Human intestinal organoids from Cronkhite-Canada syndrome patients reveal link between serotonin and proliferation.

Cronkhite-Canada Syndrome (CCS) is a rare, noninherited polyposis syndrome affecting 1 in every million individuals. Despite over 50 years of CCS cases, the etiopathogenesis and optimal treatment for CCS remains unknown due to the rarity of the disease and lack of model systems. To better understand the etiology of CCS, we generated human intestinal organoids (HIOs) from intestinal stem cells isolated from 2 patients. We discovered that CCS HIOs are highly proliferative and have increased numbers of enteroendocrine cells producing serotonin (also known as 5-hydroxytryptamine or 5HT). These features were also confirmed in patient tissue biopsies. Recombinant 5HT increased proliferation of non-CCS donor HIOs and inhibition of 5HT production in the CCS HIOs resulted in decreased proliferation, suggesting a link between local epithelial 5HT production and control of epithelial stem cell proliferation. This link was confirmed in genetically engineered HIOs with an increased number of enteroendocrine cells. This work provides a new mechanism to explain the pathogenesis of CCS and illustrates the important contribution of HIO cultures to understanding disease etiology and in the identification of novel therapies. Our work demonstrates the principle of using organoids for personalized medicine and sheds light on how intestinal hormones can play a role in intestinal epithelial proliferation.

Acss2/HIF-2 signaling facilitates colon cancer growth and metastasis.

The microenvironment of solid tumors is characterized by oxygen and glucose deprivation. Acss2/HIF-2 signaling coordinates essential genetic regulators including acetate-dependent acetyl CoA synthetase 2 (Acss2), Creb binding protein (Cbp), Sirtuin 1 (Sirt1), and Hypoxia Inducible Factor 2α (HIF-2α). We previously shown in mice that exogenous acetate augments growth and metastasis of flank tumors derived from fibrosarcoma-derived HT1080 cells in an Acss2/HIF-2 dependent manner. Colonic epithelial cells are exposed to the highest acetate levels in the body. We reasoned that colon cancer cells, like fibrosarcoma cells, may respond to acetate in a pro-growth manner. In this study, we examine the role of Acss2/HIF-2 signaling in colon cancer. We find that Acss2/HIF-2 signaling is activated by oxygen or glucose deprivation in two human colon cancer-derived cell lines, HCT116 and HT29, and is crucial for colony formation, migration, and invasion in cell culture studies. Flank tumors derived from HCT116 and HT29 cells exhibit augmented growth in mice when supplemented with exogenous acetate in an Acss2/HIF-2 dependent manner. Finally, Acss2 in human colon cancer samples is most frequently localized in the nucleus, consistent with it having a signaling role. Targeted inhibition of Acss2/HIF-2 signaling may have synergistic effects for some colon cancer patients.

Clip closure to prevent adverse events after EMR of proximal large nonpedunculated colorectal polyps: meta-analysis of individual patient data from randomized controlled trials.

BACKGROUND AND AIMS: After EMR, prophylactic clipping is often performed to prevent clinically significant post-EMR bleeding (CSPEB) and other adverse events (AEs). Prior evidence syntheses have lacked sufficient power to assess clipping in relevant subgroups or in nonbleeding AEs. We performed a meta-analysis of individual patient data (IPD) from randomized trials assessing the efficacy of clipping to prevent AEs after EMR of proximal large nonpedunculated colorectal polyps (LNPCPs) ≥20 mm. METHODS: We searched EMBASE, MEDLINE, Cochrane Central Registry of Controlled Trials, and PubMed from inception to May 19, 2021. Two reviewers screened citations in duplicate. Corresponding authors of eligible studies were invited to contribute IPD. A random-effects 1-stage model was specified for estimating pooled effects, adjusting for patient sex and age and for lesion location and size, whereas a fixed-effects model was used for traditional meta-analyses. RESULTS: From 3145 citations, 4 trials were included, representing 1248 patients with proximal LNPCPs. The overall rate of CSPEB was 3.5% and 9.0% in clipped and unclipped patients, respectively. IPD were available for 1150 patients, in which prophylactic clipping prevented CSPEB with an odds ratio (OR) of .31 (95% confidence interval [CI], .17-.54). Clipping was not associated with perforation or abdominal pain, with ORs of .78 (95% CI, .17-3.54) and .67 (95% CI, .20-2.22), respectively. CONCLUSIONS: Prophylactic clipping is efficacious in preventing CSPEB after EMR of proximal LNPCPs. Therefore, clip closure should be considered a standard component of EMR of LNPCPs in the proximal colon.

