Publications by authors named "Claudia Diniz Lopes Marques"

33 Publications

Interleukin-18 in Brazilian Rheumatoid Arthritis Patients: Can Leflunomide Reduce It?

Autoimmune Dis 2021 10;2021:6672987. Epub 2021 May 10.

Laboratory of Immunomodulation and New Therapeutic Approaches (LINAT), Research Group on Immunomodulation and New Therapeutic Approaches Suely Galdino (Nupit SG), Federal University of Pernambuco, Recife, Brazil.

Objectives: Rheumatoid arthritis affects about 1% of the world's population. This is a chronic autoimmune disease. It is predominant in females with progressive joint damage. Immune cells are involved, especially Th1/Th17 lymphocytes and their inflammatory cytokines. These proteins have different functions in the immune system, such as IL-16 is a chemotactic factor; IL-18 can activate NFB transcription producing inflammatory proteins; IL-31 can activate the JAK/STAT pathway which leads to the production of inflammatory factors in chronic diseases; IL-33 promotes IL-16 secretion which causes lymphocyte recruitment, and IL-32 and IL-34 appear to increase TNF secretion by macrophages activation in AR. The aim of this study was to evaluate serum levels of IL-16, IL-18, IL-31, IL-32, IL-33, and IL-34 and compare them with the severity and treatment of RA patients if there are any correlations.

Methods: A total of 140 RA patients and 40 healthy donors were recruited from the Department of Rheumatology at Hospital das Clínicas from the Federal University of Pernambuco. 60 AR patients were naïve for any treatment. Serum cytokine levels were determined using an ELISA kit.

Results: Serum IL-16 ( = 0.0491), IL-18 ( < 0.0001), IL-31 ( = 0.0004), and IL-32 ( = 0.0040) levels were significantly increased in RA patients compared with healthy donors. It was observed that patients using leflunomide had the lowest IL-18 levels, close to controls levels ( = 0.0064).

Conclusion: IL-16, IL-18, IL-31, and IL-32 are increased in the serum of RA patients. IL-18 is at lower levels in those AR who are taking leflunomide as treatment.
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http://dx.doi.org/10.1155/2021/6672987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131162PMC
May 2021

Long-Term Persistence of Serum-Specific Anti-Chikungunya IgM Antibody - A Case Series of Brazilian Patients.

Rev Soc Bras Med Trop 2021 12;54:e0855. Epub 2021 Apr 12.

Universidade Federal de Pernambuco, Hospital das Clínicas, Recife, PE, Brasil.

The persistence of serum-specific anti-chikungunya IgM antibodies (CHIKV-IgM) can vary after chikungunya fever (CHIK) infection. However, the factors related to its production are not yet known. We described a case series drawn up from data collected from 57 patients between 12 and 36 months after the acute phase of CHIK infection in Northeastern Brazil. CHIKV-IgM was detectable in 7/57 (12.3%) patients after 28.3 months of infection. No frequency differences in chronic musculoskeletal manifestations and underlying conditions were detected between patients with or without CHIKV-IgM. CHIKV-IgM was detected for up to 35 months in Brazilian patients after CHIK infection.
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http://dx.doi.org/10.1590/0037-8682-0855-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047711PMC
April 2021

High levels of immunosuppression are related to unfavourable outcomes in hospitalised patients with rheumatic diseases and COVID-19: first results of ReumaCoV Brasil registry.

RMD Open 2021 01;7(1)

Rheumatology, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil.

Objectives: To evaluate risk factors associated with unfavourable outcomes: emergency care, hospitalisation, admission to intensive care unit (ICU), mechanical ventilation and death in patients with immune-mediated rheumatic disease (IMRD) and COVID-19.

Methods: Analysis of the first 8 weeks of observational multicentre prospective cohort study (ReumaCoV Brasil register). Patients with IMRD and COVID-19 according to the Ministry of Health criteria were classified as eligible for the study.

Results: 334 participants were enrolled, a majority of them women, with a median age of 45 years; systemic lupus erythematosus (32.9%) was the most frequent IMRD. Emergency care was required in 160 patients, 33.0% were hospitalised, 15.0% were admitted to the ICU and 10.5% underwent mechanical ventilation; 28 patients (8.4%) died. In the multivariate adjustment model for emergency care, diabetes (prevalence ratio, PR 1.38; 95% CI 1.11 to 1.73; p=0.004), kidney disease (PR 1.36; 95% CI 1.05 to 1.77; p=0.020), oral glucocorticoids (GC) (PR 1.49; 95% CI 1.21 to 1.85; p<0.001) and pulse therapy with methylprednisolone (PR 1.38; 95% CI 1.14 to 1.67; p=0.001) remained significant; for hospitalisation, age >50 years (PR 1.89; 95% CI 1.26 to 2.85; p=0.002), no use of tumour necrosis factor inhibitor (TNFi) (PR 2.51;95% CI 1.16 to 5.45; p=0.004) and methylprednisolone pulse therapy (PR 2.50; 95% CI 1.59 to 3.92; p<0.001); for ICU admission, oral GC (PR 2.24; 95% CI 1.36 to 3.71; p<0.001) and pulse therapy with methylprednisolone (PR 1.65; 95% CI 1.00 to 2.68; p<0.043); the two variables associated with death were pulse therapy with methylprednisolone or cyclophosphamide (PR 2.86; 95% CI 1.59 to 5.14; p<0.018).

Conclusions: Age >50 years and immunosuppression with GC and cyclophosphamide were associated with unfavourable outcomes of COVID-19. Treatment with TNFi may have been protective, perhaps leading to the COVID-19 inflammatory process.
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http://dx.doi.org/10.1136/rmdopen-2020-001461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844930PMC
January 2021

Brazilian recommendations for the use of nonsteroidal anti-inflammatory drugs in patients with axial spondyloarthritis.

Adv Rheumatol 2021 01 19;61(1). Epub 2021 Jan 19.

Universidade Federal de São Paulo (UNIFESP/ EPM), São Paulo, SP, Brazil.

