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Ballul T, Sabato V, Valent P, Hermine O, Lortholary O, Rossignol J. Characterization of patients with clonal mast cells in the bone marrow with clinical significance not otherwise specified. EClinicalMedicine 2025; 80:103043. [PMID: 39877259 PMCID: PMC11773267 DOI: 10.1016/j.eclinm.2024.103043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 12/06/2024] [Accepted: 12/17/2024] [Indexed: 01/31/2025] Open
Abstract
Background Systemic mastocytosis (SM) diagnosis requires the presence of 3 minor criteria or 1 major and 1 minor criterion according to the WHO 2016 classification. The aim of this study was to characterize patients with 1 or 2 minor SM criteria including KIT 816 mutation and/or aberrant expression of CD2 and/or CD25 on bone marrow (BM) mast cells (MCs), but without MC activation syndrome (MCAS) criteria. Methods We included eligible patients from two countries diagnosed between 2011 and 2021. These patients are reported herein as monoclonal MC with clinical significance (MMCS). MMCS patients were compared with 432 patients with indolent SM (ISM) and 51 with BM mastocytosis (BMM) from the CEREMAST database. Findings Overall, 51 patients with MMCS were included. MMCS patients with (n = 29) or without (n = 22) KIT 816 mutation did not differ significantly with regard to the prevalence of anaphylaxis and basal tryptase level. Anaphylaxis, often in the context of hymenoptera venom allergy, was more frequent in MMCS than in ISM (78% vs 35%, respectively; p < 0.001). Osteoporosis was similarly prevalent in MMCS and BMM (45% vs 32%, p = ns). The median baseline serum tryptase level was lower in MMCS compared with ISM or BMM (13 vs 26 vs 23 ng/mL, respectively; p < 0.001). Hereditary alpha-tryptasemia was similarly represented in MMCS and BMM (14.3% vs 19.7% respectively, p = ns). Interpretation Clonal BMMCs may be associated with clinically relevant symptoms even if criteria for SM or MCAS are not fulfilled. These MMCS patients may require specific management and follow-up to capture potential transition to SM and/or MCAS. Funding None.
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Affiliation(s)
- Thomas Ballul
- French Reference Center for Mastocytosis (CEREMAST), Paris Cité University, Necker – Enfants Malades University Hospital, APHP, Paris, France
| | - Vito Sabato
- Department of Immunology Allergology and Rheumatology University of Antwerp and Antwerp University Hospital, Antwerp, Belgium
| | - Peter Valent
- Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Austria
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Austria
| | - Olivier Hermine
- French Reference Center for Mastocytosis (CEREMAST), Paris Cité University, Necker – Enfants Malades University Hospital, APHP, Paris, France
| | - Olivier Lortholary
- French Reference Center for Mastocytosis (CEREMAST), Paris Cité University, Necker – Enfants Malades University Hospital, APHP, Paris, France
| | - Julien Rossignol
- French Reference Center for Mastocytosis (CEREMAST), Paris Cité University, Necker – Enfants Malades University Hospital, APHP, Paris, France
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2
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Tanasi I, Crosera L, Taus F, Orsolini G, Adami G, Olivieri F, Bernardelli A, Bonadonna P, Nalin F, Sella S, Giannini S, Liu Y, Mannelli F, Vanderwert F, Bonifacio M, Krampera M, Rossini M, Lyons JJ, Zanotti R. Underlying systemic mastocytosis in patients with unexplained osteoporosis: score proposal. Bone 2024; 186:117141. [PMID: 38823568 PMCID: PMC11854854 DOI: 10.1016/j.bone.2024.117141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 05/12/2024] [Accepted: 05/29/2024] [Indexed: 06/03/2024]
Abstract
BACKGROUND A score to predict the association between unexplained osteoporosis and an underlying systemic Mastocytosis (SM) is lacking. OBJECTIVE This study aimed at identifying criteria able to predict the diagnosis of SM without skin involvement and provide an indication for bone marrow (BM) assessment. METHODS We included 139 adult patients with unexplained osteoporosis and suspected SM. After BM evaluation, 63 patients (45.3 %) were diagnosed with SM, while the remaining 76 patients (54.7 %) negative for clonal mast cell (MC) disorders, constituted our control group. Univariate and multivariate analysis identified three independent predictive factors: age (<54 years: +1 point, >64 years: -1 point), serum basal tryptase (sBT) levels >19 ng/mL (+2 points) and vertebral fractures (+2 points). RESULTS These variables were used to build the OSTEO-score, able to predict the diagnosis of SM before BM assessment with a sensitivity of 73.5 % and a specificity of 67.1 %. Patients with a score < 3 had a lower probability of having SM compared to patients with a score ≥ 3 (28.5 % and 71.4 %, respectively, p < 0.0001). When sBT levels were corrected for the presence of hereditary alpha-tryptasemia (HαT) using the BST calculater (https://bst-calculater.niaid.nih.gov/) recently published [1,2], the sensitivity of ΗαT-adjusted OSTEO-score increased to 87.8 %, and the specificity reached 76.1 %. Also, the positive predictive value of a score ≥ 3 increased to 85.2 %. CONCLUSIONS Further studies are needed to validate these results and characterize the role of tryptase genotyping in patients with unexplained osteoporosis in reducing the risk of misdiagnosing patients with SM. Our proposed scoring model allows the identification of patients with the highest probability of having SM, avoiding unnecessary BM studies.
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Affiliation(s)
- Ilaria Tanasi
- Unità Operativa di Ematologia, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy; Gruppo Interdisciplinare per lo Studio della Mastocitosi (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy.
| | - Lara Crosera
- Unità Operativa di Ematologia, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy; Gruppo Interdisciplinare per lo Studio della Mastocitosi (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Francesco Taus
- Department of Diagnostic and Public Health, Section of Epidemiology and Medical Statistics, University of Verona, Verona, Italy
| | - Giovanni Orsolini
- Gruppo Interdisciplinare per lo Studio della Mastocitosi (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy; Unità Operativa di Reumatologia, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Giovanni Adami
- Unità Operativa di Reumatologia, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Francesco Olivieri
- Gruppo Interdisciplinare per lo Studio della Mastocitosi (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy; Unità Operativa di Allergologia e Asma Center, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Andrea Bernardelli
- Unità Operativa di Ematologia, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy; Gruppo Interdisciplinare per lo Studio della Mastocitosi (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Patrizia Bonadonna
- Gruppo Interdisciplinare per lo Studio della Mastocitosi (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy; Unità Operativa di Allergologia e Asma Center, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Francesca Nalin
- Gruppo Interdisciplinare per lo Studio della Mastocitosi (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy; Unità Operativa di Allergologia e Asma Center, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Stefania Sella
- Clinica Medica 1, Azienda Ospedale Università di Padova, Padova, Italy
| | - Sandro Giannini
- Clinica Medica 1, Azienda Ospedale Università di Padova, Padova, Italy
| | - Yihui Liu
- Translational Allergic Immunopathology Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA
| | - Francesco Mannelli
- CRIMM, Centro di Ricerca e Innovazione per le Malattie Mieloproliferative, Università di Firenze, Dipartimento di Medicina Sperimentale e Clinica, Denothe Excellence Center, Università degli Studi di Firenze, Firenze, Italy
| | - Fiorenza Vanderwert
- CRIMM, Centro di Ricerca e Innovazione per le Malattie Mieloproliferative, Università di Firenze, Dipartimento di Medicina Sperimentale e Clinica, Denothe Excellence Center, Università degli Studi di Firenze, Firenze, Italy
| | - Massimiliano Bonifacio
- Unità Operativa di Ematologia, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy; Gruppo Interdisciplinare per lo Studio della Mastocitosi (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy; Department of Engineering for Innovation Medicine, Section of Innovation Biomedicine, Hematology Area, University of Verona, Verona, Italy
| | - Mauro Krampera
- Unità Operativa di Ematologia, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy; Department of Engineering for Innovation Medicine, Section of Innovation Biomedicine, Hematology Area, University of Verona, Verona, Italy
| | - Maurizio Rossini
- Gruppo Interdisciplinare per lo Studio della Mastocitosi (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy; Unità Operativa di Reumatologia, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Jonathan J Lyons
- Translational Allergic Immunopathology Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA
| | - Roberta Zanotti
- Gruppo Interdisciplinare per lo Studio della Mastocitosi (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
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Sato M, Kurokawa R, Okimoto N, Tokushige J, Ikemura M, Abe O. CT and Fluorine-18-Fluorodeoxyglucose (18F-FDG) PET/CT Imaging Findings of Aggressive Systemic Mastocytosis: A Case Report. Cureus 2024; 16:e64879. [PMID: 39156319 PMCID: PMC11330563 DOI: 10.7759/cureus.64879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/18/2024] [Indexed: 08/20/2024] Open
Abstract
Aggressive systemic mastocytosis (ASM) is an advanced subtype of systemic mastocytosis characterized by organ involvement. In this article, we report a case with ASM in a 54-year-old woman with characteristic findings on computed tomography (CT) and fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET)/CT. Contrast-enhanced CT on admission revealed hepatosplenomegaly, generalized osteosclerosis, colonic edema, edematous thickening of the wall in the ascending colon and edema in the surrounding regions of these organs and mesentery, ileus, subcutaneous edema, periportal collar sign, and multiple mesenteric lymphadenopathies. There was no 18F-FDG uptake in the lesions other than mild 18F-FDG uptake in the vertebrae, making the possibility of differential diagnoses such as metastasis, lymphoma, and extramedullary leukemia lower. Based on bone marrow biopsy results and clinical findings, the diagnosis of ASM was established. ASM can be a potentially fatal disease with a poor prognosis, and understanding its distinctive clinical course and imaging findings is crucial for early therapeutic intervention.
