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Research ArticleArticle

Smoking Is Associated with Higher Disease Activity in Rheumatoid Arthritis: A Longitudinal Study Controlling for Time-varying Covariates

Milena A. Gianfrancesco, Laura Trupin, Stephen Shiboski, Mark van der Laan, Jonathan Graf, John Imboden, Jinoos Yazdany and Gabriela Schmajuk
The Journal of Rheumatology December 2018, jrheum.180262; DOI: https://doi.org/10.3899/jrheum.180262
Milena A. Gianfrancesco
From the Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA. This work was supported by the US National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH; grant number F32 AR070585 to MG and K23 AR063770 to GS) and the Agency for Healthcare Research and Quality (grant number R01 HS024412 to JY). Drs. Graf, Yazdany, and Schmajuk are also supported by the Russell/Engleman Medical Research Center for Arthritis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality or the NIH. M.A. Gianfrancesco, PhD, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; L. Trupin, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; S. Shiboski, PhD, Department of Epidemiology and Biostatistics, University of California, San Francisco; M. van der Laan, PhD, Division of Biostatistics, School of Public Health, University of California, Berkeley; J. Graf, MD, Division of Rheumatology, Department of Medicine, University of California, San Francisco; J. Imboden, MD, Division of Rheumatology, Department of Medicine, University of California, San Francisco; J. Yazdany, MD, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; G. Schmajuk, MD, MS, Division of Rheumatology, Department of Medicine, University of California, San Francisco, and Veterans Affairs Medical Center, San Francisco, California, USA. Address correspondence to Dr. M.A. Gianfrancesco, Division of Rheumatology, Department of Medicine, University of California, San Francisco; 513 Parnassus Ave., San Francisco, California 94143, USA. E-mail: Milena.Gianfrancesco@ucsf.edu. Accepted for publication August 10, 2018.
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Laura Trupin
From the Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA. This work was supported by the US National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH; grant number F32 AR070585 to MG and K23 AR063770 to GS) and the Agency for Healthcare Research and Quality (grant number R01 HS024412 to JY). Drs. Graf, Yazdany, and Schmajuk are also supported by the Russell/Engleman Medical Research Center for Arthritis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality or the NIH. M.A. Gianfrancesco, PhD, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; L. Trupin, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; S. Shiboski, PhD, Department of Epidemiology and Biostatistics, University of California, San Francisco; M. van der Laan, PhD, Division of Biostatistics, School of Public Health, University of California, Berkeley; J. Graf, MD, Division of Rheumatology, Department of Medicine, University of California, San Francisco; J. Imboden, MD, Division of Rheumatology, Department of Medicine, University of California, San Francisco; J. Yazdany, MD, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; G. Schmajuk, MD, MS, Division of Rheumatology, Department of Medicine, University of California, San Francisco, and Veterans Affairs Medical Center, San Francisco, California, USA. Address correspondence to Dr. M.A. Gianfrancesco, Division of Rheumatology, Department of Medicine, University of California, San Francisco; 513 Parnassus Ave., San Francisco, California 94143, USA. E-mail: Milena.Gianfrancesco@ucsf.edu. Accepted for publication August 10, 2018.
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Stephen Shiboski
From the Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA. This work was supported by the US National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH; grant number F32 AR070585 to MG and K23 AR063770 to GS) and the Agency for Healthcare Research and Quality (grant number R01 HS024412 to JY). Drs. Graf, Yazdany, and Schmajuk are also supported by the Russell/Engleman Medical Research Center for Arthritis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality or the NIH. M.A. Gianfrancesco, PhD, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; L. Trupin, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; S. Shiboski, PhD, Department of Epidemiology and Biostatistics, University of California, San Francisco; M. van der Laan, PhD, Division of Biostatistics, School of Public Health, University of California, Berkeley; J. Graf, MD, Division of Rheumatology, Department of Medicine, University of California, San Francisco; J. Imboden, MD, Division of Rheumatology, Department of Medicine, University of California, San Francisco; J. Yazdany, MD, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; G. Schmajuk, MD, MS, Division of Rheumatology, Department of Medicine, University of California, San Francisco, and Veterans Affairs Medical Center, San Francisco, California, USA. Address correspondence to Dr. M.A. Gianfrancesco, Division of Rheumatology, Department of Medicine, University of California, San Francisco; 513 Parnassus Ave., San Francisco, California 94143, USA. E-mail: Milena.Gianfrancesco@ucsf.edu. Accepted for publication August 10, 2018.
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Mark van der Laan
From the Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA. This work was supported by the US National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH; grant number F32 AR070585 to MG and K23 AR063770 to GS) and the Agency for Healthcare Research and Quality (grant number R01 HS024412 to JY). Drs. Graf, Yazdany, and Schmajuk are also supported by the Russell/Engleman Medical Research Center for Arthritis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality or the NIH. M.A. Gianfrancesco, PhD, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; L. Trupin, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; S. Shiboski, PhD, Department of Epidemiology and Biostatistics, University of California, San Francisco; M. van der Laan, PhD, Division of Biostatistics, School of Public Health, University of California, Berkeley; J. Graf, MD, Division of Rheumatology, Department of Medicine, University of California, San Francisco; J. Imboden, MD, Division of Rheumatology, Department of Medicine, University of California, San Francisco; J. Yazdany, MD, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; G. Schmajuk, MD, MS, Division of Rheumatology, Department of Medicine, University of California, San Francisco, and Veterans Affairs Medical Center, San Francisco, California, USA. Address correspondence to Dr. M.A. Gianfrancesco, Division of Rheumatology, Department of Medicine, University of California, San Francisco; 513 Parnassus Ave., San Francisco, California 94143, USA. E-mail: Milena.Gianfrancesco@ucsf.edu. Accepted for publication August 10, 2018.