Spondyloarthritis (SpA) is a group of chronic inflammatory systemic diseases characterized by axial and/or peripheral joints inflammation, as well as extra-articular manifestations. Over some decades, nonsteroidal anti-inflammatory drugs (NSAIDs) have been the basis for the pharmacological treatment of patients with axial spondyloarthritis (axSpA). However, the emergence of the immunobiologic agents brought up the discussion about the role of NSAIDs in the management of these patients. The objective of this guideline is to provide recommendations for the use of NSAIDs for the treatment of axSpA. A panel of experts from the Brazilian Society of Rheumatology conducted a systematic review and meta-analysis of randomized clinical trials for 15 predefined questions. The Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations were used, and at least 70% agreement of the voting panel was needed. Fourteen recommendations for the use of NSAIDs in the treatment of patients with axSpA were elaborated. The purpose of these recommendations is to support clinicians' decision making, without taking out his/her autonomy when prescribing for an individual patient.
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http://dx.doi.org/10.1186/s42358-020-00160-6DOI Listing
January 2021

Chikungunya fever and COVID-19: Oral ulcers are a common feature.

Oral Dis 2020 Nov 11. Epub 2020 Nov 11.

Rheumatology Unit, Hospital das Clínicas, Universidade Federal de Pernambuco, Recife, Brazil.

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http://dx.doi.org/10.1111/odi.13717DOI Listing
November 2020

Update on the treatment of musculoskeletal manifestations in chikungunya fever: a guideline.

Rev Soc Bras Med Trop 2020 31;53:e20190517. Epub 2020 Jul 31.

Departamento de Medicina Clínica, Universidade Federal de Pernambuco, Recife, PE, Brasil.

Since the emergence of the chikungunya virus in Brazil in 2014, more than 700,000 cases have been reported throughout the country, corresponding to one-third of all cases reported in the Americas. In addition to its high attack rates, resulting in hundreds of thousands of cases, the disease has high chronicity rates with persistent joint manifestations for more than 3 months, which can spread to more than half of the patients affected in the acute phase. Pain associated with musculoskeletal manifestations, often disabling, has an effect on patients' quality of life at different stages of the disease. Currently, the challenge faced by specialists is identifying the best therapy to be instituted for symptom relief despite the limited number of published intervention studies. In 2016, a multidisciplinary group published pharmacological treatment protocols for pain in patients with chikungunya, which was incorporated into the guidelines for clinical management of the Brazilian Ministry of Health in 2017; in that same year, a consensus was published by the Brazilian Society of Rheumatology about diagnosis and treatment. After 5 years of experience with chikungunya epidemics, in 2019, specialists involved in the protocols of the Brazilian Society of Rheumatology and Brazilian Ministry of Health prepared an update with the main objective of developing flowcharts for the therapeutic approach of musculoskeletal manifestations in adult patients to enable specialists at different levels of healthcare to spread and apply this guideline in a systematic and simplified manner.
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http://dx.doi.org/10.1590/0037-8682-0517-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405653PMC
August 2020

Increased serum levels of galectin-9 in patients with chikungunya fever.

Virus Res 2020 09 18;286:198062. Epub 2020 Jun 18.

Programa de Pós-Graduação em Inovação Terapêutica (PPGIT)/ UFPE, Brazil; Núcleo de Pesquisa em Inovação Terapêutica - Sueli Galdino (Nupit-SG), Brazil.

Chikungunya fever (CHIKF) is an arboviral disease that has caused an epidemic burst of chronic inflammatory joint disease in Latin America in the last few years. Efforts are being spent in understanding the mechanisms by which it may cause such articular damage and in determining possible biomarkers of the disease. Galectins (GAL) are a family of animal lectins with an affinity for beta-galactosides. They have multiple functions including working as receptors in innate immunity and as a control for inflammatory responses in both innate and adaptive immunity. They regulate functions of immune cells, such as lymphocytes and macrophages, which have a main role in the chikungunya inflammatory process. Galectins are also involved in chronification of viral diseases, participate in the immunopathogenesis of chronic joint diseases such as rheumatoid arthritis, and have a role in inflammation in other arboviral diseases, such as dengue. Thus, we intended to determine the serum levels of galectin-1, -3, -4, -7, and -9 in patients with subacute and chronic articular manifestations of CHIKF and to evaluate their associations with clinical manifestations. We evaluated 44 patients with clinical manifestations of CHIKF and serological confirmation with IgM and/or IgG chikungunya virus (CHIKV) antibodies. Forty-nine age- and gender-matched healthy individuals served as controls. Anti-CHIKV IgM and IgG antibodies and galectins serum levels were measured by ELISA. We found higher levels of GAL-9 (patients median 2192 [1500-2631] pg/mL, controls median 46.88 [46.88-46.88] pg/mL, p < 0.0001) and lower levels of GAL-3 (patients median 235.5 [175.5-351.8] pg/mL, controls median 2236.0 [1256.0-2236.0] pg/mL, p < 0.0001) in patients than in controls. There was no statistical difference in levels of GAL-1, -4 and -7 between patients and control groups. There was no difference in GAL-9 serum levels between patients with subacute or chronic symptoms (median 2148 [1500-2722] pg/mL x 2212 [1844-2500] pg/mL, p = 0.3626). A significant association of GAL-9 with joint stiffness, both in its duration and intensity, was found. These results may reflect the participation of GAL-9 in the immunopathogenesis of the inflammatory process in chikungunya fever, as morning stiffness may reflect the systemic inflammatory process.
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http://dx.doi.org/10.1016/j.virusres.2020.198062DOI Listing
September 2020

Revisiting hydroxychloroquine and chloroquine for patients with chronic immunity-mediated inflammatory rheumatic diseases.

Adv Rheumatol 2020 06 9;60(1):32. Epub 2020 Jun 9.

Pontifícia Universidade Católica de Campinas, Campinas, Brazil.

Hydroxychloroquine and chloroquine, also known as antimalarial drugs, are widely used in the treatment of rheumatic diseases and have recently become the focus of attention because of the ongoing COVID-19 pandemic. Rheumatologists have been using antimalarials to manage patients with chronic immune-mediated inflammatory rheumatic diseases for decades. It is an appropriate time to review their immunomodulatory and anti-inflammatory mechanisms impact on disease activity and survival of systemic lupus erythematosus patient, including antiplatelet effect, metabolic and lipid benefits. We also discuss possible adverse effects, adding a practical and comprehensive approach to monitoring rheumatic patients during treatment with these drugs.
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http://dx.doi.org/10.1186/s42358-020-00134-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282202PMC
June 2020

Arboviruses related with chronic musculoskeletal symptoms.

