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    AT-1001 Shows Promise for those with Celiac Disease, But Likely not a Silver Bullet


    Jefferson Adams

    Celiac.com 05/27/2008 - People with celiac disease know all too well that the only effective treatment at present is faithfully following a gluten-free diet. There’s been a lot of talk about various therapies and enzyme treatments that would allow people with celiac disease to return to a normal diet. Talk to anyone who suffers from celiac disease and they’ll likely have a personal horror story about a time when they had an unhappy episode of cross-contamination.


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    So, the idea of a drug that would prevent such symptoms is appealing, and the goal, desirable. The chief cause of recurring symptoms in celiac disease is accidental gluten exposure, usually through cross-contamination. Cross-contamination doesn’t always mean food. Gluten is a common ingredient in many medicines and vitamins, and exposure in celiacs can cause diarrhea, weight loss, abdominal pain, anemia and oral ulcerations in the short-term, and myriad other problems in the long-run.

    The drug AT-1001 is a good example of how the realities are playing out on the front-lines of science. AT-1001 is an enzyme therapy that has promised some degree of protection from gluten exposure in people with celiac disease.

    A team of researches recently set out to assess the effectiveness of AT-1001 in preventing gluten from crossing the gut barrier by reversing the defective barrier mechanism. This required evaluating intestinal permeability between those exposed to gluten after taking AT-1001, those exposed without AT-1001, and control groups. The of intestinal function is done by gauging the absorption rates of various sugars.

    Early testing of AT-1001 showed some progress and a significant rate of protection of celiac patients exposed to wheat proteins. The research team looked at 86 subjects with celiac disease. The patients were divided into three groups. The first group was given placebo AT-1011 and challenged with gluten, the second group was given either active or placebo AT-1001, while the third group was given gluten and active AT-1001.

    After the first week, all subjects showed improvement, possibly due to closer adherence to a gluten-free diet. At three weeks, those given AT-1001 showed substantial improvement over the group given gluten and placebo AT-1001, including reduced intestinal permeability and fewer symptoms of gluten toxicity.

    The problem is that while AT-1001 shows a degree of promise, the results are so far underwhelming. The research team noted that the degree of improvement did not match the primary study. The results are, however, strong enough to encourage researchers to conduct a larger trial of AT-1001, which is currently underway.

    It’s important to remember that celiac disease is an immune disorder and no immune disorder has ever been fully cured. So, the idea of people with celiac disease being able to take a pill and head out for a night of pizza and beer without the standard celiac-related reactions is far-fetched at best. At best, such drugs would likely help to prevent cross-contamination, rather than conveying immunity to gluten proteins.

    Until then, stay tuned…best of luck with the gluten-free diet!

    Presented by Dr. Leffler at the 2009 Digestive Disease Week on Tuesday, May 20 at 10:45 a.m. Pacific Time in room 10, San Diego Convention Center.

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    Guest Aunt Babe

    Posted

    Well, if my celiac aunt can go out and have grilled chicken, a salad with Gluten Free dressing, and a baked potato without getting sick by taking this drug then it's a winner in my book!!

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    Guest Bonnie M

    Posted

    I have been recently diagnosed with celiac disease. I don't have trouble as long as I'm eating what I fix, it's getting it by accident somewhere that scares me. I hope they perfect this soon!

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    Guest lildrmr2

    Posted

    I have had the celiac diagnosis for over 1 year now. If we go out I get sick. I'm only safe if we stay home. I look forward to this medication. Then I could pretend to eat normal.

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  • Related Articles

    Scott Adams
    Journal of Clinical Gastroenterology 2003; 36(3):219-221
    Celiac.com 03/28/2003 - A study by Antonio Tursi, M.D, et al, was recently conducted to evaluate the correlation between the degree of histologic intestinal damage in celiac patients and their level of positivity (serum value) to anti-tissue transglutaminase antibodies (anti-tTG). The study looked at 119 adult celiac patients who were diagnosed consecutively (47 men and 72 women; mean age, 28 years; range, 22-51 years), and were stratified for histologic damage according to Marsh classification. The final step was to compare their Marsh histologic intestinal damage classification with their anti-tTG serum values. Here are their results:


