Efficacy and Safety of Allopurinol and Febuxostat in Patients With Gout and CKD: Subgroup Analysis of the STOP Gout Trial.

RATIONALE & OBJECTIVE: We conducted a prespecified examination of the efficacy and safety of allopurinol and febuxostat administered using a treat-to-target strategy in trial participants with chronic kidney disease (CKD). STUDY DESIGN: Prespecified sub cohort analysis of a randomized controlled trial. SETTING: & Participants: A sub study of the STOP Gout trial in participants with CKD. CKD was defined as an eGFR 30-59 mL/min/1.73 m2 at baseline. EXPOSURE: Trial participants with CKD and gout and serum urate (sUA) concentration ≥6.8 mg/dL were randomized 1:1 to receive allopurinol or febuxostat. Urate lowering therapy (ULT) was titrated during weeks 0-24 to achieve a goal sUA of <6.0 mg/dl (<5.0 mg/dl with tophi) (Phase 1) and maintained during weeks 25-48 (Phase 2). Gout flare was assessed between weeks 49-72 (Phase 3). OUTCOME: Gout flare between weeks 49-72 (Phase 3) was the primary outcome. Secondary outcomes included sUA goal achievement and ULT dosing at end of Phase 2, and serious adverse events (SAEs). ANALYTICAL APPROACH: Outcomes between treatment groups were compared using logistic regression models for binary outcomes, and Poisson regression for flare rates. Multivariable models were subsequently used, adjusting for factors identified to be imbalanced by treatment arm. RESULTS: 351 of 940 participants (37.3%) had CKD; 277 were assessed for the primary outcome. Fewer patients randomized to allopurinol had a flare during phase 3 (32% vs 45%; p=0.02) despite similar attainment of sUA goal (79% vs. 81%; p=0.6) by the end of Phase 2. Acute kidney injury (AKI) was more common in participants with stage 3 CKD randomized to allopurinol compared to febuxostat. LIMITATIONS: Limited power to assess infrequent safety events, largely male, older population. CONCLUSIONS: Allopurinol and febuxostat are similarly efficacious and well-tolerated in the treatment of gout in people with CKD when used in a treat-to-target regimen.

Dexamethasone prodrug nanomedicine (ZSJ-0228) treatment significantly reduces lupus nephritis in mice without measurable side effects - A 5-month study.

Lupus nephritis (LN) is a major cause of morbidity and mortality among systemic lupus erythematosus patients. Glucocorticoids (GCs) are uniformly used in clinical LN management. Their notorious toxicities, however, have hampered the long-term clinical application. To circumvent GC side effects while maintaining their potent therapeutic efficacy, we have developed a macromolecular prodrug nanomedicine based on dexamethasone (ZSJ-0228). The focus of this study was to investigate its long-term efficacy and, most importantly, safety in the lupus-prone NZB/W F1 mouse. Monthly ZSJ-0228 treatment for five months significantly reduced the incidence of nephritis in NZB/W F1 mice with an improved survival rate. In contrast to treatment with dose equivalent daily free dexamethasone, long-term monthly ZSJ-0228 did not result in any measurable GC-associated side effects. With its outstanding efficacy and exceptional safety, it is anticipated that ZSJ-0228 may be a novel therapy for long-term clinical management of LN.

Head-to-head comparative pharmacokinetic and biodistribution (PK/BD) study of two dexamethasone prodrug nanomedicines on lupus-prone NZB/WF1 mice.

HPMA copolymer-based dexamethasone prodrug (P-Dex) and PEG-based dexamethasone prodrug (PEG-Dex, ZSJ-0228) were previously found to passively target the inflamed kidney and provide potent and sustained resolution of nephritis in NZB/WF1 lupus-prone mice. While both prodrug nanomedicines effectively ameliorate lupus nephritis, they have demonstrated distinctively different safety profiles. To explore the underlining mechanisms of these differences, we conducted a head-to-head comparative PK/BD study of P-Dex and PEG-Dex on NZB/WF1 mice. Overall, the systemic organ/tissue exposures to P-Dex and Dex released from P-Dex were found to be significantly higher than those of PEG-Dex. The high prodrug concentrations were sustained in kidney for only 24 h, which cannot explain their lasting therapeutic efficacy (>1 month). P-Dex showed sustained presence in liver, spleen and adrenal gland, while the presence of PEG-Dex in these organs was transient. This difference in PK/BD profiles may explain PEG-Dex' superior safety than P-Dex.

