Publications by authors named "Ted R Mikuls"

264 Publications

The Safety and Immunologic Effectiveness of the Live Varicella-Zoster Vaccine in Patients Receiving Tumor Necrosis Factor Inhibitor Therapy : A Randomized Controlled Trial.

Ann Intern Med 2021 Sep 28. Epub 2021 Sep 28.

Oregon Health & Science University, Portland, Oregon (A.D., S.A.S., K.L.W.).

Background: The safety and effectiveness of live virus vaccines, such as the varicella-zoster vaccine, are unknown in patients with inflammatory diseases receiving immunomodulatory therapy such as tumor necrosis factor inhibitors (TNFis).

Objective: To evaluate the safety and immunogenicity of the live attenuated zoster vaccine (ZVL) in patients receiving TNFis.

Design: Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02538341).

Setting: Academic and community-based rheumatology, gastroenterology, and dermatology practices.

Patients: Adults aged 50 years or older receiving TNFis for any indication.

Intervention: Random assignment to ZVL versus placebo.

Measurements: Glycoprotein enzyme-linked immunosorbent assay (gpELISA) and enzyme-linked immunosorbent spot (ELISpot) from serum and peripheral blood mononuclear cells measured at baseline and 6 weeks after vaccination. Suspected varicella infection or herpes zoster was clinically assessed using digital photographs and polymerase chain reaction on vesicular fluid.

Results: Between March 2015 and December 2018, 617 participants were randomly assigned in a 1:1 ratio to receive ZVL ( = 310) or placebo ( = 307) at 33 centers. Mean age was 62.7 years (SD, 7.5); 66.1% of participants were female, 90% were White, 8.2% were Black, and 5.9% were Hispanic. The most common TNFi indications were rheumatoid arthritis (57.6%) and psoriatic arthritis (24.1%); TNFi medications were adalimumab (32.7%), infliximab (31.3%), etanercept (21.2%), golimumab (9.1%), and certolizumab (5.7%). Concomitant therapies included methotrexate (48.0%) and oral glucocorticoids (10.5%). Through week 6, no cases of confirmed varicella infection were found; cumulative incidence of varicella infection or shingles was 0.0% (95% CI, 0.0% to 1.2%). At 6 weeks, compared with baseline, the mean increases in geometric mean fold rise as measured by gpELISA and ELISpot were 1.33 percentage points (CI, 1.17 to 1.51 percentage points) and 1.39 percentage points (CI, 1.07 to 1.82 percentage points), respectively.

Limitation: Potentially limited generalizability to patients receiving other types of immunomodulators.

Conclusion: This trial informs safety concerns related to use of live virus vaccines in patients receiving biologics.

Primary Funding Source: The National Institute of Arthritis and Musculoskeletal and Skin Diseases and the American College of Rheumatology.
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http://dx.doi.org/10.7326/M20-6928DOI Listing
September 2021

Evaluating associations of joint swelling, joint stiffness and joint pain with physical activity in first-degree relatives of patients with rheumatoid arthritis: Studies of the Aetiology of Rheumatoid Arthritis (SERA), a prospective cohort study.

BMJ Open 2021 Sep 14;11(9):e050883. Epub 2021 Sep 14.

Department of Epidemiology, Colorado School of Public Health, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, USA.

Objective: Physical activity (PA) in preclinical rheumatoid arthritis (RA) is associated with lower RA risk and disease severity. As joint signs and symptoms of inflammatory arthritis serve as a barrier to PA in RA, it is important to consider whether they affect PA in the time prior to RA. Therefore, we investigated whether joint swelling, stiffness or pain were associated with PA in first-degree relatives (FDRs) of patients with RA, a population at higher risk for future RA.

Design: Prospective study design.

Setting: We recruited FDRs of patients with RA from academic centres, Veterans' hospitals and rheumatology clinics or through responses to advertising from six sites across the USA.

Participants: We evaluated associations of joint stiffness, joint swelling and joint pain with PA time in 268 FDRs with ≥2 visits over an average 1.2 years. Clinicians confirmed joint swelling. Participants self-reported joint stiffness and/or pain.

Primary Outcome Measures: PA during a typical 24-hour day was quantified via questionnaire, weighted to reflect metabolic expenditure, where 24 hours was the minimum PA time. Linear mixed models evaluated associations between symptoms and change in PA over time, adjusting for age, sex, race, body mass index, smoking and RA-related autoantibodies.

Results: Average weighted PA time was 37±7 hours. In the cross-sectional analysis, PA time was 1.3±0.9 hours higher in FDRs reporting joint pain (p=0.15); and 0.8±1.6 and 0.4±1 hours lower in FDRs with joint swelling (p=0.60) and stiffness (p=0.69), respectively. Longitudinally, adjusting for baseline PA time, baseline symptoms were not significantly associated with changes in PA time. However, on average over time, joint stiffness and pain were associated with lower PA time (p=0.0002, p=0.002), and joint swelling was associated with higher PA time (p <0.0001).

Conclusion: Baseline symptoms did not predict future PA time, but on average over time, joint symptoms influenced PA time.
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http://dx.doi.org/10.1136/bmjopen-2021-050883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442039PMC
September 2021

The impact of airborne endotoxin exposure on rheumatoid arthritis-related joint damage, autoantigen expression, autoimmunity, and lung disease.

Int Immunopharmacol 2021 Aug 27;100:108069. Epub 2021 Aug 27.

Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address:

Airborne biohazards are risk factors in the development and severity of rheumatoid arthritis (RA) and RA-associated lung disease, yet the mechanisms explaining this relationship remain unclear. Lipopolysaccharide (LPS, endotoxin) is a ubiquitous inflammatory agent in numerous environmental and occupational air pollutant settings recognized to induce airway inflammation. Combining repetitive LPS inhalation exposures with the collagen induced arthritis (CIA) model, DBA1/J mice were assigned to either: sham (saline injection/saline inhalation), CIA (CIA/saline), LPS (saline/LPS 100 ng inhalation), or CIA + LPS for 5 weeks. Serum anti-citrullinated (CIT) protein antibody (ACPA) and anti-malondialdehyde-acetaldehyde (MAA) antibodies were strikingly potentiated with co-exposure (CIA + LPS). CIT- and MAA-modified lung proteins were increased with co-exposure and co-localized across treatment groups. Inhaled LPS exacerbated arthritis with CIA + LPS > LPS > CIA versus sham. Periarticular bone loss was demonstrated in CIA and CIA + LPS but not in LPS alone. LPS induced airway inflammation and neutrophil infiltrates were reduced with co-exposure (CIA + LPS). Potentially signaling transition to pro-fibrotic processes, there were increased infiltrates of activated CD11cCD11b macrophages and transitioning CD11cCD11b monocyte-macrophage populations with CIA + LPS. Moreover, several lung remodeling proteins including fibronectin and matrix metalloproteinases as well as complement C5a were potentiated with CIA + LPS compared to other treatment groups. IL-33 concentrations in lung homogenates were enhanced with CIA + LPS with IL-33 lung staining driven by LPS. IL-33 expression was also significantly increased in lung tissues from patients with RA-associated lung disease (N = 8) versus controls (N = 7). These findings suggest that patients with RA may be more susceptible to developing interstitial lung disease following airborne biohazard exposures enriched in LPS.
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http://dx.doi.org/10.1016/j.intimp.2021.108069DOI Listing
August 2021

Vehicle Control as a Measure of Real-World Driving Performance in Patients with Rheumatoid Arthritis.

Arthritis Care Res (Hoboken) 2021 Aug 16. Epub 2021 Aug 16.

Department of Neurological Sciences, University of Nebraska Medical Center, Omaha.

Objective: To quantify vehicle control as a metric of automobile driving performance in patients with rheumatoid arthritis (RA).

Methods: Naturalistic driving assessments were completed in patients with active RA and controls without disease. Data were collected using in-car, sensor-based instrumentation installed in the participants' own vehicles to observe typical driving habits. RA disease status, disease activity, and functional status were associated with vehicle control (lateral [steering] and longitudinal [braking/accelerating] acceleration variability [AV]) using mixed-effect linear regression models stratified by road type (defined by roadway speed limit).

Results: Across 1,292 driving hours, RA drivers (n=33) demonstrated differences in vehicle control compared to controls (n=23) with evidence of significant statistical interaction between disease status and road type (p<0.001). On residential roads, participants with RA demonstrated overall lower braking/accelerating variability than controls (p≤0.004) and, when disease activity was low, lower steering variability (p=0.03). On interstates/highways, RA was associated with increased steering variability among those with moderate/high CDAI scores (p=0.04). In models limited to RA, increases in disease activity and physical disability over 12-weeks of observation were associated with a significant increase in braking/accelerating variability on interstate/highways (both p<0.05).

Conclusions: Using novel naturalistic assessments, we linked RA and worsening RA disease severity with aberrant vehicle control. These findings support the need for further research to map these observed patterns in vehicle control to metrics of driver risk, and, in turn, to link patterns of real-world driving behavior to diagnosis and disease activity.
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http://dx.doi.org/10.1002/acr.24769DOI Listing
August 2021

American College of Rheumatology Guidance for COVID-19 Vaccination in Patients With Rheumatic and Musculoskeletal Diseases: Version 3.

Arthritis Rheumatol 2021 10 4;73(10):e60-e75. Epub 2021 Aug 4.

University of Nebraska Medical Center and VA Nebraska-Western Iowa Health Care System, Omaha.

Objective: To provide guidance to rheumatology providers on the use of coronavirus disease 2019 (COVID-19) vaccines for patients with rheumatic and musculoskeletal diseases (RMDs).

Methods: A task force was assembled that included 9 rheumatologists/immunologists, 2 infectious disease specialists, and 2 public health physicians. After agreeing on scoping questions, an evidence report was created that summarized the published literature and publicly available data regarding COVID-19 vaccine efficacy and safety, as well as literature for other vaccines in RMD patients. Task force members rated their agreement with draft consensus statements on a 9-point numerical scoring system, using a modified Delphi process and the RAND/University of California Los Angeles Appropriateness Method, with refinement and iteration over 2 sessions. Consensus was determined based on the distribution of ratings.

Results: Despite a paucity of direct evidence, 74 draft guidance statements were developed by the task force and agreed upon with consensus to provide guidance for use of the COVID-19 vaccines in RMD patients and to offer recommendations regarding the use and timing of immunomodulatory therapies around the time of vaccination.

Conclusion: These guidance statements, made in the context of limited clinical data, are intended to provide direction to rheumatology health care providers on how to best use COVID-19 vaccines and to facilitate implementation of vaccination strategies for RMD patients.
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http://dx.doi.org/10.1002/art.41928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426685PMC
October 2021

Influence of Multimorbidity on New Treatment Initiation and Achieving Target Disease Activity Thresholds in Active Rheumatoid Arthritis: A Cohort Study Using the Rheumatology Informatics System for Effectiveness (RISE) Registry.

Arthritis Care Res (Hoboken) 2021 Aug 2. Epub 2021 Aug 2.

University of Alabama at Birmingham, Birmingham, AL, USA.

Objective: To determine whether multimorbidity is associated with treatment changes and achieving target disease activity thresholds in patients with active rheumatoid arthritis (RA).

