Urate-lowering therapy, serum urate, inflammatory biomarkers, and renal function in patients with gout following pegloticase discontinuation.

BACKGROUND/PURPOSE: Little is known about long-term clinical outcomes or urate-lowering (ULT) therapy use following pegloticase discontinuation. We examined ULT use, serum urate (SU), inflammatory biomarkers, and renal function following pegloticase discontinuation. METHODS: We conducted a retrospective analysis of gout patients who discontinued pegloticase using the Rheumatology Informatics System for Effectiveness (RISE) registry from 1/2016 to 6/2022. We defined discontinuation as a gap ≥ 12 weeks after last infusion. We examined outcomes beginning two weeks after last dose and identified ULT therapy following pegloticase discontinuation. We evaluated changes in lab values (SU, eGFR, CRP and ESR), comparing on- treatment (≤ 15 days of the second pegloticase dose) to post-treatment. RESULTS: Of the 375 gout patients discontinuing pegloticase, median (IQR) laboratory changes following discontinuation were: SU: +2.4 mg/dL (0.0,6.3); eGFR: -1.9 mL/min (- 8.7,3.7); CRP: -0.8 mg/L (-12.8,0.0); and ESR: -4.0 mm/hr (-13.0,0.0). Therapy post-discontinuation included oral ULTs (86.0%), restarting pegloticase (4.5%), and no documentation of ULT (9.5%), excluding patients with multiple same-day prescriptions (n = 17). Oral ULTs following pegloticase were: 62.7% allopurinol, 34.1% febuxostat. The median (IQR) time to starting/restarting ULT was 92.0 days (55.0,173.0). Following ULT prescribing (≥ 30 days), only 51.0% of patients had SU < 6 mg/dL. Patients restarting pegloticase achieved a median SU of 0.9 mg/dL (IQR:0.2,9.7) and 58.3% had an SU < 6 mg/dL. CONCLUSION: Pegloticase treats uncontrolled gout in patients with failed response to xanthine oxidase inhibitors, but among patients who discontinue, optimal treatment is unclear. Based on this analysis, only half of those starting another ULT achieved target SU. Close follow-up is needed to optimize outcomes after pegloticase discontinuation.

Targeting transitioning lung monocytes/macrophages as treatment strategies in lung disease related to environmental exposures.

BACKGROUND: Environmental/occupational exposures cause significant lung diseases. Agricultural organic dust extracts (ODE) and bacterial component lipopolysaccharide (LPS) induce recruited, transitioning murine lung monocytes/macrophages, yet their cellular role remains unclear. METHODS: CCR2 RFP+ mice were intratracheally instilled with high concentration ODE (25%), LPS (10 µg), or gram-positive peptidoglycan (PGN, 100 µg) for monocyte/macrophage cell-trafficking studies. CCR2 knockout (KO) mice and administration of intravenous clodronate liposomes strategies were employed to reduce circulating monocytes available for lung recruitment following LPS exposure. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected. Pro-inflammatory and/or pro-fibrotic cytokines, chemokines, and lung extracellular matrix mediators were quantitated by ELISA. Infiltrating lung cells including monocyte/macrophage subpopulations, neutrophils, and lymphocytes were characterized by flow cytometry. Lung histopathology, collagen content, vimentin, and post-translational protein citrullination and malondialdehyde acetaldehyde (MAA) modification were quantitated. Parametric statistical tests (one-way ANOVA, Tukey'smultiple comparison) and nonparametric statistical (Kruskal-Wallis, Dunn's multiple comparison) tests were used following Shapiro-Wilk testing for normality. RESULTS: Intratracheal instillation of ODE, LPS, or PGN robustly induced the recruitment of inflammatory CCR2+ CD11cintCD11bhi monocytes/macrophages and both CCR2+ and CCR2- CD11c-CD11bhi monocytes at 48 h. There were also increases in CCR2+ CD4+ and CD8+ T cells and NK cells. Despite reductions in LPS-induced lung infiltrating CD11cintCD11bhi cells (54% reduction), CCR2 knockout (KO) mice were not protected against LPS-induced inflammatory and pro-fibrotic consequences. Instead, compensatory increases in lung neutrophils and CCL2 and CCL7 release occurred. In contrast, the depletion of circulating monocytes through the administration of intravenous clodronate (vs. vehicle) liposomes 24 h prior to LPS exposure reduced LPS-induced infiltrating CD11cintCD11bhi monocyte-macrophage subpopulation by 59% without compensatory changes in other cell populations. Clodronate liposome pre-treatment significantly reduced LPS-induced IL-6 (66% reduction), matrix metalloproteinases (MMP)-3 (36%), MMP-8 (57%), tissue inhibitor of metalloproteinases (61%), fibronectin (38%), collagen content (22%), and vimentin (40%). LPS-induced lung protein citrullination and MAA modification, post-translational modifications implicated in lung disease, were reduced (39% and 48%) with clodronate vs. vehicle liposome. CONCLUSION: Highly concentrated environmental/occupational exposures induced the recruitment of CCR2+ and CCR2- transitioning monocyte-macrophage and monocyte subpopulations and targeting peripheral monocytes may reduce the adverse lung consequences resulting from exposures to LPS-enriched inhalants.