Innovation in early medical education, no bells or whistles required.

BACKGROUND: Despite a paucity of evidence to support a multitude of educational innovations, curricular leaders are pressured to find innovative solutions to better prepare medical students for an evolving twenty-first century health care system. As part of this effort, this study directly compared student-rated effectiveness scores of six different learning modalities. METHODS: Study participants included 286 medical students enrolled in the second-year rheumatology core at a single academic medical center between 2013 and 2017. Students were surveyed at the end of the core with a 15-item questionnaire, and student perceived effectiveness of six different learning modalities were compared. RESULTS: The modality that outperformed all others was Live Patient Encounters (LPE), with significantly higher student-rated effectiveness scores when compared to the referent modality of Problem-Based Learning (PBL). Using a 5-point Likert scale with responses ranging from "not effective" to "highly effective," LPE received a mean effectiveness score of 4.77 followed by Augenblick (4.21), PBL (4.11), Gout Racer video game (3.49), Rheumatology Remedy e-module (3.49), and simulation knee injection (3.09). CONCLUSIONS: Technologically advanced novel learning strategies were outperformed in this study by the more traditional active learning modality of LPE. This finding highlights the importance of testing innovative learning strategies at the level of the learner. Three additional conclusions can be drawn from this result. First, conflation of technology with innovation may lead to a myopic view of educational reform. Second, human factors seem to be responsible for the success of LPE and may have far-reaching educational rewards. Third, further applications of LPE should be tested in non-rheumatologic curricula. The relevance of this study is innately tied to the humanities-based application. While a formal qualitative analysis was not performed in this study, preliminary results suggest that live, structured patient interactions in the pre-clinical years of medical education may not only promote the learning of important educational objectives but also foster professional development, empathy, reflection, leadership, agency, and interpersonal skills. This "win-win" scenario (if true) would stand out as a rarity among strategic educational initiatives.

Triple Therapy Versus Biologic Therapy for Active Rheumatoid Arthritis: A Cost-Effectiveness Analysis.

Background: The RACAT (Rheumatoid Arthritis Comparison of Active Therapies) trial found triple therapy to be noninferior to etanercept-methotrexate in patients with active rheumatoid arthritis (RA). Objective: To determine the cost-effectiveness of etanercept-methotrexate versus triple therapy as a first-line strategy. Design: A within-trial analysis based on the 353 participants in the RACAT trial and a lifetime analysis that extrapolated costs and outcomes by using a decision analytic cohort model. Data Sources: The RACAT trial and sources from the literature. Target Population: Patients with active RA despite at least 12 weeks of methotrexate therapy. Time Horizon: 24 weeks and lifetime. Perspective: Societal and Medicare. Intervention: Etanercept-methotrexate first versus triple therapy first. Outcome Measures: Incremental costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). Results of Base-Case Analysis: The within-trial analysis found that etanercept-methotrexate as first-line therapy provided marginally more QALYs but accumulated substantially higher drug costs. Differences in other costs between strategies were negligible. The ICERs for first-line etanercept-methotrexate and triple therapy were $2.7 million per QALY and $0.98 million per QALY over 24 and 48 weeks, respectively. The lifetime analysis suggested that first-line etanercept-methotrexate would result in 0.15 additional lifetime QALY, but this gain would cost an incremental $77 290, leading to an ICER of $521 520 per QALY per patient. Results of Sensitivity Analysis: Considering a long-term perspective, an initial strategy of etanercept-methotrexate and biologics with similar cost and efficacy is unlikely to be cost-effective compared with using triple therapy first, even under optimistic assumptions. Limitation: Data on the long-term benefit of triple therapy are uncertain. Conclusion: Initiating biologic therapy without trying triple therapy first increases costs while providing minimal incremental benefit. Primary Funding Source: The Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development, Canadian Institutes for Health Research, and an interagency agreement with the National Institutes of Health-American Recovery and Reinvestment Act.

Novel Antioxidant Properties of Doxycycline.

