluated the efficacy of mesalazine Eudragit L in reducing gastrointestinal symptoms after an acute attack of diverticulitis. In this 1-year double-blind, randomised, placebo-controlled study in which patients with CT scan confirmed acute diverticulitis received placebo, mesalazine, or mesalazine + Bifidobacterium infantis 35 624 for 12 weeks and followed up for nine additional months, the rate of complete response by a global symptom score (GSS) of 10 symptoms (abdominal pain, abdominal tenderness, nausea/vomiting, bloating, constipation, diarrhoea, mucus, urgency, painful straining and dysuria) (GSS = 0) was significantly higher with mesalazine than placebo at weeks 6 and 52 (P < 0.05), and was particularly high for rectosigmoid symptoms at weeks 6, 12, 26 and 52. Surprisingly, probiotic in combination with mesalazine did not provide additional efficacy, and why this occurs is unknown. We eagerly await the results of other ongoing randomised trials in preventing diverticulitis relapses.
With respect to other symptoms assessed in this study, no difference was found between the active treatment arms and placebo. In particular, the lack of effect of both mesalazine and probiotics in terms of controlling diarrhoea and constipation is surprising, and we do not currently know the reason for this. Papi et al. did not find any difference between rifaximin and placebo in terms of control of diarrhoea in patients complaining of SUDD; therefore, further studies are needed to investigate this specific point.
This trial has some limitations. Definition of SUDD is still debatable. SUDD, also known as 'symptomatic diverticulosis', is characterised by abdominal symptoms (abdominal pain, particularly in the lower left abdominal quadrant and alteration of bowel habits) without macroscopic signs of inflammation (no mucosal inflammation on colonoscopy, no increases in erythrocyte sedimentation rate or C-reactive Protein, no fever). However, we know that episodes of prolonged pain were more frequently associated with diverticular disease than irritable bowel syndrome. The experience of prolonged abdominal pain in diverticular disease patients suggests that these abdominal symptoms may originate from diverticular inflammatory foci, the intensity and severity of which remain subclinical without reaching well-defined acute diverticulitis.
Although the use of faecal calprotectin would overcome this limitation in terms of clinical diagnosis of SUDD, this was not available for each centre when the trial started, necessitating the use of a clinical classification for defining SUDD and its recurrence.
In conclusion, this study showed that both cyclic mesalazine and L. casei subsp. DG appear to be better than placebo for maintaining remission in SUDD, especially when used in combination. Moreover, both treatments, alone or in combination, are significantly better than placebo in preventing occurrence of acute diverticulitis in SUDD patients. Further studies are warranted to investigate the best dose of these drugs for the treatment and prevention of SUDD recurrence, as well as their role in preventing diverticulitis occurrence.
Discussion
The natural history of diverticular disease remains largely unknown. The lack of any placebo-controlled studies has precluded any meaningful conclusion regarding the appropriate management of this disease. For example, we know that SUDD may recur in up to 35% of cases, and acute diverticulitis may occur in up to 11% of SUDD cases, yet Current Practical Guidelines from the American College of Gastroenterology do not provide any advice regarding treatment for the prevention of recurrence.
Changes in GI microflora are hypothesised to influence the aetiology of diverticular disease. It is hypothesised that microbial imbalance, associated with colonic bacterial overgrowth, may be key for the development of diverticular disease. More recently, it has been hypothesised that chronic inflammation may play a role in the aetiology of diverticular disease. The association between inflammation and diverticular disease was first suggested following detection of both chronic inflammatory infiltrate and increased faecal calprotectin in patients with diverticular disease and acute diverticulitis.
The use of both mesalazine and probiotics was recently proposed for the treatment of SUDD and for the prevention of diverticulitis occurrence. In 2006, we found that both mesalazine and L. casei DG appeared to be effective for the prevention of recurrence of SUDD, but their combined use showed greater promise. This combination was thought to have a synergistic effect, but the small sample size, lack of a placebo group and the open-label enrolment were limiting factors in this early study.
In this way, we chose to replicate this study, using the same mesalazine and probiotic dosage but in a double-blind way and adding a placebo arm.
Recent placebo-controlled trials help further to clarify the conflicting evidence on the role of mesalazine in diverticular disease. For example, Kruis et al. found a trend towards significance in using mesalazine granules 3 g daily rather than placebo on controlling abdominal pain in SUDD; Gaman et al. found mesalazine granules 514.7 ± 30.5 mg daily better than placebo in preventing diverticulitis occurrence, diverticulitis flares and occurrence of surgical treatment; Smith et al. found mesalazine better than placebo in reducing the duration of abdominal pain in SUDD and in reducing the relative quantity of inflammatory genes expression in colonic biopsies. This study found mesalazine to be effective in preventing the recurrence of SUDD, obtaining a significantly higher rate of remission maintenance than placebo.
