Accepted Manuscript. Correlation or Causation: Sex Hormones and Microscopic Colitis. Baldeep Pabla, Reid M. Ness

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1 Accepted Manuscript Correlation or Causation: Sex Hormones and Microscopic Colitis Baldeep Pabla, Reid M. Ness PII: S (18) DOI: Reference: YGAST To appear in: Gastroenterology Please cite this article as: Pabla B, Ness RM, Correlation or Causation: Sex Hormones and Microscopic Colitis, Gastroenterology (2018), doi: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 <DOC>Editorials <AT>Correlation or Causation: Sex Hormones and Microscopic Colitis <AU>Baldeep Pabla <AFN>Division of Gastroenterology, Hepatology, and Nutrition Vanderbilt University Medical Center <AU>Reid M. Ness <AFN>Division of Gastroenterology, Hepatology, and Nutrition Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center and VA Tennessee Valley Healthcare System Nashville, Tennessee <COR>Reprint requests Address requests for reprints to: Reid M. Ness, MD, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, TN. <TXBX>See Identification of menopausal and reproductive risk factors for microscopic colitis results from the Nurses Health Study, by Burke KE, Ananthakrishnan AN, Lochhead P, et al, on page 000. <BEGIN ARTICLE>Microscopic colitis (MC) was first described in 1980 in patients with chronic watery diarrhea. 1 Consisting of 2 subtypes namely, collagenous colitis and lymphocytic colitis the reported incidence of this disease increased steadily after its initial description, but has stabilized recently in the United States. 2,3 Older age and female sex are both associated with an increased incidence of MC. Results presented in this issue of Gastroenterology by Burke et al 4 from 2 separate cohorts, the Nurses Health Study (NHS) and

3 NHS II, provide convincing evidence of an association between menopausal hormone therapy (MHT), oral contraceptive (OCP) use, and the development of this disease. Although there are several proposed biologic mechanisms of how exogenous reproductive hormone therapy may influence the development of MC, the lack of understanding of the pathophysiology that leads to this disease and the study design of the current article limit the conclusions we can safely draw from these data. There are several proposed mechanisms as to the pathophysiology of MC, among which are a reaction to specific luminal antigens such as occurs in celiac disease, 5 a nonspecific autoimmune component such as a generalized response to luminal enteric bacteria, and medication side effects. 6 Exogenous estrogen and progesterone have been shown to effect the mucosal immune system and intestinal barrier integrity, which may play a role in the development of MC. Specifically, estrogens have been shown to decrease intestinal permeability, which may affect the maturation of the gut through antigen stimulation, sampling, and development of tolerance. 7 Progesterone has also been shown to increase colonic inflammation by increasing the tissue level of macrophage migration inhibitory factor, a proinflammatory cytokine. 8 This role is further suggested by the associations reported between exogenous reproductive hormonal therapy and an increased risk of inflammatory bowel disease A metaanalysis of OCP use and inflammatory bowel disease risk found a significant association that was stronger for Crohn s disease than for ulcerative colitis. Another study employing the NHS cohort reported an increase in the risk of ulcerative colitis, but not Crohn s disease with MHT. Although not intended to assess the relationship between those with MC and those without disease, a previous case control study from Sweden attempting to identify differences between phenotypes of MC did note that OCP use was more associated with MC, but actually

4 showed an inverse relationship with exposure to MHT. 12 The current article by Burke et al calculated hazard ratios of for developing MC in patients currently using MHT after adjusting for other reproductive factors, smoking, body mass index, and other medications commonly associated with the development of MC. Significant results were also seen for OCP use; however, the results were more modest, with multivariate-adjusted hazard ratios of Additionally, the authors demonstrated that the hazard increases with duration of use and decreases with time since discontinuation. These trends are highly suggestive but not proof of causality. Several medications have been shown to have high or intermediate levels of association with MC including nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors/serotonin norepinephrine reuptake inhibitors, and proton pump inhibitors Multivariate odds ratios assessing the risk of MC based on exposure to these medications have previously been derived from both retrospective cohort and case control studies and are between 1.76 and 3.37 (Table 1). The current study estimated hazard ratios of similar and significant magnitude for nonsteroidal anti-inflammatory drugs and selective serotonin reuptake inhibitors, but not for proton pump inhibitors. In a prior publication, the NHS reported a hazard ratio for tobacco smoking of 2.52 ( ). 17 This result was similar to a previous odds ratio calculated for current tobacco use of 2.67 ( ). 14 The similarity of these risk estimates from different studies again suggests but does not prove causality for MC. In interpreting the results of this study, it is important to remember lessons from past epidemiologic studies. Despite the authors efforts to control for various confounding factors that may bias their findings, the cohort design of the current study limits our ability to determine causation. Importantly, data from the NHS were previously used to advocate for the use of MHT

