Introduction and Aims: Hemodialysis (HD) sessions involve some risk of adverse hypersensitivity reactions as large amounts of blood are in contact with different synthetic materials. Our aim was to study the mechanisms of the allergic or "pseudoallergic" reactions to synthetic helixone (HX) dialysis membranes in "HX-allergic" patients who tolerated cellulose triacetate (CTA) membranes. As only exceptionally we had the opportunity of studying the acute phase of the allergic reaction we designed an "ex-vivo" approach to compare immune responses to both HX and CTA. Methods: Ten patients with adverse reactions to HX and 8 control non-allergic patients in hemodialysis were studied. 50 ml of blood was collected into heparin tubes. Ex-vivo HD were performed on experimental external circuits with low or high priming volumes and pediatric membranes (Fx-Paed helixone 0.2 m 2 and Sureflux 30L). Pre-dialysis and post-dialysis samples were collected. Serum tryptase levels, basophil degranulation (%HLA-DR -CD123 + CD63 + leukocytes), and T cell activation (CD69 expression on CD4 + and CD8 + subpopulations) were analyzed by flow cytometry Results: Basal serum tryptase levels were higher in HX-allergic patients as compared to

Exome-based panels (exome slices) are becoming the preferred diagnostic strategy in clinical laboratories, especially for genetically heterogeneous disorders.

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier will develop the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we applied clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias displayed effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers averaged below 60% in both studies for all conditions except monogenic diabetes. We assessed additional epidemiologic and genetic factors contributing to risk prediction, demonstrating that inclusion of common polygenic variation significantly improved biomarker estimation for two monogenic dyslipidemias.

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BackgroundSeveral factors influence on the pharmacokinetics(PK) of TNF inhibitors(TNFi). One of the most relevant influencing factors is the development of antidrug- antibodies(ADA), which is associated with low circulating drug levels and loss of clinical efficacy. Previous studies, mostly about Adalimumab (Ada), have demonstrated a beneficial effect of concomitant use of methotrexate(MTX) in patients(pts) under TNFi therapy by reduction of immunogenicity. There are other csDMARDs(OD) as leflunomide, hydroxycloroquine or sulfasalazine which may have also an effect on PK.ObjectivesTo investigate the effect of csDMARDs on the presence of serum TNFi levels and on the clinical response during the first year of Ada or Infliximab(Ifx) treatment in RA pts. Secondly, to evaluate if MTX has a dose-dependent effect on these outcomes.MethodsThis is an inception cohort including pts with RA starting Ifx or Ada in a tertiary hospital since 1999. At baseline, 6 and 12 months clinical(DAS28, EULAR response and ΔDAS28) and serological(drug and ADA levels) parameters were measured. Patients were clustered according to the use of concomitant csDMARDs at baseline in three groups: i)TNFi monotherapy;ii)TNFi +MTX;iii)TNFi +OD. Pts within the TNFi +MTX group were also classified according to the MTX dose:MTX <15 mg/week(TNFi +MTX <15) and MTX ≥15 mg/week(TNFi +MTX ≥15).ResultsA total of 92 RA pts[Ada(n=25) or Ifx(n=67)] under TNFi were included. The number and percentage of pts in each group were as follows:TNFi monotherapy,12 pts(13%);TNFi +MTX, 59 pts(64%);TNFi +OD 21 pts(23%). According to MTX dose, the distribution was:TNFi +MTX <15,18 pts(20%);TNFi +MTX ≥15, 41 pts(45%). Considering the overall of pts receiving any dose of MTX, the percentage of them with drug levels after 12 months(71%) was numerically higher than in the other groups(20% in TNFi +OD and 9% in TNFi monotherapy,p=0.1). However, after stratifying pts by MTX dose, we observed that circulating drug levels at 12 months were more frequent in higher dose of MTX(54% of the pts with TNFi +MTX ≥15) compared to patients with TNFi +MTX <15 (17%), with TNFi +OD(20%) and with TNFi monotherapy (9%);p=0.002). According to EULAR response, pts treated with TNFi +MTX(81%) achieved more frequently a good response compared with the other groups (11% on TNFi +OD and 8% on TNFi monotherapy, p=0.6). Moreover, differences on clinical response were observed depending on MTX dose. While 58% with TNFi +MTX ≥15 were good EULAR responders, 23% with TNFi +MTX <15 achieved this. Overall, the best effect on clinical response was observed in the group of MTX; p=0.4. Finally, the TNFi median survival time(mst) was significantly higher in pts with TNFi +MTX than in pts with TNFi +OD or on TNFi monotherapy(5 years vs 2 years vs 2.15 years, respectively;p=0.03). Analysing by MTX dose, drug survival was superior for high (≥15)and low MTX doses(<15) (mst 5.2 and 3.3, respectively)compared to OD and/or TNFi monotherapy although the difference was not statistically significant p=0.09.ConclusionsIn RA pts...