Publications by authors named "António Marinho"

49 Publications

Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases.

Authors:
Guillermo Barturen Sepideh Babaei Francesc Català-Moll Manuel Martínez-Bueno Zuzanna Makowska Jordi Martorell-Marugán Pedro Carmona-Sáez Daniel Toro-Domínguez Elena Carnero-Montoro María Teruel Martin Kerick Marialbert Acosta-Herrera Lucas Le Lann Christophe Jamin Javier Rodríguez-Ubreva Antonio García-Gómez Jorge Kageyama Anne Buttgereit Sikander Hayat Joerg Mueller Ralf Lesche Maria Hernandez-Fuentes Maria Juarez Tania Rowley Ian White Concepción Marañón Tania Gomes Anjos Nieves Varela Rocío Aguilar-Quesada Francisco Javier Garrancho Antonio López-Berrio Manuel Rodriguez Maresca Héctor Navarro-Linares Isabel Almeida Nancy Azevedo Mariana Brandão Ana Campar Raquel Faria Fátima Farinha António Marinho Esmeralda Neves Ana Tavares Carlos Vasconcelos Elena Trombetta Gaia Montanelli Barbara Vigone Damiana Alvarez-Errico Tianlu Li Ricardo Blanco Alonso Alfonso Corrales Martínez Fernanda Genre Raquel López Mejías Miguel A Gonzalez-Gay Sara Remuzgo Begoña Ubilla Garcia Ricard Cervera Gerard Espinosa Ignasi Rodríguez-Pintó Ellen De Langhe Jonathan Cremer Rik Lories Doreen Belz Nicolas Hunzelmann Niklas Baerlecken Katja Kniesch Torsten Witte Michaela Lehner Georg Stummvoll Michael Zauner Maria Angeles Aguirre-Zamorano Nuria Barbarroja Maria Carmen Castro-Villegas Eduardo Collantes-Estevez Enrique de Ramon Isabel Díaz Quintero Alejandro Escudero-Contreras María Concepción Fernández Roldán Yolanda Jiménez Gómez Inmaculada Jiménez Moleón Rosario Lopez-Pedrera Rafaela Ortega-Castro Norberto Ortego Enrique Raya Carolina Artusi Maria Gerosa Pier Luigi Meroni Tommaso Schioppo Aurélie De Groof Julie Ducreux Bernard Lauwerys Anne-Lise Maudoux Divi Cornec Valérie Devauchelle-Pensec Sandrine Jousse-Joulin Pierre-Emmanuel Jouve Bénédicte Rouvière Alain Saraux Quentin Simon Montserrat Alvarez Carlo Chizzolini Aleksandra Dufour Donatienne Wynar Attila Balog Márta Bocskai Magdolna Deák Sonja Dulic Gabriella Kádár László Kovács Qingyu Cheng Velia Gerl Falk Hiepe Laleh Khodadadi Silvia Thiel Emanuele de Rinaldis Sambasiva Rao Robert J Benschop Chris Chamberlain Ernst R Dow Yiannis Ioannou Laurence Laigle Jacqueline Marovac Jerome Wojcik Yves Renaudineau Maria Orietta Borghi Johan Frostegård Javier Martín Lorenzo Beretta Esteban Ballestar Fiona McDonald Jacques-Olivier Pers Marta E Alarcón-Riquelme

Arthritis Rheumatol 2020 Dec 8. Epub 2020 Dec 8.

Department of Medical Genomics, Center for Genomics and Oncological Research (GENYO), Granada, Spain.

Objective: Clinical heterogeneity, a hallmark of systemic autoimmune diseases (SADs) impedes early diagnosis and effective treatment, issues that may be addressed if patients could be grouped into a molecular defined stratification.

Methods: With the aim of reclassifying SADs independently of the clinical diagnoses, unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data of 955 patients with 7 SADs and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed for 6 and 14 months to validate the results and analyze if cluster assignment changed or not with time.

Results: Four clusters were identified and validated. Three were pathological representing 'inflammatory', 'lymphoid', and 'interferon' patterns each including all diagnoses and defined by genetic, clinical, serological, and cellular features. A fourth cluster with no specific molecular pattern associated with low activity, and accumulated also healthy controls. A longitudinal and independent inception cohort showed a relapse-remission pattern, where patients remained in their pathological cluster, moving only to the healthy one, thus showing that with time, the molecular clusters remain stable and that single pathogenic molecular signatures characterize each individual patient.

Conclusions: Patients with SADs can be jointly stratified into three stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of therapy non-responsiveness marking a paradigm shift in our view of SADs.
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http://dx.doi.org/10.1002/art.41610DOI Listing
December 2020

Subclinical ventricular dysfunction in rheumatoid arthritis.

Int J Cardiovasc Imaging 2021 Mar 14;37(3):847-859. Epub 2020 Oct 14.

Department of Surgery and Physiology, Cardiovascular Research and Development Center, Faculty of Medicine, University of Porto, Porto, Portugal.

