Effectiveness and safety of dupilumab in patients with chronic rhinosinusitis with nasal polyps and associated comorbidities: a multicentric prospective study in real life.

BACKGROUND: Biologics are currently one of the main treatment options for a number of diseases. The IgG4 monoclonal antibody dupilumab targets the Interleukin-4 receptor alpha chain, thus preventing the biological effects of the cytokines IL-4 and IL-13, that are essential for the Th2 response. Several controlled trials showed that dupilumab is effective and safe in patients with atopic dermatitis (AD), severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), thus resulting in approval by regulatory agencies. Aim of the study was to evaluate the efficacy and safety of dupilumab in adult patients with CRSwNP stratified by common overlapping comorbid conditions. METHODS: We performed a multicenter, observational, prospective study enrolling adult patients with severe CRSwNP who had started dupilumab treatment in the context of standard care from January 2021 to October 2021. Data were collected from twentynine Italian secondary care centers for allergy and clinical immunology, all of which were part of the Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC). A number of efficacy parameters were used. Patient data were compared using the Wilcoxon test for paired data. All statistical analyses were performed with SPSS version 20 (IBM, Armonk, NY, USA). RESULTS: In total, 82 patients with nasal polyposis were identified. A significant improvement was detected for all the applied efficacy parameters, i.e. 22-item Sino-Nasal Outcome Test (SNOT-22) and bilateral endoscopic nasal polyp score (NPS) scores for CRSwNP, Rhinitis Control Scoring System (RCSS) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores for allergic perennial rhinitis, Forced Expiratory Volume in the 1st second (FEV1) and Asthma Quality of Life Questionnaire (AQLQ) scores for asthma, Eczema Area and Severity Index (EASI) and Dermatology Life Quality Index (DLQI) scores for AD. A non-significant improvement was also obtained in the Urticaria Activity Score over 7 days (UAS7) for chronic spontaneous urticaria. Treatment with dupilumab was well tolerated. CONCLUSIONS: These data suggest that dupilumab treatment in patients suffering from CRSwNP and associated comorbidities may be suitable. Such outcome, although confirmation by trials is warranted, suggests the possibility to treat different disorders with a single therapy, with favorable effects especially under the cost-effectiveness aspect.

Angioedema associated with dipeptidyl peptidase-IV inhibitors.

BACKGROUND: Dipeptidyl peptidase-IV (DPP-IV) inhibitors, also known as gliptins, are a class of oral antidiabetic agents. Postmarketing reports have documented the occurrence of angioedema in patients treated with gliptins and it was found that these drugs increased the risk of angioedema in patients concurrently treated with angiotensin-converting enzyme inhibitors (ACEIs). The aim of this manuscript is to provide an overview of the risk of angioedema associated with gliptins. METHODS: The keywords used for the literature search in the PubMed database included "angioedema" and "dipeptidyl peptidase", "gliptins", or the name of each DPP-IV inhibitor. Articles in English published up to December 2020 were taken into consideration. RESULTS: The available data appear to rule out a higher risk of angioedema associated with gliptin monotherapy and have revealed an increased susceptibility in patients simultaneously treated with gliptins and ACEIs. However, one single multicenter phase IV trial and case reports, even if very limited in number, have shown that angioedema can also occur during treatment with DPP-IV inhibitors without the concomitant use of ACEIs. The involvement of other drugs and drug interactions has occasionally been suggested. In a few patients, deficiency of enzymes involved in bradykinin catabolism was detected and this finding can constitute a risk factor for angioedema exacerbated by treatment with DPP-IV inhibitors. CONCLUSIONS: This risk of angioedema associated with the use of gliptins has mostly been related to the concurrent administration of ACEIs, and has been considered rare, but it might be underestimated and underreported. The role of additional risk factors or drug interactions deserves further investigations. Caution should be taken when considering the use of DPP-IV inhibitors in patients treated with ACEIs or presenting with other known risk factors for angioedema.

Dupilumab elicits a favorable response in type-2 inflammatory comorbidities of severe atopic dermatitis.