Optimizing Nutrition to Enhance the Treatment of Patients With Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) consists of chronic, relapsing-remitting autoimmune diseases of the gastrointestinal (GI) tract with an increasing global disease burden. Pathogenetic mechanisms are not well understood, but current hypotheses involve the role of environmental factors, including dietary antigens, in immune dysregulation and proinflammatory shifts in microbial composition (gut dysbiosis) in genetically susceptible individuals. Increased metabolic demand and malabsorption secondary to systemic inflammation, coupled with significant GI symptoms that lead to reduced oral food intake, may leave patients with IBD vulnerable to developing malnutrition. The use of diet as therapy for potential induction or maintenance of remission in IBD has risen to prominence in the past several decades, especially as patients explore diet as a means to improve their symptoms and overall quality of life. However, these nutritional therapies remain underutilized by many gastroenterologists, and randomized controlled trials (RCTs) for most popular diets are lacking. Moreover, formal and consistent assessments of the nutritional status of patients with IBD in the inpatient and outpatient settings are often overlooked. To address these gaps, this article aims to discuss the progress of diet therapy and considerations for optimizing nutrition in patients with IBD, as well as summarize current RCTs evaluating efficacy for the most popular diets in IBD therapy.

Diet in the Pathogenesis and Management of Crohn's Disease.

Crohn's disease (CD) is chronic immune-related disease of the gastrointestinal tract hypothesized to be caused by an interplay of genetic predisposition and environmental exposures. With the global incidence increasing, more patients are exploring dietary exposures to explain and treat CD. However, most patients report minimal nutritional education from their provider, and providers report few nutritional resources to help them educate patients. This highlights the previous deficit of literature describing the role and influence of diet in CD. To address this need, this article reviews available literature on the possible roles of diet in the pathogenesis, exacerbation, and treatment of CD.

Timing of Resumption of Anticoagulation After Polypectomy and Frequency of Post-procedural Complications: A Post-hoc Analysis.

BACKGROUND: Optimal timing for anticoagulation resumption after polypectomy is unclear. We explored the association between timing of anticoagulation resumption and occurrence of delayed post-polypectomy bleeding (PPB) and thromboembolic (TE) events. METHODS: We performed a post-hoc analysis of patients in an earlier study whose anticoagulants were interrupted for polypectomy. We compared rates of clinically important delayed PPB and TE events in relationship to timing of anticoagulant resumption. Late resumption was defined as > 2 days after polypectomy. RESULTS: Among 437 patients, 351 had early and 86 late resumption. Compared to early resumers, late resumers had greater polypectomy complexity. PPB rate was higher (but not significantly) in the late versus early resumers (2.3% vs. 0.9%, 1.47% greater, 95% CI [- 2.58 to 5.52], p = 0.26). TE events were more frequent in late versus early resumers [0% vs. 1.2% at 30 days, 0% vs. 2.3%, 95% CI 0.3-8, (p = 0.04) at 90 days]. On multivariate analysis, timing of restarting anticoagulation was not a significant predictor of PPB (OR 0.97, 95% CI 0.61-1.44, p = 0.897). Significant predictors were number of polyps ≥ 1 cm (OR 4.14, 95% CI 1.27-13.66, p = 0.014) and use of fulguration (OR 11.43, 95% CI 1.35-80.80, p = 0.014). CONCLUSIONS: Physicians delayed anticoagulation resumption more commonly after complex polypectomies. The timing of restarting anticoagulation was not a significant risk factor for PPB and late resumers had significantly higher rates of TE events within 90 days. Considering the potentially catastrophic consequences of TE events and the generally benign outcome of PPBs, clinicians should be cautious about delaying resumption of anticoagulation after polypectomy.

Visceral Adipose Tissue Volumetrics Inform Odds of Treatment Response and Risk of Subsequent Surgery in IBD Patients Starting Antitumor Necrosis Factor Therapy.

