Comparative effectiveness of baricitinib and alternative biological DMARDs in a Swiss cohort study of patients with RA.

OBJECTIVES: This observational study compares the effectiveness of baricitinib (BARI), a targeted synthetic disease-modifying antirheumatic drug (tsDMARD), with alternative biological DMARDs (bDMARDs) in patients with rheumatoid arthritis (RA), from a prospective, longitudinal cohort. METHODS: We compared patients initiating a treatment course (TC) of BARI, tumour necrosis factor inhibitors (TNFi) or bDMARDs with other modes of action (OMA), during a period when all these DMARDs were available in Switzerland. The primary outcome was drug maintenance; secondary outcomes included discontinuation rates related specifically to ineffectiveness and adverse events. We further analysed rates of low disease activity (LDA) and remission (REM) at 12 months and drug maintenance in bDMARD-naïve and tsDMARD-naïve population. RESULTS: A total of 1053 TCs were included: 273 on BARI, 473 on TNFi and 307 on OMA. BARI was prescribed to older patients with longer disease duration and more previous treatment failures than TNFi. Compared with BARI, the adjusted drug maintenance was significantly shorter for TNFi (HR for discontinuation: 1.76; 95% CI, 1.32 to 2.35) but not compared with OMA (HR 1.27; 95% CI, 0.93 to 1.72). These results were similar in the b/tsDMARD-naïve population. The higher discontinuation of TNFi was mostly due to increased discontinuation for ineffectiveness (HR 1.49; 95% CI, 1.03 to 2.15), with no significant differences in drug discontinuation for adverse events (HR 1.46; 95% CI, 0.83 to 2.57). The LDA and REM rates at 12 months did not differ significantly between the three groups. CONCLUSIONS: BARI demonstrated a significantly higher drug maintenance compared with TNFi, mainly due to lower drug discontinuations for ineffectiveness. We found no difference in drug maintenance between BARI and OMA. Clinical outcomes did not differ between the three groups. Our results suggest that BARI is an appropriate therapeutic alternative to bDMARDs in the management of RA.

Gut microbiome and intestinal inflammation in preclinical stages of rheumatoid arthritis.

BACKGROUND: Faecal Prevotellaceae, and other microbes, have been associated with rheumatoid arthritis (RA) and preclinical RA. We have performed a quantitative microbiome profiling study in preclinical stages of RA. METHODS: First-degree relatives of patients with RA (RA-FDRs) from the SCREEN-RA cohort were categorised into four groups: controls, healthy asymptomatic RA-FDRs; high genetic risk, asymptomatic RA-FDRs with two copies of the shared epitope; autoimmunity, asymptomatic RA-FDRs with RA-associated autoimmunity; and symptomatic, clinically suspect arthralgias or untreated new-onset RA.Faecal samples were collected and frozen. 16S sequencing was performed, processed with DADA2 pipeline and Silva database. Cell counts (cytometry) and faecal calprotectin (enzyme-linked immunosorbent assay, ELISA) were also obtained. Microbial community analyses were conducted using non-parametric tests, such as permutational multivariate analysis of variance (PERMANOVA), Wilcoxon and Kruskal-Wallis, or Aldex2. RESULTS: A total of 371 individuals were included and categorised according to their preclinical stage of the disease. Groups had similar age, gender and body mass index. We found no significant differences in the quantitative microbiome profiles by preclinical stages (PERMANOVA, R2=0.00798, p=0.56) and, in particular, no group differences in Prevotellaceae abundance. Results were similar when using relative microbiome profiling data (PERMANOVA, R2=0.0073, p=0.83) or Aldex2 on 16S sequence counts. Regarding faecal calprotectin, we found no differences between groups (p=0.3). CONCLUSIONS: We could not identify microbiome profiles associated with preclinical stages of RA. Only in a subgroup of individuals with the most pronounced phenotypes did we modestly retrieve the previously reported associations.

A genetically encoded sensor for visualizing leukotriene B4 gradients in vivo.

Leukotriene B4 (LTB4) is a potent lipid chemoattractant driving inflammatory responses during host defense, allergy, autoimmune and metabolic diseases. Gradients of LTB4 orchestrate leukocyte recruitment and swarming to sites of tissue damage and infection. How LTB4 gradients form and spread in live tissues to regulate these processes remains largely elusive due to the lack of suitable tools for monitoring LTB4 levels in vivo. Here, we develop GEM-LTB4, a genetically encoded green fluorescent LTB4 biosensor based on the human G-protein-coupled receptor BLT1. GEM-LTB4 shows high sensitivity, specificity and a robust fluorescence increase in response to LTB4 without affecting downstream signaling pathways. We use GEM-LTB4 to measure ex vivo LTB4 production of murine neutrophils. Transgenic expression of GEM-LTB4 in zebrafish allows the real-time visualization of both exogenously applied and endogenously produced LTB4 gradients. GEM-LTB4 thus serves as a broadly applicable tool for analyzing LTB4 dynamics in various experimental systems and model organisms.

Brief report: Assessment of mucosal barrier integrity using serological biomarkers in preclinical stages of rheumatoid arthritis.