Doxycycline (DOX), a derivative of tetracycline, is a broad-spectrum antibiotic that exhibits a number of therapeutic activities in addition to its antibacterial properties. For example, DOX has been used in the management of a number of diseases characterized by chronic inflammation. One potential mechanism by which DOX inhibits the progression of these diseases is by reducing oxidative stress, thereby inhibiting subsequent lipid peroxidation and inflammatory responses. Herein, we tested the hypothesis that DOX directly scavenges reactive oxygen species (ROS) and inhibits the formation of redox-mediated malondialdehyde-acetaldehyde (MAA) protein adducts. Using a cell-free system, we demonstrated that DOX scavenged reactive oxygen species (ROS) produced during the formation of MAA-adducts and inhibits the formation of MAA-protein adducts. To determine whether DOX scavenges specific ROS, we examined the ability of DOX to directly scavenge superoxide and hydrogen peroxide. Using electron paramagnetic resonance (EPR) spectroscopy, we found that DOX directly scavenged superoxide, but not hydrogen peroxide. Additionally, we found that DOX inhibits MAA-induced activation of Nrf2, a redox-sensitive transcription factor. Together, these findings demonstrate the under-recognized direct antioxidant property of DOX that may help to explain its therapeutic potential in the treatment of conditions characterized by chronic inflammation and increased oxidative stress.

Omega-3 fatty acids are associated with a lower prevalence of autoantibodies in shared epitope-positive subjects at risk for rheumatoid arthritis.

OBJECTIVES: Previously, we found that omega-3 fatty acids (n-3 FAs) were inversely associated with anti-cyclic citrullinated peptide (anti-CCP) positivity in participants at risk for future rheumatoid arthritis (RA). We investigated whether n-3 FAs were also associated with rheumatoid factor (RF) positivity and whether these associations were modified by shared epitope (SE) positivity. METHODS: The Studies of the Etiology of RA (SERA) cohort includes RA-free participants who are at increased risk for RA. We conducted a nested case-control study (n=136) to determine the association between RF and anti-CCP2 positivity and n-3 FA percentage in erythrocyte membranes (n-3 FA% in red blood cells (RBCs)). Additionally, in the baseline visit of the SERA cohort (n=2166), we evaluated the association between reported n-3 FA supplement use and prevalence of RF and anti-CCP2. We assessed SE positivity as an effect modifier. RESULTS: In the case-control study, increasing n-3 FA% in RBCs was inversely associated with RF positivity in SE-positive participants (OR 0.27, 95% CI 0.10 to 0.79), but not SE-negative participants. Similar associations were seen with anti-CCP positivity in SE-positive participants (OR 0.42, 95% CI 0.20 to 0.89), but not SE-negative participants. In the SERA cohort at baseline, n-3 FA supplement use was associated with a lower prevalence of RF positivity in SE-positive participants (OR 0.32, 95% CI 0.12 to 0.82), but not SE-negative participants; similar but non-significant trends were observed with anti-CCP2. CONCLUSIONS: The potential protective effect of n-3 FAs on RA-related autoimmunity may be most pronounced in those who exhibit HLA class II genetic susceptibility to RA.

Rheumatoid arthritis triple therapy compared with etanercept: difference in infectious and gastrointestinal adverse events.

Objective: The main aim of this study was to examine the differences between triple therapy (T: SSZ and HCQ added to MTX) and etanercept (E) added to MTX with regard to the infectious and gastrointestinal (GI) adverse events (AEs) reported in The Rheumatoid Arthritis Comparison of Active Therapies Trial. Methods: The patients were 353 RA MTX incomplete responders who were randomized to T (n = 178) or E (n = 175). Of these, 88 patients were switched to the alternative treatment from the initial treatment (E or T) at 24 weeks per protocol. Infectious and GI serious AEs (SAEs) and non-serious AEs (NAEs) were reported during 48 and 4 weeks after the intervention period. Generalized linear models were used to estimate the incidence rate ratios (IRRs) of AEs between the two therapies. Results: Patients on E therapy were more likely to have infectious NAEs (IRR = 1.56, 95% CI: 1.11, 2.19). There was a greater number of infectious SAEs that occurred when patients received E than T therapy [12 E (6.9%) vs 4 T (2.2%), P = 0.19]. Pneumonia was the most common infectious SAE for both treatments [6 E (3.4%) and 2 T (1.1%)]. Conversely, patients who were on E were less likely to have GI NAEs than those on T therapy (IRR = 0.62, 95% CI: 0.40, 0.94). The most common GI SAE reported was GI haemorrhage, which occurred among three patients on E (1.7%). Conclusion: This study provides evidence of different likelihoods of infectious and GI AEs associated with two common, equally effective treatments for RA patients who have had incomplete responses to MTX. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov , NCT00405275.

