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Dry eye disease (DED) is common in Rheumatoid Arthritis (RA) patients. The application of conjunctival goblet cell count as a clinical biomarker to diagnose and respond to treatment can take place in rheumatoid arthritis patients under TNF-inhibitors (TNFi) therapy. This study aimed to investigate the ocular surface parameters and the long-term effects of TNFi therapy on ocular surface features and goblet cell count of rheumatoid arthritis patients. At baseline, rheumatoid arthritis patients eligible to TNFi were compared to healthy controls (similar age/gender), regarding Ocular Surface Disease Index (OSDI) questionnaire, Schirmer I test, tear break-up time test, vital dye staining of the ocular surface, and conjunctival impression cytology. DED severity grade, impression cytology score, and goblet cell count were analyzed. Rheumatoid arthritis patients were followed after three (3 M) and 12 months (12 M), during TNFi treatment. Sixteen rheumatoid arthritis patients and 24 controls were compared: a higher frequency of abnormal OSDI (68.8% vs. 16.7%, p  = 0.002), Schirmer’s test < 10 mm (37.5% vs. 8.3%, p  = 0.042), meibomian gland dysfunction (50% vs. 8.3%, p  = 0.007), abnormal impression cytology (75% vs. 8.3%, p  < 0.001), and mild to moderate DED (81.3% vs. 4.2%, p  < 0.001) were observed in rheumatoid arthritis patients, who also had lower goblet cell count [325 (274–707) cells/mm 2 vs. 742 (562–863) cells/mm 2 , p  = 0.004]. The presence of Meibomian gland dysfunction was associated with higher disease activity scores ( p  < 0.05). The prospective early observation of these patients at 3 M showed an increase improvement in tear production by Schirmer’s test [13 (7.5–17.5) vs. 23.5 (16–35); p  = 0.001], and an improvement in impression cytology score [1 (0.5–2) vs. 1 (0–1), p  = 0.031] and in goblet cell count [325 (274–707) vs. 931 (656–1,244), p  < 0.001]. Eight RA responders to TNFi were also re-evaluated at 12 M with further improvement in goblet cell count [393 (275–827) vs. 872 (502–1,185) vs. 1,079 (867–1,244), p  = 0.047]. Multifactorial DED is frequent in RA patients, comprising aqueous, lipid, and mucin components. TNFi prompt improves tear production and recovers the goblet cells, which can be a biomarker of the pathological process and response to therapy in this population.

ObjectivesTo evaluate the tuberculin skin test (TST) conversion in chronic inflammatory arthropathies (CIA) patients on TNFα inhibitors (TNFi) and without previous latent tuberculosis infection (LTBI) treatment.MethodsPatients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) with negative LTBI were retrospectively evaluated for TST conversion and active tuberculosis (TB) after six months of exposition to TNFi. Two groups were compared: patients who repeated TST (TST-repetition) during the follow-up and patients who did not (non-TST-repetition).ResultsA total of 355 CIA patients on TNFi were screened and 138 (38.9%) did not fulfill the inclusion criteria. Of the remaining 217 CIA patients, 81 (37.3%) repeated TST during TNFi treatment. TST conversion rate was observed in 18 (22.2%) patients without significant differences among CIA (p = 0.578). The number of TB cases was low (n = 10; 4.6%) and was similar in TST-repetition and non-TST-repetition groups [2 (2.5%) vs. 8 (5.9%), p = 0.328]. Of note, 30% of active TB occurred early (6–12 months of TNFi exposure) and the median (full range) time to incident TB was 1.3 (0.6–10.6) years, whereas the median (full range) time to TST repetition was later [3.3 (0.5–13.4) years]. The incidence of active TB was lower among RA patients than AS patients [342 (95% CI 41 − 1446) vs. 1.454 (95% CI 594-2993)/100,000 patient-years, p = 0.049].ConclusionThese results indicate that TST repetition is associated with a high conversion rate, suggesting the need for recommended treatment. The delayed repetition of TST and low number of active TB cases hampered the evaluation of this strategy effectiveness to prevent active infection. Larger studies with systematic repetition patterns are necessary. In addition, the study highlights the need for a greater surveillance for TB in AS patients.• TST repetition is associated with a high conversion rate for positive LTBI after long-term TNFi.• Active tuberculosis diagnosis occurs early (1.3 years) during TNFi therapy.• AS patients require greater surveillance for incident TB.

