Vitamin D Presented In Vitro Immunomodulatory Property on T Lymphocyte-Related Cytokines in Systemic Lupus Erythematosus.

Inflammatory T lymphocyte cytokines contribute to tissue damage in SLE patients. Vitamin D (Vit D) has a well-established immunomodulatory action, but few studies have addressed the effect of 1,25 dihydroxyvitamin D3 (1,25 (OH)2D3) on peripheral blood mononuclear cells (PBMCs) in SLE patients. The aim of this study was to evaluate the immnunomodulatory effect of 1,25 (OH)2D3 on T lymphocyte-related cytokines. Blood from 27 female SLE patients was collected for PBMC isolation and anti-DNA, complement, and serum 25 (OH)D3 level measurements. PBMCs were stimulated with anti-CD3/anti-CD28 in the presence or absence of dexamethasone or various concentrations of 1,25 (OH)2D3 for 48 h. We assessed IL-17A, IL-22, IL-21, IL-9, IFN-γ, IL-4, IL-10, IL-2, IL-6, and TNF by cytometric bead assay (CBA) and enzyme immune assay (ELISA) on culture supernatant. The mean age of patients was 36.2 (± 10.5 years) and the median Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) was 4 (0-6). The addition of 1,25 (OH)2D3 in PBMC culture reduced IL-17 A, IL-22, IL-9, and IFN-γ levels at 100 nM (p ≤ 0.0001). Furthermore, the addition of 1,25 (OH)2D3 at all concentrations increased IL-4 (p ≤ 0.0006), and 0.1 and 1 nM increased IL-10 (p ≤ 0.0004) and 0.1 nM increased IL-2 levels (p ≤ 0.0001). There was no difference regarding IL-21 and TNF levels. The addition of 1,25 (OH)2D3 in PBMC culture presented an inhibitory effect on proinflammatory cytokines and increased immunoregulatory cytokines in SLE patients, suggesting the beneficial effect of this vitamin.

Association between autoimmune rheumatic diseases and head and neck cancer: Systematic review and meta-analysis.

BACKGROUND: Personal history of autoimmune rheumatic diseases has been implicated in the development of malignant neoplasms. Our aim was to assess the risk of head and neck (H&N) cancers in patients with autoimmune rheumatic diseases. METHODS: The articles search included PubMed, EMBASE, LILACS, The Cochrane Library, CINAHL, Scopus, Web of Science, and Google Scholar with no language restrictions for studies published from inception of the databases to August 20, 2022, assessing the risk of H&N cancer in patients with autoimmune rheumatic diseases. Studies were included if they reported the standardized incidence ratio (SIR) with corresponding 95% confidence intervals (CIs). The primary outcome was risk of H&N cancers in patients with autoimmune rheumatic diseases compared with the general population. Pooled summary estimates were calculated using a random-effects model, and subgroup analyses were done to establish whether risk of H&N cancers varied according to study site. RESULTS: Our search identified 5378 records, of which 32 cohort studies were eligible for systematic review and 24 for meta-analysis (including 273 613 patients). A significant association was found between H&N cancer and autoimmune rheumatic diseases (SIR = 2.35; 95% CI: 1.57-3.50; p < 0.01, I2  = 94%). CONCLUSION: Our study suggests that patients with autoimmune rheumatic diseases had a significantly increased risk of H&N cancer compared with the general population, including thyroid, oral, and nasopharyngeal cancers. These findings have implications for the individualized screening of these patients and the planning of oncology units. The protocol is registered with PROSPERO, number CRD42020197827.

VI Brazilian consensus guidelines for detection of anti-cell autoantibodies on HEp-2 cells

Abstract Background: The VI Brazilian Consensus on Autoantibodies against HEp-2 cells for determination of autoantibodies against cellular constituents on HEp-2 cells was held on September, 2019, in Fortaleza (CE, Brazil). The guidelines in this edition were formulated by the group of Brazilian experts discussing the classification of complex patterns, the classification of the nuclear discrete dots (few and multiple), the identification of the discrete fine speckled pattern (AC-4a) and improvements on the ANA report. Mainbody: Sixteen Brazilian researchers and experts from universities and clinical laboratories representing the various geographical regions of Brazil participated in the meeting. Four main topics were discussed: (1) How to classify patterns with fluorescence in more than one cell compartment considering three relevant categoris: composite patterns, mixed patterns and multiple patterns; (2) The splitting of the discrete nuclear dots pattern into the multiple discrete nuclear dots (AC-6) and few discrete nuclear dots (AC-7) patterns, respectively; (3) Inclusion of a novel nuclear pattern characterized by discrete fine speckled pattern highly associated with antibodies to SS-A/Ro60, classified as AC-4a. In addition, adjustments on the Brazilian Consensus nomenclature were implemented aiming to harmonize the designation of some patterns with the International Consensus on ANA Patterns (ICAP). Furthermore, the designations of the PCNA-like pattern (AC-13), CENP-F-like pattern (AC-14) and Topo I-like pattern (AC-29) were adjusted in accordance to ICAP. Finally, there was a recommendation for adjustment in the test report in order to address the status of nuclear envelope staining. For all topics, the aim was to establish specific guidelines for laboratories and clinicians. All recommendations were based on consensus among participants. All recommendations from the V Consensus were maintained and there was relevant progress in the BCA/HEp-2 guidelines and further harmonization with ICAP. Conclusion: The VI BCA/HEp-2 edition was successful in establishing important recommendations regarding the classification of complex patterns, in supporting the identification of a novel pattern within the AC-4 group and in the harmonization process with the ICAP terminology.

