Myths and facts in mastocytosis: Studying dilemmas in the care for patients with mastocytosis

Variety of studies into common myths and dilemmas in daily clinical practice of the care for patients with indolent systemic mastocytosi

A unique presentation of pulmonary disease in advanced systemic mastocytosis, proven by the presence of mast cells in bronchoalveolar lavage: A case report

Background: Systemic mastocytosis is a rare myeloproliferative disease characterized by the uncontrolled proliferation of aberrant mast cells. It has varying clinical manifestations. For unknown reasons, pulmonary localization of mastocytosis is extremely rare. Case presentation: In this report, we describe a case of a young Caucasian female with systemic mastocytosis who had an associated hematological non-mast-cell lineage disease with pulmonary interstitial disease directly related to her mastocytosis. The diagnosis was proven by the presence of mast cells in bronchoalveolar lavage. The treatment of her associated hematological disease (myelofibrosis with myelodysplasia) was hampered by rapidly declining pulmonary function and progressive organ dysfunction due to aggressive systemic mastocytosis. She died approximately 1 year after the diagnosis. Conclusions: To our knowledge, this is the first case in which mast cells were detected in bronchoalveolar lavage. Moreover, to date, only two other cases of pulmonary interstitial disease due to mastocytosis have been published. Juggling therapies for systemic mastocytosis and myelofibrosis is very difficult; however, aggressive therapy for both diseases is essential to give these patients a chance to survive

Nonsteroidal anti-inflammatory drug hypersensitivity: Not always an allergy!

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a major cause of hypersensitivity reactions. Several distinct clinical syndromes are described regarding NSAID hypersensitivity. Such a reaction is generally caused by a non-immunological mechanism. In susceptible patients, COX-1 inhibition leads to an imbalance in lipid mediators such as leukotrienes and prostaglandins. It is essential to distinguish multiple nonspecific NSAID hypersensitivity from single NSAID hypersensitivity, since the management of these respective syndromes is essentially different. This review provides an overview on all the aspects of NSAID hypersensitivity reactions, from pathophysiology to clinical symptoms, leading practical recommendations

The Basophil Activation Test Is Not a Useful Screening Tool for Hymenoptera Venom-Related Anaphylaxis in Patients with Systemic Mastocytosis

Background: Systemic mastocytosis (SM) patients are at a high risk for anaphylaxis, with Hymenoptera as the main culprit. A screening instrument to identify which patients are sensitized to Hymenoptera before they experience anaphylaxis would therefore be of great value. The basophil activation test (BAT) is proposed as a possible tool for diagnosing Hymenoptera venom-related allergy (HVA), especially in patients in whom conventional allergy tests yield contradictory results. Methods: We included outpatients with SM, according to WHO criteria, from September 2011 to January 2012. Next, to obtain various clinical data including intradermal test results, specific immunoglobulin E (sIgE) measurements and BAT were performed. Results: We included 29 patients, 9 of whom had a history of HVA and 4 of whom had experienced anaphylaxis due to other triggers. Sixteen patients had no history of anaphylaxis. sIgE was detected in 6 patients with HVA and in 2 patients with anaphylaxis due to other triggers. The BAT was positive in only 1 patient, in whom the skin test and sIgE were also positive. Compared to patients with skin lesions, those without skin lesions had significantly more anaphylaxis and sIgE to Hymenoptera. During a 3-year follow-up, no one experienced new anaphylactic episodes. Conclusion: The BAT is not a reliable tool for randomly screening SM patients for HVA

Routine abdominal ultrasonography has limited value in the care for patients with indolent systemic mastocytosis

