Publications by authors named "Moises Labrador-Horrillo"

45 Publications

A Comparative Study of Sex Distribution, Autoimmunity, Blood, and Inflammatory Parameters in Chronic Spontaneous Urticaria with Angioedema and Chronic Histaminergic Angioedema.

J Allergy Clin Immunol Pract 2021 Jun 5;9(6):2284-2292. Epub 2021 Apr 5.

Department of Allergy and Clinical Immunology, Clínica Universidad de Navarra, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; RETIC de Asma, Reacciones Adversas y Alérgicas (ARADYAL), Madrid, Spain. Electronic address:

Background: Recurrent idiopathic histaminergic angioedema is currently classified as a subtype of angioedema, as well as a subtype of chronic spontaneous urticaria (CSU), based on the fact that both are mast cell-mediated and respond to the same treatments.

Objective: In the present work, we sought to verify whether chronic histaminergic angioedema (CHA) is an entity distinct from CSU or represents a CSU subtype that lacks hives.

Methods: We performed a prospective study comparing 68 CHA patients, angioedema without hives, with 63 CSU patients, with hives and angioedema, from whom we collected demographic and clinical data, as well as blood and serum markers.

Results: We found key pathogenic features that differentiate CHA from CSU: gender distribution, basophil number, and antibodies against the IgE receptor. The male/female ratio in CHA was 0.78, whereas in CSU it was 0.36 (P = .0466). Basopenia was more often seen in CSU (n = 13 [20%]) than in CHA (n = 5 [7%]). Finally, 31.15% of CSU sera induced basophil activation, whereas no CHA sera were able to activate normal basophils. By contrast, nonspecific inflammation or immune markers, for example, erythrocyte sedimentation rate, C-reactive protein, or IgG antithyroid antibodies, were very similar between both groups. IgE anti-IL-24 could not be assessed because a control population did not differ from CSU.

Conclusions: Inclusion of CHA as part of the spectrum of CSU is an assumption not evidence-based, and when studied separately, important differences were observed. Until there is further evidence, CHA and CSU should not necessarily be considered the same disorder, and it is our opinion that review articles and guidelines should reflect that possibility.
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http://dx.doi.org/10.1016/j.jaip.2021.03.038DOI Listing
June 2021

Simple predictive models identify patients with COVID-19 pneumonia and poor prognosis.

PLoS One 2020 28;15(12):e0244627. Epub 2020 Dec 28.

Universitat Autònoma de Barcelona, Barcelona, Spain.

Background And Aims: Identification of SARS-CoV-2-infected patients at high-risk of poor prognosis is crucial. We aimed to establish predictive models for COVID-19 pneumonia severity in hospitalized patients.

Methods: Retrospective study of 430 patients admitted in Vall d'Hebron Hospital (Barcelona) between 03-12-2020 and 04-28-2020 due to COVID-19 pneumonia. Two models to identify the patients who required high-flow-oxygen-support were generated, one using baseline data and another with also follow-up analytical results. Calibration was performed by a 1000-bootstrap replication model.

Results: 249 were male, mean age 57.9 years. Overall, 135 (31.4%) required high-flow-oxygen-support. The baseline predictive model showed a ROC of 0.800 based on: SpO2/FiO2 (adjusted Hazard Ratio-aHR = 8), chest x-ray (aHR = 4), prior immunosuppressive therapy (aHR = 4), obesity (aHR = 2), IL-6 (aHR = 2), platelets (aHR = 0.5). The cut-off of 11 presented a specificity of 94.8%. The second model included changes on the analytical parameters: ferritin (aHR = 7.5 if ≥200ng/mL) and IL-6 (aHR = 18 if ≥64pg/mL) plus chest x-ray (aHR = 2) showing a ROC of 0.877. The cut-off of 12 exhibited a negative predictive value of 92%.

Conclusions: SpO2/FiO2 and chest x-ray on admission or changes on inflammatory parameters as IL-6 and ferritin allow us early identification of COVID-19 patients at risk of high-flow-oxygen-support that may benefit from a more intensive disease management.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244627PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769554PMC
January 2021

Digital technology for anaphylaxis management impact on patient behaviour: A randomized clinical trial.

Allergy 2021 05 4;76(5):1507-1516. Epub 2020 Nov 4.

Allergy Section, Vall d'Hebron University Hospital, Barcelona, Spain.

Background: Epinephrine is the first-line treatment for anaphylaxis. Patients at risk should always carry an epinephrine autoinjector (EAI). Several EAI gaps have been identified. We sought to evaluate satisfaction using a medical device (digital technology comprising an EAI smart case connected to a mobile APP) with functions that overcome most of the EAI limitations and to determine whether patient behaviour and anaphylaxis management improve with its use.

Methods: This was a randomized, open-label, crossover clinical trial in a tertiary hospital involving patients with history of anaphylaxis carrying an EAI. The study was conducted in two three-month periods, one with and one without the medical device. The primary endpoint was satisfaction with the medical device. Usability, adherence, anxiety and anaphylaxis episodes were evaluated as secondary endpoints.

Results: A total of 100 patients were included (mean age 38.1 years, 74% female), and 95 completed the trial. The satisfaction visual analogue scale (VAS) after using the medical device was higher than before its use (89.1 [95% CI, 60.2-99.1] vs 56.3 [95% CI, 48.1-81.4]; P < .0001). The adherence VAS improved from 59.7 (95% CI, 54.0-65.3) to 88.6 (95% CI, 84.2-92.9) (P < .0001). Overall, 90% patients found the medical device easy to use. Patients' anxiety decreased from 52.2% to 29.3% (P < .001). Seven episodes of anaphylaxis occurred during the study, all in patients without the medical device (P = .025). Eighty-eight per cent of patients felt more involved in the management of anaphylaxis when using the medical device.

