Muscle fibre morphometric analysis (MusMA) correlates with muscle function and cardiovascular risk prognosis.

Morphometry of striated muscle fibres is critical for monitoring muscle health and function. Here, we evaluated functional parameters of skeletal and cardiac striated muscle in two experimental models using the Morphometric Analysis of Muscle Fibre tool (MusMA). The collagen-induced arthritis model was used to evaluate the function of skeletal striated muscle and the non-alcoholic fatty liver disease model was used for cardiac striated muscle analysis. After euthanasia, we used haeamatoxylin and eosin stained sections of skeletal and cardiac muscle to perform muscle fibre segmentation and morphometric analysis. Morphometric analysis classified muscle fibres into six subpopulations: normal, regular hypertrophic, irregular hypertrophic, irregular, irregular atrophic and regular atrophic. The percentage of atrophic fibres was associated with lower walking speed (p = 0.009) and lower body weight (p = 0.026), respectively. Fibres categorized as normal were associated with maximum grip strength (p < 0.001) and higher march speed (p < 0.001). In the evaluation of cardiac striated muscle fibres, the percentage of normal cardiomyocytes negatively correlated with cardiovascular risk markers such as the presence of abdominal adipose tissue (p = .003), miR-33a expression (p = .001) and the expression of miR-126 (p = .042) Furthermore, the percentage of atrophic cardiomyocytes correlated significantly with the Castelli risk index II (p = .014). MusMA is a simple and objective tool that allows the screening of striated muscle fibre morphometry, which can complement the diagnosis of muscle diseases while providing functional and prognostic information in basic and clinical research.

CCR5 promoter region polymorphisms in systemic lupus erythematosus.

This study investigated the impacts of CCR5 promoter region polymorphisms on the development of systemic lupus erythematosus (SLE) by comparing CCR5 genotypes and haplotypes from SLE patients with ethnically matched controls. A total of 382 SLE patients (289 European-derived and 93 African-derived) and 375 controls (243 European-derived and 132 African-derived) were genotyped for the CCR2-64I G > A (rs1799864), CCR5-59353 C > T (rs1799988), CCR5-59356 C > T (rs41469351), CCR5-59402 A > G (rs1800023) and CCR5-59653 C > T (rs1800024) polymorphisms through polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. Previous data from CCR5Δ32 analysis was included in the study to infer the CCR5 haplotypes and as a possible confounding factor in the binary logistic regression. European-derived patients showed a higher frequency of CCR5 wild-type genotype (conversely, a reduced frequency of Δ32 allele) and a reduced frequency of the HHG*2 haplotype compared to controls; both factors significantly affecting disease risk [p = .003 (OR 3.5, 95%CI 1.6-7.5) and 2.0% vs. 7.2% (residual p = 2.9E - 5), respectively]. Additionally, the HHA/HHB, HHC and HHG*2 haplotype frequencies differed between African-derived patients and controls [10% vs. 20.5% (residual p = .003), 29.4% vs. 17.4% (residual p = .003) and 3.9% vs. 0.8% (residual p = .023), respectively]. Considering the clinical manifestations of the disease, the CCR5Δ32 presence was confirmed as a susceptibility factor to class IV nephritis in the African-derived group and when all patients were grouped for comparison [pcorrected  = .012 (OR 3.0; 95%CI 3.0-333.3) and pcorrected  = .0006 (OR 6.8; 95%CI 1.9-24.8), respectively]. In conclusion, this study indicates that CCR5 promoter polymorphisms are important disease modifiers in SLE. Present data reinforces the CCR5Δ32 polymorphism as a protective factor for the development of the disease in European-derived patients and as a susceptibility factor for class IV nephritis in African-derived patients. Furthermore, we also described a reduced frequency of HHA/HHB and an increased frequency of HHC and HHG*2 haplotypes in African-derived patients, which could modify the CCR5 protein expression in specific cell subsets.

Factors Associated With Mortality in Patients With Immune-Mediated Rheumatic Diseases and COVID-19 From Latin America: Data From Argentina, Mexico, and Brazil.