Methods: We conducted a retrospective cohort study of adults with active RA within the Rheumatology Informatics System for Effectiveness (RISE) registry. Multimorbidity was measured using RxRisk, a medication-based index of chronic disease. We used multivariable logistic regression models to assess the associations of multimorbidity with the odds of initiating a new DMARD in active RA and, among those initiating a new DMARD, the odds of achieving low disease activity or remission.

Results: We identified 15,626 (RAPID3 cohort) and 5,733 (CDAI cohort) patients with active RA, of which 1,558 (RAPID3) and 834 (CDAI) initiated a new DMARD and had follow-up disease activity measures. Patients were middle aged, female and Caucasian predominant, and on average received medications from 6-7 RxRisk categories. Multimorbidity was not associated with new DMARD initiation in active RA. However, a greater burden of multimorbidity was associated with lower odds of achieving treatment targets (per 1-unit RxRisk OR 0.95 [95% CI 0.91-0.98] RAPID3 cohort; OR 0.94 [95% CI 0.90-0.99] CDAI cohort). Those with the highest burden of multimorbidity had the lowest odds of achieving target RA disease activity (OR 0.54 [0.34-0.85] RAPID3 cohort; OR 0.65 [0.37-1.15] CDAI cohort).

Conclusions: These findings from a large, real-world registry illustrate the potential impact of multimorbidity on treatment response and indicate that a more holistic management approach targeting multimorbidity may be needed to optimize RA disease control in these patients.
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http://dx.doi.org/10.1002/acr.24762DOI Listing
August 2021

Combinations of Anticyclic Citrullinated Protein Antibody, Rheumatoid Factor, and Serum Calprotectin Positivity Are Associated With the Diagnosis of Rheumatoid Arthritis Within 3 Years.

ACR Open Rheumatol 2021 Oct 20;3(10):684-689. Epub 2021 Jul 20.

University of Colorado, Aurora, Colorado.

Objective: To evaluate the prevalence of elevations of anti-cyclic citrullinated peptide-3 (anti-CCP3) antibody, rheumatoid factor IgM (RF-IgM) and serum calprotectin (sCP) in pre-rheumatoid arthritis (RA) as well as the diagnostic accuracies of these biomarkers for the timing of diagnosis of future RA.

Methods: A total of 215 RA cases, each with approximately three pre-RA diagnoses and one post-RA diagnosis serum sample, and controls were identified from the Department of Defense Serum Repository. All case samples and a single sample from each control subject were tested for anti-CCP3 (IgG), RF-IgM, and sCP. The diagnostic accuracies of biomarkers for future RA were evaluated.

Results: Anti-CCP3, RF-IgM, and sCP were elevated in pre-RA, with anti-CCP3 and sCP significantly elevated compared with RF-IgM at the earliest time points. Within the cases, the combination of anti-CCP3 and RF-IgM positivity had a positive predictive value (PPV) of 35.6% for a diagnosis of RA in 3 years or less, which is significantly higher than the PPV of 18.7% for anti-CCP3 positivity alone (P < 0.001). A combination of anti-CCP3, RF-IgM, and sCP had the highest PPV (53.0%) for a diagnosis of RA in 3 years or less; however, this was not significantly higher than the PPV for anti-CCP3 and RF-IgM positivity (P = 0.248).

Conclusion: Anti-CCP3, RF-IgM, and sCP are elevated in pre-RA; furthermore, combinations of elevations of these biomarkers are more commonly seen in the period of less than or equal to 3 years to diagnosis. This may be considered in creating inclusion criteria in prevention trials in RA. In addition, the biologic relationships of these biomarkers in pre-RA need exploration.
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http://dx.doi.org/10.1002/acr2.11309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516104PMC
October 2021

Reply.

Arthritis Care Res (Hoboken) 2021 Jul 20. Epub 2021 Jul 20.

McMaster University, Hamilton, Ontario, Canada.

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http://dx.doi.org/10.1002/acr.24753DOI Listing
July 2021

American College of Rheumatology Guidance for COVID-19 Vaccination in Patients With Rheumatic and Musculoskeletal Diseases: Version 2.

Arthritis Rheumatol 2021 08 15;73(8):e30-e45. Epub 2021 Jun 15.

University of Nebraska Medical Center and VA Nebraska-Western Iowa Health Care System, Omaha.

Objective: To provide guidance to rheumatology providers on the use of coronavirus disease 2019 (COVID-19) vaccines for patients with rheumatic and musculoskeletal diseases (RMDs).

Methods: A task force was assembled that included 9 rheumatologists/immunologists, 2 infectious disease specialists, and 2 public health physicians. After agreeing on scoping questions, an evidence report was created that summarized the published literature and publicly available data regarding COVID-19 vaccine efficacy and safety, as well as literature for other vaccines in RMD patients. Task force members rated their agreement with draft consensus statements on a 9-point numerical scoring system, using a modified Delphi process and the RAND/University of California Los Angeles Appropriateness Method, with refinement and iteration over 2 sessions. Consensus was determined based on the distribution of ratings.

Results: Despite a paucity of direct evidence, 74 draft guidance statements were developed by the task force and agreed upon with consensus to provide guidance for use of the COVID-19 vaccines in RMD patients and to offer recommendations regarding the use and timing of immunomodulatory therapies around the time of vaccination.

Conclusion: These guidance statements, made in the context of limited clinical data, are intended to provide direction to rheumatology health care providers on how to best use COVID-19 vaccines and to facilitate implementation of vaccination strategies for RMD patients.
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http://dx.doi.org/10.1002/art.41877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427105PMC
August 2021

Gout Flare Burden, Diagnosis, and Management: Navigating Care in Older Patients with Comorbidity.

Drugs Aging 2021 07 9;38(7):545-557. Epub 2021 Jun 9.