BACKGROUND: This case is the first report describing rapid, successful treatment of severe atopic dermatitis (AD) and comorbid type-2 inflammatory diseases in the same patient, with dupilumab treatment, with no side-effects. CASE PRESENTATION: We report on effects of dupilumab in a patient with severe AD, a long-standing history of a mild, perennial allergic rhino-conjunctivitis, moderate asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). CONCLUSIONS: Patients suffering from AD, asthma, allergic rhinitis and CRSwNP may be eligible for dupilumab single treatment that is possibly advantageous also from the pharmaco-economic standpoint.

Quality of life in patients with allergic and immunologic skin diseases: in the eye of the beholder.

Allergic and immunologic skin diseases negatively impact the quality of life (QoL) of affected patients with detrimental consequences. Nonetheless, in everyday clinical practice the evaluation of QoL is often overlooked. Considering the increasing prevalence of atopic dermatitis, allergic contact dermatitis, hereditary angioedema, cutaneous mastocytosis, and urticaria, it is essential to determine the effects of allergic and immunologic skin diseases on QoL. A joint meeting (GET TOGETHER 2021) of the Italian Society of Allergology, Asthma and Clinical Immunology (SIAAIC) and the Italian Society of Allergological, Occupational and Environmental Dermatology (SIDAPA) aimed to summarize the features of the main QoL tools used in these diseases and to describe the extent of QoL impairment as well as the impact of treatments on QoL, particularly biologic therapies. The assessment of QoL in patients with allergic and immunologic skin diseases relies on generic, organ-specific and disease-specific questionnaires. While generic and organ-specific questionnaires allow comparison between different diseases, disease-specific questionnaires are designed and validated for specific cohorts: the QoL Index for Atopic Dermatitis (QoLIAD) and the Childhood Atopic Dermatitis Impact Scale (CADIS) in atopic dermatitis, the ACD-11 in allergic contact dermatitis, the Angioedema QoL Questionnaire (AE-QoL) and the Hereditary Angioedema QoL questionnaire (HAE-QoL) in hereditary angioedema, the Mastocytosis QoL Questionnaires (MCQoL e MQLQ) in cutaneous mastocytosis, and the Chronic Urticaria QoL questionnaire (CU-Q2oL) in urticaria. Among the many factors that variably contribute to QoL impairment, pruritus can represent the leading cause of patient discomfort. Biologic therapies significantly ameliorate QoL in atopic dermatitis, hereditary angioedema, mastocytosis and chronic urticaria. In general, adequate management strategies are essential for improving QoL in patients with allergic and immunologic skin diseases.

Efficacy of dupilumab in atopic comorbidities associated with moderate-to-severe adult atopic dermatitis.

BACKGROUND: Dupilumab is an anti-IL-4Rα antibody used in the treatment of patients with moderate-to-severe atopic dermatitis (msAD). This study explored the potential benefit of dupilumab in perennial allergic rhinoconjunctivitis (PAR) and perennial allergic asthma (PAA) caused by indoor allergens in adults with msAD. METHODS: This multicentric, prospective, observational, real-life study included adult patients with msAD who had been treated with dupilumab in 16 Italian care centres. Efficacy outcomes regarding AD, PAR and PAA were collected at baseline and 16 weeks. Safety was also assessed. RESULTS: We enrolled 123 patients with msAD. Between baseline and 16 weeks of treatment, the following measurements decreased statistically significantly: Eczema Area and Severity Index, SCOring AD, Patient-Oriented Eczema Measure, pruritus score, sleep score, Dermatology Life Quality Index and IgE. Dupilumab treatment in patients with comorbid PAR (n = 41) was associated with significant improvements in PAR disease control (measured using a Rhinitis Control Scoring System) and in PAR Quality of life (QoL) (measured using the Rhinoconjunctivitis QoL Questionnaire scores). In 32 patients with comorbid PAA, dupilumab significantly improved PAA control (measured using the Asthma Control Test and five-item Asthma Control Questionnaire scores) and disease-related QoL (measured using the Asthma QoL Questionnaire scores). Thirty-five patients (28.5%) developed conjunctivitis during the study period. CONCLUSION: These results support the benefits of dupilumab for adult patients with PAR and/or PAA associated with msAD.

Safety of measles, mumps, and rubella vaccine in egg allergy: in vivo and in vitro management.

