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.

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.

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.

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 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.

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.

The Multimorbidity Web in rheumatoid arthritis.

Multimorbidity, the presence of multiple chronic conditions, is highly prevalent in people with RA. An essential characteristic of multimorbidity is the interrelatedness of the different conditions that may develop in a multimorbid person. Recent studies have begun to identify and describe the Multimorbidity Web by elucidating unique multimorbidity patterns in people with RA. The primary multimorbidity patterns in this web are cardiopulmonary, cardiometabolic, and mental health and chronic pain multimorbidity. Once caught in the Multimorbidity Web, the consequences can be devastating, with reduced quality of life, physical function, survival, and treatment responses observed in multimorbid RA persons. The development of effective management and preventive approaches for multimorbidity in people with RA is in its infancy. Determining how best to assess, intervene, and prevent multimorbidity in RA is crucial to optimize long-term outcomes in people with RA.

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.

Elevations in adipocytokines and mortality in rheumatoid arthritis.

OBJECTIVES: This study assessed whether circulating levels of adiponectin and leptin are associated with higher mortality in patients with RA. METHODS: Participants were adults from the Veterans Affairs RA Registry. Adipokines and inflammatory cytokines were measured as part of a multi-analyte panel on banked serum at enrolment. Dates and causes of death were derived from the Corporate Data Warehouse and the National Death Index. Covariates were derived from medical record, biorepository and registry databases. Multivariable Cox proportional hazard models evaluated associations between biomarkers and all-cause and cause-specific mortality. RESULTS: A total of 2583 participants were included. Higher adiponectin levels were associated with older age, male sex, white race, lower BMI, autoantibody seropositivity, radiographic damage, longer disease duration, prednisone use and osteoporosis. Higher adiponectin concentrations were also associated with higher levels of inflammatory cytokines but not higher disease activity at enrolment. Leptin was primarily associated with greater BMI and comorbidity. The highest quartile of adiponectin (vs lowest quartile) was associated with higher all-cause mortality [hazard ratio (HR): 1.46 (95% CI: 1.11, 1.93), P = 0.009] and higher cardiovascular mortality [HR: 1.85 (95% CI: 1.24, 2.75), P = 0.003], after accounting for covariates. Higher leptin levels were also associated with greater all-cause and cancer mortality. CONCLUSIONS: Elevations in adipokines are associated with age, BMI, comorbidity and severe disease features in RA and independently predict early death. Associations between adiponectin and inflammatory cytokines support the hypothesis that chronic subclinical inflammation promotes metabolic changes that drive elevations in adipokines and yield adverse health outcomes.

The impact of disease severity measures on survival in U.S. veterans with rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: To determine whether RA and interstitial lung disease (ILD) severity measures are associated with survival in patients with RA-ILD. METHODS: We studied US veterans with RA-ILD participating in a multicentre, prospective RA cohort study. RA disease activity (28-joint DAS [DAS28-ESR]) and functional status (multidimensional HAQ [MDHAQ]) were collected longitudinally while pulmonary function tests (forced vital capacity [FVC], diffusing capacity for carbon monoxide) were obtained from medical records. Vital status and cause of death were determined from the National Death Index and administrative data. Predictors of death were assessed using multivariable Cox regression models adjusting for age, sex, smoking status, ILD duration, comorbidity burden and medications. RESULTS: We followed 227 RA-ILD participants (93% male and mean age of 69 years) over 1073 person-years. Median survival after RA-ILD diagnosis was 8.5 years. Respiratory diseases (28%) were the leading cause of death, with ILD accounting for 58% of respiratory deaths. Time-varying DAS28-ESR (adjusted hazard ratio [aHR] 1.21; 95% CI: 1.03, 1.41) and MDHAQ (aHR 1.85; 95% CI: 1.29, 2.65) were separately associated with mortality independent of FVC and other confounders. Modelled together, the presence of either uncontrolled disease activity (moderate/high DAS28-ESR) or FVC impairment (<80% predicted) was significantly associated with mortality risk. Those with a combination of moderate/high disease activity and FVC <80% predicted had the highest risk of death (aHR 4.43; 95% CI: 1.70, 11.55). CONCLUSION: Both RA and ILD disease severity measures are independent predictors of survival in RA-ILD. These findings demonstrate the prognostic value of monitoring the systemic features of RA-ILD.