Outcomes of COVID-19 in patients with primary systemic vasculitis or polymyalgia rheumatica from the COVID-19 Global Rheumatology Alliance physician registry: a retrospective cohort study.

BACKGROUND: Patients with primary systemic vasculitis or polymyalgia rheumatica might be at a high risk for poor COVID-19 outcomes due to the treatments used, the potential organ damage cause by primary systemic vasculitis, and the demographic factors associated with these conditions. We therefore aimed to investigate factors associated with COVID-19 outcomes in patients with primary systemic vasculitis or polymyalgia rheumatica. METHODS: In this retrospective cohort study, adult patients (aged ≥18 years) diagnosed with COVID-19 between March 12, 2020, and April 12, 2021, who had a history of primary systemic vasculitis (antineutrophil cytoplasmic antibody [ANCA]-associated vasculitis, giant cell arteritis, Behçet's syndrome, or other vasculitis) or polymyalgia rheumatica, and were reported to the COVID-19 Global Rheumatology Alliance registry were included. To assess COVID-19 outcomes in patients, we used an ordinal COVID-19 severity scale, defined as: (1) no hospitalisation; (2) hospitalisation without supplemental oxygen; (3) hospitalisation with any supplemental oxygen or ventilation; or (4) death. Multivariable ordinal logistic regression analyses were used to estimate odds ratios (ORs), adjusting for age, sex, time period, number of comorbidities, smoking status, obesity, glucocorticoid use, disease activity, region, and medication category. Analyses were also stratified by type of rheumatic disease. FINDINGS: Of 1202 eligible patients identified in the registry, 733 (61·0%) were women and 469 (39·0%) were men, and their mean age was 63·8 years (SD 17·1). A total of 374 (31·1%) patients had polymyalgia rheumatica, 353 (29·4%) had ANCA-associated vasculitis, 183 (15·2%) had giant cell arteritis, 112 (9·3%) had Behçet's syndrome, and 180 (15·0%) had other vasculitis. Of 1020 (84·9%) patients with outcome data, 512 (50·2%) were not hospitalised, 114 (11·2%) were hospitalised and did not receive supplemental oxygen, 239 (23·4%) were hospitalised and received ventilation or supplemental oxygen, and 155 (15·2%) died. A higher odds of poor COVID-19 outcomes were observed in patients who were older (per each additional decade of life OR 1·44 [95% CI 1·31-1·57]), were male compared with female (1·38 [1·05-1·80]), had more comorbidities (per each additional comorbidity 1·39 [1·23-1·58]), were taking 10 mg/day or more of prednisolone compared with none (2·14 [1·50-3·04]), or had moderate, or high or severe disease activity compared with those who had disease remission or low disease activity (2·12 [1·49-3·02]). Risk factors varied among different disease subtypes. INTERPRETATION: Among patients with primary systemic vasculitis and polymyalgia rheumatica, severe COVID-19 outcomes were associated with variable and largely unmodifiable risk factors, such as age, sex, and number of comorbidities, as well as treatments, including high-dose glucocorticoids. Our results could be used to inform mitigation strategies for patients with these diseases. FUNDING: American College of Rheumatology and the European Alliance of Associations for Rheumatology.

Validation of the Toronto Psoriatic Arthritis Screen II (ToPAS II) questionnaire in a Brazilian population.

