OBJECTIVE:Patients with acute gout are frequently treated in the emergency department (ED) and represent a typically underresourced and understudied population. A key limitation for gout research in the ED is the timely ability to identify acute gout patients. Our goal was to refine a multicriteria, electronic medical record alert for gout flares and to determine its diagnostic characteristics in the ED.METHODS:The gout flare alert used electronic medical record data from ED nursing notes and was triggered by the term 'gout' preceding past medical history in the chief complaint, the term 'gout' and a musculoskeletal problem in the chief complaint, or the term 'gout' in the problem list and a musculoskeletal chief complaint. We validated its diagnostic properties to assess presence/absence of gout through manual medical record review using adjudicated expert consensus as the gold standard.RESULTS:In January 2020, we analyzed 202 patient records from 2 university-based EDs; from these records, 57 patients were identified by our gout flare alert, and 145 were identified by other means as potentially having an acute gout flare. The gout flare alert's positive predictive value was 47% (95% confidence interval [95% CI] 34-60%), negative predictive value was 94% (95% CI 90-98%), sensitivity was 75% (95% CI 61-89%), and specificity was 82% (95% CI 76-88%). The diagnostic properties were similar at both institutions.CONCLUSION:Our multicomponent gout flare alert had reasonable sensitivity and specificity, albeit a modest positive predictive value. An electronic gout flare alert may help enable the conduct of gout research in the ED setting.

Background:Methotrexate (MTX) is the most common anchor drug for rheumatoid arthritis (RA), but the risk of missing the opportunity for early effective treatment with alternative medications is substantial given the delayed onset of MTX action and 30-40% inadequate response rate. There is a compelling need to accurately predicting MTX response prior to treatment initiation, which allows for effectively identifying patients at RA onset who are likely to respond to MTX.Objectives:To test the ability of machine learning approaches with clinical and genomic biomarkers to predict MTX response with replications in independent samples.Methods:Age, sex, clinical, serological and genome-wide association study (GWAS) data on patients with early RA of European ancestry from 647 patients (336 recruited in United Kingdom [UK]; 307 recruited across Europe; 70% female; 72% rheumatoid factor [RF] positive; mean age 54 years; mean baseline Disease Activity Score with 28-joint count [DAS28] 5.65) of the PhArmacogenetics of Methotrexate in RA (PAMERA) consortium was used in this study. The genomics data comprised 160 genome-wide significant single nucleotide polymorphisms (SNPs) with p<1×10-5 associated with risk of RA and MTX metabolism. DAS28 score was available at baseline and 3-month follow-up visit. Response to MTX monotherapy at the dose of ≥15 mg/week was defined as good or moderate by the EULAR response criteria at 3 months’ follow up visit. Supervised machine-learning methods were trained with 5-repeats and 10-fold cross-validation using data from PAMERA’s 336 UK patients. Class imbalance (higher % of MTX responders) in training was accounted by using simulated minority oversampling technique. Prediction performance was validated in PAMERA’s 307 European patients (not used in training).Results:Age, sex, RF positivity and baseline DAS28 data predicted MTX response with 58% accuracy of UK and European patients (p = 0.7). However, supervised machine-learning methods that combined demographics, RF positivity, baseline DAS28 and genomic SNPs predicted EULAR response at 3 months with area under the receiver operating curve (AUC) of 0.83 (p = 0.051) in UK patients, and achieved prediction accuracies (fraction of correctly predicted outcomes) of 76.2% (p = 0.054) in the European patients, with sensitivity of 72% and specificity of 77%. The addition of genomic data improved the predictive accuracies of MTX response by 19% and achieved cross-site replication. Baseline DAS28 scores and following SNPs rs12446816, rs13385025, rs113798271, and rs2372536 were among the top predictors of MTX response.Conclusion:Pharmacogenomic biomarkers combined with DAS28 scores predicted MTX response in patients with early RA more reliably than using demographics and DAS28 scores alone. Using pharmacogenomics biomarkers for identification of MTX responders at early stages of RA may help to guide effective RA treatment choices, including timely escalation of RA therapies. Further studies on personalized prediction of response to MTX and other anti-rheumatic treatments are warranted to optimize control of RA disease and improve outcomes in patients with RA.Disclosure of Interests:Elena Myasoedova: None declared, Arjun Athreya: None declared, Cynthia S. Crowson Grant/research support from: Pfizer research grant, Richard Weinshilboum Shareholder of: co-founder and stockholder in OneOme, Liewei Wang: None declared, Eric Matteson Grant/research support from: Pfizer, Consultant of: Boehringer Ingelheim, Gilead, TympoBio, Arena Pharmaceuticals, Speakers bureau: Simply Speaking