Best Pract Res Clin Rheumatol 2020 08 18;34(4):101502. Epub 2020 Apr 18.

Rheumatology Department, Hospital das Clínicas, Universidade Federal de Pernambuco, Brazil.

Arboviruses (ARthropods BOrne VIRUSES) are disease-causing viruses transmitted through the bite of hematophagous arthropods, such as mosquitoes and ticks. Among these, the alphavirus, genus of the Togaviridae family, is considered the most arthritogenic species, responsible for diseases such as chikungunya fever (CHIK), O'nyong-nyong virus fever, Ross River virus disease, Barmah Forest virus disease, Sindbis virus disease, and Mayaro fever. These arboviral diseases, especially CHIK, have impacted public health in recent decades, leading to devastating epidemics, particularly in developing countries, due to their high potential for chronicity, functional impairment, and great impact on the quality of life. In a similar way, chronic musculoskeletal symptoms have been described in all alphavirus infections. However, CHIK is the best studied. The purpose of this article is to review physiopathology, clinical manifestations, diagnosis, and treatment of alphaviruses, focusing on CHIK and chronic evolution of musculoskeletal symptoms.
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http://dx.doi.org/10.1016/j.berh.2020.101502DOI Listing
August 2020

The Brazilian Society of Rheumatology guidelines for axial spondyloarthritis - 2019.

Adv Rheumatol 2020 02 21;60(1):19. Epub 2020 Feb 21.

Universidade de São Paulo (USP), São Paulo, Brazil.

Spondyloarthritis is a group of chronic inflammatory systemic diseases characterized by axial and/or peripheral joints inflammation, as well as extra-articular manifestations. The classification axial spondyloarthritis is adopted when the spine and/or the sacroiliac joints are predominantly involved. This version of recommendations replaces the previous guidelines published in May 2013.A systematic literature review was performed, and two hundred thirty-seven studies were selected and used to formulate 29 recommendations answering 15 clinical questions, which were divided into four sections: diagnosis, non-pharmacological therapy, conventional drug therapy and biological therapy. For each recommendation the level of evidence supporting (highest available), the strength grade according to Oxford, and the degree of expert agreement (inter-rater reliability) is informed.These guidelines bring evidence-based information on clinical management of axial SpA patients, including, diagnosis, treatment, and prognosis.
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http://dx.doi.org/10.1186/s42358-020-0116-2DOI Listing
February 2020

Galectin-1, -4, and -7 Were Associated with High Activity of Disease in Patients with Rheumatoid Arthritis.

Autoimmune Dis 2019 22;2019:3081621. Epub 2019 Jul 22.

Laboratory of Immunomodulation and New Therapeutic Approaches (LINAT), Suely-Galdino Therapeutic Innovation Research Center (NUPIT-SG), Federal University of Pernambuco (UFPE), Recife, PE, Brazil.

Background: Due to the variety of functions that galectins (Gal) possess, it is clear that they participate in the pathogenesis of rheumatoid arthritis (RA). Although some studies demonstrate their functions, there is still no correlation with the clinical data of the disease, having the physiological meaning still unknown.

Objectives: To compare serum levels of Gal-1, -4, and -7 in patients with RA and healthy controls and to correlate them with clinical parameters.

Methods: Serum samples were collected from patients with RA and healthy donors to determine the serum levels of Gal-1, -4, and -7.

Results: Serum levels of Gal-1, -4, and -7 were significantly higher in RA patients compared to controls. We evaluated disease activity (CDAI) with serum levels of galectins and found that patients who were high in disease activity had high levels of galectin compared to the moderate activity group. Galectin-4 had higher levels in patients who were in high activity when compared to the group in remission or low activity. Evaluating the activity of the individual disease (DAS28), patients in high individual activity had high levels of Gal-4 when compared to the group in remission or low activity. We also found an association between positive rheumatoid factor and Gal-1 and Gal-4 levels.

Conclusion: Our results show for the first time the relationship between serum levels of galectin and the clinical parameters of patients with RA. Demonstrating their role in pathogenesis, new studies with galectins are needed to assess how they function as a biomarker in RA.
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http://dx.doi.org/10.1155/2019/3081621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681614PMC
July 2019

Pilates method in the treatment of patients with Chikungunya fever: a randomized controlled trial.

Clin Rehabil 2019 Oct 24;33(10):1614-1624. Epub 2019 Jun 24.

Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal de Pernambuco, Recife, Brasil.

Objective: The aim of this study was to evaluate the effects of the Pilates method on the reduction of pain, improvement of joint function, and quality of life of patients with chronic Chikungunya fever.

Design: This is a randomized, controlled, blind trial for the evaluators.

Setting: The study was conducted at the Advanced Laboratory in Physical Education and Health at Federal University of Pernambuco, Brazil.

Subjects: A total of 51 patients were allocated randomly and divided into 2 groups: a Pilates group (26 patients) and a control group (25 patients). After 12 weeks, 4 patients in the Pilates group and 5 in the control group were lost to follow-up.

Intervention: The Pilates group performed 24 Pilates method intervention sessions; the control group continued to receive standard clinical treatment at the outpatient clinic.

Main Measures: The main measures were as follows: visual analogue scale (VAS) for pain, functional capacity evaluated by Health Assessment Questionaire (HAQ), quality of life measured by the 12-Item Short-Form Health Survey (SF-12), and range of joint motion by goniometry.

Results: After 12 weeks, patients in the Pilates group presented lower VAS ( < 0.001), lower HAQ scores ( < 0.001), and higher quality-of-life scores ( < 0.001) compared with the control group. We found statistically significant results for the Pilates group in the range of movement for shoulder, knee, ankle, and lumbar spine ( < 0.001). In the intragroup analysis, there was a significant improvement in all outcomes evaluated.

Conclusion: In this study, patients undertaking Pilates method for 12 weeks had less pain, better function and quality of life, and increased range of joint movement.
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http://dx.doi.org/10.1177/0269215519856675DOI Listing
October 2019

IL-27 in patients with Chikungunya fever: A possible chronicity biomarker?

