Lower body mass and lower adiposity are associated with differential responses to two treatment strategies for rheumatoid arthritis.

PURPOSE: To determine if body mass index (BMI) and adipokine levels identify rheumatoid arthritis (RA) patients most likely to benefit from initiation of tumour necrosis factor inhibitors (TNFi) after methotrexate inadequate response. METHODS: This is a secondary analysis of the Rheumatoid Arthritis Comparison of Active Treatments (RACAT) trial and the (TEAR) trial. Both studies compared treatment strategies starting with conventional disease-modifying anti-rheumatic drugs (DMARDs) (triple therapy) versus etanercept plus methotrexate. We compared response rates between TNFi and triple therapy among patients with different BMI. Adipokines were measured at enrolment and associations with treatment response were examined using regression, adjusting for age, sex, BMI and baseline disease activity. RESULTS: In RACAT (n=306), participants who were normal/underweight were more likely to benefit from TNFi versus triple therapy, with greater change in Disease Activity Score in 28 and greater ACR20 response (ACR 20: 64% vs 23%, p=0.001). In contrast, overweight/obese participants had similar response to TNFi versus triple therapy (p-for-interaction=0.001). Similarly, but modest patterns were observed in TEAR (n=601; ACR20: 67% vs 52%, p=0.05). In RACAT, adipokine scores consistent with lower adiposity also predicted greater response to TNFi (ACR20: 58% vs 37%, p=0.01) with better model fit compared with BMI alone. CONCLUSIONS: Lower BMI and evidence of lower adiposity based on adipokine profiles were associated with a superior response to TNFi compared with triple therapy. There was no difference between treatments among overweight/obese participants. The results support TNFi being a particularly important therapeutic among normal/underweight patients, with implications for clinical decisions and trial design.

Factors Associated With Antiretroviral Adherence Among Youth Living With HIV.

BACKGROUND: Youth living with HIV (YLH) have an increased risk for psychosocial stressors that can affect their antiretroviral (ARV) adherence. We examined factors associated with self-reported ARV adherence among YLH ages 12-24 years old. SETTING: YLH (N = 147) were recruited in Los Angeles, CA, and New Orleans, LA from 2017 to 2020. METHODS: YLH whose self-reported recent (30 days) ARV adherence was "excellent" or "very good" were compared with nonadherent YLH on sociodemographic, clinical, and psychosocial factors using univariate and multivariate analyses. RESULTS: Participants were predominantly male (88%), and 81% identified as gay, bisexual, transgender, queer, or other. The mean duration on ARV was 27 months (range 0-237 months). Most YLH (71.2%) self-reported being adherent, and 79% of those who self-reported adherence were also virally suppressed (<200 copies/mL). Multivariate analysis indicated being adherent was significantly associated with white race [aOR = 8.07, confidence intervals (CI): 1.45 to 74.0], Hispanic/Latinx ethnicity [aOR = 3.57, CI: 1.16 to 12.80], more social support [aOR = 1.11, CI: 1.05 to 1.18], and being on ARV for a shorter duration [aOR = 0.99, CI: 0.97 to 0.99]. Mental health symptoms, substance use, age, and history of homelessness or incarceration were unrelated to adherence. CONCLUSIONS: Enhancing efforts to provide support for adherence to non-white youth, and those with limited social support and who have been on ARV treatment longer, may help increase viral suppression among YLH.

J. Claude Bennett, MD: Scholar, Physician, and Leader.

Dr Claude Bennett provided local, national, and international leadership in rheumatology when it was developing as a subspecialty of internal medicine. His early contributions included work in helping to understand at the molecular level how antibodies are formed. Under his leadership, UAB grew into a nationally respected institution known for its high-quality clinical care, impactful research, and outstanding training programs. His many contributions have had a lasting effect on the fields of rheumatology, medicine, and immunology. Throughout his career, he served as a role model and was widely respected for his wise advice and superb mentorship.

Muscle Inflammation Susceptibility: A Potential Phenotype for Guiding Precision Rehabilitation After Total Hip Arthroplasty in End-Stage Osteoarthritis.