IntroductionAlthough Rheumatoid Arthritis (RA) extra-articular manifestations (ExtRA) occurrence has been decreasing over time, they are still a major mortality risk factor for patients.ObjectiveTo determine the prevalence of ExtRA in a large cohort, and its association with demographic and clinical variables.MethodCross-sectional and observational study, based on a multi-centric database from a prospective cohort, in which 11 public rheumatology centres enrolled RA patients (1987 ARA or 2010 ACR-EULAR). Data collection began in 08-2015, using a single online electronic medical record. Continuous variables were compared using Mann–Whitney U-test, and Fisher’s exact test or chi-square test, as appropriate, were used for categorical variables. The level of significance was set at 5% (p < 0.05).Results1115 patients were included: 89% women, age [mean ± SD] 58.2 ± 11.5 years, disease duration 14.5 ± 12.2 years, positive Rheumatoid Factor (RF, n = 1108) in 77%, positive anti-cyclic citrullinated peptide (ACPA, n = 477) in 78%. Regarding ExtRA, 334 occurrences were registered in 261 patients, resulting in an overall prevalence of 23.4% in the cohort. The comparison among ExtRA and Non-ExtRA groups shows significant higher age (p < 0.001), disease duration (p < 0.001), RF high titers (p = 0.018), Clinical Disease Activity index (CDAI) (p < 0.001), Disease Activity Index 28 (DAS 28) (p < 0.001), and Health Assessment Questionnaire (HAQ) (p < 0.001) in ExtRA group. Treatment with Azathioprine (p = 0.002), Etanercept (p = 0.049) Glucocorticoids (GC) (‘p = 0.002), and non-steroidal anti-inflammatory drugs (NSAIDs) (p < 0.001) were more frequent in ExtRA group.ConclusionsExtRA manifestations still show an expressive occurrence that should not be underestimated. Our findings reinforce that long-term seropositive disease, associated with significant disability and persistent inflammatory activity are the key factors related to ExtRA development.

ObjectivesTo evaluate the distinct impact of disease modifying antirheumatic drugs (DMARD) combination and monotherapy in immune response to an inactivated SARS-CoV-2 vaccine in patients with rheumatoid arthritis (RA).MethodsThis phase 4 prospective study analysed seroconversion (SC) of anti-SARS-CoV-2 immunoglobulin G (IgG) and neutralising antibodies (NAb) induced by the inactivated vaccine (CoronaVac) in patients with RA in comparison to controls (CG). Disease activity and treatment were also assessed. Only participants with baseline negative IgG/NAb were included.ResultsPatients with RA (N=260) and CG (N=104) had comparable median ages (59 years (50–65 years) vs 58 years (49.8–64 years), p=0.483). Patients with RA had moderate but lower SC (61.8% vs 94.2%, p<0.001) and NAb positivity (45% vs 78.6%, p<0.001) in comparison to CG after full vaccination. Baseline disease activity did not influence immunogenicity (p>0.05). After multivariate analyses, factors independently related to reduced SC were: older age (OR=0.79 (0.70–0.89) for each 5-year interval, p<0.001), methotrexate (OR=0.54 (0.29–0.98), p=0.044), abatacept (OR=0.37 (0.19–0.73), p=0.004) and number of DMARD (OR=0.55 (0.33–0.90), p=0.018). Regarding NAb, age (OR=0.87 (0.78–0.96) for each 5-year interval, p=0.007) and prednisone >7.5 mg/day (OR=0.38 (0.19–0.74), p=0.004) were negatively related to the presence of NAb. Further comparison of SC/NAb positivity among RA treatment subgroups and CG revealed that methotrexate/tofacitinib/abatacept/tocilizumab use, in monotherapy or in combination, resulted in lower responses (p<0.05), while tumour necrosis factor inhibitor and other conventional synthetic DMARD interfered solely when combined with other therapies.ConclusionsPatients with RA under DMARD have a moderate immunogenicity to CoronaVac. We identified that nearly all DMARD combinations have a deleterious effect in immunogenicity, whereas a more restricted number of drugs (methotrexate/tofacitinib/abatacept/tocilizumab) also hampered this response as monotherapy. These findings reinforce the need of a broader approach, not limited to specific drugs, to improve vaccine response for this population.Trial registration details NCT04754698.