Acta Trop 2019 Aug 7;196:48-51. Epub 2019 May 7.

Serviço de Reumatologia - Hospital das Clínicas da Universidade Federal de Pernambuco, Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino (Nupit-SG)/ UFPE, Endereço: Av. Prof. Moraes Rego, 1235 - Cidade Universitária, Recife, PE, CEP: 50670-901, Brazil.

Background/purpose: Although many patients with chikungunya virus disease (CHIKVD), an arboviral disease characterized by sudden fever and incapacitating poliartralgia, develop chronic articular symptoms, the mechanisms involved in CHIKVD's chronification and its possible biomarkers remain poorly understood. Interleukin (IL)-17A, IL-21, IL-22, IL-29, and transforming growth factor (TGF)-β have been implicated in the pathogenesis of other inflammatory joint diseases, including rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Since chronic manifestations of CHIKVD share many clinical and immunological characteristics with those diseases, we assessed the serum levels of those cytokines and analyzed their associations with clinical manifestations in patients with CHIKVD.

Methods: We evaluated 45 patients (36 female, mean age: 55.2 ± 13.8 years) with CHIKVD serologically confirmed by enzyme-linked immunosorbent assay (ELISA), articular manifestations upon evaluation, and no previous history of inflammatory rheumatologic diseases, along with 49 healthy age- and sex-matched controls. We tested anti-Chikungunya IgM and IgG antibodies and measured IL-17A, IL-21, IL-22, IL-27, IL-29, and TGF-β serum levels with specific ELISA kits.

Results: IL-27, IL-17A, and IL-29 appeared in most patients but not in controls. IL-27 serum levels were higher in patients with chronic symptoms (median: 523.0 pg/mL [62.5-1,048]) than in ones in the acute or subacute stage (median: 62.5 pg/mL [62.5-483.8], p = .008). In patients with CHIKVD, we found significant correlations between IL-27 levels and tender joint counts (r = .32, p = .006), along with associations between IL-17A levels and swollen joint counts (r = .315, p = .0352). Furthermore, patients with arthritis had higher IL-17A levels (median: 23.14 pg/mL [20.6-25.86]) than ones without (median: 20.29 pg/mL [3.91-22.43], p = .0352). We did not detect IL-22 in either group or IL-21 in patients with CHIKVD.

Conclusion: Serum levels of IL-17A, IL-27, and IL-29 were high in patients with CHIKVD and had important associations with articular manifestations, which might indicate the inflammatory nature of Chikungunya infection in patients with joint symptoms and the roles of those cytokines in the disease's pathophysiology.
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http://dx.doi.org/10.1016/j.actatropica.2019.05.005DOI Listing
August 2019

Brazilian recommendations on the safety and effectiveness of the yellow fever vaccination in patients with chronic immune-mediated inflammatory diseases.

Adv Rheumatol 2019 04 29;59(1):17. Epub 2019 Apr 29.

SBR. Presidente da SRRJ. Chefe do Serviço de Reumatologia do Hospital Estadual Eduardo Rabelo RJ, Rio de Janeiro, Brazil.

Background: In Brazil, we are facing an alarming epidemic scenario of Yellow fever (YF), which is reaching the most populous areas of the country in unvaccinated people. Vaccination is the only effective tool to prevent YF. In special situations, such as patients with chronic immune-mediated inflammatory diseases (CIMID), undergoing immunosuppressive therapy, as a higher risk of severe adverse events may occur, assessment of the risk-benefit ratio of the yellow fever vaccine (YFV) should be performed on an individual level. Faced with the scarcity of specific orientation on YFV for this special group of patients, the Brazilian Rheumatology Society (BRS) endorsed a project aiming the development of individualized YFV recommendations for patients with CIMID, guided by questions addressed by both medical professionals and patients, followed an internationally validated methodology (GIN-McMaster Guideline Development). Firstly, a systematic review was carried out and an expert panel formed to take part of the decision process, comprising BRS clinical practitioners, as well as individuals from the Brazilian Dermatology Society (BDS), Brazilian Inflammatory Bowel Diseases Study Group (GEDIIB), and specialists on infectious diseases and vaccination (from Tropical Medicine, Infectious Diseases and Immunizations National Societies); in addition, two representatives of patient groups were included as members of the panel. When the quality of the evidence was low or there was a lack of evidence to determine the recommendations, the decisions were based on the expert opinion panel and a Delphi approach was performed. A recommendation was accepted upon achieving ≥80% agreement among the panel, including the patient representatives. As a result, eight recommendations were developed regarding the safety of YFV in patients with CIMID, considering the immunosuppression degree conferred by the treatment used. It was not possible to establish recommendations on the effectiveness of YFV in these patients as there is no consistent evidence to support these recommendations.

Conclusion: This paper approaches a real need, assessed by clinicians and patient care groups, to address specific questions on the management of YFV in patients with CIMID living or traveling to YF endemic areas, involving specialists from many areas together with patients, and might have global applicability, contributing to and supporting vaccination practices. We recommended a shared decision-making approach on taking or not the YFV.
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http://dx.doi.org/10.1186/s42358-019-0056-xDOI Listing
April 2019

IL-17 and related cytokines involved in systemic sclerosis: Perspectives.

Autoimmunity 2018 02 19;51(1):1-9. Epub 2017 Dec 19.

b Laboratório de Imunomodulação e Novas Abordagens Terapêuticas Suely Galdino , Universidade Federal de Pernambuco , Recife , Brazil.

Systemic sclerosis (SSc) is a multisystemic, complex, and rare disease of connective tissue, with high morbidity and mortality, and without specific treatment. The disease is characterized by three main principles: vascular disease, autoantibody production and inflammation, and fibrosis. Since it is well defined that SSc is characterized by elevated production of TGF-β, IL-6, and IL-1, all of them cytokines related to Th17 differentiation, the hypothesis is that this disease may be strongly related to a polarization of the immune response towards the Th17 pathway. Considering the importance of a better understanding of the pathophysiology of Th17 pathway in SSc, this article aims to propose an update for a better understanding of current knowledge on main cytokines secreted by the Th17 cells (IL-17 A, IL-21, and IL-22) and the future prospects in the current disease.
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http://dx.doi.org/10.1080/08916934.2017.1416467DOI Listing
February 2018

Corticosteroid inhibits chemokines production in systemic sclerosis patients.

