Severe cases of sprue- like enteropathy associated with angiotensin receptor blockers other than olmesartan

Background: Sprue- like enteropathy (SLE) has been reported in patients with arterial hypertension who are treated with the angiotensin receptor blocker (ARB) olmesartan. It is currently controversial whether this is a class effect or specific to olmesartan. Methods: systematic literature in Medline/PubMed, Web of Science Scopus status to publications on SLE related to all ARBs olmesartan. the


| INTRODUC TI ON
Angiotensin receptor blockers (ARBs) are widely used for the treatment of arterial hypertension. International guidelines for the management of hypertension recommend ARBs as monotherapy or in combination with other anti-hypertensive drugs. ARBs are recognised to be highly effective and appreciated for their favourable safety profile. 1 Their mode of action is via the renin-angiotensinaldosterone pathway by selectively blocking the action of angiotensin II at the receptor level thereby reducing vasoconstriction. 2 In 2012, Rubio-Tapia and colleagues reported an association between olmesartan treatment and severe sprue-like enteropathy (SLE), a syndrome characterised by chronic non-bloody diarrhoea, weight loss, the frequent presence of nausea, vomiting, abdominal pain, bloating and fatigue. 3 In the original study, >50% of patients (14/22) required hospitalisation due to the severity of gastrointestinal symptoms and malabsorption. The characteristic histological findings in these patients were partial or total duodenal villous atrophy with crypt architectural distortion. 3 In some patients with olmesartan-induced SLE, chronic inflammatory changes were found at other locations in the gastrointestinal tract and included microscopic colitis, lymphocytic and collagenous gastritis. Anaemia, hypoalbuminaemia and electrolyte imbalances were frequently detected due to severe malabsorption in the treated patients. 3 Olmesartan-related SLE presents characteristics similar to coeliac disease. Furthermore, patients with olmesartan-induced SLE often have a positive result on HLA-DQ2/DQ8 testing. However, there are two critical parameters that distinguish olmesartan-related SLE from coeliac disease: patients with olmesartan-related SLE have negative serology (ie absence of antibodies to transglutaminase) for coeliac disease and do not respond to a gluten-free diet. Although a rare condition, [4][5][6] olmesartan-related SLE is a serious clinical entity that may require hospitalisation. 4 The onset of olmesartan-related SLE is usually delayed several weeks or even years after starting treatment with olmesartan (mean 3.3 years), but prompt clinical recovery occurs following treatment cessation. 7 In contrast, histological recovery usually takes weeks to several months. 5,8 In the study by Rubio-Tapia and colleagues, all patients showed a clinical response following olmesartan withdrawal and regained weight (median 12.2 kg), while 17 of 21 patients who underwent follow-up biopsies showed histological recovery or improvement. 3 None of the treated patients were restarted on a different ARB after olmesartan withdrawal. 3 Following the study by Rubio-Tapia and other publications and analysis of pharmacovigilance data, the US Food and Drug Administration included olmesartan-induced SLE as an adverse event in the product label for olmesartan-containing products. 9 Similarly, during the renewal procedure for olmesartan (18 August 2014), the European Authorities requested revisions to the Summary of Product Characteristics (SmPC) to include SLE in Section 4.8 as an undesirable effect with a 'very rare' incidence (<1/10 000), and specific warning on the management of patients who develop chronic diarrhoea when on olmesartan treatment in Section 4.4. 10 Despite the evidence of SLE cases associated with other ARBs (the described variations), these notifications were adopted for olmesartan only.
This report aims to systematically review the published literature and to examine the evidence for SLE related to ARBs other than olmesartan. Special attention is paid to the question of whether olmesartan and other ARBs-related SLE are similar or distinct in their clinical and histological features. precisely frame and answer relevant clinical or health care-related questions. 11 The PICO framework approach was adhered to while developing the search strategies, with the resulting questions used to frame the search strategy ( Table 1)

| RE SULTS
A flow diagram of the search process and results is presented in   Symptomatic treatment (including antibiotics and corticosteroids) and dietary modifications failed to significantly improve enteropathy symptoms in the treated patients (Table 3)   SLE with ARBs other than olmesartan has also been described in the context of previous olmesartan case reports. In a Mayo Clinic case series on the association of SLE and olmesartan intake (n = 35), many patients were susceptible to coeliac disease according to HLA-DQ2 genotype, and three patients who presented with clinical symptoms similar to olmesartan-associated SLE were on other ARBs (ie irbesartan, valsartan and telmisartan). 32 In another case report of a patient who developed SLE during olmesartan treatment, intestinal symptoms continued even after olmesartan had been replaced with a different ARB. 33 It is notable that, in this patient, clinical recovery was seen only after discontinuation of the alternate ARB, 33 which lends support to the argument that SLE is a class effect.

| D ISCUSS I ON
Although only a small number of SLE cases with ARBs other than olmesartan have been reported to date, the available evidence suggests a class effect. A further indication for this comes from a retrospective study in patients with abdominal pain who underwent upper gastrointestinal endoscopy with duodenal biopsies. In this cohort, no statistically significant differences were found for any single histopathological abnormality between olmesartan and users of other ARBs. 34 In this context, it needs to be stressed that the incidence of any type of ARBinduced SLE is rare. In an endoscopic database, no association with SLE was found for olmesartan or other ARBs. 35

| CON CLUS ION
The evidence from the clinical cases presented in this review suggests that SLE is not restricted to olmesartan alone but can also occur with other ARBs, and thus it should be considered a class effect. The paucity of data for SLE related to 'other' ARBs is likely to be due to the rare incidence of severe enteropathy cases with this class of drugs in general. The fact that more cases are reported with olmesartan may be consequent to the likely bias associated with 'first come, first served' (or 'notoriety effect'). 38 In clinical practice, physicians should be aware of the rare but possible cause of SLE induced by ARBs. This will facilitate the diagnosis of ARB-induced SLE without delay and the subsequent implementation of proper treatment. Withdrawal of the ARB usually achieves a rapid resolution of clinical symptoms and reversal of intestinal damage.

ACK N OWLEG EM ENTS
The authors thank Nishad Parkar, PhD, of Springer Healthcare

AUTH O R S H I P
Guarantor of the article: Peter Malfertheiner.
Author contributions: PM undertook the study concept and design and was involved in the acquisition, analysis and interpretation of the data, drafted and critically revised the manuscript for important intellectual content and approved the final draft. CF performed the bibliographic research and approved the final draft.

E TH I C A L CO N S I D ER ATI O N S
The authors confirm that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to. No ethical approval was required as this is a review article with no original research data.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing not applicable to this article as no data sets were generated or analysed during the current study.