To the Editor: We thank Huang and colleagues1 for their interest in our study on the changes in the presentation of incident gout and the risk of subsequent flare1. We reported changes over time in gout presentation with podagra becoming less frequent, whereas hyperuricemia and chronic kidney disease were predictors of future flares … Address correspondence to Dr. M.M. Elfishawi, Mayo Clinic, Division of Rheumatology, 200 1st St. SW, Rochester, Minnesota 55905-0002, USA. Email: Elfishawi.Mohanad{at}mayo.edu.

Objective.To examine whether a change in the presentation of incident gout happened over the last 20 years and to determine the risk of subsequent gout flares after an initial gout attack.Methods.All incident cases of gout were identified among residents of Olmsted County, Minnesota, diagnosed in 1989–1992 and 2009–2010 according to the earliest date fulfilling the 1977 American Rheumatism Association preliminary criteria, or the New York or Rome criteria for gout. Patients in both cohorts were then followed for up to 5 years. Cumulative incidence and person-year methods were used to compare flare rates, and conditional frailty models were used to examine predictors.Results.A total of 429 patients with incident gout (158 patients in 1989–1992 and 271 patients in 2009–2010) were identified and followed for a mean of 4.2 years. The majority of patients were male (73%) and the mean age (SD) at gout onset was 59.7 (17.3) years. Classic podagra decreased significantly from 74% to 59% (p < 0.001). Cumulative incidence of first flare was similar in both cohorts (62% vs 60% by 5 yrs in 1989–1992 and 2009–2010, respectively; p = 0.70), but overall flare rate was marginally higher in 2009–2010 compared to 1989–1992 (rate ratio: 1.24). Hyperuricemia (HR 1.59) and kidney disease (HR 1.34) were significant predictors of future flares.Conclusion.Gout flares were common in both time periods. Hyperuricemia and kidney disease were predictors of future flares in patients with gout. Podagra as a presentation of gout has become relatively less frequent in recent years.

Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10−7 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.

Aromatase inhibitor (AI)-induced arthralgia (AIA) is a common reason for AI noncompliance. Retrospective analysis of MA.27 study revealed no clear correlation between vitamin D levels and AIA. However, patients with a Fok-I vitamin D receptor polymorphism were more likely to have lower interleukin 1 beta, and less likely to develop AIA. Through this type of risk stratification, future AIA clinical trials might be able to focus on high-risk populations. Background: Approximately half of women taking aromatase inhibitor (AI) therapy develop AI-induced arthralgia (AIA), and many might discontinue AI therapy because of the pain. Using plasma samples from the MA. 27 study, we assessed several factors potentially associated with AIA. Patients and Methods: MA. 27 is a phase III adjuvant trial comparing 2 AIs, exemestane versus anastrozole. Within an 893-participant nested case-control AIA genome-wide association study, we nested a 72 AIA case-144 control assessment of vitamin D plasma concentrations, corrected for seasonal and geographic variation. We also examined 9 baseline inflammatory cytokines: interleukin (IL)-1 beta, IL-6, tumor necrosis factor-a, interferon (IFN)gamma, IL-10, IL-12p70, IL-17, IL-23, and chemokine ligand (CCL)-20. Finally, we analyzed the multivariate effects of baseline factors: vitamin D level, previously identified musculoskeletal single nucleotide polymorphisms, age, body mass index, and vitamin D receptor (VDR) Fok-I variant genotype on AIA development. Results: Changes in vitamin D from baseline to 6 months were not significantly different between cases and controls. Elevated inflammatory cytokine levels were not associated with development of AIA. The multivariate model included no clinical factors associated with AIA. However, women with the VDR Fok-I variant genotype were more likely to have a lower IL-1 beta level (P = .0091) and less likely to develop AIA after 6 months of AI compared with those with the wild type VDR (P < .0001). Conclusion: In this nested case-control correlative study, vitamin D levels were not significantly associated with development of AIA; however, patients with the Fok-I VDR variant genotype were more likely to have a significant reduction in IL-1 beta level, and less likely to develop AIA. (C) 2017 Elsevier Inc. All rights reserved.

