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Research ArticleArticle

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

Alan M. Rathbun, Bryant R. England, Ted R. Mikuls, Alice S. Ryan, Jennifer L. Barton, Michelle D. Shardell and Marc C. Hochberg
The Journal of Rheumatology November 2020, jrheum.200743; DOI: https://doi.org/10.3899/jrheum.200743
Alan M. Rathbun
This study was supported by the Rheumatology Research Foundation’s Scientist Development Award and grants from the National Institute on Aging (NIA; K01 AG064041, R01 AG048069, P30 AG028747), Veterans Affairs (VA) Clinical Science Research and Development Service (I01 BX004660), and National Institute of General Medical Sciences (U54 GM115458). 1A.M. Rathbun, PhD, MPH, Department of Epidemiology and Public Health, and Department of Medicine, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland; 2B.R. England, MD, PhD, T.R. Mikuls, MD, MSPH, VA Nebraska-Western Iowa Health Care System, and Department of Internal Medicine, University of Nebraska Medical Center, College of Medicine, Omaha, Nebraska; 3A.S. Ryan, PhD, Department of Medicine, University of Maryland Baltimore, School of Medicine, and VA Maryland Health Care System, Baltimore, Maryland; 4J.L. Barton, MD, MCR, VA Portland Health Care System, and Department of Medicine, Oregon Health & Science University, School of Medicine, Portland, Oregon; 5M.D. Shardell, PhD, Department of Epidemiology and Public Health, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland; 6M.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. AMR is supported by grants from the Rheumatology Research Foundation and National Institute on Aging (NIA; K01 AG064041). BRE and TRM are supported by grants from the Rheumatology Research Foundation, VA Clinical Science Research and Development Service (I01 BX004660), and National Institute of General Medical Sciences (U54 GM115458). JLB is supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23 AR064372). ASR is supported by grants from the VA Rehabilitation Research and Development Service (N9273, I01 RX002790, I01 RX001461, I21 RX002870), NIA (P30 AG028747), and National Institute on Diabetes and Digestive and Kidney Disease (P30 DK072488). MDS is supported by grants from NIA (R01 AG048069). MCH is the President of Rheumcon Corporation and receives consulting fees from Bioiberica SA, Bristol Myers Squibb, Eli Lilly, EMD Serono, Galapagos, IBSA Biotechniq SA, Novartis Pharma AG, Pfizer, Plexxikon, Samumed LLC, Theralogix LLC, and TissueGene Inc. Address correspondence to Dr. A.M. Rathbun, Howard Hall Suite 200, 660 W. Redwood Street, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Email: arathbun@som.umaryland.edu. Accepted for publication November 3, 2020.
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Bryant R. England
This study was supported by the Rheumatology Research Foundation’s Scientist Development Award and grants from the National Institute on Aging (NIA; K01 AG064041, R01 AG048069, P30 AG028747), Veterans Affairs (VA) Clinical Science Research and Development Service (I01 BX004660), and National Institute of General Medical Sciences (U54 GM115458). 1A.M. Rathbun, PhD, MPH, Department of Epidemiology and Public Health, and Department of Medicine, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland; 2B.R. England, MD, PhD, T.R. Mikuls, MD, MSPH, VA Nebraska-Western Iowa Health Care System, and Department of Internal Medicine, University of Nebraska Medical Center, College of Medicine, Omaha, Nebraska; 3A.S. Ryan, PhD, Department of Medicine, University of Maryland Baltimore, School of Medicine, and VA Maryland Health Care System, Baltimore, Maryland; 4J.L. Barton, MD, MCR, VA Portland Health Care System, and Department of Medicine, Oregon Health & Science University, School of Medicine, Portland, Oregon; 5M.D. Shardell, PhD, Department of Epidemiology and Public Health, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland; 6M.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. AMR is supported by grants from the Rheumatology Research Foundation and National Institute on Aging (NIA; K01 AG064041). BRE and TRM are supported by grants from the Rheumatology Research Foundation, VA Clinical Science Research and Development Service (I01 BX004660), and National Institute of General Medical Sciences (U54 GM115458). JLB is supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23 AR064372). ASR is supported by grants from the VA Rehabilitation Research and Development Service (N9273, I01 RX002790, I01 RX001461, I21 RX002870), NIA (P30 AG028747), and National Institute on Diabetes and Digestive and Kidney Disease (P30 DK072488). MDS is supported by grants from NIA (R01 AG048069). MCH is the President of Rheumcon Corporation and receives consulting fees from Bioiberica SA, Bristol Myers Squibb, Eli Lilly, EMD Serono, Galapagos, IBSA Biotechniq SA, Novartis Pharma AG, Pfizer, Plexxikon, Samumed LLC, Theralogix LLC, and TissueGene Inc. Address correspondence to Dr. A.M. Rathbun, Howard Hall Suite 200, 660 W. Redwood Street, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Email: arathbun@som.umaryland.edu. Accepted for publication November 3, 2020.
