Background Anti-TNF drugs are effective treatments for the management of Crohn's disease but treatment failure is common. We aimed to identify clinical and pharmacokinetic factors that predict primary non-response at week 14 after starting treatment, non-remission at week 54, and adverse events leading to drug withdrawal.Methods The personalised anti-TNF therapy in Crohn's disease study (PANTS) is a prospective observational UK-wide study. We enrolled anti-TNF-naive patients (aged ≥6 years) with active luminal Crohn's disease at the time of first exposure to infliximab or adalimumab between March 7, 2013, and July 15, 2016. Patients were evaluated for 12 months or until drug withdrawal. Demographic data, smoking status, age at diagnosis, disease duration, location, and behaviour, previous medical and drug history, and previous Crohn's disease-related surgeries were recorded at baseline. At every visit, disease activity score, weight, therapy, and adverse events were recorded; drug and total anti-drug antibody concentrations were also measured. Treatment failure endpoints were primary non-response at week 14 ,non-remission at week 54, and adverse events leading to drug withdrawal. We used regression analyses to identify which factors were associated with treatment failure. Findings We enrolled 955 patients treated with infliximab (753 with originator; 202 with biosimilar) and 655 treated with adalimumab. Primary non-response occurred in 295 (23•8%, 95% CI 21•4-26•2) of 1241 patients who were assessable at week 14. Non-remission at week 54 occurred in 764 (63•1%, 60•3-65•8) of 1211 patients who were assessable, and adverse events curtailed treatment in 126 (7•8%, 6•6-9•2) of 1610 patients. In multivariable analysis, the only factor independently associated with primary non-response was low drug concentration at week 14 (infliximab: odds ratio 0•35 [95% CI 0•20-0•62], p=0•00038; adalimumab: 0•13 [0•06-0•28], p<0•0001); the optimal week 14 drug concentrations associated with remission at both week 14 and week 54 were 7 mg/L for infliximab and 12 mg/L for adalimumab. Continuing standard dosing regimens after primary non-response was rarely helpful; only 14 (12•4% [95% CI 6•9-19•9]) of 113 patients entered remission by week 54. Similarly, week 14 drug concentration was also independently associated with non-remission at week 54 (0•29 [0•16-0•52] for infliximab; 0•03 [0•01-0•12] for adalimumab; p<0•0001 for both). The proportion of patients who developed anti-drug antibodies (immunogenicity) was 62•8% (95% CI 59•0-66•3) for infliximab and 28•5% (24•0-32•7) for adalimumab. For both drugs, suboptimal week 14 drug concentrations predicted immunogenicity, and the development of anti-drug antibodies predicted subsequent low drug concentrations. Combination immuno-modulator (thiopurine or methotrexate) therapy mitigated the risk of developing anti-drug antibodies (hazard ratio 0•39 [95% CI 0•32-0•46] for infliximab; 0•44 [0•31-0•64] for adalimumab; p<0•0001 for both). For infliximab, multivariable analysis of immunododulator ...

BACKGROUND & AIMS: Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies. METHODS: We performed a genomewide association study to identify variants associated with time to development of anti-drug antibodies in a discovery cohort of 1240 biologic-naïve patients with Crohn's disease starting infliximab or adalimumab therapy. Immunogenicity was defined as an anti-drug antibody titer !10 AU/mL using a drug-tolerant enzyme-linked immunosorbent assay. Significant association signals were confirmed in a replication cohort of 178 patients with inflammatory bowel disease. RESULTS: The HLA-DQA1*05 allele, carried by approximately 40% of Europeans, significantly increased the rate of immunogenicity (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60-2.25; P ¼ 5.88 Â 10-13). The highest rates of immunogenicity, 92% at 1 year, were observed in patients treated with infliximab monotherapy who carried HLA-DQA1*05; conversely the lowest rates of immunogenicity, 10% at 1 year, were observed in patients treated with adalimumab combination therapy who did not carry HLA-DQA1*05. We confirmed this finding in the replication cohort (HR, 2.00; 95% CI, 1.35-2.98; P ¼ 6.60 Â 10-4). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33), and for patients treated with anti-TNF therapy alone

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.

I Tiwari, Z Mazhar, W Uddin, PJH Fletcher, Comparison of Dual and Triple Therapy for the Eradication of Helicobacter Pylori in Duodenal Ulcer Patients. 1997; 17(6): 656-658 Helicobacter pylori (H. pylori) is thought to be responsible for 95% of duodenal ulcers. It is also thought that eradication of this organism will lead to the cure for duodenal ulcers.1 The optimal treatment regime for the eradication of H. pylori has not yet been defined, but the treatment which is effective in developed countries may not be suitable for patients in the developing world. The attempted eradication of H. pylori with antibacterial monotherapy has been not been encouraging. Because of poor compliance and higher side effects from the standard "triple therapy," consisting of bismuth, tetracycline and metronidazole, 2 there is a need to develop a simple, welltolerated regime for the eradication of H. pylori. Recently, a combination therapy with proton pump inhibitors and antibiotics has shown good results for the eradication of this infection. An eradication rate of 98% has been reported with a combination of omeprazole, clarithromycin, and tinidazole for one week.3 Dual therapy with omeprazole and clarithromycin for two weeks gave an eradication rate of 80%. 4 A combination of lansoprazole 30 mg daily for four weeks, and clarithromycin 500 mg three times daily for two weeks, eradicated H. pylori in 54% of patients, 5 while triple therapy with lansoprazole, clarithromycin and metronidazole for one week eradicated the infection in 92% of patients. 6 This combination of therapy has not been tested in patients in the Middle East. We conducted this study to compare the eradication of H. pylori with dual (lansoprazole and clarithromycin) and triple (lansoprazole, clarithromycin and tinidazole) therapy in patients with duodenal ulcer. Patients and MethodsPatients found to have duodenal ulcer on routine gastrointestinal endoscopy were selected for the study. Those with a history of gastrointestinal bleeding, pregnancy or H2 blocker, or antibiotic therapy in the preceding four weeks were excluded. From the eligible patients, three gastric and antral biopsies were taken, one for urease activity (CLO test, Delta West, West Australia), and the other two for histopathology. The tissue for histopathology was fixed in routine formalin fixative and embedded in paraffin wax. Sections were cut at several levels, and stained by hematoxylin and eosin for routine examination, and by the modified Giemsa method for the demonstration of H. pylori. Patients were considered H. pylori-positive if both CLO test and histology were positive. Patients with negative CLO test and histology for H. pylori were excluded from the study. Informed consent was obtained from the H. pylori-positive patients. The study was approved by the local ethics committee.Patients accepted for the study were randomized into two treatment groups by the selection of sealed envelopes. Group A received lansoprazole 30 mg daily for four weeks, and clarithromycin 500 mg twice daily for ...