Real-world keystroke dynamics are a potentially valid biomarker for clinical disability in multiple sclerosis

Background: Clinical measures in multiple sclerosis (MS) face limitations that may be overcome by utilising smartphone keyboard interactions acquired continuously and remotely during regular typing. Objective: The aim of this study was to determine the reliability and validity of keystroke dynamics to assess clinical aspects of MS. Methods: In total, 102 MS patients and 24 controls were included in this observational study. Keyboard interactions were obtained with the Neurokeys keyboard app. Eight timing-related keystroke features were assessed for reliability with intraclass correlation coefficients (ICCs); construct validity by analysing group differences (in fatigue, gadolinium-enhancing lesions on magnetic resonance imaging (MRI), and patients vs controls); and concurrent validity by correlating with disability measures. Results: Reliability was moderate in two (ICC = 0.601 and 0.742) and good to excellent in the remaining six features (ICC = 0.760–0.965). Patients had significantly higher keystroke latencies than controls. Latency between key presses correlated the highest with Expanded Disability Status Scale (r = 0.407) and latency between key releases with Nine-Hole Peg Test and Symbol Digit Modalities Test (ρ = 0.503 and r = −0.553, respectively), ps < 0.001. Conclusion: Keystroke dynamics were reliable, distinguished patients and controls, and were associated with clinical disability measures. Consequently, keystroke dynamics are a promising valid surrogate marker for clinical disability in MS

Mastocytosis presenting with mast cell-mediator release-associated symptoms elicited by cyclo oxygenase inhibitors: prevalence, clinical, and laboratory features

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently avoided in mastocytosis, because of a potential increased risk for drug hypersensitivity reactions (DHRs) due to inhibition of cyclo-oxygenase (COX), subsequent depletion of prostaglandin E2 and release of leukotrienes. Objectives: Here, we aimed at determining the prevalence of mast cell (MC) mediator release symptoms triggered by NSAIDs in mastocytosis patients and the associated clinical and laboratory features of the disease. Methods: Medical records from 418 adults to 223 pediatric mastocytosis patients were retrospectively reviewed. Patients were classified according to tolerance patterns to NSAIDs and other COX inhibitors (COXi) and compared for epidemiological, clinical and laboratory findings. Results: Overall, 87% of adults and 91% of pediatric patients tolerated NSAIDs and other COXi. Among adult and pediatric patients presenting DHRs, 5% and 0% reacted to multiple NSAIDs, 4% and 0.7% were single reactors, and 3% and 8% were single reactors with known tolerance to paracetamol but unknown tolerance to other COXi, respectively. Among adults, hypersensitivity to ≥2 drugs was more frequent among females (p = 0.009), patients with prior history of anaphylaxis to triggers other than NSAIDs or other COXi and Hymenoptera venom (p = 0.009), presence of baseline flushing (p = 0.02), baseline serum tryptase ≥48 ng/ml (p = 0.005) and multilineage KIT mutation (p = 0.02). In contrast, tolerance to NSAIDs and other COXi was more frequent among males (p = 0.02), in patients with anaphylaxis caused by Hymenoptera venom (p = 0.02), among individuals who had skin lesions due to mastocytosis (p = 0.01), and in cases that had no baseline pruritus (p = 0.006). Based on these parameters, a score model was designed to stratify mastocytosis patients who have never received NSAIDs or other COXi apart from paracetamol, according to their risk of DHR. Conclusions: Our results suggest that despite the frequency of MC mediator related symptoms elicited by NSAIDs and other COXi apart from paracetamol is increased among mastocytosis patients versus the general population, it is lower than previously estimated and associated with unique disease features. Patients that tolerated NSAIDs and other COXi following disease onset should keep using them. In turn, adults with unknown tolerance to such drugs and a positive score should be challenged with a preferential/selective COX-2 inhibitor, while the remaining may be challenged with ibuprofen. © 2022 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.Funding text 1: This work was supported by grants from the Carlos III Health Institute co‐financed by the European Regional Development Fund (PI19/01166) and CIBERONC CB16/12/00400, Ministerio de Ciencia e Innovación (Madrid, Spain), Asociación Española de Mastocitosis y Enfermedades Relacionadas (AEDM 2019), Fondos de Investigación para Enfermedades Raras del Ministerio de Sanidad, Servicios Sociales e Igualdad (Madrid, Spain). ; Funding text 2: This work was supported by grants from the Carlos III Health Institute co-financed by the European Regional Development Fund (PI19/01166) and CIBERONC CB16/12/00400, Ministerio de Ciencia e Innovación (Madrid, Spain), Asociación Española de Mastocitosis y Enfermedades Relacionadas (AEDM 2019), Fondos de Investigación para Enfermedades Raras del Ministerio de Sanidad, Servicios Sociales e Igualdad (Madrid, Spain)

