Factors associated with poor outcomes in SLE patients with COVID-19: Data from ReumaCoV-Brazil register.

OBJECTIVES: To evaluate factors associated with COVID-19 severity outcomes in patients with systemic lupus erythematosus (SLE). METHODS: This was a cross-sectional analysis of baseline data of a prospective, multi-stage cohort study-"The ReumaCoV Brazil"-designed to monitor patients with immune-mediated rheumatologic disease (IMRD) during the SARS-CoV-2 pandemic. SLE adult patients with COVID-19 were compared with those without COVID-19. SLE activity was evaluated by the patient global assessment (PGA) and SLE Disease Activity Index 2000 (SLEDAI-2K). RESULTS: 604 SLE patients were included, 317 (52.4%) with COVID-19 and 287 (47.6%) in the control group. SLE COVID-19 patients reported a lower frequency of social isolation and worked more frequently as health professionals. There was no difference in the mean SLEDAI-2K score between groups in the post-COVID-19 period (5.8 [8.6] vs. 4.5 [8.0]; p = 0.190). However, infected patients reported increased SLE activity according to the Patient Global Assessment (PGA) during this period (2.9 [2.9] vs. 2.3 [2.6]; p = 0.031. Arterial hypertension (OR 2.48 [CI 95% 1.04-5.91], p = 0.041), cyclophosphamide (OR 14.32 [CI 95% 2.12-96.77], p = 0.006), dyspnea (OR: 7.10 [CI 95% 3.10-16.23], p < 0.001) and discontinuation of SLE treatment medication during infection (5.38 [CI 95% 1.97-15.48], p = 0.002), were independently associated with a higher chance of hospitalization related to COVID-19. Patients who received telemedicine support presented a 67% lower chance of hospitalization (OR 0.33 [CI 95% 0.12-0.88], p = 0.02). CONCLUSION: Hypertension and cyclophosphamide were associated with a severe outcome, and telemedicine can be a useful tool for SLE patients with COVID-19.

Incidence and risk factors for moderate/severe COVID-19 in rheumatic diseases patients on hydroxychloroquine: a 24-week prospective cohort.

OBJECTIVES: To evaluate the incidence of COVID-19 and its main outcomes in rheumatic disease (RD) patients on hydroxychloroquine (HCQ) compared to household cohabitants (HC). METHODS: This is a 24-week nationwide prospective multi-centre cohort with a control group without RD and not using HCQ. All participants were monitored through scheduled phone interviews performed by health professionals. Details regarding COVID-19 symptoms, and epidemiological, clinical, and demographic data were recorded on a specific web-based platform. COVID-19 was defined according to the Brazilian Ministry of Health criteria and classified as mild, moderate or severe. RESULTS: A total of 9,585 participants, 5,164 (53.9%) RD patients on HCQ and 4,421 (46.1%) HC were enrolled from March 29th, 2020 to September 30th, 2020, according to the eligibility criteria. COVID-19 confirmed cases were higher in RD patients than in cohabitants [728 (14.1%) vs. 427 (9.7%), p<0.001] in a 24-week follow-up. However, there was no significant difference regarding outcomes related to moderate/ severe COVID-19 (7.1% and 7.3%, respectively, p=0.896). After multiple adjustments, risk factors associated with hospitalisation were age over 65 (HR=4.5; 95%CI 1.35-15.04, p=0.014) and cardiopathy (HR=2.57; 95%CI 1.12-5.91, p=0.026). The final survival analysis demonstrated the probability of dying in 180 days after a COVID-19 diagnosis was significantly higher in patients over 65 years (HR=20.8; 95%CI 4.5-96.1) and with 2 or more comorbidities (HR=10.8; 95%CI 1.1-107.9 and HR=24.8; 95%CI 2.5-249.3, p=0.006, respectively). CONCLUSIONS: Although RD patients have had a higher COVID-19 incidence than individuals from the same epidemiological background, the COVID-19 severity was related to traditional risk factors, particularly multiple comorbidities and age, and not to underlying RD and HCQ.

Infection in Hospitalized Patients With Systemic Lupus Erythematosus: Proposal of an Algorithm for Diagnosis.

