CLINICAL REVIEW ARTICLE
Potential Immunomodulatory Effects of Statins in Inflammatory Bowel Disease Justin Côté-Daigneault, MD, Saurabh Mehandru, MD, Ryan Ungaro, MD, Ashish Atreja, MD, and Jean-Frédéric Colombel, MD
Abstract: Statins are among the most widely prescribed medications in the world. In addition to lowering cholesterol, statins have been shown to have immunomodulatory effects in multiple studies. For example, statins modulate the interaction between T cells and antigen-presenting cells, resulting in decreased T-cell activation and reduced levels of inflammatory cytokines. Statins have also been demonstrated to inhibit the migration of leukocytes across vascular endothelium into tissues. Although most research on the immune effects of statins has been conducted in the context of cardiovascular, rheumatological, or metabolic disease, various studies have shown that statins may have a significant impact on intestinal immunity and mucosal inflammation. Clinical research has suggested that statins may have benefit in inflammatory bowel disease. In this article, we review the effect of statins on the immune system and gastrointestinal tract, highlighting the potential for novel therapeutic applications in inflammatory bowel disease. (Inflamm Bowel Dis 2016;22:724–732) Key Words: statin, Crohn’s disease, ulcerative colitis, colitis and colorectal cancer
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tatins are some of the most widely prescribed medications with more than 200 million people on statin therapy worldwide.1 Statins act by competitively inhibiting 3-hydroxy3-methylglutaryl coenzyme A (HMG-CoA) reductase, the ratelimiting enzyme in the cholesterol synthetic pathway.2 Current indications for statin use include primary and secondary prevention of cardiovascular disease and hypercholesterolemia.3–5 Although the original rationale for treating cardiovascular disease with statins was the reduction in low-density lipoproteins, it is increasingly evident that the beneficial effects of statins are more complex and likely include an immunomodulatory component.6 In addition to limiting the biosynthesis of cholesterol, HMG-CoA reductase inhibition also decreases other intermediate metabolites including isoprenoids such as farnesyl pyrophosphate. Isoprenoids serve as essential adjuncts in the posttranslational modification of numerous key proteins that serve as molecular switches. Because of this, statin treatment may have efficacy in immune-mediated diseases such as chronic obstructive pulmonary disease, rheumatoid arthritis, and vasculitis.1,2,7 Importantly, statins have been shown to modulate inflammation Received for publication August 22, 2015; Accepted September 22, 2015. From the The Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York. The authors have no conflict of interest to disclose. Reprints: Jean-Frédéric Colombel, MD, The Leona M. and Harry B. Helmsley Inflammatory Bowel Disease Center, The Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029 (e-mail: [email protected]). Copyright © 2016 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000640 Published online 25 January 2016.
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in the gastrointestinal tract, raising the possibility that they could have benefits in inflammatory bowel disease (IBD). In this article, we review the anti-inflammatory and antineoplastic effects of statins with a focus on potential therapeutic implications for IBD. We discuss the impact of statins on immune cells and function, in animal models of IBD, and in clinical and translational studies with patients with IBD. Additionally, we summarize studies investigating statins and colitisassociated colorectal cancer.
IMMUNOMODULATORY EFFECTS OF STATINS Antigen-Presenting Function Statins inhibit cytokine inducible expression of major histocompatibility complex II by inhibiting the class II transactivator on antigen-presenting cells such as dendritic cells (DCs), which decreases antigen presentation to T cells.8 Importantly, interferon gamma–induced expression of major histocompatibility complex II was inhibited by statins while its constitutive expression remained unaffected in mature DCs. Statins have also been shown to reduce the expression of costimulatory molecules such as HLA-DR, CD40, CD80, and CD86 on DCs.9 Expression of these costimulatory molecules on antigenpresenting cells is essential for T-cell response to antigens. Other effects of statins on DCs include decreasing DC maturation, impairing phagocytosis and endocytosis of antigens, and limiting formation of immunological synapses.9,10 The combined effects of statins result in an overall decrease in T-cell activation through inhibition of DC-mediated antigen presentation. These data suggest that statins could have a therapeutic role in T-cell– mediated diseases such as IBD. Inflamm Bowel Dis Volume 22, Number 3, March 2016
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T-Cell Proliferation and Phenotype Statins have pronounced effects on T-cell proliferation through modulation of GTPases linked to cell-cycle progression, cytoskeletal organization, and formation of immunological synapses.11 Additionally, statins decrease the production of signal transducers and activators of transcription-4 (STAT-4) and t-box expression in T cells.12 T-bet–dependent proinflammatory TH1 cytokines such as interferon gamma are diminished by statins, whereas anti-inflammatory TH2 cytokines such as interleukin (IL)-4 and IL-10 are increased through the activation of STAT-6 and GATA3.12 These proinflammator and antiinflammatory cytokines have been shown to be altered in IBD.
Leukocyte Adhesion Molecules and Cellular Migration As evidenced by the recent success of homing inhibitors such as vedolizumab in patients with IBD, leukocyte infiltration of target organs is a critical event in the perpetuation of inflammation. Reduction in the migration of leukocytes to sites of inflammation is one of the most consistent effects of statins. Statins decrease the expression of cellular adhesion molecules on leukocytes and endothelial cells, resulting in reduced cellular adhesion and transvascular migration. Mechanisms for this phenomenon include inhibition of endothelial RAS homolog (Rho) GTPase-dependent platelet (P)- and endothelial (E)-selectins, decreased NFkB-dependent expression of CXCL8 and CCL2 on endothelial cells, and downregulation of intercellular adhesion molecule-1 and endothelial vascular cell adhesion molecule1.13–16 In addition, statins decrease the expression of CD11b, an integrin involved in the adhesion of monocytes to endothelium, thereby curtailing the recruitment of these important cells to sites of inflammation.17 Statins also seem to cause a Rho-GTPase– dependent inhibition of leukocyte motility and function.18 The expression of matrix metalloproteases (MMPs) such as MMP-9 on cells of monocyte/macrophage lineage is also decreased by statins.19 Notably, these MMPs enable the passage of leukocytes through the basal membrane and extracellular matrix. Thus, statins may affect migration of the leukocytes through both cellintrinsic and cell-extrinsic mechanisms.
Effects on Endothelial Nitric Oxide Synthase and Nitric Oxide Although the role of nitric oxide (NO) in inflammatory disease is not entirely clear, there is evidence that endothelial expression of NO prevents leukocyte chemotaxis.20 NO may also downregulate leukocyte adhesion to the vascular wall.21 Statins may affect NO levels by increasing endothelial nitric oxide synthases production.22
STATINS IN ANIMAL MODELS OF IBD Studies have investigated the anti-inflammatory effects of statins in murine models of intestinal inflammation, including colitis induced by dextran sulphate sodium (DSS), trinitrobenzene
Immunomodulatory Effects of Statins in IBD
sulfonic acid (TNBS), oxalazone (OXA), and acid acetic (AA) as well as Toxoplasma gondii–induced ileitis23–33 (Fig. 1) (Table 1). These studies have found that statins modify the macroscopic and microscopic inflammation, change the cytokine and chemokine profile, modify lymphocyte subsets, decrease lymphocyte adhesion, alter the intestinal epithelium, cause changes in the microflora and mitigate intestinal fibrosis.