    Marsh I lesions were present in 13 patients (10.92%), Marsh II in 24 anti-tTG (20.16%), Marsh IIIa in 27 anti-tTG (22.68%), Marsh IIIb in 31 anti-tTG (26.05%) and Marsh IIIc in 24 anti-tTG (20.16%). Anti-tTG positivity was ranging from 1 of 13 anti-tTG (7.69%) in Marsh I lesions to 23 of 24 anti-tTG (95.83%) in Marsh IIIc lesions respectively (P
    The researchers conclude that the mean serum value in celiacs with severe enteropathy (Marsh IIIb-c lesions) was higher than in those with only slight enteropathy (Marsh I-IIIa). Further, serologic test results in the absence of histologic evaluation (biopsy) may "underestimate the real prevalence of celiac disease," thus delaying a proper diagnosis and putting patients at risk for a large variety of serious health problems.

    Scott Adams
    Celiac.com 02/09/2006 - Do not try this at home. If you have celiac disease you need to remain on a gluten-free diet. This particular study, as indicated below, involved only one person--which is far too small of a sample to draw any solid conclusions from. It does, however, offer some hope that there may be other unknown factors that cause this disease--perhaps factors that can be reversed or kept in check. Many more studies will be needed to determine this. After reading and publishing much of Roy Jamrons work, we thought his comments on this study were very interesting and have reproduced them here.
    Comments by Roy Jamron:
    This is interesting, a case of reintroducing gluten to a celiac woman after a 10 year gluten-free diet with no symptoms of celiac disease showing up during a 15 month follow up study. It would be interesting if she remains symptom free in subsequent years.
    It does bring up the idea of a gluten-ingesting bacteria link which I proposed in my article, Are Commensal Bacteria with a Taste for Gluten the Missing Link in the Pathogenesis of Celiac Disease?. In that article I proposed that a bacteria capable of transporting and internalizing gluten peptides resistant to breakdown could initiate a T cell immune response to gluten. Antigen presenting cells (dendritic cells) might present gluten peptides internalized by the bacteria along with peptides and chemical signals from the bacteria to T cells. The T cells would not be able to distinguish the gluten peptides from the bacteria peptides and would, therefore, initiate an immune response to gluten peptides as though they were components from pathogenic bacteria. The presence or non-presence of such a bacteria in twins offered an explanation as to why one identical twin could develop celiac disease and not the other.
    After 10 years on a gluten-free diet, it is possible that the numbers of such gluten-ingesting bacteria might diminish to a level too few to initiate a gluten immune response, especially if the bacteria largely depend on gluten for nutrition. So, like the twin who does not develop celiac disease, she remains symptom free.
    I urged researchers to look for such gluten-ingesting bacteria in my article, and I continue to urge such research. Such bacteria could be found through the use of immunogold electron microscopy. This technique permits gluten peptides to be bound to and labeled with gold particles which show up as distinct opaque spots under the electron microscope. Such spots found within microscopic cross sections of fecal bacteria samples would identify gluten-ingesting bacteria.
    Abstract of Study:


    An Attempt of Specific Desensitizing Treatment with Gliadin in Celiac Disease
    Int J Immunopathol Pharmacol. 2005 Oct-Dec;18(4):709-14.
    Gluten-free diet is the current treatment of celiac disease. We decided to verify the occurrence of histological and serological modification and/or clinical manifestations during a gradual and progressive introduction of gliadin in the diet and if it may induce a tolerance to food, as it occurs in allergic patients. We studied the case of a celiac woman with complete clinical and histological remittance after 10 years of gluten free diet. She took increasing daily doses of gliadin, reaching the final dose of 9 g of gliadin (15 g of gluten) in 6 months. Then she started a free dietary regimen. During the 15-month follow-up period esophago-gastro-duodenoscopy showed normal Kerckring folds and villi. Anti-gliadin, anti-endomysium and anti-tissue-transglutaminase antibodies, as well as the haematological and biochemical parameters remained normal. Our results represent a new approach in research concerning celiac disease, and could provide a future line of study for its management.