Risk of Venous Thromboembolism With Tofacitinib Versus Tumor Necrosis Factor Inhibitors in Cardiovascular Risk-Enriched Rheumatoid Arthritis Patients.

OBJECTIVE: The ORAL Surveillance trial found a dose-dependent increase in venous thromboembolism (VTE) and pulmonary embolism (PE) events with tofacitinib versus tumor necrosis factor inhibitors (TNFi). We aimed to assess VTE incidence over time and explore risk factors of VTE, including disease activity, in ORAL Surveillance. METHODS: Patients with rheumatoid arthritis (RA) aged 50 years or older with at least one additional cardiovascular risk factor received tofacitinib 5 or 10 mg twice daily (BID) or TNFi. Post hoc, cumulative probabilities and incidence rates (patients with first events/100 patient-years) by 6-month intervals were estimated for adjudicated VTE, deep vein thrombosis, and PE. Cox regression models identified risk factors. Clinical Disease Activity Index leading up to the event was explored in patients with VTE. RESULTS: Cumulative probabilities for VTE and PE were higher with tofacitinib 10 mg BID, but not 5 mg BID, versus TNFi. Incidence rates were consistent across 6-month intervals within treatments. Across treatments, risk factors for VTE included prior VTE, body mass index greater than or equal to 35 kg/m2, older age, and history of chronic lung disease. At the time of the event, most patients with VTE had active disease as defined by Clinical Disease Activity Index. CONCLUSION: Incidences of VTE and PE were higher with tofacitinib (10 > 5 mg BID) versus TNFi and were generally consistent over time. Across treatments, VTE risk factors were aligned with previous studies in the general RA population. These data highlight the importance of assessing VTE risk factors, including age, body mass index, and VTE history, when considering initiation of tofacitinib or TNFi in patients with active RA.

Plasma Matrix Metalloproteinase Concentrations and Risk of Interstitial Lung Disease in a Prospective Rheumatoid Arthritis Cohort.

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.

Lower body mass and lower adiposity are associated with differential responses to two treatment strategies for rheumatoid arthritis.

PURPOSE: To determine if body mass index (BMI) and adipokine levels identify rheumatoid arthritis (RA) patients most likely to benefit from initiation of tumour necrosis factor inhibitors (TNFi) after methotrexate inadequate response. METHODS: This is a secondary analysis of the Rheumatoid Arthritis Comparison of Active Treatments (RACAT) trial and the (TEAR) trial. Both studies compared treatment strategies starting with conventional disease-modifying anti-rheumatic drugs (DMARDs) (triple therapy) versus etanercept plus methotrexate. We compared response rates between TNFi and triple therapy among patients with different BMI. Adipokines were measured at enrolment and associations with treatment response were examined using regression, adjusting for age, sex, BMI and baseline disease activity. RESULTS: In RACAT (n=306), participants who were normal/underweight were more likely to benefit from TNFi versus triple therapy, with greater change in Disease Activity Score in 28 and greater ACR20 response (ACR 20: 64% vs 23%, p=0.001). In contrast, overweight/obese participants had similar response to TNFi versus triple therapy (p-for-interaction=0.001). Similarly, but modest patterns were observed in TEAR (n=601; ACR20: 67% vs 52%, p=0.05). In RACAT, adipokine scores consistent with lower adiposity also predicted greater response to TNFi (ACR20: 58% vs 37%, p=0.01) with better model fit compared with BMI alone. CONCLUSIONS: Lower BMI and evidence of lower adiposity based on adipokine profiles were associated with a superior response to TNFi compared with triple therapy. There was no difference between treatments among overweight/obese participants. The results support TNFi being a particularly important therapeutic among normal/underweight patients, with implications for clinical decisions and trial design.