Macroscopic and Microscopic Inflammation Statins decreased histological disease activity in 2 studies of DSS colitis, 3 studies of TNBS colitis, one study of AA colitis, and one study of T. gondii–induced ileitis.24,25,29–33 However, a study by Jahovic et al did not have similar findings in TNBS colitis, perhaps because of that the statin dose was 5 to 40 times lower than previous studies (0.1 and 1.0 mg/kg per day versus 5 mg/kg to 40 mg/kg per day).28 The effect of statins may be dose-dependent, as 2 studies only found a decrease in histological activity with high dose regimens.29,31 Although statins increased colonic length (decreased colonic length can reflect colonic inflammation) in 5 studies,23–26,33 one study by Oishi et al27 did not find a statistically significant impact on the colonic weight/length ratio. Finally, statins have been shown to prevent weight loss in the DSS, TNBS, AA, and T. gondii animal models.23,25,29,31–33
Cytokines, Chemokines, and Lymphocyte Subsets Tumor necrosis factor-alpha (TNF-a), a key inflammatory cytokine targeted by biological treatments in IBD, was consistently decreased by statins in animal studies.24,27,28,30,31 Other proinflammatory cytokines such as IL-17, IL-23, and interferon gamma were also decreased by statin treatment.29,30,33 Aktunc et al30 illustrated a switch in the cytokine profile from TH1 to TH2, with increased production of IL-10 leading to attenuation of inflammation. Levels of chemokines, such as cytokine-induced neutrophilic chemoattractant 1 (CXCL-1), may also be reduced by statin treatment.27 Finally, statin therapy was associated with an increase in intestinal forkhead box P3 (FOXP3) TREG cells in the T. gondii–induced ileitis model.33
Lymphocyte Adhesion
Drugs that alter cell recruitment to the gut, such as the a4b7 integrin inhibitor vedolizumab, have demonstrated efficacy in patients with IBD.34 There is evidence that statins may specifically inhibit the interaction between a4b7 and mucosal addressin cell adhesion molecule (MAdCAM) by reducing colonic expression of MAdCAM-positive vessels in DSS-mediated colitis.23
Intestinal Epithelium Alterations in the integrity of the intestinal epithelium may contribute to the pathogenesis of IBD. In a study by Sasaki et al,23 statin therapy was associated with a Rho-kinase (ROCK)-dependent decrease in intestinal permeability and reduction in bacterial translocation. Notably, ROCK, by phosphorylating myosin light chain, www.ibdjournal.org |
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FIGURE 1. Mechanisms of statins in IBD experimental models. Adapted from: Valatas et al. The value of experimental models of colitis in predicting efficacy of biological therapies for inflammatory bowel diseases. Am J Physiol Gastrointest Liver Physiol. 2013. This figure illustrates the possible mechanisms by which statins may modulate the pathogenesis of IBD. Red arrows indicate inhibition while green arrows indicate activation. Notably, statins inhibit epithelial factors such as intestinal permeability, luminal proinflammatory bacteria, NFkB and CXCL-10 activity. They inhibit proinflammatory cytokines such as TNF-a, IFN-g, IL-17, and IL-23. They also inhibit MAdCAM. Statins increase anti-inflammatory luminal bacteria, IL-10 (an anti-inflammatory cytokine) and Treg lymphocyte. Other mechanisms not included in this figure are a decrease in oxidative stress, decrease in myeloperoxidase and a decrease in proinflammatory chemokines such as monocyte chemoattractant protein 1 (MCP-1) and cytokineinduced neutrophilic chemoattractant 1 (CXCL-1). Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
increases contractility of actomyosin fibers that anchor the tight junction in the apical region of epithelial cells and maintain gut barrier function.35 Another study found that statins prevent ROCK/ myosin-light-chain phosphatase (MLC-P) mediated epithelial reorganization and decreased intestinal permeability.36
Microflora In addition to a dysregulated immune system and genetic susceptibility, environmental triggers play an important role in IBD.37,38 A likely important environmental factor triggers may disrupt the balance of intestinal microflora. Bareswill et al reported that statins improved the enteric dysbiosis associated with T. gondii–induced ileitis.33 Although putative anti-inflammatory bacteria such as lactobacilli and bifidobacteria were increased, there was a concomitant decrease in proinflammatory bacteria such as enterobacteria and enterococci in the ileum of statintreated animals.33
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Intestinal Fibrosis Intestinal fibrosis, a consequence of chronic inflammation in IBD, is characterized by extracellular matrix deposition and the expansion of intestinal myofibroblasts within the muscularis mucosa.39 This can lead to severe complications such as strictures and intestinal obstruction where surgery is the only therapeutic option. Interestingly, statin therapy resulted in a reduction in tissue collagen content in TNBS colitis.28 Furthermore, Abe et al31 found a decrease in fibrosis-related growth factor in mice treated with statins independent of their anti-inflammatory effects. This effect appeared to be dose-dependent and was likely mediated by the induction of apoptosis in fibroblasts and myofibroblasts.
Other Observations Oxidative stress reflects an imbalance between reactive oxygen species and antioxidants. This imbalance can lead to cell damage because of free radicals and peroxides. Naito et al24
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Effect of Statins on
Author DSS colitis model Sasaki et al23
Naito et al24
Lee et al25
Kanagarajan et al26 Oishi et al27
TNBS colitis model Jahovic et al28
Ikeda et al29
Decrease DAI; decrease weight loss; increase colonic length; decrease histological activity (NS) Decrease DAI; increase colonic length; decrease histological activity Decrease DAI; decrease weight loss; increase colonic length; decrease histological activity Decrease DAI; decrease macroscopic manifestations; increase colonic length Decrease DAI; no change in body weight; no change in colonic weight/length ratio Decrease macroscopic manifestations; no change in colonic weight; no change in histological activity Decrease weight loss; decrease macroscopic manifestations (prophylactic protocol); decrease histological activity Decrease macroscopic manifestations, not preventing weight loss, decrease histological activity
Cytokines, Chemokines and Lymphocyte Subset
NA
Decrease TNF-a
Lymphocyte Adhesion
Intestinal Epithelium
Decrease MAdCAM-1positive vessels
Decrease intestinal permeability
Intestinal Fibrosis
Other
NA
Increase eNOS mRNA
Decrease TBA reactive substance; decrease MPO; increase e-NOS mRNA NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
Decrease TNF-a; decrease CXCL-1
NA
NA
NA
Decrease iNOS
Decrease TNF-a
NA
NA
Decrease IFN-g; no change in TNF-a
NA
NA
NA
NA
Decrease TNF-a, IL17, IL-23, IFN-g, increase IL-10, no change in IL-4, Il-5, IL-6, IL-1b
NA
NA
NA
NA
Decrease tissue collagen content
Decrease MDA; increase GSH; decrease MPO
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Immunomodulatory Effects of Statins in IBD
Aktunc et al30
Macroscopic and Microscopic
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TABLE 1. Experimental Data on Statins and Animal Models of IBD
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Effect of Statins on
Author Abe et al31
Oxalazone colitis model Ikeda et al29 Acid acetic induced colitis model Malekinejad et al32 Toxoplasma gondii ileitis model Bareswill et al33
Macroscopic and Microscopic Increase body weight; decrease DAI; decrease macroscopic manifestations; no difference in colonic length; decrease histologic activity
Cytokines, Chemokines and Lymphocyte Subset Decrease TNF-a,
Lymphocyte Adhesion
Intestinal Epithelium
Intestinal Fibrosis
Other
NA
NA
Increase apoptosis in fibroblasts and myofibroblasts, No difference in TGF2b, Decrease CTGF
NA
NA
No effect on weight loss; no effect on inflammatory grade
NA
NA
NA
NA
Increase body weight; decrease macroscopic manifestations; decrease histological activity
NA
NA
NA
NA
Decrease MPO; decrease NO; decrease MDA
Decrease weight loss; increase small intestinal length; decrease macroscopic manifestations; decrease histological activity
Decrease IFN-g, MCP1; increase Treg; increase IL-10
NA
Decrease proinflammatory bacteria; increase anti-inflammatory bacteria
NA
Decrease MPO-7
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CTGF, fibrosis-related growth factor; CXCL-1, Cytokine-induced neutrophil; CXCL10, C-X-C motif chemokine 10; DAI, disease activity index (score including rectal bleeding, weight lost and stool consistency); DSS, dextran sulphate sodium; eNOS, endothelial nitric oxide synthases; iNOS, isoform nitric oxide synthase; GSH, glutathione; MCP-1, monocyte chemoattractant protein 1; MDA, malondialdehyde; MPO, myeloperoxidase; NA, not available; NO, nitric oxide; TBA, thiobarbituric acid; TNBS, trinitrobenzene sulfonic acid.
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TABLE 1 (Continued)
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demonstrated that statins reduce thiobarbituric acid (TBA), a marker of oxidative stress, and myeloperoxidase (MPO), a key enzyme expressed in neutrophils that generates of reactive oxygen species. Furthermore, Jahovic et al28 found that statins decrease malondialdehyde (MDA), another marker of oxidative stress, and increase glutathione (GSH), a well-known antioxidant. Other studies have also showed that statins can reduce MPO levels.28,32 Finally, Ikeda et al29 studied the effect of statins in an OXA colitis model and found no changes in weight loss or inflammation. OXA-induced colitis is TH2-mediated and therefore may resemble ulcerative colitis (UC).40 In contrast, DSS and TNBS colitis are TH1- and TH17-mediated and may thus be more similar to Crohn’s disease (CD).41 These data raise the possibility that statins may have more likely to have an effect in CD than in UC.