Steroids 2017 11 1;127:24-30. Epub 2017 Sep 1.

Laboratório de Imunomodulação e Novas Abordagens Terapêuticas, Núcleo de Pesquisa em Inovação Terapêutica (NUPIT), Universidade Federal de Pernambuco, Recife, PE, Brazil.

In this study, we evaluated glucocorticoids (GC) effects on cytokine/chemokine levels in serum samples and peripheral blood mononuclear cell (PBMC) production from systemic sclerosis (SSc) patients. We evaluated cytokine and chemokine levels in serum samples from SSc patients taking or not taking systemic glucocorticoids. PBMCs response to methylprednisolone (MP) was examined from 15 SSc patients and 8 healthy control subjects following PBMC stimulation with anti-CD3/CD28. Cytokine (IFN-γ, TNF, IL-2, IL-4, IL-6, IL-10, and IL-17A) and chemokine (CXCL8/IL-8, CCL5/RANTES, CXCL9/MIG, CCL2/MCP-1, and CXCL10/IP-10) levels were quantified in serum and in PBMC culture supernatants by CBA or ELISA. Compared with patients not taking corticosteroids, we did not observe any significant differences in cytokines/chemokines serum levels in patients using systemic corticosteroids. After stimulation with anti-CD3/CD28, PBMCs treated with MP (100μM), showed a significant reduction of CCL2/MCP-1 (p=0.001), CCL5/RANTES (p=0.04), and CXCL8/IL-8 (p=0.003) levels in SSc patients. In PBMC from healthy controls, we observed decreased IFN-γ, TNF, IL-2, and IL-10 levels after MP treatment, compared with stimulated condition (p<0.01 for all). However in SSc patients, we did not find any significant reduction in these cytokine levels after MP treatment. In conclusion, CCL2/MCP-1, CCL5/RANTES, and CXCL8/IL-8 are chemokines that are potentially modulated by corticosteroids in vitro in SSc patients, but no effect was observed on IL-2, IL-4, IL-6, IL-10, IL-17A, TFN, and IFN-γ secretion. These results suggest a potential effect of GCs on SSc treatment and may reflect the benefit of their use in some patients.
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http://dx.doi.org/10.1016/j.steroids.2017.08.012DOI Listing
November 2017

Recommendations of the Brazilian Society of Rheumatology for diagnosis and treatment of Chikungunya fever. Part 1 - Diagnosis and special situations.

Rev Bras Reumatol Engl Ed 2017 25;57 Suppl 2:421-437. Epub 2017 Jul 25.

Instituto de Medicina Integral Professor Fernando Figueira (IMIP), Hospital Miguel Arraes, Paulista, PE, Brazil.

Chikungunya fever has become a relevant public health problem in countries where epidemics occur. Until 2013, only imported cases occurred in the Americas, but in October of that year, the first cases were reported in Saint Marin island in the Caribbean. The first autochthonous cases were confirmed in Brazil in September 2014; until epidemiological week 37 of 2016, 236,287 probable cases of infection with Chikungunya virus had been registered, 116,523 of which had serological confirmation. Environmental changes caused by humans, disorderly urban growth and an ever-increasing number of international travelers were described as the factors responsible for the emergence of large-scale epidemics. Clinically characterized by fever and joint pain in the acute stage, approximately half of patients progress to the chronic stage (beyond 3 months), which is accompanied by persistent and disabling pain. The aim of the present study was to formulate recommendations for the diagnosis and treatment of Chikungunya fever in Brazil. A literature review was performed in the MEDLINE, SciELO and PubMed databases to ground the decisions for recommendations. The degree of concordance among experts was established through the Delphi method, involving 2 in-person meetings and several online voting rounds. In total, 25 recommendations were formulated and divided into 3 thematic groups: (1) clinical, laboratory and imaging diagnosis; (2) special situations; and (3) treatment. The first 2 themes are presented in part 1, and treatment is presented in part 2.
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http://dx.doi.org/10.1016/j.rbre.2017.05.006DOI Listing
August 2019

Recommendations of the Brazilian Society of Rheumatology for the diagnosis and treatment of chikungunya fever. Part 2 - Treatment.

Rev Bras Reumatol Engl Ed 2017 22;57 Suppl 2:438-451. Epub 2017 Jul 22.

Instituto de Medicina Integral Professor Fernando Figueira (IMIP), Hospital Miguel Arraes, Paulista, PE, Brazil.

Chikungunya fever has become an important public health problem in countries where epidemics occur because half of the cases progress to chronic, persistent and debilitating arthritis. Literature data on specific therapies at the various phases of arthropathy caused by chikungunya virus (CHIKV) infection are limited, lacking quality randomized trials assessing the efficacies of different therapies. There are a few studies on the treatment of musculoskeletal manifestations of chikungunya fever, but these studies have important methodological limitations. The data currently available preclude conclusions favorable or contrary to specific therapies, or an adequate comparison between the different drugs used. The objective of this study was to develop recommendations for the treatment of chikungunya fever in Brazil. A literature review was performed via evidence-based selection of articles in the databases Medline, SciELO, PubMed and Embase and conference proceedings abstracts, in addition to expert opinions to support decision-making in defining recommendations. The Delphi method was used to define the degrees of agreement in 2 face-to-face meetings and several online voting rounds. This study is part 2 of the Recommendations of the Brazilian Society of Rheumatology (Sociedade Brasileira de Reumatologia - SBR) for the Diagnosis and Treatment of chikungunya fever and specifically addresses treatment.
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http://dx.doi.org/10.1016/j.rbre.2017.06.004DOI Listing
August 2019

Reassessing the Role of the Active TGF-1 as a Biomarker in Systemic Sclerosis: Association of Serum Levels with Clinical Manifestations.

Dis Markers 2016 14;2016:6064830. Epub 2016 Nov 14.

Laboratório de Imunomodulação e Novas Abordagens Terapêuticas, Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino, Recife, PE, Brazil.

