Mast cell silencing: A novel therapeutic approach for urticaria and other mast cell-mediated diseases.

Chronic urticaria (CU) is a mast cell (MC)-dependent disease with limited therapeutic options. Current management strategies are directed at inhibiting IgE-mediated activation of MCs and antagonizing effects of released mediators. Due to the complexity and heterogeneity of CU and other MC diseases and mechanisms of MC activation-including multiple activating receptors and ligands, diverse signaling pathways, and a menagerie of mediators-strategies of MC depletion or MC silencing (i.e., inhibition of MC activation via binding of inhibitory receptors) have been developed to overcome limitations of singularly targeted agents. MC silencers, such as agonist monoclonal antibodies that engage inhibitory receptors (e.g., sialic acid-binding immunoglobulin-like lectin8 -[Siglec-8] [lirentelimab/AK002], Siglec-6 [AK006], and CD200R [LY3454738]), have reached preclinical and clinical stages of development. In this review, we (1) describe the role of MCs in the pathogenesis of CU, highlighting similarities with other MC diseases in disease mechanisms and response to treatment; (2) explore current therapeutic strategies, categorized by nonspecific immunosuppression, targeted inhibition of MC activation or mediators, and targeted modulation of MC activity; and (3) introduce the concept of MC silencing as an emerging strategy that could selectively block activation of MCs without eliciting or exacerbating on- or off-target, immunosuppressive adverse effects.

Stress Affects Mast Cell Proteases in Murine Skin in a Model of Atopic Dermatitis-like Allergic Inflammation.

Stress exposure worsens allergic inflammatory diseases substantially. Mast cells (MCs) play a key role in peripheral immune responses to neuroendocrine stress mediators such as nerve growth factor (NGF) and substance P (SP). Mast cell proteases (MCPs) and cholinergic factors (Chrna7, SLURP1) were recently described to modulate MC stress response. We studied MCPs and Chrna7/SLURP1 and their interplay in a mouse model for noise induced stress (NiS) and atopic dermatitis-like allergic inflammation (AlD) and in cultured MC lacking Chrna7. We found that the cholinergic stress axis interacts with neuroendocrine stress mediators and stress-mediator cleaving enzymes in AlD. SP-cleaving mMCP4+ MC were upregulated in AlD and further upregulated by stress in NiS+AlD. Anti-NGF neutralizing antibody treatment blocked the stress-induced upregulation in vivo, and mMCP4+ MCs correlated with measures of AlD disease activity. Finally, high mMCP4 production in response to SP depended on Chrna7/SLURP1 in cultured MCs. In conclusion, mMCP4 and its upstream regulation by Chrna7/SLURP1 are interesting novel targets for the treatment of allergic inflammation and its aggravation by stress.

Virus-infected mast cells activate virus-specific CD8+ T cells.

Efficient anti-viral responses of CD8+ T cells require signals that promote their effector cell differentiation, that are mainly provided by dendritic cells (DCs). Mast cells (MCs) are key drivers of DC maturation, but also influence their migration and antigen presenting properties and therefore indirectly mediate CD8+ T cell activation. MCs initiate innate immune responses at pathogen entry sites, promote the development of adaptive immune responses after infection, and release mediators including chemokines that recruit and activate immune cells including T cells during viral infections. However, whether MCs can directly activate virus-specific CD8+ T cells remains largely unknown. Here, we used an in vitro viral infection model with lymphocytic choriomeningitis virus (LCMV)-infected MCs or DCs co-cultured with either LCMV-specific CD8+ T cells or with WT (unspecific) CD8+ T cells. Similar to LCMV-infected DCs, LCMV-infected MCs clustered with virus-specific CD8+ T cells and induced their activation and production of antiviral cytokines. In addition, the co-stimulatory molecules CD86 and OX40L, but not CD80, were upregulated on MCs and an increased production of IL-6 and type I interferons after LCMV infection was shown. Our findings suggest that MCs can promote CD8+ T cell activation during viral infections. MC-mediated CD8+ T cell activation might be especially important within infected tissues where direct cellular interaction can take place. A better understanding of anti-viral functions of MCs may help developing new strategies to better treat viral infections.

Safety and efficacy of lirentelimab in patients with refractory indolent systemic mastocytosis: a first-in-human clinical trial.

