Screening with urine Histoplasma antigen test in asymptomatic patients starting TNF-alpha inhibitor therapy: a cohort study.

Background: Histoplasmosis is the second most frequent granulomatous disease in patients treated with tumor necrosis factor (TNF)-α inhibitors, second only to tuberculosis. However, there is limited information about pre-therapy screening procedures and the need for preventive treatments for patients who will start immunobiologicals. Methods: This is a cohort study that evaluated the prevalence of histoplasmosis in asymptomatic HIV-negative patients before initiation of TNF-α inhibitors by testing for Histoplasma antigen in urine samples. The patients included completed a 180-day follow-up after the initiation of the biologics to assess the onset of symptoms suggestive of histoplasmosis. Results: From January 2021 to December 2022, 54 patients who were prescribed a TNF-α inhibitor agent for treating autoimmune diseases in centers in southern Brazil were included. In the screening before therapy, the prevalence of a positive urinary Histoplasma antigen test was 14.8%. None of the 54 patients developed histoplasmosis after 6 months of immunobiological therapy, including the eight patients who tested positive. Conclusion: The prevalence of Histoplasma capsulatum infection in chronic patients may be higher than expected, but the impact of latent infection in asymptomatic patients is still uncertain, including those starting treatment with immunobiological drugs such as TNF-α inhibitors. Our study did not identify risk factors for the diagnosis of disseminated histoplasmosis in this group, including a positive result in an antigen test performed before immunobiological therapy. To date, there is no evidence to recommend routine antigen-based screening or preventive therapy for histoplasmosis before initiating a TNF-α inhibitor.

Using a urine test for fungal infection to screen people without symptoms who are about to start taking immunobiologic medications This study looked at the prevalence of histoplasmosis, a fungal infection, in asymptomatic patients who were about to start treatment with TNF-α inhibitors, which are medications used for autoimmune diseases. The researchers tested urine samples for Histoplasma antigen before the patients started the treatment and followed them for 180 days after starting the medication to see if they developed any symptoms of histoplasmosis. The study included 54 patients in southern Brazil, and they found that 14.8% of the patients tested positive for the Histoplasma antigen before starting the treatment. However, none of the patients, including those who tested positive, developed histoplasmosis during the 6-month follow-up. The researchers concluded that histoplasmosis infection may be more common in these patients than previously thought, but it's still not clear if asymptomatic patients with a positive antigen test will develop the infection when starting TNF-α inhibitor treatment. The study did not find any specific risk factors for developing histoplasmosis in this group of patients, and based on their findings, they did not recommend routine screening or preventive therapy for histoplasmosis before starting TNF-α inhibitor treatment.

The effect of antimalarials on the safety and persistence of treatment with biologic agents or Janus kinase inhibitors in rheumatoid arthritis.

OBJECTIVES: To test the association of use of antimalarials with the overall safety of treatment in RA patients receiving one or multiple courses of biologic (b)DMARDs or a Janus kinase inhibitor (JAKi). METHODS: BiobadaBrasil is a multicentric registry-based cohort study of Brazilian patients with rheumatic diseases starting their first bDMARD or JAKi. The present analysis includes RA patients recruited from January 2009 to October 2019, followed up over one or multiple (up to six) courses of treatment (latest date, 19 November 2019). The primary outcome was the incidence of serious adverse events (SAEs). Total and system-specific adverse events (AEs) and treatment interruption served as secondary outcomes. Negative binomial regression with generalized estimating equations (to estimate multivariate incidence rate ratios, mIRR) and frailty Cox proportional hazards models were used for statistical analyses. RESULTS: The number of patients enrolled was 1316 (2335 treatment courses, 6711 patient-years [PY]; 1254.5 PY on antimalarials). The overall incidence of SAEs was 9.2/100 PY. Antimalarials were associated with reduced risk of SAEs (mIRR: 0.49; 95% CI: 0.36, 0.68; P < 0.001), total AEs (0.68; 95% CI: 0.56, 0.81; P < 0.001), serious infections (0.53; 95% CI: 0.34, 0.84; P = 0.007) and total hepatic AEs (0.21; 95% CI: 0.05, 0.85; P = 0.028). Antimalarials were also related to better survival of treatment course (P = 0.003). There was no significant increase in the risk of cardiovascular AEs. CONCLUSION: Among RA patients on treatment with bDMARDs or JAKi, concomitant use of antimalarials was associated with reduced the incidence of serious and total AEs and with longer treatment course survival.