Serum tryptase monitoring in indolent systemic mastocytosis: association with disease features and patient outcome

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.[Background]: Serum baseline tryptase (sBT) is a minor diagnostic criterion for systemic mastocytosis (SM) of undetermined prognostic impact. We monitored sBT levels in indolent SM (ISM) patients and investigated its utility for predicting disease behaviour and outcome. [Methods]: In total 74 adult ISM patients who were followed for ≥48 months and received no cytoreductive therapy were retrospectively studied. Patients were classified according to the pattern of evolution of sBT observed. [Results]: Overall 16/74 (22%) cases had decreasing sBT levels, 48 (65%) patients showed increasing sBT levels and 10 (13%) patients showed a fluctuating pattern. Patients with significantly increasing sBT (sBT slope ≥0.15) after 48 months of follow-up showed a slightly greater rate of development of diffuse bone sclerosis (13% vs. 2%) and hepatomegaly plus splenomegaly (16% vs. 5%), as well as a significantly greater frequency of multilineage vs. mast cells (MC)-restricted KIT mutation (p = 0.01) together with a greater frequency of cases with progression of ISM to smouldering and aggressive SM (p = 0.03), and a shorter progression-free survival (p = 0.03). [Conclusions]: Monitoring of sBT in ISM patients is closely associated with poor prognosis disease features as well as with disease progression, pointing out the need for a closer follow-up in ISM patients with progressively increasing sBT values.This work was supported by grants from the Fondo de Investigaciones Sanitarias (FIS) of the Ministerio de Ciencia e Innovación of Spain (RETICS RD06/0020/0035-FEDER and PS09/00032); Fundación Sociosanitaria de Castilla-La Mancha (FISCAM 2007/36, FISCAM 2010/008 and G-2010/C-002); Instituto de Salud Carlos III of the Ministerio de Economía y Competitividad of Spain (PI11/02399); Junta de Castilla y León (SAN/103/2011); Fundación Ramón Areces; Fundación Española de Mastocitosis (FEM 2010); Hospital Virgen de la Salud Biobank (BioB-HVS) supported by grant of RETICS RD09/0076/00074, (Toledo, Spain).Peer Reviewe

Smartphone-derived keystroke dynamics are sensitive to relevant changes in multiple sclerosis

BACKGROUND: To investigate smartphone keystroke dynamics (KD), derived from regular typing, on sensitivity to relevant change in disease activity, fatigue, and clinical disability in multiple sclerosis (MS). METHODS: Preplanned interim analysis of a cohort study with 102 MS patients assessed at baseline and 3-month follow-up for gadolinium-enhancing lesions on MRI, relapses, fatigue and clinical disability outcomes. Keyboard interactions were unobtrusively collected during typing using the Neurokeys App. From these interactions 15 keystroke features were derived and aggregated using 16 summary and time series statistics. Responsiveness of KD to clinical anchor-based change was assessed by calculating the area under the receiver operating characteristic curve (AUC). The optimal cut-point was used to determine the minimal clinically important difference (MCID) and compared to the smallest real change (SRC). Commonly used clinical measures were analyzed for comparison. RESULTS: 94 patients completed the follow-up. The five best performing keystroke features had AUC-values ranging from 0.72 to 0.78 for change in gadolinium-enhancing lesions, 0.67-0.70 for the Checklist Individual Strength Fatigue subscale, 0.66-0.79 for the Expanded Disability Status Scale, 0.69-0.73 for the Ambulation Functional System, and 0.72-0.75 for Arm function in MS Questionnaire. The MCID of these features exceeded the SRC on group level. KD had higher AUC-values than comparative clinical measures for the study outcomes, aside from ambulatory function. CONCLUSIONS: KD demonstrated good responsiveness to changes in disease activity, fatigue, and clinical disability in MS, and detected important change beyond measurement error on group level. Responsiveness of KD was better than commonly used clinical measures

