UNASSIGNED: The aim of this case-control study was to determine if exposure to tumor necrosis factor alpha inhibitors (TNFIs) or immunomodulators (thiopurines or methotrexate) was associated with development of primary gastrointestinal lymphoma (PGIL) in patients with chronic inflammatory conditions.
UNASSIGNED: Patients with PGIL and controls evaluated at a tertiary care center over 20 years were matched 1:3 using a medical record informatics search engine based on their chronic inflammatory condition (Crohn\'s disease [CD], ulcerative colitis [UC], rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis) and duration of follow-up. Patients who started on TNFI within 3 months of PGIL diagnosis were excluded. We extracted demographics, medical history, and medications used. Univariate models using conditional logistic regression were used due to the small number of matched pairs.
UNASSIGNED: Twenty PGIL cases matched with 60 controls were followed for a mean 9.9 ± 6.9 and 9.7 ± 8.6 years, respectively. Mean age at time of PGIL diagnosis was 47.5 ± 22.0 (standard deviation) years and the majority (75%) were males. The most common inflammatory diagnosis was inflammatory bowel disease (80% of cases; 45% with UC and 35% with CD). Development of PGIL was not associated with TNFI (odds ratio [OR] = 2.6; 95% confidence interval [CI] 0.69-11.01; P = .18), but with use of TNFI in combination with thiopurines (OR = 8.93; 95% CI 1.43-80.25; P = .014). Risk of PGIL increased with every additional TNFI (2.277 (1.002-5.713); P = .0494). All cases exposed to multiple TNFI were also exposed to thiopurines. Use of thiopurines (alone or in combination) was the greatest risk factor (OR = 6.32; 95% CI 1.55-37.05; P = 0.006) to develop PGIL.
UNASSIGNED: TNFI therapy was not associated with increased risk for PGIL unless used in combination with thiopurines and with every switch to a different TNFI.

BACKGROUND: Risk factors for developing pancreatitis due to thiopurines in patients with inflammatory bowel disease (IBD) are not clearly identified. Our aim was to evaluate the predictive pharmacogenetic risk of pancreatitis in IBD patients treated with thiopurines.
METHODS: We conducted an observational pharmacogenetic study of acute pancreatitis events in a cohort study of IBD patients treated with thiopurines from the prospectively maintained ENEIDA registry biobank of GETECCU. Samples were obtained and the CASR, CEL, CFTR, CDLN2, CTRC, SPINK1, CPA1, and PRSS1 genes, selected based on their known association with pancreatitis, were fully sequenced.
RESULTS: Ninety-five cases and 105 controls were enrolled; a total of 57% were women. Median age at pancreatitis diagnosis was 39 years. We identified 81 benign variants (50 in cases and 67 in controls) and a total of 35 distinct rare pathogenic and unknown significance variants (10 in CEL, 21 in CFTR, 1 in CDLN2, and 3 in CPA1). None of the cases or controls carried pancreatitis-predisposing variants within the CASR, CPA1, PRSS1, and SPINK1 genes, nor a pathogenic CFTR mutation. Four different variants of unknown significance were detected in the CDLN and CPA1 genes; one of them was in the CDLN gene in a single patient with pancreatitis and 3 in the CPA1 gene in 5 controls. After the analysis of the variants detected, no significant differences were observed between cases and controls.
CONCLUSIONS: In patients with IBD, genes known to cause pancreatitis seem not to be involved in thiopurine-related pancreatitis onset.

BACKGROUND: Patients with Cohn\'s disease (CD) treated with thiopurines are at an increased risk of developing cancer. Leukemias are less frequent than other hematopoietic tumors and the development of Chronic myeloid leukemia (CML) after immunosuppression has not been proven.
METHODS: We describe the case of a 61-year-old female who developed a CML after 8 years of treatment with azathioprine (AZA) for ileal Crohn\'s disease associated with a duodenal localization. We reviewed the current evidence on the interactions between CD, CML and AZA as well as the potential underlying mechanisms of leukemia in AZA-treated patients.
CONCLUSIONS: We concluded that the pathogenesis of CML is multifactorial in CD. The nature of the association between AZA and CML in CD patients warrants further investigation.