OBJECTIVE: To describe characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with rheumatic immune-mediated inflammatory diseases (IMIDs) from Argentina, Mexico and Brazil, and to assess factors associated with mortality in this population. METHODS: Data from 3 national registries, SAR-COVID (Argentina), CMR-COVID (Mexico), and ReumaCoV-Brasil (Brazil), were combined. Adult patients with IMIDs and SARS-CoV-2 infection were recruited. Sociodemographic data, comorbidities, IMID clinical characteristics and treatment, and SARS-CoV-2 infection presentation and outcomes were recorded. RESULTS: A total of 4827 individuals were included: 2542 (52.7%) from SAR-COVID, 1167 (24.2%) from CMR-COVID, and 1118 (23.1%) from ReumaCoV-Brasil. Overall, 82.1% were female with a mean age of 49.7 (SD, 14.3) years; 22.7% of the patients were hospitalized, and 5.3% died because of COVID-19 (coronavirus disease 2019). Argentina and Brazil had both 4% of mortality and Mexico 9.4%. In the multivariable analysis, older age (≥60 years; odds ratio [OR], 7.4; 95% confidence interval [CI], 4.6-12.4), male sex (OR, 1.5; 95% CI, 1.1-2.1), living in Mexico (OR, 3.0; 95% CI, 2.0-4.4), comorbidity count (1 comorbidity: OR, 1.5; 95% CI, 1.0-2.1), diagnosis of connective tissue disease or vasculitis (OR, 1.8; 95% CI, 1.3-2.4), and other diseases (OR, 2.6; 95% CI, 1.6-4.1) compared with inflammatory joint disease, high disease activity (OR, 4.2; 95% CI, 2.5-7.0), and treatment with glucocorticoids (OR, 1.9; 95% CI, 1.4-2.5) or rituximab (OR, 4.2; 95% CI, 2.7-6.6) were associated with mortality. CONCLUSIONS: Mortality in patients with IMIDs was particularly high in Mexicans. Ethnic, environmental, societal factors, and different COVID-19 mitigation measures adopted have probably influenced these results.

Sarcopenia in Immune-Mediated Rheumatic Diseases-Review.

INTRODUCTION: Sarcopenia is a condition characterized by decreased muscle strength and muscle mass, which can impact physical function. Sarcopenia develops as a consequence of age-related decline (primary sarcopenia) and has a major impact on physical, social, and emotional well-being. In addition, patients with rheumatic diseases may suffer from sarcopenia independently of aging (secondary sarcopenia). Exercise, pharmacological treatments, and nutritional supplementation are some of the strategies used for the management of sarcopenia in the general population. The aim of this review is to summarize the evidence around the prevalence and impact of sarcopenia in patients with rheumatic diseases. CONCLUSIONS: From our review, we can state that sarcopenia is a common and prevalent condition among the rheumatic diseases. Furthermore, the impacts of sarcopenia are not well-appreciated, and the implementation of treatment strategies has not been widespread. Strategies such as exercise and some pharmacological treatments are effective in improving physical and functional impairment related to these conditions. FUTURE RESEARCH DIRECTIONS IN THE FIELD: New pharmacological treatments are being actively studied and may contribute in the future to the management of sarcopenia.

MBL2 gene polymorphisms and its relation to infection in Brazilian systemic lupus erythematosus patients: A 10-years follow-up study.

INTRODUCTION: Systemic lupus erythematosus (SLE) is a multifactorial disease and MBL2 genetic variants, which are associated to differential peripheral MBL levels, potentially affect its etiology and increase infection risk in this population. OBJECTIVE: To evaluate the potential association of MBL2 polymorphisms of the coding and promoter gene region and haplotypes on hospitalization, number of admission and days of admission for major infection causes in Brazilian SLE patients. Methods: 325 SLE patients from a southern Brazilian outpatient SLE clinic were genotyped in 2006 for MBL2 gene polymorphisms from coding and promoter region (rs1800450, rs1800451, rs5030737, rs11003125, and rs7096206) and followed until 2016. Clinical and laboratory data from each patient were obtained and information regarding the need for hospitalization, the number of admissions and number of days admitted for infection treatment were compiled and compared with MBL2 gene polymorphisms and haplotypes. A linear regression analysis was constructed considering the variables of bivariate which demonstrated an association (p<0.05) and variables which had a theoretical basement. RESULTS: No difference was found in polymorphism prevalence when comparing the group that was admitted for infection treatment and the group who did not. Allele C, and haplotypes LY and HY correlated with more infection hospitalizations [wild-type homozygosis for C: 2 (IQR 1-3), heterozygosis for C: 3 (IQR 2-6) p=0.038; LY 2 (IQR 1-3) p=0.049; HY 2 (IQR 1-3) p=0.005] and haplotype HY carriers stayed fewer days in hospital for infection treatment: 18 (IQR 10-38) p=0.041. When linear regression was applied HY associated with shorter admission time for infections (-18.11 days, p=0.021) and HY (-1.52 admission, p 0.001) carriers with older age at diagnosis had less admissions for infection (HY regression model: -0.42, p=0.006; LY regression model -0.04, p=0.010; -0.04, p=0.013). CONCLUSION: The presence of the HY promoter haplotype associated to fewer in hospital care for infection treatment probably due to higher MBL plasma levels. Also, HY haplotype and older age at SLE diagnosis is related to less admissions for infection. This factor should be taken into consideration, since infection is a very import cause of mortality in SLE patients being also related to aggressive immunosuppressive treatment.

