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ObjectiveLinked metabolic and cardiovascular comorbidities are prevalent in hyperuricemia and gout. For mechanistic insight into impact on inflammatory processes and cardiometabolic risk factors of xanthine oxidase inhibitor urate-lowering therapy (ULT) titration to target, we performed a prospective study of gout serum metabolomes from a ULT trial.MethodsSera of gout patients meeting the 2015 ACR/EULAR gout classification criteria (n = 20) and with hyperuricemia were studied at time zero and weeks 12 and 24 of febuxostat or allopurinol dose titration ULT. Ultrahigh performance liquid chromatography-tandem mass spectroscopy acquired the serum spectra. Data were assessed using the Metabolon and Metaboloanalyst software. Lipolysis validation assays were done in febuxostat and/or colchicine-treated 3T3-L1 differentiated adipocytes.ResultsSerum urate decreased from time zero (8.21 ±1.139 SD) at weeks 12 (5.965 ± 1.734 SD) and 24 (5.655 ±1.763 SD). Top metabolites generated by changes in nucleotide and certain amino acid metabolism and polyamine pathways were enriched at 12 and 24 weeks ULT, respectively. Decreases in multiple fatty acid metabolites were observed at 24 weeks, linked with obesity. In cultured adipocytes, febuxostat significantly decreased while colchicine increased the lipolytic response to β-adrenergic-agonism or TNF.ConclusionMetabolomic profiles linked xanthine oxidase inhibitor-based ULT titration to target with reduced serum free fatty acids. In vitro validation studies revealed that febuxostat, but not colchicine, reduced lipolysis in cultured adipocytes. Since soluble urate, xanthine oxidase inhibitor treatment, and free fatty acids modulate inflammation, our findings suggest that by suppressing lipolysis, ULT could regulate inflammation in gout and comorbid metabolic and cardiovascular disease.

Objectives To assess the impact of baseline RF level on drug concentrations and efficacy of certolizumab pegol [CZP; TNF inhibitor (TNFi) without a crystallizable fragment (Fc)] and adalimumab (ADA; Fc-containing TNFi) in patients with RA. Methods The phase 4 EXXELERATE study (NCT01500278) was a 104-week, randomized, single-blind (double-blind until week 12; investigator-blind thereafter), head-to-head study of CZP vs ADA in patients with RA. In this post hoc analysis, we report drug concentration and efficacy outcomes stratified by baseline RF quartile (≤Q3 or >Q3). Results Baseline data by RF quartiles were available for 453 CZP-randomized and 454 ADA-randomized patients (≤Q3: ≤204 IU/ml; >Q3: >204 IU/ml). From week 12, the area under the curve (AUC) of ADA concentration was lower in patients with RF >204 IU/ml vs patients with RF ≤204 IU/ml; the AUC of CZP concentration was similar in patients with RF ≤204 IU/ml and >204 IU/ml. For patients with RF ≤204 IU/ml, disease activity score (DAS28)-CRP was similar between CZP- and ADA-treated patients through week 104. For patients with RF >204 IU/ml, mean DAS28-CRP was lower in CZP- vs ADA-treated patients at week 104. The proportion of patients with RF >204 IU/ml achieving DAS28-CRP low disease activity at week 104 was greater in CZP- vs ADA-treated patients. Conclusion CZP was associated with maintained drug concentration and efficacy in patients with RA and high RF and may therefore be a more suitable therapeutic option than TNFis with an Fc fragment in these patients. Trial registration Clinicaltrials.gov, http://clinicaltrials.gov , NCT01500278 [ABSTRACT FROM AUTHOR]

Background: Malondialdehyde–acetaldehyde (MAA) adducts lead to generation of anti‐MAA autoantibodies and have been independently identified in inflamed periodontal and rheumatoid arthritis (RA) tissues. This study evaluates serum samples from RA cases and osteoarthritis (OA) controls to quantify associations between periodontal clinical measures, alveolar bone loss (ABL), and anti‐Porphyromonas gingivalis, anti‐Prevotella intermedia, and anti‐Fusobacterium nucleatum antibody concentrations with anti‐MAA antibody concentrations. Methods: Participants (n = 284 RA cases, n = 330 OA controls) underwent periodontal clinical assessments and ABL measurements. Serum immunoglobulin (Ig) A, IgG, and IgM anti‐MAA and serum IgG antibacterial antibody concentrations were quantified by enzyme‐linked immunosorbent assay (ELISA). Analyses utilized simple linear regression and multivariable adjusted models. Results: No significant associations of periodontal clinical measures with serum anti‐MAA were found. Moderate (p = 0.038 and p = 0.036, respectively) and high ABL (p = 0.012 and p = 0.014, respectively) in RA cases (but not in OA) were positively associated with IgG and IgM anti‐MAA. Anti‐P. gingivalis and anti‐P. intermedia antibody concentrations were positively associated with IgA (p = 0.001 for both), IgG (p = 0.007 and p = 0.034, respectively), and IgM anti‐MAA antibody concentrations (p < 0.001 and p = 0.020, respectively), while anti‐F. nucleatum was positively associated with IgG anti‐MAA (p = 0.042), findings that were similar across groups. Conclusions: A positive association was demonstrated between ABL and serum IgG and IgM anti‐MAA antibody concentrations that was unique to RA and not observed in OA. Serum anti‐P. gingivalis, anti‐P. intermedia, and anti‐F. nucleatum antibody concentrations displayed significant associations with anti‐MAA antibody in both groups. These findings suggest MAA may play a role in the interrelationship between the periodontium and RA. [ABSTRACT FROM AUTHOR]

