Roles of IRF4 in various immune cells in systemic lupus erythematosus.

Interferon regulatory factor 4 (IRF4) is a member of IRF family of transcription factors which mainly regulates the transcription of IFN. IRF4 is restrictively expressed in immune cells such as T and B cells, macrophages, as well as DC. It is essential for the development and function of these cells. Since these cells take part in the homeostasis of the immune system and dysfunction of them contributes to the initiation and progress of systemic lupus erythematosus (SLE), the roles of IRF4 in the SLE development becomes an important topic. Here we systemically discuss the biological characteristics of IRF4 in various immune cells and analyze the pathologic effects of IRF4 alteration in SLE and the potential targeting therapeutics of SLE.

miRNA-148a-containing GMSC-derived EVs modulate Treg/Th17 balance via IKKB/NF-κB pathway and treat a rheumatoid arthritis model.

Mesenchymal stem cells (MSCs) have demonstrated potent immunomodulatory properties that have shown promise in the treatment of autoimmune diseases, including rheumatoid arthritis (RA). However, the inherent heterogeneity of MSCs triggered conflicting therapeutic outcomes, raising safety concerns and limiting their clinical application. This study aimed to investigate the potential of extracellular vesicles derived from human gingival mesenchymal stem cells (GMSC-EVs) as a therapeutic strategy for RA. Through in vivo experiments using an experimental RA model, our results demonstrate that GMSC-EVs selectively homed to inflamed joints and recovered Treg and Th17 cell balance, resulting in the reduction of arthritis progression. Our investigations also uncovered miR-148a-3p as a critical contributor to the Treg/Th17 balance modulation via IKKB/NF-κB signaling orchestrated by GMSC-EVs, which was subsequently validated in a model of human xenograft versus host disease (xGvHD). Furthermore, we successfully developed a humanized animal model by utilizing synovial fibroblasts obtained from patients with RA (RASFs). We found that GMSC-EVs impeded the invasiveness of RASFs and minimized cartilage destruction, indicating their potential therapeutic efficacy in the context of patients with RA. Overall, the unique characteristics - including reduced immunogenicity, simplified administration, and inherent ability to target inflamed tissues - position GMSC-EVs as a viable alternative for RA and other autoimmune diseases.

Mycophenolate mofetil withdrawal in patients with systemic lupus erythematosus: a multicentre, open-label, randomised controlled trial.

