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

The overall cerebral palsy rate was 9%: 0% in the singleton survivors group and 13.3% in the twin survivors group. This pilot data highlights the need for careful long term follow up of children affected by twin-to-twin transfusion syndrome.

Objective To examine the postnatal development of a group of children born after in utero laser ablation therapy for severe twin-to-twin transfusion syndrome. Design Retrospective cohort outcome study involving assessment of neurodevelopment and physical well being.Setting Harris Birthright Centre, King's College Hospital, London.Participants Twins and singleton survivors treated via laser ablation therapy for twin-to-twin transfusion syndrome over a four-year period. Methods Of 54 families contacted to participate in the study, who had been treated for twin-to-twin transfusion syndrome during a four-year period, 24 families attended for paediatric assessment; 12 pairs of twins and 12 singleton survivors were assessed for perinatal, neurological and neurodevelopmental outcome using the Griffiths scales of mental development. A further 20 families were assessed via a proforma after contact with their general practitioner. A comparison of these groups showed no significant differences in sociodemographic factors or severity of disease between responders (44 families, 81.5%) and non-responders (10 families). Results The group of children assessed by a paediatrician had low birthweight (1619g donor, 1814g recipient, 1877g singleton) and had been born preterm (33 weeks twins, 31.2 weeks singleton) with attendant increased resuscitation, neonatal unit admission (mean 40 days) and instrumental delivery. Mean Griffiths scores were within the normal range of ability (91.2 donor vs 97.7 recipient and 101.6 singletons) with the only significant difference being in the locomotor subscale where donor (82.6) and recipient (85.3) were less than singletons: -99.1 (P , 0.05). There was no cerebral palsy in the singleton survivors, but there were five cases in the twin group. All except one affected child (with quadriplegia) had mean Griffiths scores in the normal range. In the GP proforma group there was one case, in a twin, of cerebral palsy. Conclusion The overall cerebral palsy rate was 9%: 0% in the singleton survivors group and 13.3% in the twin survivors group. This pilot data highlights the need for careful long term follow up of children affected by twin-to-twin transfusion syndrome.

Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) is a highly pleiotropic disorder, particularly affecting the eye, brain, bone, and gut. The potential catastrophic sequelae of the associated gastrointestinal phenotype, variably characterised by both chronic bleeding and liver failure, is becoming increasingly apparent. Here we report a probable case of CRMCC with pre- and postnatal growth restriction, bilateral exudative retinopathy, a pathognomonic pattern of intracranial calcification, white matter disease, osteopenia with a tendency to fractures, and chronic gastrointestinal bleeding secondary to abnormal dilated vasculature. The gastrointestinal endoscopic findings were characteristic of gastric antral vascular ectasia (GAVE). Treatment with a combination of oral oestrogen and progesterone ameliorated the gastrointestinal blood loss such that monthly blood transfusions could be stopped. The benefit of this relatively benign therapy in managing the potentially life-limiting consequences of an abnormal gastrointestinal vasculature in CRMCC is of great interest.