Identifying flares in rheumatoid arthritis: Reliability and construct validation of the OMERACT RA Flare Core Domain Set

Objective: To evaluate the reliability of concurrent flare identification using 3 methods (patient, rheumatologist and Disease Activity Score (DAS)28 criteria), and construct validity of candidate items representing the Outcome Measures in Rheumatology Clinical Trials (OMERACT) RA Flare Core Domain Set. Methods: Candidate flare questions and legacy measures were administered at consecutive visits to Canadian Early Arthritis Cohort (CATCH) patients between November 2011 and November 2014. The American College of Rheumatology (ACR) core set indicators were recorded. Concordance to identify flares was assessed using the agreement coefficient. Construct validity of flare questions was examined: convergent (Spearman's r); discriminant (mean differences between flaring/non-flaring patients); and consequential (proportions with prior treatment reductions and intended therapeutic change postflare). Results: The 849 patients were 75% female, 81% white, 42% were in remission/low disease activity (R/LDA), and 16-32% were flaring at the second visit. Agreement of flare status was low-strong (κ's 0.17-0.88) and inversely related to RA disease activity level. Flare domains correlated highly (r's≥0.70) with each other, patient global (r's≥0.66) and corresponding measures (r's 0.49-0.92); and moderately highly with MD and patient-reported joint counts (r's 0.29-0.62). When MD/patients agreed the patient was flaring, mean flare domain between-group differences were 2.1-3.0; 36% had treatment reductions prior to flare, with escalation planned in 61%. Conclusions: Flares are common in rheumatoid arthritis (RA) and are often preceded by treatment reductions. Patient/MD/DAS agreement of flare status is highest in patients worsening from R/LDA. OMERACT RA flare questions can discriminate between patients with/without flare and have strong evidence of construct and consequential validity. Ongoing work will identify optimal scoring and cut points to identify RA flares

pGALS Training Increases Canadian and Kenyan Physicians\u27 Confidence in Examining the Musculoskeletal System in Children

Background/Purpose: pGALS (paediatric Gait Arms Legs Spine) is a simple, validated musculoskeletal (MSK) assessment tool for the school-aged child. Studies have shown physicians lack confidence in the pediatric MSK examination. We evaluated the effect of a pGALS teaching session on enhancing physicians’ confidence in examining the MSK system in children. We compared the impact of the intervention on two culturally distinct groups of physicians. We explored preferred methods of learning and applying pGALS in clinical practice. Methods: Physicians enrolled in a pGALS workshop in Canada (Quebec) and Kenya (Nairobi) completed anonymous questionnaires on-site before and after the teaching session. Canadian participants were also asked to complete an anonymous electronic follow-up survey 6 months later. Results: A total of 103 physicians completed the questionnaires (51 Canadian; 52 Kenyan); 68.4% were family physicians (FP), 31.6% were pediatricians (P). Among Canadians, FP and P were similar in number (P 53.2%, FP 46.8%); most Kenyan participants were FPs (88.2%) (p\u3c 0.001). Canadian participants had more years of practice (Canadian:17.2±10.3 vs Kenyan:4.3±3.6, p\u3c 0.0001). MSK examination was previously taught in 98/103 (95.2%); however only 60.8% were taught the MSK exam in children (Canadian:66% vs Kenyan:55.8%, p=n.s). Before the workshop, only 26.5% (26/98) felt ‘confident’ or ‘very confident’ in evaluating the pediatric MSK system (Canadian:28.3% vs. Kenyan:25%, p=n.s). Confidence in examining the MSK exam was significantly lower than that of the following systems: cardiovascular, respiratory or abdominal. Following the teaching session, increased level of confidence was seen, with 88.8% feeling ‘confident’ and ‘very confident” (Canadian:80.4% vs Kenyan:96.2%, p=0.014). Most common barrier identified for its use was that it was time-consuming (Canadian:37.3% vs Kenyan:53.9%, p=n.s). More Kenyan physicians reported that an office poster could facilitate pGALS use (Canadian:51% vs Kenyan:71.2%, p=0.041); a pocket card was suggested equally (Canadian:67.4% vs Kenyan:50%, p=n.s). Over half of participants agreed that web-based demonstrations (Canadian:55.3% vs Kenyan:57.7%; p=n.s) could improve confidence in pediatric MSK examination; workshops were preferred by Canadians (Canadian:72.3% vs Kenyan:46.2%; p=0.004). Only 27.5% (14/51) of Canadian participants responded to a follow-up survey. Among those, improved confidence was maintained in 92.9% (13/14). Most respondents (78.6%, 11/14) were using pGALS in clinical practice and 75% found it ‘useful’ or ‘very useful’ in evaluating MSK symptoms. Conclusion: Self-perceived confidence in examining the pediatric MSK system was low in both Canadian and Kenyan physicians. pGALS training improved practitioners’ confidence regardless of type of physician, experience or culture. pGALS reminders may be useful to ensure pGALS implementation into clinical practice