Conclusion: This is the first clinical trial evaluating digital technology for EAIs, showing a change of behaviour in patients at risk of anaphylaxis, increasing satisfaction, improving adherence, and reducing anxiety, with good usability.
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http://dx.doi.org/10.1111/all.14626DOI Listing
May 2021

Antihistamine-resistant chronic spontaneous urticaria remains undertreated: 2-year data from the AWARE study.

Clin Exp Allergy 2020 10 3;50(10):1166-1175. Epub 2020 Sep 3.

Novartis Pharma AG, Basel, Switzerland.

Background: Real-world evidence describing the benefits of recommended therapies and their impact on the quality of life (QoL) of chronic urticaria (CU) patients is limited.

Objective: To investigate disease burden, current treatment schedule, and the use of clinical resources by patients with H -antihistamine-refractory CU in Europe.

Methods: AWARE (A World-wide Antihistamine-Refractory chronic urticaria patient Evaluation) is a global, prospective, non-interventional study in the real-world setting, sponsored by the manufacturer of omalizumab. Disease characteristics, pharmacological treatments, and health-related QoL of patients (N = 2727) ≥18 years of age diagnosed with H -antihistamine-refractory chronic spontaneous urticaria (without inducible urticaria) for >2 months are reported here.

Results: Of the 2727 patients included, 1232 (45.2%) and 1278 (46.9%) were successfully followed up for any assessment and for the key outcome, the urticaria control test (UCT) score, respectively, and patients with complete remission (14.1%) were excluded from analyses.The proportion of patients with uncontrolled CSU (UCT score <12) dropped from 78% (n/N = 1641/2104) at baseline to 28.7% (n/N = 269/936) after two years of participation in the AWARE study. In addition, the proportion of patients with no impact of CSU on their QoL (assessed by the Dermatological Life Quality Index) increased to 57% (n/N = 664/1164) from 18.7% (n/N = 491/2621) at baseline. Emergency room visits (2.4% [n/N = 7/296] vs 33.5% [n/N = 779/2322]) and hospital stays (1.7% [n/N = 5/296] vs 24.2% [n/N = 561/2322]) reduced at Month 24 vs baseline. Overall, 23.2% (n/N = 26/112) patients on non-sedating H -antihistamines (nsAH) and 41.9% (n/N = 44/105) patients on up-dosed nsAH had uncontrolled CSU (UCT <12) at Month 24. In omalizumab-treated patients, 27.1% (n/N = 78/288) had uncontrolled CSU at Month 24.

Conclusion: These data confirm improvements for most patients with CSU over a 2-year follow-up period. Further studies are needed to understand the differences between guideline recommendations and reported management.
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http://dx.doi.org/10.1111/cea.13716DOI Listing
October 2020

Molecular diagnosis usefulness for idiopathic anaphylaxis.

Curr Opin Allergy Clin Immunol 2020 06;20(3):248-252

Allergy Section, Department of Internal Medicine, Hospital Universitari Vall d'Hebron.

Purpose Of Review: Molecular diagnosis has become an indispensable tool in allergy. In suspected idiopathic anaphylaxis, it is mandatory to extend the diagnostic search to its limits. The current review evaluates how molecular diagnosis allows to identify a number of difficult to prove potential culprits.

Recent Findings: Depending on different geographical areas, it has been shown that the number of anaphylaxis labelled as idiopathic may decrease by the use of molecular diagnosis. The most relevant allergens identified are alpha-gal, omega-5-gliadin, Anisakis, lipid transfer proteins and oleosins. The role of cofactors has been shown to be relevant in a high proportion of cases. Mast cell disorders should always be ruled out.

Summary: There is a need to provide further molecular diagnostic tests for use in clinical practice to identify sensitization to allergens not well represented in current commercial assays.
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http://dx.doi.org/10.1097/ACI.0000000000000625DOI Listing
June 2020

Anti-transcriptional intermediary factor 1 gamma antibodies in cancer-associated myositis: a longitudinal study.

Clin Exp Rheumatol 2020 Jan-Feb;38(1):67-73. Epub 2019 Jul 30.

Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.

Objectives: To investigate anti-TIF1-γ antibodies in longitudinally followed patients with myositis and cancer.

Methods: Serum levels of anti-TIF1-γ antibodies at different time-points in relation to myositis and cancer diagnosis were analysed by ELISA in 79 patients from a Swedish cohort with polymyositis (PM) and dermatomyositis (DM) and a Spanish cohort restricted to DM patients. Anti-TIF1-γ positive and negative patients were compared with Fisher's exact test, student t-tests and Wilcoxon test.

Results: Thirty-six patients (17 from cohort 1 and 19 from cohort 2) with myositis and cancer were anti-TIF1-γ antibody positive; all had DM. In 88% of anti-TIF1-γ positive patients, cancer was diagnosed within 3 years from DM diagnosis compared to 63% in anti-TIF1-γ negative. Four DM patients, anti-TIF1-γ positive at cancer diagnosis had positive serum samples even antedating cancer diagnosis up to five years. In cohort 1 the median (interquartile range) antibody level was higher, 2.13 au (1.82-2.15), in the seven patients who died <1 year after cancer diagnosis, compared to the seven that died >1 year after cancer diagnosis, 1.34 au (0.92-1.59), (p=0.004). Three patients were still alive and in remission from cancer and DM 14-16 years after cancer treatment of whom two became negative for anti-TIF1-γ antibodies. In the second cohort remission of cancer coincided with remission of DM and low or negative serum levels of autoantibodies.