Division of Rheumatology, Department of Internal Medicine, University of Nebraska Medical Center, 986270 Nebraska Medical Center, Omaha, NE, 68198-6270, USA.

Gout is the most common form of inflammatory arthritis, and its incidence is highest in middle-aged and older patients. Adding to the diagnostic complexity, up to 50% of patients aged > 65 years present atypically, with subacute oligo- or polyarticular flares. Comorbidity and polypharmacy, common in older populations, affect real-world treatment decisions in gout management, and no specific guidelines are available to address these issues in these at-risk groups. Despite the growing public health burden posed by gout, suboptimal management has led to increased morbidity and substantial healthcare utilization and cost burden, as reflected by an increased incidence of emergency department visits and hospitalizations in recent years. Colchicine, nonsteroidal anti-inflammatory drugs, or glucocorticoids (oral, intraarticular, or intramuscular) should be considered as first-line agents for gout flare management. Urate-lowering therapy, with the goal of lowering and maintaining serum urate concentrations at < 6 mg/dL (< 360 μmol/L), is recommended to achieve optimal outcomes, including regression of tophi, reduction (or elimination) of flares, and reductions in total urate burden. In this review, we summarize the current burden posed by gout and discuss best practices in its diagnosis and management, focusing on best practices in the context of gout flare in older patients with comorbid conditions.
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http://dx.doi.org/10.1007/s40266-021-00866-2DOI Listing
July 2021

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

Ann Rheum Dis 2021 Nov 28;80(11):1385-1392. Epub 2021 May 28.

Medicine & Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA

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.
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http://dx.doi.org/10.1136/annrheumdis-2021-220125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516691PMC
November 2021

Reply.

Arthritis Rheumatol 2021 09 16;73(9):1769-1770. Epub 2021 Jul 16.

University of Nebraska Medical Center and VA Nebraska-Western Iowa Health Care System, Omaha, NE.

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http://dx.doi.org/10.1002/art.41805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239631PMC
September 2021

Risk of COVID-19 in Rheumatoid Arthritis: A National Veterans Affairs Matched Cohort Study in At-Risk Individuals.

Arthritis Rheumatol 2021 May 5. Epub 2021 May 5.

VA Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha.

Objective: Rheumatoid arthritis (RA) and its treatments are associated with an increased risk of infection, but it remains unclear whether these factors have an impact on the risk or severity of COVID-19. The present study was undertaken to assess the risk and severity of COVID-19 in a US Department of Veterans Affairs (VA) cohort of patients with RA and those without RA.

Methods: A matched cohort study using national VA data was conducted. Patients diagnosed as having RA were identified among nondeceased individuals who were active in the VA health care system as of January 1, 2020 and who had received care in a VA medical center in 2019; patients for whom no RA diagnostic code was indicated were matched to the RA patients (1:1) by age, sex, and VA site (non-RA controls). Patients diagnosed as having COVID-19 and those with severe COVID-19 (defined as requiring hospitalization or leading to death) were ascertained from a national VA COVID-19 surveillance database through December 10, 2020. Multivariable Cox models were used to compare the risk of COVID-19 and COVID-19 hospitalization or death between RA patients and non-RA controls, after adjusting for demographic characteristics, comorbidities, health care utilization and access, and county-level COVID-19 incidence rates.

Results: This VA cohort of RA patients and non-RA controls (n = 33,886 subjects per group) predominantly comprised male patients (84.5%), and the mean age was 67.8 years. During follow-up, 1,503 patients in the cohort were diagnosed as having COVID-19; among them, 388 patients had severe COVID-19 (hospitalization or death), while in 228 patients, the deaths were not related to COVID-19. In the multivariable model, RA was associated with a higher risk of COVID-19 (adjusted hazard ratio [HR] 1.25 [95% confidence interval (95% CI) 1.13-1.39]) and a higher risk of COVID-19 hospitalization or death (adjusted HR 1.35 [95% CI 1.10-1.66]) as compared to non-RA controls. Use of disease-modifying antirheumatic drugs and prednisone, as well as self-reported Black race, self-reported Hispanic ethnicity, and presence of several chronic conditions, but not seropositivity for RA autoantibodies, were each associated with risk of COVID-19 and severe COVID-19 (hospitalization or death).

Conclusion: Patients with RA are at higher risk of developing COVID-19 and severe COVID-19 (leading to hospitalization or death) compared to those without RA. With a risk of COVID-19 that approaches that of other recognized chronic conditions, these findings suggest that RA patients should be prioritized for COVID-19 prevention and management strategies.
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http://dx.doi.org/10.1002/art.41800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239709PMC
May 2021

Associations of serum cytokines and chemokines with the risk of incident cancer in a prospective rheumatoid arthritis cohort.

Int Immunopharmacol 2021 Aug 29;97:107719. Epub 2021 Apr 29.

VA Nebraska-Western Iowa Healthcare System, Omaha, NE, USA; Division of Rheumatology & Immunology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.

Objectives: We aimed to assess whether serum cytokine/chemokine concentrations predict incident cancer in RA patients.

Methods: Data from cancer-free enrollees in the Veterans Affairs Rheumatoid Arthritis (VARA) Registry were linked to a national VA oncology database and the National Death Index (NDI) to identify incident cancers. Seventeen serum cytokines/chemokines were measured from enrollment serum and an overall weighted cytokine/chemokine score (CK score) was calculated. Associations of cytokines/chemokines with all-site, lung, and lymphoproliferative cancers were assessed in Cox regression models accounting for relevant covariates including age, sex, RA disease activity, and smoking.