EFFECTS OF STATINS IN IBD In Vitro Data Lee et al25 examined the effect of statins on intestinal epithelial cells in vitro using the human colon cancer cell line COLO 205 and demonstrated that statins reduce TNF-a-induced IL-8 gene expression (Table 1 and Fig. 1). Additionally, the transcriptional activity of NFkB, a master regulator of multiple proinflammatory cytokines and adhesion molecules, was also reduced in statin-treated COLO 205 cells.
Clinical Studies A few studies have investigated the effect of statins on patients with IBD (Table 2). Higgins et al conducted the only randomized, placebo controlled trial on statins in IBD. Thirtysix patients with mild to moderate UC were included in the study.42 The effect of statins was assessed after 24 weeks of treatment and was measured using the Seo index activity score. Patients treated with atorvastatin 40 mg daily improved their Seo index activity score compared with placebo, although the difference did not meet statistical significance (P ¼ 0.06). After controlling for disease duration, the Seo index decreased 46 points in the atorvastatin group compared with the placebo group (P ¼ 0.02). Patients on statin therapy were also more likely to be in clinical remission than placebo treated patients (45% versus 25%). Although these results are intriguing, the study was limited by the small number of patients and the absence of endoscopic endpoints. Two uncontrolled studies looked at the effect of statins in reducing inflammatory markers in patients with CD.43,44 One study investigated how atorvastatin 80 mg daily for 13 weeks affected the C-reactive protein and fecal calprotectin levels in 10 patients.43 Baseline IBD medications were unchanged during the study. No endoscopic evaluation was included in the evaluation. Six of 10 patients had their CD diagnosed less than 1 year before enrollment and the mean Crohn’s disease activity
Immunomodulatory Effects of Statins in IBD
index was 176 6 122. Disease was located only in the ileum in 2 patients, the ileum and colon in 6 patients, the ileum and rectum in 1 patient, and the entire gastrointestinal tract in 1 patient. A mean decrease in Crohn’s disease activity index of 82 points was observed (P ¼ 0.105) with a 44% reduction in C-reactive protein levels after atorvastatin treatment (P ¼ 0.008). Eight of 10 patients also had a decrease in their calprotectin levels. Interestingly, calprotectin increased after atorvastatin was stopped in 5 of 6 patients (2 patients did not have a follow-up stool sample because immunosuppressive therapy had been started). The second study involved the same group of patients but instead measured plasma levels of CXCL10, a ligand for the CXCR3 receptor that promotes recruitment of monocytes, macrophages, T cells, and natural killer cells.45 Additionally, CXCL10 increases adhesion of lymphocytes to endothelial cells.46 In this study, treatment with atorvastatin reduced plasma levels of CXCL10, which correlated with decreasing C-reactive protein levels.44 The impact of statins on established IBD was also examined in a large retrospective cohort study.47 Crockett et al47 used a large administrative data set to evaluate the effect of statin exposure on clinical outcomes in 11,857 patients with IBD. Statin exposure was defined by any prescription of one of the 6 statin drugs (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin). Outcomes included steroid prescription, initiation of an anti-TNF, hospitalization, and abdominal surgery. Forty-two percent of patients had CD, 57% had UC, and 1% had indeterminate colitis. Medications were similar in both statin-exposed and unexposed groups with the majority taking 5-ASA (67%). Seventeen percent were on steroids, 23% were on thiopurines, and only 6% were on an antiTNF. Statin exposure was significantly associated with an 18% reduction in steroid prescriptions (hazard ratio [HR]: 0.82, 95% confidence interval [CI], 0.71–0.94). This finding was the strongest among patients with UC (HR: 0.75, 95% CI, 0.62–0.91). Statin exposure was also associated with trends toward decreased anti-TNF use (HR: 0.72, 95% CI, 0.46–1.11), abdominal surgery (HR: 0.80, 95% CI, 0.63–1.02), and hospitalization (HR: 0.88, 95% CI, 0.74–1.05). The association between statins and incidence of IBD was evaluated in 2 retrospective studies.48,49 Khalil et al performed a retrospective cohort study using military health care system records of 43,438 patients from the San Antonio Military MultiMarket Area. The analysis cohort included 6342 statin users and 6342 nonusers matched by propensity score. The 2 treatment groups were identified in an initial baseline period of 2 years and then were followed for up to an additional 7 years with the primary outcome being an ICD-9 code for IBD. During the follow-up period, 93 statin users and 92 nonusers were had an IBD ICD-9 (odds ratio [OR] 1.01, 95% CI, 0.76–1.35). This study was limited by its retrospective design and the use of a geographically limited cohort. We conducted a case–control study using a large national health claims database that included 87,579 new IBD cases and 189,526 age, gender, race, and geographically www.ibdjournal.org |
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TABLE 2. Clinical Studies on Statins in IBD and Colitis-associated Colorectal Cancer Author IBD Higgins et al42
Design
Primary Outcome
Patients
Statin Dose Used
Results
Randomized controlled trial
Seo index improvement at week 24
36 patients (UC)
Atorvastatin 40 mg
Grip et al43
Open, single center, uncontrolled, exploratory study
10 patients (CD)
Atorvastatin 80 mg
Grip et al44
Open, single center, uncontrolled, exploratory study Retrospective cohort study
Reduction of inflammatory markers a week 8 after a 13 weeks treatment Plasma levels of chemokines after a 13 weeks treatment Oral steroids prescription
10 patients (CD)
Atorvastatin 80 mg
Statins reduce plasma levels of CXCL10
Statins exposure
Statins decrease oral steroids prescriptions
Khalil et al48
Retrospective cohort study
Incidence of IBD diagnosis
Statins exposure
No difference in IBD incidence between statin users and nonusers
Ungaro et al49
Retrospective case– control study
Risk factors of new onset IBD
11,857 patients (CD: 5000/UC: 6676/ IC: 181) 12,684 patients (93 with IBD and statins, 92 with IBD without statins) 92,933 New IBD cases and 929,330 IBD controls
Statins exposure
Statins decrease risk of new onset IBD
Retrospective case– control study (IBD patients ¼ subanalysis) Retrospective case– control study
Association between statins use and colorectal cancer
39 IBD with colorectal cancer, 16 IBD without colorectal cancer 39 IBD with colorectal cancer, 21 IBD without colorectal cancer
Statins exposure
Statins decrease colorectal cancer risk in the general population and IBD
Statins exposure
Statins decrease colorectal cancer risk in IBD (NS when adjusteda)
Crockett et al47
Colitis-associated colorectal cancer Poynter et al62
Samadder et al64
Colorectal cancer risk in IBD
Statins improve Seo index activity score after controlling for disease duration and improve clinical remission Statins reduce CDAI (NS), CRP plasma levels and calprotectin levels (NS)
a Adjusted for age, sex, ethnicity, sports participation, level of vegetable consumption, smoking status, and history of first-degree colorectal cancer. CDAI, Crohn’s disease activity index; IC, indeterminate colitis; NA, not available; SEO index ¼ 60 · blood stool + 13 · bowel movements + 0.5 · (erythrocyte sedimentation rate) 2 4 · HB 2 15 · albumin + 200.
matched controls.49 New IBD cases were defined as at least 3 separate IBD ICD-9 codes with no previous IBD codes or IBDrelated medications. Exposure to statins was associated with a significantly decreased risk of new onset IBD (OR 0.59, 95% CI, 0.58–0.61). Limitations include retrospective study design and inability to directly validate cases because of deidentified data. Further studies are needed to better elucidate this possible association. Statins are widely prescribed and their safety has been well studied. Most adverse effects are related to liver or muscle toxicity and are usually reversible after statin discontinuation.50 Few case reports have related statins with drug-induced colitis.51–53 The mechanism of action proposed was ischemia based on endoscopy results and the clinical course of the colitis.52,53 However, the
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Federal Drug and Food Administration does not recognize this as a possible adverse event with statin therapy.54
STATINS AND COLITIS-ASSOCIATED COLORECTAL CANCER Patients with IBD are at increased risk for colorectal cancer compared with the general population.55 Statins have been studied as a possible chemopreventive agent in breast cancer and prostate cancer.56,57 The antiproliferative and proapoptotic effects of statins may explain how statins could be protective against cancer.58 Some research has suggested that statins may be protective against the development of colitisassociated colorectal cancer.