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Affiliation(s)
- Mai Sato
- Radiology, The University of Tokyo, Tokyo, JPN
| | | | | | - Junji Tokushige
- Hematology and Oncology, The University of Tokyo, Tokyo, JPN
| | | | - Osamu Abe
- Radiology, The University of Tokyo, Tokyo, JPN
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Parker JA, Hou R. A 48-Year-Old Man With a Hip Fracture and Skin Rash: A Case Report. AACE Clin Case Rep 2024; 10:2-6. [PMID: 38303771 PMCID: PMC10829777 DOI: 10.1016/j.aace.2023.10.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 09/11/2023] [Accepted: 10/09/2023] [Indexed: 02/03/2024] Open
Abstract
Background/Objective Patients with systemic mastocytosis are at high risk of developing osteoporosis and fractures. Herein, we report a case of hip fragility fracture in a patient with indolent systemic mastocytosis and normal bone density. Case Report A 48-year-old man experienced a left femoral neck fracture after a fall. After a dose of oxycodone/hydromorphone postoperatively, he developed an anaphylactic reaction. Previously, he experienced a few other episodes of flushing, dizziness, and syncope precipitated by stress and alcohol. His examination was notable for pink and brown macules on his chest, back, arms, and legs. His laboratory test revealed a markedly elevated tryptase level of 171 ng/mL (<11 ng/mL). Treatment including cetirizine, montelukast, and ranitidine controlled his symptoms. His bone density test result was normal. Ten months after hip surgery, his c-terminal telopeptide of collagen type 1 and bone-specific alkaline phosphatase levels significantly increased. The bone scan demonstrated diffusely increased radiotracer uptake throughout the osseous structures. Given high bone turnover and the prior hip fracture, he received zoledronic acid yearly for 3 years, and no further fractures have occurred. Discussion The case is unusual as the fracture occurred despite normal bone density and significant osteosclerosis, which was previously considered protective against fractures. Additionally, rather than the spine, the fracture occurred in the hip, which is an uncommon site for mastocytosis-induced fractures. Conclusion Mastocytosis is a rare cause of osteoporosis, and it is important to keep this condition in the differential diagnosis of osteoporosis, particularly when the fracture presentation is atypical.
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Affiliation(s)
- J. Anthony Parker
- Division of Nuclear Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Runhua Hou
- Thyroid Associates, Massachusetts General Hospital, Boston, Massachusetts
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Mannelli F, Crupi F, Zanotti R, Pagano L, Rapezzi D, Tanasi I, Criscuolo M, Bonifacio M, Fresa A, Guglielmelli P, Vannucchi AM. The clinical experience of compassionate use program for avapritinib: implications for drug positioning in the therapeutic scenario of systemic mastocytosis. Ther Adv Hematol 2023; 14:20406207231205643. [PMID: 37929078 PMCID: PMC10623899 DOI: 10.1177/20406207231205643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 09/19/2023] [Indexed: 11/07/2023] Open
Abstract
In systemic mastocytosis, cytoreductive treatment is indicated for advanced systemic mastocytosis (AdvSM) variants. The treatment scenario is rapidly diversifying especially with the introduction of KIT tyrosine kinase inhibitors. Avapritinib is a second-generation potent and selective inhibitor of the mutant KIT D816V that, based on the results of pivotal clinical trials, was approved for the treatment of adults with AdvSM by the regulatory agencies US FDA and EMA. The present article reports the experience of treating SM patients with avapritinib in an Italian compassionate use program. The data from our case series confirm the drug as being active after multiple lines of treatment allowing rapid achievement of profound responses, making it also an effective bridging strategy to allogeneic transplant in eligible patients. However, the anticipated wider use of avapritinib in the near future will require careful monitoring of side effects, especially in heavily pretreated patients.
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Affiliation(s)
- Francesco Mannelli
- SOD Ematologia, Centro Ricerca e Innovazione Malattie Mieloproliferative, AOU Careggi, Università di Firenze, Largo Brambilla 3, Firenze 50134, Italy
| | - Francesca Crupi
- SOD Ematologia, Centro di Ricerca e Innovazione per le Malattie Mieloproliferative, Azienda Ospedaliero Universitaria Careggi, Firenze, Italy
- Dipartimento di Medicina Sperimentale e Clinica, Denothe Excellence Center, Università degli Studi, Firenze, Italy
| | - Roberta Zanotti
- Unità di Ematologia, Dipartimento di Medicina, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
- Gruppo Interdisciplinare per lo Studio della Mastocitosi, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Livio Pagano
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Davide Rapezzi
- Unità di Ematologia, Ospedale S. Croce e Carle, Cuneo, Italy
| | - Ilaria Tanasi
- Unità di Ematologia, Dipartimento di Medicina, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
- Gruppo Interdisciplinare per lo Studio della Mastocitosi, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Marianna Criscuolo
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Massimiliano Bonifacio
- Unità di Ematologia, Dipartimento di Medicina, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
- Gruppo Interdisciplinare per lo Studio della Mastocitosi, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Alberto Fresa
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Paola Guglielmelli
- SOD Ematologia, Centro di Ricerca e Innovazione per le Malattie Mieloproliferative, Azienda Ospedaliero Universitaria Careggi, Firenze, Italy
- Dipartimento di Medicina Sperimentale e Clinica, Denothe Excellence Center, Università degli Studi, Firenze, Italy
| | - Alessandro M. Vannucchi
- SOD Ematologia, Centro di Ricerca e Innovazione per le Malattie Mieloproliferative, Azienda Ospedaliero Universitaria Careggi, Firenze, Italy
- Dipartimento di Medicina Sperimentale e Clinica, Denothe Excellence Center, Università degli Studi, Firenze, Italy
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Franco AS, Murai IH, Takayama L, Caparbo VF, Marchi LL, Velloso EDRP, Pereira RMR. Assessment of Bone Microarchitecture in Patients with Systemic Mastocytosis and its Association with Clinical and Biochemical Parameters of the Disease. Calcif Tissue Int 2023; 113:276-285. [PMID: 37294314 DOI: 10.1007/s00223-023-01107-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 05/30/2023] [Indexed: 06/10/2023]
Abstract
Patients with systemic mastocytosis (SM) are at high risk of bone deterioration. However, the evaluation of bone microarchitecture in this disease remains unclear. We aimed to assess bone microarchitecture in patients with SM. This was a cross-sectional study of 21 adult patients with SM conducted in a quaternary referral hospital in Sao Paulo, Brazil. A healthy, age-, weight-, and sex-matched cohort of 63 participants was used to provide reference values for bone microarchitecture, assessed by high resolution peripheral quantitative computed tomography (HR-pQCT). Total volumetric bone mineral density (vBMD), cortical vBMD, and cortical thickness at the radius were significantly lower in the control group compared with the SM group (all P < 0.001). Patients with aggressive SM had significantly lower trabecular number (Tb.N) (P = 0.035) and estimated failure load (F.load) (P = 0.032) at the tibia compared with those with indolent SM. Handgrip strength was significantly higher in patients who had more Tb.N at the radius (ρ, 0.46; P = 0.036) and tibia (ρ, 0.49; P = 0.002), and lower who had more trabecular separation at the radius (ρ, -0.46; P = 0.035) and tibia (ρ, -0.52; P = 0.016). Strong and positive associations between F.load (ρ, 0.75; P < 0.001) and stiffness (ρ, 0.70; P < 0.001) at the radius, and between F.load at the tibia (ρ, 0.45; P = 0.038) were observed with handgrip strength. In this cross-sectional study, aggressive SM was more susceptible to bone deterioration compared with indolent SM. In addition, the findings demonstrated that handgrip strength was associated with bone microarchitecture and bone strength.
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Affiliation(s)
- Andre S Franco
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil.
- Faculdade de Medicina, FMUSP da Universidade de São Paulo, Av Dr Arnaldo, 455 - Reumatologia, 3º Andar, Sala 3193, Cerqueira César, Sao Paulo, 01246-903, Brazil.