Emerging protein kinase inhibitors for the treatment of rheumatoid arthritis.

INTRODUCTION: Protein tyrosine kinase inhibitors are emergent drugs in the treatment of rheumatoid arthritis (RA); they block the signal transduction in immune cells preventing the production and release of pro-inflammatory cytokines. AREAS COVERED: The current research aims to review the role of Janus, Bruton's and spleen kinase inhibitors for the treatment of RA. Mechanism of action, rationale for usage, and the main efficacy and safety outcomes in phase II and III clinical trials are described. EXPERT OPINION: In RA, the development of Bruton kinase inhibitors was interrupted because they failed to demonstrate superiority versus placebo. The spleen kinase inhibitors had their development deprioritized because their risk/benefit profile was unfavorable compared to janus kinase inhibitors (JAKi). JAKi proved to be effective in treatment naïve patients and in those with previous failure to methotrexate and/or biological therapy. There still remain important points about JAKi that need more studies: the clinical importance of JAKi selectivity should be further evaluated in head-to-head trials and the safety profile of JAKi, mainly regarding the risk of malignancy and thromboembolic events, must be analyzed in long-term real-life studies.

The landscape of systemic lupus erythematosus in Brazil: An expert panel review and recommendations.

PURPOSE: The objective of this review is to address the barriers limiting access to diagnosis and treatment of systemic lupus erythematosus (SLE) and lupus nephritis (LN) in Brazil, specifically for patients in the public healthcare system, arguably those with the least access to innovation. DESIGN: A selected panel of Brazilian experts in SLE/LN were provided with a series of relevant questions to address in a multi-day conference. During the conference, responses were discussed and edited by the entire group through numerous drafts and rounds of discussion until a consensus was achieved. RESULTS: The authors propose specific and realistic recommendations for implementing access to innovative diagnostic tools and treatment alternatives for SLE/LN in Brazil. Moreover, in creating these recommendations, the authors strived to address barriers and impediments for technology adoption. The multidisciplinary care required for SLE/LN necessitates the collective participation of all involved stakeholders. CONCLUSION: A great need exists to expand the adoption of innovative diagnostic tools and treatments for SLE/LN not only in Brazil but also in most countries, as access issues remain an urgent demand. The recommendations presented in this article can serve as a strategy for new technology adoption in other countries in a similar situation.

CIITA gene polymorphism (rs3087456) in systemic lupus erythematosus and rheumatoid arthritis: A population-based cohort study.

Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are influenced by genetic variants in immune system HLA genes. The Class II Major Histocompatibility Complex Transactivator (CIITA) is an important co-activator of the HLA transcriptional complex; the single nucleotide variant (SNV) rs3087456 localized in the gene promoter region (-168 A/G) has been reported as able to modify its transcription level. In our study, we assessed CIITA rs3087456 SNV in 1,044 Brazilians from two Brazilian regions (Northeast and South) to verify the association with susceptibility and clinical manifestations of (SLE) and (RA) using TaqMan SNP Genotyping Assays System. We observed a protection for a recessive model (GG x AA+AG) for RA susceptibility and increased risk for erosion development in AG genotype patients. No significant association was observed for SLE susceptibility; however, we observed significant increased risk for Class IV and V nephritis development in G allele and GG genotype patients. In conclusion, we showed the contribution of CIITA rs3087456 to SLE or RA clinical features and RA susceptibility in the studied populations.

Vitamin D and Cytokine Profiles in Patients With Systemic Sclerosis.