BACKGROUND: Identification of infection in patients with systemic lupus erythematosus (SLE) is a major challenge in clinical practice. OBJECTIVE: This medical records review study evaluated clinical markers, including the performance of C-reactive protein (CRP), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) in the diagnosis of infection in SLE patients. METHODS: One hundred four SLE patients hospitalized between 2014 and 2018 were allocated into 3 groups, namely, infection, infection and disease activity, and isolated disease activity. Groups were compared in relation to clinical and laboratory variables. Accuracy measures were calculated for CRP, NLR, and PLR. RESULTS: C-reactive protein, NLR, and PLR differed between the groups with higher values observed in the infected group, intermediate values in the mixed group, and lower values in the group with isolated activity-CRP (56 vs 26 vs 15 mg/dL, p = 0.002), NLR (7.9 vs 4.0 vs 3.1, p = 0.005), and PLR (270 vs 227 vs 134, p = 0.025). Fever, tachypnea, and PLR were independently associated with infection. The cutoff points of the CRP of 20 mg/L, NLR of 3.5, and PLR of 151.4 presented values of sensitivity and specificity for the prediction of infection equal to 67% and 67%, 65% and 58%, and 71% and 53%, respectively. The developed algorithm showed a sensitivity of 86.6% and specificity of 81% for the diagnosis of infection. CONCLUSIONS: The combined use of clinical and laboratory markers presented superior accuracy than their isolated use, suggesting a great potential for the application of the algorithm in clinical practice.

Clinical and microbiological effects of non-surgical periodontal treatment in individuals with rheumatoid arthritis: a controlled clinical trial.

The effect of periodontal treatment on clinical, microbiological and serological parameters of patients with rheumatoid arthritis (RA) are scarce and controversial. The aim of this study was to investigate the influence of non-surgical periodontal treatment on clinical periodontal status, subgingival bacterial levels of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola and RA activity through a controlled clinical trial on individuals with RA and periodontitis (PE). From a convenience sample, 107 individuals were considered eligible and consecutively allocated in four groups: (1) individuals without PE and RA (- PE-RA, n = 30); (2) individuals without PE and with RA (- PE + RA, n = 23); (3) individuals with PE and RA (+ PE + RA, n = 24); and (4) individuals with PE and without RA (+ PE-RA, n = 30). Full-mouth periodontal clinical examinations, microbiological analysis and Disease Activity Score (DAS-28) evaluations were performed at baseline (T1) and 45 days after non-surgical periodontal treatment (T2). At T1, individuals + PE + RA showed greater severity of PE than + PE-RA individuals. At T2, significant reductions were observed in all periodontal clinical parameters in both groups (p < 0.001) with a significant reduction in DAS-28 in + PE + RA (p = 0.011). Individuals + PE-RA and + PE-RA showed significant reductions for all bacteria (p < 0.001). Additionally, P. gingivalis demonstrated an expressively significant reduction in + PE + RA (p < 0.001). Non-surgical periodontal treatment was effective on improving the clinical periodontal condition, improving the RA clinical status and reducing the presence of periodontal pathogens. Brazilian Registry of Clinical Trials (ReBEC) protocol #RBR-8g2bc8 ( https://www.ensaiosclinicos.gov.br/rg/RBR-8g2bc8/ ).

Immunological signatures in saliva of systemic lupus erythematosus patients: influence of periodontal condition.

OBJECTIVES: The immune system has an important role in the development of systemic lupus erythematosus (SLE) and chronic periodontitis (CP). Altered cytokines levels characterise both diseases and contributes to periodontal tissue damage in CP and to macrocomplexes deposition with connective tissue destruction in SLE. This study aimed to evaluate the production of salivary cytokines in patients with SLE and its association with periodontal status. METHODS: The sample comprised 70 SLE patients and 70 paired controls. SLE activity and damage were scored using Systemic Lupus Erythematosus Disease Activity Index 2000 and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. Subjects were classified as without or with CP. Salivary concentrations of IL-33, MMP2/TIMP2, RANK and OPG were measured by ELISA, while IL-2, IFNγ, TNFα, IL-4, IL-6, IL-10 and IL-17A were determined by Cytometric Bead Array. Linear regression models analysed association among SLE, CP and salivary cytokines. RESULTS: IL-6 and IL-17A concentrations were significantly higher in SLE/CP patients than controls/CP. Concentrations of IL-6, IL-17A and IL-33 were increased in SLE/CP individuals when compared to SLE without CP. Multivariate model revealed association of cumulative dose of corticoids with periodontal damage and of IL-33 salivary concentration with SLE activity. CONCLUSIONS: Our findings suggest that long-term therapy with corticoids would contribute with periodontal destruction in SLE patients. Moreover, the increased levels of IL-6, IL-17A and IL-33 in saliva of SLE subjects with CP may signal it as possible inflammatory pathways in this process.

