OBJECTIVE:Exacerbations and suboptimal disease control are common in severe asthma with an eosinophilic phenotype (SAep). Mepolizumab, an anti-interleukin-5 monoclonal antibody, has demonstrated efficacy and safety in randomized controlled trials (RCTs). We aimed to strengthen the real-world evidence base for mepolizumab in SAep. METHODS:We analyzed data from Italian participants of REALITI-A, a global, real-world, prospective, observational study (primary outcome: rate of clinically significant exacerbations [CSEs]). Using these data and those from Italian real-world studies of mepolizumab (identified by systematic literature review), we performed a meta-analysis. RESULTS:In the Italian cohort of REALITI-A (n = 244), mean CSE rate was lower 12 months post-mepolizumab initiation versus 12 months pre-mepolizumab (0.67 vs. 3.74 CSEs/patient/year; relative risk [RR], 0.18; 95% confidence interval (CI), 0.15-0.22; p < .001). The meta-analysis included 863 patients. Mean CSE rate decreased from 4.2/patient/year at baseline to 0.71/patient/year post-mepolizumab initiation. Mean oral corticosteroid (OCS) dose reduced by 8.66 mg/day (95% CI, 6.17-11.16 mg/day; p < .0001) from baseline (10.0 mg/day). The RR for OCS maintenance, post- versus pre-mepolizumab, was 0.37 (95% CI, 0.27-0.52; p < .0001). A mean increase in Asthma Control Test score of 6.50 (95% CI, 5.67-7.33; p < .00001) was observed. Proportions of patients reporting adverse events were low. CONCLUSIONS:Real-world experience in this unified health care system identifies that mepolizumab has a low adverse event rate and provides consistent clinical benefits. Mepolizumab represents an important treatment option for patients with SAep.

INTRODUCTION:Acyclovir is a synthetic purine nucleoside analog that is used to treat infections caused by herpes simplex virus (HSV) and varicella zoster virus (VZV) by targeting the viral enzyme thymidine kinase. However, its use can lead to hypersensitivity reactions (HR) in rare cases, resulting in treatment discontinuation. Rapid drug desensitization (DD) by intravenous or oral administration protocols are used in these patients in order to avoid treatment discontinuation. This approach has been proven to be effective and safe. Here, we review all the desensitization strategies adopted so far, and also report our experience. METHODOLOGY:We reviewed all reports related to acyclovir desensitization; focusing on skin test results, protocols and premedication performed, and their effectiveness. We also report on the case of a 74-year-old woman affected by multiple myeloma who developed HR to acyclovir. She underwent skin tests, and lymphocyte proliferation test (LPT) with acyclovir, and was subsequently subjected to oral desensitization. RESULTS:Six articles met the inclusion criteria and were analyzed in this review, along with a case report. All DD procedures were well-tolerated, with only mild reactions reported in one patient. Skin tests gave negative results but one result was deemed doubtful response. Moreover, the LPT performed in our case had positive result, indicating a hypersensitive immune response to acyclovir. CONCLUSIONS:Acyclovir desensitization is a safe and effective approach for patients experiencing HR. Standardized in vivo and in vitro testing are required to better estimate the risk of DD and find the safest individualized DD protocol.

•What is already known about this topic

Autoimmune skin disorders, including Psoriasis, Lichen Planus, Vitiligo, Atopic Dermatitis, and Alopecia Areata, arise from a combination of genetic predisposition, external factors, and immunological dysfunction. It is well-documented that there is a strong correlation between autoimmune thyroid diseases and a range of dermatological disorders, especially urticaria. This review investigates possible links between autoimmune thyroiditis and a broader spectrum of autoimmune skin conditions, analyzing shared genetic markers, immunological mechanisms, and clinical correlations. Common pathogenic mechanisms include disrupted immune tolerance and oxidative stress, leading to chronic inflammation. Genetic factors, such as IL-23 receptor gene variants, increase the risk for Psoriasis, Alopecia Areata, and Hashimoto’s thyroiditis. Additionally, CTLA-4 mutations enhance susceptibility to autoimmune thyroid and skin disorders. Shared genetic susceptibility was also reported in Lichen Planus and Vitilgo, even if different genetic loci might be involved. The breakdown of the immune system can determine a pro-inflammatory state, facilitating the development of autoimmunity and auto-antibody cross-reactions. The presence of similar antigens in skin cells and thyrocytes might explain why both tissues are affected. The significant overlap between these conditions emphasizes the necessity for a comprehensive diagnosis workup and treatment. Future research should focus on clarifying specific immunological pathways and identifying novel biomarkers.