Objective. To assess in-hospital gout flares in patients with gout. Methods. Hospitalizations were evaluated for gout flares in a cohort of Olmsted County, Minnesota, residents with incident gout in 1989-1992 or 2009-2010. Results. There were 429 patients followed up to 5 years. Of these, 169 patients experienced 454 hospitalizations. Hospitalization rates increased without reaching statistical significance from 1989-1992 to 2009-2010 [rate ratio (RR) 1.19, 95% CI 0.98-1.45]. The gout flare rate increased significantly during hospitalization (RR 10.2, 95% CI 6.8-14.5). In-hospital gout flare increased the average hospital stay by 1.8 days (p < 0.001). Conclusion. Hospitalization increased the risk of gout flares 10-fold. In-hospital gout flares were associated with longer hospitalization.

In a previous genome-wide association study (GWAS) for musculoskeletal adverse events during aromatase inhibitor therapy for breast cancer, we reported that single nucleotide polymorphisms (SNPs) near the TCL1A gene were associated with this adverse drug reaction. Functional genomic studies showed that TCL1A expression was induced by estradiol, but only in cells with the variant sequence for the top GWAS SNP (rs11849538), a SNP that created a functional estrogen response element. In addition, TCL1A genotype influenced the downstream expression of a series of cytokines and chemokines and had a striking effect on nuclear factor κB (NF-κB) transcriptional activity. Furthermore, this SNP-dependent regulation could be reversed by selective ER modulators (SERMs). The present study was designed to pursue mechanisms underlying TCL1A SNP-mediated, estrogen-dependent NF-κB activation. Functional genomic studies were performed using a panel of 300 lymphoblastoid cell lines for which we had generated genome-wide SNP and gene expression data. It is known that toll-like receptors (TLRs) can regulate NF-κB signaling by a process that requires the adaptor protein MYD88. We found that TLR2, TLR7, TLR9, and TLR10 expression, as well as that of MYD88, could be modulated by TCL1A in a SNP and estrogen-dependent fashion and that these effects were reversed in the presence of SERMs. Furthermore, MYD88 inhibition blocked the TCL1A SNP and estrogen-dependent NF-κB activation, as well as protein-protein interaction between TCL1A and MYD88. These observations greatly expand the range of pathways influenced by TCL1A genotype and raise the possibility that this estrogen- and SNP-dependent regulation might be altered pharmacologically by SERMs.

Objective. To examine the incidence of gout over the last 20 years and to evaluate possible changes in associated comorbid conditions. Methods. The medical records were reviewed of all adults with a diagnosis of incident gout in Olmsted County, Minnesota, USA, during 2 time periods (January 1, 1989–December 31, 1992, and January 1, 2009–December 31, 2010). Incident cases had to fulfill at least 1 of 3 criteria: the American Rheumatism Association 1977 preliminary criteria for gout, the Rome criteria, or the New York criteria. Results. A total of 158 patients with new-onset gout were identified during 1989–1992 and 271 patients during 2009–2010, yielding age- and sex-adjusted incidence rates of 66.6/100,000 (95% CI 55.9–77.4) in 1989–1992 and 136.7/100,000 (95% CI 120.4–153.1) in 2009–2010. The incidence rate ratio was 2.62 (95% CI 1.80–3.83). At the time of their first gout flare, patients diagnosed with gout in 2009–2010 had higher prevalence of comorbid conditions compared with 1989–1992, including hypertension (69% vs 54%), diabetes mellitus (25% vs 6%), renal disease (28% vs 11%), hyperlipidemia (61% vs 21%), and morbid obesity (body mass index ≥ 35 kg/m2; 29% vs 10%). Conclusion. The incidence of gout has more than doubled over the recent 20 years. This increase together with the more frequent occurrence of comorbid conditions and cardiovascular risk factors represents a significant public health challenge.

Discordance between patients with rheumatoid arthritis (RA) and their rheumatology health care providers is a common and important problem. The objective of this study was to perform a comprehensive clinical evaluation of patient-provider discordance in RA.