Results: In 1216 patients, 146 incident cancers (42 lung and 23 lymphoproliferative cancers) occurred over 10,072 patient-years of follow-up with a median time of 4.6 years from enrollment (cytokine/chemokine measurement) to cancer incidence. In fully adjusted models, CK score was associated with a higher risk of all-site (aHR 1.32, 95% CI 1.01-1.71, p < 0.001), lung (aHR 1.81, 1.40-2.34, p = 0.001), and lung/lymphoproliferative (aHR 1.54 [1.35-1.75], p < 0.001) cancer. The highest quartile of CK score was associated with a higher risk of all-site (aHR 1.91, 0.96-3.81, p = 0.07; p-trend = 0.005), lung (aHR 8.18, 1.63-41.23, p = 0.01; p-trend < 0.001), and lung/lymphoproliferative (aHR 4.56 [1.84-11.31], p = 0.001; p-trend < 0.001) cancer. Thirteen of 17 individual analytes were associated with incident cancer risk.

Conclusion: Elevated cytokine/chemokine concentrations are predictive of future cancer in RA patients, particularly lung and lymphoproliferative cancers. These results suggest that the measurement of circulating cytokines/chemokines could be informative in cancer risk stratification and could provide insight into future cancer prevention strategies in RA, and possibly individuals without RA.
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http://dx.doi.org/10.1016/j.intimp.2021.107719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324526PMC
August 2021

Performance of a commercially available multiplex platform in the assessment of circulating cytokines and chemokines in patients with rheumatoid arthritis and osteoarthritis.

J Immunol Methods 2021 08 30;495:113048. Epub 2021 Apr 30.

University of Nebraska Medical Center (UNMC) Department of Internal Medicine, Division of Rheumatology, Omaha, NE, United States of America; Veterans Affairs (VA) Nebraska-Western Iowa Health Care System, Omaha, NE, United States of America. Electronic address:

Background/objective: Cytokines and chemokines (cytokines) are central to rheumatoid arthritis (RA) pathogenesis, with increasing use of multiplex immunoassays in clinical/research settings. Rheumatoid factor (RF) may interfere with assay outcomes by nonspecifically binding detection analytes. We evaluated the performance of a commercially available multiplex platform, including assessment of the impact of RF depletion.

Methods: Forty-five cytokines were tested using Meso Scale Discovery V-PLEX™ and samples from 40 RA and 40 osteoarthritis (OA) patients. Select samples were depleted of RF using a commercial binder. Performance was assessed using intra-assay coefficients of variation (CV), intraclass correlation coefficients (ICC), percent change following RF depletion, and disease discrimination. Values above or below quantification thresholds were imputed.

Results: Of the 45 cytokines analyzed, 31 yielded CVs <10%; none demonstrated CVs >30%. ICCs universally exceeded 0.85 with the exception of eight analytes. RF depletion altered cytokine values by <15% for 40 analytes with larger changes (>30%) only seen for one analyte. Twenty-three cytokines differed significantly based on measurement in plasma vs. serum. Three analytes were higher in the serum of RA vs. OA (IL-10, IP-10, TNFα), and none were significantly greater in OA vs. RA. Seventeen analytes required imputation for >50% of the samples tested, primarily related to concentrations below the lower limit of quantification threshold.

Conclusion: The results from this commercially available multiplex assay were generally highly reproducible and interference induced by RF only meaningfully impacted the quantification of five of the analytes examined.
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http://dx.doi.org/10.1016/j.jim.2021.113048DOI Listing
August 2021

American College of Rheumatology Guidance for COVID-19 Vaccination in Patients With Rheumatic and Musculoskeletal Diseases: Version 1.

Arthritis Rheumatol 2021 07 24;73(7):1093-1107. Epub 2021 May 24.

University of Nebraska Medical Center and VA Nebraska-Western Iowa Health Care System, Omaha.

Objective: To provide guidance to rheumatology providers on the use of coronavirus disease 2019 (COVID-19) vaccines for patients with rheumatic and musculoskeletal diseases (RMDs).

Methods: A task force was assembled that included 9 rheumatologists/immunologists, 2 infectious disease specialists, and 2 public health physicians. After agreeing on scoping questions, an evidence report was created that summarized the published literature and publicly available data regarding COVID-19 vaccine efficacy and safety, as well as literature for other vaccines in RMD patients. Task force members rated their agreement with draft consensus statements on a 9-point numerical scoring system, using a modified Delphi process and the RAND/University of California Los Angeles Appropriateness Method, with refinement and iteration over 2 sessions. Consensus was determined based on the distribution of ratings.

Results: Despite a paucity of direct evidence, 74 draft guidance statements were developed by the task force and agreed upon with consensus to provide guidance for use of the COVID-19 vaccines in RMD patients and to offer recommendations regarding the use and timing of immunomodulatory therapies around the time of vaccination.

Conclusion: These guidance statements, made in the context of limited clinical data, are intended to provide direction to rheumatology health care providers on how to best use COVID-19 vaccines and to facilitate implementation of vaccination strategies for RMD patients.
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http://dx.doi.org/10.1002/art.41734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250724PMC
July 2021

Response to: 'Correspondence on 'Disease activity, cytokines, chemokines and the risk of incident diabetes in rheumatoid arthritis'' by Ruscitti .

Ann Rheum Dis 2021 Feb 22. Epub 2021 Feb 22.

Department of Medicine, University of Nebraska System, Lincoln, Nebraska, USA.

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http://dx.doi.org/10.1136/annrheumdis-2021-220114DOI Listing
February 2021

High-throughput analysis of lung immune cells in a combined murine model of agriculture dust-triggered airway inflammation with rheumatoid arthritis.

PLoS One 2021 12;16(2):e0240707. Epub 2021 Feb 12.

Division of Allergy and Immunology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States of America.

