Analysis of 1060 Cases of Drug-Induced Acute Pancreatitis
2020; Elsevier BV; Volume: 159; Issue: 5 Linguagem: Inglês
10.1053/j.gastro.2020.07.016
ISSN1528-0012
AutoresÁgnes Meczker, Lilla Hanák, Andrea Párniczky, Andrea Szentesi, Bálint Erőss, Péter Hegyi, Dalma Erdősi, Alexandra Mikó, Szakács Zs, Dalma Dobszai, László Szapáry, Judit Bajor, Alexandra Mikó, Áron Vincze, M Matuz, Dezső Csupor, Gábor Pethö, Heim Pál,
Tópico(s)Gastroesophageal reflux and treatments
ResumoAcute pancreatitis (AP) has a mortality of approximately 3%.1Parniczky A. et al.PLoS One. 2016; 11e0165309Crossref PubMed Scopus (154) Google Scholar Its reported incidence is variable across countries (10 to 100/100,000 inhabitants), and in the United States, AP is a significant cause of acute hospitalization for gastrointestinal disorders.2Peery A.F. et al.Gastroenterology. 2019; 156: 254-272.e11Abstract Full Text Full Text PDF PubMed Scopus (904) Google Scholar Drug-induced AP (DIAP) is regarded as a rare and mild entity; yet, it is estimated to account for approximately 2% to 5% of AP episodes worldwide.3Nitsche C. et al.Curr Gastroenterol Rep. 2012; 14: 131-138Crossref PubMed Scopus (75) Google Scholar,4Badalov N. et al.Clin Gastroenterol Hepatol. 2007; 5: 648-661Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar Because DIAP has no unique features, rechallenge with the offending drug would be the only way to provide the most robust evidence to confirm the etiology. However, giving back the drug only for understanding the etiology of index AP is ethically unacceptable.3Nitsche C. et al.Curr Gastroenterol Rep. 2012; 14: 131-138Crossref PubMed Scopus (75) Google Scholar Therefore, unsurprisingly, DIAP often remains a speculative diagnosis. A more detailed introduction of DIAP can be found in Supplementary Document 1. We aimed to systematically search the medical literature, analyze the outcomes of all reported cases of DIAP, and compare them against a general cohort of AP. We comprehensively searched the literature for reported cases of proven DIAP and extracted detailed data of each case on both first episodes and rechallenges. We compared DIAP to the large cohort of AP cases collected by the Hungarian Pancreatic Study Group. Details of the methods are in Supplementary Document 1. As a result of the comprehensive search and selection, we identified and analyzed 1060 eligible patients in 856 reports (details of the articles can be found in Supplementary Document 2). In a large proportion of the 1060 patients, antineoplastic (179 [16.89%]), antibiotic (128 [12.08%]), and anticonvulsant (103 [9.72%]) drugs caused DIAP. A combination of drugs caused 78 (7.36%) of the DIAP episodes (Figure 1A). In approximately half of the 1060 patients, drugs were given to manage the diseases of the gastrointestinal tract (214 [20.19%]) or neurologic (158 [14.91%]) or hematologic (155 [14.62%]) conditions (Figure 1B). The 10 most common drugs resulting in AP are shown in Figure 1C. Male patients comprised 536 of 1054 patients (50.85%) affected by DIAP (Figure 1D). Interestingly, 228 of 1054 cases (21.63%) were reported in children (aged <18 years), and cases were seen at a younger age than in AP of other common etiologies (Figure 1E). Among the 1060 patients, DIAP was severe in 213 (20.09%), moderately severe in 118 (11.13%), and mild in 729 (68.77%), if the first episodes were analyzed (Figure 1F). DIAP had a mortality of 90 of 1033 (8.71%) for all severities (Figure 1G). There was a significant difference in the median (interquartile range [IQR]) length of hospitalization (LOH) between mild and moderately severe (7 days [IQR, 4–11.5 days] vs 16 days [IQR, 7–25 days], P .001) and between mild and severe DIAP (7 days [IQR, 4 –11.5 days] vs 18 days [IQR, 6.5–42 days], P < .001). There was no difference in the LOH between moderately severe and severe DIAP (Figure 1H). We found information on rechallenge in 960 of the 1060 patients in our analysis. Epidemiology (indication, sex, and age) and outcome parameters (severity, mortality, and LOH) of the rechallenge episodes of DIAP can be found in Figure 2A–F. The association of the drug categories and primary conditions with the severity and mortality rates of DIAP can be found in Supplementary Document 1 and Supplementary Tables 1 and 2. In 147 of 241 