Objective: 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, noninferiority trial comparing the efficacy of allopurinol and febuxostat. For this analysis, the occurrence of flares was examined during weeks 0 to 24 when ULT was initiated and titrated to a serum urate (sUA) goal of less than 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 (hazard ratio [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. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to ascertain pegloticase persistence and adverse events associated with concomitant immunomodulatory drug treatment in patients with gout. Methods: We conducted a retrospective analysis of patients with gout using the American College of Rheumatology's Rheumatology Informatics System for Effectiveness registry from January 2016 through June 2020. The first pegloticase infusion defined the index date. Based on concomitant immunomodulatory drug treatment, we identified three exposure groups: (1) immunomodulatory drug initiators (patients initiating an immunomodulatory prescription ±60 days from the index date), (2) prevalent immunomodulatory drug recipients (patients receiving their first immunomodulatory drug prescription >60 days before the index date with at least one prescription within ±60 days of the index date), and (3) immunomodulatory nonrecipients (patients receiving pegloticase without concomitant immunomodulatory drugs). We calculated the proportion of patients who achieved serum urate levels ≤6 mg/dL and who had laboratory abnormalities (white blood cell count <3.4 x 109/L, platelet count <135,000, hematocrit level <30%, alanine aminotransferase or aspartate aminotransferase level ≥1.5 times the upper limit normal value) within 180 days after the index date. Cox regression analyzed time to pegloticase discontinuation, controlling for potential confounders. Results: We identified 700 pegloticase recipients (91 immunomodulatory drug initiators, 33 prevalent immunomodulatory drug recipients, and 576 nonrecipients), with a median follow‐up of 14 months. Immunomodulatory drug recipients were less likely to discontinue pegloticase. The adjusted hazard ratios of pegloticase discontinuation associated with concomitant immunomodulatory drug initiation and prevalent treatment were 0.52 (95% confidence interval [CI] 0.37–0.75) and 0.69 (95% CI 0.42–1.16), respectively. Laboratory abnormalities were uncommon (<5%) and were not higher in concomitant immunomodulatory drug treatment. Conclusion: Consistent with clinical trials, results from this large observational registry suggest that concomitant immunomodulatory drug treatment improves pegloticase persistence. [ABSTRACT FROM AUTHOR]

Purpose We evaluated associations between adiponectin and the risk of diabetes among patients with rheumatoid arthritis (RA), a systemic inflammatory disease associated with metabolic disturbance. Methods This prospective cohort study included adults with RA from the Veterans Affairs Rheumatoid Arthritis Registry. Adiponectin and inflammatory cytokines/chemokines were measured at enrollment on stored serum samples. Adiponectin levels were categorized, and clinical variables were described across categories (<10 μg/mL; 10-40 μg/mL; >40 μg/mL). Multivariable Cox proportional hazard models evaluated associations between adiponectin and incident diabetes adjusting for age, sex, race, smoking status, body mass index (BMI), disease-modifying therapy use, calendar year, and comorbidity. Testing for modification of effect in the context of elevated cytokines/chemokines was performed. Results Among 2595 patients included in the analysis, those with adiponectin levels >40 μg/mL (N = 379; 15%) were older and had lower BMI. There were 125 new cases of diabetes among 1689 patients without prevalent disease at enrollment. There was an inverse association between adiponectin and incident diabetes; however, the association was positive among patients with adiponectin levels >40 μg/mL. Patients with levels >40 μg/mL were at higher risk compared to those with levels 10-40 μg/mL (HR: 1.70 [1.34, 2.16] P <.001). Those with adiponectin levels >40 μg/mL had significantly higher levels of inflammatory cytokines with evidence of a modified effect of adiponectin on diabetes risk in the setting of inflammation. Conclusion The relationship between adiponectin and incident diabetes risk is U-shaped in RA. Patients with very high adiponectin levels have greater systemic inflammation and an altered relationship between adiponectin and diabetes risk. [ABSTRACT FROM AUTHOR]