Incidence of histoplasmosis in patients receiving TNF-alpha inhibitors: A systematic review and meta-analysis.

BACKGROUND: Immunobiological drugs such as TNF-α inhibitors are valuable in rescue therapy for autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease (IBD), but they increase the risk of infectious complications. Histoplasmosis is a significant concern in patients living in endemic regions, however, few studies have assessed the incidence of Histoplasma infection during therapy, and classic estimates may underestimate the risk. This study aimed to produce an updated risk estimate of histoplasmosis in patients on TNF-α blocking therapy. METHODS: This is a systematic review and meta-analysis of studies that contain parameters for calculating the risk of histoplasmosis in people who use TNF-α inhibitors, to produce a risk estimate. RESULTS: We identified 11 studies with the necessary parameters for inclusion in the meta-analysis, most of which were from North America. The incidence rate of histoplasmosis found was 33.52 cases per 100,000 patients treated with TNF-ɑ inhibitors (95% CI 12.28-91.46). Considering only studies evaluating monoclonal antibodies, the calculated incidence was 54.88/100,000 patients treated (95%CI 23.45-128.34). In subgroup analysis, the incidence was much higher in patients with IBD compared to rheumatic diseases. There was significant heterogeneity among the studies. CONCLUSION: The risk of histoplasmosis during TNF-α inhibitory therapy may be considerably higher than that found in classical estimates, especially in patients with IBD. There is a lack of studies evaluating histoplasmosis in large endemic areas, such as Central and South America.

Funcionality assessed by the core set of the international classification of functionality and health for rheumatoid arthritis: A cohort study.

OBJECTIVE: The aim of this study was to evaluate the function of a cohort of patients with rheumatoid arthritis (RA) from the core set of the International Classification of Functioning and Health (ICF) for RA over 12 months. METHODS: We used prospective longitudinal data to conduct a cohort study among a well-characterized group of RA patients. Ninety RA patients aged between 40 and 70 years were included in the study. Patients were evaluated at baseline and after 12 months. Age, disease duration, current smoking, erosions, disease activity, functional test, disability and physical activity were evaluated. Then, the ICF core set classification for RA was applied. RESULTS: 81 patients completed the assessments, the majority of patients were female (88.9%) and the mean age was 56.5 ± 7.3 years. At baseline, the median disease activity was 3.0. There was a statistically significant (p < 0.02) improvement in "Exercise tolerance functions" over 12 months and also a statistically significant (p < 0.001) decrease in "Muscle strength functions" over 12 months. The activity and participation domain showed a weak correlation with the clinical data of the DAS28-PCR (p<0.02). CONCLUSION: We conclude that relevant aspects of the ICF Core Set for RA were able to adequately express the physical and functional factors of the RA cohort. This tool provides a common language for the interdisciplinary team, which can enhance the use of timely interventions to prevent physical disability in clinical practice.

