To the editor,

Mucopolysaccharidosis (MPS) type 1 S and type 2 are rare lysosomal storage diseases caused by impaired enzyme production, leading to glycosaminoglycan accumulation within lysosomes. In MPS type 1 S, reduced function of the alpha-L-iduronidase gene occurs, while MPS type 2 is characterized by a mutation in the iduronate-2-sulfatase gene [1]. Enzyme replacement therapy (ERT) is the only available therapeutic approach for these patients which consist of the weekly intravenous administration of the specific recombinant enzyme: laronidase for MPS type 1 S and idursulfase for MPS type 2. However, ERT is often associated with infusion-related hypersensitivity reactions (HR) like urticaria, skin rash, flushing, wheezing, and anaphylaxis [2, 3].

In MPS patients with HR history, rapid desensitization (RD) can be a valid approach to avoid ERT discontinuation [4]. RD induces temporary tolerance with slow administration (about 6 h) of the offending medication and is performed for both IgE- and non-IgE-mediated HR [5]. Additionally, subcutaneous allergen immunotherapy (AIT), used for Hymenoptera venom-related allergies to induce long-term immune tolerance, includes an induction phase and a maintenance phase, in which a fixed dose of allergen is administered at longer intervals (every 4 weeks). This procedure has been successfully used with protein drugs like laronidase, idursulfase, and trastuzumab for IgE-mediated HR [6, 7]. Recently, omalizumab, an anti-IgE monoclonal antibody, proved to be a valid option in two MPS type 4 A patients who experienced HR to Elosulfase α and were resistant to desensitization approach [8, 9]. This drug acts by binding IgE and prevents its attaching to FceRI (high-affinity IgE receptor), thereby reducing the amount of free IgE that is available to trigger the allergic cascade. Currently, omalizumab is indicated for severe asthma, chronic spontaneous urticaria and chronic rhinosinusitis with nasal polyps [10].

We present findings on two-year follow-up and management about 2 MPS patients (Patient 2 and Patient 3) reported in Spataro et al. 2022, who initially developed HR to ERT and were subjected to a combined desensitization approach (rapid desensitization plus AIT-like desensitization); the third patient was lost to follow-up for his personal reasons [6]. In this letter, we have maintained the same patient identifiers and sequence as used in the previously published article.

Patient 2 is the 35-year-old man who was diagnosed with MPS type 1 S at age 13 and was safely treated with laronidase administration since July 2021, when he developed diffuse urticaria and lip angioedema during laronidase infusion resulting in drug suspension. The patient was then referred to our Allergy Unit and skin tests with laronidase were performed yielding a positive result and was successfully desensitized with the combined approach: 3-bag, 12-step RD plus a subcutaneous 11-step AIT-like desensitization protocol. After completion of the combined approach, we gradually reduce the laronidase infusion time to reach a standard infusion schedule with only chlorphenamine 10 mg as premedication; simultaneously, we administered laronidase subcutaneously, monthly, as for the classic AIT. Under these conditions, the standard protocol had been performed for 13 months without any HR until December 2022, when he developed generalized urticaria, face angioedema and chest constriction. Then, skin tests were performed again with positive results at 1:100 and 1:10 IDT dilutions (average wheal diameter: 9 and 10.5 mm, respectively). The same combined desensitization approach was begun immediately, but this time unsuccessfully. Thus, we administered omalizumab at the dose of 300 mg two days before the subsequent infusion. Surprisingly, the patient immediately tolerated the subsequent 4 weekly laronidase infusions through standard protocol. Due to the observed benefits, omalizumab 300 mg was administered every 4 weeks (Fig. 1). Moreover, after 6 months, omalizumab was tapered to 150 mg monthly according to the absence of HR occurrence. Under these conditions, the patient is still tolerating ERT.

Evolution and management over two years of the two MPS patients allergic to ERT. AIT, allergen immunotherapy; CDA, combined desensitization approach; HR, hypersensitivity reaction; OMA, omalizumab. The blue line represents Patient 2. The red line represents Patient 3

Patient 3 is the 9-year-old child who was diagnosed with MPS type 2 in 2017 and started the weekly ERT with idursulfase till July 2021, when he developed diffuse urticaria during the last minutes of infusion. In December 2021, the patient was referred to our Allergy Clinic, and an allergy workup with skin tests for idursulfase was carried out with positive test results. Thus, a 3-bag, 12-step RD and, at the same time, the AIT-like desensitization was started. This combined approach allowed the patient to reduce infusion time to a standard infusion protocol with oral cetirizine 7.5 mg as premedication; simultaneously, a monthly administration of the AIT-like desensitization maintenance dose was maintained, subcutaneously. As result, after one year, no HR occurred. Then, we decided to subject the patient to an allergy reevaluation by skin tests with idursulfase (January 2023): both SPT and IDT deemed negative results. AIT-like desensitization was stopped given the patient achieved complete desensitization to idursulfase. The patient is still taking ERT without HR occurrence.

Figure 1 shows a summary of the progression of allergic reactions and their management in the two patients.

In conclusion, ERT represents the only available treatment for MPS, but HR may occur precluding its continuation. Thus, while RD can be a valid approach for the immediate restoration ERT, AIT-like desensitization could be effective in inducing a longer tolerance.

In this experience, the combined desensitization approach proved effective in both cases for at least one year. While Patient 2 lost immune tolerance after 13 months, requiring omalizumab administration, in Patient 3 the combined approach led to complete desensitization, as evidenced by negative skin tests.

This study aims to offer guidance for MPS patients who develop HR to ERT, with the goal of optimizing management and preventing therapy discontinuation. The management algorithm was previously detailed in Spataro et al. 2023 [4]. For patients unable to resume the standard protocol despite RD or a combined approach, omalizumab has shown effectiveness. Here, we propose a practical management strategy for using this monoclonal antibody in similar cases: (i) a monthly omalizumab dose of 300 mg (for adults); (ii) after 6 months, a 50% dose reduction following careful reassessment.

Further studies will be essential to evaluate the efficacy and durability of the combined approach over time, and to determine which patients may benefit the most. Additionally, omalizumab may prove valuable in managing more resistant HR cases, as observed with other treatments, such as chemotherapy [11].