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Experimental Models A few basic science studies have tried to elucidate the role of statins in colitis-associated colorectal cancer. Suzuki et al59 studied statins in the azoxymethane (AOM)/DSS murine model of colitisassociated colorectal cancer. In addition to reducing histological inflammation, statins significantly decreased rates of high-grade dysplasia. Another study using the AOM/DSS model found that statins reduced the number of colonic tumors, decreased proliferation rate (by immunochemistry for proliferating cell nuclear antigen), and increased apoptotic indices in colonic epithelium at week 20.60 However, there was no significant reduction in the incidence rate of colonic dysplasia or tumors. Statins have also been shown to induce apoptosis and inhibit angiogenesis in a tumor xenograft model.61 This same study also demonstrated that statins induce NFkB dependent-apoptotic pathways in vitro using the human colon cancer cell lines COLO 205 and HCT 116.61
Clinical Studies Two clinical studies evaluated the possible protective effect of statins against colitis-associated colorectal cancer (Table 2). A landmark case–control study found that statins may protect against colorectal cancer in the general population (OR 0.50, 95% CI, 0.40–0.63).62 In a subgroup analysis of patients with IBD, statins had an even stronger protective effect (OR 0.06, 95% CI, 0.006–0.550). However, the number of patients with IBD was limited in this study (55 patients). In contrast, a population-based cohort study from Canada looked at the relationship between statins and colorectal cancer in the general population.63 They did not find a protective effect in regular statin users (incidence rate ratio 0.89, 95% CI, 0.70–1.13). Although 2762 patients with IBD were included in this cohort, subgroup analysis focusing on patients with IBD was not reported. The second study looking at colitis-associated colorectal cancer found that long-term statin use was associated with a reduced risk of colorectal cancer (OR 0.07, 95% CI, 0.01–0.78). When adjusted for possible confounders such as age, sex, ethnicity, sports participation, level of vegetable consumption, and family history of colorectal cancer, statins still trended toward a protective; however, the finding no longer reached statistical significance (OR 0.10, 95% CI, 0.01–1.31).64
CONCLUSIONS The treatment of IBD is evolving with new therapeutic agents being developed. The possibility of using statins as a treatment in IBD is intriguing. We attempted to cautiously search the literature on this topic, but this article remains in essence a narrative review, and as such some relevant studies may have been omitted and important sources of bias overlooked. However, our search showed that the immunomodulatory effect of statins on experimental models, its excellent safety profile combined with its oral administration route make statins an attractive potential IBD therapy. Clinical studies showed that statins may improve disease activity scores, reduce the need for steroids, and offer protection against new onset IBD.
Immunomodulatory Effects of Statins in IBD
Furthermore, some evidence suggests that statins could be chemopreventive agents against colitis-associated colorectal cancer. The promising research outlined in this article highlights the need for further investigation on a possible role for statins in IBD. Well-controlled clinical studies are needed to evaluate statins as monotherapy for mild disease or as add-on medications with other therapies such biologics.
REFERENCES 1. Desai CS, Martin SS, Blumenthal RS. Non-cardiovascular effects associated with statins. BMJ. 2014;349:g3743–g3743. 2. Ferri N, Corsini A. Clinical evidence of statin therapy in non-dyslipidemic disorders. Pharmacol Res. 2014;88:20–30. 3. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;1: CD004816. 4. Anderson TJ, Grégoire J, Hegele RA, et al. 2012 update of the Canadian cardiovascular society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol. 2013;29:151–167. 5. TH Lim, Orija IB, Pearlman BL; American College of Cardiology. The new cholesterol treatment guidelines from the american College of Cardiology/American heart association, 2013: what clinicians need to know. Postgrad Med. 2014;126:35–44. 6. Vaughan CJ, Murphy MB, Buckley BM. Statins do more than just lower cholesterol. Lancet. 1996;348:1079–1082. 7. Khattri S, Zandman-Goddard G. Statins and autoimmunity. Immunol Res. 2013;56:348–357. 8. Kwak B, Mulhaupt F, Myit S, et al. Statins as a newly recognized type of immunomodulator. Nat Med. 2000;6:1399–1402. 9. Yilmaz A, Reiss C, Weng A, et al. Differential effects of statins on relevant functions of human monocyte-derived dendritic. J Leukoc Biol. 2006;79:529–538. 10. Leuenberger T, Pfueller CF, Luessi F, et al. Modulation of dendritic cell immunobiology via inhibition of 3-hydroxy-3-methylglutaryl-CoA (HMGCoA) reductase. PLoS One. 2014;9:e100871. 11. Ghittoni R, Patrussi L, Pirozzi K, et al. Simvastatin inhibits T-cell activation by selectively impairing the function of Ras superfamily GTPases. FASEB J. 2005;19:605–607. 12. Youssef S, Stüve O, Patarroyo JC, et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature. 2002;420:78–84. 13. Nübel T, Dippold W, Kleinert H, et al. Lovastatin inhibits Rho-regulated expression of E-selectin by TNFalpha and attenuates tumor cell adhesion. FASEB J. 2004;18:140–142. 14. Romano M, Diomede L, Sironi M. Inhibition of monocyte chemotactic protein-1 synthesis by statins. Lab Invest. 2000;80:1095–1100. 15. Greenwood J, Walters CE, Pryce G, et al. Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. FASEB J. 2003;17:905–907. 16. Wagner a H, Köhler T, Rückschloss U, et al. Improvement of nitric oxidedependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol. 2000;20: 61–69. 17. Weber C, Erl W, Weber KS, et al. HMG-CoA reductase inhibitors decrease CD11b expression and CD11b- dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. J Am Coll Cardiol. 1997;30:1212–1219. 18. Wong B, Lumma WC, Smith a M, et al. Statins suppress THP-1 cell migration and secretion of matrix metalloproteinase 9 by inhibiting geranylgeranylation. J Leukoc Biol. 2001;69:959–962. 19. Bellosta S, Via D, Canavesi M, et al. HMG-coa reductase inhibitors reduce MMP-9 secretion by macrophages. Arterioscler Thromb Vasc Biol. 1998;18:1671–1678. 20. Bath PM, Hassall DG, Gladwin A, et al. Nitric oxide and prostacyclin. Divergence of inhibitory effects on monocyte chemotaxis and adhesion to endothelium in vitro. Arterioscler Thromb Vasc Biol. 1991;11:254–260. www.ibdjournal.org |
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21. Kubes P, Suzuki M, Granger DN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A. 1991;88: 4651–4655. 22. Laufs U, La Fata V, Plutzky J, et al. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998;97: 1129–1135. 23. Sasaki M, Bharwani S, Jordan P, et al. The 3-hydroxy-3-methylglutarylCoA reductase inhibitor pravastatin reduces disease activity and inflammation in dextran-sulfate induced colitis. J Pharmacol Exp Ther. 2003; 305:78–85. 24. Naito Y, Katada K, Takagi T, et al. Rosuvastatin, a new HMG-CoA reductase inhibitor, reduces the colonic inflammatory response in dextran sulfate sodium-induced colitis in mice. Int J Mol Med. 2006;17:997–1004. 25. Lee JY, Kim JS, Kim JM, et al. Simvastatin inhibits NF-KappaB signaling in intestinal epithelial cells and ameliorates acute murine colitis. Int Immunopharmacol. 2007;7:241–248. 26. Kanagarajan N, Nam JH, Al Noah Z, et al. Disease modifying effect of statins in dextran sulfate sodium model of mouse colitis. Inflamm Res. 2008;57:34–38. 27. Oishi M, Tokuhara K, Miki H, et al. Temporal and spatial dependence of inflammatory biomarkers and suppression by fluvastatin in dextran sodium sulfate-induced rat colitis model. Dig Dis Sci. 2014;59:2126–2135. 28. Jahovic N, Gedik N, Ercan F, et al. Effects of statins on experimental colitis in normocholesterolemic rats. Scand J Gastroenterol. 2006;41:954–962. 29. Ikeda M, Takeshima F, Isomoto H, et al. Simvastatin attenuates trinitrobenzene sulfonic acid-induced colitis, but not Oxazalone-induced colitis. Dig Dis Sci. 2008;53:1869–1875. 30. Aktunc E, Kayhan B, Arasli M, et al. The effect of atorvastatin and its role on systemic cytokine network in treatment of acute experimental colitis. Immunopharmacol Immunotoxicol. 2011;33:667–675. 31. Abe Y, Murano M, Murano N, et al. Simvastatin attenuates intestinal fibrosis independent of the anti-inflammatory effect by promoting fibroblast/myofibroblast apoptosis in the regeneration/healing process from TNBS-induced colitis. Dig Dis Sci. 2012;57:335–344. 32. Malekinejad H, Shafie-Irannejad V, Hobbenaghi R, et al. Comparative protective effect of hawthorn berry hydroalcoholic extract, atorvastatin, and mesalamine on experimentally induced colitis in rats. J Med Food. 2013;16:593–601. 33. Bereswill S, Muñoz M, Fischer A, et al. Anti-inflammatory effects of Resveratrol, Curcumin and simvastatin in acute small intestinal inflammation. PLoS One. 2010;5:e15099. 34. Berlin C, Bargatze RF, Campbell JJ, et al. Alpha 4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell. 1995;80:413–422. 35. Kosako H, Yoshida T, Matsumura F, et al. Rho-kinase/ROCK is involved in cytokinesis through the phosphorylation of myosin light chain and not ezrin/radixin/moesin proteins at the cleavage furrow. Oncogene. 2000;19: 6059–6064. 36. Mirza H, Wu Z, Teo JDW, et al. Statin pleiotropy prevents rho kinasemediated intestinal epithelial barrier compromise induced by Blastocystis cysteine proteases. Cell Microbiol. 2012;14:1474–1484. 37. Dalal SR, Chang EB. The microbial basis of inflammatory bowel diseases. J Clin Invest. 2014;124:1–7. 38. Nguyen HT, Dalmasso G, Müller S, et al. Crohn’s disease-associated adherent invasive escherichia coli modulate levels of microRNAs in intestinal epithelial cells to reduce autophagy. Gastroenterology. 2014;146:508–519. 39. Floer M, Binion DG, Nelson VM, et al. Role of MutS homolog 2 (MSH2) in intestinal myofibroblast proliferation during Crohn’s disease stricture formation. Am J Physiol Gastrointest Liver Physiol. 2008;295:G581–G590. 40. Heller F, Fuss IJ, Nieuwenhuis EE, et al. Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity. 2002;17:629–638.
