The Pathogenesis, Diagnosis, And Treatment of Systemic Mast Cell Disorders

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Patients with mastocytosis exhibit multiple organ manifestations including those effecting the gastrointestinal tract such as diarrhea, abdominal pain, and gastroesophageal reflux disease (GERD), which are likely associated with alterations in gut permeability. In FY2021, we identified that there is an increase in serum levels of the microbial translocation markers zonulin, I-FABP, sCD14 and LPS and sought to determine if this finding could serve as surrogate indicators of GI integrity. In this first report we showed, similar to those with inflammatory bowel syndrome, that patients with indolent systemic mastocytosis (ISM) display an increase in multiple markers associated with abnormal GI permeability which with regard specifically to IgA and IgM, correlated with clinical findings. Further studies include how mast cell activation may lead to disturbances in GI permeability and contribute to GI inflammation in patients with clonal mast cell disorders. Patients with non-aggressive ISM are not candidates for cytoreductive therapy and are generally treated with symptomatic therapy that only partly decreases symptoms. There is, however, a documented association between severity of mastocytosis and elevated serum levels of interleukin IL-6. Furthermore, mast cells have been shown to double their rate of division and exhibit increased reactivity and release of mediators when cultured in the presence of IL-6. In addition, in an animal model of mastocytosis, anti-IL-6 has been shown to slow disease progression. In 2019, we initiated a clinical trial of adults with indolent systemic mastocytosis that are randomized and treated with sarilumab which binds to the IL 6 receptor and inhibits IL 6 associated human mast cell signaling, proliferation and reactivity (decreased mediator release). In FY2021, several of our patients completed our clinical trial and others have been newly enrolled. So far based on nearly 10 subjects, the safety profile has been favorable. In addition to quality of life and symptom assessments, patients undergo measurement of serum tryptase levels and bone marrow examinations are performed at the onset and conclusion of the study. MRGPRX2 is a G protein coupled receptor highly expressed in human skin mast cells and activated by wide spectrum of ligands including antimicrobial and neuropeptides, hymenoptera venom, neuromuscular blocking agents and quinolone family antibiotics. Based on anecdotal evidence, we proposed that patients with cutaneous forms of mastocytosis may have increase expression of MRGPRX2 expression in dermal mast cells. In FY2021, we determined that patients, (both adult and children) with maculopapular cutaneous mastocytosis (MPCM) had an increase in the number of mast cells and expression of MGRPRX2 over controls which suggests that MRGPRX2-expression is upregulated in MPCM skin together with an increase in the number of mast cells. We proposed MRGPRX2 expression in mast cells (MCs) of patients with cutaneous forms of mastocytosis may provide a future target for treatment of skin manifestations associated with mastocytosis. In FY2021, we published a report that identified a unique signature of extracellular vesicles (EVs) that are released from mast cells present in the serum of patients with systemic mastocytosis that attenuate osteoblastic maturation by suppressing expression of RUNX2 and SMAD1/5, essential drivers of osteogenesis. These EVs are proposed to interfere with bone formation and can contribute to bone mass reduction identified in many patients with systemic mastocytosis and may provide possibilities for novel therapies in mast cell proliferative disorders. In addition to other debilitating manifestations involving multiple organs, patients with systemic mastocytosis suffer from osteoporosis and increased risk of fractures. In FY 2021, utilizing several imaging modalities such as dual energy x-ray absorptiometry (DXA), and Trabecular Bone Scores, laboratory tests and a fracture questionnaire, we assessed fracture risk in 50 patients with mastocytosis enrolled in this protocol. We developed a model for predicting fracture risk based on DXA spine T-scores, alkaline phosphatase, and designed a clinically relevant calculator to evaluate fracture risk using these modalities, the results of which are currently in review. In FY2021, The European Competence Network on Mastocytosis and American Initiative in Mast Cell Diseases expert panels, which included staff of the mast cell biology section, analyzed the risk-benefit ratio of vaccination to COVID-19 and have concluded that patients suffering from mastocytosis should be vaccinated to COVID-19 safely with available vaccines with an awareness of specific cases that may require precautionary measures. The recommendations provided by this study are based on expert opinion but are subject to re-evaluation as more data is generated and safety regarding children receiving vaccinations becomes more widespread. Patients with pediatric-onset mastocytosis are uniquely evaluated at our center which enables our staff to provide practitioners the knowledge and experience to care for these patients, especially those children complex and severe manifestations of mastocytosis. In FY 2021 we participated in collaboration with our European colleagues to develop a comprehensive guide to the management of mastocytosis in a pediatric population.