The Toronto Psoriatic Arthritis Screen II (ToPAS II) was developed as a tool to screen patients with probable psoriatic arthritis. We aimed to evaluate the validation of the ToPAS II questionnaire in a Brazilian population. The Portuguese translation of the ToPAS II was sent to us by the developer authors of the original index, and adapted to Brazilian Portuguese. Subjects were recruited from dermatology, general, and rheumatology outpatient clinics. After patients completed the questionnaire, they were assessed by a rheumatologist, according to standard protocol. Receiver operating characteristics (ROC) was used to obtain the sensitivity and specificity of the Brazilian Portuguese version of the ToPAS II questionnaire. One hundred and eighty-four subjects were recruited in the study. There were 70 subjects from the psoriasis group, 44 subjects from the psoriatic arthritis (PsA) group, 40 subjects from the rheumatology (non-PsA) group, and 45 healthy controls. Twenty-four patients (34.3%) in the psoriasis group had inflammatory pain and met the CASPAR classification criteria. The area under the ROC curve was 0.96, which indicates that an excellent predictor and optimum cutoff threshold to discriminate patients diagnosed with PsA used was eight as originally chosen. The overall sensitivity and specificity based on the cutoff threshold of eight were 91.3 and 90.9%, respectively. The Portuguese Brazilian version of the ToPAS II has good sensitivity and specificity and is a useful tool to screen for PsA. Key Points • Among these psoriasis patients, almost 35% in fact had psoriatic arthritis without correct diagnosis. Keeping alert of the need to disclose screening tool's use. • The TOPAS II can facilitate the screening of patients suggestive of inflammatory joint disease (with high probability of rheumatologic diagnosis) decreasing morbidity of these patients.

Differential expression of the inflammasome complex genes in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder involving heterogeneous clinical manifestations and numerous susceptibility genes. Several findings evidence the critical role of inflammasomes in the predisposition to autoimmune diseases and in SLE. We investigated whether inflammasome polymorphins could affect susceptibility to develop and/or severity SLE. Moreover, differences in inflammasome activation in peripheral blood were also evaluated in SLE patients and controls. The distribution of 13 SNPs in eight inflammasome genes was evaluated. To assess inflammasome priming in peripheral blood monocytes of SLE and controls, differential expression of selected inflammasome genes and IL-1ß production was analyzed in resting condition as well as after LPS and ATP stimulation. Results showed that the gain-of-function variant rs10754558 (NLRP3) was significantly more frequent in SLE patients with nephritis, reinforcing the concept of a key role of NLRP3 inflammasome not only in SLE but also especially in kidney disease. SLE monocytes in resting condition showed a higher level of IL-1ß expression and produced higher levels of IL-1ß when stimulated with LPS+ATP comparing to controls. The stimulation induced a significant expression of NLRP1, AIM2, CASP1, and IL1B genes, suggesting that the NLRP1 inflammasome is responsible for the IL-1ß production observed in monocytes. These data emphasized once more the important contribution of inflammasome in SLE-associated inflammation.

Epidemiologic Features of Systemic Vasculitides in the Southeast Region of Brazil: Hospital-Based Survey.

BACKGROUND/OBJECTIVE: The epidemiology of vasculitis is variable in different geographic areas, and this issue has not been approached in Brazil yet. The objective of this study was to assess the frequency of vasculitis in specialized centers in Brazil. METHODS: This cross-sectional study was performed in 9 vasculitis outpatient clinics from 6 different states mainly from the Southeast and the Northeast regions of Brazil between 2015 and 2017. Diagnosis and/or classification criteria for Behçet disease (BD), Takayasu arteritis (TA), giant cell arteritis (GCA), polyarteritis nodosa (PAN), granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and cryoglobulinemic vasculitis (CryoVas) were used to include patients with at least 6 months of follow-up in this hospital-based survey. RESULTS: A total of 1233 patients with systemic vasculitis were included from the Southeast region. Behçet disease was the most frequent vasculitis (35.0%) followed by TA (26.4%), GPA (16.2%), PAN (5.8%), GCA (5.8%), EGPA (4.3%), MPA (3.4%), and CryoVas (3.0%). Up to 7.8% of vasculitis patients had a juvenile onset, and the frequency of vasculitides found in children and adolescents was as follows: TA (52.6%), BD (24.7%), GPA (12.4%), and PAN (10.3%). No cases of EGPA, MPA, and CryoVas were diagnosed before the age of 18 years. As a comparator, 103 vasculitis patients were included in the Northeast of Brazil where TA was found in 36.9% and BD in 31.1% of vasculitis cases. No GCA cases were found in the Northeast part of Brazil. CONCLUSIONS: Similar to the epidemiology of vasculitis in Asia, BD and TA are the most frequent vasculitis in Southeastern Brazilian referral centers.

Lupus Nephritis Class IV-Global Is Associated with a Higher Risk of End-Stage Renal Disease than Class IV-Segmental.