INTRODUCTION: Hypovitaminosis D has been frequently described in systemic sclerosis (SSc). Cytokines are important mediators of tissue damage and clinical dysfunction in SSc and may be influenced by vitamin D levels. OBJECTIVE: To evaluate the serum levels of vitamin D and its correlation with the clinical features and cytokine profiles in SSc patients. METHODS: Case-control study, including 50 SSc patients and 35 healthy non matched controls. Serum levels of 25(OH) vitamin D were measured by chemiluminescence assay, and serum concentrations of interleukin 2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor, and interferon γ were determined by flow cytometry. RESULTS: Fourteen patients (28%) had diffuse cutaneous SSc, 94% were female, 80% European derived, with a mean age of 57.2 ± 12.8 years. The serum vitamin D levels in SSc patients were 23.9 ± 8.5 ng/mL and 30.2 ± 6.2 ng/mL in the control group (standardized mean difference -6.19; 95% confidence interval, -9.9 to -2.3; p = 0.002), despite the more frequent supplementation of vitamin D in SSc patients (p = 0.014). No significant associations were found among vitamin D concentrations and cytokine levels. Serum levels of IL-6 were significantly elevated in SSc patients (p = 0.024) and were positively correlated with the modified Rodnan skin score (rs = 0.291, p =0.041). CONCLUSIONS: Despite lower vitamin D levels in SSc patients, there was no clear association with any cytokine. Serum levels of IL-6 were significantly elevated and positively correlated with the extent of skin involvement in SSc patients.

Nasal Administration of Cationic Nanoemulsions as Nucleic Acids Delivery Systems Aiming at Mucopolysaccharidosis Type I Gene Therapy.

PURPOSE: This study demonstrates the nasal administration (NA) of nanoemulsions complexed with the plasmid encoding for IDUA protein (pIDUA) as an attempt to reach the brain aiming at MPS I gene therapy. METHODS: Formulations composed of DOPE, DOTAP, MCT (NE), and DSPE-PEG (NE-PEG) were prepared by high-pressure homogenization, and assessed in vitro on human fibroblasts from MPS I patients and in vivo on MPS I mice for IDUA production and gene expression. RESULTS: The physicochemical results showed that the presence of DSPE-PEG in the formulations led to smaller and more stable droplets even when submitted to dilution in simulated nasal medium (SNM). In vitro assays showed that pIDUA/NE-PEG complexes were internalized by cells, and led to a 5% significant increase in IDUA activity, besides promoting a two-fold increase in IDUA expression. The NA of pIDUA/NE-PEG complexes to MPS I mice demonstrated the ability to reach the brain, promoting increased IDUA activity and expression in this tissue, as well as in kidney and spleen tissues after treatment. An increase in serum IL-6 was observed after treatment, although with no signs of tissue inflammatory infiltrate according to histopathology and CD68 assessments. CONCLUSIONS: These findings demonstrated that pIDUA/NE-PEG complexes could efficiently increase IDUA activity in vitro and in vivo after NA, and represent a potential treatment for the neurological impairment present in MPS I patients.

Neuromuscular fatigue is weakly associated with perception of fatigue and function in patients with rheumatoid arthritis.

To assess electromyographic parameters of neuromuscular fatigue in knee extensors and their association with clinical, functional and emotional features in patients with rheumatoid arthritis (RA). Thirty-eight female patients with RA participated. Electromyography parameters (changes in signal amplitude, represented by the root mean square, and frequency content, represented by median frequency-MDF) were assessed during a submaximal (60%) isometric contraction of the knee extensors, sustained for 60 s. Clinical characteristics; the 28-joint Disease Activity Score (DAS-28) in which includes count of swollen joints (out of the 28) and tender joints (out of the 28), the erythrocyte sedimentation rate and global disease activity measured on a visual analogue scale; serum C reactive protein (CRP); information on treatment; the Health Assessment Questionnaire; the Functional Assessment of Chronic Illness Therapy fatigue scale (FACIT-F); the Short Form Health Survey (SF-36) and the International Physical Activity Questionnaire (IPAQ), were also assessed. The mean patient age was 51.0 ± 8.2 years, mean disease activity score was 11.5 ± 7.1, and mean CRP level was 8.0 ± 7.8 mg/dL. There was a moderate correlation between MDF and age (r = 0.5), as well as weak correlations of MDF with FACIT-F (r = 0.3), physical functioning (r = - 0.3) and vitality domains (r = - 0.3) of the SF-36, and IPAQ (r = - 0.3) (p ≤ 0.05 for all). No association was observed between electromyography measurements and clinical or treatment features. The electromyographic parameter MDF was correlated with perception of fatigue, age, physical functioning and vitality domains of SF-36, and physical activity level in this sample. These results indicate that primary muscle factors should also be considered when managing perceived fatigue in patients with RA.

Long-term outcomes of treat-to-target strategy in established rheumatoid arthritis: a daily practice prospective cohort study.