Serum calprotectin is a biomarker of carotid atherosclerosis in patients with primary Sjögren's syndrome.

OBJECTIVES: We aimed to identify the association of carotid atherosclerosis with the traditional risk factors, disease features, cytokine profile, and calprotectin in patients with primary Sjögren's syndrome (pSS). METHODS: 63 primary pSS patients and 63 age- and sex-matched healthy controls underwent carotid ultrasound, clinical and laboratory examination. The presence of carotid plaques was taken as carotid atherosclerosis. The covariates of carotid atherosclerosis were identified in univariate and multivariate regressions. RESULTS: Patients with pSS had higher prevalence of carotid atherosclerosis (13% vs. 2%, p<0.05) and higher serum levels of calprotectin, tumour necrosis factor receptor 2 (TNF-R2), hepatocyte growth factor (HGF), and monocyte chemoattractant protein-1 (MCP-1) than controls. Sex, menopause, and the prevalence of traditional cardiovascular did not differ between groups (all p>0.05). In univariate analyses, serum calprotectin, most traditional cardiovascular (age, male sex, metabolic syndrome, hypertension, hypertriglyceridaemia, and serum creatinine), and some disease-associated risk factors (glucocorticoid or saliva substitute use, constitutional domain of Eular-Sjögren's syndrome disease activity index - EULAR) were associated with a higher risk for plaque. In a multivariate analysis, having pSS and higher serum calprotectin were associated with carotid atherosclerosis independent of traditional risk factors. CONCLUSIONS: pSS have a higher prevalence of carotid atherosclerosis, which is associated with higher serum calprotectin level independent of traditional cardiovascular risk factors. Our findings suggest calprotectin as a biomarker of subclinical atherosclerosis in pSS.

Regular menstrual cycles do not rule out ovarian damage in adult women with systemic lupus erythematosus.

The aim of this study was to evaluate ovarian reserve markers in women with systemic lupus erythematosus (SLE) and regular menstrual cycles, and explore the relationship of such markers with clinical and treatment features. This was a case-control study including 27 women with SLE and 27 controls. All participants were aged 18-40 years, were eumenorrheic and had not used hormone therapy or hormone contraceptives in the past six months. Clinical manifestations of SLE, past and current use of immunosuppressive therapy and organ damage index were assessed at a regular follow-up visit, while antral follicle count (AFC), serum anti-Mullerian hormone (AMH) and follicle-stimulating hormone (FSH) were assessed at early follicular phase of menstrual cycle. AFC was significantly reduced in SLE women [median (interquartile interval) 7 (5-11) versus 11 (7-12), p = 0.029]. AMH levels were more heterogeneous in SLE patients compared to the control group [1.23 (0.24-4.63) ng/ml versus 1.52 (1.33-1.88) ng/ml]. The SLE and control groups had similar serum FSH levels [6.44 (4.19-7.69) versus 7.5 (6.03-8.09) IU/L, p = 0.135]. AFC was inversely correlated with organ damage index (p = 0.046) and cumulative dose of cyclophosphamide (p = 0.028), while AMH levels were negatively correlated with the maximal dose of corticosteroid ever used (p = 0.003). These findings suggest that ovarian reserve may be decreased in women with SLE despite regular menstrual cycles.

Oral health education for systemic sclerosis patients: A booklet report.