BACKGROUND: Indolent systemic mastocytosis (ISM) is characterized by excessive mast cell (MC) accumulation and MC-driven signs and symptoms. Currently used therapies are not approved and have limited efficacy. Lirentelimab (AK002) is a monoclonal antibody against sialic acid-binding immunoglobulin-like lectin (Siglec)-8 that inhibits MC activation. OBJECTIVES: To determine the safety, tolerability and efficacy of lirentelimab in reducing the symptoms of ISM. METHODS: At a specialty centre for mastocytosis in Germany, we conducted a phase I first-in-human single-ascending and multidose clinical trial of lirentelimab in patients with ISM. Eligible adults had World Health Organization-confirmed ISM and an unsatisfactory response to available treatment. In part A, patients received a single dose of lirentelimab 0.0003, 0.001, 0.003, 0.01 or 0.03 mg kg-1; in part B, patients received one lirentelimab dose of 0.3 mg kg-1 or 1.0 mg kg-1; and in part C, patients received either 1.0 mg kg-1 lirentelimab every 4 weeks for 6 months or ascending doses of lirentelimab (one dose of 1 mg kg-1 followed by five doses of 3-10 mg kg-1 every 4 weeks). The primary endpoint was safety/tolerability. Secondary endpoints included changes from baseline in Mastocytosis Symptom Questionnaire (MSQ), Mastocytosis Activity Score (MAS) and Mastocytosis Quality of Life Questionnaire (MC-QoL) scores at 2 weeks after the final dose. RESULTS: In 25 patients with ISM (13 in parts A + B and 12 in part C; median age 51 years, 76% female, median 4.6 years from diagnosis), the most common treatment-related adverse events (AEs) were feeling hot (76%) and experiencing a headache (48%). No serious AEs occurred. Median MSQ and MAS symptom severity scores in part C improved (vs. baseline) across all symptoms [MSQ: skin (38-56%), gastrointestinal (49-60%), neurological (47-59%), musculoskeletal (26-27%); MAS: skin (53-59%), gastrointestinal (72-85%), neurological (20-57%), musculoskeletal (25%)]. Median MC-QoL scores improved across all domains: symptoms (39%), social life/functioning (42%), emotions (57%) and skin (44%). CONCLUSIONS: Lirentelimab was generally well tolerated and improved symptoms and quality of life in patients with ISM. The therapeutic potential of lirentelimab should be considered for ISM.

An open-label, proof-of-concept study of lirentelimab for antihistamine-resistant chronic spontaneous and inducible urticaria.

BACKGROUND: Chronic urticaria (CU) is a debilitating mast cell-driven disease, often refractory to standard therapy (ie, antihistamines). Lirentelimab, an anti-sialic acid-binding immunoglobulin-like lectin 8 mAb, selectively inhibits mast cells and depletes eosinophils. OBJECTIVE: We sought to determine safety and efficacy of lirentelimab in patients with CU. METHODS: This phase 2a study enrolled patients with CU refractory to up to 4-fold H1-antihistamine doses. Patients received 6 monthly intravenous doses of lirentelimab (0.3, 1, and up to 3 mg/kg). Primary efficacy end point was change in Urticaria Control Test score at week 22. Urticaria Activity Score weekly average (UAS7) was assessed in patients with chronic spontaneous urticaria (CSU), and Cholinergic UAS7 was used for patients with cholinergic urticaria (CholU). RESULTS: A total of 45 patients were enrolled in 4 cohorts (n = 13 omalizumab-naive CSU, n = 11 omalizumab-refractory CSU, n = 11 CholU, n = 10 symptomatic dermographism). Urticaria Control Test scores increased with lirentelimab across cohorts, with mean changes at week 22 of 11.1 ± 4.1, 4.8 ± 7.0, 6.5 ± 6.2, and 3.4 ± 4.1 and complete response rates (Urticaria Control Test score ≥ 12) of 92%, 36%, 82%, and 40%, respectively. In omalizumab-naive and omalizumab-refractory patients with CSU, disease activity decreased at week 22 (mean UAS7 change, -73% and -47%, respectively), with UAS7 response rates (≥50% reduction) of 77% and 45%, respectively. In patients with symptomatic dermographism, 50% (5 of 10) and 40% (4 of 10) had complete itch and hive resolution by FricTest, respectively, and 100% (7 of 7) evaluable patients with CholU had negative responses to Pulse-Controlled Ergometry exercise test. Most common adverse events included infusion-related reactions (43%; all mild/moderate and transient), nasopharyngitis (21%), and headache (19%). No treatment-related serious adverse events occurred. CONCLUSIONS: Lirentelimab demonstrated activity across 3 forms of antihistamine-refractory CU.