| | - Igor H Murai
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Liliam Takayama
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Valeria F Caparbo
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Luan L Marchi
- Service of Hematology, Transfusion and Cell Therapy and Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31) HCFMUSP, University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Elvira D R P Velloso
- Service of Hematology, Transfusion and Cell Therapy and Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31) HCFMUSP, University of Sao Paulo Medical School, Sao Paulo, Brazil
- Hospital Israelita Albert Einstein, Sao Paulo, Brazil
| | - Rosa M R Pereira
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
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Beyens M, Elst J, van der Poorten ML, Van Gasse A, Toscano A, Verlinden A, Vermeulen K, Maes MB, Oude Elberink JNGH, Ebo D, Sabato V. Mastocytosis and related entities: a practical roadmap. Acta Clin Belg 2023; 78:325-335. [PMID: 36259506 DOI: 10.1080/17843286.2022.2137631] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Mastocytosis is a complex heterogenous multisystem disorder that is characterized by pathologic activation or accumulation of neoplastic mast cells (MCs) in one or more organs. This clonal MC expansion is often associated with a somatic gain-of-function mutation (D816V in most of the cases) in the KIT gene, encoding for the MC surface receptor KIT (CD117), a stem cell growth factor receptor. Based on clinical and biochemical criteria, the World Health Organization (WHO) divided mastocytosis into different subclasses. The exact prevalence of mastocytosis remains elusive, but it is estimated that the disease affects approximately 1 in 10,000 persons. The clinical presentation of mastocytosis varies significantly, ranging from asymptomatic patients to a life-threatening disease with multiple organ involvement, potentially leading to cytopenia, malabsorption, hepatosplenomegaly, lymphadenopathy, ascites or osteolytic bone lesions with pathological fractures. Patients with mastocytosis may experience symptoms related to release of MC mediators, such as flushing or diarrhea or even more severe symptoms such as anaphylaxis. Recently, a new genetic trait, hereditary alpha tryptasemia (HaT), was described which involves a copy number variation in the TPSAB1-gene. Its role as standalone multisystem syndrome is heavily debated. There is emerging evidence suggesting there might be a link between HaT and due to the increased prevalence of HaT in patients with SM. The aim of this review is to provide a practical roadmap for diagnosis and management of mastocytosis and its associated entities, since there are still many misconceptions about these topics.Abbreviations: AdvSM: Advanced systemic mastocytosis; ASM: Aggressive systemic mastocytosis; aST: acute serum tryptase; BM: Bone marrow; BMM: Bone marrow mastocytosis; bST: baseline serum tryptase; CM: Cutaneous mastocytosis; DCM: Diffuse cutaneous mastocytosis; HVA: Hymenoptera venom allergy; HaT: Hereditary alpha tryptasemia; ISM: Indolent systemic mastocytosis; MC: Mast cell; MCA: Mast cell activation; MCAS: Mast cell activation syndrome; MCL: Mast cell leukemia; MIS: Mastocytosis in the skin; MMAS: Monoclonal mast cell activation syndrome; MPCM: Maculopapular cutaneous mastocytosis; SM: Systemic mastocytosis; SM-AHN: Systemic mastocytosis with associated hematological neoplasm; SSM: Smouldering systemic mastocytosis; VIT: Venom immunotherapy.
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Affiliation(s)
- Michiel Beyens
- Department of Immunology, Allergology, Rheumatology and the Infla-Med Centre of Excellence, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
- Department of Immunology, Allergology, Rheumatology, Antwerp University Hospital, Antwerp, Belgium
| | - Jessy Elst
- Department of Immunology, Allergology, Rheumatology and the Infla-Med Centre of Excellence, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
- Department of Immunology, Allergology, Rheumatology, Antwerp University Hospital, Antwerp, Belgium
| | - Marie-Line van der Poorten
- Department of Immunology, Allergology, Rheumatology and the Infla-Med Centre of Excellence, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
- Department of Immunology, Allergology, Rheumatology, Antwerp University Hospital, Antwerp, Belgium
- Faculty of Medicine and Health Sciences, Department of Paediatrics and the Infla-Med Centre of Excellence, Antwerp, Belgium
- Department of Paediatrics, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
| | - Athina Van Gasse
- Department of Immunology, Allergology, Rheumatology and the Infla-Med Centre of Excellence, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
- Department of Immunology, Allergology, Rheumatology, Antwerp University Hospital, Antwerp, Belgium
- Faculty of Medicine and Health Sciences, Department of Paediatrics and the Infla-Med Centre of Excellence, Antwerp, Belgium
- Department of Paediatrics, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
| | - Alessandro Toscano
- Department of Immunology, Allergology, Rheumatology and the Infla-Med Centre of Excellence, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
- Department of Immunology, Allergology, Rheumatology, Antwerp University Hospital, Antwerp, Belgium
| | - Anke Verlinden
- Department of Haematology, Antwerp University Hospital, Antwerp, Belgium
| | - Katrien Vermeulen
- Department of Clinical Biology, Antwerp University Hospital, Antwerp, Belgium
| | - Marie-Berthe Maes
- Department of Clinical Biology, Antwerp University Hospital, Antwerp, Belgium
| | - J N G Hanneke Oude Elberink
- Department of Allergology, University Medical Center Groningen, University of Groningen, and Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands
| | - Didier Ebo
- Department of Immunology, Allergology, Rheumatology and the Infla-Med Centre of Excellence, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
- Department of Immunology, Allergology, Rheumatology, Antwerp University Hospital, Antwerp, Belgium
- Department of Immunology and Allergology, AZ Jan Palfijn Gent, Ghent, Belgium
| | - Vito Sabato
- Department of Immunology, Allergology, Rheumatology and the Infla-Med Centre of Excellence, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
- Department of Immunology, Allergology, Rheumatology, Antwerp University Hospital, Antwerp, Belgium
- Department of Immunology and Allergology, AZ Jan Palfijn Gent, Ghent, Belgium
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Rama TA, Henriques AF, Matito A, Jara-Acevedo M, Caldas C, Mayado A, Muñoz-González JI, Moreira A, Cavaleiro-Rufo J, García-Montero A, Órfão A, Sanchez-Muñoz L, Álvarez-Twose I. Bone and Cytokine Markers Associated With Bone Disease in Systemic Mastocytosis. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2023; 11:1536-1547. [PMID: 36801493 DOI: 10.1016/j.jaip.2023.02.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 01/05/2023] [Accepted: 02/03/2023] [Indexed: 02/19/2023]
Abstract
BACKGROUND Mastocytosis encompasses a heterogeneous group of diseases characterized by tissue accumulation of clonal mast cells, which frequently includes bone involvement. Several cytokines have been shown to play a role in the pathogenesis of bone mass loss in systemic mastocytosis (SM), but their role in SM-associated osteosclerosis remains unknown. OBJECTIVE To investigate the potential association between cytokine and bone remodeling markers with bone disease in SM, aiming at identifying biomarker profiles associated with bone loss and/or osteosclerosis. METHODS A total of 120 adult patients with SM, divided into 3 age and sex-matched groups according to their bone status were studied: (1) healthy bone (n = 46), (2) significant bone loss (n = 47), and (3) diffuse bone sclerosis (n = 27). Plasma levels of cytokines and serum baseline tryptase and bone turnover marker levels were measured at diagnosis. RESULTS Bone loss was associated with significantly higher levels of serum baseline tryptase (P = .01), IFN-γ (P = .05), IL-1β (P = .05), and IL-6 (P = .05) versus those found in patients with healthy bone. In contrast, patients with diffuse bone sclerosis showed significantly higher levels of serum baseline tryptase (P < .001), C-terminal telopeptide (P < .001), amino-terminal propeptide of type I procollagen (P < .001), osteocalcin (P < .001), bone alkaline phosphatase (P < .001), osteopontin (P < .01), and the C-C Motif Chemokine Ligand 5/RANTES chemokine (P = .01), together with lower IFN-γ (P = .03) and RANK-ligand (P = .04) plasma levels versus healthy bone cases. CONCLUSIONS SM with bone mass loss is associated with a proinflammatory cytokine profile in plasma, whereas diffuse bone sclerosis shows increased serum/plasma levels of biomarkers related to bone formation and turnover, in association with an immunosuppressive cytokine secretion profile.
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Affiliation(s)
- Tiago Azenha Rama
- Serviço de Imunoalergologia, Centro Hospitalar Universitário São João, Porto, Portugal; Serviço de Imunologia Básica e Clínica, Departamento de Patologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal; EPIUnit - Institute of Public Health, University of Porto, Porto, Portugal; Laboratory for Integrative and Translational Research in Population Health (ITR), Porto, Portugal.