Abstract Background Mucopolysaccharidosis (MPS) type 1 S and type 2 are rare lysosomal storage disorders characterized by impaired enzyme production, resulting in glycosaminoglycans accumulation within lysosomes. Enzyme Replacement Therapy (ERT) with laronidase and idursulfase are first line treatments, respectively. However, infusion-related hypersensitivity reactions (HR) may lead to ERT discontinuation. Thus, desensitization can be performed to restore ERT. Methods We report on a two-year follow-up after a combined desensitization approach in two MPS patients experiencing HR to ERT. This approach consists of intravenous rapid desensitization combined with the subcutaneous allergen immunotherapy-like desensitization with the culprit recombinant enzyme. Results The first patient, suffering from MPS type I, underwent to the combined desensitization approach, and subsequently tolerated weekly standard laronidase infusions for 13 months when HR occurred again. Then, a monthly omalizumab (anti-IgE monoclonal antibody) administration was implemented allowing the patient to restore ERT. The second patient, diagnosed with MPS type 2, was subjected to a similar combined desensitization strategy with idursulfase, and achieved a total desensitization after one year, confirmed by negative skin tests. Thus, he continued standard ERT infusions without HR occurrence. Conclusion The combined desensitization approach proved effective in conferring immunotolerance for at least one year in both MPS patients, also demonstrated by the negative skin tests in one patient. However, when immunotolerance to ERT is lost, omalizumab administration can be a valid option in restoring ERT.

Lysosomal storage diseases (LSDs) are rare genetic metabolic disorders that cause the accumulation of glycosaminoglycans in lysosomes due to enzyme deficiency or reduced function. Enzyme replacement therapy (ERT) represents the gold standard treatment, but hypersensitivity reaction can occur resulting in treatment discontinuation. Thus, desensitization procedures for different culprit recombinant enzymes can be performed to restore ERT. We searched desensitization procedures performed in LSDs and focused on skin test results, protocols and premedication performed, and breakthrough reactions occurred during infusions. Fifty-two patients have been subjected to desensitization procedures successfully. Skin tests, with the culprit recombinant enzyme, deemed positive in 29 cases, doubtful in two cases, and not performed in four patients. Moreover, 29 of the 52 desensitization protocols used at the first infusion were breakthrough reaction free. Different desensitization strategies have proved safe and effective in restoring ERT in patients with previous hypersensitivity reactions. Most of these events seem to be Type I hypersensitivity reactions (IgE-mediated). Standardized in vivo and in vitro testing is necessary to better estimate the risk of the procedure and find the safest individualized desensitization protocol.

Nonrandomized studies (NRS) on allergen immunotherapy (AIT) particularly lend themselves to evaluate outcomes that are insufficiently addressed in randomized controlled studies (RCTs). However, NRS are prone to several sources of bias, which limit their validity. We aimed at comparing AIT effects between RCTs and NRS and evaluate the reasons for discrepancies in study results. In this analysis, we compared NRS on AIT (including subcutaneous and sublingual immunotherapy, SCIT and SLIT, respectively) with SLIT and SCIT RCTs from published meta‐analyses, assessing the Risk of Bias (RoB) for each study and the certainty of evidence from NRS and RCTs using the GRADE approach. We found: (1) very serious RoB in the 7 NRS included in the meta‐analysis showing a large difference between AIT and controls (standardized mean difference [SMD] for symptom score [SS], −1.77; 95% CI, −2.30, −1.24; p < .001; I2 = 95%) with very low certainty evidence; (2) serious RoB in the 13 SCIT‐RCTs reporting a moderate‐to‐high difference between SCIT and controls (SMD for SS, −0.81; 95% CI, −1.12, −0.49; p < .001; I2 = 88%) with moderate certainty evidence; (3) low RoB in the 13 SLIT‐RCTs reporting a small benefit (SMD for SS, −0.28; 95% CI, −0.37, −0.19; p < .001; I2 = 54.2%) with high certainty evidence. Similar results were reported for medication score. Our evidence is sufficient to conclude that the magnitude of effect estimates of NRS and RCTs directly correlate with the degree of RoB and inversely with the overall evidence certainty. NRS, which are more affected than RCTs by bias resulting in low certainty evidence, showed the largest effect size. Sound NRS are needed to complement RCTs.

