Citations

5000 Background: It is clinically challenging to integrate genomic classifier results that report a continuous numerical risk of recurrence into treatment decisions for prostate cancer (PCa). We aimed to develop a novel clinical-genomic risk system that can readily be incorporated into treatment guidelines for localized PCa. Methods: Four multi-center cohorts (n = 6928 men; 5937 prospective samples and 991 retrospective samples with long-term follow-up) were utilized to identify and validate our clinical-genomic risk system in radical prostatectomy (RP) samples and subsequently in pre-treatment biopsy samples. All patients’ FFPE tissue underwent microarray analysis, and the expression values for 22 prespecified biomarkers that constitute Decipher were extracted. Cumulative incidence curves were constructed to estimate metastasis risk. C-indices were calculated to compare NCCN and CAPRA score to our clinical-genomic system. Results: With a median follow-up of 8 years for men in our RP cohort, the 10-year distant metastasis rates for NCCN low, favorable-intermediate, unfavorable-intermediate, and high-risk were 7.8%, 9.4%, 40.1%, and 41.4%, respectively. Our 3-tier clinical-genomic risk groups had 10-year distant metastasis rates of 3.7%, 30.7%, and 57.7%, for low, intermediate, and high-risk, which were validated in our pre-treatment biopsy cohort with 10-year rate of distant metastasis of 0%, 30.3%, and 63.2%, respectively. C-indices for the clinical-genomic system (0.84, 95%CI 0.62-0.92) were significantly improved over NCCN (0.71, 95%CI 0.59-0.84) and CAPRA (0.71, 95%CI 0.60-0.81) score. A total of 33.4% of men would be reclassified by the clinical-genomic system, and specifically 17.1%, 41.3%, and 19.4% of men in NCCN low, intermediate and high risk groups would be reclassified by our new system. Conclusions: The use of a readily available genomic classifier in combination with clinicopathologic variables can generate a simple to use 3-tier clinical-genomic risk system that is highly prognostic for distant metastasis, is more accurate than clinical risk, and can be easily incorporated into NCCN guidelines to inform treatment decisions.

125 Background: Men with lymph node involvement (LNI) at prostatectomy (RP) are at high risk of dying from prostate cancer. However, survival following RP is highly variable, with some men apparently cured. Nomograms developed for men with LNI have been based on series where all or the vast majority of men received adjuvant treatment. Because administration of adjuvant treatment is not universal, even for LNI, we evaluated whether the Decipher genomic classifier (GC) can improve upon clinical models to predict metastasis within 5 years (MET5) and prostate cancer specific mortality within 10 years (PCSM10) in a cohort of LNI patients, the majority of whom did not receive adjuvant treatment. Methods: 141 patients from 4 institutions (Johns Hopkins, Mayo Clinic, Leuven, MD Anderson) had LNI at RP, had adequate tissue and clinical data for analysis of MET5, and 86 were analyzed for PCSM10. 43% of men received adjuvant therapy. RP tumor tissue was analyzed by Affymetrix Human Exon 1.0 ST GeneChip; the GC was calculated based on 22 genes in the previously trained and validated algorithm. Logistic regression evaluated whether the GC, dichotomized as high risk (GC score > 0.6) vs low-intermediate risk (≤0.6), improved prediction of MET5 and PCSM10 beyond that achieved with established clinical prognostic factors. Results: 62 men (43%) developed MET5, and 35 (41%) developed PCSM10. For both MET5 and PCSM10 CAPRA-S, number of positive lymph nodes, and age were significant; adjuvant therapy was not significant. GC was a significant independent strong prognostic factor when added to the clinical model for prediction of MET5, odds ratio = 4.04 (95% CI: 1.48, 11.02), p = 0.006, and prediction of PCSM10, odds ratio = 6.71 (95% CI: 2.01, 22.38), p = 0.002. Addition of GC to the clinical model improved the AUC from 0.77 to 0.79 for MET5, and from 0.65 to 0.74 for PCSM10. Conclusions: The Decipher GC significantly improves upon clinical variables to predict metastasis and prostate cancer specific mortality in men at high risk due to LNI. This is the first study to show a genomic classifier predicts outcomes in men with LNI; validation is needed to determine if Decipher can improve treatment decisions in men with LNI.