The progression of osteoarthritis of the hip to its end stage and ultimately to total hip arthroplasty (THA) is complex; the multifactorial pathophysiology involves myriad collaborating tissues in and around the diseased joint. We have named the heightened state of periarticular muscle inflammation at the time of surgery "muscle inflammation susceptibility" (MuIS) because it is distinct from systemic inflammation. In this review article, we discuss how MuIS and heightened atrophy-associated signaling in the periarticular skeletal muscles may contribute to reduced muscle mass, impaired muscle quality (ie, through fibrosis), and a muscle microenvironment that challenges regenerative capacity and thus functional recovery from THA. We also review directions for future research that should advance understanding of the key determinants of precision for optimized success of THA for each individual.

Cystic fibrosis autoantibody signatures associate with Staphylococcus aureus lung infection or cystic fibrosis-related diabetes.

Introduction: While cystic fibrosis (CF) lung disease is characterized by persistent inflammation and infections and chronic inflammatory diseases are often accompanied by autoimmunity, autoimmune reactivity in CF has not been studied in depth. Methods: In this work we undertook an unbiased approach to explore the systemic autoantibody repertoire in CF using autoantibody microarrays. Results and discussion: Our results show higher levels of several new autoantibodies in the blood of people with CF (PwCF) compared to control subjects. Some of these are IgA autoantibodies targeting neutrophil components or autoantigens linked to neutrophil-mediated tissue damage in CF. We also found that people with CF with higher systemic IgM autoantibody levels have lower prevalence of S. aureus infection. On the other hand, IgM autoantibody levels in S. aureus-infected PwCF correlate with lung disease severity. Diabetic PwCF have significantly higher levels of IgA autoantibodies in their circulation compared to nondiabetic PwCF and several of their IgM autoantibodies associate with worse lung disease. In contrast, in nondiabetic PwCF blood levels of IgA autoantibodies correlate with lung disease. We have also identified other autoantibodies in CF that associate with P. aeruginosa airway infection. In summary, we have identified several new autoantibodies and associations of autoantibody signatures with specific clinical features in CF.

Deep immunophenotyping reveals circulating activated lymphocytes in individuals at risk for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease with currently no universally highly effective prevention strategies. Identifying pathogenic immune phenotypes in 'At-Risk' populations prior to clinical disease onset is crucial to establishing effective prevention strategies. Here, we applied mass cytometry to deeply characterize the immunophenotypes in blood from At-Risk individuals identified through the presence of serum antibodies to citrullinated protein antigens (ACPA) and/or first-degree relative (FDR) status (n=52), as compared to established RA (n=67), and healthy controls (n=48). We identified significant cell expansions in At-Risk individuals compared with controls, including CCR2+CD4+ T cells, T peripheral helper (Tph) cells, type 1 T helper cells, and CXCR5+CD8+ T cells. We also found that CD15+ classical monocytes were specifically expanded in ACPA-negative FDRs, and an activated PAX5 low naïve B cell population was expanded in ACPA-positive FDRs. Further, we developed an "RA immunophenotype score" classification method based on the degree of enrichment of cell states relevant to established RA patients. This score significantly distinguished At-Risk individuals from controls. In all, we systematically identified activated lymphocyte phenotypes in At-Risk individuals, along with immunophenotypic differences among both ACPA+ and ACPA-FDR At-Risk subpopulations. Our classification model provides a promising approach for understanding RA pathogenesis with the goal to further improve prevention strategies and identify novel therapeutic targets.

Hypertension severity, apparent treatment resistant hypertension and hyperuricemia in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study.