INTRODUCTION: The International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification of lupus nephritis (LN) divides class IV into segmental and global (IV-S and IV-G) based on evidence suggesting different renal outcomes. However, subsequent studies have shown conflicting results. OBJECTIVE: This study was performed to compare long-term renal outcomes between the IV-S and IV-G classes. METHODS: This is a retrospective cohort study of adult patients with biopsy-proven class IV LN using the ISN/RPS classification. The primary end point was end-stage renal disease (ESRD). RESULTS: Among the 89 patients, rapidly progressive glomerulonephritis was twice as frequent in the IV-G group (60 vs. 29%; p = 0.005) than that in the IV-S group. Moreover, the IV-G group had a higher rate of biopsy with cellular and fibrocellular crescents (70.9 vs. 47.1%, p = 0.024) and more crescentic glomerulonephritis (34.5 vs. 5.8%, p = 0.007) than the IV-S group. After a mean follow-up of 57 months, the IV-G group had a greater risk of ESRD (RR 3.9; 95% CI 1.2-12.2, p = 0.006) than the IV-S group. Multivariate analysis indicated that class IV-G was an independent predictor of ESRD. CONCLUSIONS: Patients with class IV-G have a higher risk of ESRD than patients with class IV-S.

Sensitivity and specificity of Interleukin 29 in patients with rheumatoid arthritis and other rheumatic diseases.

BACKGROUND: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic and progressive inflammation that can cause a high degree of disability in affected individuals. Proinflammatory cytokines play central roles in the development of degradative and inflammatory responses in RA. IL-29 has been identified in RA and reported as a biomarker of the disease. OBJECTIVE: To analyze serum levels and accuracy of IL-29 in RA patients compared to healthy subjects and patients with other rheumatic diseases. METHODS: IL-29 serum levels were measured in 121 patients with RA, 53 patients with systemic lupus erythematosus (SLE), 60 patients with systemic sclerosis (SSc), 29 patients with fibromyalgia (FM), 50 patients with osteoarthritis (OA) and 68 healthy individuals as controls. IL-29 levels in serum were investigated by ELISA. Sensitivity, specificity and likelihood ratios (LR) for having RA were calculated. RESULTS: Serum levels of IL-29 were increased in RA patients 113.6 (IQR = 31.25-308.5) pg/ml compared to non-RA patients (SLE, SSc, OA, and FM) (31.25 pg/ml) and healthy controls (31.25 pg/ml, p < 0.001). The IL-29 cut-off values to distinguish patients with RA from non-RA patients were 61.11 pg/ml (sensitivity 57.02, specificity 92.71, LR: 7.82) and for all subjects 32.96 pg/ml (sensitivity 64.46, specificity 87.31, LR: 5.08). Additionally, IL-29 correlated negatively with age (r=-0189, p = 0.038) and disease duration (-0.192, p = 0.037). Interestingly, IL-29 correlated positively with neutrophil count in RA patients positive for rheumatoid factor (r = 0.259, p = 0.022). CONCLUSION: IL-29 is higher in the serum of patients with RA compared to non-RA subjects and may have potential for use as a biological marker.

Recommendations of the Brazilian Society of Rheumatology for the induction therapy of ANCA-associated vasculitis.

The purpose of these recommendations is to guide the appropriate induction treatment of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) patients with active disease. The recommendations proposed by the Vasculopathies Committee of the Brazilian Society Rheumatology for induction therapy of AAV, including granulomatosis with polyangiitis, microscopic polyangiitis and renal-limited vasculitis, were based on systematic literature review and expert opinion. Literature review was performed using Medline (PubMed), EMBASE and Cochrane database to retrieve articles until October 2016. PRISMA guidelines were used for the systematic review and articles were assessed according to the Oxford levels of evidence. Sixteen recommendations were made regarding different aspects of induction therapy for AAV. The purpose of these recommendations is to serve as a guide for therapeutic decisions by health care professionals in the management of AAV patients presenting active disease.

Recommendations of the Brazilian Society of Rheumatology for the induction therapy of ANCA-associated vasculitis / Recomendações da Sociedade Brasileira de Reumatologia para a terapia de indução para vasculite associada a ANCA

Abstract The purpose of these recommendations is to guide the appropriate induction treatment of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) patients with active disease. The recommendations proposed by the Vasculopathies Committee of the Brazilian Society Rheumatology for induction therapy of AAV, including granulomatosis with polyangiitis, microscopic polyangiitis and renal-limited vasculitis, were based on systematic literature review and expert opinion. Literature review was performed using Medline (PubMed), EMBASE and Cochrane database to retrieve articles until October 2016. PRISMA guidelines were used for the systematic review and articles were assessed according to the Oxford levels of evidence. Sixteen recommendations were made regarding different aspects of induction therapy for AAV. The purpose of these recommendations is to serve as a guide for therapeutic decisions by health care professionals in the management of AAV patients presenting active disease.