BACKGROUND: Egg allergy is the second most prevalent form of food allergy in childhood. In spite of the evidence accumulated, inoculating egg allergy children with attenuated vaccines grown on chick embryo cell cultures, such as the measles, mumps, and rubella (MMR) vaccine, is regarded (erroneously) as potentially dangerous or even anaphylactogenic, by many. An issue perceived as particularly conflicting also by Health Professionals. CASE PRESENTATION: A 15-year-old boy, with a history of severe egg allergy in early infancy, who was still sensitized to egg allergens, including baked egg, had never received MMR vaccination, in fear of possible anaphylaxis, in spite of the fact that this vaccination is mandatory in the first year of life, in Italy. Because of that, he was not allowed to attend school, longer, and was referred to us in order to assess the potential risk of MMR vaccination. Upon thorough allergologic workup, sensitization to MMR vaccine components was excluded by an in vivo approach, consisting in skin prick tests, intradermal tests, and subcutaneous injection test, corroborated by vaccine-specific B-lymphocyte proliferation assay, ex vivo. T-cell proliferation in response to MMR vaccine was also excluded. Eventually, the boy was inoculated with MMR vaccine and was readmitted to school. CONCLUSIONS: The diagnostic strategy adopted appears feasible and easy-to-perform and may be adopted in controversial cases (as the one reported), characterized by previous severe allergic reactions to egg. The B-lymphocyte proliferation assay we developed may represent a useful and reliable tool not only in research but also in clinical practice.

SIRM-SIAAIC consensus, an Italian document on management of patients at risk of hypersensitivity reactions to contrast media.

Hypersensitivity reactions (HRs) to contrast media (CM) can be distinguished in immune-mediated (including allergic reactions) and non-immune-mediated reactions, even if clinical manifestations could be similar. Such manifestations range from mild skin eruptions to severe anaphylaxis, making it important for radiologists to know how to identify and manage them. A panel of experts from the Società Italiana di Radiologia Medica e Interventistica (SIRM) and the Società Italiana di Allergologia, Asma e Immunologia Clinica (SIAAIC) provided a consensus document on the management of patients who must undergo radiological investigations with CM. Consensus topics included: the risk stratification of patients, the identification of the culprit CM and of a safe alternative by an allergy workup, as well as the use of premedication and the correct procedure to safely perform an elective (i.e., scheduled) or urgent examination. The most important recommendations are: (1) in all patients, a thorough medical history must be taken by the prescribing physician and/or the radiologist to identify at-risk patients; (2) in patients with hypersensitivity reactions to CM, the radiologist must consider an alternative, non-contrast imaging study with a comparable diagnostic value, or prescribe a different investigation with another class of CM; (3) if such options are not feasible, the radiologist must address at-risk patients to a reference centre for an allergy evaluation; (4) if timely referral to an allergist is not viable, it is recommended to use a CM other than the responsible one, taking into account cross-reactivity patterns; in the case of patients with histories of severe reactions, the presence of an anesthesiologist is also recommended and a premedication is suggested.

Urticaria: recommendations from the Italian Society of Allergology, Asthma and Clinical Immunology and the Italian Society of Allergological, Occupational and Environmental Dermatology.

BACKGROUND: Urticaria is a disorder affecting skin and mucosal tissues characterized by the occurrence of wheals, angioedema or both, the latter defining the urticaria-angioedema syndrome. It is estimated that 12-22% of the general population has suffered at least one subtype of urticaria during life, but only a small percentage (estimated at 7.6-16%) has acute urticaria, because it is usually self-limited and resolves spontaneously without requiring medical attention. This makes likely that its incidence is underestimated. The epidemiological data currently available on chronic urticaria in many cases are deeply discordant and not univocal, but a recent Italian study, based on the consultation of a national registry, reports a prevalence of chronic spontaneous urticaria of 0.02% to 0.4% and an incidence of 0.1-1.5 cases/1000 inhabitants/year. METHODS: We reviewed the recent international guidelines about urticaria and we described a methodologic approach based on classification, pathophysiology, impact on quality of life, diagnosis and prognosis, differential diagnosis and management of all the types of urticaria. CONCLUSIONS: The aim of the present document from the Italian Society of Allergology, Asthma and Clinical Immunology (SIAAIC) and the Italian Society of Allergological, Occupational and Environmental Dermatology (SIDAPA) is to provide updated information to all physicians involved in diagnosis and management of urticaria and angioedema.