What is the impact of switching between biologics and biosimilars of adalimumab, etanercept, and infliximab on efficacy and safety for rheumatoid arthritis? A systematic review and network meta-analysis were performed to compare switching and non-switching groups of treatments. Pooled Risk Relative (RR) or standardised mean differences (SMD) with 95% credible intervals (95% CrIs) were obtained. Seventeen randomized trials with a switching phase involving 6,562 patients were included. Results showed that a single switch from biologics to biosimilars compared to continuing biologics had comparable effects for primary and co-primary outcomes, the American College of Rheumatology criteria with 20% response (ACR20) (7 trials, 1,926 patients, RR 0.98, 95% CrIs 0.93 to 1.03) and the Health Assessment Questionnaire—Disability Index (HAQ-DI) (5 trials, 1,609 patients, SMD − 0.07, 95% CrIs − 0.23 to 0.1), and within the equivalence margins: ACR20 [RR 0.94, 1.06] and HAQ-DI [SMD − 0.22, 0.22]. The risk of treatment-emergent adverse events, discontinuation, and positive anti-drug antibodies were comparable after switching. Safety results were imprecise, and the follow-up period might not be sufficient to evaluate long-term effects, especially malignancies. Overall, the practice of single switching between approved biologics and biosimilars of Tumour Necrosis Factor inhibitors is efficacious and safe for rheumatoid arthritis.

Importance Biosimilar drugs are potentially lower-cost versions of biologics that may improve access to therapy. However, there is a lack of adequate systematic reviews demonstrating equivalence between these drugs for the treatment of rheumatoid arthritis (RA). Objectives To assess the efficacy, safety, and immunogenicity associated with biosimilars of adalimumab, etanercept, and infliximab compared with their reference biologics in patients with RA. Data Sources MEDLINE via PubMed, Embase, Cochrane Central Register of Controlled Trials, and LILACS databases were searched from inception to September 2021. Study Selection Head-to-head randomized clinical trials (RCTs) of biosimilars of adalimumab, etanercept, and infliximab and their biologic reference drugs for RA were assessed. Data Extraction and Synthesis Two authors independently abstracted all data. Meta-analysis was conducted with bayesian random effects using relative risks (RRs) for binary outcomes and standardized mean differences (SMDs) for continuous outcomes, with 95% credible intervals (CrIs) and trial sequential analysis. Specific domains were assessed for the risk of bias in equivalence and noninferiority trials. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. Main Outcomes and Measures Equivalence was tested using prespecified margins for the American College of Rheumatology criteria, with at least 20% improvement in the core set measures (ACR20) (ie, RR, 0.94 to 1.06), and for the Health Assessment Questionnaire–Disability Index (HAQ-DI) (ie, SMD, −0.22 to 0.22). Secondary outcomes included 14 items measuring safety and immunogenicity. Results A total of 25 head-to-head trials provided data on 10 642 randomized patients with moderate to severe RA. Biosimilars met equivalence with reference biologics in terms of ACR20 response (24 RCTs with 10 259 patients; RR, 1.01; 95% CrI, 0.98 to 1.04; τ2 = 0.000) and change of HAQ-DI scores (14 RCTs with 5579 patients; SMD, −0.04; 95% CrI, −0.11 to 0.02; τ2 = 0.002) considering prespecified margins of equivalence. Trial sequential analysis found evidence for equivalence for ACR20 since 2017 and HAQ-DI since 2016. Overall, biosimilars were associated with similar safety and immunogenicity profiles compared with reference biologics. Conclusion and Relevance In this systematic review and meta-analysis, biosimilars of adalimumab, infliximab, and etanercept were associated with clinically equivalent treatment effects compared with their reference biologics for the treatment of RA.