BACKGROUND: Mycophenolate mofetil is an immunosuppressant commonly used to treat systemic lupus erythematosus (SLE) and lupus nephritis. It is a known teratogen associated with significant toxicities, including an increased risk of infections and malignancies. Mycophenolate mofetil withdrawal is desirable once disease quiescence is reached, but the timing of when to do so and whether it provides a benefit has not been well-studied. We aimed to determine the effects of mycophenolate mofetil withdrawal on the risk of clinically significant disease reactivation in patients with quiescent SLE on long-term mycophenolate mofetil therapy. METHODS: This multicenter, open-label, randomised trial was conducted in 19 centres in the USA. Eligible patients were aged between 18 and 70 years old, met the American College of Rheumatology (ACR) 1997 SLE criteria, and had a clinical SLEDAI score of less than 4 at screening. Mycophenolate mofetil therapy was required to be stable or decreasing for 2 years or more if initiated for renal indications, or for 1 year or more for non-renal indications. Participants were randomly allocated in a 1:1 ratio to a withdrawal group, who tapered off mycophenolate mofetil over 12 weeks, or a maintenance group who maintained their baseline dose (1-3g per day) for 60 weeks. Adaptive random allocation ensured groups were balanced for study site, renal versus non-renal disease, and baseline mycophenolate mofetil dose (≥2 g per day vs <2 g per day). Clinically significant disease reactivation by week 60 following random allocation, requiring increased doses or new immunosuppressive therapy was the primary endpoint, in the modified intention-to-treat population (all randomly allocated participants who began study-provided mycophenolate mofetil). Non-inferiority was evaluated using an estimation-based approach. The trial was registered at ClinicalTrials.gov (NCT01946880) and is completed. FINDINGS: Between Nov 6, 2013, and April 27, 2018, 123 participants were screened, of whom 102 were randomly allocated to the maintenance group (n=50) or the withdrawal group (n=52). Of the 100 participants included in the modified intention-to-treat analysis (49 maintenance, 51 withdrawal), 84 (84%) were women, 16 (16%) were men, 40 (40%) were White, 41 (41%) were Black, and 76 (76%) had a history of lupus nephritis. The average age was 42 (SD 12·7). By week 60, nine (18%) of 51 participants in the withdrawal group had clinically significant disease reactivation, compared to five (10%) of 49 participants in the maintenance group. The risk of clinically significant disease reactivation was 11% (95% CI 5-24) in the maintenance group and 18% (10-32) in the withdrawal group. The estimated increase in the risk of clinically significant disease reactivation with mycophenolate mofetil withdrawal was 7% (one-sided upper 85% confidence limit 15%). Similar rates of adverse events were observed in the maintenance group (45 [90%] of 50 participants) and the withdrawal group (46 [88%] of 52 participants). Infections were more frequent in the mycophenolate mofetil maintenance group (32 [64%]) compared with the withdrawal group (24 [46%]). INTERPRETATIONS: Mycophenolate mofetil withdrawal is not significantly inferior to mycophenolate mofetil maintenance. Estimates for the rates of disease reactivation and increases in risk with withdrawal can assist clinicians in making informed decisions on withdrawing mycophenolate mofetil in patients with stable SLE. FUNDING: The National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Obesity is an independent risk factor for cancer development following diagnosis of dermatomyositis.

Patients with dermatomyositis (DM) are at an increased risk of cancer development, especially around the time of diagnosis of DM. Obesity is also a risk factor in the general population for cancer development. This study aimed to assess the association between cancer in DM patients with and without obesity as defined by ICD code and BMI data. In this analysis of patients with DM, logistic regression modeling of the odds of cancer outcome was performed for patients with DM and obesity compared to those without obesity, adjusted for age and sex. A total of 12,722 patients with DM were identified, of whom 6,055 had available BMI data. DM patients who were coded obese at any point had significantly higher odds 1.98 (95 % Confidence interval (CI) 1.70, 2.30) of a subsequent cancer diagnosis. This association was also found in the subgroup analysis with available BMI where patients with obesity (BMI ≥30 kg/m2) had an increased odds of cancer 1.23 (1.02, 1.49) when compared to patients with BMI <30 kg/m2 with DM. In time to event analysis any obesity code was associated with a 16 % increased hazard of cancer (adjusted hazard ratio 1.16 [95 % CI 1.02, 1.31]). Overall, the most frequent type of cancer was breast cancer, however patients with DM and obesity had higher frequencies of lymphoma, colorectal, melanoma, uterine, renal cancers compared to patients with DM without obesity.

Targeting kinase ITK treats autoimmune arthritis via orchestrating T cell differentiation and function.

IL-2 inducible T cell kinase (ITK) is critical in T helper subset differentiation and its inhibition has been suggested for the treatment of T cell-mediated inflammatory diseases. T follicular helper (Tfh), Th17 and regulatory T cells (Treg) also play important roles in the development of rheumatoid arthritis (RA), while the role of ITK in the development of RA and the intricate balance between effector T and regulatory T cells remains unclear. Here, we found that CD4+ T cells from RA patients presented with an elevated ITK activation. ITK inhibitor alleviated existing collagen-induced arthritis (CIA) and reduced antigen specific antibody production. Blocking ITK kinase activity interferes Tfh cell generation. Moreover, ITK inhibitor effectively rebalances Th17 and Treg cells by regulating Foxo1 translocation. Furthermore, we identified dihydroartemisinin (DHA) as a potential ITK inhibitor, which could inhibit PLC-γ1 phosphorylation and the progression of CIA by rebalancing Th17 and Treg cells. Out data imply that ITK activation is upregulated in RA patients, and therefore blocking ITK signal may provide an effective strategy to treat RA patients and highlight the role of ITK on the Tfh induction and RA progression.