Selected recent advances in understanding the role of human mast cells in health and disease.

Mast cells are highly granular tissue-resident cells and key drivers of inflammation, particularly in allergies as well as in other inflammatory diseases. Most mast cell research was initially conducted in rodents but has increasingly shifted to the human system, with the advancement of research technologies and methodologies. Today we can analyze primary human cells including rare subpopulations, we can produce and maintain mast cells isolated from human tissues, and there are several human mast cell lines. These tools have substantially facilitated our understanding of their role and function in different organs in both health and disease. We can now define more clearly where human mast cells originate from, how they develop, which mediators they store, produce de novo, and release, how they are activated and by which receptors, and which neighboring cells they interact with and by which mechanisms. Considerable progress has also been made regarding the potential contribution of mast cells to disease, which, in turn, has led to the development of novel approaches for preventing key pathogenic effects of mast cells, heralding the era of mast cell-targeted therapeutics. In this review, we present and discuss a selection of some of the most significant advancements and remaining gaps in our understanding of human mast cells during the last 25 years, with a focus on clinical relevance.

A novel approach for studying mast cell-driven disorders: Mast cells derived from induced pluripotent stem cells.

BACKGROUND: Mast cells (MCs) are considered the main effectors in allergic reactions and well known for their contribution to the pathogenesis of various inflammatory diseases, urticaria, and mastocytosis. To study their functions in vitro, human primary MCs are isolated directly from several tissues or differentiated from hematopoietic progenitors. However, these techniques bear several disadvantages and challenges including low proliferation capacity, donor-dependent heterogeneity, and the lack of a continuous cell source. OBJECTIVE: To address this, we developed a novel strategy for the rapid and efficient differentiation of MCs from human-induced pluripotent stem cells (hiPSCs). METHODS: A 4-step protocol for the generation of hiPSC-derived MCs, based on the use of 3 hiPSC lines, was established and validated by comparison with human skin MCs and peripheral hematopoietic stem cell-derived MCs. RESULTS: hiPSC-MCs share phenotypic and functional characteristics of human skin MCs and peripheral hematopoietic stem cell-derived MCs. They display stable expression of the MC-associated receptors CD117, FcεRIα, and Mas-related G protein-coupled receptor X2 and degranulate in response to IgE/anti-IgE and substance P. CONCLUSIONS: This novel hiPSC-based approach provides a sustainable and homogeneous source for a rapid and highly productive generation of phenotypically mature, functional MCs, and its principle allows for the investigation of disease- and patient-specific MC populations.

Idiopathic mast cell activation syndrome is more often suspected than diagnosed-A prospective real-life study.

BACKGROUND: Idiopathic mast cell activation syndrome (MCAS) is characterized by three diagnostic criteria: (1) episodic mast cell (MC)-driven signs/symptoms of at least two organ systems in the absence of clonal MC expansion and definite triggers, (2) episodic increase in tryptase, and (3) response to MC-targeted treatment. Many patients believe they have MCAS, but how often this is the case remains unknown. METHODS: We prospectively investigated patients with suspected MCAS (n = 100) for the diagnostic criteria including baseline tryptase, KIT D816V mutation, and patient-reported outcome measures (PROMs) over the course of 12 weeks. Comorbid depression and anxiety were explored with the Hospital Anxiety and Depression Scale (HADS). RESULTS: In 53% of our patients (80% females), suspicion of MCAS was based on self-evaluation. In total, patients reported 87 different symptoms, mostly fatigue (n = 57), musculoskeletal pain/weakness (n = 49), and abdominal pain (n = 43), with overall high disease activity and impact. Two of 79 patients had increased tryptase (by >20% +2 ng/ml) following an episode. Only 5%, with any of the PROMs used, showed complete response to MC-targeted treatment. Depression and anxiety disorders were frequent comorbidities (n = 23 each), and 65 patients had pathological HADS values, which were linked to high disease impact and poor symptom control. CONCLUSION: Mast cell activation syndrome was confirmed in only 2% of patients, which implies that it is not MC activation that drives signs and symptoms in most patients with suspected MCAS. There is a high need for comprehensive research efforts aimed at the identification of the true underlying pathomechanism(s) in patients with suspected MCAS.