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41. Alex P, Zachos NC, Nguyen T, et al. Cytokine Patterns Identified from Multiplex Profiles of Murine DSS and Tnbs-iNBS-Induced Colitis. Inflamm Bowel Dis. 2009;15:341–352. 42. Higgins PD, Khan T, Mapili J, et al. Atorvastatin decreases seo Index in patients with short duration of disease in ulcerative colitis : a randomized placebo-controlled clinical trial. Gastroenterology. 2006;130:A120. Abstract presentation at DDW 2006. 43. Grip O, Janciauskiene S, Bredberg A. Use of atorvastatine as an antiinflammatory treatment in Crohn’s disease. Br J Pharmacol. 2008;155: 1085–1092. 44. Grip O, Janciauskiene S. Atorvastatin reduces plasma levels of chemokine (CXCL10) in patients with Crohn’s disease. PLoS One. 2009;4:1–6. 45. Luster AD, Unkeless JC, Ravetch JV. Gamma-interferon transcriptionally regulates an early-response gene containing homology to platelet proteins. Nature. 1985;315:672–676. 46. Dufour JH, Dziejman M, Liu MT, et al. IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking. J Immunol. 2002;168:3195–3204. 47. Crockett SD, Hansen RA, Stürmer T, et al. Statins are associated with reduced use of steroids in inflammatory bowel disease: a retrospective cohort study. Inflamm Bowel Dis. 2012;18:1048–1056. 48. Khalil D, Boktor M, Mortensen EM, et al. Comparison of Frequency of inflammatory bowel disease and Noninfectious gastroenteritis among statin users versus nonusers. Am J Cardiol. 2015;115:00731–00736. 49. Ungaro R, Atreja A, Chang HL, et al. Statins associated with decreased risk of new onset IBD. Presented at DDW 2015, # 2159651. 50. Wilkinson MJ, Laffin LJ, Davidson MH. Overcoming toxicity and sideeffects of lipid-lowering therapies. Best Pract Res Clin Endocrinol Metab. 2014;28:439–452. 51. Rea WE, Durrant DCS, Boldy DAR. Ulcerative colitis after statin treatment. Postgrad Med J. 2002;78:286–287. 52. Leung FW, Lieberman J, Fagen N, et al. Colonoscopic features of simvastatin-induced colitis suggest ischemia as an etiologic mechanism. Gastrointest Endosc. 2005;62:175–178. 53. Mukhopadhya A, Gilmour H, Plevris J. Pravastatin-induced colitis. Eur J Gastroenterol Hepatol. 2008, 20:810–812. 54. Available at: www.fda.gouv. Accessed February 18, 2015. 55. Bae SI, Kim YS. Colon Cancer screening and surveillance in inflammatory bowel disease. Clin Endosc. 2014:47;509–515. 56. Ahern TP, Lash TL, Damkier P, et al. Statins and breast cancer prognosis: evidence and opportunities. Lancet Oncol. 2014;15:e461–e468. 57. D1 Pon, Abe A, Gupta EK. A review of statin use and prostate cancer. Curr Atheroscler Rep. 2015;17:474. 58. Chan KKW, Oza AM, Siu LL. The statins as anticancer agents. Clin Cancer Res. 2003;9:10–19. 59. Suzuki S, Tajima T, Sassa S, et al. Preventive effect of fluvastatin on ulcerative colitis-associated carcinogenesis in mice. Anticancer Res. 2006;26:4223–4228. 60. Yasui Y, Suzuki R, Miyamoto S, et al. A lipophilic statin, pitavastatin, suppresses inflammation-associated mouse colon carcinogenesis. Int J Cancer. 2007;121:2331–2339. 61. Cho SJ, Kim JS, Kim JM, et al. Simvastatin induces apoptosis in human colon cancer cells and in tumor xenografts, and attenuates colitisassociated colon cancer in mice. Int J Cancer. 2008;123:951–957. 62. Poynter JN, Gruber SB, Higgins PDR, et al. Statins and the risk of colorectal cancer. N Engl J Med. 2005;352:2184–2192. 63. Singh H, Mahmud SM, Turner D, et al. Long-term use of statins and risk of colorectal cancer: a population-based study. Am J Gastroenterol. 2009; 104:3015–3023. 64. Samadder NJ, Mukherjee B, Huang SC, et al. Risk of colorectal cancer in self-reported inflammatory bowel disease and modification of risk by statin and NSAID use. Cancer. 2011;117:1640–1648.
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Potential Immunomodulatory Effects of Statins in Inflammatory Bowel Disease Justin Côté-Daigneault, MD, Saurabh Mehandru, MD, Ryan Ungaro, MD, Ashish Atreja, MD, and Jean-Frédéric Colombel, MD
Abstract: Statins are among the most widely prescribed medications in the world. In addition to lowering cholesterol, statins have been shown to have immunomodulatory effects in multiple studies. For example, statins modulate the interaction between T cells and antigen-presenting cells, resulting in decreased T-cell activation and reduced levels of inflammatory cytokines. Statins have also been demonstrated to inhibit the migration of leukocytes across vascular endothelium into tissues. Although most research on the immune effects of statins has been conducted in the context of cardiovascular, rheumatological, or metabolic disease, various studies have shown that statins may have a significant impact on intestinal immunity and mucosal inflammation. Clinical research has suggested that statins may have benefit in inflammatory bowel disease. In this article, we review the effect of statins on the immune system and gastrointestinal tract, highlighting the potential for novel therapeutic applications in inflammatory bowel disease. (Inflamm Bowel Dis 2016;22:724–732) Key Words: statin, Crohn’s disease, ulcerative colitis, colitis and colorectal cancer
S
tatins are some of the most widely prescribed medications with more than 200 million people on statin therapy worldwide.1 Statins act by competitively inhibiting 3-hydroxy3-methylglutaryl coenzyme A (HMG-CoA) reductase, the ratelimiting enzyme in the cholesterol synthetic pathway.2 Current indications for statin use include primary and secondary prevention of cardiovascular disease and hypercholesterolemia.3–5 Although the original rationale for treating cardiovascular disease with statins was the reduction in low-density lipoproteins, it is increasingly evident that the beneficial effects of statins are more complex and likely include an immunomodulatory component.6 In addition to limiting the biosynthesis of cholesterol, HMG-CoA reductase inhibition also decreases other intermediate metabolites including isoprenoids such as farnesyl pyrophosphate. Isoprenoids serve as essential adjuncts in the posttranslational modification of numerous key proteins that serve as molecular switches. Because of this, statin treatment may have efficacy in immune-mediated diseases such as chronic obstructive pulmonary disease, rheumatoid arthritis, and vasculitis.1,2,7 Importantly, statins have been shown to modulate inflammation Received for publication August 22, 2015; Accepted September 22, 2015. From the The Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York. The authors have no conflict of interest to disclose. Reprints: Jean-Frédéric Colombel, MD, The Leona M. and Harry B. Helmsley Inflammatory Bowel Disease Center, The Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029 (e-mail: [email protected]). Copyright © 2016 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000640 Published online 25 January 2016.