Higher Odds of Adverse Cutaneous Reactions in Patients With Dermatomyositis Treated With Hydroxychloroquine Compared With Methotrexate.

OBJECTIVE: Hydroxychloroquine (HCQ) use for the treatment of dermatomyositis (DM) has been associated with adverse cutaneous reactions. We applied a new user, active comparator, retrospective design to assess differences in adverse cutaneous reactions or hospitalizations between HCQ and methotrexate (MTX) use among patients with DM. METHODS: We used a national network of data from insurance registries (TriNetX), enrolling patients with two International Classification of Diseases (ICD) codes for DM separated by 6 months or more who had a prescription for either (but not both) HCQ or MTX on or after DM diagnosis. Outcomes were adverse cutaneous reactions (ICD codes) or hospital admission (Current Procedural Terminology (CPT) codes) within 4 months from the prescription dispense date. Logistic regression was used to produce adjusted odds ratios (aORs) and 95% confidence intervals (CIs) comparing outcomes in the HCQ group (n = 1364) and the MTX group (n = 1400), adjusted for age at first DM diagnosis, year of birth, sex, and time from DM diagnosis to first prescription. RESULTS: Overall, we found no significant difference in odds of hospitalization in those taking HCQ (aOR 1.05; 95% CI: 0.79-1.39) compared with those on MTX. Patients with DM on HCQ had 30% higher odds of adverse cutaneous reaction diagnosis compared with patients on MTX (aOR 1.30; 95% CI: 1.02-1.59). Age at DM diagnosis was an effect modifier of this association, with higher odds of adverse cutaneous reaction among patients taking HCQ who were younger at diagnosis. CONCLUSION: Compared with MTX use, HCQ use, especially in younger patients, may result in higher odds of adverse cutaneous reactions.

Clinical diagnoses associated with a positive antinuclear antibody test in patients with and without autoimmune disease.

BACKGROUND: Antinuclear antibodies (ANA) are antibodies present in several autoimmune disorders. However, a large proportion of the general population (20%) also have a positive test; very few of these individuals will develop an autoimmune disease, and the clinical impact of a positive ANA in them is not known. Thus, we test the hypothesis that ANA + test reflects a state of immune dysregulation that alters risk for some clinical disorders in individuals without an autoimmune disease. METHODS: We performed high throughput association analyses in a case-control study using real world data from the de-identified electronic health record (EHR) system from Vanderbilt University Medical Center. The study population included individuals with an ANA titer ≥ 1:80 at any time (ANA +) and those with negative results (ANA-). The cohort was stratified into sub-cohorts of individuals with and without an autoimmune disease. A phenome-wide association study (PheWAS) adjusted by sex, year of birth, race, and length of follow-up was performed in the study cohort and in the sub-cohorts. As secondary analyses, only clinical diagnoses after ANA testing were included in the analyses. RESULTS: The cohort included 70,043 individuals: 49,546 without and 20,497 with an autoimmune disease, 26,579 were ANA + and 43,464 ANA-. In the study cohort and the sub-cohort with autoimmune disease, ANA + was associated (P ≤ 5 × 10-5) with 88 and 136 clinical diagnoses respectively, including lupus (OR ≥ 5.4, P ≤ 7.8 × 10-202) and other autoimmune diseases and complications. In the sub-cohort without autoimmune diseases, ANA + was associated with increased risk of Raynaud's syndrome (OR ≥ 2.1) and alveolar/perialveolar-related pneumopathies (OR ≥ 1.4) and decreased risk of hepatitis C, tobacco use disorders, mood disorders, convulsions, fever of unknown origin, and substance abuse disorders (OR ≤ 0.8). Analyses including only diagnoses after ANA testing yielded similar results. CONCLUSION: A positive ANA test, in addition to known associations with autoimmune diseases, Raynaud's phenomenon, and idiopathic fibrosing alveolitis related disorders, is associated with decreased prevalence of several non-autoimmune diseases.