Current state of biology and diagnosis of clonal mast cell diseases in adults

[EN] Mastocytosis comprises a heterogeneous group of disorders characterized by the presence of clonal mast cells (MC) in organs such as skin, bone marrow (BM), and gastrointestinal tract, among other tissues. The clonal nature of the disease can be established in most adult patients by the demonstration of activating KIT mutations in their BM MC. When highly sensitive techniques capable of identifying cells present at very low frequencies in a sample are applied, BM MC from virtually all systemic mastocytosis patients display unique immunophenotypical features, particularly the aberrant expression of CD25. By contrast, large, multifocal BM MC aggregates (the only World Health Organization major criterion for systemic mastocytosis) are absent in a significant proportion of patients fulfilling at least three minor criteria for systemic mastocytosis, particularly in subjects studied at early stages of the disease with very low MC burden. Moreover, recent molecular and immunophenotypical investigations of BM MC from patients with indolent systemic mastocytosis have revealed a close association of some biological features (e.g., multilineage involvement of hematopoiesis by the KIT mutation and an immature mast cell immunophenotype) with an increased risk for disease progression. These observations support the fact that, although the current consensus diagnostic criteria for systemic mastocytosis have been a major advance for the diagnosis and classification of the disease, rationale usage of the most sensitive diagnostic techniques available nowadays is needed to improve the diagnosis, refine the classification, and reach objective prognostic stratification of adult mastocytosis

Mast cell-related disorders presenting with Kounis syndrome

Letter to the Editor.-- et al.Peer Reviewe

Detection of the KIT D816V mutation in peripheral blood of systemic mastocytosis: diagnostic implications

Recent studies have found the KIT D816V mutation in peripheral blood of virtually all adult systemic mastocytosis patients once highly sensitive PCR techniques were used; thus, detection of the KIT D816V mutation in peripheral blood has been proposed to be included in the diagnostic work-up of systemic mastocytosis algorithms. However, the precise frequency of the mutation, the biological significance of peripheral blood-mutated cells and their potential association with involvement of bone marrow hematopoietic cells other than mast cells still remain to be investigated. Here, we determined the frequency of peripheral blood involvement by the KIT D816V mutation, as assessed by two highly sensitive PCR methods, and investigated its relationship with multilineage involvement of bone marrow hematopoiesis. Overall, our results confirmed the presence of the KIT D816V mutation in peripheral blood of most systemic mastocytosis cases (161/190; 85%)-with an increasing frequency from indolent systemic mastocytosis without skin lesions (29/44; 66%) to indolent systemic mastocytosis with skin involvement (124/135; 92%), and more aggressive disease subtypes (11/11; 100%)-as assessed by the allele-specific oligonucleotide-qPCR method, which was more sensitive (P<.0001) than the peptide nucleic acid-mediated PCR approach (84/190; 44%). Although the presence of the KIT mutation in peripheral blood, as assessed by the allele-specific oligonucleotide-qPCR technique, did not accurately predict for multilineage bone marrow involvement of hematopoiesis, the allele-specific oligonucleotide-qPCR allele burden and the peptide nucleic acid-mediated-PCR approach did. These results suggest that both methods provide clinically useful and complementary information through the identification and/or quantification of the KIT D816V mutation in peripheral blood of patients suspected of systemic mastocytosis.This work was supported in part by grants from the Fondo de Investigaciones Sanitarias (FIS; grant number PI11/02399, FEDER) and Red Temática de Investigación Cooperativa en Cancer (RTICC; grant number RD12/0036/0048, FEDER) of the Instituto deSalud Carlos III (Ministry of Economy and Competitivity, Madrid, Spain), from Fundacion Ramon Areces (Madrid, Spain; grant number CIVP16A1806) and from Ayudas a Proyectos de Investigación en Salud de la Fundación Mutua Madrileña 2014 and Asociación Española de Enfermos de Mastocitosis (AEDM 2014). The National DNA Bank is supported by grants from the Instituto de Salud Carlos III of the Ministerio de Economia y Competitividad of Spain (grand numbers PT13/0001/0037 and PT13/0010/ 0067, FEDER). AM was supported by RTICC.Peer Reviewe

CD30 expression by bone marrow mast cells from different diagnostic variants of systemic mastocytosis

