IR (index of reactivity)-house dust mite sublingual immunotherapy liquid formulation for allergic rhinoconjunctivitis: Systematic review and meta-analysis of randomized and nonrandomized studies.

Background: Although randomized controlled trials (RCT) are the reference standard of evidence in allergen immunotherapy (AIT), nonrandomized studies (NRS) are needed to confirm their results in more representative populations, particularly for treatment duration and persistence. However, when discrepancies are observed between RCT and NRS, NRS reliability decreases because these discrepant results are generally attributed to the methodologic flaws of NRS. Objective: We compared the benefit of sublingual AIT (SLIT) for allergic rhinoconjunctivitis in NRS versus RCT focusing on a single product/allergen to reduce heterogeneity. Methods: For meta-analysis, house dust mite (HDM) SLIT liquid formulation studies were sourced from computerized (Medline, Web of Science, and LILACS databases, to January 2023) and manual literature searches. Populations, treatments, and outcome data were combined (DerSimonian-Laird method). Noncomparative NRS were compared to RCT' SLIT arm before and after treatment. Efficacy was determined as the standardized mean difference (SMD) in symptom score (SS) and medication score (MS). Results: Data from 12 NRS (682 patients) and 8 RCT (176 patients) were analyzed. The benefit with index of reactivity (IR)-HDM SLIT liquid formulation was found significant for, first, SS in both NRS (SMD = -1.27; 95% confidence interval [CI], -1.64, -0.90) and RCT (SMD = -0.56; 95% CI, -0.90, -0.21), and second, MS with SMD equal to -1.35 (95% CI, -1.77, -0.93) and -0.46 (95% CI, -0.67, -0.25), respectively. Metaregression showed that symptom improvement was correlated with treatment duration with consistent results in NRS and RCT with 12-month SS data: -0.87 (interquartile range, -1.02, -0.77) and -0.75 (interquartile range, -0.93, -0.41), respectively. Conclusion: This meta-analysis showed comparable clinical benefit of IR-HDM SLIT liquid formulation increasing over time in both NRS and RCT, suggesting that NRS may reliably integrate RCT results and be considered for guidelines.

Hypersensitivity reaction during enzyme replacement therapy in lysosomal storage disorders. A systematic review of desensitization strategies.

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.

Comparison of evidence of treatment effects in randomized and nonrandomized studies on allergen immunotherapy.

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.

Novel approach to idursulfase and laronidase desensitization in type 2 and type 1 S mucopolysaccharidosis (MPS).

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.

Severe asthma and personalized approach in the choice of biologic.

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.