Omalizumab in chronic spontaneous urticaria: Efficacy, safety, predictors of treatment outcome, and time to response.

BACKGROUND: Omalizumab is a recombinant anti-immunoglobulin E (IgE) antibody used in the treatment of patients with chronic spontaneous urticaria (CSU). OBJECTIVE: This multicentric study assessed the safety and efficacy of omalizumab in patients (n=322) with CSU refractory to second-generation antihistamines, also investigating predictors of poor treatment outcome and time lag to response to anti-IgE therapy by serum auto-reactivity. METHODS: This retrospective observational study comprised a 4-week pretreatment period, a 24-week treatment period with omalizumab (300 mg/month), and a 16-week follow-up period. Primary efficacy endpoints were mean and median change in 7-day urticaria activity score (UAS7), weekly itch severity score (ISS), and hive score from baseline to 4-, 12-, and 24-week values. Secondary endpoints included the proportion of patients (defined "responders") with well-controlled urticaria (UAS7 ≤ 6) and complete treatment response (UAS7=0). Safety in terms of side effects was also assessed. RESULTS: Omalizumab significantly and consistently reduced the mean UAS7, ISS, and hive score from baseline to weeks 4, 12, and 24, with a clear decreasing trend over time. At the end of the treatment period (week 24), 84.2% of patients had a UAS7 score of 6 or less and 66.7% had a UAS7 of 0. Higher pretreatment IgE levels were less likely to be associated with poor treatment response (ie, UAS7 > 6). Patients with a positive autologus serum skin test (ASST) were significantly more likely to be "slow responders" to omalizumab treatment (ie, response beyond 8 days since omalizumab administration) than ASST-negative patients (P < .001). No treatment-related adverse events were recorded. CONCLUSION: Monitoring baseline characteristics of patients before introduction of omalizumab therapy may help to predict treatment outcome in CSU patients.

Omalizumab in elderly patients with chronic spontaneous urticaria: An Italian real-life experience.

BACKGROUND: Omalizumab therapy is effective and safe in patients with chronic spontaneous urticaria (CSU) resistant to nonsedating histamine1 (H1) antihistamines (nsAHs). OBJECTIVE: To evaluate the efficacy and safety of omalizumab in elderly (aged ≥65 years) patients with nonsedating H1-antihistamine-refractory CSU in a real-life setting. METHODS: Patients with nonsedating H1-antihistamine-refractory CSU (n = 322) treated with omalizumab administered every 4 weeks in doses of 300 mg for 24 weeks were divided into 2 groups according to age at omalizumab treatment onset: 15 to 64 years and 65 years or older. Treatment response was assessed using a 7-day urticaria activity score (UAS7). Adverse effects of omalizumab therapy were recorded. RESULTS: Among patients, 32 (9.9%) were 65 years or older. At baseline, CSU characteristics were generally similar among the groups, although the presence of angioedema was statistically significantly lower in patients younger than 65 years. Any differences in weekly itch severity score, hive score, and UAS7 between the 2 age groups were not significant at weeks 4, 12, and 24, with the exception of the hive score at 24 weeks and the UAS7 at week 24. No significant between-group differences were seen in the proportion of patients with a UAS7 of 6 or lower and with a UAS7 score of 0 at weeks 4, 12, 24, and 40. The proportion of patients with at least one adverse event reported as suspected to be caused by study drug was 10% in the younger group vs 6.3% in the older group (P = .53). CONCLUSION: Our study found that omalizumab is a well-tolerated and effective therapy for elderly patients with nonsedating H1-antihistamine-refractory CSU.

Hypersensitivity reactions due to black henna tattoos and their components: are the clinical pictures related to the immune pathomechanism?