Development and Internal Validation of a Clinical and Genetic Risk Score for Rheumatoid Arthritis-Associated Interstitial Lung Disease.

OBJECTIVE: Although clinical and genetic risk factors have been identified for rheumatoid arthritis-associated interstitial lung disease (RA-ILD), there are no current tools allowing for risk stratification. We sought to develop and validate an ILD risk model in a large, multicentre, prospective RA cohort. METHODS: Participants in the Veterans Affairs RA (VARA) registry were genotyped for 12 single nucleotide polymorphisms (SNPs) associated with idiopathic pulmonary fibrosis. ILD was validated through systematic record review. A genetic risk score (GRS) was computed from minor alleles weighted by effect size with ILD, using backward selection. The GRS was combined with clinical risk factors within a logistic regression model. Internal validation was completed using bootstrapping, and model performance was assessed by the area under the receiver operating curve (AUC). RESULTS: Of 2,386 participants (89% male, mean age 69.5 years), 9.4% had ILD. Following backward selection, five SNPs contributed to the GRS. The GRS and clinical factors outperformed clinical factors alone in discriminating ILD (AUC 0.675 vs 0.635, p< 0.001). The shrinkage-corrected performance for combined and clinical-only models was 0.667 (95% CI 0.628, 0.712) and 0.623 (95% CI 0.584, 0.651), respectively. Twenty percent of the cohort had a combined risk score below a cut-point with >90% sensitivity. CONCLUSION: A clinical and genetic risk model discriminated ILD in a large, multicentre RA cohort better than a clinical-only model, excluding 20% of the cohort from low-yield testing. These results demonstrate the potential utility of a GRS in RA-ILD and support further investigation into individualized risk stratification and screening.

Associations between Adiponectin and the Development of Diabetes in Rheumatoid Arthritis.

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 Veteran's 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 1,689 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 < 0.001]. 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. CONCLUSIONS: 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.

Anti-citrullinated protein antibody profiles predict changes in disease activity in patients with rheumatoid arthritis initiating biologics.

OBJECTIVES: To determine whether an expanded antigen-specific ACPA profile predicts changes in disease activity in patients with RA initiating biologics. METHODS: The study included participants from a prospective, non-randomized, observational RA cohort. For this sub-study, treatment groups of interest included biologic-naïve initiating anti-TNF, biologic-exposed initiating non-TNF, and biologic-naïve initiating abatacept. ACPAs to 25 citrullinated peptides were measured using banked enrolment serum. Principal component analysis (PCA) was performed and associations of resulting principal component (PC) scores (in quartiles) and anti-CCP3 antibody (≤15, 16-250 or >250 U/ml) with EULAR (good/moderate/none) treatment response at 6 months were examined using adjusted ordinal regression models. RESULTS: Participants (n = 1092) had a mean age of 57 (13) years and 79% were women. At 6 months, 68.5% achieved a moderate/good EULAR response. There were three PCs that cumulatively explained 70% of variation in ACPA values. In models including the three components and anti-CCP3 antibody category, only PC1 and PC2 were associated with treatment response. The highest quartile for PC1 (odds ratio [OR] 1.76; 95% CI: 1.22, 2.53) and for PC2 (OR 1.74; 95% CI: 1.23, 2.46) were associated with treatment response after multivariable adjustment. There was no evidence of interaction between PCs and treatment group in EULAR responses (P-value for interaction >0.1). CONCLUSION: An expanded ACPA profile appears to be more strongly associated with biologic treatment response in RA than commercially available anti-CCP3 antibody levels. However, further enhancements to PCA will be needed to effectively prioritize between different biologics available for the treatment of RA.

Development of an Interactive Tool to Support Shared Decision-Making in Rheumatoid Arthritis: Treatment Attribute Preference.