To examine disease activity and physical function after implementation of treat-to-target (T2T) strategy in patients with established rheumatoid arthritis (RA) over a long-term period. Patients with RA were started on a T2T strategy in 2005 and followed through 2014. Patients were seen every 3-4 months until remission/low disease activity was achieved and every 6 months thereafter. Disease activity was measured by the DAS28 and CDAI, and physical function by the HAQ-DI. Results were presented as all observed data, without imputation for missing values. Changes in disease activity and physical function were evaluated by generalized estimating equations (GEE). Two hundred and twenty-nine patients were included, with a mean (SD) disease duration of 10.6 (7.4) years. Significant improvements were seen in both composite scores during the follow-up period, as demonstrated by DAS28 (ß coefficient = 0.19; 95% CI = 0.16-0.21; p < 0.01) and by CDAI (ß coefficient = 1.59; 95% CI = 1.84-1.34; p < 0.01). Physical function also improved, as demonstrated by HAQ-DI (ß coefficient = 0.03; 95% CI = 0.02-0.04; p < 0.01). Biological therapy was associated with improvement in disease activity and in physical function. Leflunomide was only associated with improvement in physical function. Clinically meaningful reductions of DAS28, CDAI and HAQ-DI were observed in patients with established rheumatoid arthritis from 2005 to 2014. Implementation of new therapeutic options, in the scenario of T2T strategy, was associated with improvement in disease activity and physical function.

Evaluation of cytokines, oxidative stress markers and brain-derived neurotrophic factor in patients with fibromyalgia - A controlled cross-sectional study.

OBJECTIVES: Previous studies measuring serum levels of biomarkers of inflammation/oxidative stress and neurotrophins levels in fibromyalgia (FM) have rendered inconsistent results. In the present study, our aim was to explore the levels of interleukins, oxidative stress markers and brain-derived neurotrophic factor (BDNF) in patients with FM in relation to depression and severity of disease. METHODS: In a prospective controlled cross-sectional study, serum concentrations of IL-6, IL-8, IL-10, TNF-α, thiobarbituric acid reactive substances (TBARS), protein carbonyl and BDNF were measured in 69 FM patients and 61 healthy controls (all women). In the FM group, the Fibromyalgia Impact Questionnaire (FIQ), the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HDRS) were applied. Mann Whitney's and Spearman correlation tests were used for statistical analysis. RESULTS: The FM patients demonstrated a significant impact of the disease on quality of life (FIQ 70.2±17.8) and most of them had depression at some level (82.6% and 87.0% as assessed by BDI and HDRS, respectively). Most biomarkers (IL-6, IL-8, TNF-α, TBARS and protein carbonyl) and BDNF did not differ significantly between patients and controls, but the IL-10 levels were higher in FM patients (adjusted p=0.041). Among FM patients, there was no correlation of HDRS, FIQ, and BDI scores with any biomarker tested here. CONCLUSION: We observed no significant differences in biomarkers between FM patients and controls, except for higher levels of IL-10 (an anti-inflammatory cytokine) in patients. The levels of biomarkers were not correlated with parameters of disease and depression severity.

Vitamin D receptor polymorphisms and expression profile in rheumatoid arthritis Brazilian patients.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and important joint commitment, being the most common systemic autoimmune disease worldwide. RA displays important genetic background with a variety of genes contributing to the immune balance breakdown. Recent studies have demonstrated that vitamin D, through its receptor (VDR), is able to regulate the immune balance and suppress the autoimmunity process, being a potential target in autoimmune diseases. In the present genetic association study, we assessed 5 Tag single nucleotide polymorphisms (SNPs) (rs11168268, rs2248098, rs1540339, rs4760648 and rs3890733), which cover most of the VDR gene, in three different Brazilian populations (from Northeast, Southeast and South Brazil). We also evaluated the VDR expression profile in whole blood and monocytes from RA patients. For genotyping study, 428 RA patients and 616 healthy controls were genotyped with fluorogenic allele specific probes on an ABI7500 platform. For gene expression study, VDR mRNA levels of 15 RA patients and 26 healthy individuals were assessed by RT-PCR. Our results showed that SNPs rs4760648 and rs3890733 are associated to RA susceptibility (p value = 0.0026, OR 1.31 and p value = 0.0091, OR 1.28 with statistical power = 0.999 and 0.993, respectively). Regarding RA clinical features, the studied SNPs did not show significant associations. The gene expression assays showed that VDR mRNA levels were down regulated in both whole blood (-3.3 fold) and monocytes (-3.2 fold) of RA patients when compared to healthy controls. Our results, the first reported for distinct Brazilian populations, support a role of the VDR gene in the susceptibility to RA.