patients (70.00%), no data were available on the dose for rechallenge. Rechallenge was performed in 49 of 241 patients (20.33%) with the same dose as given in the first DIAP episode. The dose was decreased in 33 patients (13.69%) and was increased in 12 (4.98%) compared with the drug dose given in the first episode. If the same dose was given that provoked first episode, DIAP was severe in 2 of 41 patients (4.88%), moderate in 3 (7.32%), and mild in 36 (87.80%). If decreased doses were given, we found no moderately severe cases. Rechallenge in 28 patients caused 1 (3.57%) severe case and 27 (96.43%) mild cases of DIAP (Figure 2G). The descriptive statistics of the general AP cohort are available in Supplementary Document 1 and Supplementary Figure 1. Our data showed that severity and mortality were increased in all DIAP cases compared with AP of other etiologies by 18.41% vs 5.63% (P < .001) and 7.30% vs 2.20% (P < .001), respectively. DIAP had the second highest mortality rate of all etiologies (8.49%) (Supplementary Document 1 and Supplementary Figure 1). One of the most critical findings of our study is that compared with AP of other etiologies, reported patients with DIAP have a more severe disease course. Most medications causing severe DIAP are given to treat significant preexisting pathologies and primary diseases such as cancers and autoimmune disorders. These patients will have a higher risk of organ failure. In some patients, organ failure is present at the introduction of the offending drug, before the DIAP event. We hypothesize that this accounts for the increased proportion of moderately severe and severe cases of AP in the DIAP cohort. A primary disease itself is a comorbidity and often has other comorbidities. We believe that the more severe the primary disease was, the higher doses of the offending drugs were used, leading to more severe courses of the DIAP patients. The offending drugs likely cause the DIAP in a dose-dependent way. In our recent meta-analysis, older age led to a more severe disease course,5Marta K. et al.Front Physiol. 2019; 10: 328Crossref PubMed Scopus (24) Google Scholar and our recent cohort analysis proved that comorbidities are more critical in AP than age.6Szakacs Z. et al.Front Physiol. 2018; 9: 1776Crossref PubMed Scopus (0) Google Scholar These conclusions are in line with the findings of the present study and support our above-detailed hypothesis. Besides the negative effect of comorbidities on the outcome of pancreatitis, culprit drugs have direct toxic effects on acinar cells as well. Asparaginase, for example, was shown to cause cellular necrosis.7Peng S. et al.Biol Sci. 2016; 37: 1700Google Scholar Importantly, here we report for the first time that when rechallenge was done with a decreased dose of the offending drug, it resulted in less severe outcomes. The main strength and limitations of this study are in Supplementary Document 1. Here we conclude that reported cases of DIAP have worse outcomes than AP of other etiologies and seem to be dose-dependent. If rechallenge is necessary, we recommend that patients are closely monitored and receive a reduced drug dose. Evidence-based guidelines on DIAP and rechallenge should be developed. Ágnes Meczker MSC (Conceptualization: Equal; Data curation: Equal; Investigation: Equal; Writing – original draft: Lead). Lilla Hanák MSC (Conceptualization: Equal; Data curation: Equal; Formal analysis: Lead; Writing – original draft: Equal). Andrea Párniczky, MD PhD (Formal analysis: Equal; Writing – review & editing: Equal). Andrea Szentesi, PhD (Formal analysis: Equal; Writing – review & editing: Equal). Bálint Erőss, MD, PhD (Conceptualization: Equal; Investigation: Equal; Writing – original draft: Lead). Péter Hegyi, MD, PhD, DSc, MAE (Conceptualization: Equal; Data curation: Equal; Writing – review & editing: Lead). Hungarian Pancreatic Study Group: Erdősi D, Mikó A, Szakács Zs, Dobszai D, and Szapáry L: Institute for Translational Medicine, Medical School, Szentágothai Research Centre, University of Pécs, Pécs, Hungary; Bajor J, Mikó A, and Vincze Á: Department of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary; Matuz M and Csupor D: Department of Clinical Pharmacy, Faculty of Pharmacy, University of Szeged, Hungary; Gábor Pethő: Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary; and Heim Pál: Children's Hospital, Budapest. Drug-induced acute pancreatitis (DIAP) is regarded as a rare entity; yet, it is estimated to account for approximately 2% to 5% of acute pancreatitis (AP) episodes worldwide.1Eland I.A. Van Puijenbroek E.P. Sturkenboom M.J.C.M. Wilson J.H.P. Stricker B.H.C. Drug-associated acute pancreatitis: twenty-one years of spontaneous reporting in the Netherlands.Am J Gastroenterol. 