OBJECTIVE: An interactive tool identifying treatment attributes important to patients can enhance shared decision-making (SDM) in rheumatoid arthritis (RA). A formative survey was conducted to identify the most important treatment attributes from patients' perspective, which can be used to develop an interactive SDM tool. METHODS: The survey was performed in two phases: qualitative interviews and quantitative surveys. The qualitative interviews were conducted to inform the design of the quantitative survey. In qualitative interviews, patients with RA (n = 10) and rheumatologists (n = 10) were introduced to the SDM tool concept. Feedback on the design and scope of the SDM tool was used to develop a quantitative survey, conducted in a large sample size of patients. Patient preferences for treatment attributes (route of administration and dosing frequency, serious side effects, out-of-pocket costs, efficacy, and monitoring requirement) were assessed via adaptive conjoint exercise involving ranking of hypothetical RA treatment configurations. RESULTS: A total of 944 patients (males: 43%, females: 57%) with RA participated in the quantitative survey. Route of administration and dosing frequency (38%) followed by serious side effects (33%) were the two most important treatment attributes for individual patients. The recontact survey (n = 172/944) estimated tool stability of 72% (n = 124/172) in terms of the relative importance of treatment attributes. CONCLUSION: The findings of this survey could be used in the development of an SDM tool that can potentially provide insights into patient preferences and is generally well received by patients and rheumatologists with good agreement and reliability.

Combined repetitive inhalant endotoxin and collagen-induced arthritis drive inflammatory lung disease and arthritis severity in a testosterone-dependent manner.

Respiratory-related diseases are a leading cause of death in rheumatoid arthritis (RA) and are disproportionately higher in men, which may be attributable to environmental risk factors. Animal studies have demonstrated potentiated autoimmunity, arthritis, and profibrotic/inflammatory lung disease with a combination of airborne exposures and collagen-induced arthritis (CIA). This study aimed to determine whether hormone-dependent differences explained these observations. Arthritis-prone male intact and castrated DBA/1J mice received intranasal inhalation of lipopolysaccharide (LPS) daily for 5 wk and CIA induction. Arthritis scores and serum pentraxin-2 levels were increased in castrated versus intact mice. In contrast, airway cell influx, lung tissue infiltrates, and lung levels of proinflammatory and profibrotic markers (C5a, IL-33, and matrix metalloproteinases) were reduced in castrated versus intact mice. CIA + LPS-induced lung histopathology changes and the expression of lung autoantigens including malondialdehyde acetaldehyde (MAA)- and citrulline (CIT)-modified proteins and vimentin were reduced in castrated animals. There were no differences in serum anti-MAA or anti-CIT protein antibody (ACPA) levels or serum pentraxin levels between groups. Testosterone replacement led to a reversal of several lung inflammatory/profibrotic endpoints noted earlier in castrated male CIA + LPS-treated mice with testosterone supplementation promoting neutrophil influx, MAA expression, and TNF-α, IL-6, and MMP-9. These findings imply that testosterone contributes to lung and arthritis inflammatory responses following CIA + LPS coexposure, but not to systemic autoantibody responses. The CIA + LPS model provides a paradigm for investigations focused on the mechanistic underpinnings for epidemiologic and phenotypic sex differences in RA-related lung disease.NEW & NOTEWORTHY Our study shows that testosterone acts as a key immunomodulatory hormone contributing to critical features of rheumatoid arthritis (RA)-associated lung disease in the setting of airborne endotoxin (lipopolysaccharide; LPS) exposures and concomitant arthritis induction in mice. The exaggerated airway inflammation observed following combined exposures in male mice was accompanied by increases in profibrotic mediators, netosis, and increased expression of lung autoantigens, all relevant to the pathogenesis of lung disease in arthritis.