ObjectiveTo explore the perspectives and experiences of patients with rheumatoid arthritis (RA) whose assessments of their disease differ from those of their rheumatology care provider.MethodsA total of 20 adult RA patients with patient‐provider discordance at their most recent rheumatology appointment (within 4 weeks) were recruited. Discordance was defined by an absolute difference of 25 or more between patient and provider global assessments on a visual analog scale (VAS) of disease activity. For descriptive purposes, participants completed the Health Assessment Questionnaire II, pain VAS, and Patient Health Questionnaire 9 depression scale. Interviews were conducted in person and individually with each patient with a semistructured interview guide. Topics ranged widely, including participants’ perspectives and experiences with living with RA, clinical disease assessments, patient‐provider communication, and psychosocial or other needs. Data from the interviews were analyzed using interpretive phenomenological analysis.ResultsSix major themes emerged from the patient interviews describing patient‐provider discordance and disease assessment: being misunderstood by others, limitations of provider assessments, discrepancy with provider findings, inadequate active listening on the part of health care providers, unmet psychosocial needs, and lack of patient empowerment.ConclusionPatients described discordance in terms of symptom assessment and understanding how RA affects everyday life. Typical clinical assessments did not capture their experience. The resulting conceptual framework should inform future interventional studies seeking to enhance concordance of patient‐physician communication and to optimize satisfaction with care and health‐related quality‐of‐life outcomes for patients with RA.

Objective To identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). Methods A genome‐wide association study and subsequent replication study were conducted in a total cohort of 1,986 cases of AAV (patients with granulomatosis with polyangiitis [Wegener's] [GPA] or microscopic polyangiitis [MPA]) and 4,723 healthy controls. Meta‐analysis of these data sets and functional annotation of identified risk loci were performed, and candidate disease variants with unknown functional effects were investigated for their impact on gene expression and/or protein function. Results Among the genome‐wide significant associations identified, the largest effect on risk of AAV came from the single‐nucleotide polymorphism variants rs141530233 and rs1042169 at the HLA–DPB1 locus (odds ratio [OR] 2.99 and OR 2.82, respectively) which, together with a third variant, rs386699872, constitute a triallelic risk haplotype associated with reduced expression of the HLA–DPB1 gene and HLA–DP protein in B cells and monocytes and with increased frequency of complementary proteinase 3 (PR3)–reactive T cells relative to that in carriers of the protective haplotype. Significant associations were also observed at the SERPINA1 and PTPN22 loci, the peak signals arising from functionally relevant missense variants, and at PRTN3 , in which the top‐scoring variant correlated with increased PRTN3 expression in neutrophils. Effects of individual loci on AAV risk differed between patients with GPA and those with MPA or between patients with PR3‐ANCAs and those with myeloperoxidase‐ANCAs, but the collective population attributable fraction for these variants was substantive, at 77%. Conclusion This study reveals the association of susceptibility to GPA and MPA with functional gene variants that explain much of the genetic etiology of AAV, could influence and possibly be predictors of the clinical presentation, and appear to alter immune cell proteins and responses likely to be key factors in the pathogenesis of AAV.

ObjectiveTo examine trends in glucocorticoid (GC) use and dosing among patients diagnosed with rheumatoid arthritis (RA) over time.MethodsA population‐based inception cohort of RA patients diagnosed during 1980–2007 was followed longitudinally through their medical records until death, migration, or December 31, 2008. GC start and stop dates were collected, along with doses in prednisone equivalents.ResultsThe study population comprised 349 patients (68% women) diagnosed in 1980–1994 and 464 (69% women) diagnosed in 1995–2007, with a median followup of 15.3 and 5.7 years, respectively. A higher proportion of patients started GCs in their first year of disease in 1995–2007 (68% versus 36%; P < 0.001), but the starting dose (mean 8.7 versus 10.3 mg; P = 0.08) and cumulative dose in the first year of use (mean 1.8g [mean daily dose 4.9 mg] versus 2.1 gm [mean daily dose 5.8 mg]; P = 0.48) were not different. A higher proportion also discontinued GCs in their first year of disease in the 1995–2007 cohort (P < 0.001). These differences in GC initiation and discontinuation persisted throughout followup. Prevalence of GC use was higher in the 1995–2007 cohort for the first 3 years of disease.ConclusionMore patients are starting GCs early in their disease course now compared to previously, which is consistent with established treatment guidelines. A higher proportion are also discontinuing GCs, but the proportion of patients taking GCs at any given point of disease during the first 4 years is higher now than previously. Despite early addition of a disease‐modifying antirheumatic drug, some patients may not be able to discontinue GCs over the long term.

