Clinical response to omalizumab in patients with hereditary α-tryptasemia

Abstract

Hereditary α-tryptasemia (HαT) is a genetic trait that results from increased TPSAB1 copy number encoding α-tryptase and is characterized by elevated basal serum tryptase (BST) levels of 8 ng/mL or higher with variably expressed clinical symptoms. 1 Lyons J.J. Hereditary alpha tryptasemia: genotyping and associated clinical features. Immunol Allergy Clin North Am. 2018; 38: 483-495 Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar In addition to multisystem issues that involve gastrointestinal, connective tissue, and neurologic systems, many individuals with HαT report symptoms associated with mast cell activation, such as chronic spontaneous urticaria and, less commonly, allergic asthma. Increasing α-tryptase gene dosage at TPSAB1 is associated with greater symptom severity 2 Lyons J.J. Yu X. Hughes J.D. et al. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet. 2016; 48: 1564-1569 Crossref PubMed Scopus (195) Google Scholar and increasing amounts of αβ-tryptase heterotetramers, which have unique enzymatic properties that may contribute to these symptoms. 3 Le Q.T. Lyons J.J. Naranjo A.N. Olivera A. Lazarus R.A. Metcalfe D.D. et al. Impact of naturally forming human alpha/beta-tryptase heterotetramers in the pathogenesis of hereditary alpha-tryptasemia. http://Doi:10.1084/jem.20190701 Google Scholar Multiple individuals in our cohorts with HαT have uncontrolled chronic spontaneous urticaria or asthma symptoms, which led to an on-label indication for treatment with the monoclonal anti-IgE antibody omalizumab, which binds to free IgE and reduces the expression of FcεRI on mast cells and basophils. 4 Beck L.A. Marcotte G.V. MacGlashan D. Togias A. Saini S. Omalizumab-induced reductions in mast cell Fce psilon RI expression and function. J Allergy Clin Immunol. 2004; 114: 527-530 Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar ,5 Broesby-Olsen S. Vestergaard H. Mortz C.G. et al. Omalizumab prevents anaphylaxis and improves symptoms in systemic mastocytosis: efficacy and safety observations. Allergy. 2018; 73: 230-238 Crossref PubMed Scopus (72) Google Scholar Despite the strong effect observed on symptoms of mast cell mediator release among patients with chronic spontaneous urticaria and systemic mastocytosis, a recent open-label cohort study found only modest benefit in patients identified as having idiopathic mast cell activation syndrome, with 6 of 14 having minimal to no response to omalizumab and 7 of 14 having no durable response. 6 Lemal R. Fouquet G. Terriou L. et al. Omalizumab therapy for mast cell-mediator symptoms in patients with ISM, CM, MMAS, and MCAS. http://doi:10.1016/j.jaip.2019.03.039 Google Scholar Given that many of the symptoms associated with HαT are often attributed to mast cell activation, we examined which of the symptoms commonly reported in these patients respond to this specific mast cell–targeted therapy and by inference suggest which symptoms may be more directly related to mast cells bearing heterotetrameric tryptase in these patients.