Patients with rheumatoid arthritis (RA) are at higher risk for having underdiagnosed heart failure, however there are no recommendations regarding echocardiographic screening. We aimed to determine the prevalence of subclinical ventricular dysfunction in RA applying current echocardiographic guidelines, its association with patients' characteristics, biomarkers and prognostic parameters and compare the 2016 guidelines to the recommendations from 2009. Prospective study of RA patients without known heart disease, categorized as preserved ventricular function (PVF), systolic dysfunction (SD), isolated diastolic dysfunction (DD) or indeterminate diastolic function (IDF) as per the 2016 echocardiography guidelines-or any ventricular dysfunction (AVD) comprehending the last 3. The median age was 58 years and 78% were females. The majority had PVF (73%), followed by DD (13%), IDF (11%) and SD (4%). Concordance with the 2009 echocardiographic guidelines was low. Compared with PVF, AVD patients were older (65 vs 55 years, p < 0.001), had a higher prevalence of hypertension and dyslipidaemia (56% vs 38%, p = 0.003 and 60% vs 41%, p = 0.002, respectively). In multivariable analysis, age (particularly > 57 years) was the only independent predictor of AVD or DD. AVD was significantly associated with higher NT-proBNP and lower distance in 6-min walk test. There were no significant independent associations between characteristics of RA disease and ventricular function. A total of 17% of RA patients without known cardiovascular disease presented subclinical systolic or diastolic dysfunction, which was associated with older age. The echocardiographic screening may have clinical value in identifying subclinical ventricular dysfunction, especially in older RA patients.
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http://dx.doi.org/10.1007/s10554-020-02057-3DOI Listing
March 2021

Safety and visual outcomes following Iris-claw phakic intraocular lens bilensectomy.

Eur J Ophthalmol 2020 Jul 25:1120672120944033. Epub 2020 Jul 25.

Cornea, Cataract and Refractive Surgery Department, VISSUM, Alicante, Spain.

Purpose: To evaluate the visual outcomes, safety, efficacy, and causes of bilensectomy for iris fixated phakic intraocular lenses (pIOLs).

Methods: This was a two center consecutive retrospective study that included 43 eyes that underwent iris-claw pIOL bilensectomy. Patients with follow up less than 4 months were excluded from the study. Uncorrected, corrected visual acuity (UCVA, CDVA), refractive outcomes, efficacy, safety (number of eyes in which the postoperative CDVA was worse than the preoperative CDVA), endothelial cell density (ECD), causes of bilensectomy, the time between the implantation of the pIOL and bilensectomy, intra and postoperative complications were analyzed.

Results: There was a statistically significant improvement in UCVA and CDVA after surgery ( = 0.001). The efficacy index was 0.7, four eyes had a postoperative CDVA worse than the preoperative CDVA. The mean spherical equivalent 1 year after bilensectomy was -0.78 ± 1.70 D. There was a statistically significant endothelial cell loss after iris claw lens bilensectomy ( = .003). Cataract development and endothelial cell loss were the only reasons for bilensectomy. The mean time between pIOL implantation and bilensectomy was 12.2 ± 5.5 years. One patient had corneal edema 8 months after surgery and one had a retinal detachment 11 months after surgery.

Conclusion: Bilensectomy was successful in improving UCVA and CDVA with an acceptable refractive outcome. Significant loss of ECD was found after surgery. The results recommend a larger ACD as selection criteria when choosing to implant an Artisan lens, and a close postoperative monitoring of the endothelial cell count.
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http://dx.doi.org/10.1177/1120672120944033DOI Listing
July 2020

Variable immunodeficiency study: Evaluation of two European cohorts within a variety of clinical phenotypes.

Immunol Lett 2020 07 25;223:78-88. Epub 2020 Apr 25.

Department of Immunology, IML and IdSSC, Hospital Clínico San Carlos, Madrid, Spain; Department of Immunology, Ophthalmology and ENT, School of Medicine, Complutense University, Madrid, Spain; Immunodeficiency Interdepartmental Group (GIID), Madrid, Spain. Electronic address:

Introduction: Given the wide heterogeneity of common variable immunodeficiency (CVID), several groups have proposed clinical and immunological classifications to better define follow-up and prognostic algorithms. The present study aims to validate recent clinical and laboratory algorithms, based on different combinations of CVID biomarkers, to provide more personalized treatment and follow-up strategies.

Methods: We analysed clinical and immunological features of 80 patients with suspected or diagnosed CVID, in two reference centres of Portugal and Spain. Clinical manifestations were categorized into clinical phenotyping proposed by Chapel et al. [1] that included cytopenia; polyclonal lymphocytic infiltration; unexplained enteropathy; and no disease-related complications.

Results: 76% of patients in our cohort entered one of the four categories of clinical phenotyping, without overlap (cytopenia; polyclonal lymphocytic infiltration; unexplained enteropathy; and no disease-related complications). The most prominent phenotype was "cytopenia" (40%) followed by "polyclonal lymphocytic infiltration" (19%). The remaining 24% patients of our cohort had overlap of 2 clinical phenotypes (cytopenia and unexplained enteropathy mainly). A delay of CVID diagnosis in more than 6 years presented 3.7-fold higher risk of developing lymphoproliferation and/or malignancy (p < 0.05), and was associated with increased CD8CD45RO  T-lymphocytes (p < 0.05). An association between decreased switched-memory B cells with lymphoproliferation and malignancy was observed (p < 0.03 and p < 0.05, respectively). CD4  T-lymphocytopenia correlated with autoimmune phenotype, with 30% prevalence (p < 0.05). HLA-DR7 expression was related to CVID onset in early life in our patients (13 vs 25 years), and DQ2.5 or DQ2.2 with unexplained enteropathy (p < 0.05).