Increased susceptibility to organic dust exposure-induced inflammatory lung disease with enhanced rheumatoid arthritis-associated autoantigen expression in HLA-DR4 transgenic mice.

Immunogenetic as well as environmental and occupational exposures have been linked to the development of rheumatoid arthritis (RA), RA-associated lung disease, and other primary lung disorders. Importantly, various inhalants can trigger post-translational protein modifications, resulting in lung autoantigen expression capable of stimulating pro-inflammatory and/or pro-fibrotic immune responses. To further elucidate gene-environment interactions contributing to pathologic lung inflammation, we exploited an established model of organic dust extract (ODE) exposure with and without collagen-induced arthritis (CIA) in C57BL/6 wild type (WT) versus HLA-DR4 transgenic mice. ODE-induced airway infiltration driven by neutrophils was significantly increased in DR4 versus WT mice, with corresponding increases in bronchoalveolar lavage fluid (BALF) levels of TNF-⍺, IL-6, and IL-33. Lung histopathology demonstrated increased number of ectopic lymphoid aggregates comprised of T and B cells following ODE exposure in DR4 mice. ODE also induced citrullination, malondialdehyde acetaldehyde (MAA) modification, and vimentin expression that co-localized with MAA and was enhanced in DR4 mice. Serum and BALF anti-MAA antibodies were strikingly increased in ODE-treated DR4 mice. Coupling ODE exposure with Type II collagen immunization (CIA) resulted in similarly augmented pro-inflammatory lung profiles in DR4 mice (relative to WT mice) that was accompanied by a profound increase in infiltrating lung CD4+ and CD8+ T cells as well as CD19+CD11b+ autoimmune B cells. Neither modeling strategy induced significant arthritis. These findings support a model in which environmental insults trigger enhanced post-translational protein modification and lung inflammation sharing immunopathological features with RA-associated lung disease in the selected immunogenetic background of HLA-DR4 mice.

Burden and trajectory of multimorbidity in rheumatoid arthritis: a matched cohort study from 2006 to 2015.

OBJECTIVES: To compare the onset and trajectory of multimorbidity between individuals with and without rheumatoid arthritis (RA). METHODS: A matched, retrospective cohort study was completed in a large, US commercial insurance database (MarketScan) from 2006 to 2015. Using validated algorithms, patients with RA (overall and incident) were age-matched and sex-matched to patients without RA. Diagnostic codes for 44 preidentified chronic conditions were selected to determine the presence (≥2 conditions) and burden (count) of multimorbidity. Cross-sectional comparisons were completed using the overall RA cohort and conditional logistic and negative binomial regression models. Trajectories of multimorbidity were assessed within the incident RA subcohort using generalised estimating equations. RESULTS: The overall cohort (n=277 782) and incident subcohort (n=61 124) were female predominant (76.5%, 74.1%) with a mean age of 55.6 years and 54.5 years, respectively. The cross-sectional prevalence (OR 2.29, 95% CI 2.25 to 2.34) and burden (ratio of conditions 1.68, 95% CI 1.66 to 1.70) of multimorbidity were significantly higher in RA than non-RA in the overall cohort. Within the incident RA cohort, patients with RA had more chronic conditions than non-RA (ß 1.13, 95% CI 1.10 to 1.17), and the rate of accruing chronic conditions was significantly higher in RA compared with non-RA (RA × follow-up year, ß 0.21, 95% CI 0.20 to 0.21, p<0.001). Results were similar when including the pre-RA period and in several sensitivity analyses. CONCLUSIONS: Multimorbidity is highly prevalent in RA and progresses more rapidly in patients with RA than in patients without RA during and immediately following RA onset. Therefore, multimorbidity should be aggressively identified and targeted early in the RA disease course.