BACKGROUND: Data describing the effect of obesity on antitumor necrosis factor (anti-TNF) treatment response are inconsistent. Visceral adipose tissue (VAT) is a superior marker of adiposity to body mass index. However, its effect on treatment response is unclear. We aimed to evaluate the effect of VAT on anti-TNF treatment response. METHODS: Inflammatory bowel disease (IBD) patients starting anti-TNF agents between January 1, 2009, and July 31, 2019, were included. 3-dimensional measurements of VAT volume and visceral fat index (visceral:subcutaneous adipose tissue ratio; VFI) were obtained from computed tomography (CT) scans. Subjects were categorized by predefined volume cutoffs (<1500cm3, 1500-2999cm3, ≥3000cm3) and VFI (<0.33, 0.33-0.66, ≥0.67). Primary outcomes included a composite treatment response end point at 6 and 12 months. Secondary outcomes were surgery at 6 and 12 months. Multivariable logistic regression was used to calculate adjusted odds ratio (aOR) and 95% confidence interval (CI). RESULTS: The final cohort included 176 patients. No significant differences in treatment response at 6 months was observed. At 12 months, compared with volume <1500cm3, patients with volume 1500-2999cm3 had higher odds of response (aOR, 3.52; 95% CI, 1.16-10.71; P = .023), whereas volume ≥3000cm3 did not. Compared with VFI<0.33, VFI ≥0.67 had higher odds of surgery at 6 (aOR, 48.22; 95% CI, 4.73-491.57; P = .023) and 12 months (aOR, 20.94; 95% CI, 3.14-139.67; P = .004). Post hoc analysis suggested VAT may affect drug pharmacokinetics. CONCLUSIONS: We found VAT volume is associated with anti-TNF treatment response in a nondose dependent manner, and VFI may inform risk of surgery after anti-TNF initiation. If confirmed by prospective studies, VAT volumetrics are potentially useful biomarkers to inform IBD treatment decisions.

Visceral adipose tissue volume is associated with anti-TNF treatment response in a nondose response manner. Additionally, high visceral fat index is associated with significantly increased risk of early surgery after anti-TNF initiation.

Targeting Mitochondrial Damage as a Therapeutic for Ileal Crohn's Disease.

Paneth cell defects in Crohn's disease (CD) patients (called the Type I phenotype) are associated with worse clinical outcomes. Recent studies have implicated mitochondrial dysfunction in Paneth cells as a mediator of ileitis in mice. We hypothesized that CD Paneth cells exhibit impaired mitochondrial health and that mitochondrial-targeted therapeutics may provide a novel strategy for ileal CD. Terminal ileal mucosal biopsies from adult CD and non-IBD patients were characterized for Paneth cell phenotyping and mitochondrial damage. To demonstrate the response of mitochondrial-targeted therapeutics in CD, biopsies were treated with vehicle or Mito-Tempo, a mitochondrial-targeted antioxidant, and RNA transcriptome was analyzed. During active CD inflammation, the epithelium exhibited mitochondrial damage evident in Paneth cells, goblet cells, and enterocytes. Independent of inflammation, Paneth cells in Type I CD patients exhibited mitochondrial damage. Mito-Tempo normalized the expression of interleukin (IL)-17/IL-23, lipid metabolism, and apoptotic gene signatures in CD patients to non-IBD levels. When stratified by Paneth cell phenotype, the global tissue response to Mito-Tempo in Type I patients was associated with innate immune, lipid metabolism, and G protein-coupled receptor (GPCR) gene signatures. Targeting impaired mitochondria as an underlying contributor to inflammation provides a novel treatment approach for CD.

Safety of tumor necrosis factor inhibitor use in patients with concomitant malignancy.

BACKGROUND/AIMS: Safety for tumor necrosis factor inhibitors (TNFi) in cancer has been focused on risk of incident malignancies, but studies on prognostic effects have been scarce. We determined survival and recurrence rates at 1, 2, and 5 years after cancer diagnosis in patients with and without concurrent TNFi use. METHODS: Chart reviews were performed between 1996 and 2015 at the VA North Texas Healthcare System. Cases were patients with inflammatory disease, concomitant malignancy, and TNFi use while controls were patients with inflammatory disease, concomitant malignancy but no TNFi use. Cases and controls were matched for type of malignancy. Analysis was performed with log-rank tests on Kaplan-Meier curves. RESULTS: Thirty-six cases and 72 controls were identified. For cases, survival at 1, 2, and 5 years were 32 (89%), 31 (86%), and 29 (81%) compared to 63 (90%), 61 (87%), and 51 (73%) for the control group (P=0.985). For cases, recurrence rates at 1, 2, and 5 years were 3 (8%), 5 (14%), and 6 (17%) compared to 2 (3%), 5 (7%), and 7 (10%) for the control group (P=0.158). CONCLUSIONS: Our findings suggest TNFi may be safely used in select inflammatory disease patients with concurrent cancer if therapy is needed for proper disease control. However, case-by-case consideration in conjunction with an oncologist is recommended while considering the apparent safety of TNFi for patients suffering from active inflammatory diseases despite having a concomitant malignancy.