V-Set Immunoglobulin Domain-Containing Protein 4 as a Novel Serum Biomarker of Lupus Nephritis and Renal Pathology Activity.

OBJECTIVE: To discover novel serum biomarkers that have diagnostic or predictive value in lupus nephritis (LN). METHODS: Using a quantitative protein microarray, we screened for high-abundant proteome expression in the serum of patients with LN compared to healthy controls. Top candidates from this screening were validated using a larger cohort of patients with LN compared to a disease control cohort (subjects with other chronic kidney diseases) and a healthy control cohort. Promising markers were then selected using a machine-learning model and further validated with a larger patient cohort. The corresponding autoantibodies and immune complexes containing these proteins were also examined. RESULTS: In total, 13 proteins were found to be significantly elevated in LN patient serum in the screening, among which 8 proteins were validated by enzyme-linked immunosorbent assay using 81 serum samples from LN patients and control subjects. Three serum markers with LN diagnostic potential were identified using feature importance analysis and further validated using 155 serum samples from LN patients and control subjects. V-set immunoglobulin domain-containing protein 4 (VSIG4) appeared to be the most promising marker in distinguishing LN from healthy controls, with an area under the curve of 0.93. VSIG4 could also discriminate active LN from inactive LN. Furthermore, serum VSIG4 levels were positively correlated with all of the following clinical parameters: the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score (Spearman's rank correlation rs = 0.42, P < 0.001), the renal domain score of the SLEDAI (rs = 0.46, P < 0.001), the urinary protein-to-creatinine ratio (rs = 0.56, P < 0.001), and the serum creatinine level (rs = 0.41, P < 0.001). Importantly, we found that serum VSIG4 levels tracked with LN disease activity longitudinally, and that serum VSIG4 levels reflected the renal pathology activity index (AI), particularly the AI components of crescent formation and hyaline deposits. CONCLUSION: VSIG4 may be a promising novel serum biomarker and therapeutic target in patients with LN.

Multi-ancestry and multi-trait genome-wide association meta-analyses inform clinical risk prediction for systemic lupus erythematosus.

Systemic lupus erythematosus is a heritable autoimmune disease that predominantly affects young women. To improve our understanding of genetic etiology, we conduct multi-ancestry and multi-trait meta-analysis of genome-wide association studies, encompassing 12 systemic lupus erythematosus cohorts from 3 different ancestries and 10 genetically correlated autoimmune diseases, and identify 16 novel loci. We also perform transcriptome-wide association studies, computational drug repurposing analysis, and cell type enrichment analysis. We discover putative drug classes, including a histone deacetylase inhibitor that could be repurposed to treat lupus. We also identify multiple cell types enriched with putative target genes, such as non-classical monocytes and B cells, which may be targeted for future therapeutics. Using this newly assembled result, we further construct polygenic risk score models and demonstrate that integrating polygenic risk score with clinical lab biomarkers improves the diagnostic accuracy of systemic lupus erythematosus using the Vanderbilt BioVU and Michigan Genomics Initiative biobanks.

Adapting an Evidence-Based Exercise and Education Program for Older Breast Cancer Survivors for the REJOIN Trial.