Background: The pathogenesis of rheumatoid arthritis (RA) is believed to initiate at mucosal sites. The so-called 'mucosal origin hypothesis of RA' postulates an increased intestinal permeability before disease onset. Several biomarkers, including lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (I-FABP), have been proposed to reflect gut mucosa permeability and integrity, while serum calprotectin is a new inflammation marker proposed in RA. Methods: We analyzed serum samples of individuals genetically at increased risk of RA in a nested-case-control study. Participants from a longitudinal cohort of first-degree relatives of RA patients (SCREEN-RA cohort) were divided into three pre-clinical stages of RA, based on the presence of risk factors for subsequent RA onset: 1) low-risk healthy asymptomatic controls; 2) intermediate-risk individuals without symptoms, but with RA-associated auto-immunity; 3) high-risk individuals with clinically suspect arthralgias. Five patients with newly diagnosed RA were also sampled. Serum LBP, I-FABP and calprotectin were measured using commercially available ELISA kits. Results: We included 180 individuals genetically at increased risk for RA: 84 asymptomatic controls, 53 individuals with RA-associated autoimmunity and 38 high risk individuals. Serum LBP, I-FAPB or calprotectin concentrations did not differ between individuals in different pre-clinical stages of RA. Conclusion: Based on the serum biomarkers LBP, I-FABP and calprotectin, we could not detect any evidence for intestinal injury in pre-clinical stages of RA.

Predicting the onset of rheumatoid arthritis.

Various scores have attempted to predict the onset of rheumatoid arthritis (RA). In particular, EULAR proposed a simple rule to identify new-onset arthralgia suspicious for progression to RA. However, its specificity would likely be higher if serological tests were included. In patients with clinical arthritis, reliable predictive criteria for progression to RA have also been identified. Overall, the validity of the available scores is still being debated. Such scores do not fully account for the interactions between risk factors in specific subpopulations. New technologies could help to overcome these limitations, but we need databases containing a sufficient number of RA and pre-RA patients, including pre-diagnostic monitoring. Today, the existing predictive rules cannot compete with expert opinions.

Quantitative Assessment of First Nations Drinking Water Distribution Systems for Detection and Prevalence of Thermophilic Campylobacter Species.

Water is considered a major route for transmitting human-associated pathogens. Although microbial water quality indicators are used to test for the presence of waterborne pathogens in drinking water, the two are poorly correlated. The current study investigates the prevalence of thermophilic DNA markers specific for Campylobacter spp. (C. jejuni and C. coli) in source water and throughout the water distribution systems of two First Nations communities in Manitoba, Canada. A total of 220 water samples were collected from various points of the drinking water distribution system (DWDS) between 2016 and 2018. Target Campylobacter spp. were always (100%) detected in a home with a fiberglass (CF) cistern, as well as the community standpipe (SP). The target bacteria were also frequently detected in treated water at the Water Treatment Plant (WTP) (78%), homes with polyethylene (CP) (60%) and concrete (CC) (58%) cisterns, homes with piped (P) water (43%) and water truck (T) samples (20%), with a maximum concentration of 1.9 × 103 cells 100 mL-1 (C. jejuni) and 5.6 × 105 cells 100 mL-1 (C. coli). Similarly, target bacteria were detected in 68% of the source water samples with a maximum concentration of 4.9 × 103 cells 100 mL-1 (C. jejuni) and 8.4 × 105 cells 100 mL-1 (C. coli). Neither target Campylobacter spp. was significantly associated with free and total chlorine concentrations in water. The study results indicate that there is an immediate need to monitor Campylobacter spp. in small communities of Canada and, particularly, to improve the DWDS in First Nations communities to minimize the risk of Campylobacter infection from drinking water sources. Further research is warranted in improving/developing processes and technologies to eliminate microbial contaminants from water.

Number of Months of Baseball in the Previous Year and Preseason Olecranon Tenderness: Risk Factors for Shoulder and Elbow Injuries in High-School Baseball Players.

OBJECTIVE: To identify risk factors for shoulder and elbow injuries in high-school baseball position players and pitchers in the preseason history and physical examination. DESIGN: Retrospective cohort study. SETTING: Community high-school baseball. PARTICIPANTS: Three hundred seventy-one male baseball players' mean age 15.0 ± 1.8 years. OUTCOME MEASURES: A preseason history and physical examination was performed on all athletes. Injury information was collected by weekly self-report and athletic trainer injury logs throughout the season. Comparisons between injured and noninjured players were performed using t tests and χ 2 analyses. Binary logistic regression models were developed to identify risk factors for injury. RESULTS: Seventy-six injuries were recorded over the season. In univariate analysis, the injured group had greater months of baseball participation ( P = 0.007) and shoulder visual analog scale for the past year ( P = 0.003). The injured group also had more olecranon tenderness ( P < 0.0001, odds ratio [OR] 2.9) and decreased elbow arc of motion. All other factors were not significantly different ( P > 0.05). In multivariable logistic regression, months per year of baseball participation was the only factor significantly associated with injuries ( P = 0.010, OR = 1.21). CONCLUSIONS: Baseball players who developed arm injuries during a season were more likely to play more months of baseball and report shoulder pain in the previous year. The presence of preseason olecranon tenderness was associated with nearly triple the risk of injury during the season. Every additional month of baseball participation in the previous year was associated with a 1.2× increased odds of injury. The presence of glenohumeral internal rotation deficit was not a predictor of injury.