Rheumatoid arthritis (RA)-associated lung disease is a leading cause of mortality in RA, yet the mechanisms linking lung disease and RA remain unknown. Using an established murine model of RA-associated lung disease combining collagen-induced arthritis (CIA) with organic dust extract (ODE)-induced airway inflammation, differences among lung immune cell populations were analyzed by single cell RNA-sequencing. Additionally, four lung myeloid-derived immune cell populations including macrophages, monocytes/macrophages, monocytes, and neutrophils were isolated by fluorescence cell sorting and gene expression was determined by NanoString analysis. Unsupervised clustering revealed 14 discrete clusters among Sham, CIA, ODE, and CIA+ODE treatment groups: 3 neutrophils (inflammatory, resident/transitional, autoreactive/suppressor), 5 macrophages (airspace, differentiating/recruited, recruited, resident/interstitial, and proliferative airspace), 2 T-cells (differentiating and effector), and a single cluster each of inflammatory monocytes, dendritic cells, B-cells and natural killer cells. Inflammatory monocytes, autoreactive/suppressor neutrophils, and recruited/differentiating macrophages were predominant with arthritis induction (CIA and CIA+ODE). By specific lung cell isolation, several interferon-related and autoimmune genes were disproportionately expressed among CIA and CIA+ODE (e.g. Oasl1, Oas2, Ifit3, Gbp2, Ifi44, and Zbp1), corresponding to RA and RA-associated lung disease. Monocytic myeloid-derived suppressor cells were reduced, while complement genes (e.g. C1s1 and Cfb) were uniquely increased in CIA+ODE mice across cell populations. Recruited and inflammatory macrophages/monocytes and neutrophils expressing interferon-, autoimmune-, and complement-related genes might contribute towards pro-fibrotic inflammatory lung responses following airborne biohazard exposures in setting of autoimmune arthritis and could be predictive and/or targeted to reduce disease burden.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240707PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880471PMC
July 2021

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

Ann Rheum Dis 2021 05 4;80(5):566-572. Epub 2021 Jan 4.

Department of Medicine, University of Nebraska System, Lincoln, Nebraska, USA.

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.
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http://dx.doi.org/10.1136/annrheumdis-2020-219140DOI Listing
May 2021

Association of Lipid Mediators With Development of Future Incident Inflammatory Arthritis in an Anti-Citrullinated Protein Antibody-Positive Population.

Arthritis Rheumatol 2021 06 23;73(6):955-962. Epub 2021 Apr 23.

Colorado School of Public Health, Aurora.

Objective: To determine the association of polyunsaturated fatty acid (PUFA)-derived lipid mediators with progression from rheumatoid arthritis (RA)-related autoimmunity to inflammatory arthritis (IA).

Methods: We conducted a prospective cohort study using data from the Studies of the Etiology of Rheumatoid Arthritis (SERA). SERA enrolled first-degree relatives (FDRs) of individuals with RA (FDR cohort) and individuals who screened positive for RA-related autoantibodies at health fairs (screened cohort). We followed up 133 anti-cyclic citrullinated peptide 3.1 (anti-CCP3.1)-positive participants, 29 of whom developed IA. Lipid mediators selected a priori were quantified from stored plasma samples using liquid chromatography tandem mass spectrometry. We fit multivariable Cox proportional hazards models for each lipid mediator as a time-varying variable. For lipid mediators found to be significantly associated with IA, we then examined interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor (TNF) as potential statistical mediators.

Results: For every 1 natural log pg/ml increase in the circulating plasma levels of proinflammatory 5-HETE, the risk of developing IA increased by 241% (hazard ratio 2.41 [95% confidence interval 1.43-4.07]) after adjusting for age at baseline, cohort (FDR or screened), and shared epitope status. The models examining 15-HETE and 17-HDHA had the same trend but did not reach significance. We did not find evidence that the association between 5-HETE and IA risk was influenced by the proinflammatory cytokines tested.

Conclusion: In a prospective cohort of anti-CCP-positive individuals, higher levels of 5-HETE, an important precursor to proinflammatory leukotrienes, is associated with subsequent IA. Our findings highlight the potential significance of these PUFA metabolites in pre-RA populations.
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http://dx.doi.org/10.1002/art.41631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169523PMC
June 2021

Associations between an expanded autoantibody profile and treatment responses to biologic therapies in patients with rheumatoid arthritis.

Int Immunopharmacol 2021 Feb 23;91:107260. Epub 2020 Dec 23.

University of Nebraska Medical Center & VA Nebraska-Western Iowa Health Care System, 986270 Nebraska Medical Center, Omaha, NE 68198-6270, United States. Electronic address:

Background: Although biologics represent a major advance in rheumatoid arthritis (RA), many patients fail to achieve adequate responses to these agents. We examined whether combined positivity to three well-characterized autoantibodies predicts treatment response among RA patients initiating biologics.

Methods: The study included biologic-naïve patients initiating anti-TNF treatment, biologic-exposed patients switching to rituximab or tocilizumab, and patients (biologic naïve or exposed) initiating abatacept. Rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP) antibody, and IgG antibodies to malondialdehyde-acetaldehyde (MAA) were measured using banked enrollment serum. The relationship between the number of autoantibodies positive (0-3) and treatment response (absolute improvement in 28-joint Disease Activity Score [DAS28-CRP] or improvement > 1.2) at 6 months was examined using multivariable linear and logistic regression.

Results: Of 1,229 patients initiating biologics, 79% were women; 89% were Caucasian. The number of baseline RA-related autoantibodies positive was associated with improved treatment response in a dose-dependent fashion. Compared to patients seronegative for all autoantibodies, adjusting for covariates, those positive for all three were more than twice (OR 2.35; 95% CI 1.57-3.51) as likely to achieve DAS28 improvement > 1.2 units. Associations of autoantibody positivity with biologic treatment response were strongest for anti-CCP antibody, persisted in analyses limited to biologic naïve patients, and did not appear to differ markedly among different agents examined.