Expansion of distinct peripheral blood myeloid cell subpopulations in patients with rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: Interstitial lung disease (ILD) is associated with significant mortality in rheumatoid arthritis (RA) patients with key cellular players remaining largely unknown. This study aimed to characterize inflammatory and myeloid derived suppressor cell (MDSC) subpopulations in RA-ILD as compared to RA, idiopathic pulmonary fibrosis (IPF) without autoimmunity, and controls. METHODS: Peripheral blood was collected from patients with RA, RA-ILD, IPF, and controls (N = 60, 15/cohort). Myeloid cell subpopulations were identified phenotypically by flow cytometry using the following markers:CD45,CD3,CD19,CD56,CD11b,HLA-DR,CD14,CD16,CD15,CD125,CD33. Functionality of subsets were identified with intracellular arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS) expression. RESULTS: There was increased intermediate (CD14++CD16+) and nonclassical (CD14+/-CD16++) and decreased classical (CD14++CD16-) monocytes in RA, RA-ILD, and IPF vs. control. Intermediate monocytes were higher and classical monocytes were lower in RA-ILD vs. RA but not IPF. Monocytic (m)MDSCs were higher in RA-ILD vs. control and RA but not IPF. Granulocytic (g)MDSCs did not significantly differ. In contrast, neutrophils were increased in IPF and RA-ILD patients with elevated expression of Arg-1 sharing similar dimensional clustering pattern. Eosinophils were increased in RA-ILD vs. controls, RA and IPF. Across cohorts, iNOS was decreased in intermediate/nonclassical monocytes but increased in mMDSCs vs. classical monocytes. In RA-ILD, iNOS positive mMDSCs were increased versus classic monocytes. CONCLUSIONS: Myeloid cell subpopulations are significantly modulated in RA-ILD patients with expansion of CD16+ monocytes, mMDSCs, and neutrophils, a phenotypic profile more aligned with IPF than other RA patients. Eosinophil expansion was unique to RA-ILD, potentially facilitating disease pathogenesis and providing a future therapeutic target.

Health disparities in gout.

PURPOSE OF REVIEW: Gout, the most common type of inflammatory arthritis in the world, is characterized by painful episodes of arthritis linked by asymptomatic intercritical periods of hyperuricemia. Once characterized as a disease of wealthy white men, contemporary evidence demonstrates gout disproportionately afflicts racial/ethnic minorities, Indigenous populations and other underrepresented groups leading to significant health disparities. RECENT FINDINGS: Herein, we review the current literature reporting a higher incidence and prevalence of gout in racial/ethnic minorities and Indigenous populations, in addition to a growing gout burden reported in females. We also examine how these population are more likely to receive suboptimal treatment for flares and chronic phases of gout. Additionally, we examine biologic and social health determinants that may be contributing to these findings. SUMMARY: Racial/ethnic minorities, Indigenous populations, and females have experienced a disproportionate rise in the prevalence and incidence of gout in recent years, are more likely to seek acute medical care and are less likely to receive optimal long-term care for gout with urate lowering therapy. Mechanisms underpinning these findings appear to be multifactorial and include differences in social determinants of care and in some cases may be due to population differences in select biologic factors such as differences in age, sex, genetics.

Extracting forced vital capacity from the electronic health record through natural language processing in rheumatoid arthritis-associated interstitial lung disease.

PURPOSE: To develop a natural language processing (NLP) tool to extract forced vital capacity (FVC) values from electronic health record (EHR) notes in patients with rheumatoid arthritis-interstitial lung disease (RA-ILD). METHODS: We selected RA-ILD patients (n = 7485) in the Veterans Health Administration (VA) between 2000 and 2020 using validated ICD-9/10 codes. We identified numeric values in proximity to FVC string patterns from clinical notes in the EHR. Subsequently, we performed processing steps to account for variability in note structure, related pulmonary function test (PFT) output, and values copied across notes, then assigned dates from linked administrative procedure records. NLP-derived FVC values were compared to values recorded directly from PFT equipment available on a subset of patients. RESULTS: We identified 5911 FVC values (n = 1844 patients) from PFT equipment and 15 383 values (n = 4982 patients) by NLP. Among 2610 date-matched FVC values from NLP and PFT equipment, 95.8% of values were within 5% predicted. The mean (SD) difference was 0.09% (5.9), and values strongly correlated (r = 0.94, p < 0.001), with a precision of 0.87 (95% CI 0.86, 0.88). NLP captured more patients with longitudinal FVC values (n = 3069 vs. n = 1164). Mean (SD) change in FVC %-predicted per year was similar between sources (-1.5 [30.0] NLP vs. -0.9 [16.6] PFT equipment; standardized response mean = 0.05 for both). CONCLUSIONS: NLP of EHR notes increases the capture of accurate, longitudinal FVC values by three-fold over PFT equipment. Use of this NLP tool can facilitate pharmacoepidemiologic research in RA-ILD and other lung diseases by capturing this critical measure of disease severity.