Conclusions: Anti-TIF1-γ antibodies may be detected before clinical symptoms of cancer and may disappear after successful treatment of cancer with remission of DM supporting DM being a paramalignant phenomenon.
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March 2020

Anaphylactic shock to meropenem with ertapenem tolerance: A case report.

J Allergy Clin Immunol Pract 2019 Jul - Aug;7(6):2057-2058. Epub 2019 Feb 11.

Allergy Section, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Vall d'Hebron Research Institute (VHIR), Barcelona, Spain; ARADyAL Research Network (RD16/0006/0020), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2019.01.052DOI Listing
September 2020

Delayed drug hypersensitivity to bortezomib: Desensitization and tolerance to its analogue carfilzomib.

Allergy 2019 07 14;74(7):1384-1386. Epub 2019 Mar 14.

Allergy Section, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain.

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http://dx.doi.org/10.1111/all.13735DOI Listing
July 2019

Psychometric properties of the Spanish version of the once-daily Urticaria Activity Score (UAS) in patients with chronic spontaneous urticaria managed in clinical practice (the EVALUAS study).

Health Qual Life Outcomes 2019 Jan 31;17(1):23. Epub 2019 Jan 31.

Allergy Unit, Pneumology Department, Hospital Clinic, University of Barcelona, Barcelona, Spain.

Background: The daily diary Urticaria Activity Score (UAS) and its weekly score (UAS7) are widely used to assess signs and symptoms in patients with chronic spontaneous urticaria (CSU). The objective of this study was to assess the psychometric properties of a Spanish version of the once-daily UAS.

Methods: Observational study in patients ≥18 years old receiving usual care for CSU (daily or almost daily occurrence of generalized hives or angioedema for ≥6 weeks). Patients were included consecutively and completed the UAS, EQ-5D, and the Chronic Urticaria Quality of Life scale (CU-QoL) at two study visits 6 weeks apart. On each occasion, the UAS was completed once-daily for 7 consecutive days to be able to calculate the UAS7 score. Psychometric properties of reliability, construct validity, and responsiveness were assessed. The Minimal Important Difference (MID) was estimated for the UAS7 using anchor- and distribution-based approaches.

Results: Data from 166 patients was available for analysis (mean age 49 years, 65.7% female). Floor (5.4% of patients with the lowest possible score) and ceiling (1.2%) effects were low; 15% of patients had missing values. Internal consistency and test-retest reliability were good (Cronbach's alpha of 0.83 and an ICC of 0.84, respectively). Convergent validity was demonstrated through the pattern of correlations with the EQ-5D and CU-QoL and known groups' validity was demonstrated by the instrument's ability to discriminate between patients with different overall levels of urticaria severity, with between-group effect-sizes (ES) ranging from 0.36 to 1.19. The UAS7 proved responsive to change with effect sizes ranging from 0.3 to 1.52 in patients reporting improvement or deterioration in overall urticaria status. The MID for the UAS7 score was estimated at 7-8 points, on a scale of 0-42.

Conclusions: The Spanish version of the UAS score has demonstrated a robust psychometric performance in patients with CSU managed in conditions of usual care. It can therefore be considered a suitable instrument to assess disease activity in clinical practice in Spanish-speaking patients. The Spanish version's reliability and validity are similar to those reported for other language versions of the once- and twice-daily variants of the UAS.
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http://dx.doi.org/10.1186/s12955-019-1087-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357477PMC
January 2019

Efficacy and Safety of Omalizumab (Xolair) for Cholinergic Urticaria in Patients Unresponsive to a Double Dose of Antihistamines: A Randomized Mixed Double-Blind and Open-Label Placebo-Controlled Clinical Trial.

J Allergy Clin Immunol Pract 2019 May - Jun;7(5):1599-1609.e1. Epub 2019 Jan 15.

Department of Allergy and Clinical Immunology, Clinica Universidad de Navarra, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; RETIC de Asma, Reacciones adversas y Alérgicas (ARADYAL), Madrid, Spain. Electronic address:

Background: Cholinergic urticaria (UCOL) is a highly disabling inducible urticaria triggered by an increase in core body temperature.

Objective: To explore the safety and efficacy of omalizumab in controlling UCOL.

Methods: We conducted a multicenter randomized mixed double-blind and open-label (first 4 months blinded followed by 8 months open-label) placebo-controlled clinical trial in 22 patients suffering from UCOL who were unresponsive to a double dose of antihistamines. We performed an exercise challenge test during each visit as our main outcome variable.

Results: The overall rate of exercise challenge test negative at week 48 was 31.3%, with an average increase in exercise challenge test negative rate of 2.9% points (95% CI, 1.5-4.2) per visit. Statistically significant differences in the negative exercise challenge test rate between the placebo and active intervention groups were not observed during the blinded period (first 4 months of the study). However, from the fourth dose, a progressive improvement was observed. When comparing before and after treatment, statistically significant improvements in all secondary outcome measures were noted after 4 doses (UCOL score: P = .0015; visual analog scale score: P = .0108; days with symptoms: P = .0125) and after 8 doses (UCOL score: P = .0005; chronic urticaria quality of life questionnaire: P = .0105; visual analog scale score: P = .0008; and days with symptoms: P = .0144). In the follow-up visit after the cessation of treatment, the symptoms reappeared, with positive exercise challenge test result and significant increases in all variables. Only 4 of 22 patients remained asymptomatic after 3 months of no treatment. No adverse effects were reported.