. To determine active TGF-1 (aTGF-1) levels in serum, skin, and peripheral blood mononuclear cell (PBMC) culture supernatants and to understand their associations with clinical parameters in systemic sclerosis (SSc) patients. . We evaluated serum samples from 56 SSc patients and 24 healthy controls (HC). In 20 SSc patients, we quantified spontaneous or anti-CD3/CD28 stimulated production of aTGF-1 by PBMC. The aTGF-1 levels were measured by ELISA. Skin biopsies were obtained from 13 SSc patients and six HC, and TGFB1 expression was analyzed by RT-PCR. . TGF-1 serum levels were significantly higher in SSc patients than in HC ( < 0.0001). Patients with increased TGF-1 serum levels were more likely to have diffuse subset ( = 0.02), digital ulcers ( = 0.02), lung fibrosis ( < 0.0001), positive antitopoisomerase I ( = 0.03), and higher modified Rodnan score ( = 0.046). Most of our culture supernatant samples had undetectable levels of TGF-1. No significant difference in TGFB1 expression was observed in the SSc skin compared with HC skin. . Raised active TGF-1 serum levels and their association with clinical manifestations in scleroderma patients suggest that this cytokine could be a marker of fibrotic and vascular involvement in SSc.
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http://dx.doi.org/10.1155/2016/6064830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124685PMC
February 2017

High frequency of asymptomatic hyperparathyroidism in patients with fibromyalgia: random association or misdiagnosis?

Rev Bras Reumatol Engl Ed 2016 Sep - Oct;56(5):391-397. Epub 2016 Apr 8.

Departamento de Reumatologia, Hospital das Clínicas, Universidade Federal de Pernambuco (UFPE), Recife, PE, Brazil.

Fibromyalgia (FM) and hyperparathyroidism may present similar symptoms (musculoskeletal pain, cognitive disorders, insomnia, depression and anxiety), causing diagnostic confusion.

Objectives: To determine the frequency of asymptomatic hyperparathyroidism in a sample of patients with FM and to evaluate the association of laboratory abnormalities to clinical symptoms.

Methods: Cross-sectional study with 100 women with FM and 57 healthy women (comparison group). Parathyroid hormone (PTH), calcium and albumin levels were accessed, as well as symptoms in the FM group.

Results: In FM group, mean serum calcium (9.6±0.98mg/dL) and PTH (57.06±68.98pg/mL) values were considered normal, although PTH levels had been significantly higher than in the comparison group (37.12±19.02pg/mL; p=0.001). Hypercalcemic hyperparathyroidism was diagnosed in 6% of patients with FM, and 17% of these women exhibited only high levels of PTH, featuring a normocalcemic hyperparathyroidism, with higher frequencies than those expected for their age. There was no significant association between hyperparathyroidism and FM symptoms, except for epigastric pain, which was more frequent in the group of patients concomitantly with both diseases (p=0.012).

Conclusions: A high frequency of hyperparathyroidism was noted in women with FM versus the general population. Normocalcemic hyperparathyroidism was also more frequent in patients with FM. Longitudinal studies with greater number of patients are needed to assess whether this is an association by chance only, if the increased serum levels of PTH are part of FM pathophysiology, or even if these would not be cases of FM, but of hyperparathyroidism.
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http://dx.doi.org/10.1016/j.rbre.2016.03.008DOI Listing
October 2018

Improvement of Articular Pain, Stiffness, and Function in Obese Patients Submitted to Bariatric Surgery.

J Clin Rheumatol 2016 Sep;22(6):344

Faculdade Pernambucana de Saúde Recife, Pernambuco, Brazil Hospital das Clínicas da Universidade Federal do Pernambuco Recife, Pernambuco, Brazil

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http://dx.doi.org/10.1097/RHU.0000000000000375DOI Listing
September 2016

Cytokine Profile in Gout: Inflammation Driven by IL-6 and IL-18?

Immunol Invest 2016 Jul 24;45(5):383-95. Epub 2016 May 24.

b Laboratório de Imunomodulação e Novas Abordagens Terapêuticas (LINAT), Núcleo de Pesquisa em Inovação Suely Galdino (NUPIT-SG), Centro de Ciências Biológicas, Universidade Federal de Pernambuco , Recife , Brazil.

Introduction: Gout is considered to be an autoinflammatory disease and the presence of monosodium urate (MSU) crystals stimulates activation of NPRL3 inflammasome and subsequently caspase-1, generating production of active IL-1β and IL-18. However, the association between serum cytokines levels and clinical manifestations of the disease is not yet well understood. We evaluated the serum profile of proinflammatory cytokines (IL-1β, IL-6, IL-8, IL-17A, IL-18, IL-22, and IL-23) and described their relationship with clinical and laboratory data.

Methodology: Thirty-nine male patients with gout (GG) were assessed for clinical and laboratory variables and cytokine levels were measured by ELISA. For the purposes of comparison, 34 males with no previous history of arthritis were also included in the study (CG).

Results: Seventeen participants (43%) exhibited active arthritis on evaluation. Levels of IL-18 were significantly higher in patients in relation to the CG (p = 0.0013). No statistically significant differences were found between the GG and CG for the other measured cytokines. There was a moderate correlation between IL-18 and ESR (R = 0.43, p = 0.0073), CRP (R = 0.47, p = 0.0025), and serum levels of IL-6 (R = 0.36, p = 0.023). An association was observed between serum levels of IL-6 and the presence of tophi (p = 0.005) and deformities (p = 0.0008), as well as a correlation between this cytokine and ESR (R = 0.41, p = 0.011) and CRP (R = 0.48, p = 0.02).

Conclusions: IL-18 is associated with inflammatory activity in gout, as well as with IL-6 levels, while IL-6 is associated with clinical and laboratory activity, the presence of tophi and articular deformities, and may be a prognostic marker of this pathology.
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http://dx.doi.org/10.3109/08820139.2016.1153651DOI Listing
July 2016

Clinical and cytokine profile evaluation in Northeast Brazilian psoriasis plaque-type patients.

Eur Cytokine Netw 2016 Mar;27(1):1-5

Laboratory of Immunomodulation and Novel Therapeutic Approaches (LINAT), Research Center for Therapeutic Innovation Suely Galdino (NUPIT-SG), UFPE, Recife, Brazil.