1999; 94: 2417-2422Crossref PubMed Scopus (115) Google Scholar, 2Trivedi C.D. Pitchumoni C.S. Drug-induced pancreatitis: an update.J Clin Gastroenterol. 2005; 39: 709-716Crossref PubMed Scopus (314) Google Scholar, 3Nitsche C. Maertin S. Scheiber J. Ritter C.A. Lerch M.M. Mayerle J. Drug-induced pancreatitis.Curr Gastroenterol Rep. 2012; 14: 131-138Crossref PubMed Scopus (110) Google Scholar, 4Balani A.R. Grendell J.H. Drug-induced pancreatitis: incidence, management and prevention.Drug Saf. 2008; 31: 823-837Crossref PubMed Scopus (154) Google Scholar, 5Vinklerová I. Procházka M. Procházka V. Urbánek K. Incidence, severity, and etiology of drug-induced acute pancreatitis.Dig Dis Sci. 2010; 55: 2977-2981Crossref PubMed Scopus (87) Google Scholar However, estimates vary due to the challenging diagnosis and the difficulties of causality assessment.6Badalov N. Baradarian R. Iswara K. Li J. Steinberg W. Tenner S. Drug-induced acute pancreatitis: an evidence-based review.Clin Gastroenterol Hepatol. 2007; 5 (quiz 664): 648-661Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar, 7Naranjo C.A. Busto U. Sellers E.M. et al.A method for estimating the probability of adverse drug reactions.Clin Pharmacol Ther. 1981; 30: 239-245Crossref PubMed Scopus (9017) Google Scholar, 8Karch F.E. Lasagna L. Adverse drug reactions. A critical review.JAMA. 1975; 234: 1236-1241Crossref PubMed Scopus (461) Google Scholar Because DIAP has no unique features that would help in distinguishing a case of DIAP from other etiologies, a rechallenge with the offending drug resulting a relapse of DIAP still means the most reliable evidence in confirming the etiology.3Nitsche C. Maertin S. Scheiber J. Ritter C.A. Lerch M.M. Mayerle J. Drug-induced pancreatitis.Curr Gastroenterol Rep. 2012; 14: 131-138Crossref PubMed Scopus (110) Google Scholar,9Jones M.R. Hall O.M. Kaye A.M. Kaye A.D. Drug-induced acute pancreatitis: a review.Ochsner J. 2015; 15: 45-51PubMed Google Scholar In most cases, intentional rechallenge is considered unethical due to the potentially life-threatening complications of AP; therefore, DIAP remains a speculative diagnosis of exclusion. The subject of past reviews is usually the categorization of the drugs based on their reported frequency of provoking DIAP4Balani A.R. Grendell J.H. Drug-induced pancreatitis: incidence, management and prevention.Drug Saf. 2008; 31: 823-837Crossref PubMed Scopus (154) Google Scholar,10Spanier B.W. Tuynman H.A. van der Hulst R.W. Dijkgraaf M.G. Bruno M.J. Acute pancreatitis and concomitant use of pancreatitis-associated drugs.Am J Gastroenterol. 2011; 106: 2183-2188Crossref PubMed Scopus (46) Google Scholar and the analysis of the strength of the causal relationship between the drug intake and the AP episode.11Mallory A. Kern Jr., F. Drug-induced pancreatitis: a critical review.Gastroenterology. 1980; 78: 813-820Abstract Full Text PDF PubMed Scopus (354) Google Scholar, 12McArthur K.E. Review article: drug-induced pancreatitis.Aliment Pharmacol Ther. 1996; 10: 23-38Crossref PubMed Scopus (95) Google Scholar, 13Wilmink T. Frick T.W. Drug-induced pancreatitis.Drug Saf. 1996; 14: 406-423Crossref PubMed Scopus (139) Google Scholar According to the literature, most cases of DIAP are mild, self-limited, and dose-independent, with a rapid resolution upon discontinuation of the offending drug.14Lankisch P.G. Dröge M. Gottesleben F. Drug induced acute pancreatitis: incidence and severity.Gut. 1995; 37: 565-567Crossref PubMed Scopus (222) Google Scholar However, in our previous study on 5-aminosalicylic acid–induced DIAP, we found that DIAP might not be dose-independent, and we saw more moderately severe cases than expected.15Meczker A. Miko A. Hegyi P. 5-ASA induces mild acute pancreatitis. Case report and review of the literature.J Gastrointestin Liver Dis. 2018; 27: 189-194Crossref PubMed Scopus (11) Google Scholar We performed a systematic literature search according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline.16Moher D. Shamseer L. Clarke M. et al.Preferred Reporting Items for Systematic Review and Meta-analysis protocols (PRISMA-P) 2015 statement.Syst Rev. 2015; 4: 1Crossref PubMed Scopus (14963) Google Scholar The review was registered on PROSPERO under the ID number CRD42017079196. The following PECO items were used: P = patients with AP; E = DIAP; C = AP caused by other etiologies; and O = severity, mortality, length of hospitalization (LOH), imaging alterations, symptoms, and time to resolution of AP. The search was performed in May 2019 on PubMed, EMBASE, and Cochrane Library with the search terms "acute pancreatitis" and "drug" and was limited to English-language and human studies (if applicable), regardless of the date of publication. Study selection was performed in parallel by 2 independent researchers. Studies that contained pooled statistical data of DIAP were excluded because they did not provide relevant data for our analysis. Records that contained relevant data on patients with DIAP were eligible for our study irrespective of study design (case reports included as well). Cases reported as DIAP in which alcoholic or gallstone or different obvious etiology could be suspected were not included. We developed an assessment tool for the reporting quality of the identified articles to exclude poorly reported cases, which would threaten data quality and the analysis. We identified 3 categories of reporting quality, based on the reported symptoms and signs of AP (abdominal pain, pancreatic enzyme elevation, imaging changes) and their causality with the offending drug. Strong evidence: The report contained data sufficient to reevaluate the event as DIAP. Moderate evidence: The report described the event as DIAP, but data only partially confirmed it (could not be reevaluated as AP). Weak evidence: The report described the event as DIAP, but there was no detailed data for reevaluation. In our analysis, we included in the statistical analysis only cases with strong evidence levels. We reevaluated all events documented by the authors as AP. Each was considered as AP if it met the criteria detailed in the evidence-based guidelines for the management of AP.17Working Group IAP/APA Acute Pancreatitis GuidelinesIAP/APA evidence-based guidelines for the management of acute pancreatitis.Pancreatology. 2013; 13: e1-e15PubMed Google Scholar,18Hritz I. Czakó L. Dubravcsik Z. et al.Acute pancreatitis. Evidence-based practice guidelines, prepared by the Hungarian Pancreatic Study Group.Orv Hetil. 2015; 156 ([in Hungarian]): 244-261Crossref PubMed Scopus (44) Google Scholar To assess severity, any organ failure reported by the authors was accepted, even if there were no supporting data. Persistent organ failure was defined that lasted longer than 48 hours or was described as persistent by the original authors themselves, transient organ failure was defined that resolved within 48 hours, or described as transient by the authors. We accepted the pancreatic enzyme level elevation as higher than triple the upper limit of normal if (1) the exact enzyme level and the upper limit of normal were described and the enzyme level exceeded more than 3 times, (2) the precise extent of elevation compared with the upper limit of normal was provided and was more than 3-fold, and (3) the exact pancreatic enzyme levels were given without their references but were higher than 300 U/L in the case of amylase and 180 U/L in the case of lipase. We considered the result of rechallenge positive if a trial with the suspected offending drug resulted in the increase of the pancreatic enzyme levels, with or without abdominal pain, nausea, or vomiting. To determine the severity of DIAP, we performed an evaluation using the data provided by the authors. We screened each case for the description of local and systemic complications and organ failure. If the detailed clinical data were available, the severity of DIAP was determined by the modified Atlanta criteria, irrespective of the classification by the original authors. If the lack of clinical data did not allow us to determine the severity of DIAP, we used the severity grade reported by the authors. The offending drugs were given to manage specific disorders. We defined these as the primary diseases. For the comparative statistical analysis of the DIAP cases to analyze them against AP of other etiologies, we used the detailed clinical data of the AP cohort of the Hungarian Pancreatic Study Group, as described in our previous studies19Szakacs Z. Gede N. Pecsi D. et al.Aging and comorbidities in acute pancreatitis II: a cohort-analysis of 1203 prospectively collected cases.Front Physiol. 