Published online Feb 28, 2019. doi: 10.3748/wjg.v25.i8.967
Peer-review started: November 27, 2018
First decision: December 20, 2018
Revised: January 22, 2019
Accepted: January 26, 2019
Article in press: January 26, 2019
Published online: February 28, 2019
Drug-induced colitis is a common and even serious problem, but the knowledge about associated triggers is scarce.
Withdrawal of the respective trigger should cure the disease, so that its identification is crucial. Therefore, deeper insights into the aetiopathogenesis and knowledge about potential triggers is mandatory.
Consequently, the study aimed to identify potential triggers of histologically suspected drug-induced colitis.
A retrospective case control study of 211 patients with histologically suspected drug-induced colitis and two age- and gender matched control groups was performed. The drug-induced colitis (DiC) patients showed histological changes attributable to drug-induced pathology, i.e., mixed, predominantly neutrophilic or lymphocytic inflammatory infiltrates, erosions, absence of granulomas, absence of basal plasmacellular infiltration and absence of crypt architectural distortion. The control groups consisted of patients with inflammatory colitis other than DiC and inflammatory bowel disease (i.e., diverticulitis, ischaemic colitis) and of patients without substantial histological changes (i.e., irritable bowel syndrome, cancer screening). Clinical data including drug history was obtained from the electronic data base.
In a second approach, patients were divided into three groups from a clinical perspective: DiC without atherosclerotic comorbidity, DiC with atherosclerotic comorbidity, and ischaemic colitis. Patients from the first two groups derived from the DiC group while the latter group was gathered from the inflammatory controls.
A total of 633 patients (291 male patients, mean age 62.1 ± 16.1 years) were included. Patients with DiC took more drugs (mean 4.5 ± 2.8) than patients from both other groups (mean 3.9 ± 3.0 and 3.9 ± 3.2, respectively). In univariate analysis, DiC was associated with diuretics, dihydropyridines, glycosides, ASS, platelet aggregation inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), statins and fibrates. In addition to NSAIDs, that are well established to induce DiC, several drugs that are indicated for the treatment of heart failure, atherosclerosis and related conditions were associated with DiC. Cardiac and vascular comorbidity might, therefore, be a substantial confounding factor or the cause of the disease itself. In fact, atherosclerosis was more common among patients with DiC. In multivariate analysis, atherosclerosis (OR = 2.1) and the intake of NSAIDs (OR = 6.7) and fibrates (OR = 9.1) were associated most strongly with DiC. Since a subset of DiC patients with atherosclerosis exhibited histological features of both DiC without atherosclerosis and ischaemia, we propose that focal disturbances of the microcirculation play a substantial role in the pathogenesis of a subgroup of DiC patients. A total of 28 age- and gender-matched triplets were assembled for the histological reassessment. Some DiC patients with atherosclerosis exhibited histological features of both control groups, DiC without atherosclerosis and ischaemia.
While most knowledge of drug-induced colitis relies on case reports and case series this is the first study that systematically investigates potential triggers of DiC. This large case control study reveals that patients with the histopathological suspicion of drug-induced colitis take more different drugs than age- and gender-matched control patients. Associated remedies include drugs that are indicated for the treatment of heart failure, atherosclerosis and related conditions. Furthermore, atherosclerosis was more common among DiC patients. We therefore hypothesise that focal disturbances of the microcirculation play a substantial role in the pathogenesis of a subgroup of DiC patients, but the study design is not suitable to prove this hypothesis.
Prospective studies including larger cohorts with clearly defined cardiac function, pattern and severity of atherosclerosis and related comorbidities, such as hyperlipoprotenaemia, are warranted to unravel the underlying aetiology and pathophysiology of this under-recognised entity. Meanwhile, the histological suspicion of DiC might not necessarily reveal a drug-related mechanism but could also reflect focal ischaemia that is supported by macroangiopathy at least in a subset of patients.