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Ted R. Mikuls
This study was supported by the Rheumatology Research Foundation’s Scientist Development Award and grants from the National Institute on Aging (NIA; K01 AG064041, R01 AG048069, P30 AG028747), Veterans Affairs (VA) Clinical Science Research and Development Service (I01 BX004660), and National Institute of General Medical Sciences (U54 GM115458). 1A.M. Rathbun, PhD, MPH, Department of Epidemiology and Public Health, and Department of Medicine, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland; 2B.R. England, MD, PhD, T.R. Mikuls, MD, MSPH, VA Nebraska-Western Iowa Health Care System, and Department of Internal Medicine, University of Nebraska Medical Center, College of Medicine, Omaha, Nebraska; 3A.S. Ryan, PhD, Department of Medicine, University of Maryland Baltimore, School of Medicine, and VA Maryland Health Care System, Baltimore, Maryland; 4J.L. Barton, MD, MCR, VA Portland Health Care System, and Department of Medicine, Oregon Health & Science University, School of Medicine, Portland, Oregon; 5M.D. Shardell, PhD, Department of Epidemiology and Public Health, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland; 6M.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. AMR is supported by grants from the Rheumatology Research Foundation and National Institute on Aging (NIA; K01 AG064041). BRE and TRM are supported by grants from the Rheumatology Research Foundation, VA Clinical Science Research and Development Service (I01 BX004660), and National Institute of General Medical Sciences (U54 GM115458). JLB is supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23 AR064372). ASR is supported by grants from the VA Rehabilitation Research and Development Service (N9273, I01 RX002790, I01 RX001461, I21 RX002870), NIA (P30 AG028747), and National Institute on Diabetes and Digestive and Kidney Disease (P30 DK072488). MDS is supported by grants from NIA (R01 AG048069). MCH is the President of Rheumcon Corporation and receives consulting fees from Bioiberica SA, Bristol Myers Squibb, Eli Lilly, EMD Serono, Galapagos, IBSA Biotechniq SA, Novartis Pharma AG, Pfizer, Plexxikon, Samumed LLC, Theralogix LLC, and TissueGene Inc. Address correspondence to Dr. A.M. Rathbun, Howard Hall Suite 200, 660 W. Redwood Street, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Email: arathbun@som.umaryland.edu. Accepted for publication November 3, 2020.
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Alice S. Ryan
This study was supported by the Rheumatology Research Foundation’s Scientist Development Award and grants from the National Institute on Aging (NIA; K01 AG064041, R01 AG048069, P30 AG028747), Veterans Affairs (VA) Clinical Science Research and Development Service (I01 BX004660), and National Institute of General Medical Sciences (U54 GM115458). 1A.M. Rathbun, PhD, MPH, Department of Epidemiology and Public Health, and Department of Medicine, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland; 2B.R. England, MD, PhD, T.R. Mikuls, MD, MSPH, VA Nebraska-Western Iowa Health Care System, and Department of Internal Medicine, University of Nebraska Medical Center, College of Medicine, Omaha, Nebraska; 3A.S. Ryan, PhD, Department of Medicine, University of Maryland Baltimore, School of Medicine, and VA Maryland Health Care System, Baltimore, Maryland; 4J.L. Barton, MD, MCR, VA Portland Health Care System, and Department of Medicine, Oregon Health & Science University, School of Medicine, Portland, Oregon; 5M.D. Shardell, PhD, Department of Epidemiology and Public Health, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland; 6M.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. AMR is supported by grants from the Rheumatology Research Foundation and National Institute on Aging (NIA; K01 AG064041). BRE and TRM are supported by grants from the Rheumatology Research Foundation, VA Clinical Science Research and Development Service (I01 BX004660), and National Institute of General Medical Sciences (U54 GM115458). JLB is supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23 AR064372). ASR is supported by grants from the VA Rehabilitation Research and Development Service (N9273, I01 RX002790, I01 RX001461, I21 RX002870), NIA (P30 AG028747), and National Institute on Diabetes and Digestive and Kidney Disease (P30 DK072488). MDS is supported by grants from NIA (R01 AG048069). MCH is the President of Rheumcon Corporation and receives consulting fees from Bioiberica SA, Bristol Myers Squibb, Eli Lilly, EMD Serono, Galapagos, IBSA Biotechniq SA, Novartis Pharma AG, Pfizer, Plexxikon, Samumed LLC, Theralogix LLC, and TissueGene Inc. Address correspondence to Dr. A.M. Rathbun, Howard Hall Suite 200, 660 W. Redwood Street, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Email: arathbun@som.umaryland.edu. Accepted for publication November 3, 2020.