Objective: Rheumatoid arthritis (RA) has a "pre‐RA" period in which multiple autoantibodies, including antibodies to citrullinated (cit) proteins (ACPA), rheumatoid factor (RF), anti–peptidyl arginine deiminase (anti‐PAD), among others, have been described; however, few studies have tested all autoantibodies in a single pre‐RA cohort. This study aims to evaluate the prevalence of multiple autoantibodies in pre‐RA and potentially identify an autoantibody profile in pre‐RA that indicates imminent onset of clinical RA. Methods: We evaluated 148 individuals with two pre‐ and one post‐RA diagnosis samples available from the Department of Defense Serum Repository and matched controls. Samples were tested for immuglobulin (Ig) G anti–cyclic cit peptide‐3 (anti‐CCP3), five ACPA fine specificities, five anti‐PAD isoforms, as well as RF IgA and RF IgM using commercial platforms; cutoffs were determined using levels present in <1% of controls. Results: Positivity of anti‐CCP3, RF IgA and RF IgM, anti‐PAD1, anti–cit‐vimentin 2, anti–cit‐fibrinogen, and anti–cit‐histone 1 increased over time in pre‐RA, although anti‐PAD and ACPA fine specificities were predominately present within anti‐CCP3–positive individuals. Within anti‐CCP3–positive samples from the pre‐RA period, positivity for RFs as well as anti‐PAD and ACPA fine specificities classified samples as being closer to the time of RA diagnosis. Conclusion: Multiple autoantibodies are present in pre‐RA and increase in positivity as the time of RA diagnosis approaches. These results confirm previous findings predicting imminent RA and provide a pathway using commercial‐grade assays to assess the risk for and timing of development of clinical RA. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study is to determine the associations of protein‐specific anti–malondialdehyde‐acetaldehyde (MAA) antibodies with prevalent and incident rheumatoid arthritis–interstitial lung disease (RA‐ILD). Methods: Within a multicenter, prospective cohort of US veterans with RA, RA‐ILD was validated by medical record review of clinical diagnoses, chest imaging, and pathology. Serum antibodies to MAA‐albumin, MAA‐collagen, MAA‐fibrinogen, and MAA‐vimentin (IgA, IgM, and IgG) were measured by a standardized enzyme‐linked immunosorbent assay. Associations of anti‐MAA antibodies with prevalent and incident RA‐ILD were assessed using multivariable regression models adjusting for established RA‐ILD risk factors. Results: Among 2,739 participants with RA (88% male, mean age of 64 years), there were 114 with prevalent and 136 with incident RA‐ILD (average time to diagnosis: 6.6 years). Higher IgM anti–MAA‐collagen (per 1 SD: adjusted odds ratio [aOR] 1.28, 95% confidence interval [CI] 1.02–1.61), IgA anti–MAA‐fibrinogen (aOR 1.48, 95% CI 1.14–1.92), and IgA (aOR 1.78, 95% CI 1.34–2.37) and IgG (aOR 1.48, 95% CI 1.14–1.92) anti–MAA‐vimentin antibodies were associated with prevalent RA‐ILD. In incident analyses, higher IgA (per one SD: adjusted hazards ratio [aHR] 1.40, 95% CI 1.11–1.76) and IgM (aHR 1.29, 95% CI 1.04–1.60) anti–MAA‐albumin antibody concentrations were associated with increased ILD risk. Participants with IgA (aHR 2.13, 95% CI 1.16–3.90) or IgM (aHR 1.98, 95% CI 1.08–3.64) anti–MAA‐albumin antibody concentrations in the highest quartile had an approximately two‐fold increased risk of incident RA‐ILD. Across all isotypes, anti–MAA‐fibrinogen, anti–MAA‐collagen, and anti–MAA‐vimentin antibodies were not significantly associated with incident RA‐ILD. Conclusion: Protein‐specific anti‐MAA antibodies to collagen, fibrinogen, and vimentin were associated with prevalent RA‐ILD. IgA and IgM anti–MAA‐albumin antibodies were associated with a higher risk of incident RA‐ILD. These findings suggest that MAA modifications and resultant immune responses may contribute to RA‐ILD pathogenesis. [ABSTRACT FROM AUTHOR]