Conclusions: This randomized mixed double-blind and open-label placebo-controlled trial showed evidence of the safety and potential efficacy of omalizumab in patients with UCOL.
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http://dx.doi.org/10.1016/j.jaip.2018.12.025DOI Listing
August 2020

Management of asthma in the emergency department: a consensus statement.

Emergencias 2018 Ago;30(4):268-277

Servicio de Urgencias, Hospital Miguel Servet, Zaragoza, España.

En: The purpose of this consensus statement is to provide a tool to assist in the management of asthma in Spanish emergency departments and to improve care of patients with asthma. A multidisciplinary team of 3 emergency medicine specialists, 3 respiratory medicine specialists, and 3 allergy specialists made a list of clinical questions and chose 4 clinical practice guidelines on asthma management to prioritize when answering the questions. The team members first worked individually and then discussed their findings in a meeting to reach consensus about the content of the present statement. The recommendations and clinical algorithms in the statement contribute to detecting the asthmatic patient on arrival at the emergency department, establishing the diagnosis, following unified treatment criteria, and referring the patient to a respiratory medicine specialist, an allergy specialist, or a primary care physician, as appropriate. The definitions used in this statement provide a common language for asthma in the interest of helping to unify care practices in emergency departments. The diagnostic criteria, treatment guidelines, and criteria for discharging and admitting patients provided should be useful for managing asthma in Spanish emergency departments.
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June 2019

Cancer-associated Dermatomyositis: Does the PD-1 Checkpoint Pathway Play a Role?

J Rheumatol 2018 06;45(6):731-732

Systemic Autoimmune Diseases Unit, Vall D'Hebron General Hospital, Internal Medicine Department, Universitat Autonoma de Barcelona, Barcelona, Spain.

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http://dx.doi.org/10.3899/jrheum.180007DOI Listing
June 2018

Statin-induced myalgia and myositis: an update on pathogenesis and clinical recommendations.

Expert Rev Clin Immunol 2018 03 23;14(3):215-224. Epub 2018 Feb 23.

e Internal Medicine Department, Hospital Clinic , Universitat de Barcelona , CIBERER , Barcelona , Spain.

Introduction: Musculoskeletal manifestations are well-recognized side effects of treatment with statins. New advances in this field have appeared in recent years. This review focuses on the diagnosis of these conditions and their underlying pathogenesis, in particular immune-mediated necrotizing myopathy. Areas covered: Clinical phenotypes including rhabdomyolysis, myalgia and/or mild hyperCKemia, self-limited toxin statin myopathy, and immune-mediated necrotizing myopathy are herein described. Therapeutic recommendations and a diagnostic algorithm in statin-associated myopathy are also proposed. The etiology and pathogenesis of statin-induced myopathy has mainly focused on the anti-HMGCR antibodies and the responsibility of the immune-mediated necrotizing myopathy is discussed. The fact that patients who have not been exposed to statins may develop statin-associated autoimmune myopathy with anti-HMGCR antibodies is also addressed. The literature search strategy included terms identified by searches of PubMed between 1969 and December 2017. The search terms 'myositis', 'statin-induced autoimmune myopathy', 'immune-mediate necrotizing myopathy', 'statins', 'muscular manifestations', and 'anti-HMGCR antibodies' were used. Expert commentary: Full characterization of the known phenotypes of statin toxicity and the specific role of the anti-HMGCR in those exposed and not exposed (i.e. juvenile forms) to statins and in some types of neoplasms is of paramount relevance.
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http://dx.doi.org/10.1080/1744666X.2018.1440206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019601PMC
March 2018

Tumour TIF1 mutations and loss of heterozygosity related to cancer-associated myositis.

Rheumatology (Oxford) 2018 02;57(2):388-396

Internal Medicine Department, Vall d'Hebron University Hospital, Barcelona, Spain.

Objectives: To analyse the influence of genetic alterations and differential expression of transcription intermediary factor 1 (TIF1) genes in the pathophysiology of cancer-associated myositis (CAM).

Methods: Paired blood and tumour DNA samples from patients with anti-TIF1γ-positive CAM and from controls were analysed by whole-exome sequencing for the presence of somatic mutations and loss of heterozygosity (LOH) in their TIF1 genes. The genesis and maintenance of the autoimmune process were investigated immunohistochemically by studying TIF1γ expression in the different tissues involved in CAM (skin, muscle and tumour) based on the immunohistochemical H-score.

Results: From seven patients with anti-TIF1γ-positive CAM, we detected one somatic mutation and five cases of LOH in one or more of the four TIF1 genes compared with just one case of LOH in tumours from TIF1γ-negative myositis patients (86% vs 17%; P = 0.03). Compared with type-matched control tumours from non-myositis patients, TIF1γ staining was more intense in tumours from anti-TIF1γ-positive patients (H-score 255 vs 196; P = 0.01). Also, TIF1γ staining in muscle was slightly more intense in anti-TIF1γ-positive than in anti-TIF1γ-negative myositis (H-score 22 vs 5; P = 0.03). In contrast, intense TIF1γ staining was detected in the skin of both myositis and control patients.

Conclusion: Tumours from paraneoplastic anti-TIF1γ-positive patients showed an increased number of genetic alterations, such as mutations and LOH, in TIF1 genes. These genetic alterations, in the context of a high expression of TIF1γ in the tumour, muscle and skin of these patients may be key to understanding the genesis of paraneoplastic myositis.
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http://dx.doi.org/10.1093/rheumatology/kex413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850766PMC
February 2018

The Mast Cell, Contact, and Coagulation System Connection in Anaphylaxis.