BACKGROUND: Prior studies have identified an association between hypertension and hyperuricemia; however, there has been limited research on the association between hypertension severity and hyperuricemia. METHOD: We studied 997 Black and white adults with serum urate data from the reasons for geographic and racial differences in stroke (REGARDS) study. Hypertension was defined as SBP ≥ 140 mmHg or DBP ≥ 90 mmHg or self-reported use of antihypertensive medication. Apparent treatment-resistant hypertension (aTRH) was defined as a SBP ≥ 140 mmHg or DBP ≥ 90 mmHg with concurrent use of three classes of antihypertensive medications, or taking four or more classes of antihypertensive medication regardless of BP level. Controlled BP was defined as SBP <140 mmHg and DBP <90 mmHg. RESULTS: Overall 5.9% of participants had aTRH and 36.6% had hyperuricemia, defined as serum urate >7.0 mg/dl for men and >6.0 mg/dl for women. After full multivariable adjustment, the odds ratio (OR) for hyperuricemia associated with hypertension was 1.60 [95% confidence interval (95% CI): 1.06-2.40]. Compared to participants not taking antihypertensive medication, the ORs for hyperuricemia for participants taking one, two and three classes of antihypertensive medication without aTRH were 1.98 (95% CI: 1.23-3.20), 2.08 (95% CI: 1.25-3.43), 4.31 (95% CI: 2.07-8.97), respectively, and 3.96 (95% CI: 1.75-8.96) for aTRH. Compared to participants without hypertension, the odds ratios for hyperuricemia were 1.67 (95% CI: 1.08-2.58) and 1.46 (95% CI: 0.88-2.44) among those with hypertension with and without controlled BP, respectively. Diuretic use was associated with a higher odds of hyperuricemia. CONCLUSION: This study suggests that individuals taking more classes of antihypertensive medication may benefit from monitoring for hyperuricemia.

2022 American College of Rheumatology Guideline for Vaccinations in Patients With Rheumatic and Musculoskeletal Diseases.

OBJECTIVE: To provide evidence-based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs). METHODS: This guideline follows American College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review for the PICO questions, graded the quality of evidence, and produced an evidence report. An expert Voting Panel reviewed the evidence and formulated recommendations. The panel included adult and pediatric rheumatology providers, infectious diseases specialists, and patient representatives. Consensus required ≥70% agreement on both the direction and strength of each recommendation. RESULTS: This guideline includes expanded indications for some vaccines in patients with RMDs, as well as guidance on whether to hold immunosuppressive medications or delay vaccination to maximize vaccine immunogenicity and efficacy. Safe approaches to the use of live attenuated vaccines in patients taking immunosuppressive medications are also addressed. Most recommendations are conditional and had low quality of supporting evidence. CONCLUSION: Application of these recommendations should consider patients' individual risk for vaccine-preventable illness and for disease flares, particularly if immunosuppressive medications are held for vaccination. Shared decision-making with patients is encouraged in clinical settings.

2022 American College of Rheumatology Guideline for Vaccinations in Patients With Rheumatic and Musculoskeletal Diseases.

OBJECTIVE: To provide evidence-based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs). METHODS: This guideline follows American College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review for the PICO questions, graded the quality of evidence, and produced an evidence report. An expert Voting Panel reviewed the evidence and formulated recommendations. The panel included adult and pediatric rheumatology providers, infectious diseases specialists, and patient representatives. Consensus required ≥70% agreement on both the direction and strength of each recommendation. RESULTS: This guideline includes expanded indications for some vaccines in patients with RMDs, as well as guidance on whether to hold immunosuppressive medications or delay vaccination to maximize vaccine immunogenicity and efficacy. Safe approaches to the use of live attenuated vaccines in patients taking immunosuppressive medications are also addressed. Most recommendations are conditional and had low quality of supporting evidence. CONCLUSION: Application of these recommendations should consider patients' individual risk for vaccine-preventable illness and for disease flares, particularly if immunosuppressive medications are held for vaccination. Shared decision-making with patients is encouraged in clinical settings.

Associations of Socioeconomic Status With Disease Progression in African Americans With Early Rheumatoid Arthritis.

