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Although more than 500 different medications have been reported to be associated with AP, the risk of most of these drugs remains unclear, as many data derive from case reports, case series or summaries of them. In 2003, Lancashire et al. conducted one of the first case–control studies in this field using the UK General Practitioner Research Database (GPRD). Their results indicated that a few drugs commonly reported as suspected to cause AP either did not have an increased risk at all (statins), or did not have an increased risk compared with other, more seldom reported drugs of the same class (valproic acid), highlighting the need for further epidemiological studies. Possible limitations of this study were that it could not verify the diagnosis of AP in the cases and that it did not exclude alternative aetiologies of AP such as alcohol or gallstones, whereas our study included cases of IAP based on laboratory, clinical or imaging findings in which alternative aetiologies had been ruled out.
Based on the case–control analysis or the individual causality assessment, we corroborated known risks for a number of drugs, including azathioprine, mesalazine, mercaptopurine and ACE inhibitors. Furthermore, the results indicated a pancreatic toxicity also for substances rarely being reported associated with AP, such as fenofibrate or leflunomide. Moreover, this study is the first one to the best of our knowledge alluding to a pancreatotoxic potential for the herbal remedies harpagophytum and valerian radix as well as for tocilizumab. As more than 90% of the patients included in the case–control analysis were recruited until the end of 2010, the pancreatotoxic risk of newer drugs such as the antidiabetic agents gliptins or glucagon-like peptide-1 (GLP-1) agonists could not be quantified. However, we did find one case of exenatide-induced AP with probable causality. Similarly, some of the older drugs not commonly used nowadays may not have been assessed well.
Analysis of the DIAP cases with only one offending drug regarding duration of drug use led to the detection of a wide range spanning from few days to several months. Hence, we corroborate previous findings that suggest an absence of fixed duration of drug use in DIAP.
Data on drug dosage in the same DIAP cases imply that pancreatic toxicity relies rather on an idiosyncratic and not a dose-dependent mode, but the small amount of respective data makes further conclusions challenging.
In all three patients with a positive rechallenge, the offending medication was re-administered as it was initially unclear whether drug toxicity had been the cause of AP. Thus, the respective medical therapy was re-initiated to treat the underlying diseases.
The thiopurines azathioprine and mercaptopurine, as well as the derivative of salicylic acid mesalazine, have been repeatedly reported being associated with AP in case reports in the past. Several times, a positive rechallenge was documented, and, therefore, a certain causality was indicated.[18, 19] Azathioprine has also shown an increased risk in the population-based case–control study conducted by Floyd et al. Moreover, in a retrospective cohort study including only patients with inflammatory bowel disease (IBD), thiopurine medication was the main aetiological factor for the development of AP. Concerning mesalazine, its association with AP remains controversial. Muff Munk et al. found no increased risk for mesalazine using data from a Danish hospital discharge registry. In contrast, the UK study on AP mentioned above showed a nine-fold increased risk in patients receiving mesalazine up to 3 months before the onset of the disease.
Our case–control analysis showed significantly increased risks for angiotensin-converting enzyme (ACE) inhibitors as a group, for lisinopril, as well as for the ramipril/hydrochlorothiazide combination. Based on the respective 95% CI, increased risk estimates cannot be ruled out also for ramipril and enalapril. Furthermore, lisinopril was considered once probably and once possibly associated with AP in the standardised causality assessment of individual cases. These findings corroborate the results of a European, multi-centre, population-based case–control study, which has shown a slightly increased risk for ACE inhibitors. Moreover, this is the first study to our knowledge detecting a significant risk estimate for lisinopril; in recent reviews on DIAP based on case reports, this ACE inhibitor was either not considered as a possible cause at all or it has been ascribed a comparably low risk.
Fenofibrate illustrated the highest risk estimate in our case–control analysis, whereas the two statins included (simvastatin, atorvastatin) showed either no increased risk or failed to reach statistical significance. These findings are consistent with a large retrospective cohort study, showing that fenofibrate has a several fold increased risk compared with statins. On the other hand, a recent meta-analysis depicted no significantly increased risk for fibrates. However, as the studies recruited were randomised controlled trials evaluating the effects of fibrates on cardiovascular events, incidence of pancreatitis was not documented in a standardised way, posing the question of possible variation in results among trials.
Interestingly, several cephalosporins, including cefuroxime, cefotaxime and cefixime, showed a possible or probable causal relationship in our causality assessment of individual cases. To this day, ceftriaxone has been the only antibiotic of this class to be reported associated with AP,[23-28] possibly via formation of gallstones. As cases of biliary AP were excluded from our study, it seems that this pathomechanism of ceftriaxone-induced AP may not apply to all other cephalosporins. In the case–control analysis, we demonstrated a nonsignificantly increased risk estimate for cephalosporins as a group – however, the low number of exposed cases makes an interpretation of this result challenging.