Disease activity, cytokines, chemokines and the risk of incident diabetes in rheumatoid arthritis.

PURPOSE: Rheumatoid arthritis (RA) is associated with a higher risk of diabetes mellitus (DM). Our aim was to determine associations between inflammatory disease activity (including evaluation of specific cytokines and chemokines) and incident DM. METHODS: Participants were adults with physician-confirmed RA from Veteran's Affairs Rheumatoid Arthritis Registry. Disease activity and clinical assessments occur longitudinally as part of clinical care. Thirty cytokines and chemokines were measured in banked serum obtained at the time of enrolment. Cytokine/chemokine values were log-adjusted and standardised (per SD). Incident DM was defined based on validated algorithms using diagnostic codes and medications. Multivariable Cox proportional hazard models evaluated associations between clinical factors and incident DM. Independent associations between cytokines/chemokines and incident DM were assessed adjusting for age, sex, race, smoking, body mass index (BMI) and medication use at baseline. RESULTS: Among 1866 patients with RA without prevalent DM at enrolment, there were 130 incident cases over 9223 person-years of follow-up. High Disease Activity Score (DAS28)-C reactive protein (CRP), obese BMI, older age and male sex were associated with greater risk for incident DM while current smoking and methotrexate use were protective. Patients using methotrexate were at lower risk. Several cytokines/chemokines evaluated were independently associated (per 1 SD) with DM incidence including interleukin(IL)-1, IL-6 and select macrophage-derived cytokines/chemokines (HR range 1.11-1.26). These associations were independent of the DAS28-CRP. CONCLUSIONS: Higher disease activity and elevated levels of cytokines/chemokines are associated with a higher risk of incident DM in patients with RA. Future study may help to determine if targeted treatments in at-risk individuals could prevent the development of DM.

Investigating changes in disease activity as a mediator of cardiovascular risk reduction with methotrexate use in rheumatoid arthritis.

OBJECTIVE: Examine the association of methotrexate (MTX) use with cardiovascular disease (CVD) in rheumatoid arthritis (RA) using marginal structural models (MSM) and determine if CVD risk is mediated through modification of disease activity. METHODS: We identified incident CVD events (coronary artery disease (CAD), stroke, heart failure (HF) hospitalisation, CVD death) within a multicentre, prospective cohort of US Veterans with RA. A 28-joint Disease Activity Score with C-reactive protein (DAS28-CRP) was collected at regular visits and medication exposures were determined by linking to pharmacy dispensing data. MSMs were used to estimate the treatment effect of MTX on risk of incident CVD, accounting for time-varying confounders between receiving MTX and CVD events. A mediation analysis was performed to estimate the indirect effects of methotrexate on CVD risk through modification of RA disease activity. RESULTS: Among 2044 RA patients (90% male, mean age 63.9 years, baseline DAS28-CRP 3.6), there were 378 incident CVD events. Using MSM, MTX use was associated with a 24% reduced risk of composite CVD events (HR 0.76, 95% CI 0.58 to 0.99) including a 57% reduction in HF hospitalisations (HR 0.43, 95% CI 0.24 to 0.77). Individual associations with CAD, stroke and CVD death were not statistically significant. In mediation analyses, there was no evidence of indirect effects of MTX on CVD risk through disease activity modification (HR 1.03, 95% CI 0.80 to 1.32). CONCLUSIONS: MTX use in RA was associated with a reduced risk of CVD events, particularly HF-related hospitalisations. These associations were not mediated through reductions in RA disease activity, suggesting alternative MTX-related mechanisms may modify CVD risk in this population.

Applying SLICC and ACR/EULAR systemic lupus erythematosus classification criteria in a cohort of patients with undifferentiated connective tissue disease.