Conclusions: The phenotypic and genetic study is crucial for an adequate clinical orientation of CVID patients. In these two independent cohorts of patients, classification based in clinical and laboratory algorithms, provides more personalized treatment and follow-up strategies.
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http://dx.doi.org/10.1016/j.imlet.2020.03.006DOI Listing
July 2020

Not All ENT Granulomas Are Wegener's - Keep Tuberculosis in Mind.

Eur J Case Rep Intern Med 2020 19;7(3):001469. Epub 2020 Feb 19.

Clinical Immunology Unit, Hospital de Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal.

affects the middle ear in rare cases and is a challenging diagnosis. In this case, we present a 57-year-old patient diagnosed with anti-neutrophil cytoplasmic antibody (ANCA)-negative granulomatosis with polyangiitis (GPA) following a biopsy result of nasal granulomas, who was immediately started on immunosuppressive treatment. Years later, she developed progressive hypoacusis. Magnetic resonance imaging (MRI) revealed an extensive mass in the tympanic cavity extending to the mastoid. A biopsy of the mass was positive for Immunosuppressants were weaned and the patient was started on anti-tuberculous therapy with resolution of the complaints and findings. Tuberculous infections are difficult to diagnose and frequently mimic other illnesses, but in our case, we believe that an indolent tuberculous process was present from the beginning and evolved under immunosuppressive therapy.

Learning Points: The differential diagnosis of rhinosinus granulomatous findings includes inflammatory and infectious diseases (for example, tuberculous infections), in addition to neoplasms, cocaine abuse and trauma.A comprehensive differential diagnosis list is essential to mitigate diagnostic errors, especially in patients where auto-immune studies are negative or there is any doubt in the diagnosis.Latent tuberculosis screening should be a concern for physicians treating patients with immunosuppressive therapy, especially in endemic countries.
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http://dx.doi.org/10.12890/2020_001469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083184PMC
February 2020

Inclusion Body Myositis Treated with Alemtuzumab.

Eur J Case Rep Intern Med 2019 12;6(12):001368. Epub 2019 Dec 12.

Centro Hospitalar do Porto, Porto, Portugal.

Inclusion body myositis (IBM) is a chronic inflammatory myopathy with a progressive course. It is more common in the later years of life and usually presents with limb weakness. We present the case of a patient who developed proximal weakness in the lower limbs and, four years later, facial asymmetry. Blood analysis revealed high lactate dehydrogenase and creatinine kinase values. The diagnosis was obtained through muscle biopsy which met the histological criteria for IBM. The patient started treatment with alemtuzumab, leading to stabilisation of the symptoms in two years.

Learning Points: IBM should be considered in the differential diagnosis of muscle weakness.Patients may present uncommon symptoms, such as prominent facial involvement.Alemtuzumab may potentially be beneficial in limiting the progression of IBM.
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http://dx.doi.org/10.12890/2019_001368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936915PMC
December 2019

Pulmonary sequestration: Two case reports.

Rev Port Cardiol 2019 08 3;38(8):611-612. Epub 2019 Nov 3.

Serviço de Cardiologia Pediátrica, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

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http://dx.doi.org/10.1016/j.repc.2018.09.013DOI Listing
August 2019

Impact of Treatment Modality on Vascular Function in Coarctation of the Aorta: The LOVE - COARCT Study.

J Am Heart Assoc 2019 04;8(7):e011536

7 Department of Cardiology Boston Children's Hospital and Harvard Medical School Boston MA.

Background Optimally treated patients with coarctation of the aorta remain at risk for late vascular dysfunction. The effect of treatment modality on vascular function is unknown. The LOVE-COARCT (Long-term Outcomes and Vascular Evaluation After Successful Coarctation of the Aorta Treatment) study was done to compare vascular function in patients with coarctation of the aorta treated with surgery, balloon dilation (BD), or stent implantation. Methods and Results In treated coarctation of the aorta patients without residual coarctation, we prospectively compared aortic stiffness by applanation tonometry and cardiac magnetic resonance; endothelial function by endothelial pulse amplitude testing; blood pressure ( BP ) phenotype by office BP , ambulatory BP monitoring, and BP response to exercise; left ventricular mass by cardiac magnetic resonance; and blood biomarkers of endothelial function, inflammation, vascular wall function, and extracellular matrix. Participants included 75 patients treated with surgery (n=28), BD (n=23), or stent (n=24). Groups had similar age at enrollment, coarctation of the aorta severity, residual gradient, and metabolic profile, but differed by age at treatment. Prevalence of systemic hypertension, aortic stiffness, endothelial function, and left ventricular mass were similar among treatment groups. However, BD patients had more-distensible ascending aortas, lower peak systolic BP during exercise, less impairment in diurnal BP variation, and lower inflammatory biomarkers. Results were unchanged after adjustment for potential confounders, including age at treatment. Conclusions In our cohort of patients without residual coarctation, treatment modality was not associated with major vascular outcomes, even though there were some favorable vascular characteristics in the BD patients. Although this suggests that choice of treatment modality should continue to be driven by likelihood of achieving a good anatomical result, more long-term studies are required to assess the clinical significance of the more-optimal results of secondary markers of vascular function in BD patients. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 03262753.
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http://dx.doi.org/10.1161/JAHA.118.011536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509735PMC
April 2019

Signs heralding appearance of thymomas after extended thymectomy for myasthenia gravis.