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in the gastrointestinal tract, raising the possibility that they could have benefits in inflammatory bowel disease (IBD). In this article, we review the anti-inflammatory and antineoplastic effects of statins with a focus on potential therapeutic implications for IBD. We discuss the impact of statins on immune cells and function, in animal models of IBD, and in clinical and translational studies with patients with IBD. Additionally, we summarize studies investigating statins and colitisassociated colorectal cancer.
IMMUNOMODULATORY EFFECTS OF STATINS Antigen-Presenting Function Statins inhibit cytokine inducible expression of major histocompatibility complex II by inhibiting the class II transactivator on antigen-presenting cells such as dendritic cells (DCs), which decreases antigen presentation to T cells.8 Importantly, interferon gamma–induced expression of major histocompatibility complex II was inhibited by statins while its constitutive expression remained unaffected in mature DCs. Statins have also been shown to reduce the expression of costimulatory molecules such as HLA-DR, CD40, CD80, and CD86 on DCs.9 Expression of these costimulatory molecules on antigenpresenting cells is essential for T-cell response to antigens. Other effects of statins on DCs include decreasing DC maturation, impairing phagocytosis and endocytosis of antigens, and limiting formation of immunological synapses.9,10 The combined effects of statins result in an overall decrease in T-cell activation through inhibition of DC-mediated antigen presentation. These data suggest that statins could have a therapeutic role in T-cell– mediated diseases such as IBD. Inflamm Bowel Dis Volume 22, Number 3, March 2016
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T-Cell Proliferation and Phenotype Statins have pronounced effects on T-cell proliferation through modulation of GTPases linked to cell-cycle progression, cytoskeletal organization, and formation of immunological synapses.11 Additionally, statins decrease the production of signal transducers and activators of transcription-4 (STAT-4) and t-box expression in T cells.12 T-bet–dependent proinflammatory TH1 cytokines such as interferon gamma are diminished by statins, whereas anti-inflammatory TH2 cytokines such as interleukin (IL)-4 and IL-10 are increased through the activation of STAT-6 and GATA3.12 These proinflammator and antiinflammatory cytokines have been shown to be altered in IBD.
Leukocyte Adhesion Molecules and Cellular Migration As evidenced by the recent success of homing inhibitors such as vedolizumab in patients with IBD, leukocyte infiltration of target organs is a critical event in the perpetuation of inflammation. Reduction in the migration of leukocytes to sites of inflammation is one of the most consistent effects of statins. Statins decrease the expression of cellular adhesion molecules on leukocytes and endothelial cells, resulting in reduced cellular adhesion and transvascular migration. Mechanisms for this phenomenon include inhibition of endothelial RAS homolog (Rho) GTPase-dependent platelet (P)- and endothelial (E)-selectins, decreased NFkB-dependent expression of CXCL8 and CCL2 on endothelial cells, and downregulation of intercellular adhesion molecule-1 and endothelial vascular cell adhesion molecule1.13–16 In addition, statins decrease the expression of CD11b, an integrin involved in the adhesion of monocytes to endothelium, thereby curtailing the recruitment of these important cells to sites of inflammation.17 Statins also seem to cause a Rho-GTPase– dependent inhibition of leukocyte motility and function.18 The expression of matrix metalloproteases (MMPs) such as MMP-9 on cells of monocyte/macrophage lineage is also decreased by statins.19 Notably, these MMPs enable the passage of leukocytes through the basal membrane and extracellular matrix. Thus, statins may affect migration of the leukocytes through both cellintrinsic and cell-extrinsic mechanisms.
Effects on Endothelial Nitric Oxide Synthase and Nitric Oxide Although the role of nitric oxide (NO) in inflammatory disease is not entirely clear, there is evidence that endothelial expression of NO prevents leukocyte chemotaxis.20 NO may also downregulate leukocyte adhesion to the vascular wall.21 Statins may affect NO levels by increasing endothelial nitric oxide synthases production.22
STATINS IN ANIMAL MODELS OF IBD Studies have investigated the anti-inflammatory effects of statins in murine models of intestinal inflammation, including colitis induced by dextran sulphate sodium (DSS), trinitrobenzene
Immunomodulatory Effects of Statins in IBD
sulfonic acid (TNBS), oxalazone (OXA), and acid acetic (AA) as well as Toxoplasma gondii–induced ileitis23–33 (Fig. 1) (Table 1). These studies have found that statins modify the macroscopic and microscopic inflammation, change the cytokine and chemokine profile, modify lymphocyte subsets, decrease lymphocyte adhesion, alter the intestinal epithelium, cause changes in the microflora and mitigate intestinal fibrosis.
Macroscopic and Microscopic Inflammation Statins decreased histological disease activity in 2 studies of DSS colitis, 3 studies of TNBS colitis, one study of AA colitis, and one study of T. gondii–induced ileitis.24,25,29–33 However, a study by Jahovic et al did not have similar findings in TNBS colitis, perhaps because of that the statin dose was 5 to 40 times lower than previous studies (0.1 and 1.0 mg/kg per day versus 5 mg/kg to 40 mg/kg per day).28 The effect of statins may be dose-dependent, as 2 studies only found a decrease in histological activity with high dose regimens.29,31 Although statins increased colonic length (decreased colonic length can reflect colonic inflammation) in 5 studies,23–26,33 one study by Oishi et al27 did not find a statistically significant impact on the colonic weight/length ratio. Finally, statins have been shown to prevent weight loss in the DSS, TNBS, AA, and T. gondii animal models.23,25,29,31–33
Cytokines, Chemokines, and Lymphocyte Subsets Tumor necrosis factor-alpha (TNF-a), a key inflammatory cytokine targeted by biological treatments in IBD, was consistently decreased by statins in animal studies.24,27,28,30,31 Other proinflammatory cytokines such as IL-17, IL-23, and interferon gamma were also decreased by statin treatment.29,30,33 Aktunc et al30 illustrated a switch in the cytokine profile from TH1 to TH2, with increased production of IL-10 leading to attenuation of inflammation. Levels of chemokines, such as cytokine-induced neutrophilic chemoattractant 1 (CXCL-1), may also be reduced by statin treatment.27 Finally, statin therapy was associated with an increase in intestinal forkhead box P3 (FOXP3) TREG cells in the T. gondii–induced ileitis model.33
Lymphocyte Adhesion
Drugs that alter cell recruitment to the gut, such as the a4b7 integrin inhibitor vedolizumab, have demonstrated efficacy in patients with IBD.34 There is evidence that statins may specifically inhibit the interaction between a4b7 and mucosal addressin cell adhesion molecule (MAdCAM) by reducing colonic expression of MAdCAM-positive vessels in DSS-mediated colitis.23
Intestinal Epithelium Alterations in the integrity of the intestinal epithelium may contribute to the pathogenesis of IBD. In a study by Sasaki et al,23 statin therapy was associated with a Rho-kinase (ROCK)-dependent decrease in intestinal permeability and reduction in bacterial translocation. Notably, ROCK, by phosphorylating myosin light chain, www.ibdjournal.org |
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FIGURE 1. Mechanisms of statins in IBD experimental models. Adapted from: Valatas et al. The value of experimental models of colitis in predicting efficacy of biological therapies for inflammatory bowel diseases. Am J Physiol Gastrointest Liver Physiol. 2013. This figure illustrates the possible mechanisms by which statins may modulate the pathogenesis of IBD. Red arrows indicate inhibition while green arrows indicate activation. Notably, statins inhibit epithelial factors such as intestinal permeability, luminal proinflammatory bacteria, NFkB and CXCL-10 activity. They inhibit proinflammatory cytokines such as TNF-a, IFN-g, IL-17, and IL-23. They also inhibit MAdCAM. Statins increase anti-inflammatory luminal bacteria, IL-10 (an anti-inflammatory cytokine) and Treg lymphocyte. Other mechanisms not included in this figure are a decrease in oxidative stress, decrease in myeloperoxidase and a decrease in proinflammatory chemokines such as monocyte chemoattractant protein 1 (MCP-1) and cytokineinduced neutrophilic chemoattractant 1 (CXCL-1). Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
increases contractility of actomyosin fibers that anchor the tight junction in the apical region of epithelial cells and maintain gut barrier function.35 Another study found that statins prevent ROCK/ myosin-light-chain phosphatase (MLC-P) mediated epithelial reorganization and decreased intestinal permeability.36
Microflora In addition to a dysregulated immune system and genetic susceptibility, environmental triggers play an important role in IBD.37,38 A likely important environmental factor triggers may disrupt the balance of intestinal microflora. Bareswill et al reported that statins improved the enteric dysbiosis associated with T. gondii–induced ileitis.33 Although putative anti-inflammatory bacteria such as lactobacilli and bifidobacteria were increased, there was a concomitant decrease in proinflammatory bacteria such as enterobacteria and enterococci in the ileum of statintreated animals.33
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Intestinal Fibrosis Intestinal fibrosis, a consequence of chronic inflammation in IBD, is characterized by extracellular matrix deposition and the expansion of intestinal myofibroblasts within the muscularis mucosa.39 This can lead to severe complications such as strictures and intestinal obstruction where surgery is the only therapeutic option. Interestingly, statin therapy resulted in a reduction in tissue collagen content in TNBS colitis.28 Furthermore, Abe et al31 found a decrease in fibrosis-related growth factor in mice treated with statins independent of their anti-inflammatory effects. This effect appeared to be dose-dependent and was likely mediated by the induction of apoptosis in fibroblasts and myofibroblasts.