Characterization of serum biomarkers and antibody responses against Prevotella spp. in preclinical and new-onset phase of rheumatic diseases.

Introduction: The characterization of the influence of the microbiota on the development and drug responses during rheumatic diseases has intensified in recent years. The role of specific bacteria during disease development has become a central research question. Notably, several lines of evidence point to distinct microbes, e.g., Prevotella copri (P. copri) being targeted by antibodies in clinical phases of rheumatic diseases. Methods: In the present study, we compiled a broad collection of human serum samples from individuals at risk of developing RA, chronic RA patients as well as patients with new-onset of rheumatic diseases. We evaluated the presence of inflammatory biomarkers in our serum collection as well as serum antibody responses against novel, genetically distinct isolates of P. copri and several oral pathobionts. Results: Our analysis revealed the presence of increased levels of inflammatory markers already in pre-clinical and new onset rheumatoid arthritis. However, antibody reactivity against the microbes did not differ between patient groups. Yet, we observed high variability between the different P. copri strains. We found total serum IgG levels to slightly correlate with IgG antibody responses against P. copri, but no relation between the latter and presence or prevalence of P. copri in the intestine. Discussion: In conclusion, our work underlined the importance of strain-level characterization and its consideration during further investigations of host-microbiota interactions and the development of microbiome-based therapeutic approaches for treating rheumatic diseases.

Cohort profile: SCREEN-RA: design, methods and perspectives of a Swiss cohort study of first-degree relatives of patients with rheumatoid arthritis.

PURPOSE: Rheumatoid arthritis (RA) is an insidious autoimmune disease, with an immunological onset years before diagnosis. Early interventions in preclinical stages could prevent or minimise the progression towards irreversible joint damage. The SCREEN-RA cohort (Evaluation of a SCREENing strategy for Rheumatoid Arthritis) aims to characterise the preclinical stages of the disease, to identify environmental risk factors, and to discover or validate novel biomarkers predictive for RA development. PARTICIPANTS: SCREEN-RA includes an at-risk population for RA, namely first-degree relatives of patients with established RA. FINDINGS TO DATE: The cohort started in 2009 is composed of mostly asymptomatic healthy individuals (total n=1458, 7262 person-years), with a mean age of 44 years at enrolment, 74% female and 91% Caucasian ethnicity. During the study period, 16 participants have developed RA. All participants provide baseline serum, DNA and RNA samples, and in a subset, stool samples and oral examination are performed for microbiota assessment. At enrolment, 10% of participants had asymptomatic autoimmunity associated with RA (n=147), 10% presented 'clinically suspect arthralgias' (n=143) and 3% reported arthralgias in conjunction with autoimmunity or high genetic risk (n=51). Studies with this cohort have uncovered risk factors for RA development, such as female hormonal factors, poor oral health or intestinal dysbiosis. FUTURE PLANS: Future directions include immunological and 'multiomics' approaches to discover new biological markers of progression towards RA, as well as testing preventive interventions in 'high-risk' population.

Comparative assessment of growth media and incubation conditions for enhanced recovery and isolation of Acinetobacter baumannii from aquatic matrices.

Acinetobacter baumannii causes serious multidrug resistant nosocomial infections around the world. This comprehensive comparative study was designed to assess the effect of temperature (30, 37 and 42 °C), incubation (aerobic and microaerobic) condition and selective [CHROMagar Acinetobacter (CHR) and Leeds Acinetobacter Medium (LAM)] and non-selective [Modified Karmali Agar (MKA)] growth media on the enhanced recovery of A. baumannii from a variety of water (agricultural, recreational, raw drinking intake source, pre-chlorinated and post-chlorinated wastewater effluent) samples spiked with a known number of A. baumannii cells. After spiking each water type with a known number of cells in 10 mL volume, the sample was passed through a membrane filter (pore size 0.45 µm) and filters were placed on different selective media plates and subjected to incubate at various incubation conditions. The results reported in this study show that for all water types tested (except post-chlorinated wastewater effluent), LAM was the most effective selective growth medium in combination with variable temperature and incubation conditions for yielding high recovery rates of A. baumannii cells. Overall, A. baumannii showed that it has a high adaptive capacity to grow on selective and non-selective growth media at different temperature and incubation conditions. The data described in this study suggest that no single incubation condition and growth media would efficiently recover A. baumannii from all environmental water types tested. This data also indicate that selective growth media and incubation condition can significantly affect the recovery of A. baumannii. Differences in recovery of A. baumannii observed in this study which appeared to be dependent on the temperature and environmental characteristics of incubation as well as the sample type, suggest the need for caution when comparing recovery using different protocols.