Mitochondrial dysfunction during loss of prohibitin 1 triggers Paneth cell defects and ileitis.

OBJECTIVE: Although perturbations in mitochondrial function and structure have been described in the intestinal epithelium of Crohn's disease and ulcerative colitis patients, the role of epithelial mitochondrial stress in the pathophysiology of inflammatory bowel diseases (IBD) is not well elucidated. Prohibitin 1 (PHB1), a major component protein of the inner mitochondrial membrane crucial for optimal respiratory chain assembly and function, is decreased during IBD. DESIGN: Male and female mice with inducible intestinal epithelial cell deletion of Phb1 (Phb1iΔIEC ) or Paneth cell-specific deletion of Phb1 (Phb1ΔPC ) and Phb1fl/fl control mice were housed up to 20 weeks to characterise the impact of PHB1 deletion on intestinal homeostasis. To suppress mitochondrial reactive oxygen species, a mitochondrial-targeted antioxidant, Mito-Tempo, was administered. To examine epithelial cell-intrinsic responses, intestinal enteroids were generated from crypts of Phb1iΔIEC or Phb1ΔPC mice. RESULTS: Phb1iΔIEC mice exhibited spontaneous ileal inflammation that was preceded by mitochondrial dysfunction in all IECs and early abnormalities in Paneth cells. Mito-Tempo ameliorated mitochondrial dysfunction, Paneth cell abnormalities and ileitis in Phb1iΔIEC ileum. Deletion of Phb1 specifically in Paneth cells (Phb1ΔPC ) was sufficient to cause ileitis. Intestinal enteroids generated from crypts of Phb1iΔIEC or Phb1ΔPC mice exhibited decreased viability and Paneth cell defects that were improved by Mito-Tempo. CONCLUSION: Our results identify Paneth cells as highly susceptible to mitochondrial dysfunction and central to the pathogenesis of ileitis, with translational implications for the subset of Crohn's disease patients exhibiting Paneth cell defects.

Valuing innovative endoscopic techniques: prophylactic clip closure after endoscopic resection of large colon polyps.

BACKGROUND AND AIMS: Clip closure of the mucosal defect after resecting large (≥20 mm) nonpedunculated colorectal polyps reduces postprocedure bleeding and is cost saving for payers. Clip costs are not reimbursed by payers, posing a major barrier to adoption of this technique in the community. We aimed to determine appropriate clip costs to support broader use of this procedure in practice. METHODS: We performed budget impact analysis using our recent decision analytic model, comparing prophylactic clip closure with no clip closure on national cost and outcomes data, to determine the maximum feasible clip price while maintaining cost savings in practice. Sensitivity analyses were performed on important clinical factors. RESULTS: In the original model, the baseline postprocedure bleeding risk was 6.8%, increasing cost of care by $614.11 averaged among all patients undergoing large polyp resection without clip closure. Prophylactic clip closure of only large right-sided polyps reduced postprocedure bleeding risk by 70.7% but resulted in cost saving only if the price of clips was $100 or less. Comparatively, prophylactic clip closure of large left-sided polyps had no clinical benefit and was not cost saving. Clip closure strategies focused only on extra-large polyps (≥40 mm), or patients taking antithrombotics regardless of polyp characteristics, were only minimally cost saving. Cost savings and maximum tolerated clip prices depended on medical comorbidity, which directly influences the costs of care to manage postprocedure bleeding. CONCLUSIONS: Prophylactic clip closure after endoscopic resection of large colon polyps, particularly those in the right colon segment, is cost saving but requires clip costs less than $100. Translating these findings into practice requires gastroenterology practices to obtain reimbursement from payers for improved clinical outcomes and to align commercial clip prices with this clinical indication.