Physical activity (PA) promotes survival and mitigates symptoms in older breast cancer survivors (BCS), especially to reduce joint pain associated with adjuvant hormonal treatment. The purpose is to describe the adaptation process for an evidence-based exercise and education curriculum (i.e., Fit & Strong!) to support older BCS participating in the Using Exercise to Relieve Joint Pain and Improve Aromatase Inhibitor Adherence in Older Breast Cancer Survivors trial. We reviewed all educational materials with scientific/clinical experts to identify necessary content changes. Next, we conducted semistructured phone interviews with BCS to review all educational materials and conducted a real-time pretest for the trial. Overall, BCS found the adapted materials and experience acceptable (mean score of 9.2/10 for satisfaction). Content changes included simplifying exercise instructions, prioritizing content related to the trial goals, and updating photographs. Because of COVID, the pretest was conducted via Zoom. Our multistep adaptation process provided an acceptable intervention to meet the needs of older BCS. Lessons learned will be applied to the forthcoming pilot trial.

Construction and Application of Polygenic Risk Scores in Autoimmune Diseases.

Genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with autoimmune diseases and provided unique mechanistic insights and informed novel treatments. These individual genetic variants on their own typically confer a small effect of disease risk with limited predictive power; however, when aggregated (e.g., via polygenic risk score method), they could provide meaningful risk predictions for a myriad of diseases. In this review, we describe the recent advances in GWAS for autoimmune diseases and the practical application of this knowledge to predict an individual's susceptibility/severity for autoimmune diseases such as systemic lupus erythematosus (SLE) via the polygenic risk score method. We provide an overview of methods for deriving different polygenic risk scores and discuss the strategies to integrate additional information from correlated traits and diverse ancestries. We further advocate for the need to integrate clinical features (e.g., anti-nuclear antibody status) with genetic profiling to better identify patients at high risk of disease susceptibility/severity even before clinical signs or symptoms develop. We conclude by discussing future challenges and opportunities of applying polygenic risk score methods in clinical care.

Low-Density Lipoprotein Cholesterol and the Risk of Rheumatoid Arthritis: A Prospective Study in a Chinese Cohort.

Objective: This study aimed to investigate whether low-density lipoprotein cholesterol (LDL-C) concentration was associated with the risk of rheumatoid arthritis (RA) in Chinese adults. Methods: The study included the 97,411 participants in the Kailuan Study without RA, with complete baseline LDL-C data, and who did not use lipid-lowering medications at baseline or during follow-up. We used Cox proportional hazards modeling to calculate the hazard ratio (HR) and 95% confidence interval (95% CI) of RA according to baseline LDL-C tertiles, adjusting for age, sex, body mass index, HDL-C, triglycerides, diabetes, hypertension, alcohol consumption, and smoking. We also calculated the HR and 95% CI of RA using updated LDL-C measurements prior to the end of follow-up, adjusting for covariates. Results: We identified 97 incident RA cases between 2006 and 2018. After adjusting for potential confounders, updated LDL-C concentration­rather than baseline LDL-C­was inversely associated with RA risk. The adjusted HR of RA was 0.64 (95% CI: 0.38, 1.09; p-trend = 0.10) comparing the two extreme baseline LDL-C tertiles, and 0.38 (95% CI: 0.22, 0.64; p-trend < 0.01) comparing the two extreme tertiles of the updated LDL-C concentrations. Conclusions: In this prospective study, high LDL-C concentrations, when measured closest to RA diagnosis or the end of follow-up, were associated with a low risk of RA. These findings highlight the changes in LDL-C prior to RA diagnosis, and the importance of including lipid analyses into studies of the pathogenesis of RA.

TGF-ß-induced CD4+ FoxP3+ regulatory T cell-derived extracellular vesicles modulate Notch1 signaling through miR-449a and prevent collagen-induced arthritis in a murine model.