| | - Ana Filipa Henriques
- Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast) - Reference Center (CSUR) for Mastocytosis, Hospital Virgen del Valle, Complejo Hospitalario Universitario de Toledo, Toledo, Spain; Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain
| | - Almudena Matito
- Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast) - Reference Center (CSUR) for Mastocytosis, Hospital Virgen del Valle, Complejo Hospitalario Universitario de Toledo, Toledo, Spain; Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain
| | - Maria Jara-Acevedo
- Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain; DNA Sequencing Service (NUCLEUS), Instituto de Investigación Biomédica de Salamanca (IBSAL), University of Salamanca, Salamanca, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Carolina Caldas
- Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain; DNA Sequencing Service (NUCLEUS), Instituto de Investigación Biomédica de Salamanca (IBSAL), University of Salamanca, Salamanca, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Andrea Mayado
- Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain; Cancer Research Center (IBMCC, USAL-CSIC), Department of Medicine, Cytometry Service (NUCLEUS) Instituto de Investigación Biomédica de Salamanca (IBSAL), University of Salamanca, Salamanca, Spain
| | - Javier I Muñoz-González
- Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain; Cancer Research Center (IBMCC, USAL-CSIC), Department of Medicine, Cytometry Service (NUCLEUS) Instituto de Investigación Biomédica de Salamanca (IBSAL), University of Salamanca, Salamanca, Spain
| | - André Moreira
- Serviço de Imunoalergologia, Centro Hospitalar Universitário São João, Porto, Portugal; Serviço de Imunologia Básica e Clínica, Departamento de Patologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal; EPIUnit - Institute of Public Health, University of Porto, Porto, Portugal; Laboratory for Integrative and Translational Research in Population Health (ITR), Porto, Portugal
| | - João Cavaleiro-Rufo
- EPIUnit - Institute of Public Health, University of Porto, Porto, Portugal; Laboratory for Integrative and Translational Research in Population Health (ITR), Porto, Portugal
| | - Andrés García-Montero
- Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain; Cancer Research Center (IBMCC, USAL-CSIC), Department of Medicine, Cytometry Service (NUCLEUS) Instituto de Investigación Biomédica de Salamanca (IBSAL), University of Salamanca, Salamanca, Spain
| | - Alberto Órfão
- Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain; Cancer Research Center (IBMCC, USAL-CSIC), Department of Medicine, Cytometry Service (NUCLEUS) Instituto de Investigación Biomédica de Salamanca (IBSAL), University of Salamanca, Salamanca, Spain
| | - Laura Sanchez-Muñoz
- Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast) - Reference Center (CSUR) for Mastocytosis, Hospital Virgen del Valle, Complejo Hospitalario Universitario de Toledo, Toledo, Spain; Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain
| | - Iván Álvarez-Twose
- Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast) - Reference Center (CSUR) for Mastocytosis, Hospital Virgen del Valle, Complejo Hospitalario Universitario de Toledo, Toledo, Spain; Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
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9
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Velloso EDRP, Padulla GA, de Cerqueira AMM, de Sousa AM, Sandes AF, Traina F, Seguro FS, Nogueira FL, Pereira GDF, Boechat JL, Pagnano KBB, Marchi LL, Ensina LF, Giavina-Bianchi M, Aun MV, Agondi RC, Santos FPDS, Giavina-Bianchi P. Diagnosis and treatment of systemic mastocytosis in Brazil: Recommendations of a multidisciplinary expert panel. Hematol Transfus Cell Ther 2022; 44:582-594. [PMID: 35688791 PMCID: PMC9605912 DOI: 10.1016/j.htct.2022.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 03/04/2022] [Accepted: 04/25/2022] [Indexed: 11/29/2022] Open
Abstract
INTRODUCTION Systemic Mastocytosis comprises a group of neoplastic diseases characterized by clonal expansion and infiltration of mast cells into several organs. The diagnosis and treatment of this disease may be challenging for non-specialists. OBJECTIVE Make suggestions or recommendations in Systemic Mastocytosis based in a panel of Brazilian specialists. METHOD AND RESULTS An online expert panel with 18 multidisciplinary specialists was convened to propose recommendations on the diagnosis and treatment of Systemic Mastocytosis in Brazil. Recommendations were based on discussions of topics and multiple-choice questions and were graded using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence Chart. CONCLUSION Twenty-two recommendations or suggestions were proposed based on a literature review and graded according to the findings.
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Affiliation(s)
- Elvira D Rodrigues Pereira Velloso
- Clinical Immunology and Allergy Division. Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil; Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.
| | - Geórgia A Padulla
- Clinical Immunology and Allergy Division. Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
| | | | - Adriana Martins de Sousa
- Instituto de Pediatria e Puericultura Martagão Gesteira da Universidade Federal do Rio de Janeiro (IPPMG UFRJ), Rio de Janeiro, RJ, Brazil
| | - Alex Freire Sandes
- Grupo Fleury, São Paulo, SP, Brazil; Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brazil
| | - Fabiola Traina
- Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (FMRP USP), São Paulo, SP, Brazil
| | - Fernanda Salles Seguro
- Clinical Immunology and Allergy Division. Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
| | - Frederico Lisboa Nogueira
- Hospital Luxemburgo, Instituto Mário Penna, Belo Horizonte, MG, Brazil; Grupo Oncoclínicas, Belo Horizonte, MG, Brazil
| | | | - José Laerte Boechat
- Faculdade de Medicina da Universidade Federal Fluminense (FM UFF), Niteroi, RJ, Brazil
| | | | - Luan Lima Marchi
- Clinical Immunology and Allergy Division. Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
| | | | - Mara Giavina-Bianchi
- Clinical Immunology and Allergy Division. Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
| | - Marcelo Vivolo Aun
- Clinical Immunology and Allergy Division. Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil; Faculdade Israelita de Ciências da Saúde Albert Einstein, São Paulo, SP, Brazil
| | - Rosana Câmara Agondi
- Clinical Immunology and Allergy Division. Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
| | - Fabio Pires de Souza Santos
- Hospital Israelita Albert Einstein, São Paulo, SP, Brazil; A Beneficência Portuguesa de São Paulo, BP, São Paulo, SP, Brazil
| | - Pedro Giavina-Bianchi
- Clinical Immunology and Allergy Division. Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
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10
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Elvevi A, Elli EM, Lucà M, Scaravaglio M, Pagni F, Ceola S, Ratti L, Invernizzi P, Massironi S. Clinical challenge for gastroenterologists-Gastrointestinal manifestations of systemic mastocytosis: A comprehensive review. World J Gastroenterol 2022; 28:3767-3779. [PMID: 36157547 PMCID: PMC9367223 DOI: 10.3748/wjg.v28.i29.3767] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 06/06/2022] [Accepted: 07/11/2022] [Indexed: 02/06/2023] Open
Abstract
Mastocytosis is a rare and heterogeneous disease characterized by various clinical and biological features that affect different prognoses and treatments. The disease is usually divided into 2 principal categories: cutaneous and systemic disease (SM). Clinical features can be related to mast cell (MC) mediator release or pathological MC infiltration. SM is a disease often hard to identify, and the diagnosis is based on clinical, biological, histological, and molecular criteria with different specialists involved in the patient's clinical work-up. Among all manifestations of the disease, gastrointestinal (GI) symptoms are common, being present in 14%-85% of patients, and can significantly impair the quality of life. Here we review the data regarding GI involvement in SM, in terms of clinical presentations, histological and endoscopic features, the pathogenesis of GI symptoms, and their treatment.
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Affiliation(s)
- Alessandra Elvevi
- Gastroenterology Division, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
| | - Elena Maria Elli
- Hematology Division and Bone Marrow Transplant Unit, San Gerardo Hospital, Monza 20900, Italy
| | - Martina Lucà
- Gastroenterology Division, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
| | - Miki Scaravaglio
- Gastroenterology Division, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
| | - Fabio Pagni
- Department of Medicine and Surgery, Section of Pathology, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
| | - Stefano Ceola
- Department of Medicine and Surgery, Section of Pathology, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
| | - Laura Ratti
- Gastroenterology Division, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
| | - Pietro Invernizzi
- Gastroenterology Division, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
| | - Sara Massironi
- Gastroenterology Division, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
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11
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Mast Cells and Vitamin D Status: A Clinical and Biological Link in the Onset of Allergy and Bone Diseases. Biomedicines 2022; 10:biomedicines10081877. [PMID: 36009422 PMCID: PMC9405764 DOI: 10.3390/biomedicines10081877] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 07/26/2022] [Accepted: 07/29/2022] [Indexed: 12/12/2022] Open
Abstract
The immune system is made up by an extremely composite group of cells, whose regulated and harmonious activity is fundamental to maintain health. The mast cells are an essential effector of inflammatory response which is characterized by a massive release of mediators accumulated in cytoplasmic secretory granules. However, beyond the effects on immune response, mast cells can modify bone metabolism and are capable of intervening in the genesis of pathologies such as osteoporosis and osteopenia. Vitamin D is recognized to induce changes in bone metabolism, but it is also able to influence immune response, suppressing mast cell activation and IgE synthesis from B cells and increasing the number of dendritic cells and IL-10-generating regulatory T cells. Vitamin D deficit has been reported to worsen sensitization and allergic manifestations in several different experimental models. However, in clinical situations, contradictory findings have been described concerning the correlation between allergy and vitamin D deficit. The aim of this review was to analyze the close relationships between mast cells and vitamin D, which contribute, through the activation of different molecular or cellular activation pathways, to the determination of bone pathologies and the onset of allergic diseases.
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12
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Shah A, Bhan R, Pey EP, Riordan H, Khan F. Systemic Mastocytosis Presenting as Pathologic Intertrochanteric Femur Fracture. J Am Acad Orthop Surg Glob Res Rev 2022; 6:e21.00137. [PMID: 35020710 PMCID: PMC8754187 DOI: 10.5435/jaaosglobal-d-21-00137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 12/02/2021] [Indexed: 06/14/2023]
Abstract
Systemic mastocytosis (SM) is pathologically characterized by the proliferation of mast cells with infiltrates in various organs, almost always including bone marrow, leading to defects in bone remodeling. Osteoporosis and subsequent fragility fractures are the most common and clinically relevant presentation, although pathologic fracture through the focal lytic lesions can also be observed. Here, we report the case of a 54-year-old woman, with a recent history of unexplained severe allergic reactions, presenting with intertrochanteric fracture of the left femur which on careful history, physical and radiological evaluation was determined to be pathological. The patient was found to have lytic lesions on the CT scan at the fracture site and the pelvis, bilateral femurs, ribs, and sternum, raising suspicion for malignancy. The malignancy workup failed to reveal a primary neoplasm, and the patient was indicated for intramedullary fixation of the left femur along with intraoperative biopsy. Pathologic evaluation of the femoral biopsy was positive for aggregates of mast cells with CD117 (c-KIT, D816V). This finding prompted a bone marrow biopsy, which ultimately led to the diagnosis of aggressive SM. Femoral intramedullary fixation was done with a trochanteric femoral nail, and the patient was postoperatively started on calcium, vitamin D, and physical therapy. Systemic disease was managed by the hematology-oncology team, and the patient was given an epinephrine autoinjector (EpiPen) and managed with midostaurin (Rydapt, Novartis Pharmaceuticals). Treating surgeons should be aware that a pathological long bone fracture can be the initial presentation of SM. Furthermore, surgeons should consider following patients with SM for longer than usual considering a higher risk of complications, such as implant loosening, nonunion, and refracture due to poor and progressively worsening quality of the bone. Our patient was followed with routine visits for 30 months and showed no clinical or radiographical signs of any complications.