2018; 9: 1776Crossref PubMed Scopus (21) Google Scholar, 20Farkas N. Hanák L. Mikó A. et al.A multicenter, international cohort analysis of 1435 cases to support clinical trial design in acute pancreatitis.Front Physiol. 2019; 10: 1092Crossref PubMed Scopus (21) Google Scholar, 21Parniczky A. Lantos T. Toth E.M. et al.Antibiotic therapy in acute pancreatitis: from global overuse to evidence based recommendations.Pancreatology. 2019; 19: 488-499Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 22Szentesi A. Párniczky A. Vincze Á. et al.Multiple hits in acute pancreatitis: components of metabolic syndrome synergize each other's deteriorating effects.Front Physiol. 2019; 10: 1202Crossref PubMed Scopus (47) Google Scholar We used descriptive statistical tools to characterize the population, and relative frequency and median and interquartile range were calculated. To analyze the differences between the severity groups for the LOH and the time that the enzyme level and symptoms normalized, we applied the Kruskal-Wallis test with the Mann-Whitney U test as a post hoc test. Differences between drug and disease categories and differences for DIAP against other etiologies of AP were examined using the χ2 test. We regarded a P value of <.05 as statistically significant. The available-case analysis was used for missing data. Statistical analyses were performed using IBM-SPSS for Windows 25 software (IBM Corp, Armonk, NY). We compared the severity and mortality rates of DIAP to AP caused by the more common etiologies like biliary diseases, idiopathic etiology, alcohol consumption, lipid metabolism disorder, status after endoscopic retrograde cholangiopancreatography, and the combinations of these. The detailed descriptive statistics of the AP cohort are shown in Supplementary Figure 1. We found that DIAP showed the most severe episodes if only the first episodes were analyzed (213 of 1060 [20.09%]; Supplementary Figure 1). If the severe cases of first and rechallenged events were pooled, the rate of severe cases was slightly but not significantly lower (227 of 1301 [18.41%]). Significant differences were seen between the rate of severe and mortality rates of DIAP cases if the first episodes are compared with rechallenges, at 20.09% vs 8.09% (P < .001) and 8.49% vs 2.07% (P < .001), respectively. Severity and mortality were increased in all DIAP compared with cases with all other etiologies, at 18.41% vs 5.63% (P < .001) and 7.30% vs. 2.20% (P < .001), respectively. DIAP had the second highest mortality rate of all etiologies (8.49%). Only AP of combined alcoholic and biliary etiology had a similarly high mortality rate (8.7%; Supplementary Figure 1). Antiprotozoal drugs, corticosteroids, and antiretrovirals were responsible for the most severe cases of DIAP in 12 of 26 patients (46.15%), 13 of 30 (43.33%), and 7 of 19 (36.84%), respectively. Corticosteroids, antiprotozoal drugs, and antiretrovirals had the highest mortality rates, at 12 of 30 patients (40.00%), 8 of 26 (30.77%), and 5 of 19 (26.32%), respectively. Patients who were taking antiprotozoals (46.15%; P < .01), corticosteroids (43.33%; P < .01), antihypertensives (29.51%; P < .05), and antineoplastics (24.58%; P < .001) had a higher chance of severe disease than patients taking other drugs. In contrast to this, patients taking anti-inflammatory drugs for inflammatory bowel disease (10.53%; P < .5), antibiotics (7.03%; P < .001), or other drugs than the specified ones (14.29%; P < .05) had a lower chance of a severe episode than patients taking other drugs. Patients taking anticonvulsants had a significantly higher chance of moderately severe DIAP (24.27%; P < .001) than patients taking other drugs. Patients taking corticosteroids (40.00%; P < .001), antiprotozoals (30.77%; P < .01), antiretrovirals (26.32%; P < .05), antihypertensives (21.31%; P < .01), and patients on multiple medications (15.58%; P < .05) had a higher chance of mortality than those taking other drugs. However, patients on antibiotics had a smaller chance of mortality than patients taking other drugs (3.15%; P < .05; Supplementary Table 1). The severity of DIAP was analyzed for subgroups of primary diseases, which showed that patients with breast cancer, hematologic conditions, and cardiovascular failure had the highest rates of severe DIAP, at 6 of 19 (31.58%), 45 of 155 (29.03%), and 20 of 77 (25.97%), respectively. Underlying gastrointestinal tract disease had a lower chance of severe DIAP (12.15%; P < .001) than other diseases. Hematologic disorders had a higher rate of a severe DIAP episode (29.03%; P < .001) than in other conditions. Neurologic conditions had a significantly higher chance for a moderately severe DIAP (20.89%; P < .001) than in other diseases. Mortality was lower among patients with gastrointestinal tract disease (3.38%; P < .01) and higher in multiple diseases (19.61%; P < .05), heart and circulatory diseases (19.48%; P < .001), and systemic diseases (17.65%; P < .05) than in other diseases (Supplementary Table 2). To our knowledge, this is the only study that comprehensively searched and identified all DIAP cases in the literature. We followed a rigorous methodology, including data extraction and quality analysis of each individual article, to generate an extensive database of reported cases of DIAP. We used this broad database to analyze the natural history of DIAP. Our systematic and comprehensive search identified and resulted in a very detailed data of 1060 cases of DIAP. To date, this is the largest and most comprehensive analysis of all reported cases of DIAP. Because we collected data on the first episodes of DIAP and on rechallenges, we could compare the 2 entities. This study is based on data extracted from case reports and case series, which introduces all of the limitations of the genre, most importantly, recall and publication bias.23Nissen T. Wynn R. The clinical case report: a review of its merits and limitations.BMC Res Notes. 2014; 7: 264Crossref PubMed Scopus (318) Google Scholar The publication bias was increased by the English language filter, which we had to use due to a large number of records identified by the preliminary search. Case reports and series publications, which are almost always written in retrospect, may contain insufficient data, which is a concern. The latency period between drug exposure and the start of the pancreatitis episode was not defined, and this is a limitation of our study. Owing to the lack of data, Naranjo's score could not be used,23Nissen T. Wynn R. The clinical case report: a review of its merits and limitations.BMC Res Notes. 2014; 7: 264Crossref PubMed Scopus (318) Google Scholar which is another significant limitation of the interpretation of the results. The definition of DIAP after rechallenge needs careful consideration. The fluctuation of pancreatic enzyme levels and incomplete resolution of morphologic changes after an episode of acute pancreatitis make the clinical assessment of recurrent pancreatitis difficult, following the rechallenge with the suspected drug. Preferred Reporting Items for Systematic Review and Meta-analysis Details of studiesSupplementary Table 1The Association of the Drug Categories With the Severity and Mortality Rates of Drug-Induced Acute PancreatitisDrugRanking based on severity (class of drugs)SexAge, ySeverityFrequencySeverityMortalitySevereModerateMildYesNoMaleFemale<1818-3030-5050-70≥70Antiprotozoalsn261227.6912818188013130046.15%%2.4546.15aP < .01.7.6946.1530.77aP < .01.69.2369.2330.770.0050.0050.000.000.00Corticosteroidsn301331412181812114681%2.8343.33aP < .01.10.0046.6740.00bP < .001.60.0060.0040.0036.6713.3020.0026.673.33Antiretrovirals (AIDS)n19739514118331030%1.7936.8415.7947.3726.32cP < .05.73.6857.8942.1115.7915.7952.6315.790.00Antipsychoticsn40126223372614272163%3.7730.0015.0055.007.5092.5065.0035.005.1317.9553.8515.387.69Antihypertensivesn6118142134834270713338%5.7529.51cP < .05.1.6468.8521.31aP < .01.78.6955.7444.260.0011.4821.3154.1013.11Analgesics (non-NSAIDs)n17501211631424641%1.6029.410.0070.595.8894.1217.6582.3511.7623.5335.2923.535.88Gonadal