Neurol Clin Pract 2019 Feb;9(1):48-52

Departments of Neurology (ES, AMS) and Pathology (CL), Clinical Immunology (A. Marinho) Hospital Santo Antonio/ Centro Hospitalar Universitario do Porto; Instituto de Ciencias Biomedicas de Abel Salazar (ES, AMS, GG), University of Porto, Portugal; Institute of Pathology (PS), University Medical Center Göttingen, University of Göttingen, Germany; Neurosciences Group (NW, MIL), Nuffield Department of Clinical Neurology, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, UK; and Institute of Pathology (A. Marx), University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany.

Purpose Of Review: Thymomas appear very rarely after extended thymectomy for early-onset myasthenia gravis (EOMG). We describe 2 such cases that highlight potential early warning signs.

Recent Findings: In their 20s, one woman and one man developed EOMG (AChR antibody-positive), requiring extended transsternal removal of hyperplastic thymi at ages 35 and 27, respectively. Their myasthenia gravis was readily controlled for the next 10 and 7 years before deteriorating in both, with appearance of late clinical features and anticytokine autoantibodies suggesting underlying thymomas, namely respiratory infections, genital herpes, chronic candidiasis, and alopecia in the woman and erythroderma and lichen planus in the man, followed by , , and cytomegalovirus infections plus chronic hepatitis during intensifying immunosuppressive therapy. Type B thymomas were then detected. Despite surgery or radiotherapy, and intensive drug therapy, the patients died 7 and 1 years later.

Summary: Certain infections/dermatologic manifestations that associate with long-standing thymomas may herald their late appearance, despite previous thymectomy.
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http://dx.doi.org/10.1212/CPJ.0000000000000551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382375PMC
February 2019

Scleromyxoedema: the importance of physical examination.

BMJ Case Rep 2018 Oct 12;2018. Epub 2018 Oct 12.

Unit of Clinical Immunology, Centro Hospitalar Porto, Porto, Portugal.

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http://dx.doi.org/10.1136/bcr-2018-227144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194430PMC
October 2018

Recurrent pregnancy loss and vitamin D: A review of the literature.

Am J Reprod Immunol 2018 11 27;80(5):e13022. Epub 2018 Jul 27.

UMIB, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.

Recurrent pregnancy loss (RPL) affects approximately 1%-2% of reproductive women. Auto- and cellular immune responses seem to be associated with RPL. Vitamin D (VD) has been shown to play a role in the modulation of the immune system. Effects of VD deficiency (VDD) in pregnancy have been associated with preeclampsia, gestational diabetes, fetal growth restriction, preterm labor, and sporadic spontaneous abortion (SA). We systematically reviewed articles that studied women with 2 or more SA and its association with VD. Eleven studies were included. Studies reported a high prevalence of VD insufficiency (VDI) or VDD in women with RPL and suggested that this could be associated with immunological dysregulation and consequently with RPL. Immunological benefits were reported in the peripheral blood of women with RPL after VD exposure. Thus, it is possible to speculate a beneficial role for VD supplementation in RPL. It seems that there are not differences in the vitamin D receptor (VDR) and CYP27B1 expression in endometrium of women with RPL but, in villous and decidual tissues, RPL women seem to have a decreased expression of VDR and, perhaps, a decreased expression of CYP27B1. Further randomized controlled studies are required to investigate the association between VDD or VDI and RPL.
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http://dx.doi.org/10.1111/aji.13022DOI Listing
November 2018

Rare forms of pediatric congenital right ventricular fistulae.

Rev Port Cardiol 2018 May 21;37(5):453-454. Epub 2018 Apr 21.

Serviço de Cardiologia Pediátrica, Hospital Pediátrico de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

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http://dx.doi.org/10.1016/j.repc.2017.01.015DOI Listing
May 2018

Incidental finding in a newborn with respiratory distress.

Einstein (Sao Paulo) 2017 Jul-Sep;15(3):378-379. Epub 2017 Jun 12.

Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

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http://dx.doi.org/10.1590/S1679-45082017AI4001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823058PMC
May 2018

Inflammatory myopathy associated with myasthenia gravis with and without thymic pathology: Report of four cases and literature review.

Autoimmun Rev 2017 Jun 13;16(6):644-649. Epub 2017 Apr 13.

Nuffield Department of Clinical Neurosciences, Oxford University Hospitals and University of Oxford, Oxford, United Kingdom. Electronic address:

Introduction: The association of myasthenia gravis (MG) and inflammatory myopathy is rare and often only one of the diseases is diagnosed. Thymus pathology may be in the origin of such disease association.

Methods: We described four patients with both MG and inflammatory myopathy.

Results: These cases correspond to 2.3% of our MG cohort. Case 1: MG, polymyositis and thymolipoma; case 2: MG and necrotizing myopathy without thymic pathology on a background of scleroderma, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia (CREST); case 3: MG and dermatomyositis without thymic pathology; case 4: MG and dermatomyositis with type C thymoma.

Discussion: The recognition of these neuromuscular co-morbidities contributes to (i) understanding their pathogenic mechanisms, (ii) developing better management approaches and (iii) further improving disease outcomes.
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http://dx.doi.org/10.1016/j.autrev.2017.04.009DOI Listing
June 2017

Topics on vitamin D in systemic lupus erythematosus: analysis of evidence and critical literature review.