Resumo O objetivo destas recomendações é orientar o tratamento apropriado de indução em pacientes com vasculite associada a anticorpos anticitoplasma de neutrófilos (VAA) ativa. As recomendações propostas pelo Comitê de Vasculopatias da Sociedade Brasileira de Reumatologia para a terapia de indução para vasculites associadas aos anticorpos anticitoplasma de neutrófilos (VAA), inclusive granulomatose com poliangiite, poliangiite microscópica e vasculite limitada ao rim, foram baseadas em uma revisão sistemática da literatura e na opinião de especialistas. A revisão da literatura foi feita com as bases de dados Medline (PubMed), Embase e Cochrane para consultar artigos até outubro de 2016. As diretrizes Prisma (Preferred Reporting Items for Systematic Reviews and Meta-Analyses - Principais itens para reportar revisões sistemáticas e metanálises) foram usadas para a revisão sistemática e os artigos foram avaliados de acordo com os níveis de evidência Oxford. Dezesseis recomendações foram feitas em relação a diferentes aspectos da terapia de indução para VAA. O objetivo dessas recomendações é servir como um guia para decisões terapêuticas por profissionais da saúde no tratamento de pacientes com VAA que apresentem a doença ativa.

(18)F-Fluorodeoxyglucose positron emission tomography and serum cytokines and matrix metalloproteinases in the assessment of disease activity in Takayasu's arteritis.

OBJECTIVE: To evaluate (18)F-fluorodeoxyglucose ((18)F-FDG) uptake on positron emission tomography-computed tomography (PET-CT) and serum levels of different cytokines and matrix metalloproteinases (MMPs) in patients with Takayasu arteritis (TA) and associations with disease activity. METHODS: Serum levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-2, IL-6, IL-8, IL-12, IL-18, MMP-3 and MMP-9 were measured in 36 TA patients and 36 controls. Maximum standard uptake value (SUVmax) of (18)F-FDG in arterial walls was determined by PET-CT scans. TA patients were classified as active disease, inactive disease and possible active disease. RESULTS: Serum IL-6 and MMP-3 levels were higher in TA patients than in controls (p<0.001). Serum IL-6 was higher in patients with active disease and in patients with possible active disease than in inactive disease (p<0.0001). Patients with active disease had higher serum TNFα levels than patients with inactive disease (p=0.049) while patients with possible active disease presented higher IL-18 levels than patients with inactive disease (p=0.046). Patients with active disease had higher SUVmax values than those with inactive disease (p=0.042). By receiver operating characteristic (ROC) curve SUVmax was predictive of active disease in TA and values ≥1.3 were associated with disease activity (p=0.039). Serum TNF-α levels were higher in patients with SUVmax≥1.3 than <1.3 (p=0.045) and controls (p=0.012). Serum IL-6 levels were higher in patients with SUVmax≥1.3 than in controls (p<0.001). No differences regarding other biomarkers were found between TA patients and controls. CONCLUSIONS: Higher serum IL-6 and TNFα levels as well as higher (18)F-FDG uptake in arterial wall are associated with active TA.

18F-Fluorodeoxyglucose positron emission tomography and serum cytokines and matrix metalloproteinases in the assessment of disease activity in Takayasu's arteritis / Tomografia por emissão de pósitrons com 18F-fluordesoxiglicose e citocinas séricas e metaloproteinases da matriz na avaliação da atividade da doença na arterite de Takayasu

ABSTRACT Objective: To evaluate 18F-fluorodeoxyglucose (18F-FDG) uptake on positron emission tomography–computed tomography (PET–CT) and serum levels of different cytokines and matrix metalloproteinases (MMPs) in patients with Takayasu arteritis (TA) and associations with disease activity. Methods: Serum levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-2, IL-6, IL-8, IL-12, IL-18, MMP-3 and MMP-9 were measured in 36 TA patients and 36 controls. Maximum standard uptake value (SUVmax) of 18F-FDG in arterial walls was determined by PET–CT scans. TA patients were classified as active disease, inactive disease and possible active disease. Results: Serum IL-6 and MMP-3 levels were higher in TA patients than in controls (p < 0.001). Serum IL-6 was higher in patients with active disease and in patients with possible active disease than in inactive disease (p < 0.0001). Patients with active disease had higher serum TNFα levels than patients with inactive disease (p = 0.049) while patients with possible active disease presented higher IL-18 levels than patients with inactive disease (p = 0.046). Patients with active disease had higher SUVmax values than those with inactive disease (p = 0.042). By receiver operating characteristic (ROC) curve SUVmax was predictive of active disease in TA and values ≥1.3 were associated with disease activity (p = 0.039). Serum TNF-α levels were higher in patients with SUVmax ≥ 1.3 than <1.3 (p = 0.045) and controls (p = 0.012). Serum IL-6 levels were higher in patients with SUVmax ≥ 1.3 than in controls (p < 0.001). No differences regarding other biomarkers were found between TA patients and controls. Conclusions: Higher serum IL-6 and TNFα levels as well as higher 18F-FDG uptake in arterial wall are associated with active TA.