hormonesn257315124817081610%2.3628.0012.0060.004.0096.0032.0068.000.0032.0064.004.000.00Antidiabeticsn5415633351243002142810%5.0927.7811.1161.115.5694.4444.4455.560.003.7025.9351.8518.52Antineoplasticsn179443510081478396861830378%16.8924.58bP < .001.19.5555.875.1694.8446.3753.6348.0410.0616.7620.674.47Anticonvulsantsn103192559994613962151275%9.7218.45bP < .001.24.2757.288.7491.2661.0039.0061.3914.8511.886.934.95Immunosuppressantsn3342270321913108681%3.1112.126.0681.820.00100.0059.3840.6330.3024.2418.1824.243.03NSAIDsn3741320371522657109%3.4910.812.0786.490.00100.0040.5459.4616.2213.5118.9227.0324.32Anti-inflammatory drugs for IBDn38413323616229121610%3.5810.53cP < .05.2.6386.845.2694.7442.1157.8923.6831.5842.112.630.00Antivirals (other than AIDS)n29322412817121312112%2.7410.346.9082.763.4596.5558.6241.383.4510.3441.3837.936.90Lipid-lowering drugsn212217219813013116%1.989.529.5280.959.5290.4838.1061.900.004.7814.2952.3828.57Antibioticsn12899110412358691228343022%12.087.03bP < .001.7.0385.943.15cP < .05.96.8545.6754.339.5222.2226.9823.8117.46Psychoactivesn1612131151511104016.25%%1.516.2512.5081.256.2593.7593.756.256.2562.5025.000.006.25Othern126188100512161641814373620%11.8914.29cP < .05.6.3579.373.9796.0348.8051.2014.4011.2029.6028.8016.00On multiple medicationsn78167551265413751319329%7.3620.518.9770.5115.58cP < .05.84.4252.5647.446.4116.6724.3641.0311.54Totaln106021311872990943536518228175279266106%100.0020.0911.1368.778.7191.2950.8549.1521.6316.6026.4725.2410.06IBD, inflammatory bowel disease; NSAID, non-steroidal anti-inflammatory drug.a P < .01.b P < .001.c P < .05. Open table in a new tab Supplementary Table 2The Association of the Primary Conditions With the Severity and Mortality Rates of Drug-Induced Acute PancreatitisRanking based on severity (organ systems affected by the primary diseases)Primary conditionFrequencySeverityMortalitySexAge, ySeveritySevereModerateMildYesNoMaleFemale<1818-3030-5050-70≥70Breast cancern19631001901900136031.58%%1.7931.5815.7952.630.00100.000.00100.000.000.0068.4231.580.00Hematologicn155452981151228471902322173%14.6229.03aP < .001.18.7152.2610.9589.0554.1945.8158.0614.8414.1910.971.94Heart and circulationn77203541562393819143815%7.2625.973.9070.1319.48aP < .001.80.5250.6549.351.3011.6918.1849.3519.48Respiratory tractn461033354023233614176%4.3421.746.5271.7411.1188.8950.0050.006.5213.0430.4336.9613.04Systemicn5111337942262510813146%4.8121.575.8872.5517.65bP < .05.82.3550.9849.0219.6115.6925.4927.4511.76Neurologicn158313394101488869622838209%14.9119.62aP < .001.20.8959.496.3393.6756.0543.9539.4917.8324.2012.745.73Bone, muscle, cartilage, skinn66119463623530115122016%6.2316.6713.6469.704.6295.3853.8546.1517.197.8118.7531.2525.00Genitourinary systemn8113662774265461933176%7.6416.057.4176.548.6491.3632.5067.507.4123.4640.7420.997.41Gastrointestinal tractn214261617272001121012131527930%20.1912.15aP < .001.7.4880.373.38cP < .01.96.6252.5847.429.8614.5524.4137.0914.08Thyroid glandn141112014212204537.14%%1.327.147.1485.710.00100.0014.2985.7114.290.0028.5735.1721.43Othern105218767985944142735189%9.9120.007.6272.386.6793.3357.2842.7213.5926.2133.9817.488.74Multiple diseasesn5116431104131207142172%4.8131.377.8460.7819.61bP < .05.80.3960.7839.2213.7327.4541.1813.733.92No datan232021221111215881%2.178.700.0091.308.7091.3047.8352.174.3521.7434.7834.784.35Totaln106021311872990943536518228175279266106%10020.0911.1368.778.7191.2950.8549.1521.6316.6026.4725.2410.06a P < .001.b P < .05.c P < .01. Open table in a new tab IBD, inflammatory bowel disease; NSAID, non-steroidal anti-inflammatory drug. Drug-induced Acute Pancreatitis: Anecdotal Evidence vs Prospective EvaluationGastroenterologyVol. 160Issue 7PreviewWe have read with great interest the analysis by Meczker et al1 reporting on 1060 patients with drug-induced acute pancreatitis (DIAP). The authors meticulously collected data from worldwide published case reports and case series of DIAP and compared them with a Hungarian cohort of 1225 patients with acute pancreatitis of any cause. Because case reports and case series are composed in retrospect, we were wondering why the authors did not consider data from published prospective cohort studies for their analysis, particularly because this was not explicitly excluded by the study design. Full-Text PDF
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