BackgroundAlthough systemic sclerosis (SSc) predominantly affects the female sex, male patients tend to present a more severe visceral profile and worse prognosis. This study aims to analyze the clinical and laboratory characteristics of male patients in a large single SSc cohort.MethodsThis retrospective study analyzed 700 patients followed regularly at a single tertiary outpatient SSc center. Patients were classified according to the 2013 ACR/EULAR SSc criteria, and all data were retrieved from an electronic database. Statistical analyses included comparing demographic and clinical data, Kaplan-Meier survival curves, and multivariate analyses using SigmaStat 14.5.ResultsThere were 612 women (87.4%) and 88 men (12.6%). Male patients were more frequently African-Brazilians (p = 0.005), and showed a significantly shorter disease duration compared to females (10.1 vs. 13.8 years, p < 0.001), with higher rates of environmental exposures (37.5% vs. 8.2%, p < 0.001), and more severe fibrotic manifestations, including skin thickening score (p = 0.004), diffuse SSc (p = 0.005), and extensive interstitial lung disease (p = 0.013). Men also had higher rates of group 3 pulmonary hypertension (p = 0.018), congestive heart failure (p = 0.001), and required more aggressive treatments such as cyclophosphamide (p < 0.001) and rituximab (p = 0.002). Although there were no significant sex differences in the frequency of vascular manifestations or joint involvement, men had lower rates of positivity for antinuclear antibodies (ANA) (p = 0.047) and anti-centromere antibodies (ACA) (p = 0.001). Male sex was associated with increased mortality (hazard ratio 2.3; 95% CI 1.4 to 3.8; p = 0.002) and survival rates at 1, 3, 5, and 10 years from diagnosis were 99.2%, 96%, 89%, and 75% for men, and 99%, 98%, 97%, and 93% for women (p < 0.001).ConclusionOur study reinforces the association between male sex and more severe SSc, marked by greater skin involvement, worse pulmonary and cardiac outcomes, a higher prevalence of environmental exposures, and lower ACA positivity. These factors contributed to poorer survival outcomes in men compared to women. These findings underscore the need for a more comprehensive evaluation of clinical manifestations to better assess disease progression in male SSc patients.

Objective To evaluate the frequency of anti-collagen type V in humans with early systemic sclerosis (SSc) compared to defined SSc patients and healthy controls, since collagen type V was shown to be overexpressed in early SSc patients’ skin and there is no data concerning the presence of this antibody in early stages of human SSc. Experimental studies showed that animal models immunized with collagen type V developed a disease similar to human systemic sclerosis (SSc), with antibodies production, mainly in early stages post-immunization. Methods Eighty-one female SSc patients were included and divided into two groups: early-SSc (18 patients-EULAR Preliminary Criteria) and defined-SSc (63 patients-ACR Criteria 1980). The control group consisted of 19 healthy women age-matched to Early-SSc group. Anti-collagen type V was performed by ELISA. Data was analyzed by appropriate tests. Results The prevalence of anti-collagen type V in early-SSc, defined-SSc and control groups was respectively 33, 17 and 5% (p = 0.07). SSc patients with anti-collagen type V had shorter disease duration compared to those without this antibody (8.8 ± 5.1 vs. 14.7 ± 8.9, p = 0.006). Likewise, early-SSc patients with anti-collagen V also had a shorter disease duration than patients negative for this antibody (4.6 ± 2.2 vs. 9.7 ± 5.2, p = 0.04). No association with clinical subsets or scleroderma antibodies specificities was observed (p > 0.05). Conclusion The production of anti-collagen type V in SSc seems to be an early event independent of other antibodies specificities. Further studies are necessary to determine if the underlying mechanism for this chronology involves a primary immune response to abnormal expression of collagen type V.