RESUMO Objetivo: Avaliar a captação de 18F-fluordesoxiglicose (FDG) na tomografia por emissão de pósitrons – tomografia computadorizada (PET-CT) – e os níveis séricos de diferentes citocinas e da metaloproteinases da matriz (MMP) em pacientes com arterite de Takayasu (AT) e associações com a atividade da doença. Métodos: Foram mensurados os níveis séricos do fator de necrose tumoral-α (TNF-α), interleucina (IL)-2, IL-6, IL-8, IL-12, IL-18, MMP-3 e MMP-9 em 36 pacientes com AT e 36 controles. O valor padronizado de captação máximo (SUVmax) de 18F-FDG nas paredes arteriais foi determinado por exames de PET-CT. Os pacientes com AT foram classificados como doença ativa, doença inativa e possível doença ativa. Resultados: Os níveis séricos de IL-6 e MMP-3 foram mais altos em pacientes com AT do que nos controles (p < 0,001). Os níveis séricos de IL-6 foram mais elevados em pacientes com doença ativa e em pacientes com possível doença ativa do que naqueles com doença inativa (p < 0,0001). Os pacientes com doença ativa apresentaram níveis séricos mais elevados de TNF-α do que os pacientes com doença inativa (p = 0,049), enquanto os indivíduos com possível doença ativa apresentaram maiores níveis séricos de IL-18 do que os pacientes com doença inativa (p = 0,046). Aqueles com doença ativa apresentaram maiores valores de SUVmax do que aqueles com doença inativa (p = 0,042). De acordo com a curva ROC, o SUVmax foi capaz de predizer a doença ativa na AT e valores ≥ 1,3 estavam associados à atividade da doença (p = 0,039). Os níveis séricos de TNF-α foram maiores em pacientes com SUVmax ≥ 1,3 do que naqueles com valor < 1,3 (p = 0,045) e controles (p = 0,012). Os níveis séricos de IL-6 foram mais elevados em pacientes com SUVmax ≥ 1,3 do que nos controles (p < 0,001). Não foram encontradas diferenças em relação a outros biomarcadores entre pacientes com AT e controles. Conclusões: Níveis séricos elevados de IL-6 e TNF-α, bem como uma maior captação arterial de 18F-FDG, estão associados à AT ativa.

[18F-Fluorodeoxyglucose positron emission tomography and serum cytokines and matrix metalloproteinases in the assessment of disease activity in Takayasu's arteritis]. / Tomografia por emissão de pósitrons com 18F-fluordesoxiglicose e citocinas séricas e metaloproteinases da matriz na avaliação da atividade da doença na arterite de Takayasu.

OBJECTIVE: To evaluate 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography-computed tomography (PET-CT)-and serum levels of different cytokines and matrix metalloproteinases (MMPs) in patients with Takayasu's arteritis (TA) and associations with disease activity. METHODS: Serum levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-2, IL-6, IL-8, IL-12, IL-18, MMP-3 and MMP-9 were measured in 36 TA patients and 36 controls. Maximum standard uptake value (SUVmax) of 18F-FDG in arterial walls was determined by PET-CT scans. TA patients were classified as active disease, inactive disease and possible active disease. RESULTS: Serum IL-6 and MMP-3 levels were higher in TA patients than in controls (p<0.001). Serum IL-6 was higher in patients with active disease and in patients with possible active disease than in inactive disease (p<0.0001). Patients with active disease had higher serum TNFα levels than patients with inactive disease (p=0.049) while patients with possible active disease presented higher IL-18 levels than patients with inactive disease (p=0.046). Patients with active disease had higher SUVmax values than those with inactive disease (p=0.042). By ROC curve SUVmax was predictive of active disease in TA and values ≥1.3 were associated with disease activity (p=0.039). Serum TNF-α levels were higher in patients with SUVmax ≥1.3 than<1.3 (p=0.045) and controls (p=0.012). Serum IL-6 levels were higher in patients with SUVmax ≥1.3 than in controls (p<0.001). No differences regarding other biomarkers were found between TA patients and controls. CONCLUSIONS: Higher serum IL-6 and TNFα levels as well as higher arterial 18F-FDG uptake are associated with active TA.

[Oral N-acetylcysteine in the treatment of Raynaud's phenomenon secondary to systemic sclerosis: a randomized, double-blind, placebo-controlled clinical trial]. / N-acetilcisteína oral no tratamento do fenômeno de Raynaud secundário à esclerose sistêmica: ensaio clínico randomizado, placebo-controlado e duplo-cego.