The Multifaceted Roles of Mast Cells in Immune Homeostasis, Infections and Cancers.

Mast cells (MCs) play important roles in normal immune responses and pathological states. The location of MCs on the boundaries between tissues and the external environment, including gut mucosal surfaces, lungs, skin, and around blood vessels, suggests a multitude of immunological functions. Thus, MCs are pivotal for host defense against different antigens, including allergens and microbial pathogens. MCs can produce and respond to physiological mediators and chemokines to modulate inflammation. As long-lived, tissue-resident cells, MCs indeed mediate acute inflammatory responses such as those evident in allergic reactions. Furthermore, MCs participate in innate and adaptive immune responses to bacteria, viruses, fungi, and parasites. The control of MC activation or stabilization is a powerful tool in regulating tissue homeostasis and pathogen clearance. Moreover, MCs contribute to maintaining the homeostatic equilibrium between host and resident microbiota, and they engage in crosstalk between the resident and recruited hematopoietic cells. In this review, we provide a comprehensive overview of the functions of MCs in health and disease. Further, we discuss how mouse models of MC deficiency have become useful tools for establishing MCs as a potential cellular target for treating inflammatory disorders.

Mast Cells as Drivers of Disease and Therapeutic Targets.

Mast cells (MCs) contribute to the pathogenesis of a multitude of diseases that include MC-driven disorders such as urticaria, type I allergies, and mastocytosis as well as autoimmune and other inflammatory disorders and malignant tumors. Here, we review and discuss the results of studies that identified and characterized how MCs contribute to disease and, importantly, what strategies may be used to target MCs and MC effects therapeutically. Specifically, we discuss the most common approaches for investigating the role and relevance of MCs in various diseases. We also review current therapeutic approaches aimed at modulating MC numbers, inhibiting MCs and/or preventing MC activation, modulating MC signal transduction and protection from the effects of MC mediators.

Risk and management of patients with mastocytosis and MCAS in the SARS-CoV-2 (COVID-19) pandemic: Expert opinions.

The coronavirus disease 2019 (COVID-19) (caused by severe acute respiratory syndrome coronavirus 2) pandemic has massively distorted our health care systems and caused catastrophic consequences in our affected communities. The number of victims continues to increase, and patients at risk can only be protected to a degree, because the virulent state may be asymptomatic. Risk factors concerning COVID-19-induced morbidity and mortality include advanced age, an impaired immune system, cardiovascular or pulmonary diseases, obesity, diabetes mellitus, and cancer treated with chemotherapy. Here, we discuss the risk and impact of COVID-19 in patients with mastocytosis and mast cell activation syndromes. Because no published data are yet available, expert opinions are, by necessity, based on case experience and reports from patients. Although the overall risk to acquire the severe acute respiratory syndrome coronavirus 2 may not be elevated in mast cell disease, certain conditions may increase the risk of infected patients to develop severe COVID-19. These factors include certain comorbidities, mast cell activation-related events affecting the cardiovascular or bronchopulmonary system, and chemotherapy or immunosuppressive drugs. Therefore, such treatments should be carefully evaluated on a case-by-case basis during a COVID-19 infection. In contrast, other therapies, such as anti-mediator-type drugs, venom immunotherapy, or vitamin D, should be continued. Overall, patients with mast cell disorders should follow the general and local guidelines in the COVID-19 pandemic and advice from their medical provider.

Molecular Background, Clinical Features and Management of Pediatric Mastocytosis: Status 2021.