    Jefferson Adams
    Celiac.com 11/29/2007 - Studies have documented the role of gut microbiotic bacteria in diseases involving chronic inflammation, such as celiac disease, yet there is scant data on such bacteria that is specific to people with celiac disease. A team of Spanish and Italian researchers from three different hospitals and universities made up of Yolanda Sanz, Ester Sanchez, Marta Marzotto, Miguel Calabuig, Sandra Torriani, and Franco Dellaglio set out to determine what differences might exist between the microbiotic bacteria in the guts of children with celiac disease compared to a healthy control group of their peers.
    The team conducted a denaturing gradient gel electrophoresis analysis of fecal samples from both the celiac and the control groups. They found that children with celiac disease had a more diverse profile of intestinal microbiotic bacteria than did the healthy control subjects.
    The children with celiac disease were characterized by the presence of Lactobacillus curvatus, Leuconostoc mesenteriodes, and Leuconostoc carnosum, whereas the members of the healthy control group were characterized by the presence of Lactobacillus casei. Conversely, the bifidobacterium population was much greater in the members of the healthy control group than among the children with celiac disease.
    The healthy control group showed particularly high populations of bifidobacterium adolescentis compared to the celiac patients. The team has called for more research into which populations of the various gut microbial are affected by celiac disease. This may lead to a possible role for probiotics and/or prebiotics in returning the balance of the gut microbes in those with celiac disease.
    FEMS Immunol Med Microbiol. 2007 Dec;51(3):562-8


    Jefferson Adams
    Celiac.com 09/17/2009 - Just after the turn of this century, researchers at the University of Maryland School of Medicine discovered that a mysterious human protein called zonulin played a key role in celiac disease and other autoimmune disorders, such as multiple sclerosis and diabetes.
    The situation might be likened to sailors who've an island, but not explored it. Researchers knew Zonulin existed, and some of its influences, but little else about it. Recently, a team of scientists led by Alessio Fasano, M.D., set out to isolate and decode zonulin. Their results are in, and Fasano's research team has successfully identified zonulin as a molecule called haptoglobin 2 precursor.
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    Dr. Fasano is a professor of pediatrics, medicine and physiology and director of the Mucosal Biology Research Center and the Center for Celiac Research at the University of Maryland School of Medicine.
    Haptoglobin is a molecule that has been known to scientists for many years. It was identified as a marker of inflammation in the body. Haptoglobin 1 is the original form of the haptoglobin molecule, and scientists believe it evolved 800 million years ago. Haptoglobin 2 is a version found only in humans. Scientists believe the mutation occurred in India about 2 million years ago, spreading gradually among increasing numbers of people throughout the world.
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    But Dr. Fasano's study reveals precursor haptoglobin 2 as the first precursor molecule to serve another function altogether; that of opening a gateway in the gut, permitting gluten to pass through. People with celiac disease suffer from a sensitivity to gluten.
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    According to Dr. Fasano, the haptoglobin 2 molecule "could be a critical missing piece of the puzzle to lead to a treatment for celiac disease, other autoimmune disorders and allergies and even cancer, all of which are related to an exaggerated production of zonulin/pre-haptoglobin 2 and to the loss of the protective barrier of cells lining the gut and other areas of the body, like the blood brain barrier."
    "The only current treatment for celiac disease is cutting gluten from the diet, but we have confidence Dr. Fasano's work will someday bring further relief to these patients. Zonulin, with its functions in health and disease as outlined in Dr. Fasano's paper, could be the molecule of the century," says E. Albert Reece, M.D., Ph.D., M.B.A., dean of the School of Medicine, vice president for medical affairs of the University of Maryland and John Z. and Akiko K. Bowers Distinguished Professor.
    Dr. Fasano published his findings in the online version of the Proceedings of the National Academy of Sciences, appearing the week of September 7, 2009.