OBJECTIVE: To evaluate the safety and efficacy of N-acetylcysteine (NAC) orally on digital microcirculation blood flow in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc). METHODS: This was a randomized, double-blind, placebo-controlled trial in which 42 patients with SSc received oral NAC at a dose of 600mg tid (21 patients, mean age 45.6±9.5 years) or placebo (21 patients, mean age 45.0±12.7 years) for four weeks. The primary endpoint was the change in cutaneous microcirculation blood flow before and after cold stimulation measured by laser Doppler imaging (LDI) at weeks 0 and 4. The frequency and severity of RP and the number of digital ulcers were also measured at weeks 0 and 4. The adverse events were recorded in the fourth week. RESULTS: There was no significant change in digital blood flow assessed by LDI before or after cold stimulus after four weeks of NAC or placebo. Both groups showed significant improvement in the frequency and severity of RP attacks, with no difference between the two groups. At the end of the study, the placebo group had three digital ulcers, while the NAC group showed no ulcers. NAC was well tolerated and no patient discontinued the treatment. CONCLUSIONS: NAC orally at a dose of 1800mg/day showed no vasodilator effect on hands' microcirculation after four weeks of treatment in patients with RP secondary to SSc.

N-acetilcisteína oral no tratamento do fenômeno de Raynaud secundário à esclerose sistêmica: ensaio clínico randomizado, placebo-controlado e duplo-cego / Oral N-acetylcysteine in the treatment of Raynaud's phenomenon secondary to systemic sclerosis: A randomized, double-blind, placebo-controlled clinical trial

Objetivo Avaliar a segurança e a eficácia da N-acetilcisteína (NAC) por via oral sobre o fluxo sanguíneo da microcirculação digital em pacientes com fenômeno de Raynaud (FRy) secundário à esclerose sistêmica (ES). Métodos Este foi um estudo randomizado, duplo-cego e placebo-controlado, no qual 42 pacientes com ES receberam NAC oral na dose de 600 mg, três vezes ao dia (21 pacientes, idade média 45,6±9,5 anos) ou placebo (21 pacientes, idade média 45,0±12,7 anos) durante quatro semanas. O desfecho primário do estudo foi: melhora no fluxo sanguíneo da microcirculação cutânea antes e após estímulo frio avaliado pelo laser Doppler imaging (LDI) nas semanas 0 e 4. A frequência e a gravidade do FRy e o número de úlceras digitais também foram avaliados nas semanas 0 e 4. Os efeitos adversos foram registrados na quarta semana. Resultados Não houve mudança significativa no fluxo sanguíneo digital avaliado pelo LDI antes ou depois do estímulo frio após quatro semanas de NAC ou placebo. Ambos os grupos apresentaram melhora significativa na frequência e gravidade dos ataques de FRy, sem diferença entre os dois. O grupo placebo apresentou três úlceras digitais enquanto o grupo NAC não apresentou úlceras ao final do estudo. NAC foi bem tolerada e nenhum paciente descontinuou o tratamento. Conclusões NAC por via oral na dose de 1.800mg/dia não demonstrou efeito vasodilatador sobre a microcirculação das mãos após quatro semanas de tratamento em pacientes com FRy secundário à ES. .

Objective To evaluate the safety and efficacy of oral N-acetylcysteine (NAC) on digital microcirculation blood flow in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc). Methods This was a randomized, double-blind, placebo-controlled trial in which 42 patients with SSc received oral NAC at a dose of 600mg tid (21 patients, mean age 45.6±9.5 years) or placebo (21 patients, mean age 45.0±12.7 years) for four weeks. The primary endpoint was the change in cutaneous microcirculation blood flow before and after cold stimulation measured by laser Doppler imaging (LDI) at weeks 0 and 4. The frequency and severity of RP and the number of digital ulcers were also measured at weeks 0 and 4. The adverse events were recorded in the fourth week. Results There was no significant change in digital blood flow assessed by LDI before or after cold stimulus after four weeks of NAC or placebo. Both groups showed significant improvement in the frequency and severity of RP attacks, with no difference between the two groups. At the end of the study, the placebo group had three digital ulcers, while the NAC group showed no ulcers. NAC was well tolerated and no patient discontinued the treatment. Conclusions NAC orally at a dose of 1800mg/day showed no vasodilator effect on hands’ microcirculation after four weeks of treatment in patients with RP secondary to SSc. .

Hydroxychloroquine decreases Th17-related cytokines in systemic lupus erythematosus and rheumatoid arthritis patients.