OBJECTIVE: In prior cross-sectional analyses of African American patients with rheumatoid arthritis (RA), measures of socioeconomic status (SES) were associated with clinical joint damage and poorer patient-reported outcome scores. The purpose of this study was to determine whether SES measures are associated with disease progression in a cohort of African American patients with early RA (<2 years duration). METHODS: We analyzed baseline SES and change in 60-month clinical radiographs and patient-reported outcomes data (n = 101 and 177, respectively) in individuals with early RA. SES measures were educational attainment, occupation, homeownership, household income, and block group poverty. Outcomes were based on radiographs (total erosion and joint space narrowing [JSN] scores on hands and feet) and patient-reported outcomes (pain, fatigue, disability, and learned helplessness). We used logistic regression with mixed effects accounting for study site to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Both low education and occupation status were associated with worsening pain (adjusted OR 5.86 [95% CI 3.05-11.3] and adjusted OR 2.55 [95% CI 1.54-4.21], respectively). Patients without a high-school diploma were more likely to have worsened reports of learned helplessness (OR 1.92 [95% CI 1.37-2.67]). Community measures of SES were also significantly associated with patient-reported outcomes score changes. Patients living in areas of block group poverty ≥20% were twice as likely to experience increased disability scores over 60 months of disease duration (OR 1.95 [95% CI 1.17-3.25]). We found no association between SES measures and erosion or JSN score progression. CONCLUSION: Low educational attainment and nonprofessional occupation status were associated with increased worsening of patient-reported outcomes. However, there were no corresponding increases in radiographically assessed erosion or JSN score progression.

Tapering biologic DMARDs in rheumatoid arthritis.

With the arrival of biologics and the shift toward treat-to-target therapy, the possibility of a sustained clinical response has become an achievable goal for many patients with rheumatoid arthritis (RA). Although biologics have revolutionized the treatment of RA, they are costly, potentially inconvenient, and carry risks of side effects. Whether they can or should be tapered in patients with tight disease control is a matter of clinical uncertainty. The major international rheumatology professional societies have all issued guidelines on this question, but across recommendations, consensus is lacking on how and when to consider therapy de-escalation. Recent evidence suggests that sustained remission or low disease activity is more attainable with dose reduction as opposed to outright discontinuation of biologic therapy, and certain predictors of successful taper have begun to be described. This article will (1) summarize the current evidence base for biologic tapering in RA, (2) outline real-world outcomes findings, (3) review important contextual factors relevant to therapy de-escalation, such as cost-effectiveness considerations and patient perspectives, and (4) conclude by summarizing current guidelines.

Muscle transcriptomic circuits linked to periarticular physiology in end-stage osteoarthritis.

The ability of individuals with end-stage osteoarthritis (OA) to functionally recover from total joint arthroplasty is highly inconsistent. The molecular mechanisms driving this heterogeneity have yet to be elucidated. Furthermore, OA disproportionately impacts females, suggesting a need for identifying female-specific therapeutic targets. We profiled the skeletal muscle transcriptome in females with end-stage OA (n = 20) undergoing total knee or hip arthroplasty using RNA-Seq. Single-gene differential expression (DE) analyses tested for DE genes between skeletal muscle overlaying the surgical (SX) joint and muscle from the contralateral (CTRL) leg. Network analyses were performed using Pathway-Level Information ExtractoR (PLIER) to summarize genes into latent variables (LVs), i.e., gene circuits, and link them to biological pathways. LV differences in SX versus CTRL muscle and across sources of muscle tissue (vastus medialis, vastus lateralis, or tensor fascia latae) were determined with ANOVA. Linear models tested for associations between LVs and muscle phenotype on the SX side (inflammation, function, and integrity). DE analysis revealed 360 DE genes (|Log2 fold-difference| ≥ 1, FDR ≤ 0.05) between the SX and CTRL limbs, many associated with inflammation and lipid metabolism. PLIER analyses revealed circuits associated with protein degradation and fibro-adipogenic cell gene expression. Muscle inflammation and function were linked to an LV associated with endothelial cell gene expression highlighting a potential regulatory role of endothelial cells within skeletal muscle. These findings may provide insight into potential therapeutic targets to improve OA rehabilitation before and/or following total joint replacement.