Therapies for active rheumatoid arthritis after methotrexate failure.

BACKGROUND: Few blinded trials have compared conventional therapy consisting of a combination of disease-modifying antirheumatic drugs with biologic agents in patients with rheumatoid arthritis who have active disease despite treatment with methotrexate--a common scenario in the management of rheumatoid arthritis. METHODS: We conducted a 48-week, double-blind, noninferiority trial in which we randomly assigned 353 participants with rheumatoid arthritis who had active disease despite methotrexate therapy to a triple regimen of disease-modifying antirheumatic drugs (methotrexate, sulfasalazine, and hydroxychloroquine) or etanercept plus methotrexate. Patients who did not have an improvement at 24 weeks according to a prespecified threshold were switched in a blinded fashion to the other therapy. The primary outcome was improvement in the Disease Activity Score for 28-joint counts (DAS28, with scores ranging from 2 to 10 and higher scores indicating more disease activity) at week 48. RESULTS: Both groups had significant improvement over the course of the first 24 weeks (P=0.001 for the comparison with baseline). A total of 27% of participants in each group required a switch in treatment at 24 weeks. Participants in both groups who switched therapies had improvement after switching (P<0.001), and the response after switching did not differ significantly between the two groups (P=0.08). The change between baseline and 48 weeks in the DAS28 was similar in the two groups (-2.1 with triple therapy and -2.3 with etanercept and methotrexate, P=0.26); triple therapy was noninferior to etanercept and methotrexate, since the 95% upper confidence limit of 0.41 for the difference in change in DAS28 was below the margin for noninferiority of 0.6 (P=0.002). There were no significant between-group differences in secondary outcomes, including radiographic progression, pain, and health-related quality of life, or in major adverse events associated with the medications. CONCLUSIONS: With respect to clinical benefit, triple therapy, with sulfasalazine and hydroxychloroquine added to methotrexate, was noninferior to etanercept plus methotrexate in patients with rheumatoid arthritis who had active disease despite methotrexate therapy. (Funded by the Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development, and others; CSP 551 RACAT ClinicalTrials.gov number, NCT00405275.)

Increased pretreatment serum IFN-ß/α ratio predicts non-response to tumour necrosis factor α inhibition in rheumatoid arthritis.

OBJECTIVE: Studies suggest that circulating type I interferon (IFN) may predict response to biological agents in rheumatoid arthritis (RA). Prediction of response prior to initiating therapy would represent a major advancement. METHODS: We studied sera from a test set of 32 patients with RA from the Auto-immune Biomarkers Collaborative Network Consortium and a validation set of 92 patients with RA from the Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository registry. The test set included those with good response or no response to tumour necrosis factor (TNF) inhibitors at 14 weeks by European League Against Rheumatism criteria. The validation set included subjects with good, moderate or no response at 12 weeks. Total serum type I IFN activity, IFN-α and IFN-ß activity were measured using a functional reporter cell assay. RESULTS: In the test set, an increased ratio of IFN-ß to IFN-α (IFN-ß/α activity ratio) in pretreatment serum associated with lack of response to TNF inhibition (p=0.013). Anti-cyclic citrullinated peptide antibody titre and class of TNF inhibitor did not influence this relationship. A receiver-operator curve supported a ratio of 1.3 as the optimal cut-off. In the validation set, subjects with an IFN-ß/α activity ratio >1.3 were significantly more likely to have non-response than good response (OR=6.67, p=0.018). The test had 77% specificity and 45% sensitivity for prediction of non-response compared with moderate or good response. Meta-analysis of test and validation sets confirmed strong predictive capacity of IFN-ß/α activity ratio (p=0.005). CONCLUSIONS: Increased pretreatment serum IFN-ß/α ratio strongly associated with non-response to TNF inhibition. This study supports further investigation of serum type I IFN in predicting outcome of TNF inhibition in RA.