Changes in Characteristics of Patients Initiating and Discontinuing Advanced Therapies for Rheumatoid Arthritis Following the Release of Safety Data.

OBJECTIVE: The objective of this study was to determine the impact of emerging safety data on practice patterns by describing the characteristics of patients initiating and discontinuing advanced therapies for rheumatoid arthritis (RA) before and after January 2021. METHODS: This cohort study evaluated US veterans with RA between April 2019 and September 2022. This period was divided into two 664-day periods before and after January 2021. Eligible patients had ≥1 diagnosis code for RA and initiated a tumor necrosis factor inhibitor (TNFi), non-TNFi biologic, or JAK inhibitor (JAKi). We tested for interaction within regression models to determine whether changes in patient characteristics for tofacitinib recipients were different from changes observed for other therapies. We also evaluated factors associated with therapy discontinuation in Cox models adjusted for age, sex, and duration on therapy, including assessment for effect modification. RESULTS: When comparing patients with RA initiating tofacitinib before (n = 2,111) with those initiating tofacitinib after (n = 1,664) January 2021, there was a decrease in mean age (64.1 vs 63.0 years) and in the proportion with cardiovascular comorbidities (all P < 0.01). These changes were significantly different from those observed for patients initiating TNFi or non-TNFi biologics. Among active advanced therapy recipients, the likelihood of discontinuation was higher for tofacitinib than TNFi (hazard ratio 1.18, 95% confidence interval 1.10-1.26, P < 0.001). The higher rate of tofacitinib discontinuation was more pronounced in the presence of cardiovascular comorbidities (P < 0.05). CONCLUSION: Recent safety data significantly affected prescribing practices for advanced therapies, with a reduction in JAKi initiation and an increase in JAKi discontinuation among older patients and those at high cardiovascular risk.

Rheumatoid arthritis disease activity and adverse events in patients receiving tofacitinib or tumor necrosis factor inhibitors: a post hoc analysis of ORAL Surveillance.

Background: In patients with rheumatoid arthritis (RA), persistent inflammation and increasing disease activity are associated with increased risk of adverse events (AEs). Objectives: To assess relationships between RA disease activity and AEs of interest in patients treated with tofacitinib or tumor necrosis factor inhibitors (TNFi). Design: This was a post hoc analysis of a long-term, postauthorization safety endpoint trial of tofacitinib versus TNFi. Methods: In ORAL Surveillance, 4362 patients aged ⩾50 years with active RA despite methotrexate, and ⩾1 additional cardiovascular (CV) risk factor, were randomized 1:1:1 to tofacitinib 5 or 10 mg twice daily or TNFi for up to 72 months. Post hoc time-dependent multivariable Cox analysis evaluated the relationships between disease activity [Clinical Disease Activity Index (CDAI)], inflammation [C-reactive protein (CRP)], and AEs of interest. The AEs included major adverse CV events (MACE), malignancies excluding nonmelanoma skin cancer (NMSC), venous thromboembolism (VTE), serious infections, herpes zoster (HZ), nonserious infections excluding HZ (NSI), and death. Results: Across treatments, risk for NSI was higher when patients had CDAI-defined active disease versus remission; MACE and VTE risks trended higher, but did not reach significance. Hazard ratios for MACE, malignancies excluding NMSC, VTE, infections, and death rose by 2-9% for each 5-mg/L increment in serum CRP. The interaction terms evaluating the impact of treatment assignment on the relationship between disease activity and AEs were all p > 0.05. Conclusion: In ORAL Surveillance, higher NSI risk was observed in the presence of active RA versus remission. The risk of MACE and VTE directionally increased in active disease versus remission, although statistical power was limited due to small event numbers in these categories. The relationship between active disease and AEs was not impacted by treatment with tofacitinib versus TNFi. Registration: NCT02092467.

