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

In children, fulminant hepatic failure is a rare multisystem disorder in which severe impairment of liver function, with or without encephalopathy, occurs in association with hepatocellular necrosis in a patient with no recognized underlying chronic liver disease. Recognized etiologies include infections, toxins, metabolic disorders, infiltrative diseases, autoimmune hepatitis, ischemic or irradiation damage; a proportion of cases are cryptogenic. The diagnosis of the cause is essential to institute lifesaving medical treatment, decide if transplantation is indicated, and offer genetic counseling. The maximum International Normalized Ratio *(INR) reached during the course of the illness is the most sensitive predictor of outcome, mortality being 86% with an INR > or = 4, and 27% with an INR < 4 in our own series. Prognosis is worse in children younger than 2 years. Thus, urgent transplantation should be considered when the INR reaches 4, particularly in very young children. Survival after transplantation is 60% to 68%. Children with fulminant hepatic failure must be treated in specialized centers with facilities for liver transplantation.

Diarrhoeal management practices are unsatisfactory in India especially in the slum areas. Dearth of information regarding physicians' diarrhoea-related knowledge and practice in India necessitated this cross-sectional study of allopathic practitioners in the slums of Kolkata, to assess the distribution and interrelationship between physicians' characteristics, knowledge and practice regarding diarrhoea. A total of 264 randomly selected consenting practitioners were interviewed using a field-tested questionnaire. Nineteen percent had good overall knowledge, 49% and 80% prescribed antibiotics to diarrhoea and cholera patients, respectively, and 55% advised stool examination for every case. Qualified and Government physicians had better knowledge regarding diarrhoea [MBBS: odds ratio (OR) 5·96, P < 0·001; postgraduates: OR 9·33, P < 0·001; Government physicians: OR 11·49, P < 0·0001] and were less likely to prescribe antibiotics for all diarrhoea cases (MBBS: OR 0·30, P = 0·002; postgraduates: OR 0·20, P < 0·001; Government physicians OR 0·24, P < 0·029). Better knowledge was associated with a lower likelihood of prescribing antibiotics for diarrhoea (OR 0·72, P < 0·001), cholera (OR 0·78, P = 0·027) and investigative procedure (OR 0·85, P = 0·028). In the slums of Kolkata, diarrhoea-related knowledge and practice were poor with the exception of qualified physicians, hence an improvement in the knowledge of pharmacists and unqualified practitioners is necessary for the overall improvement of diarrhoeal management in these slums.

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