Lower omega-3 fatty acids are associated with the presence of anti-cyclic citrullinated peptide autoantibodies in a population at risk for future rheumatoid arthritis: a nested case-control study.

OBJECTIVE: The aim of this study was to investigate omega-3 fatty acid (FA) supplement use and omega-3 FAs in erythrocyte membranes [omega-3 FA % in erythrocyte membranes (RBC)] and their association with anti-CCP autoantibodies in a population without RA, but who are at genetic risk for RA. METHODS: The multicentre Studies of the Etiology of RA (SERA) cohort includes RA-free subjects who are first-degree relatives of RA probands or are enriched with the HLA-DR4 allele. In a nested case-control study, 30 SERA cases were identified who were anti-CCP2 antibody positive. We further identified 47 autoantibody negative controls, frequency matched to cases on age at study visit, sex, race and study site. Anti-CCP2 status, self-reported omega-3 FA supplement use and omega-3 FA % in RBCs were obtained from a single visit. RESULTS: Anti-CCP2 positive cases were less likely than controls to report omega-3 FA supplement use (odds ratio: 0.14; 95% CI 0.03, 0.68). In addition, the likelihood of anti-CCP2 positivity was inversely associated with total omega-3 FA % in RBCs (odds ratio: 0.47; 95% CI 0.24, 0.92, for a s.d. increase). CONCLUSION: The inverse association between anti-CCP2 positivity and self-reported omega-3 FA supplement use and omega-3 FA % in RBCs suggests that omega-3 FAs may protect against the development of RA-related autoimmunity in pre-clinical RA.

Combination conventional DMARDs compared to biologicals: what is the evidence?

PURPOSE OF REVIEW: Dramatic improvement seen in the prognosis of rheumatoid arthritis has been driven by higher expectations, led by newer drugs and more intensive use of the older drugs. Although methotrexate has retained its place as the first-line agent, there has been great interest in comparing biologicals to conventional Disease Modifying Anti Rheumatic Drugs (DMARDs) over the past few years with the updated guidelines from both the American College of Rheumatology and European League Against Rheumatism. We have tried to critically summarize the findings of some landmark trials that compare these two approaches. RECENT FINDINGS: Treatment of Early Rheumatoid Arthritis, The Swedish Pharmacotherapy study and Rheumatoid Arthritis Comparison of Active Therapies are landmark trials that were designed to compare strategies using biologicals vs. conventional DMARDs. We will review the safety and efficacy data from these three trials here and also briefly the important cost differential. CONCLUSION: Methotrexate should be the first-line therapy for most rheumatoid arthritis patients and will produce the desired results in greater than one-third of the patients. When methotrexate is not adequate, triple DMARD therapy should be added which will result in control of approximately another one-third of the patients. Ultimately, and usually before 1 year of disease, the remainder of patients will require biological therapies usually added to conventional DMARDs. There is no evidence that this step-up approach results in any long-term disadvantage and good evidence that it results in substantial cost savings.

Validation of the methotrexate-first strategy in patients with early, poor-prognosis rheumatoid arthritis: results from a two-year randomized, double-blind trial.

OBJECTIVE: Methotrexate (MTX) taken as monotherapy is recommended as the initial disease-modifying antirheumatic drug for rheumatoid arthritis (RA). The purpose of this study was to examine outcomes of a blinded trial of initial MTX monotherapy with the option to step-up to combination therapy as compared to immediate combination therapy in patients with early, poor-prognosis RA. METHODS: In the Treatment of Early Rheumatoid Arthritis (TEAR) trial, 755 participants with early, poor-prognosis RA were randomized to receive MTX monotherapy or combination therapy (MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine). Participants randomized to receive MTX monotherapy stepped-up to combination therapy at 24 weeks if the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) was ≥3.2. RESULTS: Attrition at 24 weeks was similar in the MTX monotherapy and combination groups. Of the 370 evaluable participants in the initial MTX group, 28% achieved low levels of disease activity and did not step-up to combination therapy (MTX monotherapy group). The mean ± SD DAS28-ESR in participants continuing to take MTX monotherapy at week 102 was 2.7 ± 1.2, which is similar to that in participants who were randomized to immediate combination therapy (2.9 ± 1.2). Participants who received MTX monotherapy had less radiographic progression at week 102 as compared to those who received immediate combination therapy (mean ± SD change in modified Sharp score 0.2 ± 1.1 versus 1.1 ± 6.4). Participants assigned to initial MTX who required step-up to combination therapy at 24 weeks (72%) demonstrated similar DAS28-ESR values (3.5 ± 1.3 versus 3.2 ± 1.3 at week 48) and radiographic progression (change in modified Sharp score 1.2 ± 4.1 versus 1.1 ± 6.4 at week 102) as those assigned to immediate combination therapy. The results for either of the immediate combination approaches, whether triple therapy or MTX plus etanercept, were similar. CONCLUSION: These results in patients with early, poor prognosis RA validate the strategy of starting with MTX monotherapy. This study is the first to demonstrate in a blinded trial that initial MTX monotherapy with the option to step-up to combination therapy results in similar outcomes to immediate combination therapy. Approximately 30% of patients will not need combination therapy, and the 70% who will need it are clinically and radiographically indistinguishable from those who were randomized to receive immediate combination therapy.