Purpose/objectives: Systemic sclerosis (SSc) is a rare chronic autoimmune disease characterized by vascular abnormalities and connective tissue disorders. In 2021, the multidisciplinary team of the university hospital recognized a demand for oral health information among SSc patients. This study aims to describe the development of an SSc oral health booklet and its validation by people with SSc. Methods: For the development of the booklet, the project creators employed the action research methodology involving ten stages. SSc patients evaluated the material by filling out a digital form. Results: One hundred and thirty-one people with SSc evaluated the booklet. It received an average score of 9.73 (SD: 0.80) in relevance, 9.82 (SD: 0.47) in explicitness, and 9.49 (SD: 0.93) in aesthetics. The final version was emailed to the participants and posted on social media. Innovation: This is the first booklet that deeply addresses these issues in Portuguese and constitutes a soft technology to instruct and assist patients with SSc. Conclusion: The production of high-quality educational materials on oral health for patients with SSc is necessary. The online distribution increased its reach and had great importance in the context of the COVID-19 pandemic.

PET/CT and inflammatory mediators in systemic sclerosis-associated interstitial lung disease.

OBJECTIVE: To investigate the correlation of HRCT findings with pulmonary metabolic activity in the corresponding regions using 18F-FDG PET/CT and inflammatory markers in patients with systemic sclerosis (SSc)-associated interstitial lung disease (ILD). METHODS: This was a cross-sectional study involving 23 adult patients with SSc-associated ILD without other connective tissue diseases. The study also involved 18F-FDG PET/CT, HRCT, determination of serum chemokine levels, clinical data, and pulmonary function testing. RESULTS: In this cohort of patients with long-term disease (disease duration, 11.8 ± 8.7 years), a nonspecific interstitial pneumonia pattern was found in 19 (82.6%). Honeycombing areas had higher median standardized uptake values (1.95; p = 0.85). Serum levels of soluble tumor necrosis factor receptor 1, soluble tumor necrosis factor receptor 2, C-C motif chemokine ligand 2 (CCL2), and C-X-C motif chemokine ligand 10 were higher in SSc patients than in controls. Serum levels of CCL2-a marker of fibroblast activity-were correlated with pure ground-glass opacity (GGO) areas on HRCT scans (p = 0.007). 18F-FDG PET/CT showed significant metabolic activity for all HRCT patterns. The correlation between serum CCL2 levels and GGO on HRCT scans suggests a central role of fibroblasts in these areas, adding new information towards the understanding of the mechanisms surrounding cellular and molecular elements and their expression on HRCT scans in patients with SSc-associated ILD. CONCLUSIONS: 18F-FDG PET/CT appears to be unable to differentiate the intensity of metabolic activity across HRCT patterns in chronic SSc patients. The association between CCL2 and GGO might be related to fibroblast activity in these areas; however, upregulated CCL2 expression in the lung tissue of SSc patients should be investigated in order to gain a better understanding of this association.

COVID-19 was not associated or trigger disease activity in spondylarthritis patients: ReumaCoV-Brasil cross-sectional data.

OBJECTIVES: To evaluate the disease activity before and after COVID-19 and risk factors associated with outcomes, including hospitalization, intensive care unit (ICU) admission, mechanical ventilation (MV) and death in patients with spondylarthritis (SpA). METHODS: ReumaCoV Brazil is a multicenter prospective cohort of immune-mediated rheumatic diseases (IMRD) patients with COVID-19 (case group), compared to a control group of IMRD patients without COVID-19. SpA patients enrolled were grouped as axial SpA (axSpA), psoriatic arthritis (PsA) and enteropathic arthritis, according to usual classification criteria. RESULTS: 353 SpA patients were included, of whom 229 (64.9%) were axSpA, 118 (33.4%) PsA and 6 enteropathic arthritis (1.7%). No significant difference was observed in disease activity before the study inclusion comparing cases and controls, as well no worsening of disease activity after COVID-19. The risk factors associated with hospitalization were age over 60 years (OR = 3.71; 95% CI 1.62-8.47, p = 0.001); one or more comorbidities (OR = 2.28; 95% CI 1.02-5.08, p = 0.001) and leflunomide treatment (OR = 4.46; 95% CI 1.33-24.9, p = 0.008). Not having comorbidities (OR = 0.11; 95% CI 0.02-0.50, p = 0.001) played a protective role for hospitalization. In multivariate analysis, leflunomide treatment (OR = 8.69; CI = 95% 1.41-53.64; p = 0.023) was associated with hospitalization; teleconsultation (OR = 0.14; CI = 95% 0.03-0.71; p = 0.01) and no comorbidities (OR = 0.14; CI = 95% 0.02-0.76; p = 0.02) remained at final model as protective factor. CONCLUSIONS: Our results showed no association between pre-COVID disease activity or that SARS-CoV-2 infection could trigger disease activity in patients with SpA. Teleconsultation and no comorbidities were associated with a lower hospitalization risk. Leflunomide remained significantly associated with higher risk of hospitalization after multiple adjustments.