5 with early epidemiologic evidence demonstrating a decreased risk of major coronary disease, which was not borne out in later randomized clinical trials. 18,19 Although the results of the study suggest that sex hormones may play an important role in the development of this inflammatory condition, they do not prove causation or even that withdrawal of the medication will lead to an improvement in symptoms. The best clinical use for these data are in the context of the ongoing review of each patient s active medication list. As always, patients should only be on medications necessary for the control of symptoms and/or prevention or treatment of a disease process. The potential harm of medications, such as MHT or OCPs in MC, must be weighed against their potential benefit. If a medication is thought necessary, the dosage should be limited to the lowest effective dosage for that patient. The current study by the NHS, strongly suggests a possible harmful association between exogenous reproductive hormones and the development of MC. Whether or not these or any medications are causative for MC remains to be proven. Nevertheless, these findings align with previously published data in terms of the effect size conferred by the medications and suggest plausible mechanisms by which MC might arise. Further work regarding the exact mechanisms of how these hormones affect mucosal immunity and why this disease is predominantly observed in the elderly women is needed. References 1. Read NW, Krejs GJ, Read MG, et al. Chronic diarrhea of unknown origin. Gastroenterology 1980;78: Gentile NM, Khanna S, Loftus E V., et al. The epidemiology of microscopic colitis in Olmsted county from 2002 to 2010: a population-based study. Clin Gastroenterol Hepatol 2014;12:

6 3. Pardi DS, Loftus E V, Smyrk TC, et al. The epidemiology of microscopic colitis: a population based study in Olmsted County, Minnesota. Gut 2007;56: Burke KE, Ananthakrishnan AN, Lochhead P, et al. Identification of menopausal and reproductive risk factors for microscopic colitis results from the Nurses Health Study. Gastroenterology 2018;000: Järnerot G, Tysk C, Bohr J, et al. Collagenous colitis and fecal stream diversion. Gastroenterology 1995;109: Pardi DS. Diagnosis and management of microscopic colitis. Am J Gastroenterol 2017;112: Braniste V, Jouault A, Gaultier E, et al. Impact of oral bisphenol A at reference doses on intestinal barrier function and sex differences after perinatal exposure in rats. Proc Natl Acad Sci U S A 2010;107: Houdeau E, Moriez R, Leveque M, et al. Sex steroid regulation of macrophage migration inhibitory factor in normal and inflamed colon in the female rat. Gastroenterology 2007;132: Cornish JA, Tan E, Simillis C, et al. The risk of oral contraceptives in the etiology of inflammatory bowel disease: a meta-analysis. Am J Gastroenterol 2008;103: Khalili H, Higuchi LM, Ananthakrishnan AN, et al. Oral contraceptives, reproductive factors and risk of inflammatory bowel disease. Gut 2013;62: Khalili H, Higuchi LM, Ananthakrishnan AN, et al. Hormone therapy increases risk of ulcerative colitis but not Crohn s disease. Gastroenterology 2012;143: Roth B, Manjer J, Ohlsson B. Microscopic colitis and reproductive factors related to exposure to estrogens and progesterone. Drug Target Insights 2013;7:DTI.S12889.

7 13. Riddell RH, Tanaka M, Mazzoleni G. Non-steroidal anti-inflammatory drugs as a possible cause of collagenous colitis: a case-control study. Gut 1992;33: Cotter TG, Binder M, Harper EP, et al. Optimization of a scoring system to predict microscopic colitis in a cohort of patients with chronic diarrhea. J Clin Gastroenterol 2017;51: Verhaegh BPM, Vries F de, Masclee AAM, et al. High risk of drug-induced microscopic colitis with concomitant use of NSAIDs and proton pump inhibitors. Aliment Pharmacol Ther 2016;43: Beaugerie L, Pardi DS. Review article: drug-induced microscopic colitis: proposal for a scoring system and review of the literature. Aliment Pharmacol Ther 2005;22: Burke KE, Ananthakrishnan AN, Lochhead P, et al. Smoking is associated with an increased risk of microscopic colitis: results from two large prospective cohort studies of US women. J Crohns Colitis 2018;12: Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease. N Engl J Med 1991;325: Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA 2004;291:1701.

8 Table 1. Effect Sizes of Potentially Modifiable Risk Factors for Microscopic Colitis Variable Women s Health Study, Multivariate HR Previous Studies, Multivariate OR Current use of MHT 2.64 ( ) 4,a 0.42 ( ) 12 Any use of OCP 1.57 ( ) 4,a 7.49 ( ) 12 Current smoking 2.52 ( ) ( ) 14 Current use of SSRIs 1.68 ( ) 4,b 2.34 ( ) 14,c 2.03 ( ) 15 Current use of NSAIDs 1.96 ( ) 4,b 1.76 ( ) ( ) 15 Current use of PPIs 1.25 ( ) 4,b 3.37 ( ) 15 HR, hazard ratio; MHT, menopausal hormone therapy; NSAIDs, nonsteroidal anti-inflammatory drugs; OCP, oral contraceptive; OR, odds ratio; PPIs, proton pump inhibitors; SSRI, selective serotonin reuptake inhibitor. a Risk estimates reflect data representative of the duration of the study b Estimates based on analysis restricted to follow-up after 2000 when ascertainment of these medicines was reliably obtained. c Includes both SSRIs and serotonin norepinephrine reuptake inhibitors.