Changes in lipoproteins associated with methotrexate or combination therapy in early rheumatoid arthritis: results from the treatment of early rheumatoid arthritis trial.

OBJECTIVE: To study changes in lipid profiles at 24 weeks among patients with early rheumatoid arthritis (RA) participating in the Treatment of Early RA (TEAR) trial and randomized to receive methotrexate (MTX) plus etanercept, triple therapy (MTX plus sulfasalazine plus hydroxychloroquine), or aggressively titrated MTX monotherapy. METHODS: This TEAR substudy included 459 participants with biologic specimens. Serum levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol were measured at 0 and 24 weeks. RESULTS: At 24 weeks, there were statistically significant increases in mean cholesterol levels in the MTX plus etanercept, triple therapy, and MTX monotherapy arms. The observed increases were 31.4 mg/dl, 28.7 mg/dl, and 30 mg/dl in LDL cholesterol, 19.3 mg/dl, 22.3 mg/dl, and 20.6 mg/dl in HDL cholesterol, and 56.8 mg/dl, 53 mg/dl, and 57.3 mg/dl in total cholesterol (P < 0.0001 versus baseline for each comparison). There was a statistically significant decrease in the ratio of total cholesterol to HDL cholesterol at 24 weeks in all 3 treatment groups versus baseline. There was no difference in any lipid changes between the 3 treatment arms. After multivariable adjustment, change in C-reactive protein, but not the Disease Activity Score in 28 joints, was associated with change in LDL cholesterol (P = 0.03) and total cholesterol (P = 0.01). Baseline glucocorticoid use was associated with changes in HDL cholesterol (P = 0.03) and total cholesterol (P = 0.02). CONCLUSION: Levels of total cholesterol, LDL cholesterol, and HDL cholesterol increased comparably shortly after initiation of MTX plus etanercept, triple therapy, and MTX monotherapy among patients with early RA with active disease participating in a clinical trial. The clinical relevance of short-term changes in traditional lipids on cardiovascular outcomes remains to be determined.

Relatives without rheumatoid arthritis show reactivity to anti-citrullinated protein/peptide antibodies that are associated with arthritis-related traits: studies of the etiology of rheumatoid arthritis.