A potential risk for AP was found for several herbal medications or dietary supplements as well. In the case–control analysis, high-risk estimates were demonstrated for harpagophytum (devil's claw), an herb mostly used as an analgesic, and valerian radix, an herb commonly taken by patients with sleeping disorders. In addition, the individual causality assessment revealed one possible association with AP for harpagophytum, for cinnamon powder, and for hypericum perforatum (St. John's wort) respectively. Interestingly, the secondary metabolites iridoids, which represent harpagophytum's main ingredients and are also an important constituent in valerian radix, have a well-established choleretic activity. This increases the risk of gallstone formation, and could eventually lead to the development of AP. With AP of biliary origin illustrating an exclusion criterion in our study, a possible explanation could be the development of asymptomatic biliary sludge. The US prescribing information of harpagophytum contraindicates this herb for patients suffering from gallstones, but does not indicate a contraindication for patients with pancreatic disease. Furthermore, several cases of hepatotoxicity associated with valerian radix have been published in the past,[33-35] indicating a broader toxic potential of this herbal remedy. In contrast to herbal hepatotoxicity, reports of AP associated with either herbal medications or dietary supplements are rare,[36-40] a possible cause being the less stringent surveillance of such remedies. Taken together, this is the first controlled study showing an increased risk of AP for two well-known herbals. However, as the possibility of recall bias especially regarding the use of phytotherapeutics cannot be excluded in a case–control study, the results at hand should be interpreted with caution. To assess possible risks of other herbal medications or dietary supplements, further effort is needed.
DM and smoking have been associated with an increased risk for AP.[41, 42] However, it appears unlikely that difference in the prevalence of these important risk factors between cases and controls affected the current results, as the prevalence of DM and the frequency of current or past smokers did not significantly differ between out-patient cases and controls.
Several weaknesses and strengths of this study should be addressed. Biliary sludge or asymptomatic cholecystolithiasis were no exclusion criteria, as such findings can be also seen in AP patients with probable or certain drug causality.[37, 43, 44] A biliary aetiology was excluded via endoscopic ultrasound of the biliary tract in two of the nine patients with biliary sludge and in the single patient with asymptomatic cholecystolithiasis, whereas no further signs of biliary aetiology were found in the remaining seven patients with biliary sludge (for example choledocholithiasis, prior history of biliary colic, dilated biliary tract or concomitant rise of transaminases and bilirubin). However, as biliary sludge depicts a possible cause of AP in cases initially labelled as idiopathic, this remains a potential limitation of the study. We used hospital-based controls, although they may not represent a community setting, as they are usually associated with higher response rates and lower costs compared with community-based controls.
Regarding the drugs for the treatment of IBD (mesalazine, azathioprine and mercaptopurine), confounding by indication cannot be ruled out, as IBD is an established risk factor for AP.[21, 46] However, another case–control study found an increased risk for azathioprine after adjusting for IBD, indicating a ‘genuine’ risk for this drug, and most probably for its active metabolite mercaptopurine. Regarding mesalazine, a quantification of its pancreatotoxic risk in non-IBD patients was not possible, as ulcerative colitis and Crohn's disease are the only indications for its use in Germany. Therefore, all patients exposed to mesalazine in our study had an IBD diagnosis.
The thorough validation of the AP cases as well as the strict inclusion and exclusion criteria reduced the number of cases considerably, resulting in decreased statistical power for the case–control analysis. Therefore, precaution in the interpretation of results is needed. Moreover, it cannot be ruled out that recall and information bias, and unmeasured confounding may explain the findings of this study.
The increased risk estimate for the combination inhaler formoterol/budesonide is possibly a statistical artefact, although systemic adverse effects of inhaled corticosteroids are well established, and corticosteroid-induced pancreatitis for oral preparations has been already described in the 1960s.
FAKOS is one of the few controlled studies on pancreatic toxicity and merely the second one with a case–control design not narrowing its focus to specific drugs. This allowed the risk quantification of various drugs or herbal medications, including also substances that had been hardly reported or not reported at all so far. It is not uncommon for case–control studies on drug toxicity to select their ‘target’ medications based on the quantity of published case reports. However, drugs that are considered ‘harmless’ (e.g. herbal medications) are usually not monitored as thoroughly as substances with known serious adverse effects. Due to the high number of participating hospitals and the variety of medical departments, we were able to assess a wide range of drugs.
Regarding the individual causality assessment, it was always carried out by the study physician in a standardised way. Furthermore, it was not based on a suspicion of the attending physician, thus precluding a potential bias because of prior knowledge and attention to drugs as a possible cause of disease.
In summary, our study identified a few drugs as well as herbal medicines as possible causes of AP. Our findings corroborate previous results from the literature, but also indicate risks for substances not reported so far, highlighting the need for further controlled studies on pancreatic toxicity. In case of characteristic abdominal pain or an elevation of the respective laboratory parameters, drugs should be part of the differential diagnosis, especially when alcohol intake or gallstones can be ruled out as possible causes.