UNASSIGNED: Azathioprine (AZA)-induced leukopenia is a common but life-threatening complication of inflammatory bowel disease. Recent studies have found an association between leukopenia and nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) mutation in the Asian population.
UNASSIGNED: A 26-year-old Caucasian woman with Crohn\'s disease presented with severe neutropenia after initiating AZA treatment. While genetic testing did not detect any thiopurine S-methyltransferase (TPMT) mutations, sequencing of NUDT15 showed R139C homozygous mutation. The absolute neutrophil count normalised following discontinuation of AZA treatment and initiation of granulocyte-colony stimulation factor administration.
UNASSIGNED: NUDT15 R139C mutation can be used as a predictive factor for AZA-induced leukopenia in both European and Asian populations. The association between TPMT mutations and AZA-induced leukopenia is well established. However, TPMT mutations are less common among Asian patients than among Caucasian patients. The correlation between single-nucleotide mutations in NUDT15 and leukopenia during thiopurine administration was recently demonstrated. The variant allele frequency of NUDT15 is 10-20% in Asians in contrast to 0.4% in Caucasians. Recent studies have showed that AZA treatment of patients with homozygous mutations should be avoided. Moreover, further research is needed to determine the optimal dosage for patients with heterozygous mutations. Some studies have suggested that pre-treatment genotyping can reduce myelosuppression, the number of outpatient visits, and healthcare-associated costs.
UNASSIGNED: NUDT15 variant R139C is a strong predictor of thiopurine-induced neutropenia to a greater extent in individuals of Asian descent than in those of Caucasian descent. Therefore, it is recommended to perform NUDT15 genotyping before initiating AZA treatment.

BACKGROUND: Differential diagnosis between extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue and inflammatory bowel disease is mainly based on histopathologic evaluation of intestinal biopsies, although there is no single definitive diagnostic investigation and that circumstance can lead to misdiagnosis in particular cases. Herein we present a rare, ulcerative form of marginal zone lymphoma which mimics the Crohn\'s disease (CD) of upper digestive tract.
METHODS: A 50-year-old man was presented with recurrent episodes of malaise and melena also weight loss. Enteroscopy of the small bowel demonstrated an ulcer in the jejunum. Microscopically, biopsies showed lymphoplasmacytic infiltrate. Diagnosis of CD was made. Primary treatment consisted of prednisone and azathioprine and was followed by azathioprine 100 mg per day with good clinical response in the following 2 years until relapse. At this time the results of endoscopic biopsies derived from proximal wall of stomach revealed Helicobacter pylori-negative marginal zone lymphoma of the gastric fundus. Immunophenotyping confirmed atypical CD20-positive cell population. Based on these biopsies, marginal zone lymphoma of mucosa-associated lymphoid tissue was diagnosed. Unfortunately, the contact with the patient was lost until one year later he was hospitalized with nausea, vomiting and severe pain because of gastrointestinal perforation. Four months later after laparotomy, the patient was treated with a course of chemotherapy. Complete remission was observed following 6 cycles of treatment.
CONCLUSIONS: This case report highlights the clinical relevance of knowledge and awareness of marginal zone lymphoma simulating CD.

The risk of developing a lymphoproliferative disease associated with inflammatory bowel disease (IBD) has been a controversial issue for decades; it is debatable whether the risk is associated with the chronic inflammation of IBD per se or its treatment, especially with thiopurine drugs (azathioprine and mercaptopurine) and anti-TNF-α agents. We present an unusual case of a 35-year-old man who had been diagnosed with Crohn\'s disease at age 17 and treated with azathioprine, presenting years later with an intestinal Hodgkin\'s lymphoma.

Immunosuppressant medications for Inflammatory Bowel Disease can help with both symptoms and disease progression. However, like immunosuppressants used in transplant patients, they are now suspect of contributing to nonmelenoma skin cancer (NMSC). Presented is a case of a 57-year-old Jewish man with Crohn\'s Disease who was diagnosed with a total of 84 NMSCs. We hope to elucidate the risk of immunosuppressants, particularly the thiopurines, on the development of NMSC.