Long-term exposure to a mixture of industrial SO2, NO2, and PM2.5 and anti-citrullinated protein antibody positivity

Abstract Background Studies of associations between industrial air emissions and rheumatic diseases, or diseases-related serological biomarkers, are few. Moreover, previous evaluations typically studied individual (not mixed) emissions. We investigated associations between individual and combined exposures to industrial sulfur dioxide (SO2), nitrogen dioxide (NO2), and fine particles matter (PM2.5) on anti-citrullinated protein antibodies (ACPA), a characteristic biomarker for rheumatoid arthritis (RA). Methods Serum ACPA was determined for 7600 randomly selected CARTaGENE general population subjects in Quebec, Canada. Industrial SO2, NO2, and PM2.5 concentrations, estimated by the California Puff (CALPUFF) atmospheric dispersion model, were assigned based on residential postal codes at the time of sera collection. Single-exposure logistic regressions were performed for ACPA positivity defined by 20 U/ml, 40 U/ml, and 60 U/ml thresholds, adjusting for age, sex, French Canadian origin, smoking, and family income. Associations between regional overall PM2.5 exposure and ACPA positivity were also investigated. The associations between the combined three industrial exposures and the ACPA positivity were assessed by weighted quantile sum (WQS) regressions. Results Significant associations between individual industrial exposures and ACPA positivity defined by the 20 U/ml threshold were seen with single-exposure logistic regression models, for industrial emissions of PM2.5 (odds ratio, OR = 1.19, 95% confidence intervals, CI: 1.04–1.36) and SO2 (OR = 1.03, 95% CI: 1.00–1.06), without clear associations for NO2 (OR = 1.01, 95% CI: 0.86–1.17). Similar findings were seen for the 40 U/ml threshold, although at 60 U/ml, the results were very imprecise. The WQS model demonstrated a positive relationship between combined industrial exposures and ACPA positivity (OR = 1.36, 95% CI: 1.10–1.69 at 20 U/ml) and suggested that industrial PM2.5 may have a closer association with ACPA positivity than the other exposures. Again, similar findings were seen with the 40 U/ml threshold, though 60 U/ml results were imprecise. No clear association between ACPA and regional overall PM2.5 exposure was seen. Conclusions We noted positive associations between ACPA and industrial emissions of PM2.5 and SO2. Industrial PM2.5 exposure may play a particularly important role in this regard

Rheumatoid arthritis-relevant DNA methylation changes identified in ACPA-positive asymptomatic individuals using methylome capture sequencing

Abstract Objective To compare DNA methylation in subjects positive vs negative for anti-citrullinated protein antibodies (ACPA), a key serological marker of rheumatoid arthritis (RA) risk. Methods With banked serum from a random subset (N = 3600) of a large general population cohort, we identified ACPA-positive samples and compared them to age- and sex-matched ACPA-negative controls. We used a custom-designed methylome panel to conduct targeted bisulfite sequencing of 5 million CpGs located in regulatory or hypomethylated regions of DNA from whole blood (red blood cell lysed). Using binomial regression models, we investigated the differentially methylated regions (DMRs) between ACPA-positive vs ACPA-negative subjects. An independent set of T cells from RA patients was used to “validate” the differentially methylated sites. Results We measured DNA methylation in 137 subjects, of whom 63 were ACPA-positive, 66 were ACPA-negative, and 8 had self-reported RA. We identified 1303 DMRs of relevance, of which one third (402) had underlying genetic effects. These DMRs were enriched in intergenic CpG islands (CGI) and CGI shore regions. Furthermore, the genes associated with these DMRs were enriched in pathways related to Epstein-Barr virus infection and immune response. In addition, 80 (38%) of 208 RA-specific DMRs were replicated in T cells from RA samples. Conclusions Sequencing-based high-resolution methylome mapping revealed biologically relevant DNA methylation changes in asymptomatic individuals positive for ACPA that overlap with those seen in RA. Pathway analyses suggested roles for viral infections, which may represent the effect of environmental triggers upstream of disease onset

Safety and Efficacy of Influenza Vaccination in Patients Receiving Immune Checkpoint Inhibitors. Systematic Review with Meta-Analysis