OBJECTIVE: To examine reactivity to anti-citrullinated protein/peptide antibodies (ACPAs) and determine associations between ACPAs and other rheumatoid arthritis (RA)-related autoantibodies and clinically assessed swollen or tender joints in unaffected first-degree relatives of RA patients. METHODS: Serum samples were obtained from first-degree relatives without RA according to the 1987 American College of Rheumatology (ACR) and the 2010 ACR/European League Against Rheumatism classification criteria. A bead-based assay was used to measure 16 separate ACPAs in sera from 111 antibody-positive first-degree relatives who were positive on at least 1 visit for any of 5 RA-related autoantibodies (rheumatoid factor [RF], anti-cyclic citrullinated peptide 2 [anti-CCP-2], and RF isotypes), and sera from 99 antibody-negative first-degree relatives who were never autoantibody positive. Cutoffs for positivity for each ACPA were determined using receiver operating characteristic curves derived from data on 200 RA patients and 98 blood donor controls, in which positivity for ≥9 ACPAs had 92% specificity and 62% sensitivity for RA. In first-degree relatives, ACPA reactivity was assessed, and associations between ACPAs (number positive, and positivity for ≥9 ACPAs) and RA-related characteristics were examined. RESULTS: Fifty-seven percent of anti-CCP-2-positive first-degree relatives and 8% of anti-CCP-2- negative first-degree relatives were positive for ≥9 ACPAs. After adjusting for age, sex, ethnicity, and pack-years of smoking, an increasing number of ACPAs was directly associated with the presence of ≥1 tender joint on examination (odds ratio [OR] 1.18, 95% confidence interval [95% CI] 1.04-1.34), with the greatest risk of having ≥1 tender joint seen in first-degree relatives positive for ≥9 ACPAs (OR 5.00, 95% CI 1.37-18.18). CONCLUSION: RA-free first-degree relatives (even those negative for RF and anti-CCP-2) demonstrate reactivity to multiple ACPAs, and the presence of an increasing number of ACPAs may be associated with signs of joint inflammation. Prospective evaluation of the relationship between these findings and the progression of classifiable RA is warranted.

Performance of anti-cyclic citrullinated Peptide assays differs in subjects at increased risk of rheumatoid arthritis and subjects with established disease.

OBJECTIVE: To compare the diagnostic accuracy and agreement of commonly available assays for anti-citrullinated protein antibodies in patients with established rheumatoid arthritis (RA) and subjects at increased risk of RA. METHODS: Tests for anti-cyclic citrullinated peptide (anti-CCP) antibodies were performed using CCP2 IgG and CCP3.1 IgA/IgG enzyme-linked immunosorbent assays in the following groups: probands with established RA (n = 340) from the Studies of the Etiology of Rheumatoid Arthritis (SERA) cohort and their first-degree relatives (FDRs) without inflammatory arthritis (n = 681), Department of Defense Serum Repository (DoDSR) RA cases with pre-RA diagnosis samples (n = 83; 47 cases also had post-RA diagnosis samples), and blood donor and DoDSR control subjects (n = 283). RESULTS: In patients with established RA, the CCP2 assay was more specific (99.2% versus 93.1%; P < 0.01) but less sensitive (58.7% versus 67.4%; P = 0.01) than the CCP3.1 assay; the specificity of the CCP3.1 assay increased to 97.2% when cutoff levels ≥3-fold the standard level were considered. In all subjects, CCP3.1 assay positivity (using standard cutoff levels) was more prevalent. Among DoDSR cases, the CCP2 assay was more specific than the CCP3.1 for predicting a future diagnosis of RA, and higher CCP levels trended toward increasing specificity for the development of RA within 2 years. At standard cutoff levels, assay agreement was good in patients with established RA (κ = 0.76) but poor in FDRs without inflammatory arthritis (κ = 0.25). CONCLUSION: Anti-CCP assays differ to an extent that may be meaningful for diagnosing RA in patients with inflammatory arthritis and evaluating the natural history of RA development in subjects at risk of RA. The mechanisms underlying these differences in test performance need further investigation.

Effective xanthine oxidase inhibitor urate lowering therapy in gout is linked to an emergent serum protein interactome of complement activation and inflammation modulators.

Background: Urate-lowering treatment (ULT) to target with xanthine oxidase inhibitors (XOIs) paradoxically causes early increase in gouty arthritis flares. Because delayed reduction in flare burden is mechanistically unclear, we tested for ULT inflammation responsiveness markers. Methods: Unbiased proteomics analyzed blood samples (baseline, 48 weeks ULT) in two, independent ULT out trial cohorts (n = 19, n = 30). STRING-db and multivariate analyses supplemented determinations of altered proteins via Wilcoxon matched pairs signed rank testing in XOI ULT responders. Mechanistic studies characterized proteomes of cultured XOI-treated murine bone marrow macrophages (BMDMs). Results: At 48 weeks ULT, serum urate normalized in all gout patients, and flares declined, with significantly altered proteins (p < 0.05) in clustering and proteome networks in sera and peripheral blood mononuclear cells. Serum proteome changes included decreased complement C8 heterotrimer C8A and C8G chains and chemokine PPBP/CXCL7, and increased urate crystal phagocytosis inhibitor sCD44. In both cohorts, a treatment-emergent serum interactome included key gouty inflammation mediators (C5, IL-1B, CXCL8, IL6). Last, febuxostat inhibited complement activation pathway proteins in cultured BMDMs. Conclusions: Reduced gout flares are kinked with a XOI-treatment emergent complement- and inflammation-regulatory serum protein interactome. Serum and leukocyte proteomes could help identify onset of anti-inflammatory responsiveness to ULT in gout. Trial registration: ClinicalTrials.gov Identifier: NCT02579096, posted October 19, 2015.