Psoriasis is a common, enigmatic, and recurrent disease. The precise etiology and pathogenesis of psoriasis are still unclear. Psoriasis has been treated as an inflammatory disorder related to an underlying Th1/Th17-dominated immune response. Interleukins are involved in the development of psoriasis lesions through Th-17-associated inflammation. Th1 and Th17 cytokines are found in skin lesions and in the peripheral blood of psoriasis patients. We sought to analyze serum levels of IL-1-β, IL-8, IL-9, IL-27, IL-29, IL-35, IFN-γ, TNF and TGF-β in patients with psoriasis and healthy control volunteers. Blood samples were collected from fifty-three patients with psoriasis and thirty-five healthy controls. Serum cytokines concentrations were determined using an enzyme-linked immunosorbent assay. Serum IL-8, IL-9, IL-27, IL-29 and TNF levels were statistically significant in psoriasis patients. Detectable serum IL-9 levels were found in 47 patients of the 53 in the psoriasis group. Interleukins-8, 27, 29 and TNF levels measured in the serum of psoriasis patients were slightly elevated as compared to healthy controls in a weakly significant way. On the other hand, there were highly significant differences in IL-9 levels between the two groups.
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http://dx.doi.org/10.1684/ecn.2016.0371DOI Listing
March 2016

Increased IL-35 serum levels in systemic sclerosis and association with pulmonary interstitial involvement.

Clin Rheumatol 2015 Sep 11;34(9):1621-5. Epub 2015 Jul 11.

Laboratório de Imunomodulação e Novas Abordagens Terapêuticas, Recife, Brazil.

The objective of this study is to assess the serum IL-35 level and its association with clinical manifestations in patients with systemic sclerosis (SSc). IL-35 serum levels were measured by ELISA from 56 patients with SSc and 53 healthy controls. Association of IL-35 serum levels were sought with clinical parameters. Serum IL-35 levels were significantly higher in SSc patients (5.08 ± 0.76 pg/ml) than in healthy individuals (1.89 ± 0.69 pg/ml; p < 0.0001). Patients with lung fibrosis had higher IL-35 levels than those without fibrosis (7.75 ± 1.36 and 3.08 ± 0.70 pg/ml, respectively, p = 0.0022). IL-35 is elevated in the serum of patients with SSc and is associated with lung fibrosis. Our findings suggest that this cytokine can have a role in fibrotic diseases, but further studies are needed to address the role of IL-35 in the pathogenesis of SSc.
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http://dx.doi.org/10.1007/s10067-015-3006-yDOI Listing
September 2015

Increased Serum Interleukin-9 Levels in Rheumatoid Arthritis and Systemic Lupus Erythematosus: Pathogenic Role or Just an Epiphenomenon?

Dis Markers 2015 19;2015:519638. Epub 2015 May 19.

Laboratório de Imunomodulação e Novas Abordagens Terapêuticas (LINAT), Núcleo de Pesquisas em Inovação Terapêutica Suely Galdino (Nupit SG), Universidade Federal de Pernambuco (UFPE), Avenida Professor Moraes Rego, s/n, 50670-901 Recife, PE, Brazil.

The purpose of this paper was to evaluate the levels of IL-9 in patients with SLE and RA compared with controls and the association of IL-9 levels with clinical and laboratory parameters. IL-9 levels were assessed in 117 SLE patients, 67 RA patients, and 24 healthy controls by ELISA. Clinical and laboratory parameters were recorded. The IL-9 serum levels were significantly higher in RA patients (4,77 ± 3,618 pg/mL) and in SLE patients (12,26 ± 25,235 pg/mL) than in healthy individuals (1,22 ± 0,706 pg/mL) (p < 0,001). In SLE patients, there were no statistically significant associations or correlations between the levels of IL-9 and SLEDAI or other clinical and laboratorial parameters, with the exception of disease time, which showed a statistically significant negative correlation with IL-9 levels (r = -0,1948; p = 0,0378). In RA patients, no association or statistically significant correlation was observed with disease duration, DAS28, HAQ, rheumatoid factor positivity, or erosions on radiography. These data demonstrated increased serum levels of IL-9 in SLE and RA patients, but further studies are needed to clarify the precise role of this cytokine and its potential use as therapeutic target.
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http://dx.doi.org/10.1155/2015/519638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452366PMC
February 2016

The Role of PPAR Gamma in Systemic Sclerosis.

PPAR Res 2015 6;2015:124624. Epub 2015 May 6.

Laboratório de Imunomodulação e Novas Abordagens Terapêuticas da Universidade Federal de Pernambuco (LINAT-UFPE), 50670-901 Recife, PE, Brazil.

Fibrosis is recognized as an important feature of many chronic diseases, such as systemic sclerosis (SSc), an autoimmune disease of unknown etiology, characterized by immune dysregulation and vascular injury, followed by progressive fibrosis affecting the skin and multiple internal organs. SSc has a poor prognosis because no therapy has been shown to reverse or arrest the progression of fibrosis, representing a major unmet medical need. Recently, antifibrotic effects of PPARγ ligands have been studied in vitro and in vivo and some theories have emerged leading to new insights. Aberrant PPARγ function seems to be implicated in pathological fibrosis in the skin and lungs. This antifibrotic effect is mainly related to the inhibition of TGF-β/Smad signal transduction but other pathways can be involved. This review focused on recent studies that identified PPARγ as an important novel pathway with critical roles in regulating connective tissue homeostasis, with emphasis on skin and lung fibrosis and its role on systemic sclerosis.
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http://dx.doi.org/10.1155/2015/124624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438188PMC
June 2015

Interferons and systemic sclerosis: correlation between interferon gamma and interferon-lambda 1 (IL-29).

Autoimmunity 2015 9;48(7):429-33. Epub 2015 Jun 9.

b Laboratório de Imunomodulação e Novas Abordagens Terapêuticas da UFPE , Brazil , and.

Background: Interferon (IFN)-λ1 is a newly described cytokine, member of type III interferons family, which is known for its antiviral, anti-proliferative and antitumor activity. Recent studies indicated that this cytokine has also immune-regulatory function, but its role in the pathogenesis of autoimmune diseases is not established yet. We evaluated serum levels of IFN-λ1 in systemic sclerosis (SSc) patients and healthy controls and its association with IFN-γ and clinical manifestations.

Methods: IFN-λ1 and IFN-γ serum levels were measured by ELISA from 52 patients with SSc and 53 healthy controls. Association of cytokines serum levels was sought with clinical parameters.