The link between disease activity and adverse medical events in people with rheumatoid arthritis taking tofacitinib or tumor necrosis factor inhibitors. Why was the study done? • People with rheumatoid arthritis (RA) who have uncontrolled symptoms (high disease activity) have a higher chance of having adverse medical events (medical problems that occur during treatment with a medication) than people who have mild symptoms (low disease activity). • We looked at the link between levels of disease activity and the risk of having adverse medical events in people with RA who took tofacitinib or a tumor necrosis factor inhibitor (TNFi) medication. What did the researchers do? • We used the results of ORAL Surveillance, a long-term safety trial in people with RA. ○ In this study, people with RA were 50 years or older and at high risk of a major cardiovascular event such as heart attack or stroke. • For up to 6 years, people took tofacitinib 5 or 10mg tablets two times a day or TNFi injections. • We used statistical tests to examine the link between different levels of RA disease activity or inflammation and different adverse medical events, such as: ○ major cardiovascular events (such as heart attack, stroke, or death due to heart failure) ○ cancers ○ blood clots ○ infections ○ deaths. What did the researchers find? • In people who took tofacitinib or TNFi: ○ People with active disease (those with RA symptoms) had a higher risk of infections that did not lead to hospitalization (nonserious infections) than people in remission (those with very mild symptoms or no symptoms at all). ○ People with active disease also had a slightly higher risk of major cardiovascular events and blood clots than those in remission. ○ Higher levels of inflammation led to increased risk of major cardiovascular events, cancers, blood clots, infections, and deaths. What do the findings mean? • Active RA disease leads to higher risk of adverse medical events. • The medication used (tofacitinib or TNFi) did not affect the link between levels of RA disease activity and adverse medical events. • This study was limited by the low number of adverse medical events recorded.

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.

Serum alarmins and the risk of incident interstitial lung disease in rheumatoid arthritis.

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 (interleukin [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 2,835 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 (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. CONCLUSIONS: 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.

Citrullinated and malondialdehyde-acetaldehyde modified fibrinogen activates macrophages and promotes an aggressive synovial fibroblast phenotype in patients with rheumatoid arthritis.

Objective: Post-translational protein modifications with malondialdehyde-acetaldehyde (MAA) and citrulline (CIT) are implicated in the pathogenesis of rheumatoid arthritis (RA). Although precise mechanisms have not been elucidated, macrophage-fibroblast interactions have been proposed to play a central role in the development and progression of RA. The purpose of our study was to evaluate the downstream effects of macrophage released soluble mediators, following stimulation with fibrinogen (FIB) modified antigens, on human fibroblast-like synoviocytes (HFLS). Methods: PMA-treated U-937 monocytes (Mϕ) and macrophage-differentiated peripheral blood mononuclear cells (MP) were stimulated with FIB, FIB-MAA, FIB-CIT, or FIB-MAA-CIT. HFLS-RA cells were stimulated directly with FIB antigens or with supernatants (SN) from macrophages (Mϕ-SN or MP-SN) stimulated with FIB antigens. Genes associated with an aggressive HFLS phenotype, extracellular matrix proteins, and activated signaling pathways were evaluated. Results: HFLS-RA cells treated with Mϕ-SNFIB-CIT and Mϕ-SNFIB-MAA-CIT demonstrated significant increases in mRNA expression of genes associated with an aggressive phenotype at 24-h as compared to direct stimulation with the same antigens. Similar results were obtained using MP-SN. Cellular morphology was altered and protein expression of vimentin (p<0.0001 vs. Mϕ-SNFIB) and type II collagen (p<0.0001) were significantly increased in HFLS-RA cells treated with any of the Mϕ-SN generated following stimulation with modified antigens. Phosphorylation of JNK, Erk1/2, and Akt were increased most substantially in HFLS-RA treated with Mϕ-SNFIB-MAA-CIT (p<0.05 vs Mϕ-SNFIB). These and other data suggested the presence of PDGF-BB in Mϕ-SN. Mϕ-SNFIB-MAA-CIT contained the highest concentration of PDGF-BB (p<0.0001 vs. Mϕ-SNFIB) followed by Mϕ-SNFIB-CIT then Mϕ-SNFIB-MAA. HFLS-RA cells treated with PDGF-BB showed similar cellular morphology to the Mϕ-SN generated following stimulation with modified FIB, as well as the increased expression of vimentin, type II collagen, and the phosphorylation of JNK, Erk1/2 and Akt signaling molecules. Conclusion: Together, these findings support the hypothesis that in response to MAA-modified and/or citrullinated fibrinogen, macrophages release soluble factors including PDGF-BB that induce fibroblast activation and promote an aggressive fibroblast phenotype. These cellular responses were most robust following macrophage activation with dually modified fibrinogen, compared to single modification alone, providing novel insights into the combined role of multiple post-translational protein modifications in the development of RA.