Objectives: Systemic mastocytosis (SM) is a myeloproliferative disease characterized by the accumulation of aberrant mast cells. Since advanced subtypes of SM can lead to organ dysfunction and shortened survival, timely recognition of progressive disease is important for the adequate treatment of SM patients. Methods: Here, we report the results of our cohort study on the value of routine abdominal ultrasonography for the detection of progression of indolent systemic mastocytosis (ISM). Results: We included 88 patients with ISM, of whom 9 developed new hepatosplenomegaly during follow-up. In this group, the median serum tryptase level increased by 11.60 μg/l, compared with a decrease of −0.20 μg/l in the 79 patients with unchanged ultrasonography results (p = 0.016). A change in liver and/or spleen size never led to a change in clinical classification, nor management. Discussion: Based on the finding that a change in ultrasonography findings did not correlate to disease progression in general, it appears that isolated hepatosplenomegaly does not have prognostic implications in patients with ISM. Conclusions: Routine abdominal ultrasonography is redundant in the follow-up of patients with ISM. A combination of physical examination with serum tryptase levels can be used to screen for hepatosplenomegaly

Mast Cells in Cardiovascular Disease: From Bench to Bedside

Mast cells are pluripotent leukocytes that reside in the mucosa and connective tissue. Recent studies show an increased prevalence of cardiovascular disease among patients with mastocytosis, which is a hematological disease that is characterized by the accumulation of mast cells due to clonal proliferation. This association suggests an important role for mast cells in cardiovascular disease. Indeed, the evidence establishing the contribution of mast cells to the development and progression of atherosclerosis is continually increasing. Mast cells may contribute to plaque formation by stimulating the formation of foam cells and causing a pro-inflammatory micro-environment. In addition, these cells are able to promote plaque instability by neo-vessel formation and also by inducing intraplaque hemorrhage. Furthermore, mast cells appear to stimulate the formation of fibrosis after a cardiac infarction. In this review, the available data on the role of mast cells in cardiovascular disease are summarized, containing both in vitro research and animal studies, followed by a discussion of human data on the association between cardiovascular morbidity and diseases in which mast cells are important: Kounis syndrome, mastocytosis and allergy

Increased group 2 innate lymphoid cells in peripheral blood of adults with mastocytosis

Background: Systemic mastocytosis is a hematological disease in which aberrant mast cells accumulate because of gain-of-function mutations in the KIT receptor. Group 2 innate lymphoid cells (ILC2s) are effector cells of type 2 immune responses that also express KIT and colocalize with mast cells at barrier tissue sites. In mouse models, mast cell-ILC2 crosstalk can drive local inflammation. However, a possible role for ILC2s in the pathophysiology of mastocytosis remains unexplored. Objective: We sought to characterize circulating ILC2s in a clinically diverse cohort of patients with mastocytosis. Methods: We included 21 adults with systemic mastocytosis and 18 healthy controls. Peripheral blood ILC2 abundance and phenotype were analyzed by flow cytometry and correlated to clinical characteristics, including the presence of the D816V KIT mutation. Results: ILC2 levels were significantly higher in D816V+ patients with mastocytosis compared with D816V− patients or healthy controls. We observed increased proportions of KIT+ ILC2s among patients with mastocytosis, regardless of D816V status. Patients with skin involvement and itch showed the highest levels of ILC2s, which was independent from atopy or serum tryptase levels. Allele-specific quantitative PCR showed that the vast majority of ILC2s did not carry the D816V mutation. Conclusions: Our findings suggest a role for ILC2s and pathogenic ILC2-mast cell crosstalk in mastocytosis. We hypothesize that a high cutaneous D816V+

The JAK1/JAK2- inhibitor ruxolitinib inhibits mast cell degranulation and cytokine release