Genetic, social, and environmental risk factors in rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVE: MUC5B and TOLLIP single nucleotide polymorphisms (SNPs) and cigarette smoking were associated with rheumatoid arthritis-interstitial lung disease (RA-ILD) in a predominantly Northern European population. We evaluated whether RA-ILD is associated with these genetic variants and HLA-DRB1 shared epitope (SE) alleles in a large RA cohort stratified by race and smoking history. METHODS: HLA-DRB1 SE alleles and MUC5B rs35705950 and TOLLIP rs5743890 SNPs were genotyped in U.S. veterans with RA. ILD was validated through medical record review. Genetic associations with ILD were assessed in logistic regression models overall and in subgroups defined by race and smoking status, with additive interactions assessed by the relative excess risk of interaction (RERI). RESULTS: Of 2,556 participants (88% male, 77% White), 238 (9.3%) had ILD. The MUC5B variant was associated with ILD (OR 2.25 [95% CI 1.69, 3.02]), whereas TOLLIP and HLA-DRB1 SE were not. The MUC5B variant was less frequent among Black/African American participants (5.8% vs. 22.6%), though its association with RA-ILD was numerically stronger (OR 4.23 [1.65, 10.86]) compared to all other participants (OR 2.32 [1.70, 3.16]). Those with the MUC5B variant and a smoking history had numerically higher odds of ILD (OR 4.18 [2.53, 6.93]) than non-smokers (OR 2.41 [1.16, 5.04]). Additive interactions between MUC5B-race and MUC5B-smoking were not statistically significant. CONCLUSION: In this large RA cohort, the MUC5B promoter variant was associated with >2-fold higher odds of RA-ILD. While this variant is less common among Black/African American patients, its presence in this population carried >4-fold higher odds of RA-ILD.

A Crowdsourcing Approach to Develop Machine Learning Models to Quantify Radiographic Joint Damage in Rheumatoid Arthritis.

Importance: An automated, accurate method is needed for unbiased assessment quantifying accrual of joint space narrowing and erosions on radiographic images of the hands and wrists, and feet for clinical trials, monitoring of joint damage over time, assisting rheumatologists with treatment decisions. Such a method has the potential to be directly integrated into electronic health records. Objectives: To design and implement an international crowdsourcing competition to catalyze the development of machine learning methods to quantify radiographic damage in rheumatoid arthritis (RA). Design, Setting, and Participants: This diagnostic/prognostic study describes the Rheumatoid Arthritis 2-Dialogue for Reverse Engineering Assessment and Methods (RA2-DREAM Challenge), which used existing radiographic images and expert-curated Sharp-van der Heijde (SvH) scores from 2 clinical studies (674 radiographic sets from 562 patients) for training (367 sets), leaderboard (119 sets), and final evaluation (188 sets). Challenge participants were tasked with developing methods to automatically quantify overall damage (subchallenge 1), joint space narrowing (subchallenge 2), and erosions (subchallenge 3). The challenge was finished on June 30, 2020. Main Outcomes and Measures: Scores derived from submitted algorithms were compared with the expert-curated SvH scores, and a baseline model was created for benchmark comparison. Performances were ranked using weighted root mean square error (RMSE). The performance and reproductivity of each algorithm was assessed using Bayes factor from bootstrapped data, and further evaluated with a postchallenge independent validation data set. Results: The RA2-DREAM Challenge received a total of 173 submissions from 26 participants or teams in 7 countries for the leaderboard round, and 13 submissions were included in the final evaluation. The weighted RMSEs metric showed that the winning algorithms produced scores that were very close to the expert-curated SvH scores. Top teams included Team Shirin for subchallenge 1 (weighted RMSE, 0.44), HYL-YFG (Hongyang Li and Yuanfang Guan) subchallenge 2 (weighted RMSE, 0.38), and Gold Therapy for subchallenge 3 (weighted RMSE, 0.43). Bootstrapping/Bayes factor approach and the postchallenge independent validation confirmed the reproducibility and the estimation concordance indices between final evaluation and postchallenge independent validation data set were 0.71 for subchallenge 1, 0.78 for subchallenge 2, and 0.82 for subchallenge 3. Conclusions and Relevance: The RA2-DREAM Challenge resulted in the development of algorithms that provide feasible, quick, and accurate methods to quantify joint damage in RA. Ultimately, these methods could help research studies on RA joint damage and may be integrated into electronic health records to help clinicians serve patients better by providing timely, reliable, and quantitative information for making treatment decisions to prevent further damage.