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Affiliation(s)
- Aadit Shah
- From the Stony Brook University Hospital, Department of Orthopaedics, Stony Brook, NY (Dr. Shah, Riordan and Dr. Khan); and the Stony Brook University Renaissance School of Medicine, Stony Brook, NY (Bhan and Pey)
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13
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Zanotti R, Bonifacio M, Isolan C, Tanasi I, Crosera L, Olivieri F, Orsolini G, Schena D, Bonadonna P. A Multidisciplinary Diagnostic Approach Reveals a Higher Prevalence of Indolent Systemic Mastocytosis: 15-Years' Experience of the GISM Network. Cancers (Basel) 2021; 13:cancers13246380. [PMID: 34944999 PMCID: PMC8699786 DOI: 10.3390/cancers13246380] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 12/09/2021] [Accepted: 12/10/2021] [Indexed: 12/13/2022] Open
Abstract
Systemic mastocytosis (SM) and other adult clonal mast cell disorders (CMD) are often underestimated, and their epidemiology data are scarce. We aimed at evaluating the impact of the activity of the Interdisciplinary Group for Study of Mastocytosis (GISM) of Verona on the prevalence and incidence of CMD. We examined the data of 502 adult patients diagnosed with CMD and residing in the Veneto Region, consecutively referred to GISM between 2006 and 2020. SM was diagnosed in 431 cases, while 71 patients had cutaneous mastocytosis or other CMD. Indolent SM represented the most frequent SM variant (91.0%), mainly with the characteristics of bone marrow mastocytosis (54.8%). The prevalence of SM in the adult population of the Veneto region and of the Verona province was 10.2 and 17.2/100,000 inhabitants, respectively. The mean incidence of new SM cases in Verona was 1.09/100,000 inhabitants/year. Hymenoptera venom allergy was the main reason (50%) leading to the CMD diagnosis. Osteoporosis, often complicated by fragility fractures, was present in 35% of cases, even in young patients, especially males. Our data show a higher prevalence and incidence of SM than previously reported, confirming that reference centers with multidisciplinary approach are essential for the recognition and early diagnosis of CMD.
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Affiliation(s)
- Roberta Zanotti
- Hematology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy; (R.Z.); (C.I.); (I.T.); (L.C.)
- Gruppo Interdisciplinare per lo Studio Della Mastocitosi (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy; (G.O.); (D.S.); (P.B.)
| | - Massimiliano Bonifacio
- Hematology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy; (R.Z.); (C.I.); (I.T.); (L.C.)
- Gruppo Interdisciplinare per lo Studio Della Mastocitosi (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy; (G.O.); (D.S.); (P.B.)
- Correspondence:
| | - Cecilia Isolan
- Hematology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy; (R.Z.); (C.I.); (I.T.); (L.C.)
| | - Ilaria Tanasi
- Hematology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy; (R.Z.); (C.I.); (I.T.); (L.C.)
- Gruppo Interdisciplinare per lo Studio Della Mastocitosi (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy; (G.O.); (D.S.); (P.B.)
| | - Lara Crosera
- Hematology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy; (R.Z.); (C.I.); (I.T.); (L.C.)
| | - Francesco Olivieri
- Allergy Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy;
| | - Giovanni Orsolini
- Gruppo Interdisciplinare per lo Studio Della Mastocitosi (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy; (G.O.); (D.S.); (P.B.)
- Rheumatology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy
| | - Donatella Schena
- Gruppo Interdisciplinare per lo Studio Della Mastocitosi (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy; (G.O.); (D.S.); (P.B.)
- Dermatology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy
| | - Patrizia Bonadonna
- Gruppo Interdisciplinare per lo Studio Della Mastocitosi (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy; (G.O.); (D.S.); (P.B.)
- Allergy Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy;
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14
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Gehlen M, Schmidt N, Pfeifer M, Balasingam S, Schwarz-Eywill M, Maier A, Werner M, Siggelkow H. Osteoporosis Caused by Systemic Mastocytosis: Prevalence in a Cohort of 8392 Patients with Osteoporosis. Calcif Tissue Int 2021; 109:685-695. [PMID: 34223956 DOI: 10.1007/s00223-021-00887-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 06/29/2021] [Indexed: 11/24/2022]
Abstract
Indolent systemic mastocytosis (ISM) is a group of heterogenous diseases characterized by abnormal accumulation of mast cells in at least one organ. ISM can be a cause of osteoporosis. The aim of this study is to determine the prevalence, and the prognosis of ISM in a cohort of patients with osteoporosis. In this monocentric and retrospective study, patients with osteoporosis who did not receive a bone biopsy (cohort 1) and patients that subsequently received a diagnostic bone biopsy for differential diagnosis (cohort 2) are compared with patients who are diagnosed with ISM (cohort 3). A total of 8392 patients are diagnosed with osteoporosis. Out of these patients 1374 underwent a diagnostic bone biopsy resulting in 43 patients with ISM. These figures indicate that ISM is diagnosed in 0.5% of patients with osteoporosis and in 3.1% (men 5.8%) of patients who underwent bone biopsies. Patients with ISM sustained significantly more vertebral fractures in comparison to patients in cohort 2 (4.4 ± 3.6 versus 2.4 ± 2.5 vertebral fractures, p < 0.001) and women were significantly younger compared to cohort 2 (57.3 ± 12 versus 63.6 ± 12 years, p < 0.05). Only 33% showed an involvement of the skin (urticaria pigmentosa). ISM is a rare cause of osteoporosis (0.5%). However, in a subgroup of rather young male patients with osteoporosis the prevalence is more than 5%. Thus, ISM should be considered in premenopausal women and men presenting with vertebral fractures even if urticaria pigmentosa is not present.
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Affiliation(s)
- Martin Gehlen
- Clinic "DER FÜRSTENHOF", Department of Rheumatology, Osteology and Orthopaedics, Am Hylligen Born 7, 31812, Bad Pyrmont, Germany.
| | - Niels Schmidt
- Clinic "DER FÜRSTENHOF", Department of Rheumatology, Osteology and Orthopaedics, Am Hylligen Born 7, 31812, Bad Pyrmont, Germany
| | - Michael Pfeifer
- Clinic "DER FÜRSTENHOF", Department of Rheumatology, Osteology and Orthopaedics, Am Hylligen Born 7, 31812, Bad Pyrmont, Germany
| | - Subathira Balasingam
- Clinic "DER FÜRSTENHOF", Department of Rheumatology, Osteology and Orthopaedics, Am Hylligen Born 7, 31812, Bad Pyrmont, Germany
| | - Michael Schwarz-Eywill
- Clinic "DER FÜRSTENHOF", Department of Rheumatology, Osteology and Orthopaedics, Am Hylligen Born 7, 31812, Bad Pyrmont, Germany
| | - Anna Maier
- Department of Rheumatology, Sankt Josef-Stift Sendenhorst, West Gate 7, 48324, Sendenhorst, Germany
| | - Mathias Werner
- Department of Pathology, Vivantes Klinikum Friedrichshain, Landsberger Allee 49, 10249, Berlin, Germany
| | - Heide Siggelkow
- Clinic of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Robert-Koch-Str. 40, 37075, Goettingen, Germany
- MVZ Endokrinologikum Goettingen, Von-Siebold-Str. 3, 37075, Goettingen, Germany
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15
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Zanotti R, Tanasi I, Crosera L, Bonifacio M, Schena D, Orsolini G, Mastropaolo F, Tebaldi M, Olivieri E, Bonadonna P. Systemic Mastocytosis: Multidisciplinary Approach. Mediterr J Hematol Infect Dis 2021; 13:e2021068. [PMID: 34804442 PMCID: PMC8577553 DOI: 10.4084/mjhid.2021.068] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 10/20/2021] [Indexed: 12/30/2022] Open
Abstract
Systemic mastocytosis (SM) is a heterogeneous group of diseases that affect almost exclusively adults and are defined by the proliferation and accumulation of clonal mast cells (MC) in various tissues. Disease subtypes range from indolent to rare aggressive forms. Although SM is classified as a rare disease, it is believed to be likely underdiagnosed. Major signs and symptoms mainly depend on MC activation and less frequent organ infiltration, typical of more aggressive variants. Diagnosis may be challenging, and symptoms can be aspecific and involve several organs. Therefore, it is advisable to refer patients to specialized centers, having sufficient knowledge of the disease, sensitive diagnostic procedures, offering a personalized and multidisciplinary diagnostic approach, including at least hematological, allergological, dermatological, and rheumatological evaluations. A precise and timely diagnosis is required for: a) adequate counseling of patients and their physicians; b) beginning of symptomatic treatment (anti-mediator therapy); c) prevention of severe manifestations of the disease (i.e., recurrent anaphylaxis, osteoporosis, and bone fractures); d) cytoreductive treatment of advanced SM variants. This review summarizes the disease's main manifestations and describes the ideal diagnostic approach for adult patients with suspected SM, giving physicians the main notions for correct patient diagnosis and management. This review also highlights the importance of a multidisciplinary approach in this very complex disease.