Pediatric mastocytosis is a heterogeneous disease characterized by accumulation of mast cells in the skin and less frequently in other organs. Somatic or germline mutations in the KIT proto-oncogene are detected in most patients. Cutaneous mastocytosis is the most common form of the disease in children. In the majority of cases, skin lesions regress spontaneously around puberty. However, in few patients, mastocytosis is not a self-limiting disease, but persists into adulthood and can show signs of systemic involvement, especially when skin lesions are small-sized and monomorphic. Children with mastocytosis often suffer from mast cell mediator-related symptoms. Severe hypersensitivity reactions can also occur, mostly in patients with extensive skin lesions and blistering. In a substantial number of these cases, the triggering factor of anaphylaxis remains unidentified. Management of pediatric mastocytosis is mainly based on strict avoidance of triggers, treatment with H1 and H2 histamine receptor blockers, and equipment of patients and their families with epinephrine auto-injectors for use in severe anaphylactic reactions. Advanced systemic mastocytosis occurs occasionally. All children with mastocytosis require follow-up examinations. A bone marrow investigation is performed when advanced systemic mastocytosis is suspected and has an impact on therapy or when cutaneous disease persists into adulthood.

Development of the Angioedema Control Test-A patient-reported outcome measure that assesses disease control in patients with recurrent angioedema.

BACKGROUND: Recurrent angioedema (AE) is an important clinical problem in the context of chronic urticaria (mast cell mediator-induced), ACE-inhibitor intake and hereditary angioedema (both bradykinin-mediated). To help patients obtain control of their recurrent AE is a major treatment goal. However, a tool to assess control of recurrent AE is not yet available. This prompted us to develop such a tool, the Angioedema Control Test (AECT). METHODS: After a conceptional framework was developed for the AECT, a list of potential AECT items was generated by a combined approach of patient interviews, literature review and expert input. Subsequent item reduction was based on impact analysis, inter-item correlation, additional predefined criteria for item performance, and a review of the item selection process for content validity. Finally, an instruction section was generated, and an US-American-English version was developed by a structured translation process. RESULTS: A 4-item AECT with recall periods of 4 weeks and 3 months was developed based on 106 potential items tested in 97 patients with mast cell mediator-induced (n = 49) or bradykinin-mediated recurrent AE (n = 48). Eighty-four items were excluded based on impact analysis. The remaining 22 items could be further reduced by a method-mix of inter-item correlation, additional predefined criteria for item performance and review for content validity. CONCLUSIONS: The AECT is the first tool to assess disease control in recurrent AE patients. Its retrospective approach, its brevity and its simple scoring make the AECT ideally suited for clinical practice and trials. Its validity and reliability need to be determined in future independent studies.

Mast cells drive IgE-mediated disease but might be bystanders in many other inflammatory and neoplastic conditions.

Mast cells (MCs) are capable of executing powerful inflammatory response programs triggered by surface IgE cross-linking or through pattern recognition receptors. The question of how MCs contribute to human disease has been intensely investigated and stimulated much controversy. Correlative evidence comes from human studies, pointing to pathogenetic or protective MC functions in patients with atopic conditions, autoimmune disorders, type 2 diabetes, chronic urticaria, mastocytosis, and cancer. Experiments in MC-deficient mice underpinned key roles for MCs in patients with IgE-mediated allergic conditions. Important pathogenetic MC contributions to other inflammatory and neoplastic conditions were suggested by studies in traditional KIT mutant MC-deficient mouse strains. However, many of these findings were not reproduced in more recently developed improved mouse models of MC deficiency, largely ruling out roles for MCs in mouse models for autoimmune disease, diabetes, and cancer. We discuss limitations of studies in mice and human subjects and provide suggestions for how they can be overcome, such as through the development of specific and selective MC-targeted treatments.

Diagnosis, Classification and Management of Mast Cell Activation Syndromes (MCAS) in the Era of Personalized Medicine.

Mast cell activation (MCA) is seen in a variety of clinical contexts and pathologies, including IgE-dependent allergic inflammation, other immunologic and inflammatory reactions, primary mast cell (MC) disorders, and hereditary alpha tryptasemia (HAT). MCA-related symptoms range from mild to severe to life-threatening. The severity of MCA-related symptoms depends on a number of factors, including genetic predisposition, the number and releasability of MCs, organs affected, and the type and consequences of comorbid conditions. In severe systemic reactions, MCA is demonstrable by a substantial increase of basal serum tryptase levels above the individual's baseline. When, in addition, the symptoms are recurrent, involve more than one organ system, and are responsive to therapy with MC-stabilizing or mediator-targeting drugs, the consensus criteria for the diagnosis of MCA syndrome (MCAS) are met. Based on the etiology of MCA, patients can further be classified as having i) primary MCAS where KIT-mutated, clonal, MCs are detected; ii) secondary MCAS where an underlying IgE-dependent allergy or other reactive MCA-triggering pathology is found; or iii) idiopathic MCAS, where neither a triggering reactive state nor KIT-mutated MCs are identified. Most severe MCA events occur in combined forms of MCAS, where KIT-mutated MCs, IgE-dependent allergies and sometimes HAT are detected. These patients may suffer from life-threatening anaphylaxis and are candidates for combined treatment with various types of drugs, including IgE-blocking antibodies, anti-mediator-type drugs and MC-targeting therapy. In conclusion, detailed knowledge about the etiology, underlying pathologies and co-morbidities is important to establish the diagnosis and develop an optimal management plan for MCAS, following the principles of personalized medicine.