10020 Background: Approximately half of the women who take aromatase inhibitor (AI) therapy will develop joint pain, termed aromatase inhibitor-induced arthralgia (AIA). AIA becomes so painful that up to 20% of women will discontinue AI’s because of it. However, there is no standard treatment for this common, though poorly understood, problem. Methods: Using plasma samples from the MA.27 study, we identified 72 cases (with AIA) and 144 matched controls. We compared change in vitamin D level between baseline and 6 months in 204 cases and controls. We also correlated inflammatory cytokines with development of AIA. We measured 9 inflammatory cytokines which are implicated in low estrogen states, arthritis, and/or vitamin D deprivation -- Il-1, IL-6, TNF-α, IFNg, IL-10, IL-12p70, IL-17, IL-23, and CCL-20. Finally, we aimed to develop a multivariate model to predict for AIA using baseline factors such as vitamin D level, previously identified musculoskeletal SNP’s, age, BMI, and vitamin D receptor polymorphism. Results: After correcting for seasonal and geographic variation, the month 6 Vitamin D plasma levels increased by 4.52 ng/mL (p = 0.049), suggesting intake of vitamin D. However, there was no difference in the change in vitamin D levels between cases and controls. Elevated inflammatory cytokines were not correlated with the development of AIA. However, those with the Vitamin D receptor (VDR) FOK-I polymorphism were more likely to have a lower IL-1β level after 6 months of use as compared to those with wildtype VDR. In the multivariate model, the clinical factors listed above did not reliably predict development of AIA in this subset of patients. Conclusions: In this retrospective study, there is no correlation between vitamin D levels and the development of AIA. However, vitamin D receptor polymorphisms may explain some of the variation in individual responses to Vitamin D replacement. Patients with the Fok-I VDR polymorphism were more likely to have a significant reduction in IL-1β level. Case Control N 68 136 Mean Δ Vit D 3.7 5.1 p =0.393 Standard Deviation 9.3 11.4 Minimum Δ Vit D -11.5 -29.7 Maximum Δ Vit D 28.9 62.57

We previously reported, on the basis of a genome-wide association study for aromatase inhibitor-induced musculoskeletal symptoms, that single-nucleotide polymorphisms (SNPs) near the T-cell leukemia/lymphoma 1A (TCL1A) gene were associated with aromatase inhibitor-induced musculoskeletal pain and with estradiol (E2)-induced TCL1A expression. Furthermore, variation in TCL1A expression influenced the downstream expression of proinflammatory cytokines and cytokine receptors. Specifically, the top hit genome-wide association study SNP, rs11849538, created a functional estrogen response element (ERE) that displayed estrogen receptor (ER) binding and increased E2 induction of TCL1A expression only for the variant SNP genotype. In the present study, we pursued mechanisms underlying the E2-SNP-dependent regulation of TCL1A expression and, in parallel, our subsequent observations that SNPs at a distance from EREs can regulate ERα binding and that ER antagonists can reverse phenotypes associated with those SNPs. Specifically, we performed a series of functional genomic studies using a large panel of lymphoblastoid cell lines with dense genomic data that demonstrated that TCL1A SNPs at a distance from EREs can modulate ERα binding and expression of TCL1A as well as the expression of downstream immune mediators. Furthermore, 4-hydroxytamoxifen or fulvestrant could reverse these SNP-genotype effects. Similar results were found for SNPs in the IL17A cytokine and CCR6 chemokine receptor genes. These observations greatly expand our previous results and support the existence of a novel molecular mechanism that contributes to the complex interplay between estrogens and immune systems. They also raise the possibility of the pharmacological manipulation of the expression of proinflammatory cytokines and chemokines in a SNP genotype-dependent fashion.