Immunol Res 2017 04;65(2):495-511

UMIB, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), U.Porto, 4099-001, Porto, Portugal.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multiorgan inflammation, linked to the loss of immune tolerance to self-antigens and the production of a diversity of autoantibodies. The phenotype and progression of SLE have been linked to a combination of environmental, genetic, and hormonal factors. One such environmental factor is vitamin D, a vital hormone with well-established effects on mineral metabolism, skeletal health, and effects on cardiovascular system. The purpose of this article is to make the analysis of evidence and literature review of the pleomorphic effects of Vitamin D in SLE. The article is structured in topics of interest based in the authors' opinion and summarizes the evidence of studies and trials of vitamin D in SLE.
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http://dx.doi.org/10.1007/s12026-017-8903-5DOI Listing
April 2017

Serum 25-hydroxyvitamin D levels in a healthy population from the North of Portugal.

J Steroid Biochem Mol Biol 2018 01 5;175:97-101. Epub 2016 Nov 5.

Unit for Multidisciplinary Research in Biomedicine (UMIB), Abel Salazar Institute of Biomedical Sciences (ICBAS), University of Porto (UP), Porto, Portugal; Unidade de Imunologia Clínica (UIC), Centro Hospitalar do Porto-Hospital de Santo António (CHP-HSA), Porto, Portugal; Department of Neurology, Centro Hospitalar do Porto-Hospital de Santo António (CHP-HSA), Porto, Portugal.

Vitamin D status in human populations has become a matter of great concern, in the wake of a multitude of published works that document widespread vitamin D deficiency across Europe, even in countries with abundant sunlight. In Portugal there are no measures of 25-hydroxyvitamin D - 25(OH)D - levels in the general adult population. The purpose of this study was to measure 25(OH)D levels in a healthy population cohort and investigate the possible association with season and selected demographic and laboratory measurements. A cohort of 198 participants (18-67 years) living in the north of Portugal, Porto, conducted in July and August 2015 (summer time) and April 2016 (winter time) was studied to evaluate serum 25(OH)D levels. Sociodemographic characteristics (age, sex and body mass index) and season of the year were taken into account as possible 25(OH)D levels codeterminants. In the whole group, the mean level of serum 25(OH)D was 55.4±23.4 nmol/L, with 48% of the population presenting levels compatible with vitamin D deficiency (below 50 nmol/L). In the winter period, this value reaches 74%. No statistically significant differences were observed between genders (57.4±23.9 vs. 53.3±22.8 nmol/L, p=0.219) as well as no statistically significant correlation was found between age and 25(OH)D levels (p=0.349). As expected higher levels of 25(OH)D were observed in summer than in winter (68.2±21.5 vs. 42.2±16.9 nmol/L; p<0.0001). Serum 25(OH)D levels were significantly lower in obese compared to non-obese subjects (46.6±17.6 vs. 57.7±24.2 nmol/L, p=0.012). Vitamin D deficiency is prevalent in this area, affecting almost half of the population. Body mass index and season are predictors for lower 25-hydroxyvitamin D levels and vitamin D status. An effective strategy to prevent vitamin D deficiency and insufficiency should be envisaged and implemented in our population.
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http://dx.doi.org/10.1016/j.jsbmb.2016.11.005DOI Listing
January 2018

Vitamin D supplementation effects on FoxP3 expression in T cells and FoxP3/IL-17A ratio and clinical course in systemic lupus erythematosus patients: a study in a Portuguese cohort.

Immunol Res 2017 02;65(1):197-206

UMIB, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), UPorto, Porto, Portugal.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multi-organ inflammation, linked to loss of immune tolerance to self-antigens and the production of a diversity of autoantibodies, with a negative impact on the patients' quality of life. Regulatory T cells have been reported as deficient in number and function in SLE patients. However, some authors also described an enrichment of this cell type. The hypothesis that certain forms of autoimmunity may result from a conversion of Treg cells into a Th17 cell phenotype has been suggested by some studies. In fact, in SLE patients' sera, the IL-17 levels were observed as abnormally high when compared with healthy individuals. Environmental factors, such as vitamin D, that is considered a potential anti-inflammatory agent, combined with genetic and hormonal characteristics have been associated with SLE phenotype and with disease progression. The aim of this study was to evaluate the effect of vitamin D supplementation on FoxP3 expression and IL-17A-producing T cells, through FoxP3/IL-17A ratio. Additionally, disease evolution, serum vitamin D levels, serum autoantibodies levels and calcium metabolism (to assure safety) were also studied. We assessed 24 phenotypically well-characterized SLE patients. All patients were screened before vitamin D supplementation and 3 and 6 months after the beginning of this treatment. Peripheral blood lymphocyte's subsets were analysed by flow cytometry. Serum 25(OH)D levels significantly increased under vitamin D supplementation (p = 0.001). The FoxP3/IL-17A ratio in SLE patients after 6 months of vitamin D supplementation was higher than that in the baseline (p < 0.001). In conclusion, this study demonstrated that vitamin D supplementation provided favourable, immunological and clinical impact on SLE.
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http://dx.doi.org/10.1007/s12026-016-8829-3DOI Listing
February 2017

Eosinophilic fasciitis after parasite infection.

Reumatologia 2016 24;54(1):38-41. Epub 2016 Mar 24.

Centro Hospitalar Baixo Vouga, Aveiro, Portugal.

