Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 × 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.

IMPORTANCEUse of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM).OBJECTIVE To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). DESIGN, SETTING, AND PARTICIPANTSCase-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. EXPOSURES Genetic variants associated with TIM.MAIN OUTCOMES AND MEASURES Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 10 9 /L or less or a decline in absolute neutrophil cell count to 1.0 × 10 9 /L or less leading to a dose reduction or drug withdrawal. RESULTS Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10 −9 ). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10 −8 ), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10 −7 ) of TIM, independent of TPMT genotype and thiopurine dose.CONCLUSIONS AND RELEVANCE Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

This is the largest and most detailed study of 5-ASA-induced nephrotoxicity to date. It highlights the morbidity associated with this condition and identifies for the first time a significant genetic predisposition to drug-induced renal injury.

There is still debate about whether continuous renal replacement therapy is superior to intermittent hemodialysis (IHD) as dialytic support for the critically ill patient with acute renal failure, mainly because of lack of comparative data. We sought to address this issue by reviewing the medical records of such patients admitted to a single surgical intensive care unit treated with either continuous arteriovenous hemodiafiltration (CAVHD) or IHD between January 1, 1986, and August 31, 1993. Of 94 consecutive patients who received dialytic support for severe acute renal failure, 34 (36%) patients were treated with IHD and 60 (64%) patients with CAVHD. The patients were comparable in terms of age or gender and represented a similar case mix. Patients treated with CAVHD were more severely ill as manifested by a lower mean arterial pressure (75 ± 3 vs. 86 ± 5 mm Hg; p < 0.05), higher Apache II score (26.5 ± 0.5 vs. 22.2 ± 0.3; p < 0.05), and a higher number of organ system failures (3.4 ± 0.2 vs. 2.6 ± 0.3; p < 0.05). Despite greater illness severity and a higher probability of death (55 ± 2.6 vs. 33 ± 2.5%; p < 0.0001), in those treated with CAVHD, no difference in outcome was observed between groups: CAVHD 26/60 (43%) vs. IHD 20/34 (59%; NS). The mean Apache II score of patients treated with CAVHD who survived was similar to that of patients treated with IHD who died (24.5 ± 0.3 vs. 24.2 ± 0.4; NS). CAVHD was associated with improved hemodynamic stability, better control of fluid balance and biochemistry, increased nutritional intake, and a shorter duration of acute renal failure (p < 0.05). Our data suggest that CAVHD offers several distinct advantages over IHD which may translate in improved survival, particularly in the more severely ill patients.

Background and Aims Anti‐Tumor Necrosis Factor (TNF)‐induced lupus (ATIL) is a distinct clinical entity, increasingly recognized in patients with inflammatory bowel disease treated with anti‐TNF therapy. Our aims were to evaluate the incidence and clinical and serological markers of ATIL in this population. Methods This observational cohort study reviewed 454 patient treatment courses with anti‐TNF therapy (300 infliximab and 154 adalimumab). A diagnosis of ATIL was based on the most widely accepted diagnostic criteria: (i) a temporal relationship between symptoms and anti‐TNF therapy and resolution of symptoms following cessation of the offending medication; (ii) at least one serologic American College of Rheumatology (ACR) criterion of Systemic Lupus Erythematosus (SLE); and (iii) at least one nonserological criterion such as arthritis, serositis, or rash. Clinical, demographic, and serological predictors were evaluated. Results The incidence rate of ATIL was 5.7% for infliximab and 0.6% for adalimumab, which are much higher than previously reported postmarketing estimates. The median duration to diagnosis following commencement of anti‐TNF therapy was 15 months (3–62 months). ATIL occurs more commonly patients that commence therapy at an older age (46.47 years ± 13.79 years vs. 38.85 years ± 14.75 years, P = 0.033). Conclusions ATIL is a significant complication of anti‐TNF therapy, affecting 1 in every 20 patients who commence infliximab. A panel of serological markers is useful to confirm the diagnosis and exclude other conditions that may mimic ATIL. Clinicians using anti‐TNF medications should counsel patients about this potential risk and monitor for clinical manifestations of lupus during routine follow up.