Rates of Adverse IBD-Related Outcomes for Patients With IBD and Concomitant Prostate Cancer Treated With Radiation Therapy.

BACKGROUND: Patients with inflammatory bowel disease (IBD) may be at higher risk for complications from radiation treatment for prostate cancer. However, available data are limited, and controversy remains regarding the best treatment approach for IBD patients who develop prostate cancer. METHODS: A retrospective cohort study across 4 Department of Veterans Affairs hospital systems. Patients with established IBD who were diagnosed and treated for prostate cancer between 1996-2015 were included. We assessed for flares of IBD, IBD-related hospitalizations, and IBD-related surgeries within 6, 12, and 24 months of cancer diagnosis and survival at 1, 2, and 5 years. Flares of IBD were those documented as such by the treating physician, and treatment changed accordingly. RESULTS: One hundred patients with IBD and prostate cancer were identified. Forty-seven were treated with either treatment with external beam radiation or brachytherapy, and 53 were treated with nonradiation modalities. Comparing cohorts with or without radiation treatment, there were no differences in baseline IBD characteristics, Charlson comorbidity index, or prostate cancer stage. Inflammatory bowel disease flares were 2-fold higher for radiation-treated patients within 6 months (10.6% vs 5.7%) and 6-12 months (4.3% vs 1.9%) after cancer diagnosis. On multiple logistic regression analysis, radiation treatment (adjusted odds ratio, 4.82; 95% confidence interval, 1.15-20.26) was a significant predictor of flares. However, rates of IBD-related hospitalizations or surgeries were not significantly different. CONCLUSIONS: In this retrospective, multicenter study, 2-fold higher rates of flare were found within the first year after prostate cancer diagnosis for patients treated with radiation, but there were no differences in IBD-related hospitalizations or surgeries. Although patients should be counseled of these risks, avoidance of radiation therapy in IBD patients with prostate cancer is likely not necessary.

Dining With Inflammatory Bowel Disease: A Review of the Literature on Diet in the Pathogenesis and Management of IBD.

Inflammatory bowel diseases (IBDs) are chronic immune-related diseases hypothesized to be a sequela of an interplay of genetic predisposition and environmental exposures. The global incidence of IBD is increasing, and more patients are exploring diet as a means to explain and treat their IBD. In fact, many patients strongly believe diet plays a fundamental role in the onset and management of their IBD. However, a significant proportion of patients report limited nutritional education from their provider, and providers report limited nutritional resources to aid in discussions with patients. This imbalance between supply and demand likely reflects the previous paucity of available literature characterizing the influence of diet in IBD. To address this gap in knowledge, we review the available literature to characterize the role of diet in the pathogenesis, exacerbation, and treatment of IBD. We aim to provide patients and providers with resources to better understand and discuss the role of diet in IBD, with the overall goal of improving patient care and satisfaction.

Managing Patients with Inflammatory Bowel Disease Who Develop Prostate Cancer.

Prostate cancer is the most common cancer among men in the USA. Interestingly, recent studies suggest that patients with inflammatory bowel disease (IBD) are at increased risk of developing prostate cancer. Importantly, patients with IBD who develop prostate cancer require thoughtful care when using immunosuppressants to treat the IBD in the setting of malignancy. Further, consideration must be given to the proximity of the prostate to the gastrointestinal tract when treating with radiation where there is concern for the effects of inadvertent exposure of radiation to the diseased bowel. In general, management of immunosuppression after diagnosis of prostate cancer is contingent on the specific immunosuppressive agents, the duration of cancer remission and/or plans for cancer treatment, and the potential risks and benefits of stopping or altering the administration of those agents. Concerns that patients with IBD would have increased risk of disease exacerbation and gastrointestinal toxicity have previously limited the use of radiation. While currently no consensus has been reached regarding the safety of radiation therapy in patients with IBD, recent studies suggest that radiation therapy may be used safely in patients with IBD who develop prostate cancer, especially brachytherapy and intensity-modulated radiation therapy which may have less bowel toxicity compared to conventional methods of external beam radiation therapy. A multidisciplinary team approach including gastroenterologists, urologists, radiation oncologists, and medical oncologists should be undertaken to best treat patients with IBD and prostate cancer.