Eosinophilic fasciitis is a systemic inflammatory disease characterized by symmetrical swelling and skin induration of the distal portions of the arms and/or legs, evolving into a scleroderma-like appearance, accompanied by peripheral blood eosinophilia. It is a rare disease with a poorly understood etiology. Corticosteroid treatment remains the standard therapy, either taken alone or in association with an immunosuppressive drug. This paper presents a case of a male patient with palpebral edema and marked eosinophilia, diagnosed with intestinal parasitic infection in October 2006. He was treated with an antiparasitic drug, but both the swelling and the analytical changes remained. This was followed by a skin and muscle biopsy, which turned out to be compatible with eosinophilic fasciitis. There was progressive worsening of the clinical state, with stiffness of the abdominal wall and elevated inflammatory parameters, and the patient was referred to the Immunology Department, medicated with corticosteroids and methotrexate. Over the years there were therapeutic adjustments and other causes were excluded. Currently the patient continues to be monitored, and there is no evidence of active disease. The case described in this article is interesting because of the diagnosis of eosinophilic fasciitis probably associated/coexisting with a parasite infection. This case report differs from others in that there is an uncommon cause associated with the onset of the disease, instead of the common causes such as trauma, medication, non-parasitic infections or cancer.
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http://dx.doi.org/10.5114/reum.2016.58761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847322PMC
July 2016

The Protective Role of HLA-DRB1(∗)13 in Autoimmune Diseases.

J Immunol Res 2015 29;2015:948723. Epub 2015 Oct 29.

Immunogenetics Laboratory, Instituto de Ciências Biomédicas Abel Salazar-Universidade do Porto (ICBAS-UP), Rua de Jorge Viterbo Ferreira No. 228, 4050-313 Porto, Portugal ; Unit for Multidisciplinary Research in Biomedicine (UMIB), Abel Salazar Institute of Biomedical Sciences (ICBAS), University of Porto (UP), Rua de Jorge Viterbo Ferreira No. 228, 4050-313 Porto, Portugal.

Autoimmune diseases (AIDs) are characterized by a multifactorial aetiology and a complex genetic background, with the MHC region playing a major role. We genotyped for HLA-DRB1 locus 1228 patients with AIDs-213 with Systemic Lupus Erythematosus (SLE), 166 with Psoriasis or Psoriatic Arthritis (Ps + PsA), 153 with Rheumatoid Arthritis (RA), 67 with Systemic Sclerosis (SSc), 536 with Multiple Sclerosis (MS), and 93 with Myasthenia Gravis (MG) and 282 unrelated controls. We confirmed previously established associations of HLA-DRB1(∗)15 (OR = 2.17) and HLA-DRB1(∗)03 (OR = 1.81) alleles with MS, HLA-DRB1(∗)03 with SLE (OR = 2.49), HLA-DRB1(∗)01 (OR = 1.79) and HLA-DRB1(∗)04 (OR = 2.81) with RA, HLA-DRB1(∗)07 with Ps + PsA (OR = 1.79), HLA-DRB1(∗)01 (OR = 2.28) and HLA-DRB1(∗)08 (OR = 3.01) with SSc, and HLA-DRB1(∗)03 with MG (OR = 2.98). We further observed a consistent negative association of HLA-DRB1(∗)13 allele with SLE, Ps + PsA, RA, and SSc (18.3%, 19.3%, 16.3%, and 11.9%, resp., versus 29.8% in controls). HLA-DRB1(∗)13 frequency in the AIDs group was 20.0% (OR = 0.58). Although different alleles were associated with particular AIDs, the same allele, HLA-DRB1(∗)13, was underrepresented in all of the six diseases analysed. This observation suggests that this allele may confer protection for AIDs, particularly for systemic and rheumatic disease. The protective effect of HLA-DRB1(∗)13 could be explained by a more proficient antigen presentation by these molecules, favouring efficient clonal deletion during thymic selection.
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http://dx.doi.org/10.1155/2015/948723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641944PMC
August 2016

Sarcoid lung.

BMJ Case Rep 2015 Jun 11;2015. Epub 2015 Jun 11.

Clinical Immunology Unit, Oporto Central Hospital, Oporto, Portugal.

Sarcoidosis is a multisystem disease with a varied clinical presentation. The lung disease is common and is responsible for most of the morbidity and mortality associated with sarcoidosis. Tuberculosis remains a prevalent disease in some countries, such as Portugal. There are reports of sequential occurrence of these identities. The authors present a case of a patient with lymphatic tuberculosis who, some years after treatment of this infection, was diagnosed with sarcoidosis in an atypical pseudotumoural presentation.
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http://dx.doi.org/10.1136/bcr-2015-209566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480137PMC
June 2015

Chronic alveolar haemorrhage in a paediatric patient: a diagnostic and treatment challenge.

BMJ Case Rep 2015 Apr 21;2015. Epub 2015 Apr 21.

Department of Pediatrics, Centro Hospitalar do Porto, Porto, Portugal.

Pulmonary haemosiderosis is characterised by chronic alveolar haemorrhage, which can lead to serious cardiorespiratory complications. Although considered idiopathic in most patients, there are many possible aetiologies. We present a case of an 18-year-old woman with pulmonary haemosiderosis since 4 years of age, with an inconclusive initial study, who was treated with systemic corticosteroids and hydroxychloroquine until the age of 12 years, and azathioprine since then. Multiple exacerbations led to interstitial lung disease with restrictive functional pattern. Unilateral cochlear deafness was diagnosed at the age of 12 years and occasional polyarthralgias were recorded. When she was 16 years of age the study revealed an atypical myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) pattern. Cyclophosphamide and rituximab were administered with resolution of respiratory insufficiency and functional disability, without new episodes of alveolar haemorrhage. This case of chronic pulmonary haemorrhage was revealed to be an ANCA vasculitis, the diagnosis of which was possible only after 12 years of symptoms, with clinical and functional improvement with the association of cyclophosphamide and rituximab.
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http://dx.doi.org/10.1136/bcr-2014-206856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420834PMC
April 2015

Facing the challenges of ventricular hypertrophy: the eyes don't lie.