  • Recent Articles

    Jefferson Adams
    Celiac.com 06/18/2018 - Celiac disease has been mainly associated with Caucasian populations in Northern Europe, and their descendants in other countries, but new scientific evidence is beginning to challenge that view. Still, the exact global prevalence of celiac disease remains unknown.  To get better data on that issue, a team of researchers recently conducted a comprehensive review and meta-analysis to get a reasonably accurate estimate the global prevalence of celiac disease. 
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    Rates of celiac disease were 0.4% in South America, 0.5% in Africa and North America, 0.6% in Asia, and 0.8% in Europe and Oceania; the prevalence was 0.6% in female vs 0.4% males. Celiac disease was significantly more common in children than adults.
    This systematic review and meta-analysis showed celiac disease to be reported worldwide. Blood test data shows celiac disease rate of 1.4%, while biopsy data shows 0.7%. The prevalence of celiac disease varies with sex, age, and location. 
    This review demonstrates a need for more comprehensive population-based studies of celiac disease in numerous countries.  The 1.4% rate indicates that there are 91.2 million people worldwide with celiac disease, and 3.9 million are in the U.S.A.
    Source:
    Clin Gastroenterol Hepatol. 2018 Jun;16(6):823-836.e2. doi: 10.1016/j.cgh.2017.06.037.

    Jefferson Adams
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    Purée all ingredients together in a blender.
    Cover and refrigerate for at least 1 hour. 
    Adjust seasoning with salt and pepper, as desired. 
    Serve is a bowl with tortilla chips and guacamole.