Results: IFN-λ1 and IFN-γ levels in SSc patients were significantly higher than those in healthy individuals (24.82 ± 8.78 and 11.04 ± 3.04 pg/ml, p < 0.0001; 34.11 ± 8.11 and 10.73 ± 2.77 pg/ml, p < 0.0001, respectively). We found a positive correlation between IFN-λ1 and IFN-γ levels in SSc patients (p = 0.0103, r = 0.3526). IFN-γ levels were associated with muscle involvement (p = 0.0483).

Conclusion: We first showed raised IFN-λ1 levels in SSc patients. Furthermore, we found a correlation between IFN-λ1 and IFN-γ levels and an association between IFN-γ and myositis. Additional in vitro and in vivo studies are needed to understand IFN-λ1 role in SSc.
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http://dx.doi.org/10.3109/08916934.2015.1054028DOI Listing
August 2016

Peroxisome proliferator-activated receptor agonists (PPARs): a promising prospect in the treatment of psoriasis and psoriatic arthritis.

An Bras Dermatol 2013 Nov-Dec;88(6):1029-35

Biochemistry Department, Pernambuco Federal University, RecifePE, Brazil, Post-doctorate - Adjunct Professor Level II at the Biochemistry Department at Pernambuco Federal University (UFPE) - Recife (PE), Brazil.

Psoriasis is a polygenic, inflammatory and progressive disease, characterized by an abnormal differentiation and hyperproliferation of keratinocytes, associated with impaired immunologic activation and systemic disorders, while psoriatic arthritis is a chronic inflammatory articular disease. Pathophysiology of psoriasis comprises a dysfunction of the immune system cells with an interactive network between cells and cytokines supporting the initiation and perpetuation of disease and leading to inflammation of skin, enthesis and joints. Recent studies have shown an important role of systemic inflammation in the development of atherosclerosis. Corroborating these findings, patients with severe Psoriasis have marked incidence of psoriatic arthritis, cardiovascular diseases, hypertension, dyslipidemia, obesity and diabetes mellitus, showing an increased risk for acute myocardial infarction, which suggests that the condition is not restricted to the skin. Nuclear receptors are ligand-dependent transcription factors, whose activation affects genes that control vital processes. Among them the peroxisome proliferator-activated receptor is responsible for establishing the relationship between lipids, metabolic diseases and innate immunity. In the skin, peroxisome proliferator-activated receptors have an important effect in keratinocyte homeostasis, suggesting a role in diseases such as psoriasis. The peroxisome proliferator-activated receptors agonists represent a relevant source of research in the treatment of skin conditions, however more clinical studies are needed to define the potential response of these drugs in patients with psoriasis and psoriatic arthritis.
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http://dx.doi.org/10.1590/abd1806-4841.20132653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3900368PMC
September 2014

25-Hydroxyivitamin D3 levels in patients with systemic lupus erythematosus and its association with clinical parameters and laboratory tests.

Rev Bras Reumatol 2012 Jan-Feb;52(1):60-5

Universidade Federal de Pernambuco – UFPE.

Introduction: The immunoregulatory role of vitamin D has been the object of a growing number of studies in patients with systemic lupus erythematosus (SLE).

Objectives: To determine the serum levels of 25-hydroxyvitamin D3 [25(OH) D] in patients with SLE, and to assess the association of 25(OH)D insufficiency/deficiency with clinical parameters and laboratory tests.

Methods: Cross-sectional, prospective study performed at the SLE Clinic, Department of Rheumatology, Hospital das Clínicas, Universidade Federal de Pernambuco with convenience sampling, including 78 patients with SLE and 64 volunteers (comparison group), matched by gender and age.

Results: Insufficiency/deficiency of 25(OH)D was found in 45 (57.7%) patients with SLE and 25 (39%) individuals in the comparison group. The mean serum levels of 25(OH)D were 29.3 ng/mL (6.1-55.2 ng/mL) in patients with SLE and 33.12 ng/mL (15.9-63.8 ng/mL) in the comparison group, and this difference was statistically significant (P = 0.041). No statistically significant difference was observed between the mean ages of both groups. No statistically significant association was observed between 25(OH)D insufficiency/deficiency and the following: time to diagnosis; disease activity (SLEDAI > 6); fatigue; use of corticosteroids and antimalarials; and anti-DNA.

Conclusions: High prevalence of 25(OH)D insufficiency/deficiency was found in patients with SLE (57.7%), with statistically significant difference as compared with the comparison group. No association of vitamin D insufficiency/deficiency was observed with the clinical variables and laboratory tests studied. The authors emphasize the importance of determining 25(OH)D serum levels in all patients with SLE, regardless of where they live and time to disease diagnosis.
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May 2012

Comorbidities in patients with osteoarthritis: frequency and impact on pain and physical function.

Rev Bras Reumatol 2011 Mar-Apr;51(2):118-23

Instituto de Medicina Integral Professor Fernando Figueira, Recife, PE, Brazil.

Introduction: As the prevalence of osteoarthritis (OA) increases with age, the coexistence of other chronic diseases is common.

Objectives: To evaluate the frequency of comorbidities in OA patients and to measure their impact on pain and physical function of those patients.

Methods: Cross-sectional study in OA patients of a public rheumatology clinic. Pain was measured by use of the Visual Analogue Scale (VAS) and physical function by use of the Lequesne's and SACRAH indices. A screening for depression was performed, as were the following measurements: anthropometric data; blood pressure; fasting glycemia; and lipid profile.

Results: The study assessed 91 patients (mean age 59.3 years; 91.4% female). The metabolic syndrome frequency was 54.9%. Hypertension occurred in 75.8% of the patients, dyslipidemia in 52.6%, and obesity in 57.1%. The screening for depression was positive in 61.3% of patients. When comparing the metabolic syndrome components individually, patients with hypertension had higher SACRAH scores, with statistically significant differences (P = 0.035). For the other variables, no differences among the Lequesne's, SACRAH and VAS scores were observed.

Conclusion: This group of OA patients showed a high frequency of depression, metabolic syndrome and its components in isolation, which can impact the pain and physical function of those patients. Such results showed the need for investigating and treating those comorbidities in OA patients.
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November 2011