A genome-wide association study for rheumatoid arthritis replicates previous HLA and non-HLA associations in a cohort from South Africa.

The complex pathogenesis of rheumatoid arthritis (RA) is not fully understood, with few studies exploring the genomic contribution to RA in patients from Africa. We report a genome-wide association study (GWAS) of South-Eastern Bantu-Speaking South Africans (SEBSSAs) with seropositive RA (n = 531) and population controls (n = 2653). Association testing was performed using PLINK (logistic regression assuming an additive model) with sex, age, smoking and the first three principal components as covariates. The strong association with the Human Leukocyte Antigen (HLA) region, indexed by rs602457 (near HLA-DRB1), was replicated. An additional independent signal in the HLA region represented by the lead SNP rs2523593 (near the HLA-B gene; Conditional P-value = 6.4 × 10-10) was detected. Although none of the non-HLA signals reached genome-wide significance (P < 5 × 10-8), 17 genomic regions showed suggestive association (P < 5 × 10-6). The GWAS replicated two known non-HLA associations with MMEL1 (rs2843401) and ANKRD55 (rs7731626) at a threshold of P < 5 × 10-3 providing, for the first time, evidence for replication of non-HLA signals for RA in sub-Saharan African populations. Meta-analysis with summary statistics from an African-American cohort (CLEAR study) replicated three additional non-HLA signals (rs11571302, rs2558210 and rs2422345 around KRT18P39-NPM1P33, CTLA4-ICOS and AL645568.1, respectively). Analysis based on genomic regions (200 kb windows) further replicated previously reported non-HLA signals around PADI4, CD28 and LIMK1. Although allele frequencies were overall strongly correlated between the SEBSSA and the CLEAR cohort, we observed some differences in effect size estimates for associated loci. The study highlights the need for conducting larger association studies across diverse African populations to inform precision medicine-based approaches for RA in Africa.

Effects of end-stage osteoarthritis on markers of skeletal muscle Long INterspersed Element-1 activity.

OBJECTIVE: Long INterspersed Element-1 (L1) is an autonomous transposable element in the genome. L1 transcripts that are not reverse transcribed back into the genome can accumulate in the cytoplasm and activate an inflammatory response via the cyclic GMP-AMP (cGAS)-STING pathway. We examined skeletal muscle L1 markers as well as STING protein levels in 10 older individuals (63 ± 11 y, BMI = 30.2 ± 6.8 kg/m2) with end-stage osteoarthritis (OA) undergoing total hip (THA, n = 4) or knee (TKA, n = 6) arthroplasty versus 10 young, healthy comparators (Y, 22 ± 2 y, BMI = 23.2 ± 2.5 kg/m2). For OA, muscle was collected from surgical (SX) and contralateral (CTL) sides whereas single vastus lateralis samples were collected from Y. RESULTS: L1 mRNA was higher in CTL and SX compared to Y (p < 0.001 and p = 0.001, respectively). Protein expression was higher in SX versus Y for ORF1p (p = 0.002) and STING (p = 0.022). While these data are preliminary due to limited n-sizes and the lack of a BMI-matched younger control group, higher L1 mRNA expression, ORF1p and STING protein are evident in older versus younger adults. More research is needed to determine whether cGAS-STING signaling contributes to heightened muscle inflammation during aging and/or OA.

Heavy Chain Constant Region Usage in Antibodies to Peptidylarginine Deiminase 4 as a Marker of Disease Subsets in Rheumatoid Arthritis.