Biomarkers of cytokine storm as red flags for severe and fatal COVID-19 cases: A living systematic review and meta-analysis.

OBJECTIVE: To describe the laboratory parameters and biomarkers of the cytokine storm syndrome associated with severe and fatal COVID-19 cases. METHODS: A search with standardized descriptors and synonyms was performed on November 28th, 2020 of the MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, LILACS, and IBECS to identify studies of interest. Grey literature searches and snowballing techniques were additionally utilized to identify yet-unpublished works and related citations. Two review authors independently screened the retrieved titles and abstracts, selected eligible studies for inclusion, extracted data from the included studies, and then assessed the risk of bias using the Newcastle-Ottawa Scale. Eligible studies were those including laboratory parameters-including serum interleukin-6 levels-from mild, moderate, or severe COVID-19 cases. Laboratory parameters, such as interleukin-6, ferritin, hematology, C-Reactive Protein, procalcitonin, lactate dehydrogenase, aspartate aminotransferase, creatinine, and D-dimer, were extracted from the studies. Meta-analyses were conducted using the laboratory data to estimate mean differences with associated 95% confidence intervals. DATA SYNTHESIS: The database search yielded 9,620 records; 40 studies (containing a total of 9,542 patients) were included in the final analysis. Twenty-one studies (n = 4,313) assessed laboratory data related to severe COVID-19 cases, eighteen studies (n = 4,681) assessed predictors for fatal COVID-19 cases and one study (n = 548) assessed laboratory biomarkers related to severe and fatal COVID-19 cases. Lymphopenia, thrombocytopenia, and elevated levels of interleukin-6, ferritin, D-dimer, aspartate aminotransferase, C-Reactive-Protein, procalcitonin, creatinine, neutrophils and leucocytes were associated with severe and fatal COVID-19 cases. CONCLUSIONS: This review points to interleukin-6, ferritin, leukocytes, neutrophils, lymphocytes, platelets, C-Reactive Protein, procalcitonin, lactate dehydrogenase, aspartate aminotransferase, creatinine, and D-dimer as important biomarkers of cytokine storm syndrome. Elevated levels of interleukin-6 and hyperferritinemia should be considered as red flags of systemic inflammation and poor prognosis in COVID-19.

Characteristics associated with COVID-19 vaccine hesitancy: A nationwide survey of 1000 patients with immune-mediated inflammatory diseases.

OBJECTIVES: To identify potential predictors of COVID-19 vaccine hesitancy (C19-VH) in adults with immune-mediated inflammatory diseases (IMID). METHODS: A total of 1000 IMID patients were enrolled in this web-based cross-sectional study. A standardised and self-administered survey was designed by members of the Brazilian Society of Rheumatology Steering Committee for Infectious and Endemic diseases and distributed to IMID patients spread across Brazil. RESULTS: Of the 908 (90.8%) respondents eligible for analysis, 744 (81.9%) were willing to get vaccinated against COVID-19. In our multivariable logistic regression model, concurrent malignancy, fibromyalgia, hydroxychloroquine use, and recent corticosteroid pulse therapy were independently associated with higher odds of C19-VH. The short duration of COVID-19 vaccine clinical trials was the main reason for C19-VH. CONCLUSION: We identified novel characteristics potentially associated with C19-VH among adults with IMID. Greater awareness on the safety and efficacy of COVID-19 vaccines is needed for both IMID patients and attending physicians.