Front Immunol 2017 26;8:846. Epub 2017 Jul 26.

Allergy Section, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain.

Anaphylaxis is the most severe form of allergic reaction, resulting from the effect of mediators and chemotactic substances released by activated cells. Mast cells and basophils are considered key players in IgE-mediated human anaphylaxis. Beyond IgE-mediated activation of mast cells/basophils, further mechanisms are involved in the occurrence of anaphylaxis. New insights into the potential relevance of pathways other than mast cell and basophil degranulation have been unraveled, such as the activation of the contact and the coagulation systems. Mast cell heparin released upon activation provides negatively charged surfaces for factor XII (FXII) binding and auto-activation. Activated FXII, the initiating serine protease in both the contact and the intrinsic coagulation system, activates factor XI and prekallikrein, respectively. FXII-mediated bradykinin (BK) formation has been proven in the human plasma of anaphylactic patients as well as in experimental models of anaphylaxis. Moreover, the severity of anaphylaxis is correlated with the increase in plasma heparin, BK formation and the intensity of contact system activation. FXII also activates plasminogen in the fibrinolysis system. Mast cell tryptase has been shown to participate in fibrinolysis through plasmin activation and by facilitating the degradation of fibrinogen. Some usual clinical manifestations in anaphylaxis, such as angioedema or hypotension, or other less common, such as metrorrhagia, may be explained by the direct effect of the activation of the coagulation and contact system driven by mast cell mediators.
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http://dx.doi.org/10.3389/fimmu.2017.00846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526842PMC
July 2017

Mixed Connective Tissue Disease and Epitope Spreading: An Historical Cohort Study.

J Clin Rheumatol 2017 Apr;23(3):155-159

From the *Internal Medicine and †Immunology Departments, Vall d'Hebron General Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain.

Objectives: Mixed connective tissue disease (MCTD) is characterized by the presence of anti-U1-snRNP autoantibodies and a variable set of associated clinical features. Some MCTD patients test positive over time to autoantibodies against Sm, proteins spatially related with U1-snRNP. This situation has been attributed to expanding of the autoimmune response by a phenomenon known as epitope spreading. Our aim was to study the frequency of this phenomenon in MCTD patients and the specific clinical features of those with epitope spreading.

Methods: All anti-U1-RNP-positive patients (2010-2015) were retrospectively reviewed, and those meeting the MCTD criteria were included in the study. Patients showing epitope spreading were compared with the remainder of the MCTD cohort. In addition, the clinical features of patients with epitope spreading were compared before and after the phenomenon occurred.

Results: Among 72 anti-U1-RNP-positive patients, 40 (37 women) were diagnosed with MCTD. Thirteen MCTD patients (43%) presented epitope spreading, mainly during the first 2 years after the diagnosis of the disease (median, 1.4 years). Patients with epitope spreading had a significantly lower prevalence of skin sclerosis (0% vs. 44%, P = 0.004) and a greater prevalence of interstitial lung disease (46% vs. 15%, P = 0.05) than those without. Arthritis (92% vs. 25%, P = 0.02) and muscle involvement (67% vs. 17%, P = 0.02) were less frequent after epitope spreading had occurred.

Conclusion: Epitope spreading is common in MCTD, occurring early after the diagnosis. The clinical manifestations in patients with this phenomenon differ from those without, and their clinical features change after the immunological phenomenon has occurred.
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http://dx.doi.org/10.1097/RHU.0000000000000500DOI Listing
April 2017

Omalizumab: what benefits should we expect?

Eur J Dermatol 2016 Aug;26(4):340-4

Dermatology Department, Hospital General Universitario de Alicante, Alicante, Spain.

Chronic spontaneous urticaria (CSU) is a skin disease characterised by wheal appearance, swelling, itching, and painful skin. Omalizumab has been used for CSU treatment demonstrating good efficacy. To investigate the efficacy and safety of omalizumab treatment in CSU patients in real-life practice. A retrospective analysis was performed on 38 patients suffering from CSU who received 300 mg of omalizumab every four weeks. After omalizumab treatment, 68.4% of patients showed a complete response (UAS7 = 0). All the patients were able to stop treatment with corticosteroids, cyclosporine, and anti-leukotrienes, and only 39.5% of patients remained on anti-histamines. Omalizumab treatment led to a 96% and 65% decrease in emergency room and primary health care visits, respectively, as well as a reduction in the direct costs associated with the disease. No omalizumab-related adverse events were reported. Omalizumab exhibits good efficacy in alleviating the symptoms of CSU, leads to a decrease in concomitant medication use, restores patients' quality of life, and has economic benefits by reducing disease-related health care costs.
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http://dx.doi.org/10.1684/ejd.2016.2809DOI Listing
August 2016

Profile of omalizumab in the treatment of chronic spontaneous urticaria.

Drug Des Devel Ther 2015 25;9:4909-15. Epub 2015 Aug 25.

Department of Allergy and Clinical Immunology, Clínica Universidad de Navarra, IDISNA, Instituto de Investigación de Navarra, Pamplona, Spain.