OBJECTIVE: The study of autoantibody isotypes in autoimmune diseases is useful for identifying clinically relevant endotypes. This study was undertaken to study the prevalence and clinical significance of different isotypes and IgG subclasses of anti-peptidylarginine deiminase 4 (anti-PAD4) autoantibodies in individuals with rheumatoid arthritis (RA). METHODS: In 196 RA subjects and 64 healthy controls, anti-PAD4 antibody types were determined using enzyme-linked immunosorbent assay. We investigated associations between anti-PAD4 antibodies and clinical outcomes, and relevant features were confirmed in an independent RA cohort. RESULTS: Anti-PAD4 IgG1, anti-PAD4 IgG2, anti-PAD4 IgG3, anti-PAD4 IgG4, anti-PAD4 IgA, and anti-PAD4 IgE antibodies were more frequent in RA patients than healthy controls (P < 0.001). Anti-PAD4 IgG1, anti-PAD4 IgG3, and anti-PAD4 IgE were associated with distinct clinical features. Anti-PAD4 IgG1 was predictive of progressive radiographic joint damage (odds ratio [OR] 4.88, P = 0.005), especially in RA patients without baseline joint damage (40% versus 0%, P = 0.003) or in those negative for anti-cyclic citrullinated peptide and/or rheumatoid factor (OR 32; P = 0.009). IgG1 was also associated with higher levels of C-reactive protein (P = 0.006) and interleukin-6 (P = 0.021). RA patients with anti-PAD4 IgG3 had higher baseline joint damage scores (median Sharp/van der Heijde score 13 versus 7, P = 0.046), while those with anti-PAD4 IgE had higher Disease Activity Score in 28 joints (median 4.0 versus 3.5, P = 0.025), more frequent rheumatoid nodules (31% versus 16%, P = 0.025), and more frequent interstitial lung disease (ground-glass opacification) (24% versus 9%, P = 0.014). Anti-PAD4 IgG1 antibody associations with joint damage were corroborated in an independent RA cohort. CONCLUSION: Anti-PAD4 IgG1, anti-PAD4 IgG3, and anti-PAD4 IgE antibodies identify discrete disease subsets in RA, suggesting that heavy chain usage drives distinct effector mechanisms of anti-PAD4 antibodies in RA.

HPV Vaccination among Sexual and Gender Minority Youth Living with or at High-Risk for HIV.

BACKGROUND: Human papillomavirus (HPV) is epidemic among young people, especially those at highest risk of acquiring HPV-related cancers. METHODS: Youth aged 14-24 years old (N = 1628) were recruited from 13 clinics, community agencies, and social media sites in Los Angeles, California, and New Orleans, Louisiana, that specialized in serving sexual and gender minority youths (SGMY), especially males at risk for HIV. A cross-sectional comparison of sociodemographic and risk histories of HPV vaccinated/unvaccinated youths was conducted using both univariate and multivariate regressions. RESULTS: About half (51.9%) of youth were vaccinated, with similar percentages across states and across genders. Sexual and gender minority youths (SGMY, i.e., gay, bisexual, transgender, and non-heterosexual; 68.8%) and their heterosexual peers (15%) were equally likely to be vaccinated (54%), even though their risk for HPV-related cancers is very different. Vaccinations were higher among younger youth, those not using condoms, youth with greater education, that possessed a primary health care provider, and youth diagnosed with HIV. Vaccinations were lower among youth that were out-of-home due to mental health inpatient hospitalization, drug treatment, homelessness, or incarceration. CONCLUSIONS: Special programs are required to target youth experiencing multiple life stressors, especially out-of-home experiences, those with less education, and without the safety net of health insurance or a provider.

SCOPE 2 - Still Answering the Unanswered Questions in Oesophageal Radiotherapy? SCOPE 2: a Randomised Phase II/III Trial to Study Radiotherapy Dose Escalation in Patients with Oesophageal Cancer Treated with Definitive Chemoradiation with an Embedded Phase II Trial for Patients with a Poor Early Response using Positron Emission Tomography/Computed Tomography.

The SCOPE 2 trial of definitive chemoradiotherapy in oesophageal cancer investigates the benefits of radiotherapy dose escalation and systemic therapy optimisation. The trial opened in 2016. The landscape of oesophageal cancer treatment over the lifetime of this trial has changed significantly and the protocol has evolved to reflect this. However, with the recent results of the Dutch phase III ART DECO study showing no improvement in local control or overall survival with radiotherapy dose escalation in a similar patient group, we sought to determine if the SCOPE 2 trial is still answering the key unanswered questions for oesophageal radiotherapy. Here we discuss the rationale behind the SCOPE 2 trial, outline the trial schema and review current data on dose escalation and outline recommendations for future areas of research.