SIRT1 promoter polymorphisms as clinical modifiers on systemic lupus erythematosus.

Silent mating type Information Regulator 2 homolog 1 (SIRT1) is a deacetylase protein that participates in several physiological processes with importance in transcriptional silencing, apoptosis, immune system regulation and inflammation. Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease in which upregulated expression of SIRT1 on CD4+ T lymphocytes of active patients has been reported. Also, global hypoacetylation of histones H3 and H4, with H3 hypoacetylation was correlated with a higher disease activity index. SIRT1 promoter rs12778366 and rs3758391 may account for differential expression of this molecule and the role of these variants was investigated in SLE susceptibility and morbidity. Genomic DNA was extracted from peripheral blood of 367 SLE patients and 290 healthy controls of a Southern Brazilian population. SIRT1 rs12778366 and rs3758391 were amplified through PCR and genotyped through sequencing. No statistically significant differences were observed between patients and controls for allelic, genotypic or haplotypic frequencies. Nevertheless, SIRT1 rs3758391 was not in Hardy-Weinberg equilibrium, presenting a paucity of CT heterozygous both in patients and controls. SLE patients with TT and CT genotypes displayed a higher chance of developing lupus nephritis (Pc = 0.012, OR = 2.04 95 % CI 1.32-3.14) and presented a higher disease activity index (Mean rank 170.95 vs 137.26, Pc = 0.006) when compared with CC homozygous patients. Our results suggest that SIRT1 rs3758391 modifies SLE morbidity, with rs3758391 T allele being a risk factor for nephritis and a higher SLEDAI. Nevertheless, it remains to be elucidated how SIRT1 rs3758391 functionally influences SLE severity.

Genetic polymorphisms of glutathione S-transferases and cytochrome P450 enzymes as susceptibility factors to systemic lupus erythematosus in southern Brazilian patients.

Systemic lupus erythematosus (SLE) is an autoimmune chronic inflammatory disease that presents several clinical manifestations, affecting multiple organs and systems. Immunological, environmental, hormonal and genetic factors may contribute to disease. Genes and proteins involved in metabolism and detoxification of xenobiotics are often used as susceptibility markers to diseases with environmental risk factors. Cytochrome P450 (CYP) enzymes activate the xenobiotic making it more reactive, while the Glutathione S-transferases (GST) enzymes conjugate the reduced glutathione with electrophilic compounds, facilitating the toxic products excretion. CYP and GST polymorphisms can alter the expression and catalytic activity of enzymes. This study aimed to investigate the role of genetic variants of CYP and GST in susceptibility and clinical expression of SLE, through the analysis of GSTM1 null, GSTT1 null, GSTP1*Ile105Val, CYP1A1*2C and CYP2E1*5B polymorphisms. 371 SLE patients from Hospital de Clínicas de Porto Alegre and 522 healthy blood donors from southern Brazil were evaluated. GSTP1 and CYP variants were genotyped using PCR-RFLP and GSTT1 and GSTM1 variants were analyzed by multiplex PCR. Among European-derived individuals, a lower frequency of GSTP1*Val heterozygous genotypes was found in SLE patients when compared to controls (p = 0.005). In African-derived SLE patients, the CYP2E1*5B allelic frequency was higher in relation to controls (p = 0.054). We did not observe any clinical implication of the CYP and GST polymorphisms in patients with SLE. Our data suggest a protective role of the GSTP1*Ile/Val heterozygous genotype against the SLE in European-derived and a possible influence of the CYP2E1*5B allele in SLE susceptibility among African-derived individuals.

Comparative study of two laboratory techniques for the detection of HLA-B27 in patients with axial spondyloarthritis: a cross-sectional analysis.