Conclusion: An expanded autoantibody profile appears to significantly predict RA treatment response to biologic treatment in a dose-dependent fashion. Incorporating these serologic profiles with additional biomarkers or other informative patient characteristics could provide an opportunity to personalize RA management.
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http://dx.doi.org/10.1016/j.intimp.2020.107260DOI Listing
February 2021

American College of Rheumatology Guidance for the Management of Rheumatic Disease in Adult Patients During the COVID-19 Pandemic: Version 3.

Arthritis Rheumatol 2021 02 5;73(2):e1-e12. Epub 2020 Dec 5.

University of Alabama at Birmingham.

Objective: To provide guidance to rheumatology providers on the management of adult rheumatic disease in the context of the coronavirus disease 2019 (COVID-19) pandemic.

Methods: A task force, including 10 rheumatologists and 4 infectious disease specialists from North America, was convened. Clinical questions were collated, and an evidence report was rapidly generated and disseminated. Questions and drafted statements were reviewed and assessed using a modified Delphi process. This included asynchronous anonymous voting by email and webinars with the entire panel. Task force members voted on agreement with draft statements using a 1-9-point numerical scoring system, and consensus was determined to be low, moderate, or high based on the dispersion of votes. For approval, median votes were required to meet predefined levels of agreement (median values of 7-9, 4-6, and 1-3 defined as agreement, uncertainty, or disagreement, respectively) with either moderate or high levels of consensus.

Results: Draft guidance statements approved by the task force have been combined to form final guidance.

Conclusion: These guidance statements are provided to promote optimal care during the current pandemic. However, given the low level of available evidence and the rapidly evolving literature, this guidance is presented as a "living document," and future updates are anticipated.
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http://dx.doi.org/10.1002/art.41596DOI Listing
February 2021

Relationship Between Depression and Disease Activity in United States Veterans With Early Rheumatoid Arthritis Receiving Methotrexate.

J Rheumatol 2021 06 15;48(6):813-820. Epub 2020 Nov 15.

M.C.Hochberg, MD, MPH, Department of Epidemiology and Public Health, and Department of Medicine, University of Maryland Baltimore, School of Medicine, and VA Maryland Health Care System, Baltimore, Maryland, USA.

Objective: Depression is common in patients with rheumatoid arthritis (RA), exacerbates disease activity, and may decrease response to first-line disease-modifying antirheumatic drugs. This study aimed to determine if depression affects disease activity among veterans with early RA prescribed methotrexate (MTX).

Methods: Participants included veterans enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry with early RA (onset < 2 yrs) prescribed MTX. Depression was assessed at enrollment using the International Classification of Diseases, 9th revision codes (296.2-296.39, 300.4, 311). Disease activity was measured using the Disease Activity Score in 28 joints (DAS28) and other core measures of RA disease activity. Propensity score weights were used to adjust depressed (n = 48) and nondepressed (n = 220) patients on baseline confounders within imputed datasets. Weighted estimating equations were used to assess standardized mean differences in disease activity between depressed and nondepressed patients at 6-month, 1-year, and 2-year follow-ups.

Results: The analytic sample was composed of 268 veterans with early RA prescribed MTX who were predominantly male (n = 239, 89.2%) and older (62.7 yrs, SD 10.6) than patients with RA in the general population. Adjusted estimates indicated that depression was associated with significantly higher DAS28 at 6 months (β 0.35, 95% CI 0.01-0.68) but not at the 1- or 2-year follow-up. Also, depression was associated with significantly worse pain at 6 months (β 0.39, 95% CI 0.04-0.73) and 1 year (β 0.40, 95% CI 0.04-0.75).

Conclusion: In early RA, depression is associated with greater short-term disease activity during MTX treatment, as well as more persistent and severe pain.
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http://dx.doi.org/10.3899/jrheum.200743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121898PMC
June 2021

Reply.

Arthritis Rheumatol 2021 03 22;73(3):548-549. Epub 2021 Jan 22.

University of Alabama at Birmingham.

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http://dx.doi.org/10.1002/art.41574DOI Listing
March 2021

Association of Agricultural, Occupational, and Military Inhalants With Autoantibodies and Disease Features in US Veterans With Rheumatoid Arthritis.

Arthritis Rheumatol 2021 03 29;73(3):392-400. Epub 2021 Jan 29.

VA Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha.

Objective: To determine the association of inhalant exposures with rheumatoid arthritis (RA)-related autoantibodies and severity in US veterans.

Methods: Participants in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were mailed surveys assessing occupational, agricultural, and military inhalant exposures. Demographic characteristics, disease activity, functional status, and extraarticular features were obtained from the VARA registry, while HLA-DRB1 shared epitope (SE) status, anti-cyclic citrullinated peptide (anti-CCP) antibodies, and rheumatoid factor (RF) were measured using banked DNA/serum from enrollment. Associations between inhalant exposures and RA-related factors (autoantibodies, severity, and extraarticular features) were assessed using multivariable linear and logistic regression models adjusted for age, sex, race, and tobacco use and stratified by SE status. Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.

Results: Questionnaires were returned by 797 of 1,566 participants (50.9%). Survey respondents were older, more often White or male, and less frequently smokers, and had lower disease activity compared to nonrespondents. Anti-CCP positivity was more common among veterans exposed to burn pits (OR 1.66 [95% CI 1.02, 2.69]) and military waste disposal (OR 1.74 [95% CI 1.04, 2.93]) independent of other factors. Among participants who were positive for SE alleles, burn pit exposure (OR 5.69 [95% CI 2.73, 11.87]) and military waste disposal exposure (OR 5.05 [95% CI 2.42, 10.54]) were numerically more strongly associated with anti-CCP positivity. Several inhalant exposures were associated with the presence of chronic lung disease, but not with the presence of RF or the level of disease activity.