Rev Port Cardiol 2014 Oct 1;33(10):647.e1-5. Epub 2014 Oct 1.

Cardiology Department, Centro Hospitalar do Porto, Porto, Portugal.

We describe the case of a 47-year-old man with new-onset heart failure who was found to have severe biventricular wall thickening. We present comprehensive data from invasive and non-invasive multimodality imaging, genetic and histologic tests, and briefly describe their importance in the final diagnosis. To our knowledge, this is the first case of the Portuguese variant of familial amyloid polyneuropathy presenting with heart failure in the fifth decade of life. This is an unusual case report, but also an illustration of how to approach any patient with suspected infiltrative cardiomyopathy.
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http://dx.doi.org/10.1016/j.repc.2014.03.011DOI Listing
October 2014

[Diagnosis recommendations for late-onset Pompe disease].

Acta Med Port 2014 Jul-Aug;27(4):525-9. Epub 2014 Aug 29.

Serviço de Medicina 1. Hospital de Santa Maria. Centro Hospitalar Lisboa Norte. Lisboa. Portugal.

Introduction: Pompe disease is a progressive and debilitating autossomal recessive myopathy due to mutations in lysossomal acid-α-glucosidase. Its late-onset form has a heterogeneous presentation mimicking other neuromuscular diseases, leading to diagnostic challenge.

Objective: To develop consensus based recommendations for the diagnosis of late-onset Pompe Disease.

Material And Methods: Bibliographic review and analysis of an opinion questionnaire applied to a group of specialists with expertise in the diagnosis of several myopathies and lysossomal storage disorders. Discussed in consensus meeting.

Recommendations: Patients with a progressive limb-girdle weakness, fatigue, cramps and muscle pain should be evaluated with CK levels, electromyography, dynamic spirometry and muscle biopsy in inconclusive cases. Suspected cases and those in which muscle biopsy could not allow other diagnosis should be screened for lysossomal acid-α-glucosidase deficiency with DBS (dried blood spot). The diagnosis should be confirmed by determination of lysossomal acid-α-glucosidase activity in a second sample and lysossomal acid-α-glucosidase gene sequencing.
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July 2016

Antineutrophil cytoplasmatic antibody positive systemic vasculitis in a patient treated with propylthiouracil.

Acta Reumatol Port 2013 Oct-Dec;38(4):302-5

The development of antineutrophil cytoplasmatic antibody (ANCA) during therapy with propylthiouracil (PTU) is not uncommon but occasionally has clinical significance. Risk factors associated with the development of ANCA associated systemic vasculitis when taking PTU have been described. We report and discuss a case with PTU-induced ANCA vasculitis with severe systemic manifestations.
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April 2015

Hypertrophic cardiomyopathy associated with left ventricular noncompaction cardiomyopathy and coronary fistulae: a case report. One genotype, three phenotypes?

Rev Port Cardiol 2013 Nov 21;32(11):919-24. Epub 2013 Nov 21.

Serviço de Cardiologia, Centro Hospitalar Tondela-Viseu, Viseu, Portugal. Electronic address:

The authors present a rare case of hypertrophic cardiomyopathy associated with left ventricular noncompaction cardiomyopathy and coronary artery-left ventricular fistulae in a 42-year-old woman presenting with non-ST-elevation myocardial infarction. Coronary angiography, transthoracic echocardiography and cardiac magnetic resonance revealed the structural abnormalities of the left ventricle and the coronary tree.
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http://dx.doi.org/10.1016/j.repc.2013.05.002DOI Listing
November 2013

Opera glass hands: the phenotype of arthritis mutilans.

BMJ Case Rep 2013 Jul 4;2013. Epub 2013 Jul 4.

Department of Internal Medicine, Centro Hospitalar Porto, Porto, Portugal.

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http://dx.doi.org/10.1136/bcr-2013-200035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736562PMC
July 2013

Artiflex Toric foldable phakic intraocular lens: short-term results of a prospective European multicenter study.

Am J Ophthalmol 2012 Oct 25;154(4):730-739.e2. Epub 2012 Jul 25.

University Eye Clinic Maastricht, Maastricht University Medical Center, The Netherlands.

Purpose: To evaluate the short-term efficacy, predictability, stability, and safety of the foldable Artiflex Toric phakic intraocular lens (pIOL; Ophtec) for the correction of myopia with astigmatism.

Design: Prospective, nonrandomized multicenter study.

Methods: One hundred fifteen eyes of 73 patients were implanted with an Artiflex Toric pIOL. Mean implanted spherical and cylindrical powers were -7.10 ± 2.70 diopters (D) and -2.14 ± 0.80 D, respectively. Total follow-up was 6 months. Outcome parameters included uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), subjective manifest refraction (used for vector analysis), intraocular pressure, and endothelial cell density (ECD).