CD4+FOXP3+ Treg cells are central to the maintenance of self-tolerance and can be defective in autoimmunity. In autoimmune rheumatic diseases, dysfunctional self-tolerance, is to a large extent, caused by insufficient Treg-cell activity. Although nTregs have therapeutic effects in vivo, their relative scarcity and slow rate of in vitro expansion hinder the application of nTreg therapy. It was previously reported that EVs contribute significantly to the suppressive function of FOXP3+ Treg cells. Considering that the stability and plasticity of nTregs remain major challenges in vivo, we established EVs derived from in vitro TGF-ß-induced Treg cells (iTreg-EVs) and assessed their functions in a murine model of autoimmune arthritis. The results demonstrated that iTreg-EVs preferentially homed to the pathological joint and efficiently prevented the imbalance in Th17/Treg cells in arthritic mice. Furthermore, we found that miR-449a-5p mediated Notch1 expression modulation and that miR-449a-5p knockdown abolished the effects of iTreg-EVs on effector T cells and regulatory T cells in vitro and in vivo. Taken together, our results show that iTreg-EVs control the inflammatory responses of recipient T cells through miR-449a-5p-dependent modulation of Notch1 and ameliorate the development and severity of arthritis, which may provide a potential cell-free strategy based on manipulating iTreg-EVs to prevent autoimmune arthritis.

Alcohol Consumption and Risk of Rheumatoid Arthritis among Chinese Adults: A Prospective Study.

Alcohol consumption may be associated with the risk of rheumatoid arthritis (RA), but potential sex-related differences in this association have not been explored. Thus, we utilized 87,118 participants in the Kailuan Study, a prospective cohort initiated in 2006 to study the risk factors of cardiovascular disease in a Chinese population. We included those that did not have RA at baseline (2006), and performed cox proportional hazard modeling to calculate the hazard ratio (HR) and 95% confidence interval (95% CI) of RA according to the levels of alcohol consumption (never or past, light or moderate (<1 serving/day for women, <2 servings/day for men), and heavy (>1 serving/day for women, >2 servings/day for men), adjusting for age, sex, body mass index, and smoking. Diagnoses of RA were confirmed via medical record review by rheumatologists. From 2006 to 2018, we identified 87 incident RA cases. After adjusting for potential confounders, the HR of RA was 1.26 (95% CI: 0.62, 2.56) for participants with light or moderate alcohol consumption and 1.98 (95% CI: 0.93, 4.22) for participants with heavy alcohol consumption) versus non-drinkers. The HR of each 10 g increase in alcohol consumption was 1.11 (95% CI: 0.98, 1.26) (p-trend = 0.09). A significant association between alcohol consumption and RA risk was observed in women, but not in men (p for interaction = 0.06). Among women, each 10 g increase in alcohol consumption was significantly associated with a high risk of RA (HR: 1.56; 95% CI: 1.06, 2.29). In contrast, each 10 g increase in alcohol consumption was not significantly associated with the risk of RA in men (HR: 1.10; 95% CI: 0.97, 1.25). Excluding past drinkers generated similar results. In this prospective Chinese cohort, increasing alcohol consumption was associated with an elevated risk of RA among women, but not in men. These findings highlight the importance of incorporating analysis of sex differences into future studies of alcohol consumption and RA risk.

New developments implicating IL-21 in autoimmune disease.

Elevated interleukin (IL)-21 is a common finding in the tissues and/or sera of patients with autoimmune disease. CD4 T cells are the primary producers of IL-21; often the IL-21 producing CD4 T cells will express molecules associated with follicular helper cells (TFH). Recent work has shown that the CD4 T cell-derived IL-21 is able to promote effector functions and memory differentiation of CD8 T cells in chronic infections and cancer. Autoimmunity has similarities to chronic infections and cancer. However, CD4 T cell-derived IL-21:IL21R signaling in CD8 T cells has not been fully appreciated in the context of autoimmunity. In this review, we assess the current knowledge regarding CD4 T cell-derived IL-21 and IL21R signaling within CD8 T cells and evaluate what implications it has within several autoimmune diseases including systemic lupus erythematous, rheumatoid arthritis, juvenile idiopathic arthritis, type 1 diabetes mellitus, psoriasis, Sjögren's syndrome, vitiligo, antiphospholipid syndrome, pemphigus, and giant cell arteritis.

Study design and methods for the using exercise to relieve joint pain and improve AI adherence in older breast cancer survivors (REJOIN) trial.