Mast Cells Limit the Exacerbation of Chronic Allergic Contact Dermatitis in Response to Repeated Allergen Exposure.

Allergic contact dermatitis is a chronic T cell-driven inflammatory skin disease that is caused by repeated exposure to contact allergens. Based on murine studies of acute contact hypersensitivity, mast cells (MCs) are believed to play a role in its pathogenesis. The role of MCs in chronic allergic contact dermatitis has not been investigated, in part because of the lack of murine models for chronic contact hypersensitivity. We developed and used a chronic contact hypersensitivity model in wild-type and MC-deficient mice and assessed skin inflammatory responses to identify and characterize the role of MCs in chronic allergic contact dermatitis. Ear swelling chronic contact hypersensitivity responses increased markedly, up to 4-fold, in MC-deficient KitW-sh/W-sh (Sash) and MCPT5-Cre+iDTR+ mice compared with wild-type mice. Local engraftment with MCs protected Sash mice from exacerbated ear swelling after repeated oxazolone challenge. Chronic contact hypersensitivity skin of Sash mice exhibited elevated levels of IFN-γ, IL-17α, and IL-23, as well as increased accumulation of Ag-specific IFN-γ-producing CD8+ tissue-resident memory T (TRM) cells. The CD8+ T cell mitogen IL-15, which was increased in oxazolone-challenged skin of Sash mice during the accumulation of cutaneous TRM cells, was efficiently degraded by MCs in vitro. MCs protect from the exacerbated allergic skin inflammation induced by repeated allergen challenge, at least in part, via effects on CD8+ TRM cells. MCs may notably influence the course of chronic allergic contact dermatitis. A better understanding of their role and the underlying mechanisms may lead to better approaches for the treatment of this common, disabling, and costly condition.

Chronic urticaria - What does the new guideline tell us?

Patients with chronic urticaria experience significant impairment, and require an effective treatment. Such treatment is preceded by a thorough diagnostic workup and measurement of disease activity, disease burden and disease control using well--established tools. Treatment is subsequently adjusted according to patient needs and therapeutic response, based on the tenet "as much as necessary, as little as possible" (in that order). Once disease control has been achieved, it is recommended that intermittent attempts at medication withdrawal be made in order to identify spontaneous disease remission. Chronic urticaria should be treated until spontaneous remission occurs.

Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology.

Cutaneous lesions in patients with mastocytosis are highly heterogeneous and encompass localized and disseminated forms. Although a classification and criteria for cutaneous mastocytosis (CM) have been proposed, there remains a need to better define subforms of cutaneous manifestations in patients with mastocytosis. To address this unmet need, an international task force involving experts from different organizations (including the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology) met several times between 2010 and 2014 to discuss the classification and criteria for diagnosis of cutaneous manifestations in patients with mastocytosis. This article provides the major outcomes of these meetings and a proposal for a revised definition and criteria. In particular, we recommend that the typical maculopapular cutaneous lesions (urticaria pigmentosa) should be subdivided into 2 variants, namely a monomorphic variant with small maculopapular lesions, which is typically seen in adult patients, and a polymorphic variant with larger lesions of variable size and shape, which is typically seen in pediatric patients. Clinical observations suggest that the monomorphic variant, if it develops in children, often persists into adulthood, whereas the polymorphic variant may resolve around puberty. This delineation might have important prognostic implications, and its implementation in diagnostic algorithms and future mastocytosis classifications is recommended. Refinements are also suggested for the diagnostic criteria of CM, removal of telangiectasia macularis eruptiva perstans from the current classification of CM, and removal of the adjunct solitary from the term solitary mastocytoma.