Other Observations Oxidative stress reflects an imbalance between reactive oxygen species and antioxidants. This imbalance can lead to cell damage because of free radicals and peroxides. Naito et al24
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Effect of Statins on
Author DSS colitis model Sasaki et al23
Naito et al24
Lee et al25
Kanagarajan et al26 Oishi et al27
TNBS colitis model Jahovic et al28
Ikeda et al29
Decrease DAI; decrease weight loss; increase colonic length; decrease histological activity (NS) Decrease DAI; increase colonic length; decrease histological activity Decrease DAI; decrease weight loss; increase colonic length; decrease histological activity Decrease DAI; decrease macroscopic manifestations; increase colonic length Decrease DAI; no change in body weight; no change in colonic weight/length ratio Decrease macroscopic manifestations; no change in colonic weight; no change in histological activity Decrease weight loss; decrease macroscopic manifestations (prophylactic protocol); decrease histological activity Decrease macroscopic manifestations, not preventing weight loss, decrease histological activity
Cytokines, Chemokines and Lymphocyte Subset
NA
Decrease TNF-a
Lymphocyte Adhesion
Intestinal Epithelium
Decrease MAdCAM-1positive vessels
Decrease intestinal permeability
Intestinal Fibrosis
Other
NA
Increase eNOS mRNA
Decrease TBA reactive substance; decrease MPO; increase e-NOS mRNA NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
Decrease TNF-a; decrease CXCL-1
NA
NA
NA
Decrease iNOS
Decrease TNF-a
NA
NA
Decrease IFN-g; no change in TNF-a
NA
NA
NA
NA
Decrease TNF-a, IL17, IL-23, IFN-g, increase IL-10, no change in IL-4, Il-5, IL-6, IL-1b
NA
NA
NA
NA
Decrease tissue collagen content
Decrease MDA; increase GSH; decrease MPO
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Immunomodulatory Effects of Statins in IBD
Aktunc et al30
Macroscopic and Microscopic
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TABLE 1. Experimental Data on Statins and Animal Models of IBD
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Effect of Statins on
Author Abe et al31
Oxalazone colitis model Ikeda et al29 Acid acetic induced colitis model Malekinejad et al32 Toxoplasma gondii ileitis model Bareswill et al33
Macroscopic and Microscopic Increase body weight; decrease DAI; decrease macroscopic manifestations; no difference in colonic length; decrease histologic activity
Cytokines, Chemokines and Lymphocyte Subset Decrease TNF-a,
Lymphocyte Adhesion
Intestinal Epithelium
Intestinal Fibrosis
Other
NA
NA
Increase apoptosis in fibroblasts and myofibroblasts, No difference in TGF2b, Decrease CTGF
NA
NA
No effect on weight loss; no effect on inflammatory grade
NA
NA
NA
NA
Increase body weight; decrease macroscopic manifestations; decrease histological activity
NA
NA
NA
NA
Decrease MPO; decrease NO; decrease MDA
Decrease weight loss; increase small intestinal length; decrease macroscopic manifestations; decrease histological activity
Decrease IFN-g, MCP1; increase Treg; increase IL-10
NA
Decrease proinflammatory bacteria; increase anti-inflammatory bacteria
NA
Decrease MPO-7
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CTGF, fibrosis-related growth factor; CXCL-1, Cytokine-induced neutrophil; CXCL10, C-X-C motif chemokine 10; DAI, disease activity index (score including rectal bleeding, weight lost and stool consistency); DSS, dextran sulphate sodium; eNOS, endothelial nitric oxide synthases; iNOS, isoform nitric oxide synthase; GSH, glutathione; MCP-1, monocyte chemoattractant protein 1; MDA, malondialdehyde; MPO, myeloperoxidase; NA, not available; NO, nitric oxide; TBA, thiobarbituric acid; TNBS, trinitrobenzene sulfonic acid.
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TABLE 1 (Continued)
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demonstrated that statins reduce thiobarbituric acid (TBA), a marker of oxidative stress, and myeloperoxidase (MPO), a key enzyme expressed in neutrophils that generates of reactive oxygen species. Furthermore, Jahovic et al28 found that statins decrease malondialdehyde (MDA), another marker of oxidative stress, and increase glutathione (GSH), a well-known antioxidant. Other studies have also showed that statins can reduce MPO levels.28,32 Finally, Ikeda et al29 studied the effect of statins in an OXA colitis model and found no changes in weight loss or inflammation. OXA-induced colitis is TH2-mediated and therefore may resemble ulcerative colitis (UC).40 In contrast, DSS and TNBS colitis are TH1- and TH17-mediated and may thus be more similar to Crohn’s disease (CD).41 These data raise the possibility that statins may have more likely to have an effect in CD than in UC.
EFFECTS OF STATINS IN IBD In Vitro Data Lee et al25 examined the effect of statins on intestinal epithelial cells in vitro using the human colon cancer cell line COLO 205 and demonstrated that statins reduce TNF-a-induced IL-8 gene expression (Table 1 and Fig. 1). Additionally, the transcriptional activity of NFkB, a master regulator of multiple proinflammatory cytokines and adhesion molecules, was also reduced in statin-treated COLO 205 cells.