BACKGROUND: The diagnostic and prognostic relevance of Human Leukocyte Antigen B-27 (HLA-B27) in Axial Spondyloarthritis (AxSpA) is undeniable, with 70% of Ankylosing Spondylitis (AS) patients carrying the B27 gene, contrasted with a mere 4.35% in the general population. Flow cytometry (FC) and Polymerase Chain Reaction (PCR) have emerged as the predominant techniques for routine HLA-B27 typing. While various studies have compared these methods, none have catered to the unique characteristics of the Brazilian demographic. Therefore, this research aims to compare FC and PCR in a Brazilian cohort diagnosed with AxSpA. METHODS: An analytical cross-sectional study was undertaken involving 62 AxSpA outpatients from a Brazilian University Hospital. Both FC and PCR-SSP assays were utilized to ascertain HLA-B27 typing. The outcomes (either confirming or refuting the allele's presence) underwent rigorous scrutiny. Agreement between the methodologies was assessed using the kappa statistic. A p-value of < 0.05 was deemed statistically significant. RESULTS: Of the participants, 90.3% (n = 56) were HLA-B27 positive according to FC, while 79% (n = 49) were identified as positive using the PCR method. FC exhibited a sensitivity rate of 98% paired with a specificity of 38.5%. The Positive Predictive Value for FC stood at 85.7%, and the Negative Predictive Value was 83.5%. Consequently, the overall accuracy of the FC method was gauged at 85.5%. A kappa coefficient of κ = 0.454 was derived. CONCLUSIONS: FC demonstrated noteworthy sensitivity and satisfactory accuracy in HLA-B27 detection, albeit with a reduced specificity when contrasted with PCR-SSP. Nevertheless, given its cost-effectiveness and streamlined operation relative to PCR, FC remains a pragmatic option for preliminary screening in clinical practice, especially in low-income regions. To optimize resource allocation, we advocate for a refined algorithm that initiates by assessing the relevance of HLA-B27 typing based on Choosing Wisely recommendations. It then leans on FC, and, if results are negative yet clinical suspicion persists, advances to PCR. This approach aims to balance diagnostic accuracy and financial prudence, particularly in regions contending with escalating medical costs.

Impact of Risk Factors on COVID-19 Outcomes in Unvaccinated People With Rheumatic Diseases: A Comparative Analysis of Pandemic Epochs Using the COVID-19 Global Rheumatology Alliance Registry.

OBJECTIVE: Approximately one third of individuals worldwide have not received a COVID-19 vaccine. Although studies have investigated risk factors linked to severe COVID-19 among unvaccinated people with rheumatic diseases (RDs), we know less about whether these factors changed as the pandemic progressed. We aimed to identify risk factors associated with severe COVID-19 in unvaccinated individuals in different pandemic epochs corresponding to major variants of concern. METHODS: Patients with RDs and COVID-19 were entered into the COVID-19 Global Rheumatology Alliance Registry between March 2020 and June 2022. An ordinal logistic regression model (not hospitalized, hospitalized, and death) was used with date of COVID-19 diagnosis, age, sex, race and/or ethnicity, comorbidities, RD activity, medications, and the human development index (HDI) as covariates. The main analysis included all unvaccinated patients across COVID-19 pandemic epochs; subanalyses stratified patients according to RD types. RESULTS: Among 19,256 unvaccinated people with RDs and COVID-19, those who were older, male, had more comorbidities, used glucocorticoids, had higher disease activity, or lived in lower HDI regions had worse outcomes across epochs. For those with rheumatoid arthritis, sulfasalazine and B-cell-depleting therapy were associated with worse outcomes, and tumor necrosis factor inhibitors were associated with improved outcomes. In those with connective tissue disease or vasculitis, B-cell-depleting therapy was associated with worse outcomes. CONCLUSION: Risk factors for severe COVID-19 outcomes were similar throughout pandemic epochs in unvaccinated people with RDs. Ongoing efforts, including vaccination, are needed to reduce COVID-19 severity in this population, particularly in those with medical and social vulnerabilities identified in this study.

Assessment of muscle mass using chest computed tomography-based quantitative and qualitative measurements in patients with systemic sclerosis: A retrospective study with cross-sectional and longitudinal analyses.

