Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease.

Importance: Use 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 Participants: Case-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 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/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.

EUS-FNA versus biliary brushings and assessment of simultaneous performance in jaundiced patients with suspected malignant obstruction.

CONTEXT: Individuals with suspected malignant biliary obstruction commonly undergo ERCP for drainage and tissue sampling via biliary brushings. EUS with EUS-FNA facilitates staging and potentially more accurate tissue sampling. OBJECTIVE: The aim is to compare the diagnostic performance of EUS-FNA and ERCP with biliary brushings (ERCP-BB) in the diagnosis of pancreatobiliary carcinoma and the utility of combining the two procedures under conscious sedation. DESIGN: Retrospective analysis of a prospectively maintained database. PATIENTS: Thirty-seven patients with suspected malignant obstructive jaundice underwent 39 paired procedures, either combined (n=22) or within a few days (n=17). RESULTS: Using strict cytological criteria the sensitivity of EUS-FNA in the diagnosis of malignancy was 52.9% (95% CI: 35.1-70.2%) versus 29.4% (95% CI: 15.1-47.5%) for ERCP-BB. Combining the two tests improved sensitivity to 64.7% (95% CI: 46.5-80.3%) which was significantly better than ERCP-BB alone (P=0.001) but not EUS-FNA alone (P=0.125). When both procedures were performed under the same conscious sedation, there was a significant difference (P=0.031) between the sensitivity of EUS-FNA (52.6%; 95% CI: 28.9-75.6%) and that of ERCP-BB (21.1%; 95% CI: 6.1-45.6%). When both procedures were performed together the mean±SD in-room time was 79±14 min (range: 45-105 min). Two of the patients (9.1%) had a complication. CONCLUSIONS: In patients undergoing EUS-FNA and ERCP-BB under the same sedation, EUS-FNA was significantly more sensitive in diagnosing malignancy. Combining the results of both tests improved diagnostic accuracy. Combining therapeutic ERCP and EUS-FNA under the same conscious sedation is feasible, with a complication rate similar to that of ERCP alone.

Ocular manifestations of Wegener's granulomatosis. Analysis of nine cases.

PURPOSE: To report a series of nine patients of Wegener's granulomatosis (WG) with diverse ocular and systemic manifestations. METHODS: Retrospective analysis of nine consecutive patients seen between 1987 and 2002. RESULTS: The mean age at the time of diagnosis was 43.89 years (range: 33-56 years). Redness, pain and photophobia (8 patients) were the common presenting complaints. Sinusitis (6 patients) and arthralgia (6 patients) were the commonly associated systemic complaints. Necrotising scleritis with peripheral keratopathy (6 patients) was the most common ocular sign. Serum antibodies against the cytoplasmic component of neutrophils and monocytes (cANCA) were positive in 7 of 8 patients. Biopsy diagnosis was done in one patient for whom cANCA was not done. Cyclophosphamide and corticosteroids alleviated the symptoms in 6 patients. Ocular and systemic condition remained stable in 7 patients. One patient expired due to the severity of the disease and another patient was lost to follow-up. CONCLUSIONS: Scleritis with peripheral corneal involvement was the most commonly observed ocular manifestation of WG in our series. cANCA was a useful adjunct in the diagnosis of WG. When clinical and serologic findings were inconclusive, biopsy remained indispensable. A combination of cyclophosphamide and corticosteroids is essential and critical not only for the ocular condition but also for the survival of the patient.