    Dr. Ron Hoggan, Ed.D.
    Celiac.com 06/15/2018 - There seems to be widespread agreement in the published medical research reports that stuttering is driven by abnormalities in the brain. Sometimes these are the result of brain injuries resulting from a stroke. Other types of brain injuries can also result in stuttering. Patients with Parkinson’s disease who were treated with stimulation of the subthalamic nucleus, an area of the brain that regulates some motor functions, experienced a return or worsening of stuttering that improved when the stimulation was turned off (1). Similarly, stroke has also been reported in association with acquired stuttering (2). While there are some reports of psychological mechanisms underlying stuttering, a majority of reports seem to favor altered brain morphology and/or function as the root of stuttering (3). Reports of structural differences between the brain hemispheres that are absent in those who do not stutter are also common (4). About 5% of children stutter, beginning sometime around age 3, during the phase of speech acquisition. However, about 75% of these cases resolve without intervention, before reaching their teens (5). Some cases of aphasia, a loss of speech production or understanding, have been reported in association with damage or changes to one or more of the language centers of the brain (6). Stuttering may sometimes arise from changes or damage to these same language centers (7). Thus, many stutterers have abnormalities in the same regions of the brain similar to those seen in aphasia.
    So how, you may ask, is all this related to gluten? As a starting point, one report from the medical literature identifies a patient who developed aphasia after admission for severe diarrhea. By the time celiac disease was diagnosed, he had completely lost his faculty of speech. However, his speech and normal bowel function gradually returned after beginning a gluten free diet (8). This finding was so controversial at the time of publication (1988) that the authors chose to remain anonymous. Nonetheless, it is a valuable clue that suggests gluten as a factor in compromised speech production. At about the same time (late 1980’s) reports of connections between untreated celiac disease and seizures/epilepsy were emerging in the medical literature (9).
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    Whatever the reason that stuttering has not been reported in the medical literature in association with gluten ingestion, a number of personal disclosures and comments suggesting a connection between gluten and stuttering can be found on the Internet. Abid Hussain, in an article about food allergy and stuttering said: “The most common food allergy prevalent in stutterers is that of gluten which has been found to aggravate the stutter” (10). Similarly, Craig Forsythe posted an article that includes five cases of self-reporting individuals who believe that their stuttering is or was connected to gluten, one of whom also experiences stuttering from foods containing yeast (11). The same site contains one report of a stutterer who has had no relief despite following a gluten free diet for 20 years (11). Another stutterer, Jay88, reports the complete disappearance of her/his stammer on a gluten free diet (12). Doubtless there are many more such anecdotes to be found on the Internet* but we have to question them, exercising more skepticism than we might when reading similar claims in a peer reviewed scientific or medical journal.
    There are many reports in such journals connecting brain and neurological ailments with gluten, so it is not much of a stretch, on that basis alone, to suspect that stuttering may be a symptom of the gluten syndrome. Rodney Ford has even characterized celiac disease as an ailment that may begin through gluten-induced neurological damage (13) and Marios Hadjivassiliou and his group of neurologists and neurological investigators have devoted considerable time and effort to research that reveals gluten as an important factor in a majority of neurological diseases of unknown origin (14) which, as I have pointed out previously, includes most neurological ailments.
    My own experience with stuttering is limited. I stuttered as a child when I became nervous, upset, or self-conscious. Although I have been gluten free for many years, I haven’t noticed any impact on my inclination to stutter when upset. I don’t know if they are related, but I have also had challenges with speaking when distressed and I have noticed a substantial improvement in this area since removing gluten from my diet. Nonetheless, I have long wondered if there is a connection between gluten consumption and stuttering. Having done the research for this article, I would now encourage stutterers to try a gluten free diet for six months to see if it will reduce or eliminate their stutter. Meanwhile, I hope that some investigator out there will research this matter, publish her findings, and start the ball rolling toward getting some definitive answers to this question.
    Sources:
    1. Toft M, Dietrichs E. Aggravated stuttering following subthalamic deep brain stimulation in Parkinson’s disease--two cases. BMC Neurol. 2011 Apr 8;11:44.
    2. Tani T, Sakai Y. Stuttering after right cerebellar infarction: a case study. J Fluency Disord. 2010 Jun;35(2):141-5. Epub 2010 Mar 15.
    3. Lundgren K, Helm-Estabrooks N, Klein R. Stuttering Following Acquired Brain Damage: A Review of the Literature. J Neurolinguistics. 2010 Sep 1;23(5):447-454.
    4. Jäncke L, Hänggi J, Steinmetz H. Morphological brain differences between adult stutterers and non-stutterers. BMC Neurol. 2004 Dec 10;4(1):23.
    5. Kell CA, Neumann K, von Kriegstein K, Posenenske C, von Gudenberg AW, Euler H, Giraud AL. How the brain repairs stuttering. Brain. 2009 Oct;132(Pt 10):2747-60. Epub 2009 Aug 26.
    6. Galantucci S, Tartaglia MC, Wilson SM, Henry ML, Filippi M, Agosta F, Dronkers NF, Henry RG, Ogar JM, Miller BL, Gorno-Tempini ML. White matter damage in primary progressive aphasias: a diffusion tensor tractography study. Brain. 2011 Jun 11.
    7. Lundgren K, Helm-Estabrooks N, Klein R. Stuttering Following Acquired Brain Damage: A Review of the Literature. J Neurolinguistics. 2010 Sep 1;23(5):447-454.
    8. [No authors listed] Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 43-1988. A 52-year-old man with persistent watery diarrhea and aphasia. N Engl J Med. 1988 Oct 27;319(17):1139-48
    9. Molteni N, Bardella MT, Baldassarri AR, Bianchi PA. Celiac disease associated with epilepsy and intracranial calcifications: report of two patients. Am J Gastroenterol. 1988 Sep;83(9):992-4.
    10. http://ezinearticles.com/?Food-Allergy-and-Stuttering-Link&id=1235725 
    11. http://www.craig.copperleife.com/health/stuttering_allergies.htm 
    12. https://www.celiac.com/forums/topic/73362-any-help-is-appreciated/
    13. Ford RP. The gluten syndrome: a neurological disease. Med Hypotheses. 2009 Sep;73(3):438-40. Epub 2009 Apr 29.
    14. Hadjivassiliou M, Gibson A, Davies-Jones GA, Lobo AJ, Stephenson TJ, Milford-Ward A. Does cryptic gluten sensitivity play a part in neurological illness? Lancet. 1996 Feb 10;347(8998):369-71.