BACKGROUND/OBJECTIVE: New classification criteria for SLE have recently been developed. How these criteria affect the classification of patients with the SLE-mimicking condition UCTD is poorly understood. This study investigated the reclassification of UCTD patients using newly derived SLE criteria. METHODS: Patients with UCTD were identified within a single academic medical center using ICD9/10 codes. Medical record review was performed to confirm UCTD diagnosis and identify disease features present at diagnosis. The SLICC and ACR/EULAR criteria were applied, after which we compared the proportion of patients reclassified as SLE and determined which disease features were associated with reclassification. RESULTS: A total of 129 patients were included in the study. When applying the SLICC and ACR/EULAR criteria, 18 (14.0%) and 26 patients (20.2%) were reclassified as SLE. Comparison with McNemar's test trended toward statistical significance (p = 0.057). Cohen's kappa coefficient was 0.62 (p < 0.001), indicating substantial agreement between these criteria. Disease features associated with reclassification as SLE were renal involvement, leukopenia, thrombocytopenia, anti- dsDNA antibody, hypocomplementemia, non-scarring alopecia (SLICC), and arthritis (ACR/EULAR). CONCLUSIONS: Both the SLICC and ACR/EULAR criteria exhibit increased SLE classification. These newer classification criteria could be used to increase the number of SLE patients in future clinical studies.

Management issues in rheumatoid arthritis-associated interstitial lung disease.

PURPOSE OF REVIEW: Summarize recent evidence on the identification and management of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). RECENT FINDINGS: Clinical and subclinical interstitial lung disease (ILD) are frequent extra-articular manifestations of rheumatoid arthritis (RA). Better means of identifying and treating RA-ILD are needed to improve the prognosis, with a median survival of only 3-7 years after diagnosis. Several serum biomarkers are currently being evaluated for their ability to detect RA-ILD. Thorough evaluation and multidisciplinary discussion remains the gold standard for establishing the diagnosis of RA-ILD. Management is challenging with most RA disease-modifying antirheumatic drugs (DMARDs) linked to pneumonitis. Methotrexate is typically avoided in clinically significant ILD, although alternative therapies including leflunomide and biologic DMARDs also carry risks in RA-ILD. Antifibrotics appear to slow the progression of ILD, and a large phase II trial exclusively in RA-ILD is underway. In addition, smoking cessation, pulmonary rehabilitation, oxygen therapy, managing comorbidities, and lung transplantation evaluation are vital to improving patient outcomes in RA-ILD. SUMMARY: With little high-quality evidence to guide the management of RA-ILD, multidisciplinary teams with expertise in RA-ILD are highly valuable for diagnosing and treating RA-ILD. Clinical and translational research in RA-ILD is needed to fill the many evidence gaps.

Ultrasound Doppler and tenosynovial fluid analysis in tenosynovitis.

OBJECTIVE: To assess Doppler ultrasound (US) and tenosynovial fluid (TSF) characteristics in tenosynovitis within common rheumatic conditions, as well as their diagnostic utility. METHODS: Subjects with tenosynovitis underwent Doppler US and US-guided TSF aspiration for white cell count (WCC) and crystal analysis. Tenosynovial Doppler scores (DS) were semiquantitatively graded. TSF WCC and DS were compared using Kruskal-Wallis tests and logistic regression between non-inflammatory conditions (NIC), inflammatory conditions (IC) and crystal-related conditions (CRC). Receiver operating curves, sensitivity and specificity assessed the ability of WCC and DS to discriminate IC from NIC. RESULTS: We analysed 100 subjects from 14 sites. The mean age was 62 years, 65% were female, and the mean TSF volume was 1.2 mL. Doppler signal was present in 93.7% of the IC group and was more frequent in IC than in NIC group (OR 6.82, 95% CI 1.41 to 32.97). The TSF median WCC per 109/L was significantly higher in the IC (2.58, p<0.001) and CRC (1.07, p<0.01) groups versus the NIC group (0.38). A TSF cut-off of ≥0.67 WCC per 109/L optimally discriminated IC versus NIC with a sensitivity and specificity each of 81.3%. In the IC group, 20 of 48 (41.7%) subjects had a TSF WCC <2.00 per 109/L. CONCLUSIONS: A negative DS helps rule out IC in tenosynovitis, but a positive DS is non-specific and merits TSF testing. Unlike synovial fluid, a lower TSF WCC better discriminates IC from NIC. US guidance facilitates aspiration of minute TSF volume, which is critical for diagnosing tenosynovial CRC.