Chronic spontaneous urticaria (CSU) is a disease with significant morbidity and relative prevalence that has important effects on the quality of life (QoL) of those who suffer from it. Omalizumab is a recombinant humanized anti-immunoglobulin E (IgE) antibody that binds to the Cε3 domain of the IgE heavy chain and prevents it from binding to its high-affinity receptor FcεRI. It has been largely studied in the field of asthma and is currently approved for the treatment of both adult and pediatric (children; >6-year-old) patients. In addition, in recent, well-controlled clinical trials in patients with CSU resistant to antihistamines, add-on therapy with subcutaneous omalizumab significantly reduced the severity of itching, and the number and size of hives, and increased patients' health-related QoL and the proportion of days free from angioedema compared with placebo, with an excellent tolerance. Thus, omalizumab is an effective and well-tolerated add-on therapy for patients with CSU who are symptomatic despite background therapy with H1 antihistamines. In this review, we cover the following points: epidemiology, pathogenesis, assessment of activity, impact on QoL, and treatment of CSU, and finally, we focus on omalizumab in the treatment of CSU including the pharmacokinetic properties and mechanism of action, and use in pregnant women, nursing infants, and children.
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http://dx.doi.org/10.2147/DDDT.S56004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4554406PMC
June 2016

Inflammatory myopathy: diagnosis and clinical course, specific clinical scenarios and new complementary tools.

Expert Rev Clin Immunol 2015 Jun 30;11(6):737-47. Epub 2015 Apr 30.

1 Internal Medicine Department, Vall d'Hebron General Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain.

Idiopathic inflammatory myopathies are a heterogeneous group of rare autoimmune diseases characterized by symmetric proximal muscle weakness and inflammatory infiltrates on muscle biopsy. A meticulously collected combination of clinical, serological, and pathological data is essential to correctly diagnose and classify myositis patients, often a considerable challenge for clinicians. This article provides a comprehensive overview of the most useful tools for the diagnosis and follow-up of patients with myositis. Capillaroscopy, serological biomarkers (particularly the autoantibody profile) and imaging techniques, such as muscle magnetic resonance and chest ultrasound, are of great aid in diagnosing, classifying and managing these patients. Relevant clinical scenarios, such as interstitial lung disease, associated cancer and pregnancy are also addressed in this review. Myositis registries, identification of new autoantibodies, and genetic studies will enhance our understanding of the pathogenesis of these conditions and help to define new diagnostic and therapeutic approaches.
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http://dx.doi.org/10.1586/1744666X.2015.1035258DOI Listing
June 2015

Identification of a novel myositis-associated antibody directed against cortactin.

Autoimmun Rev 2014 Oct 27;13(10):1008-12. Epub 2014 Aug 27.

Immunology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autónoma de Barcelona, Barcelona, Spain.

Objective: The aim of this study is to describe a novel myositis-associated autoantibody (anti-cortactin antibody) and assess related clinical and immunological manifestations and its clinical significance.

Methods: Adult patients with myositis (dermatomyositis, polymyositis, immune-mediated necrotizing myopathy, and inclusion body myositis), as well as patients with other autoimmune diseases and non-inflammatory myopathies were analyzed for the presence of anti-cortactin antibody using in-house developed ELISA and immunoblotting techniques with a commercial source of purified cortactin. The cut-off for positive status was determined in a group of healthy volunteers.

Results: Antibody against cortactin was positive in 7/34 (20%) polymyositis patients, 9/117 (7.6%) dermatomyositis, 2/7 (26%) immune-mediated necrotizing myopathy, and none of the 4 patients with inclusion body myositis. The antibody also tested positive in 3/101 patients with other autoimmune diseases (2 systemic sclerosis and 1 systemic lupus erythematosus), and in 1/29 patients with non-inflammatory myopathy. No relevant association with specific clinical features was found in patients with these antibodies. Anti-cortactin antibody was more frequently positive in patients with polymyositis and immune-mediated necrotizing myopathy than in the remaining myositis patients, and was the only myositis autoantibody found in sera of 3 patients from these groups.

Conclusions: Our data indicate that cortactin is a novel target antigen in patients with autoimmune diseases, especially patients with polymyositis or immune-mediated necrotizing myopathy. Anti-cortactin can be considered a new myositis-associated antibody.
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http://dx.doi.org/10.1016/j.autrev.2014.08.038DOI Listing
October 2014

Anti-MDA5 antibodies in a large Mediterranean population of adults with dermatomyositis.

J Immunol Res 2014 4;2014:290797. Epub 2014 Feb 4.

Immunology Department, Hospital de La Santa Creu I Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain.

A new myositis-specific autoantibody directed against melanoma differentiation-associated gene 5 (anti-MDA5) has been described in patients with dermatomyositis (DM). We report the clinical characteristics of patients with anti-MDA5 in a large Mediterranean cohort of DM patients from a single center, and analyze the feasibility of detecting this autoantibody in patient sera using new assays with commercially available recombinant MDA5. The study included 117 white adult patients with DM, 15 (13%) of them classified as clinically amyopathic dermatomyositis (CADM). Clinical manifestations were analyzed, with special focus on interstitial lung disease and its severity. Determination of anti-MDA5 antibodies was performed by a new ELISA and immunoblot technique. In sera, from 14 (12%) DM patients (8 CADM), MDA5 was recognized by ELISA, and confirmed by immunoblot. Eight of the 14 anti-MDA5-positive patients (57.14%) presented rapidly-progressive interstitial lung disease (RP-ILD) versus 3 of 103 anti-MDA5-negative patients (2.91%) (P < 0.05; OR: 44.4, 95% CI 9.3-212). The cumulative survival rate was significantly lower in anti-MDA5-positive patients than in the remainder of the series (P < 0.05). Patients with anti-MDA5-associated ILD presented significantly lower 70-month cumulative survival than antisynthetase-associated ILD patients. Among the cutaneous manifestations, only panniculitis was significantly associated with the presence of anti-MDA5 antibodies (P < 0.05; OR: 3.85, 95% CI 1.11-13.27). These findings support the reliability of using commercially available recombinant MDA5 for detecting anti-MDA5 antibodies and confirm the association of these antibodies with RP-ILD in a large series of Mediterranean patients with DM.
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http://dx.doi.org/10.1155/2014/290797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987881PMC
January 2015

[Chronic spontaneous urticaria].

