Current smoking predicts inadequate response to methotrexate monotherapy in rheumatoid arthritis patients naïve to DMARDs

Abstract Identifying predictors of inadequate response to methotrexate (MTX) in rheumatoid arthritis (RA) is key to move from a “trial and error” to a “personalized medicine” treatment approach where patients less likely to adequately respond to MTX monotherapy could start combination therapy at an earlier stage. This study aimed to identify potential predictors of inadequate response to MTX in RA patients naïve to disease modifying anti-rheumatic drugs. Data from a real-life cohort of newly diagnosed RA patients starting MTX (baseline, T0) as first-line therapy were analyzed. Outcomes, assessed after 6 months (T1), were defined as failure to achieve a disease activity score 28 (DAS28) low disease activity (LDA) or a good/moderate response to MTX, according to the European League Against Rheumatism (EULAR) response criteria. Logistic regression was used to assess the associations between baseline variables and the study outcomes. Overall, 294 patients (60.5% females, median age 54.5 years) with a median disease duration of 7.9 months were recruited. At T1, 47.3% of subjects failed to achieve LDA, and 29.3% did not have any EULAR-response. In multivariate analysis, significant associations were observed between no LDA and current smoking (adjusted odds ratio [adjOR] 1.79, P = .037), female gender (adjOR 1.68, P = .048), and higher DAS28 (adjOR 1.31, P = .013); and between no EULAR-response and current smoking (adjOR: 2.04, P = .019), age (adjOR: 0.72 per 10-years increases, P = .001), and higher erythrocyte sedimentation rate (adjOR: 0.49; P = .020). By contrast, there were no associations between past smoker status and study outcomes. In summary, in our real-life cohort of disease modifying anti-rheumatic drug naïve RA patients, current smoking habit independently predicts inadequate response to MTX. This, together with other independent predictors of response to treatment identified in our study, might assist with personalized monitoring in RA patients. Further studies are required to investigate whether smoking quitting strategies enhance the therapeutic response to MTX.

[1]  Tsutomu Takeuchi,et al.  EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update , 2020, Annals of the Rheumatic Diseases.

[2]  A. Mangoni,et al.  Aging Methotrexate and Vasculoprotection: Mechanistic Insights and Potential Therapeutic Applications in Old Age. , 2019, Current pharmaceutical design.

[3]  A. Mangoni,et al.  Methotrexate therapy is not associated with increased liver stiffness and significant liver fibrosis in rheumatoid arthritis patients: A cross-sectional controlled study with real-time two-dimensional shear wave elastography. , 2019, European journal of internal medicine.

[4]  J. Jacobs,et al.  Is prediction of clinical response to methotrexate in individual rheumatoid arthritis patients possible? A systematic literature review. , 2019, Joint, bone, spine : revue du rhumatisme.

[5]  N. Wulffraat,et al.  Development and validation of a prognostic multivariable model to predict insufficient clinical response to methotrexate in rheumatoid arthritis , 2018, PloS one.

[6]  A. Barton,et al.  Prediction of primary non-response to methotrexate therapy using demographic, clinical and psychosocial variables: results from the UK Rheumatoid Arthritis Medication Study (RAMS) , 2018, Arthritis Research & Therapy.

[7]  J. Jacobs,et al.  Inadequate response to treat-to-target methotrexate therapy in patients with new-onset rheumatoid arthritis: development and validation of clinical predictors , 2018, Annals of the rheumatic diseases.

[8]  A. Mangoni,et al.  Protective Effects of Methotrexate against Proatherosclerotic Cytokines: A Review of the Evidence , 2017, Mediators of inflammation.

[9]  I. McInnes,et al.  Rheumatoid arthritis , 2016, The Lancet.

[10]  P. V. van Riel,et al.  The Disease Activity Score (DAS) and the Disease Activity Score using 28 joint counts (DAS28) in the management of rheumatoid arthritis. , 2016, Clinical and experimental rheumatology.

[11]  R. Caporali,et al.  Rheumatoid arthritis treatment: the earlier the better to prevent joint damage , 2015, RMD Open.

[12]  Se Jin Park,et al.  Smoking and Rheumatoid Arthritis , 2014, International journal of molecular sciences.

[13]  B. Combe,et al.  Association of Tobacco Exposure and Reduction of Radiographic Progression in Early Rheumatoid Arthritis: Results From a French Multicenter Cohort , 2013, Arthritis care & research.

[14]  H. Sayles,et al.  Serum cotinine as a biomarker of tobacco exposure and the association with treatment response in early rheumatoid arthritis , 2012, Arthritis care & research.

[15]  F. Ibrahim,et al.  Remission in Early Rheumatoid Arthritis: Predicting Treatment Response , 2012, The Journal of Rheumatology.

[16]  S. Bergman,et al.  Smoking at onset of rheumatoid arthritis (RA) and its effect on disease activity and functional status: experiences from BARFOT, a long-term observational study on early RA , 2011, Scandinavian journal of rheumatology.

[17]  R. Burgos-Vargas,et al.  Current smoking status is associated to a non-ACR 50 response in early rheumatoid arthritis. A cohort study , 2011, Clinical Rheumatology.

[18]  S. Saevarsdottir,et al.  Predictors of response to methotrexate in early DMARD naïve rheumatoid arthritis: results from the initial open-label phase of the SWEFOT trial , 2010, Annals of the rheumatic diseases.

[19]  S. Wedrén,et al.  Patients with early rheumatoid arthritis who smoke are less likely to respond to treatment with methotrexate and tumor necrosis factor inhibitors: observations from the Epidemiological Investigation of Rheumatoid Arthritis and the Swedish Rheumatology Register cohorts. , 2011, Arthritis and rheumatism.

[20]  A. Silman,et al.  UvA-DARE (Digital Academic Repository) 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative Aletaha, , 2010 .

[21]  A. Silman,et al.  Rheumatoid arthritis classifi cation criteria : an American College of Rheumatology / European League Against Rheumatism collaborative initiative , 2010 .

[22]  D. Sugiyama,et al.  Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies , 2009, Annals of the rheumatic diseases.

[23]  M. Barclay,et al.  Determinants of red blood cell methotrexate polyglutamate concentrations in rheumatoid arthritis patients receiving long-term methotrexate treatment. , 2009, Arthritis and rheumatism.

[24]  B. Bresnihan,et al.  Women, men, and rheumatoid arthritis: analyses of disease activity, disease characteristics, and treatments in the QUEST-RA Study , 2009, Arthritis research & therapy.

[25]  D. M. van der Heijde,et al.  Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research , 2008, Annals of the rheumatic diseases.

[26]  A. Nevill,et al.  Cigarette smoking significantly increases basal metabolic rate in patients with rheumatoid arthritis , 2007, Annals of the rheumatic diseases.

[27]  E. Karlson,et al.  Smoking intensity, duration, and cessation, and the risk of rheumatoid arthritis in women. , 2006, The American journal of medicine.

[28]  James M Robins,et al.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group , 2022 .

[29]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.