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Jonathan Graf
From the Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA. This work was supported by the US National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH; grant number F32 AR070585 to MG and K23 AR063770 to GS) and the Agency for Healthcare Research and Quality (grant number R01 HS024412 to JY). Drs. Graf, Yazdany, and Schmajuk are also supported by the Russell/Engleman Medical Research Center for Arthritis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality or the NIH. M.A. Gianfrancesco, PhD, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; L. Trupin, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; S. Shiboski, PhD, Department of Epidemiology and Biostatistics, University of California, San Francisco; M. van der Laan, PhD, Division of Biostatistics, School of Public Health, University of California, Berkeley; J. Graf, MD, Division of Rheumatology, Department of Medicine, University of California, San Francisco; J. Imboden, MD, Division of Rheumatology, Department of Medicine, University of California, San Francisco; J. Yazdany, MD, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; G. Schmajuk, MD, MS, Division of Rheumatology, Department of Medicine, University of California, San Francisco, and Veterans Affairs Medical Center, San Francisco, California, USA. Address correspondence to Dr. M.A. Gianfrancesco, Division of Rheumatology, Department of Medicine, University of California, San Francisco; 513 Parnassus Ave., San Francisco, California 94143, USA. E-mail: Milena.Gianfrancesco@ucsf.edu. Accepted for publication August 10, 2018.
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John Imboden
From the Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA. This work was supported by the US National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH; grant number F32 AR070585 to MG and K23 AR063770 to GS) and the Agency for Healthcare Research and Quality (grant number R01 HS024412 to JY). Drs. Graf, Yazdany, and Schmajuk are also supported by the Russell/Engleman Medical Research Center for Arthritis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality or the NIH. M.A. Gianfrancesco, PhD, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; L. Trupin, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; S. Shiboski, PhD, Department of Epidemiology and Biostatistics, University of California, San Francisco; M. van der Laan, PhD, Division of Biostatistics, School of Public Health, University of California, Berkeley; J. Graf, MD, Division of Rheumatology, Department of Medicine, University of California, San Francisco; J. Imboden, MD, Division of Rheumatology, Department of Medicine, University of California, San Francisco; J. Yazdany, MD, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; G. Schmajuk, MD, MS, Division of Rheumatology, Department of Medicine, University of California, San Francisco, and Veterans Affairs Medical Center, San Francisco, California, USA. Address correspondence to Dr. M.A. Gianfrancesco, Division of Rheumatology, Department of Medicine, University of California, San Francisco; 513 Parnassus Ave., San Francisco, California 94143, USA. E-mail: Milena.Gianfrancesco@ucsf.edu. Accepted for publication August 10, 2018.
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Jinoos Yazdany
From the Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA. This work was supported by the US National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH; grant number F32 AR070585 to MG and K23 AR063770 to GS) and the Agency for Healthcare Research and Quality (grant number R01 HS024412 to JY). Drs. Graf, Yazdany, and Schmajuk are also supported by the Russell/Engleman Medical Research Center for Arthritis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality or the NIH. M.A. Gianfrancesco, PhD, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; L. Trupin, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; S. Shiboski, PhD, Department of Epidemiology and Biostatistics, University of California, San Francisco; M. van der Laan, PhD, Division of Biostatistics, School of Public Health, University of California, Berkeley; J. Graf, MD, Division of Rheumatology, Department of Medicine, University of California, San Francisco; J. Imboden, MD, Division of Rheumatology, Department of Medicine, University of California, San Francisco; J. Yazdany, MD, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; G. Schmajuk, MD, MS, Division of Rheumatology, Department of Medicine, University of California, San Francisco, and Veterans Affairs Medical Center, San Francisco, California, USA. Address correspondence to Dr. M.A. Gianfrancesco, Division of Rheumatology, Department of Medicine, University of California, San Francisco; 513 Parnassus Ave., San Francisco, California 94143, USA. E-mail: Milena.Gianfrancesco@ucsf.edu. Accepted for publication August 10, 2018.
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Gabriela Schmajuk
From the Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA. This work was supported by the US National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH; grant number F32 AR070585 to MG and K23 AR063770 to GS) and the Agency for Healthcare Research and Quality (grant number R01 HS024412 to JY). Drs. Graf, Yazdany, and Schmajuk are also supported by the Russell/Engleman Medical Research Center for Arthritis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality or the NIH. M.A. Gianfrancesco, PhD, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; L. Trupin, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; S. Shiboski, PhD, Department of Epidemiology and Biostatistics, University of California, San Francisco; M. van der Laan, PhD, Division of Biostatistics, School of Public Health, University of California, Berkeley; J. Graf, MD, Division of Rheumatology, Department of Medicine, University of California, San Francisco; J. Imboden, MD, Division of Rheumatology, Department of Medicine, University of California, San Francisco; J. Yazdany, MD, MPH, Division of Rheumatology, Department of Medicine, University of California, San Francisco; G. Schmajuk, MD, MS, Division of Rheumatology, Department of Medicine, University of California, San Francisco, and Veterans Affairs Medical Center, San Francisco, California, USA. Address correspondence to Dr. M.A. Gianfrancesco, Division of Rheumatology, Department of Medicine, University of California, San Francisco; 513 Parnassus Ave., San Francisco, California 94143, USA. E-mail: Milena.Gianfrancesco@ucsf.edu. Accepted for publication August 10, 2018.
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Abstract