Background: Mastocytosis is characterized by the accumulation of aberrant mast cells (MC). Patients suffering from mastocytosis suffer from a wide range of symptoms due to increased levels of MC mediators. It would therefore be of great benefit to inhibit MC mediator release. However, to date there are few drugs available that are known to effectively lower MC mediator levels. The evidence for the involvement of the janus kinase 2 (JAK2)—signal transducer and activation of transcription 5 (STAT5) signalling pathway in MC activation is slowly accumulating. Interference with the JAK2-STAT5 pathway might inhibit MC mediator release. Ruxolitinib, a JAK1/JAK2 inhibitor, indeed decreases symptoms like pruritus and fatigue in patients with myeloproliferative neoplasms. Yet, detailed studies on how ruxolitinib affects human mast cell activity are lacking. Objective: To investigate the effect of JAK1/2-inhibition with ruxolitinib in the human mast cell lines LAD2 and HMC1. Methods: LAD2 and HMC1 were stimulated with substance P, codeine or the calcium ionophore A23817. The effect of ruxolitinib on mast cell degranulation (via measurement of β-hexosaminidase, histamine release and CD63 membrane expression) and IL-6, IL-13, MCP-1 and TNF-α production was investigated. The involvement of STAT5 activation was explored using the selective STAT5 inhibitor pimozide. Results: Ruxolitinib effectively inhibited codeine- and substance P-induced degranulation in a concentration-dependent manner. Ruxolitinib also significantly inhibited the production of IL-6, TNF-α and MCP-1 as induced by A23817 and substance P. Selective STAT5 inhibition with pimozide resulted in diminished degranulation and inhibition of cytokine production as induced by A23817 and substance P. Conclusions & clinical relevance: This study demonstrates that the JAK1/JAK2 inhibitor ruxolitinib can inhibit MCactivity, possibly through prevention of STAT5 activation. This renders the JAK-STAT pathway as an interesting target for therapy to release symptom burden in mastocytosis and many other MC mediator-related diseases

Are Patients at Risk for Recurrent Disease Activity After Switching From Remicade® to Remsima®? An Observational Study

Background: Since the late ‘90s, infliximab (Remicade®) is being used successfully to treat patients with several non-infectious immune mediated inflammatory diseases (IMIDs). In recent years, infliximab biosimilars, including Remsima® were introduced in clinical practice. Aim: To investigate the interchangeability of Remicade® (originator infliximab) and its biosimilar Remsima® in patients with rare immune-mediated inflammatory diseases (IMIDs). Methods: This two-phased prospective open label observational study was designed to monitor the transition from Remicade® to Remsima® in patients with rare IMIDs. All included patients were followed during the first 2 years. The primary endpoint was the demonstration of non-difference in quality of life and therapeutic efficacy, as measured by parameters including a safety monitoring program, physicians perception of disease activity (PPDA) and patient self-reported outcomes (PSROs). Secondary outcomes included routine blood analysis, pre-infusion serum drug concentration values and anti-drug antibody formation. Results: Forty eight patients treated with Remicade® were switched to Remsima® in June-July 2016 and subsequently monitored during the first 2 years. The group consisted of patients with sarcoidosis (n = 17), Behçet's disease (n = 12), non-infectious uveitis (n = 11), and other diagnoses (n = 8). There were no significant differences in PPDA, PSROs, clinical and laboratory assessments and pre-infusion serum drug concentrations between the groups. De novo anti-drug antibodies were observed in two patients. Seven patients with sarcoidosis and five with another diagnosis developed a significant disease relapse (n = 7) or adverse events (n = 5) within 2 years; 10 of these patients discontinued Remsima® treatment, one withdrew from the study and one received additional corticosteroid therapy. Conclusions: We observed no significant differences in PSROs, PPDA and laboratory parameters after treatment was switched from Remicade® to Remsima®. However, disease relapse or serious events were observed in 12 out of 48 patients when treatment was switched from Remicade® to Remsima®. The choice to switch anti-TNF alpha biologics in patients with rare IMIDs, particularly in sarcoidosis, requires well-considered decision-making and accurate monitoring due to a possibly higher incidence of disease worsening

Characteristics of COVID-19 infection and antibody formation in patients known at a tertiary immunology department

Background: Knowledge about COVID-19 infections is expanding, although knowledge about the disease course and antibody formation in patients with an auto-immune disease or immunodeficiency is not fully unraveled yet. It could be hypothesized that immunodeficient patients, due to immunosuppressive drugs or their disease, have a more severe disease course due to their immunocompromised state. However, it could also be hypothesized that some of the immunosuppressive drugs protect against a hyperinflammatory state. Methods: We collected data on the incidence of COVID-19, disease course and SARS-CoV-2 antibody formation in COVID-19 positive patients in a cohort of patients (n ​= ​4497) known at the Clinical Immunology outpatient clinic in a tertiary care hospital in the Netherlands. Results: In the first six months of the pandemic, 16 patients were identified with COVID-19, 14 by nasal swab PCR, and 2 pa