Results: At 6 months, 99.0% of eyes had a UCVA of ≥20/40, and 81.8% of eyes were ±0.5 D of the intended refraction. In 74.5% postoperative UCVA was equal to or better than preoperative BSCVA; 2 eyes lost 2 or more lines of BSCVA postoperatively because of the development of synechiae. In 75.5% of eyes the remaining cylinder was ±0.5 D. There was a significant decrease in ECD after 3 months (4.8% ± 11.9%), with no additional decline between 3 and 6 months. There were few complications, except for the incidence of pigment and nonpigment precipitates (14.8% and 12.2%, respectively at 6 months). Mean misalignment was 0.6 ± 1.5 degrees (range 0-8).

Conclusions: The Artiflex Toric pIOL effectively and safely corrects myopia and astigmatism in the short term, with stable and predictable visual results after 6 months, when strict inclusion criteria are applied. Deposition of pigment and nonpigment precipitates on the pIOL warrants further investigation.
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http://dx.doi.org/10.1016/j.ajo.2012.04.006DOI Listing
October 2012

Systemic lupus erythematosus, progressive multifocal leukoencephalopathy, and T-CD4+ lymphopenia.

Clin Rev Allergy Immunol 2012 Dec;43(3):302-7

Unidade de Imunologia Clínica, Department of Medicine, Hospital de Santo António, Centro Hospitalar do Porto, Largo do Professor Abel Salazar, nº 2, 4099-001, Porto, Portugal.

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection caused by the reactivation of JC virus and occurs in patients with severe primary or secondary immunosuppression. Recently, PML is becoming relevant in autoimmune disorders, particularly in patients treated with biologic agents. However, systemic lupus erythematosus (SLE) appears to be associated with susceptibility to PML that cannot be entirely explained by the immunosuppressive therapy. The authors present two patients with the diagnosis of SLE and PML: One had a heavy immunosuppressive therapy history, and the other had never experienced biologic or cytotoxic therapeutics. Both patients had a profound T-CD4+ lymphopenia during their clinical history. These two cases emphasize the importance of CD4+ lymphopenia in SLE patients with and without immunosuppressors regarding opportunistic infections.
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http://dx.doi.org/10.1007/s12016-012-8327-xDOI Listing
December 2012

Anti-ro52 antibodies and interstitial lung disease in connective tissue diseases excluding scleroderma.

ISRN Rheumatol 2012 27;2012:415272. Epub 2012 Mar 27.

Unidade de Imunologia Clínica, Hospital de Santo António, Centro Hospitalar do Porto, 4099-001 Porto, Portugal.

Introduction. The presence of anti-Ro52 antibodies has been reported in a wide variety of autoimmune diseases, particularly in myositis, scleroderma, and autoimmune liver diseases. Clinical significance of anti-Ro52 antibodies remains controversial, and studies are lacking for clarifying the association of anti-Ro52 with interstitial lung disease (ILD) in connective tissue diseases (CTD). Objectives. To determine if anti-Ro52 antibodies are associated with ILD in CTD other than scleroderma. Methods. Single-center, retrospective study based on immunoblotting panel analysis and patients clinical records. Results. In our connective tissue disease cohort, 162 patients had immunoblotting panels with anti-Ro52 reactivity analysis, 41 (25,3%) had inclusion criteria. Among the 41 selected sera, 85.4% (n = 35) had anti-Ro52 reactivity. The prevalence of ILD in the positive anti-Ro52 antibodies was 71.4% (n = 25), and 16.7% (n = 1) in the negative anti-Ro52 group (P = 0.018). Overall sensitivity (96.2%), specificity (83.3%), positive (71.4%) and negative (83.3%) predictive values of anti-Ro52 antibodies to determine ILD in CTD is detailed in this study. Conclusion. Ro52 autoantibodies are associated with ILD in CTD excluding scleroderma. We suggest that the presence of anti-Ro52 reactivity in CTD should increase the clinician curiosity for the search of ILD.
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http://dx.doi.org/10.5402/2012/415272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3328145PMC
August 2012

Hypertrophic cranial pachymeningitis and skull base osteomyelitis by pseudomonas aeruginosa: case report and review of the literature.

J Clin Med Res 2012 Apr 23;4(2):138-44. Epub 2012 Mar 23.

Medicine Department, Santo Antonios' Hospital, Largo Prof. Abel Salazar, 4099-001 Porto, Portugal.

Unlabelled: Hypertrophic cranial pachymeningitis (HCP) is an uncommon disorder characterized by localized or diffuse thickening of the dura mater, and it usually presents with multiple cranial neurophaties. It has been associated with a variety of inflammatory, infectious, traumatic, toxic and neoplasic diseases, when no specific cause is found the process is called idiopathic. The infectious cases occur in patients under systemic immunosuppression, which have an evident contiguous source or those who have undergone neurosurgical procedures. We describe a case of a 62-year-old immunosuppressed woman with diabetes and rheumatoid arthritis, which had HCP and osteomyelitis of the skull base caused by pseudomonas aeruginosa, presenting with headache and diplopia. We believe this is the second documented case of pachymeningitis secondary to this microorganism. As a multifactorial disease, it is essencial to determine the specific causative agent of HCP before making treatment decisions, and great care is needed with immunocompromised patients.

Keywords: Pseudomonas aeruginosa; Hypertrophic pachymeningitis; Ophtalmoplegia, optical neuropathy; Osteomyelitis; Skull base.
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http://dx.doi.org/10.4021/jocmr777wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320125PMC
April 2012