Conclusion: Military burn pit exposure and military waste disposal exposure were independently associated with the presence of anti-CCP antibodies in RA patients. These findings are consistent with emerging evidence that various inhalant exposures influence autoantibody expression and RA risk.
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http://dx.doi.org/10.1002/art.41559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236239PMC
March 2021

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

Ann Rheum Dis 2020 Oct 8. Epub 2020 Oct 8.

Division of Rheumatology & Immunology, University of Nebraska Medical Center, Omaha, Nebraska, USA.

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 (β 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, β 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.
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http://dx.doi.org/10.1136/annrheumdis-2020-218282DOI Listing
October 2020

Autoantibody Seropositivity and Risk for Interstitial Lung Disease in a Prospective Male-Predominant Rheumatoid Arthritis Cohort of U.S. Veterans.

Ann Am Thorac Soc 2021 04;18(4):598-605

Division of Rheumatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.

Prior studies investigating associations of rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) seropositivity with risk for rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) have mostly used cross-sectional or case-control designs. To determine whether combined autoantibody seropositivity and higher individual autoantibody concentrations were associated with increased risk for RA-ILD in a prospective RA cohort. Within the Veterans Affairs Rheumatoid Arthritis prospective registry, we performed a cross-sectional study of prevalent ILD and a retrospective cohort study of incident ILD (diagnosed after at least 12 mo of longitudinal follow-up). We used logistic and Cox regression methods to determine whether combined RF/ACPA seropositivity and higher autoantibody concentrations were independently associated with greater risk for prevalent and incident ILD, respectively. Among 2,328 participants (median age 64 yr, 89.3% male), 100 (4.3%) subjects had prevalent ILD at enrollment. During 14,281 patient-years of follow-up, 83 (3.7%) of the remaining 2,228 were subsequently diagnosed with incident ILD (5.8 cases per 1,000 person-years). Patients with combined RF/ACPA seropositivity had a higher probability of prevalent ILD compared with seronegative subjects (odds ratio [OR], 2.90; 95% confidence interval [CI], 1.24-6.78). RF titers demonstrated a monotonic association with prevalent ILD (OR, 2.69; 95% CI, 1.11-6.51 for low-positive [15-45 IU/ml] titers; OR, 3.40; 95% CI, 1.61-7.18 for high-positive [>45 IU/ml] titers; for trend 0.01). Patients with high-positive (>15 U/ml) ACPA titers were also at higher risk for prevalent ILD (OR, 1.91; 95% CI, 1.04-3.49) compared with ACPA-negative subjects. Combined RF/ACPA seropositivity was not associated with increased risk for incident ILD, nor were high- or low-positive RF or ACPA titers. In a piecewise linear spline model, however, RF titers greater than 90 IU/ml independently correlated with increased risk for incident ILD (hazard ratio, 1.68, 95% CI, 1.02-2.77). Combined RF/ACPA seropositivity and individual autoantibody concentrations were strongly associated with prevalent but not incident RA-ILD. Only patients with RF concentrations >90 IU/ml were observed to be at higher risk of incident RA-ILD.
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http://dx.doi.org/10.1513/AnnalsATS.202006-590OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009007PMC
April 2021

Reply.

Arthritis Rheumatol 2021 03 27;73(3):544-545. Epub 2021 Jan 27.

University of California, Los Angeles and VA Greater Los Angeles Health Care System, Los Angeles, CA.

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http://dx.doi.org/10.1002/art.41522DOI Listing
March 2021

Factors associated with progression to inflammatory arthritis in first-degree relatives of individuals with RA following autoantibody positive screening in a non-clinical setting.

Ann Rheum Dis 2021 02 14;80(2):154-161. Epub 2020 Sep 14.

Department of Epidemiology, Colorado School of Public Health, Aurora, Colorado, USA

Objectives: Little is known about the likelihood of developing inflammatory arthritis (IA) in individuals who screen autoantibody positive (aAb+) in a non-clinical research setting.

Methods: We screened for serum cyclic citrullinated peptide antibody (anti-CCP) and rheumatoid factor isotype aAbs in subjects who were at increased risk for rheumatoid arthritis (RA) because they are a first-degree relative of an individual with classified RA (n=1780). We evaluated combinations of aAbs and high titre aAbs, as defined by 2-times (2 x) the standard cut-off and an optimal cut-off, as predictors of our two outcomes, aAb+ persistence and incident IA.

Results: 304 subjects (17.1%) tested aAb+; of those, 131 were IA-free and had at least one follow-up visit. Sixty-four per cent of these tested aAb+ again on their next visit. Anti-CCP+ at levels ≥2 x the standard cut-off was associated with 13-fold higher likelihood of aAb +persistence. During a median of 4.4 years (IQR: 2.2-7.2), 20 subjects (15.3%) developed IA. Among subjects that screened anti-CCP+ at ≥ 2 x or ≥an optimal cut-off, 32% and 26% had developed IA within 5 years, respectively. Both anti-CCP cut-offs conferred an approximate fourfold increased risk of future IA (HR 4.09 and HR 3.95, p<0.01).

Conclusions: These findings support that aAb screening in a non-clinical setting can identify RA-related aAb+ individuals, as well as levels and combinations of aAbs that are associated with higher risk for future IA. Monitoring for the development of IA in aAb+ individuals and similar aAb testing approaches in at-risk populations may identify candidates for prevention studies in RA.
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http://dx.doi.org/10.1136/annrheumdis-2020-217066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855648PMC
February 2021
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