Med Clin (Barc) 2014 Mar 8;142(6):275-8. Epub 2013 Oct 8.

Sección de Alergia, Servicio de Medicina Interna, Hospital Vall d'Hebron, Universidad Autònoma de Barcelona, Barcelona, España. Electronic address:

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http://dx.doi.org/10.1016/j.medcli.2013.07.022DOI Listing
March 2014

Identification of thaumatin-like protein and aspartyl protease as new major allergens in lettuce (Lactuca sativa).

Mol Nutr Food Res 2013 Dec 25;57(12):2245-52. Epub 2013 Aug 25.

Department of Immunology, IIS- Fundación Jimenez Diaz, Madrid.

Scope: Today, about 2-8% of the population of Western countries exhibits some type of food allergy whose impact ranges from localized symptoms confined to the oral mucosa to severe anaphylactic reactions. Consumed worldwide, lettuce is a Compositae family vegetable that can elicit allergic reactions. To date, however, only one lipid transfer protein has been described in allergic reaction to lettuce. The aim of this study was to identify potential new allergens involved in lettuce allergy.

Methods And Results: Sera from 42 Spanish lettuce-allergic patients were obtained from patients recruited at the outpatient clinic. IgE-binding proteins were detected by SDS-PAGE and immunoblotting. Molecular characterization of IgE-binding bands was performed by MS. Thaumatin was purified using the Agilent 3100 OFFGEL system. The IgE-binding bands recognized in the sera of more than 50% of patients were identified as lipid transfer protein (9 kDa), a thaumatin-like protein (26 kDa), and an aspartyl protease (35 and 45 kDa). ELISA inhibition studies were performed to confirm the IgE reactivity of the purified allergen.

Conclusion: Two new major lettuce allergens-a thaumatin-like protein and an aspartyl protease-have been identified and characterized. These allergens may be used to improve both diagnosis and treatment of lettuce-allergic patients.
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http://dx.doi.org/10.1002/mnfr.201300139DOI Listing
December 2013

Efficacy of omalizumab in chronic spontaneous urticaria refractory to conventional therapy: analysis of 110 patients in real-life practice.

Expert Opin Biol Ther 2013 Sep 23;13(9):1225-8. Epub 2013 Jul 23.

Allergy Section, Medicine Department, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron, 119-129, 08035, Barcelona, Spain.

Objective: To collect data on the efficacy and safety of omalizumab in 110 patients from 9 Spanish hospitals suffering from chronic spontaneous urticaria (CSU) refractory to conventional treatment.

Methods: A retrospective, descriptive analysis was performed, showing the data of 110 patients suffering from refractory CSU who received omalizumab as an off-label treatment in 9 Spanish hospitals from October 2009 to September 2012.

Results: Ninety (81.8%) patients exhibited a complete or significant response, 12 (10.9%) had partial response, and 8 (7.2%) showed no response. Sixty-six (60%) patients were able to stop all concomitant medications, remaining asymptomatic treated with omalizumab alone. No serious adverse events were reported.

Conclusions: Omalizumab shows excellent efficacy and safety profile in a large series of CSU patients in real-life practice. This drug will contribute to settle the debt with CSU patients contributing to restore their quality of life.
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http://dx.doi.org/10.1517/14712598.2013.822484DOI Listing
September 2013

Calcineurin inhibitors in a cohort of patients with antisynthetase-associated interstitial lung disease.

Clin Exp Rheumatol 2013 May-Jun;31(3):436-9. Epub 2013 Mar 7.

Department of Internal Medicine, Vall d´Hebron General Hospital. Universitat Autonoma de Barcelona, Spain.

Objectives: The aim of this paper is to assess the effect of calcineurin inhibitors (tacrolimus or cyclosporine) for treating patients with interstitial lung disease (ILD) associated with antisynthetase autoantibodies.

Methods: Sixty patients with antisynthetase autoantibodies were identified in our myositis cohort of 179 patients. The medical records of 15 patients with antisynthetase autoantibody-associated ILD treated with tacrolimus/cyclosporine (11 for refractory disease and 4 as first-line therapy) between 1980 and 2011 were retrospectively reviewed. Serial pulmonary function tests were used to assess the clinical response. Qualitative data are presented as a number and percentage, and quantitative data as the median and interquartile range (IQR).

Results: Patients were classified as having probable or definite idiopathic inflammatory myopathy (8 dermatomyositis and 4 polymyositis), and pure interstitial lung disease (3 cases). The 15 patients had received tacrolimus/cyclosporine for an average of 19 (IQR 14-30) months. Median age at onset of ILD was 42.3 (IQR 32.4-56.8) years and median duration of lung disease before administration of calcineurin inhibitors was 11 (IQR: 5-49) months. Median duration of follow-up was 24 (IQR 12-32) months. Thirteen patients had anti-histidyl-transfer RNA synthetase autoantibody (anti-Jo-1) and two had anti-alanyl-transfer RNA synthetase autoantibody (anti-PL-12). A more than 10% increase in FVC or stabilisation was observed in 13 (87%; 95%CI 56-98) patients who received calcineurin inhibitors (9 [81%] refractory cases and 4 [100%] as first-line therapy).

Conclusions: Calcineurin inhibitors seem to be a good therapeutic option for managing ILD associated with antisynthetase autoantibodies, not only in refractory cases, but also as first-line treatment.
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August 2013

Usefulness and limitations of sequential serum tryptase for the diagnosis of anaphylaxis in 102 patients.

