Characterization of omalizumab updosing patterns and predictive factors in chronic spontaneous urticaria: A prospective multicentric observational study.

BACKGROUND: Limited information is available on the use of omalizumab (OMA) updosing since its introduction as a second-line therapy in chronic spontaneous urticaria (CSU) in 2014. Practical guidelines from health authorities are lacking, and the specific characteristics of patients requiring higher doses remain unknown. Our objectives were to characterize the patterns of OMA updosing (defined as changes in dose and/or injection intervals), to identify the predictive factors associated with updosing, and to improve CSU management. METHODS: We conducted a prospective, multicentric, real-life observational study, including patients diagnosed with CSU and starting OMA. The data were collected at 0, 3, 6, and 9 months. The primary endpoint was the frequency of OMA updosing at 3 months. The secondary endpoints included an analysis of updosed patients' profile, and an assessment of OMA efficacy and safety. RESULTS: We included 153 patients. Twenty percent of patients were updosed at 3 months, and 27% in total during the 9-month follow-up. Practitioners mainly chose to increase the frequency of injections (66%). At baseline, the updosed patients were more likely to have more severe CSU (UCT < 4, p < 0.030), a lower lymphocyte count (<2000/mm3, p = 0.037), and low IgE levels (<70 UI/mL, p = 0.024). The side effects of OMA were not more frequent after updosing. CONCLUSION: One in five patient underwent updosing within just 3 months. OMA updosing is frequent in particular in cases of severe disease and low IgE blood levels.

Urticaria exacerbations and adverse reactions in patients with chronic urticaria receiving COVID-19 vaccination: Results of the UCARE COVAC-CU study.

BACKGROUND: Concern about disease exacerbations and fear of reactions after coronavirus disease 2019 (COVID-19) vaccinations are common in chronic urticaria (CU) patients and may lead to vaccine hesitancy. OBJECTIVE: We assessed the frequency and risk factors of CU exacerbation and adverse reactions in CU patients after COVID-19 vaccination. METHODS: COVAC-CU is an international multicenter study of Urticaria Centers of Reference and Excellence (UCAREs) that retrospectively evaluated the effects of COVID-19 vaccination in CU patients aged ≥18 years and vaccinated with ≥1 dose of any COVID-19 vaccine. We evaluated CU exacerbations and severe allergic reactions as well as other adverse events associated with COVID-19 vaccinations and their association with various CU parameters. RESULTS: Across 2769 COVID-19-vaccinated CU patients, most (90%) received at least 2 COVID-19 vaccine doses, and most patients received CU treatment and had well-controlled disease. The rate of COVID-19 vaccination-induced CU exacerbation was 9%. Of 223 patients with CU exacerbation after the first dose, 53.4% experienced recurrence of CU exacerbation after the second dose. CU exacerbation most often started <48 hours after vaccination (59.2%), lasted for a few weeks or less (70%), and was treated mainly with antihistamines (70.3%). Factors that increased the risk for COVID-19 vaccination-induced CU exacerbation included female sex, disease duration shorter than 24 months, having chronic spontaneous versus inducible urticaria, receipt of adenovirus viral vector vaccine, having nonsteroidal anti-inflammatory drug/aspirin intolerance, and having concerns about getting vaccinated; receiving omalizumab treatment and Latino/Hispanic ethnicity lowered the risk. First-dose vaccine-related adverse effects, most commonly local reactions, fever, fatigue, and muscle pain, were reported by 43.5% of CU patients. Seven patients reported severe allergic reactions. CONCLUSIONS: COVID-19 vaccination leads to disease exacerbation in only a small number of CU patients and is generally well tolerated.

Adverse cutaneous reaction to diabetic glucose sensors and insulin pumps: Irritant contact dermatitis or allergic contact dermatitis?

BACKGROUND: Adverse cutaneous reactions to diabetes medical devices (glucose sensors and insulin pumps) are described, notably allergic contact dermatitis (ACD) with isobornyl acrylate (IBOA) and N,N dimethylacrylamide (DMAA) as the main allergen. OBJECTIVES: To determine if all cases of adverse cutaneous reactions observed with diabetes medical devices (ie FreeStyle Libre, Enlite sensors or insulin pumps), referred to our department with suspected allergies are confirmed as ACD. PATIENTS AND METHODS: Fifty-two patients who presented skin reactions to diabetes medical devices were patch tested with the European baseline series, a plastic and glues series, a (meth) acrylates series, a piece of the adhesive part of the device, as well as IBOA 0.1% and DMAA 0.1% pet. RESULTS: Seventeen patients had no positive reaction to IBOA nor to the adhesive part of the device; 11 of these also tested with DMAA with negative result. No other relevant allergen was identified. CONCLUSION: Some cutaneous reactions, otherwise very similar to those of patients sensitized to IBOA, can be explained either by the presence of an untested allergen not yet discovered, or by irritant contact dermatitis. Therefore, European legislation on the full labelling of ingredients by manufacturers, in order to facilitate the identification of allergens and irritants, is imperative.