Urinary metabolomic biomarker candidates for skeletal muscle wasting in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease that affects the joints, leading to chronic synovial inflammation and local tissue destruction. Extra-articular manifestations may also occur, such as changes in body composition. Skeletal muscle wasting is often observed in patients with RA, but methods for assessing loss of muscle mass are expensive and not widely available. Metabolomic analysis has shown great potential for identifying changes in the metabolite profile of patients with autoimmune diseases. In this setting, urine metabolomic profiling in patients with RA may be a useful tool to identify skeletal muscle wasting. METHODS: Patients aged 40-70 years with RA have been recruited according to the 2010 ACR/EULAR classification criteria. Further, the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) determined the disease activity. The muscle mass was measured by Dual X-ray absorptiometry (DXA) to generate the appendicular lean mass index (ALMI) by summing the lean mass measurements for both arms and legs and dividing them by height squared (kg/height2 ). Finally, urine metabolomic analysis by 1 H nuclear magnetic resonance (1 H-NMR) spectroscopy was performed and the metabolomics data set analysed using the BAYESIL and MetaboAnalyst software packages. Principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were applied to the 1 H-NMR data, followed by Spearman's correlation analysis. The combined receiver operating characteristic curve (ROC) was calculated, as well as the logistic regression analyses to establish a diagnostic model. The significance level at P < 0.05 was set for all analyses. RESULTS: The total set of subjects investigated included 90 patients with RA. Most patients were women (86.7%), with a mean age of 56.5 ± 7.3 years old and a median DAS28-CRP of 3.0 (IQR 1.0-3.0). Fifteen metabolites were identified in the urine samples with high variable importance in projection (VIP scores) by MetaboAnalyst. Of these, dimethylglycine (r = 0.205; P = 0.053), oxoisovalerate (r = -0.203; P = 0.055), and isobutyric acid (r = -0.249; P = 0.018) were significantly correlated with ALMI. Based on the low muscle mass (ALMI ≤6.0 kg/m2 for women and ≤8.1 kg/m2 for men) a diagnostic model have been established with dimethylglycine (area under the curve [AUC] = 0.65), oxoisovalerate (AUC = 0.49), and isobutyric acid (AUC = 0.83) with significant sensitivity and specificity. CONCLUSIONS: Isobutyric acid, oxoisovalerate, and dimethylglycine from urine samples were associated with low skeletal muscle mass in patients with RA. These findings suggest that this group of metabolites may be further tested as biomarkers for identification of skeletal muscle wasting.

Metabolomic Biomarker Candidates for Skeletal Muscle Loss in the Collagen-Induced Arthritis (CIA) Model.

There is no consensus for diagnosis or treatment of RA muscle loss. We aimed to investigate metabolites in arthritic mice urine as biomarkers of muscle loss. DBA1/J mice comprised collagen-induced arthritis (CIA) and control (CO) groups. Urine samples were collected at 0, 18, 35, 45, 55, and 65 days of disease and subjected to nuclear magnetic resonance spectroscopy. Metabolites were identified using Chenomx and Birmingham Metabolite libraries. The statistical model used principal component analysis, partial least-squares discriminant analysis, and partial least-squares regression analysis. Linear regression and Fisher's exact test via the MetaboAnalyst website were performed (VIP-score). Nearly 100 identified metabolites had CIA vs. CO and disease time-dependent differences (p < 0.05). Twenty-eight metabolites were muscle-associated: carnosine (VIPs 2.8 × 102) and succinyl acetone (VIPs 1.0 × 10) showed high importance in CIA vs. CO models at day 65; CIA pair analysis showed histidine (VIPs 1.2 × 102) days 55 vs. 65, histamine (VIPs 1.1 × 102) days 55 vs. 65, and L-methionine (VIPs 1.1 × 102) days 0 vs. 18. Carnosine was fatigue- (0.039) related, creatine was food intake- (-0.177) and body weight- (-0.039) related, and both metabolites were clinical score- (0.093; 0.050) and paw edema- (0.125; 0.026) related. Therefore, muscle metabolic alterations were detected in arthritic mice urine, enabling further validation in RA patient's urine, targeting prognosis, diagnosis, and monitoring of RA-mediated muscle loss.

High Levels of Polypharmacy in Rheumatoid Arthritis-A Challenge Not Covered by Current Management Recommendations: Data From a Large Real-Life Study.