OBJECTIVES: Hydroxychloroquine is an antimalarial agent that has been used in systemic lupus erythematosus and rheumatoid arthritis treatment for many years. Recently, novel mechanisms of action have been proposed, thereby broadening the therapeutic perspective of this medication. The purpose of this study was to evaluate the immunomodulatory activity of hydroxychloroquine in T helper 17 (Th17) cytokines in healthy individuals and patients. METHODS: Eighteen female patients with systemic lupus erythematosus (mean age 39.0±12.9 years) and 13 female patients with rheumatoid arthritis (mean age 51.5±7.7 years) were recruited from Universidade Federal de Pernambuco-Brazil. The patients were included after fulfilling four classification criteria for systemic lupus erythematosus or rheumatoid arthritis from the American College of Rheumatology. After being stimulated with phorbol 12-myristate 13-acetate and ionomycin in the absence or presence of different concentrations of hydroxychloroquine, the interleukin 6, 17 and 22 levels were quantified with an enzyme-linked immunosorbent assay in culture supernatants of peripheral blood mononuclear cells from healthy individuals and patients. RESULTS: We demonstrated that in peripheral blood mononuclear cells from healthy volunteers and in systemic lupus erythematosus and rheumatoid arthritis patients, there was a significant reduction in the IL-6, IL-17 and IL-22 supernatant levels after adding hydroxychloroquine. CONCLUSIONS Our in vitro results demonstrated that hydroxychloroquine inhibits IL-6, IL-17 and IL-22 production and contributes to a better understanding of the mechanism of action of this medication.

Hydroxychloroquine decreases Th17-related cytokines in systemic lupus erythematosus and rheumatoid arthritis patients

OBJECTIVES: Hydroxychloroquine is an antimalarial agent that has been used in systemic lupus erythematosus and rheumatoid arthritis treatment for many years. Recently, novel mechanisms of action have been proposed, thereby broadening the therapeutic perspective of this medication. The purpose of this study was to evaluate the immunomodulatory activity of hydroxychloroquine in T helper 17 (Th17) cytokines in healthy individuals and patients. METHODS: Eighteen female patients with systemic lupus erythematosus (mean age 39.0±12.9 years) and 13 female patients with rheumatoid arthritis (mean age 51.5±7.7 years) were recruited from Universidade Federal de Pernambuco-Brazil. The patients were included after fulfilling four classification criteria for systemic lupus erythematosus or rheumatoid arthritis from the American College of Rheumatology. After being stimulated with phorbol 12-myristate 13-acetate and ionomycin in the absence or presence of different concentrations of hydroxychloroquine, the interleukin 6, 17 and 22 levels were quantified with an enzyme-linked immunosorbent assay in culture supernatants of peripheral blood mononuclear cells from healthy individuals and patients. RESULTS: We demonstrated that in peripheral blood mononuclear cells from healthy volunteers and in systemic lupus erythematosus and rheumatoid arthritis patients, there was a significant reduction in the IL-6, IL-17 and IL-22 supernatant levels after adding hydroxychloroquine. CONCLUSIONS Our in vitro results demonstrated that hydroxychloroquine inhibits IL-6, IL-17 and IL-22 production and contributes to a better understanding of the mechanism of action of this medication. .

Increased serum interleukin 22 in patients with rheumatoid arthritis and correlation with disease activity.

OBJECTIVE: To analyze the role of interleukin 22 (IL-22) in rheumatoid arthritis (RA). METHODS: IL-22 serum levels were measured in 83 patients with established RA under treatment with disease-modifying antirheumatic drugs and in 30 healthy controls matched for age and sex. Patients were assessed for clinical and laboratory variables. Correlations of IL-22 serum levels with disease activity measures [Clinical Disease Activity Index (CDAI) and Disease Activity Score for 28 joints (DAS28)], serological markers, bone erosions, and demographic factors were assessed. Peripheral blood mononuclear cells (PBMC) from 30 patients with RA and 14 controls were purified and stimulated in vitro with phorbol myristate acetate (PMA)/ionomycin. IL-22 production by PBMC and in serum was investigated by ELISA. RESULTS: IL-22 levels were increased in patients with RA compared with controls (mean 432.37 pg/ml and 67.45 pg/ml, respectively; p < 0.001). Levels of IL-22 correlated with DAS28 and CDAI measures. Rheumatoid factor (RF) positivity was correlated with higher levels of IL-22 in patients with RA (mean 575.08 pg/ml; p = 0.001). The presence of bone erosions was associated with high IL-22 levels (p = 0.0001). PBMC stimulated with PMA/ionomycin expressed higher levels of IL-22 in patients with RA than controls but this was not significant (mean 584.75 pg/ml and 295.57 pg/ml; p = 0.553). CONCLUSION: IL-22 is elevated in the serum of patients with established RA. Elevated serum IL-22 allows discrimination between patients with different clinical and laboratory measures and indicates the potential of IL-22 as an additional tool for assessment of activity in RA, particularly in patients with RF antibodies and longterm disease. IL-22 is associated with bone-destructive disease.