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Jennifer L. Barton
This study was supported by the Rheumatology Research Foundation’s Scientist Development Award and grants from the National Institute on Aging (NIA; K01 AG064041, R01 AG048069, P30 AG028747), Veterans Affairs (VA) Clinical Science Research and Development Service (I01 BX004660), and National Institute of General Medical Sciences (U54 GM115458). 1A.M. Rathbun, PhD, MPH, Department of Epidemiology and Public Health, and Department of Medicine, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland; 2B.R. England, MD, PhD, T.R. Mikuls, MD, MSPH, VA Nebraska-Western Iowa Health Care System, and Department of Internal Medicine, University of Nebraska Medical Center, College of Medicine, Omaha, Nebraska; 3A.S. Ryan, PhD, Department of Medicine, University of Maryland Baltimore, School of Medicine, and VA Maryland Health Care System, Baltimore, Maryland; 4J.L. Barton, MD, MCR, VA Portland Health Care System, and Department of Medicine, Oregon Health & Science University, School of Medicine, Portland, Oregon; 5M.D. Shardell, PhD, Department of Epidemiology and Public Health, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland; 6M.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. AMR is supported by grants from the Rheumatology Research Foundation and National Institute on Aging (NIA; K01 AG064041). BRE and TRM are supported by grants from the Rheumatology Research Foundation, VA Clinical Science Research and Development Service (I01 BX004660), and National Institute of General Medical Sciences (U54 GM115458). JLB is supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23 AR064372). ASR is supported by grants from the VA Rehabilitation Research and Development Service (N9273, I01 RX002790, I01 RX001461, I21 RX002870), NIA (P30 AG028747), and National Institute on Diabetes and Digestive and Kidney Disease (P30 DK072488). MDS is supported by grants from NIA (R01 AG048069). MCH is the President of Rheumcon Corporation and receives consulting fees from Bioiberica SA, Bristol Myers Squibb, Eli Lilly, EMD Serono, Galapagos, IBSA Biotechniq SA, Novartis Pharma AG, Pfizer, Plexxikon, Samumed LLC, Theralogix LLC, and TissueGene Inc. Address correspondence to Dr. A.M. Rathbun, Howard Hall Suite 200, 660 W. Redwood Street, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Email: arathbun@som.umaryland.edu. Accepted for publication November 3, 2020.