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Affiliation(s)
- Roberta Zanotti
- Hematology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
- Interdisciplinary Study Group for Mastocytosis (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Ilaria Tanasi
- Hematology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
- Interdisciplinary Study Group for Mastocytosis (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Lara Crosera
- Hematology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Massimiliano Bonifacio
- Hematology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
- Interdisciplinary Study Group for Mastocytosis (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Donatella Schena
- Interdisciplinary Study Group for Mastocytosis (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
- Dermatology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Giovanni Orsolini
- Interdisciplinary Study Group for Mastocytosis (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
- Rheumatology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Francesca Mastropaolo
- Interdisciplinary Study Group for Mastocytosis (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
- Rheumatology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Morena Tebaldi
- Interdisciplinary Study Group for Mastocytosis (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
- Gastroenterology Unit, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Elisa Olivieri
- Interdisciplinary Study Group for Mastocytosis (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
- Allergy Unit, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Patrizia Bonadonna
- Interdisciplinary Study Group for Mastocytosis (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
- Allergy Unit, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
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16
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Systemic Mastocytosis: Radiological Point of View. Mediterr J Hematol Infect Dis 2021; 13:e2021056. [PMID: 34527208 PMCID: PMC8425380 DOI: 10.4084/mjhid.2021.056] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 08/10/2021] [Indexed: 12/27/2022] Open
Abstract
Radiological diagnosis of systemic mastocytosis (SM) can be hard to establish. This difficulty is mainly due to the variable radiological features involving many organ systems (e.g., respiratory, cardiovascular, lympho-reticular, digestive systems, and most commonly skin), and above all, to the broad spectrum of skeletal findings. Skeletal involvement is the most common and prominent imaging feature in patients with SM and represents a prognostic factor as it may entail an aggressive course of the disease. Diagnosis, largely established by histological evaluation of a bone marrow trephine biopsy, supplemented by imaging modalities such as radiography, CT, and magnetic resonance imaging, requires a team approach between the hematologist, radiologist, and pathologist. The general radiologist needs to be familiar with the imaging findings because they may be the first to suggest the correct diagnosis. The primary purpose of this review article was to equip clinicians with pertinent radiological semiotics by presenting relevant radiological features that assist early diagnosis and selection of an effective treatment.
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17
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Extracellular Vesicles as Emerging Players in Intercellular Communication: Relevance in Mast Cell-Mediated Pathophysiology. Int J Mol Sci 2021; 22:ijms22179176. [PMID: 34502083 PMCID: PMC8431297 DOI: 10.3390/ijms22179176] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/17/2021] [Accepted: 08/23/2021] [Indexed: 02/07/2023] Open
Abstract
Mast cells are major effector cells in eliciting allergic responses. They also play a significant role in establishing innate and adaptive immune responses, as well as in modulating tumor growth. Mast cells can be activated upon engagement of the high-affinity receptor FcεRI with specific IgE to multivalent antigens or in response to several FcεRI-independent mechanisms. Upon stimulation, mast cells secrete various preformed and newly synthesized mediators. Emerging evidence indicates their ability to be a rich source of secreted extracellular vesicles (EVs), including exosomes and microvesicles, which convey biological functions. Mast cell-derived EVs can interact with and affect other cells located nearby or at distant sites and modulate inflammation, allergic response, and tumor progression. Mast cells are also affected by EVs derived from other cells in the immune system or in the tumor microenvironment, which may activate mast cells to release different mediators. In this review, we summarize the latest data regarding the ability of mast cells to release or respond to EVs and their role in allergic responses, inflammation, and tumor progression. Understanding the release, composition, and uptake of EVs by cells located near to or at sites distant from mast cells in a variety of clinical conditions, such as allergic inflammation, mastocytosis, and lung cancer will contribute to developing novel therapeutic approaches.
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18
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De Puysseleyr LP, Ebo DG, Elst J, Faber MA, Poorten MLVD, Van Gasse AL, Bridts CH, Mertens C, Van Houdt M, Hagendorens MM, Verlinden A, Vermeulen K, Maes MB, Berneman ZN, Sabato V. Diagnosis of Primary Mast Cell Disorders in Anaphylaxis: Value of KIT D816V in Peripheral Blood. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2021; 9:3176-3187.e3. [PMID: 33975032 DOI: 10.1016/j.jaip.2021.04.062] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 03/30/2021] [Accepted: 04/13/2021] [Indexed: 11/18/2022]
Abstract
BACKGROUND Anaphylaxis is frequent in patients suffering from primary mast cell disorders (PMCDs). In patients without mastocytosis in the skin (MIS) and a baseline serum tryptase (bST) less than 30 ng/mL, the diagnosis of PMCD is challenging. In these patients, detection of the KIT D816V mutation in peripheral blood (PB) has been suggested as screening tool for a PMCD. OBJECTIVE In this study, we investigated whether KIT D816V in PB can contribute to the decision to perform a bone marrow (BM) biopsy in patients with anaphylaxis without MIS and a bST less than 30 ng/mL. METHODS We selected 74 patients with severe anaphylaxis without MIS and a bST less than 30 ng/mL. All underwent a BM biopsy. KIT D816V mutation was quantified in both PB and BM using digital droplet polymerase chain reaction (ddPCR). RESULTS Diagnosis of a PMCD was established in 40 patients (54%). Median bST for patients with and without PMCD was, respectively, 9.5 ng/mL (range 4.2-27 ng/mL) and 4.9 ng/mL (range 2.2-20.3 ng/mL) (P <.001). KIT D816V in PB was detected in 16 out of 40 (40%) patients with PMCD. KIT D816V in BM was detected in 22 out of 40 (55%) patients with PMCD. CONCLUSIONS In patients without MIS and a bST less than < 30 ng/mL who experience anaphylaxis, determination of KIT D816V mutation in PB is of limited help in deciding when to proceed to a BM biopsy. Therefore, KIT D816V in PB mutation analysis should be interpreted together with scoring tools to make a better assessment in identifying patients who should undergo BM biopsy.
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Affiliation(s)
- Leander P De Puysseleyr
- Faculty of Medicine and Health Sciences, Department of Immunology, Allergology, and Rheumatology and the Infla-Med Centre of Excellence University of Antwerp; and Department of Immunology, Allergology, and Rheumatology, Antwerp University Hospital, Antwerp, Belgium
| | - Didier G Ebo
- Faculty of Medicine and Health Sciences, Department of Immunology, Allergology, and Rheumatology and the Infla-Med Centre of Excellence University of Antwerp; and Department of Immunology, Allergology, and Rheumatology, Antwerp University Hospital, Antwerp, Belgium; Department of Immunology and Allergology, AZ Jan Palfijn Gent, Ghent, Belgium.
| | - Jessy Elst
- Faculty of Medicine and Health Sciences, Department of Immunology, Allergology, and Rheumatology and the Infla-Med Centre of Excellence University of Antwerp; and Department of Immunology, Allergology, and Rheumatology, Antwerp University Hospital, Antwerp, Belgium
| | - Margaretha A Faber
- Faculty of Medicine and Health Sciences, Department of Immunology, Allergology, and Rheumatology and the Infla-Med Centre of Excellence University of Antwerp; and Department of Immunology, Allergology, and Rheumatology, Antwerp University Hospital, Antwerp, Belgium
| | - Marie-Line van der Poorten
- Faculty of Medicine and Health Sciences, Department of Immunology, Allergology, and Rheumatology and the Infla-Med Centre of Excellence University of Antwerp; and Department of Immunology, Allergology, and Rheumatology, Antwerp University Hospital, Antwerp, Belgium; Faculty of Medicine and Health Sciences, Department of Paediatrics and the Infla-Med Centre of Excellence, University of Antwerp and Department of Paediatrics, Antwerp University Hospital, Antwerp, Belgium
| | - Athina L Van Gasse
- Faculty of Medicine and Health Sciences, Department of Immunology, Allergology, and Rheumatology and the Infla-Med Centre of Excellence University of Antwerp; and Department of Immunology, Allergology, and Rheumatology, Antwerp University Hospital, Antwerp, Belgium; Faculty of Medicine and Health Sciences, Department of Paediatrics and the Infla-Med Centre of Excellence, University of Antwerp and Department of Paediatrics, Antwerp University Hospital, Antwerp, Belgium
| | - Chris H Bridts
- Faculty of Medicine and Health Sciences, Department of Immunology, Allergology, and Rheumatology and the Infla-Med Centre of Excellence University of Antwerp; and Department of Immunology, Allergology, and Rheumatology, Antwerp University Hospital, Antwerp, Belgium
| | - Christel Mertens
- Faculty of Medicine and Health Sciences, Department of Immunology, Allergology, and Rheumatology and the Infla-Med Centre of Excellence University of Antwerp; and Department of Immunology, Allergology, and Rheumatology, Antwerp University Hospital, Antwerp, Belgium
| | - Michel Van Houdt
- Faculty of Medicine and Health Sciences, Department of Immunology, Allergology, and Rheumatology and the Infla-Med Centre of Excellence University of Antwerp; and Department of Immunology, Allergology, and Rheumatology, Antwerp University Hospital, Antwerp, Belgium
| | - Margo M Hagendorens
- Faculty of Medicine and Health Sciences, Department of Immunology, Allergology, and Rheumatology and the Infla-Med Centre of Excellence University of Antwerp; and Department of Immunology, Allergology, and Rheumatology, Antwerp University Hospital, Antwerp, Belgium; Faculty of Medicine and Health Sciences, Department of Paediatrics and the Infla-Med Centre of Excellence, University of Antwerp and Department of Paediatrics, Antwerp University Hospital, Antwerp, Belgium
| | - Anke Verlinden
- Department of Haematology, Antwerp University Hospital, Edegem, Belgium
| | - Katrien Vermeulen
- Department of Clinical Biology, Antwerp University Hospital, Edegem, Belgium
| | - Marie-Berthe Maes
- Department of Clinical Biology, Antwerp University Hospital, Edegem, Belgium
| | - Zwi N Berneman
- Department of Haematology, Antwerp University Hospital, Edegem, Belgium
| | - Vito Sabato
- Faculty of Medicine and Health Sciences, Department of Immunology, Allergology, and Rheumatology and the Infla-Med Centre of Excellence University of Antwerp; and Department of Immunology, Allergology, and Rheumatology, Antwerp University Hospital, Antwerp, Belgium; Department of Immunology and Allergology, AZ Jan Palfijn Gent, Ghent, Belgium
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19
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Kim DK, Bandara G, Cho YE, Komarow HD, Donahue DR, Karim B, Baek MC, Kim HM, Metcalfe DD, Olivera A. Mastocytosis-derived extracellular vesicles deliver miR-23a and miR-30a into pre-osteoblasts and prevent osteoblastogenesis and bone formation. Nat Commun 2021; 12:2527. [PMID: 33953168 PMCID: PMC8100305 DOI: 10.1038/s41467-021-22754-4] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 03/11/2021] [Indexed: 12/12/2022] Open
Abstract
Osteoporosis and other manifestations of bone disease are frequent in patients with systemic mastocytosis (SM) in association with the presence of mast cell infiltrates in bone marrow, although the mechanisms behind bone disease remain poorly understood. We find that extracellular vesicles (EVs) released by neoplastic mast cells and present in the serum of patients with SM (SM-EVs) block osteoblast differentiation and mineralization in culture, and when injected into mice diminish the expression of osteoblast markers, and trabecular bone volume and microarchitecture. We demonstrate that miRNA-30a and miRNA-23a, increased in SM-EVs and neoplastic mast cell-derived EVs, attenuate osteoblast maturation by suppressing expression of RUNX2 and SMAD1/5, essential drivers of osteogenesis. Thus, SM-EVs carry and deliver miRNAs that epigenetically interfere with bone formation and can contribute to bone mass reduction in SM. These findings also suggest possibilities for novel approaches to the management of bone disease in mast cell proliferative disorders.