BACKGROUND: Aromatase Inhibitors (AIs) are recommended for survival in post-menopausal breast cancer survivors (BCS) with hormone-sensitive disease. AI Adherence is suboptimal, especially in older BCS. Joint pain is a common AI-related symptom that is associated with low AI adherence. The Using Exercise to Relieve Joint Pain in Older Breast Cancer Survivors (REJOIN) Trial will evaluate the efficacy of a self-management intervention (exercise + education) to increase knowledge/self-efficacy for symptom management, reduce joint pain and potentially increase AI adherence in older BCS planning to take AIs. METHODS: This randomized controlled pilot trial will include sedentary BCS, 65 years and older, diagnosed with stage I-III hormone-sensitive breast cancer, who have completed primary cancer treatment and are planning to initiate AIs. We will adapt an evidence-based physical activity program for older adults that includes bi-weekly, supervised exercise sessions plus 30 min of education. The 16-week intervention program includes: 8-weeks of supervised sessions plus 8-weeks of self-guided home sessions with periodic phone coaching. We will conduct geriatric assessments plus measurements of exercise, joint pain, and AI adherence (baseline, 4, 6 and 12 months). DISCUSSION: REJOIN is one of the first trials to exclusively target older BCS using a self-management intervention, informed by geriatric assessment and exercise physiology, to improve health outcomes in survivorship. The REJOIN trial could lay the foundation for transdisciplinary research that bridges the gap between clinical and public health perspectives in healthy aging, with the opportunity to translate clinical interventions into non-pharmacological tools for a growing, yet underserved population of older survivors. TRIAL REGISTRATION: NCT03955627.

Pituitary neuropeptides and B lymphocyte function.

This review discusses the accumulated evidence that pro-opiomelanocortin (POMC) gene products as well as other pituitary neuropeptides derived from related genes (Proenkephalin, PENK; Prodynorphin, PDYN, and Pronociceptin, PNOC) can exert direct effects on B lymphocytes to modulate their functions. We also review the available data on receptor systems that might be involved in the transmission of such hormonal signals to B cells.

Arthroplasty Rates Not Increasing in Young Patients With Rheumatoid Arthritis: A National Database Review, 2005 Versus 2014.

BACKGROUND: For 20 years, authors have predicted an expansion in total knee arthroplasty (TKA) and total hip arthroplasty (THA) utilization. Over this same period, the introduction of biological disease-modifying antirheumatic drugs has dramatically altered the treatment of rheumatoid arthritis (RA) with hopes of preventing articular damage and obviating the need for prosthetic replacement. The goal of our investigation was to evaluate TKA and THA utilization in young patients with RA (<65 years) in 2005 vs 2014 compared to patients with osteoarthritis (OA). METHODS: Using relevant International Classification of Disease Ninth Revision (ICD-9) and Current Procedural Terminology codes, the Truven MarketScan Database (over 46 million enrollees) was queried to determine THA and TKA incidence rates for RA and OA patients aged <65 years during the final decade of ICD-9 use. Patients with potentially confounding ICD-9 codes were excluded to limit coding variation. Statistical analysis consisted of student t-tests, Pearson's chi-square tests, and Breslow-Day tests. RESULTS: For patients with OA, TKAs increased substantially from 0.07% in 2005 to 0.1% in 2014 (+42.9% change, P < .001). Similarly for patients with OA, THAs increased from 0.04% to 0.06% over the same time period (+66.0% change, P < .001). For young patients with RA, the rate of TKA remained relatively stable-1.06% in 2005 to 1.04% in 2014 (-1.7% change, P = .65)-as did THA-0.44% to 0.48% (+9.0% change, P = .14). CONCLUSIONS: Dramatic increases in THA and TKA rates for OA patients aged <65 years were indeed observed from 2005 to 2014. This trend, however, was not seen in the RA population where TKA and THA rates remained unchanged.