Int Arch Allergy Immunol 2013 25;160(2):192-9. Epub 2012 Sep 25.

Allergy Section, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

Background: The diagnosis of anaphylaxis is based on clinical history since no reliable biological marker is currently available to confirm the diagnosis.

Objective: It was the aim of this study to determine sequential serum tryptase concentrations during anaphylaxis and to evaluate its potential as a diagnostic marker.

Methods: We performed a prospective study including patients with acute anaphylaxis (according to the National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network criteria) attending the emergency department. Demographic characteristics, anaphylactic triggers, specific risk factors, clinical characteristics and management of anaphylaxis were recorded. Serum tryptase was measured at 1-2 h (T1), 4-6 h (T2) and 12-24 h (T3) following onset of the episode and at basal conditions (TB).

Results: A total of 102 patients were included (63 females, mean age 47.4 ± 19.1 years). Tryptase concentration at T1 (19.3 ± 15.4 µg/l) was significantly higher than at T2, T3 and TB (all <11.4 µg/l; p < 0.0001). Importantly, tryptase was not raised in 36.3% of cases; furthermore, in 60.6% of these patients, no changes were observed in tryptase levels comparing T1 and TB (ΔT1-TB = 0). Tryptase was more frequently elevated in more severe anaphylaxis (p < 0.0001) and positively correlated with the grades of severity (p < 0.001, r = 0.49). Anaphylaxis was more severe and tryptase concentration higher when the causative agent was a drug compared to food, both at T1 (p = 0.045) and at TB (p = 0.019). Age and coronary risk factors were associated with more severe anaphylaxis (p = 0.001).

Conclusion: Tryptase is a biomarker related to the severity of anaphylaxis. However, since its concentration remains unaltered in a considerable number of patients during acute anaphylaxis, there is a need for more reliable diagnostic biological tests.
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http://dx.doi.org/10.1159/000339749DOI Listing
March 2013

Involvement of Can f 5 in a case of human seminal plasma allergy.

Int Arch Allergy Immunol 2012 30;159(2):143-6. Epub 2012 May 30.

Allergy Department, Hospital Universitari Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, Spain.

Background: The existence of IgE binding to dog dander extract without IgE antibodies against the described dog allergens (Can f 1, 2, 3 and 4) implies the presence of other dog allergens yet to be identified. Recently, an IgE-binding protein was isolated from dog urine and identified as prostatic kallikrein; it has been named Can f 5. Cross-reactivity between a dog dander allergen and human prostate-specific antigen (PSA) has been described. The aim of this study was to identify the dog dander allergen that presents cross-reactivity with PSA and demonstrate its clinical relevance in our patient with human seminal plasma allergy.

Methods: SDS-PAGE immunoblotting and inhibition tests were performed. Mass spectrometry was carried out to identify the protein involved in the allergy reactions.

Results: SDS-PAGE immunoblotting-inhibition with an IgE-binding protein from dog prostatic secretion showed total IgE binding inhibition to a 28-kDa IgE-reactive band identified as PSA. The electroeluted protein from dog prostatic secretion was identified by mass spectrometry as Can f 5. IgE immunoblotting of human seminal plasma incubated with the serum of the patient revealed two IgE-binding bands (28 and 32.7 kDa). Both SDS-PAGE immunoblotting inhibition assays, with human seminal plasma or purified PSA in solid phase, showed complete IgE binding inhibition when the serum of the anaphylactic patient was preincubated with dog dander extract or recombinant Can f 5.

Conclusions: The dog dander allergen that shows cross-reactivity with human PSA has been characterized and turns out to be the recently described Can f 5. We demonstrated the clinical relevance of this cross-reactivity in a patient.
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http://dx.doi.org/10.1159/000336388DOI Listing
December 2012

Anti-TIF1γ antibodies (anti-p155) in adult patients with dermatomyositis: comparison of different diagnostic assays.

Ann Rheum Dis 2012 Jun 30;71(6):993-6. Epub 2012 Jan 30.

Department of Internal Medicine, Vall d’Hebron General Hospital. Universitat Autonoma de Barcelona, Barcelona, Spain.

Background: A new myositis-specific autoantibody (anti-p155) directed against transcriptional intermediary factor 1 γ (TIF1γ) has been described as a good marker of cancer-associated myositis (CAM).

Objective: To analyse the feasibility of detecting this autoantibody in patient serum samples using new assays with commercially available recombinant TIF1γ.

Methods: The study included 90 Spanish patients with dermatomyositis (DM), classified as clinically amyopathic DM, CAM, or DM without cancer. Anti-TIF1γ antibodies were detected by ELISA and immunoblot techniques and compared with anti-p155 antibody detection by protein immunoprecipitation assays with radiolabelled HeLa cells. The κ coefficient was used to compare the agreement between the different tests.

Results: Serum samples from 23 (25.6%) and 20 (22.2%) patients with DM recognised TIF1γ by ELISA and immunoblot, respectively. ELISA (κ=0.91) and immunoblot (κ=0.88) showed excellent agreement with immunoprecipitation analysis (anti-p155). Good concordance (κ=0.91) was also seen between ELISA and immunoblot.

Conclusions: Excellent agreement was found between anti-p155 detected by immunoprecipitation and anti-TIF1γ detected by ELISA or immunoblot. These data indicate that identification of this autoantibody can be reliably performed in a standard laboratory setting, with potential application in clinical practice for cancer screening in adult patients with DM.
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http://dx.doi.org/10.1136/annrheumdis-2011-200871DOI Listing
June 2012