The Incidence and Prevalence of Anxiety, Depression, and Post-traumatic Stress Disorder in a National Cohort of US Veterans With Inflammatory Bowel Disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are more susceptible to mental health problems than the general population; however, temporal trends in psychiatric diagnoses' incidence or prevalence in the United States are lacking. We sought to identify these trends among patients with IBD using national Veterans Heath Administration data. METHODS: We ascertained the presence of anxiety, depression, or posttraumatic stress disorder among veterans with IBD (ulcerative colitis or Crohn's disease) during fiscal years 2000-2015. Patients with prior anxiety, depression, or posttraumatic stress disorder before their first Veterans Health Administration IBD encounter were excluded to form the study cohort. We calculated annual prevalence, incidence rates, and age standardized and stratified by gender using a direct standardization method. RESULTS: We identified 60,086 IBD patients (93.9% male). The prevalence of anxiety, depression, and/or posttraumatic stress disorder increased from 10.8 per 100 with IBD in 2001 to 38 per 100 with IBD in 2015; 19,595 (32.6%) patients had a new anxiety, depression, and/or posttraumatic stress disorder diagnosis during the study period. The annual incidence rates of these mental health problems went from 6.1 per 100 with IBD in 2001 to 3.6 per 100 in 2015. This trend was largely driven by decline in depression. CONCLUSIONS: The prevalence of anxiety, depression, and posttraumatic stress disorder is high among US veterans with IBD and increasing, given the chronicity of IBD and psychological diagnoses. Incidence, particularly depression, appears to be declining. Confirmation and reasons for this encouraging trend are needed.

High Prevalence of Male Sexual Dysfunction in a Prospective Multicenter VA Inflammatory Bowel Disease Population.

Background: Aims of this study were to assess the prevalence of and risk factors for sexual dysfunction (SD) in male veterans with inflammatory bowel disease (IBD). Methods: We collected IBD history, quality of life (QOL), and sexual function surveys. Results: One hundred seventy-one men enrolled, mean age 50 years, 85% had SD, 92% had erectile dysfunction (ED). More severe ED (P = 0.0001), decreased sexual desire (P = 0.004), and decreased satisfaction (P = 0.001) were associated with poorer QOL. Biologic use was associated with increased SD; hypertension with a decrease in sexual desire. Conclusions: SD and ED are highly prevalent and associated with poorer QOL.

The Association of Medications and Vaccination with Risk of Pneumonia in Inflammatory Bowel Disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at increased risk for pneumonia, and corticosteroids are reported to amplify this risk. Less is known about the impact of corticosteroid-sparing IBD therapies on pneumonia risk or the efficacy of pneumococcal vaccination in reducing all-cause pneumonia in real-world IBD cohorts. METHODS: We performed a population-based study using an established Veterans Health Administration cohort of 29,957 IBD patients. We identified all patients who developed bacterial pneumonia. Cox survival analysis was used to determine the association of corticosteroids at study entry and as a time-varying covariate, corticosteroid-sparing agents (immunomodulators and antitumor necrosis-alpha [TNF] inhibitors), and pneumococcal vaccination with the development of all-cause pneumonia. RESULTS: Patients with IBD who received corticosteroids had a greater risk of pneumonia when controlling for age, gender, and comorbidities (hazard ratio [HR] 2.21; 95% confidence interval [CI], 1.90-2.57 for prior use; HR = 3.42; 95% CI, 2.92-4.01 for use during follow-up). Anti-TNF inhibitors (HR 1.52; 95% CI, 1.02-2.26), but not immunomodulators (HR 0.91; 95% CI, 0.77-1.07), were associated with a small increase in pneumonia. A history of pneumonia was strongly associated with subsequent pneumonia (HR = 4.41; 95% CI, 3.70-5.27). Less than 15% of patients were vaccinated against pneumococcus, and this was not associated with a reduced risk of pneumonia (HR = 1.02; 95% CI, 0.80-1.30) in this cohort. CONCLUSION: In a large US cohort, corticosteroids were confirmed to increase pneumonia risk. Tumor necrosis-alpha inhibitors were associated with a smaller increase in the risk of pneumonia. Surprisingly, pneumococcal vaccination did not reduce all-cause pneumonia in this population, though few patients were vaccinated.