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by increased risk of cardiovascular disease and hypertension (HT). A single session of aerobic exercise may reduce blood pressure (BP) in different clinical groups; however, little is known about the acute effects of exercise on BP in RA patients. This is a randomized controlled crossover study that assessed the effects of a single session of aerobic exercise on resting BP, on BP responses to stressful stimuli, and on 24-h BP in women with RA and HT. Twenty women with RA and HT (53 ± 10 years) undertook sessions of 30-min treadmill exercise (50% VO 2max ) or control (no exercise) in a crossover fashion. Before and after the sessions, BP was measured at rest, and in response to the Stroop-Color Word Test (SCWT), the Cold Pressor Test (CPT), and an isometric handgrip test. After the sessions, participants were also fitted with an ambulatory BP monitor for the assessment of 24-h BP. A single session of exercise reduced resting systolic BP (SBP) (−5 ± 9 mmHg; p  < 0.05), and reduced SBP response to the SCWT (−7 ± 14 mmHg; p  < 0.05), and to the CPT (−5 ± 11 mmHg; p  < 0.05). Exercise did not reduce resting diastolic BP (DBP), BP responses to the isometric handgrip test or 24-h BP. In conclusion, a single session of aerobic exercise reduced SBP at rest and in response to stressful stimuli in hypertensive women with RA. These results support the use of exercise as a strategy for controlling HT and, hence, reducing cardiovascular risk in women with RA. Clinical Trial Registration: This study registered at the Brazilian Clinical Trials ( https://ensaiosclinicos.gov.br/rg/RBR-867k9g ) at 12/13/2019.

BackgroundPatients with immune-mediated rheumatic diseases (IMRD) are at increased risk for infections due to both disease-related immune dysregulation and immunosuppressive therapy. Despite the benefits of vaccination, immunization rates in this population remain suboptimal, often due to concerns about safety, efficacy, and their potential for inducing disease flare. Regional-specific guidelines are necessary to address the particular epidemiological issues and aspects of the healthcare systems, especially in countries like Brazil.ObjectiveTo provide updated, evidence-based, and nationally relevant recommendations on vaccination in adult patients with IMRD in Brazil, focusing on immunogenicity, safety and disease activity outcomes.MethodsA multidisciplinary task force from the Brazilian Society of Rheumatology conducted a systematic review and meta-analysis of studies addressing eleven clinical questions related to vaccine safety and efficacy in IMRD. Studies were selected using predefined PICO criteria. Risk of bias was assessed using JBI tools, and the certainty of evidence was evaluated with the GRADE approach. Statements were developed and submitted to a Delphi-based voting process; consensus was achieved if ≥80% of the panelists voted “agree” or “strongly agree” for all the statements.ResultsEleven recommendations were developed based on a systematic review of the literature, with meta-analyses conducted when appropriate. Inactivated vaccines demonstrated a favorable safety profile, with low flare rates and no significant increase in disease activity, even under immunosuppression. Live attenuated vaccines, including yellow fever, were considered safe when administered according to timing protocols. Immunogenicity may be reduced in patients receiving methotrexate, mycophenolate, corticosteroids, rituximab, and JAK inhibitors, although this does not appear to compromise clinical protection in most cases. Temporary treatment interruption was associated with improved immunogenicity in selected contexts, but without consistent evidence of clinical benefit and with potential risks related to disease control. Specific guidance was provided for influenza and hepatitis B vaccination, as well as for prioritizing vaccination before initiating immunosuppression whenever feasible. Statements also addressed the approach to revaccination and post-vaccination serologic testing. Despite the overall very low to moderate certainty of evidence, most recommendations reached strong consensus (≥80% agreement). Shared decision-making and individualized strategies were emphasized across all scenarios.ConclusionThese recommendations offer tailored guidance for improving vaccination strategies in IMRD patients in Brazil. Given the heterogeneity of evidence, clinical decisions should be individualized, considering disease activity, treatment regimen, vaccine availability, and patient preferences. Shared decision-making is essential in all scenarios to enhance vaccine uptake and align preventive care with patient-centered management.