Hypersensitivity to para-phenylenediamine (PPD) and related compounds induced by temporary black henna tattoos has become a serious health problem worldwide. Different patterns of sensitization with various clinical aspects are described in literature due to PPD associated to henna tattoo and these manifestations are likely correlated with the immunological and dermatological pathomechanisms involved. Henna is the Persian name of the plant Lawsonia inermis, Fam. Lythraceae. It is a woody shrub that grow in regions of North Africa, South Asia, India and Sri Lanka. Nowadays it is rather frequent to see temporary "tattoos" performed with henna. To make tattoos darker and long-lasting PPD has been associated to henna in tattoo drawings mixtures, so obtaining "black henna". In these years there has been a rise of contact sensitization to PPD and in medical literature an increased number of cases have been reported on temporary henna tattoo application. Here we review the various clinical patterns related to PPD and henna tattoo, to investigate the possible link between clinic-morphological pictures and the immunological response to PPD and henna. The literature underlines that different clinical manifestations are related to black henna containing PPD, and its derivative products may cause delayed-type as well as immediate-type reactions. Further studies are needed to investigate the relationship between clinical and morphological aspects of PPD contact dermatitis and the T cell subsets predominance.

Drug induced exfoliative dermatitis: state of the art.

Drug induced exfoliative dermatitis (ED) are a group of rare and severe drug hypersensitivity reactions (DHR) involving skin and usually occurring from days to several weeks after drug exposure. Erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are the main clinical presentations of drug induced ED. Overall, T cells are the central player of these immune-mediated drug reactions. Here we provide a systematic review on frequency, risk factors, pathogenesis, clinical features and management of patients with drug induced ED.

Latex immunotherapy: state of the art.

OBJECTIVE: Latex allergy remains a significant problem, especially among certain professional categories, and specific immunotherapy has been suggested as a suitable therapeutic option. The objective of the this article is to review the available literature on clinical trials of specific immunotherapy in latex allergy. DATA SOURCES: Literature databases (PubMed, Embase, Google Scholar) were searched for latex immunotherapy clinical trials. STUDY SELECTIONS: Clinical trials (either open or randomized controlled) using subcutaneous or sublingual immunotherapy with latex extracts were selected. Only articles published in English in peer-reviewed journals were considered. Case reports quoted in the clinical trials were also described, when pertinent. RESULTS: Eleven clinical trials (3 with subcutaneous and 8 with sublingual immunotherapy) were identified. Two of the 3 randomized trials of subcutaneous immunotherapy reported some benefit in adults but a remarkable occurrence of side effects. Concerning sublingual immunotherapy (SLIT), there were 6 randomized placebo-controlled (1 in children), 1 randomized open, and 1 open trials. All but 1 trial reported positive results, and the safety profile was overall superior to injection immunotherapy. The overall quality of the study was moderate, and the number of subjects studied was low. CONCLUSION: Although guidelines do not consider allergy to latex as an accepted indication to desensitization, SLIT can be offered, in addition to symptomatic treatment, to selected patients, when avoidance measures are not feasible or effective.

The employment of leukotriene antagonists in cutaneous diseases belonging to allergological field.

Leukotrienes (LTs) are potent biological proinflammatory mediators. LTC4, LTD4, and LTE4 are more frequently involved in chronic inflammatory responses and exert their actions binding to a cysteinyl-LT 1 (CysLT1) receptor and a cysteinyl-LT 2 (CysLT2) receptor. LTs receptor antagonists available for clinical use demonstrate high-affinity binding to the CysLT1 receptor. In this paper the employment of anti-LTs in allergic cutaneous diseases is analyzed showing that several studies have recently reported a beneficial effects of these agents (montelukast and zafirlukast as well as zileuton) for the treatment of some allergic cutaneous related diseases-like chronic urticaria and atopic eczema although their proper application remains to be established.

Hypersensitivity to tranexamic acid: a wide spectrum of adverse reactions.

CASES DESCRIPTION: This is a retrospective study, based on analysis of data from patients with previous adverse drug reactions admitted to the Allergy and Clinical Immunology Division of both the University of Messina and the University of Bari in the last 4 years. We observed five patients: four of them (two males and two females) with a well documented history of tranexamic acid hypersensitivity reactions and one female who showed a positive response to an intradermal challenge test with tranexamic acid. CONCLUSIONS: Although the risk of immunogenic and severe allergic reactions to tranexamic acid is significantly lower than those associated with administration of other drugs, our experience points out that adverse reactions to tranexamic acid can occur. This drug may be responsible for a wide and various spectrum of hypersensitivity reactions characterized by different pathogenetic mechanisms (immunologic and non-immunologic). Etamsylate was a well tolerated alternative drug to tranexamic acid in all examined patients.