Allergen-specific immunotherapy (AIT) is a proven efficacy treatment for allergic rhinitis (AR), asthma, and Hymenoptera venom allergy, but its use in food allergy (FA) is still under investigation. Because some efficacy and safety concerns still remain, biologic drugs, including omalizumab and dupilumab, have been studied as an adjunctive therapy to AIT for these conditions. In this article, the evidence supporting the use of monoclonal antibodies (mAbs) as an add-on therapy to AIT for FA, AR, asthma, and Hymenoptera venom allergy has been reviewed. The review will delve into the mechanisms of action of different mAbs, their efficacy, and how they can be integrated into personalized medicine approaches to treat allergic diseases. Furthermore, future research areas will be considered. Evidence suggests that omalizumab in combination with AIT may be a beneficial option for respiratory allergies or food desensitisation, especially during the escalation or build-up phase, when adverse events are more frequent. Currently, there is a small number of well-structured clinical trials in Hymenoptera venom allergy, and the available data consist mainly of single-case reports that provide information of limited value. Dupilumab has been studied as adjunctive therapy in patients with respiratory and FAs. Clinical trials are ongoing to evaluate the efficacy of dupilumab as monotherapy or as an adjunct to oral immunotherapy (OIT) in peanut allergy. Other studies are investigating the use of dupilumab in patients with multiple FAs and as an adjunct to milk OIT. Overall, mAbs have the potential to improve outcomes in various allergic conditions when used as an add-on to AIT, especially during the build-up phase. Further research is needed to fully understand their optimal dosing and duration of treatment, as well as to identify which patients may benefit the most from these therapies.

Background: Idursulfase and laronidase are drugs used to treat Hunter syndrome (mucopolysaccharidosis type 2) and Scheie syndrome (mucopolysaccharidosis type 1 S), respectively. These are rare lysosomal storage disorders, leading to accumulation of glycosaminoglycans within lysosomes. Failure of early recognition of the disease and/or delay in starting the appropriate treatment result in severe clinical impairment and death. For almost 20 years, enzyme replacement therapy with recombinant proteins has represented the first line therapeutic option. However, administration of idursulfase and laronidase is associated with infusion-related hypersensitivity reactions, in approx. 20% of patients. In these patients, rapid desensitization by intravenous administration protocols has been used in order to avoid treatment discontinuation. This approach proved effective and safe. However, long-term tolerance could not be achieved. Thus, we decided to combine rapid desensitization with allergen immunotherapy-like desensitization. Results: Two patients with Hunter syndrome and one patient with Scheie syndrome developed severe allergy to idursulfase and laronidase, respectively, preventing them from continuing the otherwise indispensable therapy. In all three patients, the possible IgE-mediated nature of the reactions suffered was suggested by positive skin tests with the two enzymes, respectively. By devising 12-step, 3-dilution rapid desensitization protocols, we resumed the enzyme replacement therapy. However, the prolonged time required for administration (a not negligible pitfall, since therapy should be given weekly for life) and the persistent occurrence of reactions (mild but still requiring anti-allergic medication at full dosage) led us to combine rapid desensitization with a compact 11-step, 24-day allergen immunotherapy-like desensitization protocol. Thus, idursulfase and laronidase were injected subcutaneously, with a 500-fold increase from step 1 to step 11 for idursulfase and a 222-fold increase for laronidase. This strategy led to restoration of long-term tolerance, allowing weekly intravenous therapy administration under standard conditions, according to the manufacturer instructions, in the absence of side effects and with only precautionary low-dose premedication. Conclusion: Rapid desensitization is a suitable and safe option in the case of idursulfase and laronidase allergy. Combination with subcutaneous allergen immunotherapy-like desensitization afforded restoration of enzyme replacement therapy given by the normal administration schedule, by inducing sustained tolerance.

Purpose of review Severe asthma requires intensive pharmacological treatment to achieve disease control. Oral corticosteroids are effective, but their use is burdened with important side effects. Biologics targeting the specific inflammatory pathways underpinning the disease have been shown to be effective but not all patients respond equally well. As we treat more patients than those who can respond, our inability to predict responders has important healthcare costs considering that biologics are expensive drugs. Thus, a more precise choice of the ‘right patients’ to be prescribed with the ‘right biologics’ would be desirable. Recent findings Machine learning techniques showed that it is possible to increase our ability to predict outcomes in patients treated with biologics. Recently, we identified by cluster analysis four different clusters within the T2 high phenotype with differential benralizumab response. Two of these clusters, characterized by higher levels of inflammatory markers, showed the highest response rate (80–90%). Summary Machine learning holds promise for asthma research enabling us to predict which patients will respond to which drug. These techniques can facilitate the diagnostic workflow and increase the chance of selecting the more appropriate treatment option for the individual patient, enhancing patient care and satisfaction.