BACKGROUND: Rheumatoid arthritis (RA) is associated with high frequency of comorbidities and increased risk of polypharmacy. Although there is a great potential for complications, there is a gap in literature on polypharmacy in patients with rheumatic arthritis. OBJECTIVE: To evaluate the prevalence and factors associated with polypharmacy in a population in a real-life setting. METHODS: A cross-sectional multicenter study was conducted in Brazil. Patients underwent clinical evaluation and medical records analysis. Polypharmacy was considered as a dependent variable. To test independent variables, we used Poisson regression. RESULTS: We evaluated 792 patients (89% female, median age 56.6 years). Median duration of disease was 12.7 years, 78.73% had a positive rheumatoid factor. The median of disease activity score-28 was 3.5 (disease with mild activity), median of the clinical disease activity index score was 9, and median of health assessment questionnaire-disability index was 0.875; 47% used corticosteroids, 9.1% used nonsteroidal anti-inflammatory drugs, 90.9% used synthetic disease-modifying antirheumatic drugs, 35.7% used biologic disease-modifying antirheumatic drugs (DMARDs). In total, 537 (67.9%) patients used 5 or more drugs. Polypharmacy showed a relationship with a number of comorbidities and use of specific drugs (corticosteroids, methotrexate, and biological DMARDs). CONCLUSION: We found a high prevalence of polypharmacy (67.9%) in RA. Solutions to management this problem should be stimulated.

Cachexia in patients with rheumatoid arthritis: a cohort study.

BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory disease that leads to altered body composition. The loss of lean mass with a preservation or increase in fat mass has been termed rheumatoid cachexia (RC), to contrast with classic cachexia, which is characterized by severe weight loss. There are limited data on the prevalence and progression of cachexia in RA over time, as well as on associated factors. Our aim was to determine the prevalence of cachexia and to determine associations with potential factors. METHODS: This prospective cohort study recruited consecutively patients diagnosed with RA and followed for 1 year. The assessments were performed: clinical features, body composition, and physical function. RC and classic cachexia were assessed by several established diagnostic criteria. The pairwise Student's t test, Chi-square test, and GEE were performed (accepted at p ≤ 0.05). RESULTS: Of 90 patients recruited, 81 completed the study. Most patients were women (88.9%), and the mean age was 56.5 ± 7.3 years. At baseline, the median DAS28-CRP was 3.0 (IQR, 1.0-3.0), 13.3-30.0% of the included patients had RC, while none met criteria for classic cachexia. The prevalence of cachexia did not change after 12 months. Disease activity status and treatment with biologic disease-modifying antirheumatic drugs were significantly associated with changes on body composition and physical function (p < 0.05). CONCLUSIONS: In this cohort, RC was common, while classic cachexia was absent. Disease activity and use of biologic therapies were associated with changes on body composition and physical function, underscoring the importance of aiming for remission when treating RA.

Tofacitinib, an oral Janus kinase inhibitor, in patients from Brazil with rheumatoid arthritis: Pooled efficacy and safety analyses.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Efficacy and safety of tofacitinib in Brazilian patients from Phase 2 (P2) and Phase 3 (P3) global studies of up to 24 months' duration were evaluated. METHODS: Data were pooled from Brazilian patients with RA and an inadequate response to conventional synthetic or biologic disease-modifying antirheumatic drugs enrolled in P2/P3 tofacitinib studies who received tofacitinib 5 or 10 mg twice daily (BID), or placebo, as monotherapy or in combination with methotrexate. Efficacy, safety, and patient-reported outcomes were assessed over 24 months. RESULTS: Patients (226) from Brazil were treated in tofacitinib global P2/P3 studies. At Month 3, there were improvements in American College of Rheumatology 20/50/70 response rates, Disease Activity Score in 28 joints, erythrocyte sedimentation rate, and Health Assessment Questionnaire-Disability Index scores with both tofacitinib doses. Improvements from baseline in pain, fatigue, and health-related quality of life with tofacitinib 5 and 10 mg BID were reported. Efficacy improvements were sustained up to Month 24. The most frequent class of adverse events was infections and infestations. No cases of tuberculosis or other opportunistic infections were reported. CONCLUSION: In a Brazilian subpopulation of patients with RA, tofacitinib reduced disease signs and symptoms and improved physical function up to Month 24, with a safety profile consistent with findings from global studies.