Clinical Studies A few studies have investigated the effect of statins on patients with IBD (Table 2). Higgins et al conducted the only randomized, placebo controlled trial on statins in IBD. Thirtysix patients with mild to moderate UC were included in the study.42 The effect of statins was assessed after 24 weeks of treatment and was measured using the Seo index activity score. Patients treated with atorvastatin 40 mg daily improved their Seo index activity score compared with placebo, although the difference did not meet statistical significance (P ¼ 0.06). After controlling for disease duration, the Seo index decreased 46 points in the atorvastatin group compared with the placebo group (P ¼ 0.02). Patients on statin therapy were also more likely to be in clinical remission than placebo treated patients (45% versus 25%). Although these results are intriguing, the study was limited by the small number of patients and the absence of endoscopic endpoints. Two uncontrolled studies looked at the effect of statins in reducing inflammatory markers in patients with CD.43,44 One study investigated how atorvastatin 80 mg daily for 13 weeks affected the C-reactive protein and fecal calprotectin levels in 10 patients.43 Baseline IBD medications were unchanged during the study. No endoscopic evaluation was included in the evaluation. Six of 10 patients had their CD diagnosed less than 1 year before enrollment and the mean Crohn’s disease activity
Immunomodulatory Effects of Statins in IBD
index was 176 6 122. Disease was located only in the ileum in 2 patients, the ileum and colon in 6 patients, the ileum and rectum in 1 patient, and the entire gastrointestinal tract in 1 patient. A mean decrease in Crohn’s disease activity index of 82 points was observed (P ¼ 0.105) with a 44% reduction in C-reactive protein levels after atorvastatin treatment (P ¼ 0.008). Eight of 10 patients also had a decrease in their calprotectin levels. Interestingly, calprotectin increased after atorvastatin was stopped in 5 of 6 patients (2 patients did not have a follow-up stool sample because immunosuppressive therapy had been started). The second study involved the same group of patients but instead measured plasma levels of CXCL10, a ligand for the CXCR3 receptor that promotes recruitment of monocytes, macrophages, T cells, and natural killer cells.45 Additionally, CXCL10 increases adhesion of lymphocytes to endothelial cells.46 In this study, treatment with atorvastatin reduced plasma levels of CXCL10, which correlated with decreasing C-reactive protein levels.44 The impact of statins on established IBD was also examined in a large retrospective cohort study.47 Crockett et al47 used a large administrative data set to evaluate the effect of statin exposure on clinical outcomes in 11,857 patients with IBD. Statin exposure was defined by any prescription of one of the 6 statin drugs (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin). Outcomes included steroid prescription, initiation of an anti-TNF, hospitalization, and abdominal surgery. Forty-two percent of patients had CD, 57% had UC, and 1% had indeterminate colitis. Medications were similar in both statin-exposed and unexposed groups with the majority taking 5-ASA (67%). Seventeen percent were on steroids, 23% were on thiopurines, and only 6% were on an antiTNF. Statin exposure was significantly associated with an 18% reduction in steroid prescriptions (hazard ratio [HR]: 0.82, 95% confidence interval [CI], 0.71–0.94). This finding was the strongest among patients with UC (HR: 0.75, 95% CI, 0.62–0.91). Statin exposure was also associated with trends toward decreased anti-TNF use (HR: 0.72, 95% CI, 0.46–1.11), abdominal surgery (HR: 0.80, 95% CI, 0.63–1.02), and hospitalization (HR: 0.88, 95% CI, 0.74–1.05). The association between statins and incidence of IBD was evaluated in 2 retrospective studies.48,49 Khalil et al performed a retrospective cohort study using military health care system records of 43,438 patients from the San Antonio Military MultiMarket Area. The analysis cohort included 6342 statin users and 6342 nonusers matched by propensity score. The 2 treatment groups were identified in an initial baseline period of 2 years and then were followed for up to an additional 7 years with the primary outcome being an ICD-9 code for IBD. During the follow-up period, 93 statin users and 92 nonusers were had an IBD ICD-9 (odds ratio [OR] 1.01, 95% CI, 0.76–1.35). This study was limited by its retrospective design and the use of a geographically limited cohort. We conducted a case–control study using a large national health claims database that included 87,579 new IBD cases and 189,526 age, gender, race, and geographically www.ibdjournal.org |
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TABLE 2. Clinical Studies on Statins in IBD and Colitis-associated Colorectal Cancer Author IBD Higgins et al42
Design
Primary Outcome
Patients
Statin Dose Used
Results
Randomized controlled trial
Seo index improvement at week 24
36 patients (UC)
Atorvastatin 40 mg
Grip et al43
Open, single center, uncontrolled, exploratory study
10 patients (CD)
Atorvastatin 80 mg
Grip et al44
Open, single center, uncontrolled, exploratory study Retrospective cohort study
Reduction of inflammatory markers a week 8 after a 13 weeks treatment Plasma levels of chemokines after a 13 weeks treatment Oral steroids prescription
10 patients (CD)
Atorvastatin 80 mg
Statins reduce plasma levels of CXCL10
Statins exposure
Statins decrease oral steroids prescriptions
Khalil et al48
Retrospective cohort study
Incidence of IBD diagnosis
Statins exposure
No difference in IBD incidence between statin users and nonusers
Ungaro et al49
Retrospective case– control study
Risk factors of new onset IBD
11,857 patients (CD: 5000/UC: 6676/ IC: 181) 12,684 patients (93 with IBD and statins, 92 with IBD without statins) 92,933 New IBD cases and 929,330 IBD controls
Statins exposure
Statins decrease risk of new onset IBD
Retrospective case– control study (IBD patients ¼ subanalysis) Retrospective case– control study
Association between statins use and colorectal cancer
39 IBD with colorectal cancer, 16 IBD without colorectal cancer 39 IBD with colorectal cancer, 21 IBD without colorectal cancer
Statins exposure
Statins decrease colorectal cancer risk in the general population and IBD
Statins exposure
Statins decrease colorectal cancer risk in IBD (NS when adjusteda)
Crockett et al47
Colitis-associated colorectal cancer Poynter et al62
Samadder et al64
Colorectal cancer risk in IBD
Statins improve Seo index activity score after controlling for disease duration and improve clinical remission Statins reduce CDAI (NS), CRP plasma levels and calprotectin levels (NS)
a Adjusted for age, sex, ethnicity, sports participation, level of vegetable consumption, smoking status, and history of first-degree colorectal cancer. CDAI, Crohn’s disease activity index; IC, indeterminate colitis; NA, not available; SEO index ¼ 60 · blood stool + 13 · bowel movements + 0.5 · (erythrocyte sedimentation rate) 2 4 · HB 2 15 · albumin + 200.
matched controls.49 New IBD cases were defined as at least 3 separate IBD ICD-9 codes with no previous IBD codes or IBDrelated medications. Exposure to statins was associated with a significantly decreased risk of new onset IBD (OR 0.59, 95% CI, 0.58–0.61). Limitations include retrospective study design and inability to directly validate cases because of deidentified data. Further studies are needed to better elucidate this possible association. Statins are widely prescribed and their safety has been well studied. Most adverse effects are related to liver or muscle toxicity and are usually reversible after statin discontinuation.50 Few case reports have related statins with drug-induced colitis.51–53 The mechanism of action proposed was ischemia based on endoscopy results and the clinical course of the colitis.52,53 However, the
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Federal Drug and Food Administration does not recognize this as a possible adverse event with statin therapy.54
STATINS AND COLITIS-ASSOCIATED COLORECTAL CANCER Patients with IBD are at increased risk for colorectal cancer compared with the general population.55 Statins have been studied as a possible chemopreventive agent in breast cancer and prostate cancer.56,57 The antiproliferative and proapoptotic effects of statins may explain how statins could be protective against cancer.58 Some research has suggested that statins may be protective against the development of colitisassociated colorectal cancer.
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Inflamm Bowel Dis Volume 22, Number 3, March 2016
Experimental Models A few basic science studies have tried to elucidate the role of statins in colitis-associated colorectal cancer. Suzuki et al59 studied statins in the azoxymethane (AOM)/DSS murine model of colitisassociated colorectal cancer. In addition to reducing histological inflammation, statins significantly decreased rates of high-grade dysplasia. Another study using the AOM/DSS model found that statins reduced the number of colonic tumors, decreased proliferation rate (by immunochemistry for proliferating cell nuclear antigen), and increased apoptotic indices in colonic epithelium at week 20.60 However, there was no significant reduction in the incidence rate of colonic dysplasia or tumors. Statins have also been shown to induce apoptosis and inhibit angiogenesis in a tumor xenograft model.61 This same study also demonstrated that statins induce NFkB dependent-apoptotic pathways in vitro using the human colon cancer cell lines COLO 205 and HCT 116.61
Clinical Studies Two clinical studies evaluated the possible protective effect of statins against colitis-associated colorectal cancer (Table 2). A landmark case–control study found that statins may protect against colorectal cancer in the general population (OR 0.50, 95% CI, 0.40–0.63).62 In a subgroup analysis of patients with IBD, statins had an even stronger protective effect (OR 0.06, 95% CI, 0.006–0.550). However, the number of patients with IBD was limited in this study (55 patients). In contrast, a population-based cohort study from Canada looked at the relationship between statins and colorectal cancer in the general population.63 They did not find a protective effect in regular statin users (incidence rate ratio 0.89, 95% CI, 0.70–1.13). Although 2762 patients with IBD were included in this cohort, subgroup analysis focusing on patients with IBD was not reported. The second study looking at colitis-associated colorectal cancer found that long-term statin use was associated with a reduced risk of colorectal cancer (OR 0.07, 95% CI, 0.01–0.78). When adjusted for possible confounders such as age, sex, ethnicity, sports participation, level of vegetable consumption, and family history of colorectal cancer, statins still trended toward a protective; however, the finding no longer reached statistical significance (OR 0.10, 95% CI, 0.01–1.31).64
CONCLUSIONS The treatment of IBD is evolving with new therapeutic agents being developed. The possibility of using statins as a treatment in IBD is intriguing. We attempted to cautiously search the literature on this topic, but this article remains in essence a narrative review, and as such some relevant studies may have been omitted and important sources of bias overlooked. However, our search showed that the immunomodulatory effect of statins on experimental models, its excellent safety profile combined with its oral administration route make statins an attractive potential IBD therapy. Clinical studies showed that statins may improve disease activity scores, reduce the need for steroids, and offer protection against new onset IBD.
Immunomodulatory Effects of Statins in IBD
Furthermore, some evidence suggests that statins could be chemopreventive agents against colitis-associated colorectal cancer. The promising research outlined in this article highlights the need for further investigation on a possible role for statins in IBD. Well-controlled clinical studies are needed to evaluate statins as monotherapy for mild disease or as add-on medications with other therapies such biologics.
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