Background Idiopathic non-histaminergic acquired angioedema (InH-AAE) does not respond to anti-histamines and is possibly mediated by bradykinin. Objective To investigate the efficacy and safety of recombinant human C1-esterase inhibitor (rhC1-INH), for prophylaxis of InH-AAE, and to evaluate contact system parameters as biomarkers for attacks. Methods A prospective, open-label study of patients with InH-AAE with > 2 AE attacks/month. rhC1-INH (50 IU/kg was administered intravenously; maximum 4200 IU) twice weekly for 2 months, preceded and followed by a one-month period of observation. The primary endpoint was a >50% reduction in attack frequency. C1INH-function and plasma levels of high molecular weight kininogen, factor XII, plasma prekallikrein, C4, cleaved kininogen, d-dimer were evaluated as potential biomarkers. Post-trial follow-up was evaluated in all patients. Results Six patients (mean age 41 years; four female) were enrolled. One patient showed a reduction in attack frequency of 84% (3 versus 19) during rhC1-INH treatment, and showed clinical response to plasma-derived C1-INH but not to omalizumab post-trial. Restarting rhC1-INH treatment resulted in a similarly rapid response. The other 5 patients showed no improvement. No major adverse events were reported. None of the measured biomarkers were related to treatment response. Post-trial, omalizumab was administered to four patients, of which two reported response. Conclusion rhC1-INH treatment was effective in 1 of 6 InH-AAE patients, suggesting a bradykinin-dependent mechanism of attacks in this patient. Response to omalizumab or tranexamic acid during follow-up in a number of the patients points to a heterogeneous pathogenesis of InH-AAE disease requiring a personalised treatment approach.

Background 49% of clinically diagnosed allergic rhinitis (AR) patients are sensitized to house dust mite (HDM). If allergen avoidance and symptomatic medication fail, allergen immunotherapy may be indicated. We investigated safety and tolerability of HDM-sublingual immunotherapy HDM SLIT-tablets in adults in daily clinical practice in the Netherlands. Methods Daily intake of 12 SQ-HDM SLIT-tablet was investigated in the prospective, multi-center, observational study. It comprised 4 consultations in 1 year. Data on safety, tolerability, treatment satisfaction, symptomatic medication, compliance, and clinical effectiveness (Control of Allergic Rhinitis and Asthma Test; CARAT) were collected. Descriptive and longitudinal regression data analysis was performed. Results 415 adult patients, mean age 36.6 years, 61.4% female, 36% asthmatic were included. 65.3% of patients experienced possibly-related adverse events (AEs). These mostly mild (67%) AEs comprised: oral allergic reactions (58.6%), respiratory (12.4%) and gastrointestinal symptoms (9.4%). 60 (14.5%) patients stopped due to AEs and 76 (18.3%) for non-AE reasons. Mean CARAT scores improved clinically significant by 6 points and symptomatic medication use decreased from 96.1% to 77.4%. 74.5% of patients tolerated the treatment well. Most patients were compliant (>86.5%) and patients (62.4 %) and investigators (69.4%) were satisfied with treatment. Conclusions HDM-SLIT-tablet is a safe and well-tolerated AR treatment. AEs occur often but are mostly mild and decreasing during the first year. CARAT scores improved and symptomatic medication use decreased suggesting better control of AR with HDMSLIT-tablet treatment. Compliance, tolerability, and treatment satisfaction are good. However, patient follow-up and compliance remain important points of attention when starting HDM SLIT-tablet.

Background Specific IgE against a peanut 2S albumin (Ara h2 or 6) is the best predictor of clinically relevant peanut sensitization. However, sIgE levels of peanut allergic and those of peanut sensitized but tolerant patients partly overlap, highlighting the need for improved diagnostics to prevent incorrect diagnosis and consequently unnecessary food restrictions. Thus, we sought to explore differences in V(D)J gene transcripts coding for peanut 2S albumin-specific monoclonal antibodies (mAbs) from allergic and sensitized but tolerant donors Methods 2S albumin-binding B-cells were single-cell sorted from peripheral blood of peanut allergic (n=6) and tolerant (n=6) donors sensitized to Ara h2 and/or 6 (≥ 0.1 kU/l) and non-atopic controls (n=5). Corresponding heavy and light chain gene transcripts were heterologously expressed as mAbs and tested for specificity to native Ara h2 and 6. HCDR3 sequence motifs were identified by Levenshtein distances and hierarchically clustering. Results The frequency of 2S albumin-binding B-cells was increased in allergic (median: 0.01%) compared to tolerant (median: 0.006%) and non-atopic donors (median: 0.0015%, p=0.008). The majority of mAbs (74%, 29/39) bound specifically to Ara h2 and/or 6. Non-specific mAbs (9/10) were mainly derived from non-atopic controls. In allergic donors, 89% of heavy chain gene transcripts consisted of VH3-family genes, compared with only 54% in sensitized but tolerant and 63% of non-atopic donors. Additionally, certain HCDR3 sequence motifs were associated with allergy or tolerance upon hierarchical clustering of their Levenshtein distances. Conclusions HCDR3 sequence motifs associated with allergy or tolerance may support correct diagnosis of patients with suspected peanut allergy.