Objective Prior studies around the relationship between smoking and rheumatoid arthritis (RA) disease activity have reported inconsistent findings, which may be ascribed to heterogeneous study designs or biases in statistical analyses. We examined the association between smoking and RA outcomes using statistical methods that account for time-varying confounding and loss to followup.

Methods We included 282 individuals with an RA diagnosis using electronic health record data collected at a public hospital between 2013 and 2017. Current smoking status and disease activity were assessed at each visit; covariates included sex, race/ethnicity, age, obesity, and medication use. We used longitudinal targeted maximum likelihood estimation to estimate the causal effect of smoking on disease activity measures at 27 months, and compared results to conventional longitudinal methods.

Results Smoking was associated with an increase of 0.64 units in the patient global score compared to nonsmoking (p = 0.01), and with 2.58 more swollen joints (p < 0.001). While smoking was associated with a higher clinical disease activity score (2.11), the difference was not statistically significant (p = 0.22). We found no association between smoking and physician global score, or C-reactive protein levels, and an inverse association between smoking and tender joint count (p = 0.05). Analyses using conventional methods showed a null relationship for all outcomes.

Conclusion Smoking is associated with higher levels of disease activity in RA. Causal methods may be useful for investigations of additional exposures on longitudinal outcome measures in rheumatologic disease.

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Smoking Is Associated with Higher Disease Activity in Rheumatoid Arthritis: A Longitudinal Study Controlling for Time-varying Covariates
Milena A. Gianfrancesco, Laura Trupin, Stephen Shiboski, Mark van der Laan, Jonathan Graf, John Imboden, Jinoos Yazdany, Gabriela Schmajuk
The Journal of Rheumatology Dec 2018, jrheum.180262; DOI: 10.3899/jrheum.180262

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Smoking Is Associated with Higher Disease Activity in Rheumatoid Arthritis: A Longitudinal Study Controlling for Time-varying Covariates
Milena A. Gianfrancesco, Laura Trupin, Stephen Shiboski, Mark van der Laan, Jonathan Graf, John Imboden, Jinoos Yazdany, Gabriela Schmajuk
The Journal of Rheumatology Dec 2018, jrheum.180262; DOI: 10.3899/jrheum.180262
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