Determinants of Achieving Serum Urate Goal with Treat-to-Target Urate-Lowering Therapy in Gout.

OBJECTIVE: Using trial data comparing treat-to-target allopurinol and febuxostat in gout, we examined participant characteristics associated with serum urate (SU) goal achievement. METHODS: Participants with gout and SU ≥6.8 mg/dL were randomized to allopurinol or febuxostat, titrated during weeks 0 to 24, and maintained weeks 25 to 48. Participants were considered to achieve SU goal if the mean SU from weeks 36, 42, and 48 was <6.0 mg/dL or <5 mg/dL if tophi were present. Possible determinants of treatment response were preselected and included sociodemographics, comorbidities, diuretic use, health-related quality of life (HRQoL), body mass index, and gout measures. Determinants of SU response were assessed using multivariable logistic regression with additional analyses to account for treatment adherence. RESULTS: Of 764 study participants completing week 48, 618 (81%) achieved SU goal. After multivariable adjustment, factors associated with a greater likelihood of SU goal achievement included older age (adjusted odds ratio [aOR] 1.40 per 10 years), higher education (aOR 2.02), and better HRQoL (aOR 1.17 per 0.1 unit). Factors associated with a lower odds of SU goal achievement included non-White race (aORs 0.32-0.47), higher baseline SU (aOR 0.83 per 1 mg/dL), presence of tophi (aOR 0.29), and the use of diuretics (aOR 0.52). Comorbidities including chronic kidney disease, hypertension, diabetes, and cardiovascular disease were not associated with SU goal achievement. Results were not meaningfully changed in analyses accounting for adherence. CONCLUSIONS: Several patient-level factors were predictive of SU goal achievement among patients with gout who received treat-to-target urate-lowering therapy (ULT). Approaches that accurately predict individual responses to treat-to-target ULT hold promise in facilitating personalized management and improving outcomes in patients with gout.

A Comparison of Gout Flares with the Initiation of Treat-to-Target Allopurinol and Febuxostat: A Post-hoc Analysis of a Randomized Multicenter Trial.

BACKGROUND: Initiating urate-lowering therapy (ULT) in gout can precipitate arthritis flares. There have been limited comparisons of flare risk during the initiation and escalation of allopurinol and febuxostat, administered as a treat-to-target strategy with optimal anti-inflammatory prophylaxis. METHODS: This was a post-hoc analysis of a 72-week randomized, double-blind, placebo-controlled, non-inferiority trial comparing the efficacy of allopurinol and febuxostat. For this analysis, the occurrence of flares was examined during weeks 0-24 when ULT was initiated and titrated to a serum urate (sUA) goal of <6 mg/dl (<5 mg/dl if tophi). Flares were assessed at regular intervals through structured participant interviews. Predictors of flare, including treatment assignment, were examined using multivariable Cox proportional hazards regression. RESULTS: Study participants (n=940) were predominantly male (98.4%) and had a mean age of 62.1 years with approximately equal proportions receiving allopurinol or febuxostat. Mean baseline sUA was 8.5 mg/dl and all participants received anti-inflammatory prophylaxis (90% colchicine). In a multivariable model, there were no significant associations of ULT treatment (HR 1.17; febuxostat vs. allopurinol), ULT dose escalation (HR 1.18 vs. no escalation), prophylaxis type, or individual comorbidity with flare and no evidence of ULT-dose escalation interaction. Factors independently associated with flare risk during ULT initiation/escalation included younger age, higher baseline sUA, and absence of tophi. CONCLUSION: These results demonstrate that gout flare risk during the initiation and titration of allopurinol is similar to febuxostat when these agents are administered according to a treat-to-target strategy using gradual ULT dose titration and best practice gout flare prophylaxis.