Contact dermatitis caused by glucose sensors in diabetic children.

BACKGROUND: Allergic contact dermatitis caused by glucose sensors has been recently described in diabetics, mostly in adult patients. Isobornyl acrylate and N-N dimethylacrylamide are the potent causative agents. OBJECTIVES: To describe a child population with contact dermatitis caused by glucose sensors, determine the causative allergen, and assess the prevalence of isobornyl acrylate (IBOA) sensitization. PATIENTS AND METHODS: Overall, 12 children with a reaction to medical devices, either glucose sensors or insulin sets, were patch tested with the European baseline series, glues and rubber, (meth) acrylates series, and with piece of the adhesive part of the glucose sensor FreeStyle Libre. Isobornyl acrylate 0.1% pet. was patch tested in 11 patients, and N-N dimethylacrylamide in two. Some patients were tested with adhesive parts of the infusion set. RESULTS: Overall, 10 children reacted to the adhesive part of the sensor FreeStyle Libre, and 10 children were sensitized to IBOA. One patient turned out to be negative in all patch tests. CONCLUSION: Allergic contact dermatitis caused by glucose sensors is common in the pediatric diabetic patient population. Like in the adult patient population, IBOA was the culprit allergen, with 83.3% sensitization prevalence in children exhibiting adverse cutaneous reactions caused by FreeStyle Libre.

Allergic contact dermatitis caused by isobornyl acrylate in the Enlite glucose sensor and the Paradigm MiniMed Quick-set insulin infusion set.

BACKGROUND: The FreeStyle Libre glucose sensor has caused many cases of allergic contact dermatitis, and isobornyl acrylate (IBOA) in this sensor has been identified as one of the culprit allergens. OBJECTIVES: To report on the presence of IBOA in devices produced by Medtronic, namely, the Enlite sensor and the insulin infusion set Paradigm MiniMed Quick-set. PATIENTS AND METHODS: Five patients reacting to the glucose sensor Enlite and/or the insulin infusion set Paradigm MiniMed Quick-set observed in three clinics (two Belgian and one Swedish) were patch tested with the baseline and other series, as well as with IBOA; four of them also with pieces of adhesive patches from the devices, and two with a thin layer chromatogram of Enlite glucose sensor extracts. Gas chromatography-mass spectrometry (GC-MS) analyses were performed. RESULTS: Four patients reacted to IBOA and one to colophonium, a known allergen in Enlite, and three to the adhesive part of the sensor or the insulin infusion set. IBOA was identified in the sensor by GC-MS, and its presence was indicated in the infusion set. CONCLUSIONS: IBOA is a contact allergen in Enlite glucose sensor, and likely also in the infusion set. Therefore, these devices are not suitable alternatives for patients sensitized to the FreeStyle Libre sensor.

Unexpected positive patch test reactions to sesquiterpene lactones in patients sensitized to the glucose sensor FreeStyle Libre.

BACKGROUND: Most diabetic patients sensitized to FreeStyle Libre react to isobornyl acrylate (IBOA), with a considerable number of them also showing unexpected positive patch test reactions to sesquiterpene lactone (SL) mix (SLM) tested in the baseline series. OBJECTIVES: To compile patch test results of subjects affected, and provide potential explanations for this association. PATIENTS AND METHODS: Fifty-three Freestyle Libre-allergic patients were patch tested with IBOA and/or SLM, and several were also patch tested with the components of SLM. Chromatographic analyses were performed on the glucose sensor, IBOA, and the components of SLM. RESULTS: Thirty-three patients reacted positively to the components of SLM, and 11 of 27 patients reacted positively to alantolactone, in particular. Gas chromatography-mass spectrometry (GC-MS) analyses did not detect these chemicals in the different parts of the glucose sensor, or in IBOA. CONCLUSION: Significant co-sensitizations between SLs on the one hand and the glucose sensor FreeStyle Libre and/or isobornyl acrylate on the other hand exist, without evidence of the presence of SLs via GC-MS analysis. Cross-reactions between them seem improbable. As a possible hypothesis, a common precursor for both, such as camphene, may exist.

Treatment of chronic spontaneous urticaria: Immunomodulatory approaches.

This paper summarizes and reviews the mechanisms of action and data concerning efficacy of recommended treatments as well as other treatments that have been tested, independently of the outcomes, in the management of chronic spontaneous urticaria. Due to the central role of mast cells, basophils and histamine in the pathophysiology of this disease, H1-antihistamines remain the first-line treatment. However, current knowledge about this complex disease, also recognizes an important role for T lymphocytes, B lymphocytes, and autoantibodies. Implications of these others mediators thus provide further targets for treatment. Indeed, agents previously used to treat other autoimmune and inflammatory diseases, have demonstrated efficacy in chronic spontaneous urticaria and are therefore potential therapeutic alternatives for antihistamine unresponsive patients.

Allergic contact dermatitis caused by medical devices for diabetes patients: A review.