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Affiliation(s)
- Do-Kyun Kim
- Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, USA
- Center for Biomolecular and Cellular Structure, Institute for Basic Science (IBS), Daejeon, Republic of Korea
- Korea Zoonosis Research Institute, Jeonbuk National University, Iksan, Jeonbuk, Republic of Korea
| | - Geethani Bandara
- Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, USA
| | - Young-Eun Cho
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA
- Department of Food and Nutrition, Andong National University, Andong, Kyungpook, Republic of Korea
| | - Hirsh D Komarow
- Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, USA
| | - Danielle R Donahue
- Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
| | - Baktiar Karim
- Molecular Histopathology Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute, NIH, Frederick, MD, USA
| | - Moon-Chang Baek
- Department of Molecular Medicine, CMRI, Exosome Convergence Research Center (ECRC), School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Ho Min Kim
- Center for Biomolecular and Cellular Structure, Institute for Basic Science (IBS), Daejeon, Republic of Korea
| | - Dean D Metcalfe
- Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, USA
| | - Ana Olivera
- Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, USA.
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20
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Zanotti R, Tanasi I, Bernardelli A, Orsolini G, Bonadonna P. Bone Marrow Mastocytosis: A Diagnostic Challenge. J Clin Med 2021; 10:1420. [PMID: 33915965 PMCID: PMC8037514 DOI: 10.3390/jcm10071420] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 03/19/2021] [Accepted: 03/19/2021] [Indexed: 12/12/2022] Open
Abstract
Bone marrow mastocytosis (BMM) represents a provisional, indolent subvariant of systemic mastocytosis (SM). Utilizing WHO criteria, BMM requires bone marrow (BM) involvement and the absence of mastocytosis skin lesions. BMM is characterized by male sex prevalence, a slight increase of serum tryptase levels, low BM mast cells (MC) burden, and an indolent clinical course. BMM shows a strong correlation with severe anaphylaxis, mainly due to an IgE-mediated allergy to bee or wasp venom and, less frequently, to unexplained (idiopathic) anaphylaxis. Furthermore, BMM is often associated with osteoporosis which could be the only presenting symptom of the disease. BMM is an undervalued disease as serum tryptase levels are not routinely measured in the presence of unexplained osteoporosis or anaphylaxis. Moreover, BMM patients are often symptom-free except for severe allergic reactions. These factors, along with typical low BM MCs infiltration, may contribute to physicians overlooking BMM diagnosis, especially in medical centers that lack appropriately sensitive diagnostic techniques. This review highlights the need for a correct diagnostic pathway to diagnose BMM in patients with suspected symptoms but lacking typical skin lesions, even in the case of normal serum tryptase levels. Early diagnosis may prevent potential life-threatening anaphylaxis or severe skeletal complications.
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Affiliation(s)
- Roberta Zanotti
- Hematology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy; (I.T.); (A.B.)
- Gruppo Interdisciplinare per lo Studio della Mastocitosi (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy; (G.O.); (P.B.)
| | - Ilaria Tanasi
- Hematology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy; (I.T.); (A.B.)
- Gruppo Interdisciplinare per lo Studio della Mastocitosi (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy; (G.O.); (P.B.)
| | - Andrea Bernardelli
- Hematology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy; (I.T.); (A.B.)
- Gruppo Interdisciplinare per lo Studio della Mastocitosi (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy; (G.O.); (P.B.)
| | - Giovanni Orsolini
- Gruppo Interdisciplinare per lo Studio della Mastocitosi (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy; (G.O.); (P.B.)
- Reumathology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy
| | - Patrizia Bonadonna
- Gruppo Interdisciplinare per lo Studio della Mastocitosi (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy; (G.O.); (P.B.)
- Allergy Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy
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21
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Ulivieri FM, Rinaudo L, Piodi LP, Barbieri V, Marotta G, Sciumè M, Grifoni FI, Cesana BM. Usefulness of Dual X-ray Absorptiometry-Derived Bone Geometry and Structural Indexes in Mastocytosis. Calcif Tissue Int 2020; 107:551-558. [PMID: 32839841 DOI: 10.1007/s00223-020-00749-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 08/11/2020] [Indexed: 12/20/2022]
Abstract
Reduced bone mass with or without fragility fractures is a common feature of mastocytosis, particularly in adult males. However, bone mineral density does not account for all the fragility fractures, being a part of them attributable to impairment in bone quality. Aim of this study is to assess the usefulness of DXA-derived geometry and structural indexes in the assessment of bone status in mastocytosis. Ninety-six consecutive patients (46 women and 50 men) affected by cutaneous (CM) or systemic (SM) mastocytosis were studied. Mean age (± SD) was 53.3 ± 14.23. Spine lateral X-rays for Genant's scale, DXA for lumbar (L) and femoral (F) bone mineral density (BMD), bone strain index (BSI), lumbar trabecular bone score (TBS), and hip structural analysis (HSA) were performed. Among the laboratory variables, data of serum tryptase were reported. Tryptase was higher in SM (p = 0.035), inversely correlated with LBMD (r = - 0.232; p = 0.022) and TBS (r = - 0.280; p = 0.005), and directly with L-BSI (r = 0.276; p = 0.006). L-BSI remained statistically significant (p = 0.006; adjusted R2 = 0.101) together with mastocytosis (SM or CM: p = 0.034) in the multivariate regression model with tryptase as dependent variable, being LBMD and TBS not statistically significant (p = 0.887, and p = 0.245, respectively). Tryptase increased about 22 units for each unit increase of L-BSI and about 18 units for SM against CM. L-BSI was lower (p = 0.012), while FN-BSI and FT-BSI were higher in women (p < 0.001) than in men. HSA indexes were significantly higher in men, particularly with SM. SM is a risk factor for reduced bone mass, texture and strength. Since mean L-BSI and Z-modulus of all the femoral sites are statistically higher in men than in female, it could be argued that men have a better femoral bone resistance to bending forces than women, but a worse lumbar bone resistance to compressive loads. DXA indexes of bone quality are useful in mastocytosis' bone assessment and its clinical management.
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Affiliation(s)
- Fabio Massimo Ulivieri
- U.O. Medicina Nucleare, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza, 35, 20122, Milano, Italy.