Proper management of rheumatoid arthritis in Latin America. What the guidelines say?

To analyze characteristics of clinical practice guidelines (CPGs) for the management of rheumatoid arthritis (RA) developed in Latin American (LA) countries and to describe the knowledge, use, and barriers for their implementation perceived among LA rheumatologists, a comprehensive literature search including Medline, PubMed, Cochrane Library, LILACS and Scielo was performed. The Appraisal of Guidelines for Research and Evaluation (AGREE) instrument was applied for evaluation. A survey was sent to PANLAR members containing questions related to knowledge about guidelines, application of the recommendations, and difficulties in implementing CPGs. Eight guidelines were identified. Most guidelines were evidence based (62 %), but in only 37 % a systematic literature search was done. None of the guidelines included patients' views and preferences, and only few of them stated an updating procedure. Funding body independence and disclosure of conflicts of interest were rarely reported. The survey was answered by 214 rheumatologists from all Latin American countries. Most rheumatologist reported knowledge and use of clinical guidelines, mainly international ones. In general, rheumatologist felt that guidelines apply to only a minority of patients seen in daily clinical practice. Limited access expensive drugs, suggested by the guidelines, was the most frequent barrier to guidelines implementation that was reported. A good number of guidelines on the treatment of rheumatoid arthritis have been developed in Latin America. Most of them are lacking some of the components recognized for high-quality clinical guidelines development. In spite that most rheumatologist know and apply guidelines, access to drugs is still a very important barrier to their implementation in Latin America.

Association between the aggrecan gene and rheumatoid arthritis.

OBJECTIVE: Genetic and environmental factors seem to be involved in the onset of rheumatoid arthritis (RA). We analyzed whether a variable number of tandem repeats (VNTR) polymorphism in the aggrecan gene was associated to RA. METHODS: The study population comprised 170 European-derived Brazilian patients with diagnosis of RA. The control group comprised 148 European-derived Brazilian healthy blood donors. The aggrecan VNTR polymorphism was genotyped by DNA amplification by polymerase chain reaction, followed by electrophoresis in polyacrylamide gel. RESULTS: There was a statistically significant higher frequency of alleles of shorter length in the patient group compared to controls (p = 0.001), suggesting that individuals carrying short alleles are more likely to develop RA. There was no association between short alleles and clinical characteristics of RA. CONCLUSION: Our results provide evidence of an association between the aggrecan gene VNTR polymorphism and RA.

Growth velocity and interleukin 6 concentrations in juvenile idiopathic arthritis.

OBJECTIVE: .To evaluate associations of growth velocity with inflammatory markers and cumulative dose of glucocorticoid in a cohort of patients with juvenile idiopathic arthritis (JIA) followed during 1 year. METHODS: Seventy-nine patients were evaluated. Disease activity was evaluated by a pediatric rheumatologist. Anthropometric data were classified according to the World Health Organization standards. Tanner growth velocity curves were used; values below the Z-score < or = -2 were considered low growth velocity. Serum concentrations of interleukin 6 (IL-6) were measured by ELISA, and values > 1 pg/ml were considered elevated. RESULTS: The prevalence of low growth velocity was 25.3%, and it was associated with active disease on followup visit, elevated IL-6, erythrocyte sedimentation rate and C-reactive protein, and higher cumulative glucocorticoid doses. In the multiple linear regression with growth velocity as the dependent variable, only elevated IL-6 level was independently and negatively associated with growth velocity. CONCLUSION: Low growth velocity is highly prevalent in children with JIA. Elevated IL-6 levels seem to have an important negative influence on growth in these children, while total glucocorticoid exposure appears to be a secondary factor.