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Michelle D. Shardell
This study was supported by the Rheumatology Research Foundation’s Scientist Development Award and grants from the National Institute on Aging (NIA; K01 AG064041, R01 AG048069, P30 AG028747), Veterans Affairs (VA) Clinical Science Research and Development Service (I01 BX004660), and National Institute of General Medical Sciences (U54 GM115458). 1A.M. Rathbun, PhD, MPH, Department of Epidemiology and Public Health, and Department of Medicine, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland; 2B.R. England, MD, PhD, T.R. Mikuls, MD, MSPH, VA Nebraska-Western Iowa Health Care System, and Department of Internal Medicine, University of Nebraska Medical Center, College of Medicine, Omaha, Nebraska; 3A.S. Ryan, PhD, Department of Medicine, University of Maryland Baltimore, School of Medicine, and VA Maryland Health Care System, Baltimore, Maryland; 4J.L. Barton, MD, MCR, VA Portland Health Care System, and Department of Medicine, Oregon Health & Science University, School of Medicine, Portland, Oregon; 5M.D. Shardell, PhD, Department of Epidemiology and Public Health, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland; 6M.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. AMR is supported by grants from the Rheumatology Research Foundation and National Institute on Aging (NIA; K01 AG064041). BRE and TRM are supported by grants from the Rheumatology Research Foundation, VA Clinical Science Research and Development Service (I01 BX004660), and National Institute of General Medical Sciences (U54 GM115458). JLB is supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23 AR064372). ASR is supported by grants from the VA Rehabilitation Research and Development Service (N9273, I01 RX002790, I01 RX001461, I21 RX002870), NIA (P30 AG028747), and National Institute on Diabetes and Digestive and Kidney Disease (P30 DK072488). MDS is supported by grants from NIA (R01 AG048069). MCH is the President of Rheumcon Corporation and receives consulting fees from Bioiberica SA, Bristol Myers Squibb, Eli Lilly, EMD Serono, Galapagos, IBSA Biotechniq SA, Novartis Pharma AG, Pfizer, Plexxikon, Samumed LLC, Theralogix LLC, and TissueGene Inc. Address correspondence to Dr. A.M. Rathbun, Howard Hall Suite 200, 660 W. Redwood Street, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Email: arathbun@som.umaryland.edu. Accepted for publication November 3, 2020.
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Marc C. Hochberg
This study was supported by the Rheumatology Research Foundation’s Scientist Development Award and grants from the National Institute on Aging (NIA; K01 AG064041, R01 AG048069, P30 AG028747), Veterans Affairs (VA) Clinical Science Research and Development Service (I01 BX004660), and National Institute of General Medical Sciences (U54 GM115458). 1A.M. Rathbun, PhD, MPH, Department of Epidemiology and Public Health, and Department of Medicine, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland; 2B.R. England, MD, PhD, T.R. Mikuls, MD, MSPH, VA Nebraska-Western Iowa Health Care System, and Department of Internal Medicine, University of Nebraska Medical Center, College of Medicine, Omaha, Nebraska; 3A.S. Ryan, PhD, Department of Medicine, University of Maryland Baltimore, School of Medicine, and VA Maryland Health Care System, Baltimore, Maryland; 4J.L. Barton, MD, MCR, VA Portland Health Care System, and Department of Medicine, Oregon Health & Science University, School of Medicine, Portland, Oregon; 5M.D. Shardell, PhD, Department of Epidemiology and Public Health, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland; 6M.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. AMR is supported by grants from the Rheumatology Research Foundation and National Institute on Aging (NIA; K01 AG064041). BRE and TRM are supported by grants from the Rheumatology Research Foundation, VA Clinical Science Research and Development Service (I01 BX004660), and National Institute of General Medical Sciences (U54 GM115458). JLB is supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23 AR064372). ASR is supported by grants from the VA Rehabilitation Research and Development Service (N9273, I01 RX002790, I01 RX001461, I21 RX002870), NIA (P30 AG028747), and National Institute on Diabetes and Digestive and Kidney Disease (P30 DK072488). MDS is supported by grants from NIA (R01 AG048069). MCH is the President of Rheumcon Corporation and receives consulting fees from Bioiberica SA, Bristol Myers Squibb, Eli Lilly, EMD Serono, Galapagos, IBSA Biotechniq SA, Novartis Pharma AG, Pfizer, Plexxikon, Samumed LLC, Theralogix LLC, and TissueGene Inc. Address correspondence to Dr. A.M. Rathbun, Howard Hall Suite 200, 660 W. Redwood Street, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Email: arathbun@som.umaryland.edu. Accepted for publication November 3, 2020.
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Abstract

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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Relationship Between Depression and Disease Activity in United States Veterans With Early Rheumatoid Arthritis Receiving Methotrexate
Alan M. Rathbun, Bryant R. England, Ted R. Mikuls, Alice S. Ryan, Jennifer L. Barton, Michelle D. Shardell, Marc C. Hochberg
The Journal of Rheumatology Nov 2020, jrheum.200743; DOI: 10.3899/jrheum.200743

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Relationship Between Depression and Disease Activity in United States Veterans With Early Rheumatoid Arthritis Receiving Methotrexate
Alan M. Rathbun, Bryant R. England, Ted R. Mikuls, Alice S. Ryan, Jennifer L. Barton, Michelle D. Shardell, Marc C. Hochberg
The Journal of Rheumatology Nov 2020, jrheum.200743; DOI: 10.3899/jrheum.200743
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