- U.O. Endocrinologia, Università Vita-Salute San Raffaele, via Olgettina 58, 20132, Milano, Italy.
| | - Luca Rinaudo
- TECHNOLOGIC Srl, Lungo Dora Voghera, 34/36, 10153, Torino, Italy
| | | | - Valentina Barbieri
- Scuola Di Specializzazione in Medicina Fisica e Riabilitativa, Università Degli Studi Di Milano, Via Festa del Perdono, 7, 20122, Milano, Italy
| | - Giorgio Marotta
- U.O. Medicina Nucleare, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza, 35, 20122, Milano, Italy
| | - Mariarita Sciumè
- U.O. Ematologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza, 35, 20122, Milano, Italy
| | - Federica Irene Grifoni
- U.O. Ematologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza, 35, 20122, Milano, Italy
| | - Bruno Mario Cesana
- Unità Di Statistica Medica, Biometria e, Bioinformatica "Giulio A. Maccacaro", Dipartimento Di Scienze Cliniche E Salute Della Comunità, Università Degli Studi Di Milano, Via Vanzetti, 5, 20100, Milano, Italy
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22
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Leone A, Criscuolo M, Gullì C, Petrosino A, Carlo Bianco N, Colosimo C. Systemic mastocytosis revisited with an emphasis on skeletal manifestations. Radiol Med 2020; 126:585-598. [PMID: 33242205 DOI: 10.1007/s11547-020-01306-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 11/15/2020] [Indexed: 12/12/2022]
Abstract
Systemic mastocytosis (SM) is a rare form of mastocytosis that can affect various organ systems. Bone involvement is the most common and prominent imaging feature in patients with SM regardless of the subtype. Furthermore, bone involvement is a prognostic factor as it may entail an aggressive course of the disease. Diagnosis is established by bone marrow biopsy complemented by imaging modalities such as radiography, CT, and magnetic resonance (MR) imaging. The radiographic and CT appearances are that of sclerotic, lytic, or mixed patterns with focal or diffuse distribution, involving primarily the axial skeleton and the ends of the long bones. Bone marrow infiltration is best recognized on MR imaging. Osteoporosis is common in SM; thus, a bone mineral density measurement at lumbar spine and proximal femur by dual-energy X-ray absorptiometry should be obtained. Imaging plays a huge part in the diagnostic process; when skeletal imaging findings are carefully interpreted and correlated with clinical features, they can lead to the suspicion of SM. The primary aims of this review article were to focus on the role of imaging in detection and characterization of skeletal patterns of SM and to discuss relevant clinical features that could facilitate prompt and correct diagnosis.
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Affiliation(s)
- Antonio Leone
- Department of Radiological and Hematological Sciences Fondazione, Policlinico Universitario A. Gemelli, IRCCS Università Cattolica del Sacro Cuore, Largo A. Gemelli, 100168, Rome, Italy.
| | - Marianna Criscuolo
- Department of Radiological and Hematological Sciences Fondazione, Policlinico Universitario A. Gemelli, IRCCS Università Cattolica del Sacro Cuore, Largo A. Gemelli, 100168, Rome, Italy
| | - Consolato Gullì
- Department of Radiological and Hematological Sciences Fondazione, Policlinico Universitario A. Gemelli, IRCCS Università Cattolica del Sacro Cuore, Largo A. Gemelli, 100168, Rome, Italy
| | - Antonella Petrosino
- Department of Radiological and Hematological Sciences Fondazione, Policlinico Universitario A. Gemelli, IRCCS Università Cattolica del Sacro Cuore, Largo A. Gemelli, 100168, Rome, Italy
| | - Nicola Carlo Bianco
- Department of Radiological and Hematological Sciences Fondazione, Policlinico Universitario A. Gemelli, IRCCS Università Cattolica del Sacro Cuore, Largo A. Gemelli, 100168, Rome, Italy
| | - Cesare Colosimo
- Department of Radiological and Hematological Sciences Fondazione, Policlinico Universitario A. Gemelli, IRCCS Università Cattolica del Sacro Cuore, Largo A. Gemelli, 100168, Rome, Italy
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23
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Sirufo MM, Suppa M, Ginaldi L, De Martinis M. Does Allergy Break Bones? Osteoporosis and Its Connection to Allergy. Int J Mol Sci 2020; 21:E712. [PMID: 31973226 PMCID: PMC7037724 DOI: 10.3390/ijms21030712] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 01/11/2020] [Accepted: 01/16/2020] [Indexed: 12/13/2022] Open
Abstract
: Osteoporosis and allergic diseases are important causes of morbidity, and traditionally their coexistence has been attributed to causality, to independent processes, and they were considered unrelated. However, the increasing knowledge in the field of osteoimmunology and an increasing number of epidemiological and biological studies have provided support to a correlation between bone and allergy that share pathways, cells, cytokines and mediators. If the link between allergic pathology and bone alterations appears more subtle, there are conditions such as mastocytosis and hypereosinophilic or hyper-IgE syndromes characterized by the proliferation of cells or hyper-production of molecules that play a key role in allergies, in which this link is at least clinically more evident, and the diseases are accompanied by frank skeletal involvement, offering multiple speculation cues. The pathophysiological connection of allergy and osteoporosis is currently an intriguing area of research. The aim of this review is to summarize and bring together the current knowledge and pursue an opportunity to stimulate further investigation.
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Affiliation(s)
- Maria Maddalena Sirufo
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (M.M.S.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the diagnosis and treatment of Osteoporosis, AUSL 04 Teramo, 64100 Teramo, Italy
| | - Mariano Suppa
- Department of Dermatology, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium;
| | - Lia Ginaldi
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (M.M.S.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the diagnosis and treatment of Osteoporosis, AUSL 04 Teramo, 64100 Teramo, Italy
| | - Massimo De Martinis
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (M.M.S.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the diagnosis and treatment of Osteoporosis, AUSL 04 Teramo, 64100 Teramo, Italy
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Adami G, Fassio A, Rossini M, Caimmi C, Giollo A, Orsolini G, Viapiana O, Gatti D. Osteoporosis in Rheumatic Diseases. Int J Mol Sci 2019; 20:E5867. [PMID: 31766755 PMCID: PMC6928928 DOI: 10.3390/ijms20235867] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 11/16/2019] [Accepted: 11/21/2019] [Indexed: 12/17/2022] Open
Abstract
Osteoporosis is a chronic disease characterized by an increased risk of fragility fracture. Patients affected by rheumatic diseases are at greater risk of developing osteoporosis. The purpose of the present review is to discuss the pathogenesis, epidemiology, and treatment of osteoporosis in patients affected by rheumatic diseases with special focus for rheumatoid arthritis, psoriatic arthritis, spondyloarthritis, systemic lupus erythematosus, systemic sclerosis, vasculitides, Sjogren syndrome, and crystal-induced arthritis.
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Affiliation(s)
- Giovanni Adami
- Rheumatology Unit, University of Verona, Policlinico Borgo Roma, Pz Scuro 10, 37134 Verona, Italy; (A.F.); (M.R.); (C.C.); (A.G.); (G.O.); (O.V.); (D.G.)
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Abstract
Bone pathology can be challenging because the skeleton is a living tissue prone to developing a diverse array of inflammatory, metabolic, genetic, reactive, circulatory, and neoplastic abnormalities. Several areas of bone pathology are particularly difficult or problematic for hematopathologists given the close resemblance of some hematologic entities to primary/metastatic bone lesions; examples include plasmacytic disorders versus osteoblastic tumors and lymphoma/leukemia versus round cell tumors of bone. This article provides a conceptual and practical overview of selective bone disorders commonly encountered in the differential diagnosis of hematologic diseases.
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Affiliation(s)
- Deniz Peker
- Department of Pathology, University of Alabama at Birmingham, 619 19th Street South, Birmingham, AL 35249, USA
| | - Shi Wei
- Department of Pathology, University of Alabama at Birmingham, 619 19th Street South, Birmingham, AL 35249, USA
| | - Gene P Siegal
- Department of Pathology, University of Alabama at Birmingham, 619 19th Street South, Birmingham, AL 35249, USA.
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Valent P, Akin C, Gleixner KV, Sperr WR, Reiter A, Arock M, Triggiani M. Multidisciplinary Challenges in Mastocytosis and How to Address with Personalized Medicine Approaches. Int J Mol Sci 2019; 20:E2976. [PMID: 31216696 PMCID: PMC6627900 DOI: 10.3390/ijms20122976] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 06/05/2019] [Accepted: 06/16/2019] [Indexed: 12/27/2022] Open
Abstract
Mastocytosis is a hematopoietic neoplasm defined by abnormal expansion and focal accumulation of clonal tissue mast cells in various organ-systems. The disease exhibits a complex pathology and an equally complex clinical behavior. The classification of the World Health Organization (WHO) divides mastocytosis into cutaneous forms, systemic variants, and localized mast cell tumors. In >80% of patients with systemic mastocytosis (SM), a somatic point mutation in KIT at codon 816 is found. Whereas patients with indolent forms of the disease have a normal or near-normal life expectancy, patients with advanced mast cell neoplasms, including aggressive SM and mast cell leukemia, have a poor prognosis with short survival times. In a majority of these patients, multiple somatic mutations and/or an associated hematologic neoplasm, such as a myeloid leukemia, may be detected. Independent of the category of mastocytosis and the serum tryptase level, patients may suffer from mediator-related symptoms and/or osteopathy. Depending on the presence of co-morbidities, the symptomatology in such patients may be mild, severe or even life-threatening. Most relevant co-morbidities in such patients are IgE-dependent allergies, psychiatric, psychological or mental problems, and vitamin D deficiency. The diagnosis and management of mastocytosis is an emerging challenge in clinical practice and requires vast knowledge, a multidisciplinary approach, and personalized medicine procedures. In this article, the current knowledge about mastocytosis is reviewed with special emphasis on the multidisciplinary aspects of the disease and related challenges in daily practice.
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Affiliation(s)
- Peter Valent
- Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria.
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria.
| | - Cem Akin
- Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, MI 48106, USA.
| | - Karoline V Gleixner
- Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria.
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria.
| | - Wolfgang R Sperr
- Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria.
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria.
| | - Andreas Reiter
- III. Medizinische Klinik, Universitätsmedizin Mannheim, 68167 Mannheim, Germany.
| | - Michel Arock
- Department of Hematological Biology, Pitié-Salpêtrière Hospital, Pierre et Marie Curie University (UPMC), 75005 Paris, France.
| | - Massimo Triggiani
- Division of Allergy and Clinical Immunology, University of Salerno, 84131 Salerno, Italy.
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