ObjectiveThe C-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR) are important disease activity biomarkers in rheumatoid arthritis (RA). This study aimed to determine to what extent obesity biases these biomarkers.MethodsBody mass index (BMI) associations with CRP level and ESR were assessed in 2 RA cohorts: the cross-sectional Body Composition (BC) cohort (n = 451), including whole-body dual x-ray absorptiometry measures of fat mass index; and the longitudinal Veterans Affairs Rheumatoid Arthritis (VARA) registry (n = 1,652), using multivariable models stratified by sex. For comparison, associations were evaluated in the general population using the National Health and Nutrition Examination Survey.ResultsAmong women with RA and in the general population, greater BMI was associated with greater CRP levels, especially among women with severe obesity (P < 0.001 for BMI ≥35 kg/m2 versus 20-25 kg/m2 ). This association remained after adjustment for joint counts and patient global health scores (P < 0.001 in BC and P < 0.01 in VARA), but was attenuated after adjustment for fat mass index (P = 0.17). Positive associations between BMI and ESR in women were more modest. In men with RA, lower BMI was associated with higher CRP levels and ESR, contrasting with positive associations among men in the general population.ConclusionObesity is associated with higher CRP levels and ESR in women with RA. This association is related to fat mass and not RA disease activity. Low BMI is associated with higher CRP levels in men with RA; this unexpected finding remains incompletely explained but likely is not a direct effect of adiposity.

Objective: To evaluate the associations of plasma matrix metalloproteinases (MMPs) with prevalent and incident interstitial lung disease (ILD) in people with rheumatoid arthritis (RA). Methods: Within a multicenter, prospective cohort of US veterans with RA, we performed a cross‐sectional study of prevalent ILD and cohort study of incident ILD. ILD diagnoses were validated by medical record review of provider diagnoses and chest imaging and/or pathology reports. MMP‐1, 3, 7, and 9 concentrations were measured in plasma samples, then standardized and categorized into quartiles. The associations of MMPs with prevalent and incident ILD were assessed with logistic (prevalent) and Cox (incident) regression models adjusted for RA‐ILD risk factors. Results: Among 2,312 participants (88.9% male; mean age 63.8 years), 96 had prevalent ILD. Incident ILD developed in 130 participants over 17,378 person‐years of follow‐up (crude incidence rate 7.5/1,000 person‐years). Participants with the highest quartile of MMP‐7 concentrations had a nearly four‐fold increased odds of prevalent ILD (adjusted odds ratio 3.78 [95% confidence interval (95% CI) 1.86–7.65]) and over two‐fold increased risk of incident ILD (adjusted hazard ratio 2.33 [95% CI 1.35–4.02]). Higher MMP‐9 concentrations were also associated with prevalent and incident ILD, as well as negatively correlated with forced vital capacity among those with prevalent ILD (r = −0.30, P = 0.005). Conclusion: MMP‐7 and MMP‐9 were strongly associated with both prevalent and incident ILD in this large, multicenter RA cohort after adjustment for other RA‐ILD risk factors. These population‐level findings further support a potential pathogenic role for MMPs in RA‐ILD and suggest that their measurement could facilitate RA‐ILD risk stratification. [ABSTRACT FROM AUTHOR]

Objectives To quantify associations of serum alarmins with risk of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Methods Using serum collected at enrolment, three alarmins (IL-33, thymic stromal lymphopoietin [TSLP] and IL-25) were measured in a multicentre prospective RA cohort. ILD was classified using systematic medical record review. Cross-sectional associations of log-transformed (IL-33, TSLP) or quartile (IL-25) values with RA-ILD at enrolment (prevalent RA-ILD) were examined using logistic regression, while associations with incident RA-ILD developing after enrolment were examined using Cox proportional hazards. Covariates in multivariate models included age, sex, race, smoking status, RA disease activity score and anti-cyclic citrullinated antibody positivity. Results Of 2835 study participants, 115 participants (4.1%) had prevalent RA-ILD at baseline and an additional 146 (5.1%) developed incident ILD. There were no associations between serum alarmin concentrations and prevalent ILD in unadjusted or adjusted logistic regression models. In contrast, there was a significant inverse association between IL-33 concentration and the risk of developing incident RA-ILD in unadjusted (hazard ratio [HR] 0.73 per log-fold increase; 95% CI: 0.57, 0.95; P  = 0.018) and adjusted (HR 0.77; 95% CI: 0.59, 1.00; P  = 0.047) models. No significant associations of TSLP or IL-25 with incident ILD were observed. Conclusion In this study, we observed a significant inverse association between serum IL-33 concentration and the risk of developing incident RA-ILD, but no associations with prevalent ILD. Additional investigation is required to better understand the mechanisms driving this relationship and how serum alarmin IL-33 assessment might contribute to clinical risk stratification in patients with RA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]