Changes in Patterns of Use of Advanced Therapies Following Emerging Data About Adverse Events in Patients With Rheumatoid Arthritis From the Veterans Affairs Health System.

OBJECTIVE: To determine whether prescribing practices for Janus kinase inhibitors (JAKi), tumor necrosis factor inhibitors (TNFi), and non-TNFi biologic agents changed after the results of the Oral Rheumatoid Arthritis Trial (ORAL) Surveillance trial were released in January 2021. METHODS: This is a retrospective study in adult patients with rheumatoid arthritis (RA) receiving advanced therapies within the Veterans Affairs Health System from January 2012 through September 2022. Eligible patients were required to have at least one diagnosis code for RA and to have received a biologic disease-modifying antirheumatic drug or JAKi. Treatment courses were defined from pharmacy dispensing data and the number of new courses of each advanced therapy was quantified over time. We assessed changes in the use of each therapy before and after the release of safety data (January 2021). RESULTS: A total of 88,253 individual drug courses (in 34,656 unique patients) were included in the study. There was a consistent increase in the number and proportion of new courses of JAKi leading up to January 2021, which was followed by a significant net decrease in JAKi use through September 2022. There was significantly less tofacitinib use after the release of safety data, with a significant difference in the slope of change in use with time. In contrast, whereas TNFi use declined leading up to 2021, its use significantly increased after January 2021. CONCLUSION: Changes in prescribing in response to new evidence emphasize the impact that safety trials have on prescribing practices. Ongoing study in this area, with attention to specific patient characteristics and risk profiles, will help characterize these changes in practice.

Multimorbidity Patterns and Rheumatoid Arthritis Disease Outcomes: Findings From a Multicenter, Prospective Cohort.

OBJECTIVE: To determine whether unique multimorbidity patterns are associated with long-term rheumatoid arthritis (RA) disease severity. METHODS: We conducted a cohort study within the Veterans Affairs Rheumatoid Arthritis registry. We applied previously derived multimorbidity patterns based on the presence of diagnostic codes for relevant conditions prior to enrollment using linked administrative data. Disease activity and functional status were assessed longitudinally up to 5 years after enrollment. The association of multimorbidity patterns with disease activity and functional status were assessed using generalized estimating equations models adjusting for relevant confounders. RESULTS: We studied 2,956 participants, of which 88.2% were male, 76.9% reported white race, and 79.3% had a smoking history. Mental health and substance abuse (ß 0.12 [95% confidence interval {CI} 0.00, 0.23]), cardiovascular (ß 0.25 [95% CI 0.12, 0.38]), and chronic pain (ß 0.21 [95% CI 0.11, 0.31]) multimorbidity were associated with higher Disease Activity Score in 28 joints (DAS28) scores. Mental health and substance abuse (ß 0.09 [0.03, 0.15]), cardiovascular (ß 0.11 [95% CI 0.04, 0.17]), and chronic pain multimorbidity (ß 0.15 [95% CI 0.10, 0.20]) were also associated with higher Multidimensional Health Assessment Questionnaire (MDHAQ) scores. The metabolic pattern of multimorbidity was not associated with DAS28 or MDHAQ. The number of multimorbidity patterns present was highly associated with DAS28 and MDHAQ (P trend < 0.001), and patients with all four multimorbidity patterns had the highest DAS28 (ß 0.59 [95% CI 0.36, 0.83]) and MDHAQ (ß 0.27 [95% CI 0.16, 0.39]) scores. CONCLUSION: Mental health and substance abuse, chronic pain, and cardiovascular multimorbidity patterns are associated with increased RA disease activity and poorer functional status. Identifying and addressing these multimorbidity patterns may facilitate achieving RA treatment targets.