INTEGRATING METABOLOMICS AND GENOMICS REVEALS NOVEL BIOMARKERS OF HYDROCHLOROTHIAZIDE RESPONSE IN PHARMACOGENOMIC EVALUATION OF ANTIHYPERTENSIVE RESPONSES (PEAR) STUDY. M. H. Shahin, D. M. Rotroff, Y. Gong, T. Langaee, C. W. McDonough, A. L. Beitelshees, T. J. Garrett, A. B. Chapman, J. G. Gums, S. T. Turner, A. Motsinger-Reif, R. F. Frye, S. E. Scherer, W. Sadee, O. Fiehn, R. M. Cooper-DeHoff, R. Kaddurah-Daouk, J. A. Johnson; Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, Bioinformatics Research Center, North Carolina State University, Raleigh, NC, Department of Medicine, University of Maryland, Baltimore, MD, Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, Department of Medicine, Emory University, Atlanta, GA, College of Medicine, Mayo Clinic, Rochester, MN, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, Program in Pharmacogenomics, Department of Pharmacology, The Ohio State University, Columbus, OH, Genome Center, University of California at Davis, Davis, CA, Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC.M.H. Shahin: None.D.M. Rotroff: None. Y. Gong: None. T. Langaee: None. C.W. McDonough: None. A.L. Beitelshees: None. T.J. Garrett: None. A.B. Chapman: None. J.G. Gums: None. S.T. Turner: None. A. Motsinger-Reif: None. R.F. Frye: None. S.E. Scherer: None. W. Sadee: None. O. Fiehn: None. R.M. Cooper-DeHoff: None. R. Kaddurah-Daouk: None. J.A. Johnson: None. BACKGROUND: Hydrochlorothiazide (HCTZ) is among the most commonly prescribed antihypertensives in the US, yet, less than 50% of HCTZ treated patients achieve blood pressure (BP) control. In this study, we used a genomics-metabolomics integrative approach to identify novel biomarkers of HCTZ BP response. METHODS: This study included 228 white hypertensive PEAR participants with BP determined at baseline and after 9 weeks of HCTZ treatment. Genomewide genotyping was determined via Illumina Omni 1M Quad Chip. Untargeted metabolomics analysis was performed on fasting plasma samples using a GC TOF MS platform. Pathway analysis was conducted to integrate the BP GWAS signals at P< 1x10-4 with the metabolomics findings. Gene expression was also tested using RNA-Seq in extreme BP responders (25 responders and 25 nonresponders). RESULTS: Metabolomics analysis revealed 212 known metabolites, of which 13 were significantly associated with systolic and diastolic BP response (FDR< .05). Integrative pathway analysis identified metabolites in the platelet activation pathway (p5 .009) and Rho Kinase 1 gene (ROCK1) as a potential factor influencing HCTZ BP response. ROCK1 rs8085654 variant carriers had a poor BP response vs non carriers (DSBP/DDBP: -5.8/-2.7 vs 10.7/-5.9 mmHg, respectively, DSBP p5 5x10-5 and DDBP p5 9x10-4). Additionally, ROCK1 baseline expression levels were significantly different between HCTZ BP responders vs non responders (23.765.8 vs 20.063.2 FPKM, respectively, p5 .01). CONCLUSION: These results align with recent animal studies showing ROCK1 contribution to increased BP. Moreover, this study highlights the strength of using different omics to identify novel biomarkers of drug response, and suggests that ROCK1 might be an important determinant of HCTZ BP response.

Abstract Background: The use of anti-estrogen (AE) therapies (selective estrogen receptor modulators [SERMs], aromatase inhibitors [AIs]) in breast cancer (BC) patients was recently associated with risk of developing rheumatoid arthritis (RA) (J Rheum 2015;42:55-9). We attempted to replicate and extend these results using electronic health record (EHR) enhanced cancer registry data that assessed specific AE therapies and also accounted for potential confounding by age, smoking status, and chemotherapy use. Methods: Using cancer registry and EHR data, we identified a cohort of BC patients who were newly diagnosed and treated at Mayo Clinic Rochester from 1998-2011 and had no previous diagnosis of RA. Smoking status at diagnosis, BC treatments and RA at diagnosis and during follow-up were identified using validated EHR-based algorithms. Hazard ratios (HRs) and 95% confidence intervals (CI) from a multivariate Cox model were used to estimate the association of AE use with risk of RA, controlling for age, smoking status at BC diagnosis, and BC chemotherapy use. Results: The analytic cohort of 9,244 newly diagnosed BC patients treated and followed at Mayo Clinic had a median age at diagnosis of 59 years (range 18-97); 32% were smokers; and 29% were treated with chemotherapy. During a median follow-up of 49 months (range 1-191), 19 patients developed RA. Compared to BC patients not receiving any AE therapy, those receiving AI monotherapy, but not SERM monotherapy or both SERMs and AIs, were at significantly increased risk of developing RA (Table). AE Therapy# of RA Cases / # patientsHR* (95% CI)P-valueNo AE therapy6/4,0711.00 (reference)SERMs only5/2,5371.20 (0.36 - 3.95)0.77AIs only5/7126.37 (1.77 - 22.92)0.005SERMs then AIs3/1,8750.90AI then SERMs0/490.91 (0.21 - 3.86)*Adjusted for age, smoking status and use of chemotherapy Conclusions: Our findings indicate that the use of AIs for BC therapy, but not SERMs or SERMs followed by AIs, is associated with increased risk for development of RA, when controlling for smoking status and use of chemotherapy. While needing replication, these findings suggest a specific role for AIs in RA development and suggest pathways that could be targeted to prevent this potential treatment complication. Citation Format: Matthew K. Breitenstein, Ming-Fen Ho, Richard M. Weinshilboum, James R. Cerhan, Jyotishman Pathak, Tim Bongartz, Liewei Wang, James N. Ingle. Association of anti-estrogen therapy in breast cancer patients and subsequent risk of rheumatoid arthritis: An electronic health record study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-191. doi:10.1158/1538-7445.AM2015-LB-191