The potential increased risk of immune-related adverse events (irAEs) post-influenza vaccine is a concern in patients receiving immune checkpoint inhibitors (ICI). We conducted a systematic review with meta-analysis of studies reporting the effects of influenza vaccination in patients with cancer during ICI treatment. We searched five electronic databases until 01/2022. Two authors independently selected studies, appraised their quality, and collected data. The primary outcome was the determination of pooled irAE rates. Secondary outcomes included determination of immunogenicity and influenza infection rates and cancer-related outcomes. Nineteen studies (26 publications, n = 4705) were included; 89.5% were observational. Vaccinated patients reported slighter lower rates of irAEs compared to unvaccinated patients (32% versus 41%, respectively). Seroprotection for influenza type A was 78%–79%, and for type B was 75%. Influenza and irAE-related death rates were similar between groups. The pooled proportion of participants reporting a laboratory-confirmed infection was 2% (95% CI 0% to 6%), and influenza-like illness was 14% (95% CI 2% to 32%). No differences were reported on the rates of laboratory-confirmed infection between vaccinated and unvaccinated patients. Longer progression-free and overall survival was also observed in vaccinated compared with unvaccinated patients. Current evidence suggests that influenza vaccination is safe in patients receiving ICIs, does not increase the risk of irAEs, and may improve survival

Perceptions and Challenges Experienced by African Physicians When Prescribing Methotrexate for Rheumatic Disease: An Exploratory Study

OBJECTIVE: Guidelines for methotrexate (MTX) use in rheumatic disease may not be feasible for physicians practicing in the least developed countries. We aimed to understand the experiences of MTX prescribers relating to MTX use for rheumatic disease in African countries to inform the development of culturally and geographically appropriate recommendations. METHODS: African physicians who self-identified as MTX prescribers from countries classified as having a low versus a medium or high Human Development Index (L-HDI versus MH-HDI) participated in semistructured interviews between August 2016 and September 2017. Interviews were transcribed verbatim, coded thematically, and stratified by HDI. RESULTS: Physicians (23 rheumatologists; six internists) from 29 African countries were interviewed (15 L-HDI; 14 MH-HDI). Identified barriers to MTX use included inconsistent MTX supply (reported by 87% L-HDI versus 43% MH-HDI), compounded by financial restrictions (reported by 93% L-HDI versus 64% MH-HDI), patient hesitancy based partly on cultural beliefs and societal roles (reported by 71%), few prescribers (reported by 33%), prevalent infections (especially viral hepatitis, tuberculosis, and human immunodeficiency virus), and both availability and cost of monitoring tests. MTX pretreatment evaluation and starting and maximal doses were similar between L-HDI countries and MH-HDI countries. CONCLUSION: The challenges of treating rheumatic disease in African countries include unreliable drug availability and cost, limited subspecialists, and patient beliefs. Adapting recommendations for MTX use in the context of prevalent endemic infections; ensuring safe but feasible MTX monitoring strategies, enhanced access to stable drug supply, and specialized rheumatology care; and improving patient education are key to reducing the burden of rheumatic diseases in L-HDI countries

Novel insights into systemic autoimmune rheumatic diseases using shared molecular signatures and an integrative analysis

<p>We undertook this study to identify DNA methylation signatures of three systemic autoimmune rheumatic diseases (SARDs), namely rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis, compared to healthy controls. Using a careful design to minimize confounding, we restricted our study to subjects with incident disease and performed our analyses on purified CD4⁺ T cells, key effector cells in SARD. We identified differentially methylated (using the Illumina Infinium HumanMethylation450 BeadChip array) and expressed (using the Illumina TruSeq stranded RNA-seq protocol) sites between cases and controls, and investigated the biological significance of this SARD signature using gene annotation databases. We recruited 13 seropositive rheumatoid arthritis, 19 systemic sclerosis, 12 systemic lupus erythematosus subjects, and 8 healthy controls. We identified 33 genes that were both differentially methylated and expressed (26 over- and 7 under-expressed) in SARD cases versus controls. The most highly overexpressed gene was <i>CD1C</i> (log fold change in expression = 1.85, adjusted <i>P</i> value = 0.009). In functional analysis (Ingenuity Pathway Analysis), the top network identified was lipid metabolism, molecular transport, small molecule biochemistry. The top canonical pathways included the mitochondrial L-carnitine shuttle pathway (<i>P</i> = 5E-03) and PTEN signaling (<i>P</i> = 8E-03). The top upstream regulator was HNF4A (<i>P</i> = 3E-05). This novel SARD signature contributes to ongoing work to further our understanding of the molecular mechanisms underlying SARD and provides novel targets of interest.</p