    Jefferson Adams
    Celiac.com 06/14/2018 - Refractory celiac disease type II (RCDII) is a rare complication of celiac disease that has high death rates. To diagnose RCDII, doctors identify a clonal population of phenotypically aberrant intraepithelial lymphocytes (IELs). 
    However, researchers really don’t have much data regarding the frequency and significance of clonal T cell receptor (TCR) gene rearrangements (TCR-GRs) in small bowel (SB) biopsies of patients without RCDII. Such data could provide useful comparison information for patients with RCDII, among other things.
    To that end, a research team recently set out to try to get some information about the frequency and importance of clonal T cell receptor (TCR) gene rearrangements (TCR-GRs) in small bowel (SB) biopsies of patients without RCDII. The research team included Shafinaz Hussein, Tatyana Gindin, Stephen M Lagana, Carolina Arguelles-Grande, Suneeta Krishnareddy, Bachir Alobeid, Suzanne K Lewis, Mahesh M Mansukhani, Peter H R Green, and Govind Bhagat.
    They are variously affiliated with the Department of Pathology and Cell Biology, and the Department of Medicine at the Celiac Disease Center, New York Presbyterian Hospital/Columbia University Medical Center, New York, USA. Their team analyzed results of TCR-GR analyses performed on SB biopsies at our institution over a 3-year period, which were obtained from eight active celiac disease, 172 celiac disease on gluten-free diet, 33 RCDI, and three RCDII patients and 14 patients without celiac disease. 
    Clonal TCR-GRs are not infrequent in cases lacking features of RCDII, while PCPs are frequent in all disease phases. TCR-GR results should be assessed in conjunction with immunophenotypic, histological and clinical findings for appropriate diagnosis and classification of RCD.
    The team divided the TCR-GR patterns into clonal, polyclonal and prominent clonal peaks (PCPs), and correlated these patterns with clinical and pathological features. In all, they detected clonal TCR-GR products in biopsies from 67% of patients with RCDII, 17% of patients with RCDI and 6% of patients with gluten-free diet. They found PCPs in all disease phases, but saw no significant difference in the TCR-GR patterns between the non-RCDII disease categories (p=0.39). 
    They also noted a higher frequency of surface CD3(−) IELs in cases with clonal TCR-GR, but the PCP pattern showed no associations with any clinical or pathological feature. 
    Repeat biopsy showed that the clonal or PCP pattern persisted for up to 2 years with no evidence of RCDII. The study indicates that better understanding of clonal T cell receptor gene rearrangements may help researchers improve refractory celiac diagnosis. 
    Source:
    Journal of Clinical Pathologyhttp://dx.doi.org/10.1136/jclinpath-2018-205023

    Jefferson Adams
    Celiac.com 06/13/2018 - There have been numerous reports that olmesartan, aka Benicar, seems to trigger sprue‐like enteropathy in many patients, but so far, studies have produced mixed results, and there really hasn’t been a rigorous study of the issue. A team of researchers recently set out to assess whether olmesartan is associated with a higher rate of enteropathy compared with other angiotensin II receptor blockers (ARBs).
    The research team included Y.‐H. Dong; Y. Jin; TN Tsacogianis; M He; PH Hsieh; and JJ Gagne. They are variously affiliated with the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School in Boston, MA, USA; the Faculty of Pharmacy, School of Pharmaceutical Science at National Yang‐Ming University in Taipei, Taiwan; and the Department of Hepato‐Gastroenterology, Chi Mei Medical Center in Tainan, Taiwan.
    To get solid data on the issue, the team conducted a cohort study among ARB initiators in 5 US claims databases covering numerous health insurers. They used Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for enteropathy‐related outcomes, including celiac disease, malabsorption, concomitant diagnoses of diarrhea and weight loss, and non‐infectious enteropathy. In all, they found nearly two million eligible patients. 
    They then assessed those patients and compared the results for olmesartan initiators to initiators of other ARBs after propensity score (PS) matching. They found unadjusted incidence rates of 0.82, 1.41, 1.66 and 29.20 per 1,000 person‐years for celiac disease, malabsorption, concomitant diagnoses of diarrhea and weight loss, and non‐infectious enteropathy respectively. 
    After PS matching comparing olmesartan to other ARBs, hazard ratios were 1.21 (95% CI, 1.05‐1.40), 1.00 (95% CI, 0.88‐1.13), 1.22 (95% CI, 1.10‐1.36) and 1.04 (95% CI, 1.01‐1.07) for each outcome. Patients aged 65 years and older showed greater hazard ratios for celiac disease, as did patients receiving treatment for more than 1 year, and patients receiving higher cumulative olmesartan doses.
    This is the first comprehensive multi‐database study to document a higher rate of enteropathy in olmesartan initiators as compared to initiators of other ARBs, though absolute rates were low for both groups.
    Source:
    Alimentary Pharmacology & Therapeutics