The rationale for using probiotics in the treatment of diverticular disease is related to the pathogenesis of the disease. Stasis of luminal contents occurs in colonic diverticula, and is probably combined with changes in the spectrum of intestinal microflora. This process may be followed by the occurrence of abnormal metabolites, causing functional changes leading to abdominal symptoms. The action of probiotics includes the production of antimicrobials, competitive metabolic interactions with proinflammatory organisms, and inhibition of adherence and translocations of pathogens. Probiotics may also influence mucosal defence at the levels of immune and epithelial function, such as decreasing several proinflammatory cytokines. This is the first placebo-controlled study assessing the effectiveness and safety of probiotics in preventing the recurrence of SUDD. In this study, we used L. casei as a single probiotic strain. We chose this particular strain as it has previously been shown to colonise the human intestine and resist hydrochloric acid and bile salts, and it appears to persist in the gastrointestinal tract for approximately 2 weeks after discontinuation of treatment. This is an important point, because this persistence permits cyclic administration with adequate patient compliance, without the risk of developing bacterial resistance. Moreover, it seems to be effective against Gram-negative anaerobes. The results obtained confirm this hypothesis: L. casei is significantly better than placebo in maintaining SUDD remission.
The remission rate in group LM is particularly impressive. The combination of mesalazine and probiotics acts against inflammation in two ways: mesalazine down-regulates the inflammatory cascade by inhibition of several proinflammatory factors, whereas L. casei maintains adequate and balanced colonisation of the gastrointestinal tract, inhibiting both colonic bacterial overgrowth and metabolism of pathogens, as well as reducing some proinflammatory cytokines. This approach appears able to maintain an optimal colonic microenvironment, and to keep virtually all patients symptom free.
Regarding secondary endpoints, an interesting finding was that neither the presence of comorbidities nor concomitant therapies (including ASA) were a risk factor for SUDD recurrence. This study confirms recent findings from Etzioni et al. and Humes et al., who did not find any increased risk of diverticulitis recurrence or diverticular perforation in patients with higher Charlson's score or taking ASA. Neither severity nor extent of diverticulosis was a risk factor for SUDD recurrence. This finding differs from that of Hall et al., who found that an involved diverticular segment >5 cm in length was associated with a higher risk of diverticulitis recurrence. This discrepancy may be due to differences in the severity of the disease in the patient populations in the two studies. SUDD is associated with low-grade inflammation, with lower risk of recurrence and complication, whereas diverticulitis is associated with high-grade inflammation, with risk of recurrence and complication related to the severity and the extent of the inflammation. This study showed that acute diverticulitis occurred significantly more frequently in the placebo group than in the active treatment groups. This reinforces the hypothesis that inflammation plays a key role in the pathogenesis of diverticular disease, and that only by controlling inflammation rather than controlling bacteria, we can prevent diverticular disease complications. On the contrary, a recent large trial of mesalazine (MMX 5-ASA) was reported negative in preventing relapses of diverticulitis. However, the study focused on diverticulitis attacks rather than on abdominal symptoms. In this way, the recent DIVA trial evaluated the efficacy of mesalazine Eudragit L in reducing gastrointestinal symptoms after an acute attack of diverticulitis. In this 1-year double-blind, randomised, placebo-controlled study in which patients with CT scan confirmed acute diverticulitis received placebo, mesalazine, or mesalazine + Bifidobacterium infantis 35 624 for 12 weeks and followed up for nine additional months, the rate of complete response by a global symptom score (GSS) of 10 symptoms (abdominal pain, abdominal tenderness, nausea/vomiting, bloating, constipation, diarrhoea, mucus, urgency, painful straining and dysuria) (GSS = 0) was significantly higher with mesalazine than placebo at weeks 6 and 52 (P < 0.05), and was particularly high for rectosigmoid symptoms at weeks 6, 12, 26 and 52. Surprisingly, probiotic in combination with mesalazine did not provide additional efficacy, and why this occurs is unknown. We eagerly await the results of other ongoing randomised trials in preventing diverticulitis relapses.
With respect to other symptoms assessed in this study, no difference was found between the active treatment arms and placebo. In particular, the lack of effect of both mesalazine and probiotics in terms of controlling diarrhoea and constipation is surprising, and we do not currently know the reason for this. Papi et al. did not find any difference between rifaximin and placebo in terms of control of diarrhoea in patients complaining of SUDD; therefore, further studies are needed to investigate this specific point.
This trial has some limitations. Definition of SUDD is still debatable. SUDD, also known as 'symptomatic diverticulosis', is characterised by abdominal symptoms (abdominal pain, particularly in the lower left abdominal quadrant and alteration of bowel habits) without macroscopic signs of inflammation (no mucosal inflammation on colonoscopy, no increases in erythrocyte sedimentation rate or C-reactive Protein, no fever). However, we know that episodes of prolonged pain were more frequently associated with diverticular disease than irritable bowel syndrome. The experience of prolonged abdominal pain in diverticular disease patients suggests that these abdominal symptoms may originate from diverticular inflammatory foci, the intensity and severity of which remain subclinical without reaching well-defined acute diverticulitis.
Although the use of faecal calprotectin would overcome this limitation in terms of clinical diagnosis of SUDD, this was not available for each centre when the trial started, necessitating the use of a clinical classification for defining SUDD and its recurrence.
In conclusion, this study showed that both cyclic mesalazine and L. casei subsp. DG appear to be better than placebo for maintaining remission in SUDD, especially when used in combination. Moreover, both treatments, alone or in combination, are significantly better than placebo in preventing occurrence of acute diverticulitis in SUDD patients. Further studies are warranted to investigate the best dose of these drugs for the treatment and prevention of SUDD recurrence, as well as their role in preventing diverticulitis occurrence.
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