ObjectiveTo 1) describe the distribution of patient global assessment (PtGA) scores of disease activity in patients with granulomatosis with polyangiitis (GPA; Wegener's), 2) explore the discordance between PtGA scores and physician global assessment (PhGA) scores of disease activity, and 3) explore whether PtGA scores during disease remission are associated with future disease relapse.MethodsData from the Wegener's Granulomatosis Etanercept Trial (WGET) were used. PtGA and PhGA scores were assessed on 100‐mm visual analog scales (VAS). Presence of active disease was determined using the Birmingham Vasculitis Activity Score for WG (BVAS/WG), and remission was defined as a BVAS/WG score of 0. Disease relapse was defined as a BVAS/WG score of >0 after remission had been achieved. Discordance between PtGA and PhGA scores was defined as a difference of ≥20 points between the two measures. Mixed linear models were used in longitudinal analysis of PtGA scores.ResultsData were obtained from 180 patients in the WGET cohort, seen at a total of 1,719 study visits. The mean ± SD PtGA and PhGA disease activity scores (on 100‐mm VAS) at baseline were 64.2 ± 27.4 and 55.5 ± 23.4, respectively. PtGA–PhGA discordance occurred in 53% of patients at baseline, and this was inversely associated with newly diagnosed disease (as opposed to relapsing disease) at baseline (odds ratio 0.37, 95% confidence interval [95% CI] 0.20–0.68) but not with age, sex, or presence of renal or pulmonary disease. Patients were in disease remission during 62% of the study visits. The mean PtGA score during visits immediately prior to relapse was 4.52 points higher (95% CI 0.66–8.4) than that at other remission visits (P = 0.03).ConclusionPtGA–PhGA discordance is common in GPA. A rise in the PtGA disease activity score during times defined by physicians as periods of remission is associated with subsequent occurrence of disease relapse. These findings support the addition of PtGA as an outcome measure for GPA.

ObjectiveTo determine whether the impact of aging on cardiovascular disease (CVD) risk in patients with rheumatoid arthritis (RA) differs from that in the general population (as estimated by the Framingham Risk Score [FRS]).MethodsA population‐based inception cohort of Olmsted County, Minnesota residents ages ≥30 years who fulfilled the American College of Rheumatology 1987 criteria for RA in 1988–2008 was assembled and followed up until death, migration, or July 1, 2012. Data on CVD events were collected by medical records review. The 10‐year FRS for CVD was calculated. Cox models adjusted for FRS were used to examine the influence of age on CVD risk.ResultsThe study included 563 patients with RA without prior CVD (mean age 55 years, 72% women, and 69% seropositive [i.e., rheumatoid factor and/or anti–citrullinated protein antibody positive]). During a mean followup of 8.2 years, 98 patients developed CVD (74 seropositive and 24 seronegative), but the FRS predicted only 59.7 events (35.4 seropositive and 24.3 seronegative). The gap between observed and predicted CVD risk increased exponentially across age, and the effect of age on CVD risk in seropositive RA was nearly double its effect in the general population, with additional log(age) coefficients of 2.91 for women (P = 0.002) and 2.06 for men (P = 0.027).ConclusionOur findings indicate that age exerts an exponentially increasing effect on CVD risk in seropositive RA, but no increased effect among seronegative patients. The causes of accelerated aging in patients with seropositive RA deserve further investigation.