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Tocilizumab as a possible cause of ischemic colitis
Tocilizumab como posible causa de colitis isquémica
Rocío Forneiro Pérez
Corresponding author
rocio.forneiro@gmail.com

Corresponding author.
, Pablo Dabán López, María Sol Zurita Saavedra, María Dolores Hernández García, Benito Mirón Pozo
Hospital Universitario Clínico San Cecilio, Granada, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">In December 2019&#44; a novel coronavirus&#44; called SARS-CoV-2&#44; was isolated as a causative agent of a new form of pneumonia that has spread globally since then and was subsequently renamed COVID-19 by the World Health Organization&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> According to data from the Spanish Ministry of Health&#44; as of 1 May 2020&#44; the number of cases diagnosed by PCR in Spain surpassed 215&#44;000 and the number of deaths stood at around 25&#44;000&#44; representing a mortality rate of 11&#46;6&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Some patients experience cytokine release syndrome&#46; Interleukin-6 &#40;IL-6&#41; is the key molecule in this cytokine storm&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Tocilizumab&#44; a humanised recombinant monoclonal antibody&#44; acts against the IL-6 receptor&#46; For that reason&#44; it has come to be used in patients with serious COVID-19 and elevated IL-6&#46; Despite the apparent benefits reported&#44; the possible adverse effects of this agent should be borne in mind&#46; We report the case of a patient treated with tocilizumab for serious COVID-19 who presented signs and symptoms consistent with segmental ischaemic colitis&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">A 59-year-old man was admitted to the intensive care unit for bilateral pneumonia due to SARS-CoV-2&#44; complicated by moderate to severe acute respiratory distress syndrome &#40;ARDS&#41; requiring prolonged orotracheal intubation&#46; Notable elements of his medical history were hypertension and ischaemic cardiomyopathy&#44; for which he underwent revascularisation in February 2020 and was on dual antiplatelet therapy&#46; After three days with boluses of methylprednisolone&#44; the patient&#39;s condition worsened&#44; with unfavourable laboratory and radiological test results&#44; for which a single dose of 600<span class="elsevierStyleHsp" style=""></span>mg of intravenous tocilizumab was prescribed&#46; Ten days following administration of this drug&#44; the patient started to have episodes of haematochezia which required transfusion of four units of packed red blood cells and one unit of platelets &#40;two units of packed red blood cells approximately every 48&#8722;72<span class="elsevierStyleHsp" style=""></span>h&#41; due to the onset of multifactorial anaemia&#44; as he reached haemoglobin levels of 7&#46;2<span class="elsevierStyleHsp" style=""></span>g&#47;dl&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">He underwent a colonoscopy 24<span class="elsevierStyleHsp" style=""></span>h after the first episode of haematochezia&#46; The procedure revealed digested blood debris &#40;with no active bleeding&#41; up to the hepatic flexure and signs in the mucosa of ischaemic colitis with two ulcers and an adhered clot 55&#8211;65<span class="elsevierStyleHsp" style=""></span>cm from the external anal margin &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; This colonoscopy was complete&#44; although ileoscopy was not performed&#46; A gastroscopy showed several gastric ulcers measuring around a millimetre suggestive of acute gastric mucosa lesions with no blood debris and no signs of active bleeding&#46; In view of the endoscopic findings and the patient&#8217;s context&#44; he was put on digestive rest with parenteral nutrition and broad-spectrum empirical antibiotic therapy&#46; Days later&#44; given the persistence of the patient&#8217;s haematochezia&#44; a computed tomography &#40;CT&#41; angiography of the abdomen was ordered&#46; This ruled out active bleeding and artery occlusion&#46; It also found no segmental thickening or signs of a poor prognosis in the colon wall&#46; As of that day&#44; the patient&#39;s antiplatelet therapy was suspended&#46; Two weeks from the first episode&#44; the bleeding from the patient&#39;s rectum had been self-limited&#44; so a decision was made to perform another colonoscopy &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; This test showed the same lesions&#44; now fibrinated&#44; and improvement of the mucosal impairment in the same colon segment that was reported in the first endoscopy and classified as segmental ischaemic colitis&#46; The colonoscopies found no diverticula in the colon&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">The most common form of intestinal ischaemia is ischaemic colitis&#46; It typically presents with colicky pain&#44; defecation urgency and rectal bleeding&#46; Most patients have mild forms that resolve within a few days with the mucosa recovering in two to three weeks&#46; However&#44; in more serious cases&#44; recovery from the lesions may take up to six months&#44; even if the patient remains asymptomatic&#46; In addition&#44; it must not be forgotten that a possible complication is bowel perforation&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The recent COVID-19 outbreak has been deemed a global health emergency&#46; As of the time of writing&#44; there is still no effective treatment or available vaccine&#46; Tocilizumab is useful in selected cases&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Some possible adverse effects of a gastrointestinal nature of this drug are gastric ulcers &#40;&#60;2&#37;&#41;&#44; diverticulitis and gastrointestinal perforation&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In our case&#44; the patient presented colonic ulcers with episodes of haematochezia resulting in anaemia&#44; which lasted for two weeks and ultimately were self-limiting&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The Naranjo algorithm was applied to determine the probability of a causal relationship between tocilizumab administration and ischaemic colitis&#44; with a result of four points&#46; Given all this&#44; the possibility of an association must be taken into account&#46; There are other limitations&#44; such as the absence of a histological diagnosis of said ulcers&#44; the presence of prior vascular disease and the patient&#39;s exposure to other events promoting possible ischaemic colitis &#40;sepsis&#44; hypotension&#44; systemic impairment that required intensive care&#44; etc&#46;&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">At present&#44; in Spain there are several studies for evaluating the effects of tocilizumab in critically ill patients&#46; Future lines of research could lead to studying the possible relationship between tocilizumab and ischaemic colitis&#46; Few studies have observed an increase in gastrointestinal perforation in patients with rheumatoid arthritis who receive tocilizumab&#44; although the mechanism by which such damage occurs is unknown&#46; One hypothesis points to inhibition by IL-6 of vascular endothelial growth factor&#44; which plays an important role in maintaining the integrity of the intestinal mucosa when it is damaged&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0045" class="elsevierStylePara elsevierViewall">There were no sources of funding for this work&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflicts of interest</span><p id="par0050" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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