Mesalamine is the most commonly prescribed medication among patients with inflammatory bowel disease (IBD), as it is the cornerstone of remission treatment and antioncogenic prophylaxis for cases with ulcerative colitis (UC). As the first-line treatment option in mild to moderate UC, mesalamine provides a sufficient safety profile, with 13%-73% of patients experiencing mild adverse events including nausea, abdominal extension or discomfort, headache, rash, fever, and liver dysfunction (Tian et al., 2020; Ungaro, Mehandru, Allen, Peyrin-Biroulet, & Colombel, 2017), thus achieving compliance of more than 80% (Kruis et al., 2003). Mesalamine-induced myocarditis, pericarditis or both (myopericarditis), is a rare, though potentially fatal, complication (Brown, 2016). The current case concerns a patient with first manifestation of UC and a confirmed myopericarditis after mesalamine administration.
Case Report
A 20-year-old Greek male patient, with no medical history or regular medication, presented to our department complaining of 10 episodes of bloody diarrhea per day starting and gradually worsening during the last 2 months. Physical examination revealed mild lower abdominal tendency and plain abdominal radiography was unremarkable. Blood tests revealed leukocytosis with normal C-reactive protein and erythrocyte sedimentation rate. Fecal calprotectin was elevated (>1,000 [mu]g/g) and infectious agents were not detected in stool samples, by using cultures, parasitological tests, and real-time polymerase chain reaction (PCR) (BioFire FilmArray Gastrointestinal Panel, Salt Lake City, Utah) to detect common pathogens (Escherichia coli, Salmonella spp, Shigella spp, Campylobacter spp, Clostridium difficile, Entamoeba histolytica, Giardia lamblia, or other pathogens).
Colonoscopy demonstrated mucosal erythema, erosions, and friability along the large bowel and a normal terminal ileum. Empirical treatment with mesalamine 4 g orally and enema (sachet Salofalk Granu-Stix and rectal sus, Galenica, Greece) was introduced as a treatment regimen. Histopathological report was not clarifying and required further assessment of a specialized pathologist.
After 5 days of the mesalamine and enema regimen and despite the gradual remission of diarrhea, the patient developed fever and dull thoracic pain exacerbating during inspiration. Despite normal electrocardiogram (ECG), pronounced elevation (1600 ng/L) of troponin (hsTnI- PATHFAST, Mitsubishi Chemical Medience Co., Japan) was identified. The patient was transferred to the cardiological enhanced care unit. Transthoracic echocardiogram was suggestive of myocardial edema and pericardial effusion without functional deficits, and magnetic resonance imaging (MRI) confirmed the diagnosis of myocarditis by illustrating myocardial edema in T2-weighted images and late gadolinium enhancement of lateral epimyocardial region (Figure 1).
A broad-spectrum of viral causes was excluded by real-time PCR testing (among others Epstein-Barr, herpes simplex virus 1 and 2, echoviruses, Cytomegalovirus, and coxsackieviruses A and B). Considering UC as the most probable diagnosis, UC-related myopericarditis was incompatible to the clinical course of colitis. Mesalamine was therefore discontinued with gradual clinical and enzymic recovery of myopericarditis, whereas colitis recurred clinically. Upon histopathological confirmation of UC and the patient's preference to avoid corticosteroids, mesalamine was administered again with close monitoring.
Four days after initiation of treatment, the chest pain improved, with normal ECG, echocardiogram, hsTnI serial values, and elevation of serum cardiac creatine kinase (CK-MB) indicative of pericarditis. Mesalamine was withdrawn and the patient consented to systemic corticosteroids administration, leading to relief of his chest pain. The second UC exacerbation was steroid refractory (methylprednisolone 60 mg iv) and a rescue therapy with infliximab (Inflectra, Pfizer, Gladstone, New Jersey) 5 mg/kg IV was initiated carefully due to its cardiac side effects including pericarditis. The patient achieved sufficient remission without cardiac concerns. Six months later, a follow-up MRI was performed and exhibited complete myocardial rehabilitation.
Discussion
Given the absence of confirmed mesalamine-induced myopericarditis cases, we presented a young male patient with acute onset of UC and recurrent myopericarditis. To clarify the relevant diagnostic and therapeutic dilemmas, the patient was diagnosed by means of cardiac MRI after mesalamine challenge. The broad administration of mesalamine in IBD has revealed some rare, though severe, complications, which have not been described by initial randomized controlled trials. In addition to aforementioned mild adverse events, real-world experience demonstrated cases with interstitial nephritis, nephrotic syndrome, acute pancreatitis, agranulocytosis, aplastic anemia, drug-induced liver injury, and myopericarditis (Brown, 2016; Ham & Moss, 2012). Therefore, monitoring features should include: renal function test before and throughout mesalamine use; liver function tests for hepatotoxicity; and complete blood counts for bone marrow suppression, particularly in aging patients (Tripathi & Feuerstein, 2019).
Regarding myopericarditis, limited cases of confirmed mesalamine cardiac hypersensitivity are known including mainly myocarditis and rarely myopericarditis (Brown, 2016; Okoro, Roby, & Bankole, 2018; Radhakrishnan, Mohanaruban, & Hoque, 2018). Pathophysiological pathways have not been investigated, although eosinophil stimulation and myocardial infiltration seem to be the common end point of all approaches instead of direct drug toxicity. The initial triggering event is suggested to be arachidonic acid-based lipoxygenase overproduction after cyclooxygenase inhibition by mesalamine, immunological cross-reaction after antibodies formation against mesalamine, or immediate hypersensitivity reaction, type I mediated by immunoglobulin E (Brown, 2016).
The establishment of diagnosis remains challenging, especially in the inflammatory and immunosuppressive environment of IBD, where differential diagnosis from other etiologies with the same semiology/clinical picture such as infections and extraintestinal IBD-related cardiac manifestation is difficult. Notably, contrary to normal ECG findings in our case, ECG frequently shows nonspecific ST-segment alterations or T-wave alterations, which appear to be flat, depressed, or elevated T waves (Qanneta, Pardo, & Serra, 2013). Accurate diagnosis warrants high clinical suspicion index by the treatment team. A detailed medical history to recognize signs of acute infection, sensitive methods to rule out the common myocardial pathogens, and strict evaluation of IBD course and activity contribute to successful and thorough evaluation.
In our case, mesalamine reinduction, after the patient's initial refusal to corticosteroids, triggered a recurrent episode of myopericarditis, thus confirming the diagnosis, though diagnostic provocation is not generally recommended. Although necessary, mesalamine withdrawal in active mild to moderate colitis combined with a delay in medical decisions creates a therapeutic gap. This could exacerbate and further burden the course of IBD. Diagnostic vagueness, due to limitations in obtaining clinical data, such as distinct histopathological findings, especially during IBD onset, enhances clinicians' uncertainty and indecisiveness.
Conclusion
Although mesalamine is an established and generally safe therapeutic agent, upon myocarditis occurrence with potentially lethal outcome, especially in cases of active colitis or cardiological comorbidities, further management seems like a "double-edged sword," thus necessitating decisive, targeted, and multidisciplinary interventions.
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