[Aims]: CD30 expression by bone marrow (BM) mast cells (MC) has been reported recently in systemic mastocytosis (SM) patients. The aim of this study was to investigate the potential diagnostic and prognostic value of CD30 expression in SM as assessed by multiparameter flow cytometry. [Methods and results]: A total of 163 consecutive BM samples corresponding to 142 SM patients and 21 non-mastocytosis cases were studied. CD30 was positive in most SM patients (80%), but in only one non-mastocytosis case (4.8%). When combined with CD25, CD30 contributed to an improved accuracy over that of CD25 alone (98% versus 93%) mainly because most (eight of nine) of the well-differentiated SM (WDSM), who lacked CD25, were CD30+. Similar levels of expression of CD30 were observed among all different subgroups of SM except mast cell leukaemia; among indolent SM (ISM) patients, no significant association was observed between the levels of CD30 expression and other clinical and biological features of the disease. [Conclusions]: The increased expression of CD30 associated with absence of CD25 contributes to the diagnosis of WDSM and its distinction from other subtypes of SM. By contrast, CD30 expression did not contribute either to prognostic stratification of ISM or to the differential diagnosis between ISM and aggressive SM cases.This work was supported by grants from the Fondo de Investigaciones Sanitarias (FIS) PI11/02399, PS09/00032 and RETICs RD09/0076/00133, RD09/0076/00074 and RD12/0036/0048 (FEDER) from the Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Spain; Fundacion Sociosanitaria de Castilla-La Mancha (2010/008 y G-2010/C-002); Fundación Espanola de Mastocitosis (FEM 2010); and by a grant from Fundaçao para a Ciência e Tecnologia (FCT) of Portugal (SFRH/BD/22972/2005).Peer Reviewe

Clinical, immunophenotypic, and molecular characteristics of well-differentiated systemic mastocytosis

[Background]: Well-differentiated systemic mastocytosis (WDSM) is a rare variant of systemic mastocytosis (SM) characterized by bone marrow (BM) infiltration by mature-appearing mast cells (MCs) often lacking exon 17 KIT mutations. Because of its rarity, the clinical and biological features of WDSM remain poorly defined. [Objective]: We sought to determine the clinical, biological, and molecular features of a cohort of 33 patients with mastocytosis in the skin in association with BM infiltration by well-differentiated MCs and to establish potential diagnostic criteria for WDSM. Methods Thirty-three patients with mastocytosis in the skin plus BM aggregates of round, fully granulated MCs lacking strong CD25 and CD2 expression in association with clonal MC features were studied. [Results]: Our cohort of patients showed female predominance (female/male ratio, 4:1) and childhood onset of the disease (91%) with frequent familial aggregation (39%). Skin involvement was heterogeneous, including maculopapular (82%), nodular (6%), and diffuse cutaneous (12%) mastocytosis. KIT mutations were detected in only 10 (30%) of 33 patients, including the KIT D816V (n = 5), K509I (n = 3), N819Y (n = 1), and I817V (n = 1) mutations. BM MCs displayed a unique immunophenotypic pattern consisting of increased light scatter features, overexpression of cytoplasmic carboxypeptidase, and aberrant expression of CD30, together with absent (79%) or low (21%) positivity for CD25, CD2, or both. Despite only 9 (27%) of 33 patients fulfilling the World Health Organization criteria for SM, our findings allowed us to establish the systemic nature of the disease, which fit with the definition of WDSM. [Conclusions]: WDSM represents a rare clinically and molecularly heterogeneous variant of SM that requires unique diagnostic criteria to avoid a misdiagnosis of cutaneous mastocytosis per current World Health Organization criteria.Supported by grants from Asociación Española de Mastocitosis, Madrid, Spain (grant AEDM 2014); Instituto de Salud Carlos III, FEDER, Ministry of Economy and Competitivity, Madrid, Spain (grant PI11/02399); Fundación Ramón Areces, Madrid, Spain (grant CIVP16A1806); and Novartis Farmacéutica, S.A., Spain. I. Alvarez-Twose has received research support from Novartis Farmacéutica, S.A., Spain. A. García-Montero has received research support from Fundacion Ramon Areces (grant no. CIVP16A1806) and ISCIII Ministerio de Economia y Competitividad (grant no. PI11/02399). A. Orfao has received research support from Fundacion Ramon Areces (grant no. CIVP16A1806).Peer Reviewe