Allergic contact dermatitis caused by medical devices for diabetes patients has been increasingly described in the literature in the last few years. This article reviews the cases of allergic contact dermatitis caused by insulin pumps and glucose sensors reported since the 1970s, the culprit allergen(s), the results of patch tests and/or chromatographic analysis, and preventive measures.

Increased expression of interleukin-9 in patients with allergic contact dermatitis caused by p-phenylenediamine.

BACKGROUND: Allergic contact dermatitis has been described as a type IV reaction caused by antigen-specific T cells. Central roles for CD8+ cytotoxic T cells as effector cells and CD4+ T cells as regulatory cells have been suggested. T helper (Th) 2 and Th1 cytokines have been implicated; however, the nature of the allergen influences the Th response. OBJECTIVE: To determine the types of T cells and cytokines expressed in patients allergic to p-phenylenediamine (PPD). METHODS: Serial skin biopsies of areas with positive patch test reactions in 29 PPD-sensitized patients were collected. T cell markers and cytokine expression were analysed by flow cytometry and quantitative reverse transcription polymerase chain reaction in both skin and peripheral blood mononuclear cells (PBMCs) of sensitized patients. RESULTS: We observed increased expression of T cell markers and Th2/Th9-associated cytokines in both skin and stimulated PBMCs of PPD-allergic patients. Moreover, interleukin (IL)-9 was mainly produced by Th9 cells, in both skin and PBMCs. Further investigations showed that Il9r-deficient mice were more affected in a PPD contact hypersensitivity model than wild-type mice. CONCLUSION: We did not confirm the preclinical presence of CD8+ T cells. However, the expression of different T cell markers positively correlated with patch test reactions. IL-9 expression was strongly upregulated and directly related to patch test severity. In addition, we showed that IL-9 has an anti-inflammatory role in a mouse model of PPD contact hypersensitivity.

Encapsulation of hydrophobic allergens into nanoparticles improves the in vitro immunological diagnosis of allergic contact dermatitis.

The diagnosis of allergic contact dermatitis (ACD) relies on in vivo patch testing. In vitro immunological assays based on the characterization of circulating allergen-specific memory T cells represent a promising alternative to patch testing. However, their development is hampered by the technical challenge of assessing hydrophobic allergens in serum-based assays. In this study, we show that the encapsulation of fragrance mix 1 (FMI, a mixture of 8 hydrophobic allergens) into poly-ε-caprolactone nanoparticle (NP) vectors: (1) dramatically increases the solubilization of allergens in conventional cell culture media and (2) allows for a robust in vitro reactivation of allergen-specific T cells in large numbers of fragrance allergic patients. Therefore, the encapsulation of hydrophobic allergens into NP vectors opens new avenues to improve the in vitro immunobiological diagnosis of ACD. FROM THE CLINICAL EDITOR: Allergic Contact Dermatitis (ACD) is a delayed-type hypersensivity reaction prevalent in many individuals. Currently, skin patch testing has been the mainstay for diagnosis clinically. In this study, the authors described an improvement to in vitro immunological assays measuring circulating allergen-specific memory T cells, using nanoparticle vectors. The positive data might provide an exciting alternative to current practice of patch-testing.

Real-Life Effectiveness and Tolerance of Upadacitinib for Severe Atopic Dermatitis in Adolescents and Adults.

INTRODUCTION: The efficacy and safety of upadacitinib in atopic dermatitis have been defined in clinical trials, but long-term real-life experience, essential for clinical decision-making, is still limited. We aimed to assess the effectiveness and tolerance of upadacitinib in a real-life cohort of adults and adolescents with severe atopic dermatitis in whom previous systemic therapies largely failed. METHODS: Retrospective cohort study collecting data from adults and adolescents treated with upadacitinib 15 or 30 mg per day between July 2021 to August 2022. The outcomes for effectiveness were evaluated by the percentage of patients who achieved a validated Investigator's Global Assessment for atopic dermatitis (vIGA-AD) of 0 (clear) or 1 (almost clear) and/or an improvement of at least 75% on the Eczema Area and Severity Index (EASI 75) at the end of the follow-up. All treatment-emergent adverse events were collected. RESULTS: A total of 29 patients were included (22 adults and 7 adolescents), with a median follow-up of 54.4 weeks. At the end of the follow-up, 23 patients (79.3%) reached a vIGA-AD of 0/1, and 24 patients (82.7%) achieved EASI 75. Among patients treated with upadacitinib after initial failure of first- and/or second-line treatment with biologics or baricitinib, 5/7 patients (71.4%) reached a vIGA-AD score of 0/1. Disease control was slightly better in adults than in adolescents (81.8% vs 71.4% reached the efficacy endpoint, respectively). Response rate in patients with upadacitinib 15 mg seemed better than in clinical trials or network meta-analysis. Safety data were reassuring; lipid changes were the most frequent adverse event. CONCLUSION: This real-life study confirms the effectiveness of upadacitinib, particularly for the treatment of atopic dermatitis recalcitrant to conventional systemic agents, biologics or baricitinib. Induced lipid changes require close follow-up.