BACKGROUND/ PURPOSE: Sarcopenia has been increasingly studied in systemic sclerosis (SSc), which is one of the most lethal autoimmune diseases, mainly due to lung involvement. Our objective was to study the associations of myopenia and/or myosteatosis with clinical features of SSc and subsequent adverse outcomes. METHODS: This is a retrospective study with cross-sectional and longitudinal analyses, in which patients with SSc were consecutively included in the outpatient clinic of a tertiary university hospital between 2012 and 2021. Clinical and laboratory parameters of patients with SSc were collected from their medical records. Skeletal muscle mass was assessed on chest computed tomography (CT) at the level of the first lumbar vertebra (L1) by skeletal muscle area (SMA), skeletal muscle index ([SMI] SMA/height2), and skeletal muscle radiation attenuation (SMRA). Cut-off values for myopenia in women and men were SMA <70.1 cm² and <110.4 cm², and SMI <25.9 cm²/m² and <34.6 cm²/m², respectively; values for myosteatosis in women and men were SMRA <29.8 HU and <36.3 HU, respectively. In a subgroup of 31 patients followed-up between 2017 and 2019, the diagnostic properties of SMA, SMI, and SMRA by CT were compared with the appendicular skeletal muscle mass index (ASMI) by dual-energy X-ray absorptiometry (DXA). Low muscle quantity was defined according to the European Working Group on Sarcopenia in Older People 2: ASMI <5.5 kg/m2 in women and <7.0 kg/m2 in men. Afterwards, a better tomographic index was used for correlating with clinical and laboratory parameters. RESULTS: Myopenia and/or myosteatosis were present in 75.7 % of patients with SSc. The prevalence rates according to each index were SMA 25.2%, SMI 12.1%, and SMRA 69.2%. In 73% of the patients with overweight/obesity (body mass index [BMI] ≥25 kg/m²), only SMRA was reduced. Considering ASMI as the gold standard, the sensitivity, specificity, positive and negative predictive values for SMA were 60%, 96.2%, 75% and 92.6%, respectively; for SMI, they were 40%, 96.2%, 66.7%, and 89.3%, respectively; for SMRA, these values were 60%, 34.6%, 15%, and 81.8%. Pearson's correlation coefficients were 0.73, 0.74, and 0.10 for SMA, SMI, and SMRA, respectively, and ASMI significantly agreed with SMA (kappa 0.611, p < 0.001) and SMI (kappa 0.431, p = 0.012). After adjustments in a multivariate model, BMI (p < 0.001) and female sex (p < 0.001) remained significantly associated with myopenia by SMA; BMI (p =0.010) remained significantly associated with low muscle mass by ASMI. CONCLUSION: The SMA index at L1 level on chest CT was demonstrated to be an accurate measure that is useful for detecting myopenia in patients with SSc. BMI and male sex predicted low SMA and BMI was associated with low ASMI on DXA. STATEMENT OF CLINICAL SIGNIFICANCE: In recent years, great advances have been made in sarcopenia-related research, resulting in broader knowledge on its definition, causes, diagnosis, and treatment options. Regarding the techniques used for assessing muscle composition, computed tomography (CT) was demonstrated by many studies to be an efficient and easy-to-use method that can be employed by professionals of different specialties, including rheumatologists. This study was able to demonstrate that although the L3 image was not present on CT, the analysis of SMA at the L1 level on chest CT proved to be an accurate and useful measure to detect myopenia in patients with SSc. This study identified some associated factors of myopenia and/or myosteatosis according to each method employed for assessing muscle composition. Reduced BMI and male sex were associated factors of myopenia when using SMA, and reduced BMI was associated with myopenia when employing ASMI by DXA. Finally, we highlight the need not to generalize the term "sarcopenia" in clinical studies assessing imaging parameters of body composition. The use of the terms myopenia and/or myosteatosis would be more adequate, because CT allows the assessment of muscle composition and not strength or physical performance.

Systemic lupus erythematosus: a systematic review with meta-analysis on muscle strength, muscle mass, and physical function.

To perform a systematic review with meta-analysis to verify muscle strength, muscle mass, and physical function of patients with systemic lupus erythematosus (SLE) and compare then with healthy individuals and patients with rheumatoid arthritis (RA). A systematic review with meta-analysis of observational studies published in English up to 2022 was performed using MEDLINE (via PubMed) and other relevant sources. Search strategies were based on pre-defined keywords and medical subject headings. The methodological quality of the studies was assessed using the Newcastle-Ottawa Scale. Mean difference (MD) or standardized mean difference (SMD) and 95% confidence intervals (CI) were combined using a random-effects model. Sensitivity analyses were performed when necessary. The significance level was set at p < 0.05. The systematic review included 19 studies and the meta-analysis included 11 studies. SLE patients appear to have less muscle strength assessed by handgrip than healthy controls (SLE = 21.74 kg; healthy controls = 29.34 kg; p < 0.05). SLE patients seem to have greater strength than patients with RA, but this difference was not statistically significant (RA = 17.24 kg; p = 0.210). However, in the sensitivity analysis, SLE group without deforming arthropathy showed higher muscle strength than the RA (p = 0.0001). SLE patients with deforming arthropathy have lower muscle strength compared to SLE patients without deforming arthropathy (p < 0.01). Muscle mass was similar in SLE patients compared to the RA group and healthy controls (p > 0.05). However, RA patients have a higher BMI than the two groups (p < 0.05). Patients with SLE have regular physical function. Muscle strength is affected in SLE patients. SLE patients with deforming arthropathy have less muscle strength than patients without deforming arthropathies.