PET/CT and inflammatory mediators in systemic sclerosis-associated interstitial lung disease / PET/TC e mediadores inflamatórios na doença pulmonar intersticial associada à esclerose sistêmica

ABSTRACT Objective: To investigate the correlation of HRCT findings with pulmonary metabolic activity in the corresponding regions using 18F-FDG PET/CT and inflammatory markers in patients with systemic sclerosis (SSc)-associated interstitial lung disease (ILD). Methods: This was a cross-sectional study involving 23 adult patients with SSc-associated ILD without other connective tissue diseases. The study also involved 18F-FDG PET/CT, HRCT, determination of serum chemokine levels, clinical data, and pulmonary function testing. Results: In this cohort of patients with long-term disease (disease duration, 11.8 ± 8.7 years), a nonspecific interstitial pneumonia pattern was found in 19 (82.6%). Honeycombing areas had higher median standardized uptake values (1.95; p = 0.85). Serum levels of soluble tumor necrosis factor receptor 1, soluble tumor necrosis factor receptor 2, C-C motif chemokine ligand 2 (CCL2), and C-X-C motif chemokine ligand 10 were higher in SSc patients than in controls. Serum levels of CCL2-a marker of fibroblast activity-were correlated with pure ground-glass opacity (GGO) areas on HRCT scans (p = 0.007). 18F-FDG PET/CT showed significant metabolic activity for all HRCT patterns. The correlation between serum CCL2 levels and GGO on HRCT scans suggests a central role of fibroblasts in these areas, adding new information towards the understanding of the mechanisms surrounding cellular and molecular elements and their expression on HRCT scans in patients with SSc-associated ILD. Conclusions: 18F-FDG PET/CT appears to be unable to differentiate the intensity of metabolic activity across HRCT patterns in chronic SSc patients. The association between CCL2 and GGO might be related to fibroblast activity in these areas; however, upregulated CCL2 expression in the lung tissue of SSc patients should be investigated in order to gain a better understanding of this association.

RESUMO Objetivo: Investigar a correlação entre achados de TCAR e a atividade metabólica pulmonar nas regiões correspondentes por meio de PET/TC com 18F-FDG e marcadores inflamatórios em pacientes com doença pulmonar intersticial (DPI) associada à esclerose sistêmica (ES). Métodos: Estudo transversal envolvendo 23 pacientes adultos com DPI associada à ES sem outras doenças do tecido conjuntivo. O estudo também envolveu PET/TC com 18F-FDG, TCAR, dosagem sérica de quimiocinas, dados clínicos e testes de função pulmonar. Resultados: Nessa coorte de pacientes com doença de longa duração (11,8 ± 8,7 anos), 19 (82,6%) apresentaram o padrão de pneumonia intersticial não específica. A mediana dos valores padronizados de captação foi maior nas áreas de faveolamento (1,95; p = 0,85). Os níveis séricos de soluble tumor necrosis factor receptor 1, soluble tumor necrosis factor receptor 2, C-C motif chemokine ligand 2 (CCL2) e C-X-C motif chemokine ligand 10 foram maiores nos pacientes com ES que nos controles. Os níveis séricos de CCL2 - um marcador de atividade fibroblástica - correlacionaram-se com áreas de opacidade em vidro fosco (OVF) pura na TCAR (p = 0,007). A PET/TC com 18F-FDG mostrou atividade metabólica significativa para todos os padrões de TCAR. A correlação entre níveis séricos de CCL2 e OVF na TCAR sugere que os fibroblastos desempenham um papel fundamental nessas áreas, acrescentando novas informações para a compreensão dos mecanismos que envolvem elementos celulares e moleculares e sua expressão na TCAR em pacientes com DPI associada à ES. Conclusões: A PET/TC com 18F-FDG aparentemente não consegue diferenciar a intensidade da atividade metabólica nos diferentes padrões de TCAR em pacientes com ES crônica. A associação entre CCL2 e OVF pode estar relacionada à atividade fibroblástica nessas áreas; entretanto, a expressão suprarregulada de CCL2 no tecido pulmonar de pacientes com ES deve ser investigada para que se compreenda melhor essa associação.