Current and early life weight and associations with mortality in rheumatoid arthritis.

OBJECTIVES: Obesity is paradoxically associated with a lower risk of mortality in chronic illnesses including rheumatoid arthritis (RA). Weight loss in patients with poor health, however, may in part explain this observation. This study evaluated the impact of weight early in life and weight loss on mortality in patients with RA. METHODS: Patients with RA (age >40 years) were active participants in a prospective clinical registry with up to 17 years of follow-up. Current and age-30 body mass index (BMI) were determined from self-report of height and weight from semi-annual questionnaires. Mortality was assessed from National Death Index. Risks of obesity reported from both early in life and at enrolment in the registry were evaluated using Cox proportional hazards models. RESULTS: Among 12,679 participants (80% female), there were 1,520 deaths in 80,502 person-years. Obesity at enrolment (BMI >30 kg/m2) was modestly associated with greater mortality [HR: 1.34 (1.18,1.53) p=0.001]. Adjusting for disability and comorbidities hypothesised to be mediators in the causal pathway between obesity and mortality further attenuated this association [HR: 0.92 (0.80,1.06) p=0.24]. In contrast, obesity at age 30 was strongly associated with mortality [HR: 2.00 (1.65,2.42) p<0.001]. Additionally, weight loss since age-30 was a strong, dose-dependent predictor of mortality independent of enrolment BMI. CONCLUSIONS: The risk of obesity is substantially underestimated when epidemiologic methods do not account for long-term weight changes. Both obesity and weight loss are strongly associated with mortality risk in patients with RA.

Body mass index and persistence of conventional DMARDs and TNF inhibitors in rheumatoid arthritis.

OBJECTIVES: Obese patients with rheumatoid arthritis (RA) may be more likely to discontinue therapy than non-obese patients, possibly signifying a more refractory phenotype. The purpose of this study was to examine the association between body mass index (BMI) and discontinuation rates for different RA treatments accounting for confounding factors. METHODS: Veterans Affairs administrative databases were used to define initial courses of methotrexate (MTX), hydroxychloroquine, sulfasalazine, prednisone, and self-injectable tumour necrosis factor inhibitors (TNFi). Discontinuation was defined as a lapse in drug refill >90 days. Using overweight BMI (25-30 kg/m2) as the referent group, multivariable Cox proportional hazards models were used to evaluate associations between BMI category and time to treatment discontinuation. RESULTS: There were 46,970 initial RA treatment courses identified from 2005-2014 among 23,669 Veterans with RA. In multivariable models, severe obesity (BMI >35 kg/m2), compared to overweight BMI, was not associated with treatment discontinuation with the exception of prednisone [HR 1.10 (1.04, 1.17) p<0.001]. Patients with low (<20 kg/m2) and normal BMI (20-25 kg/m2) were more likely to discontinue MTX, TNFi, and HCQ compared to overweight patients. Other factors associated with earlier MTX and/or TNFi discontinuation included female sex, black race, greater comorbidity, depression, malignancy, congestive heart failure, current smoking, and more recent calendar year. CONCLUSIONS: Obesity was not associated with therapy discontinuation among veterans with RA after accounting for confounding factors, suggesting that obesity is not a biological mediator of more refractory disease. Conversely, low BMI, comorbidity, and depression were identified as important predictors of drug discontinuation.