Dr. Curtis has received consultancy fees, speaking fees, and/or honoraria (less than $10,000 each) from Abbott, Bristol-Myers Squibb, Crescendo, and Pfizer, and (more than $10,000 each) from Amgen, Centocor, the Consortium of Rheumatology Researchers of North America, Roche/ Genentech, and UCB.
Cigarette smoking has emerged as a risk factor for the development of rheumatoid arthritis (RA). Recent studies have suggested that cigarette smoking may lead to lower treatment response rates with methotrexate (MTX) and some biologic agents in RA. Knowledge of whether tobacco exposure reduces treatment efficacy is important, since smoking could represent a modifiable factor in optimizing RA treatment.
The study participants included patients with early RA (<3 years in duration) enrolled in the Treatment of Early Aggressive Rheumatoid Arthritis study, a randomized, blinded, placebo-controlled clinical trial comparing early intensive therapy (MTX + etanercept or MTX + hydroxychloroquine + sulfasalazine triple therapy) versus initial treatment with MTX with step-up to MTX + etanercept or to triple therapy if the disease was still active at 24 weeks. Serum cotinine was measured using a commercially available enzyme-linked immunosorbent assay at baseline and at 48 weeks, with detectable concentrations at both visits serving as an indicator of smoking status. The mean Disease Activity Score in 28 joints (DAS28) was compared by smoking status, adjusting for baseline disease activity.
Of the 412 subjects included in the analysis, 293 (71%) were categorized as nonsmokers and 119 (29%) as current smokers. There were no differences in the mean DAS28 score between 48 and 102 weeks based on smoking status for the overall group (P = 0.881) or by specific treatment assignment.
Among patients enrolled in a large randomized controlled trial of early RA with poor prognostic factors, smoking status did not impact treatment responses for those receiving early combination or initial MTX with step-up therapy at 24 weeks if the disease was still active.
Cigarette smoking is now widely accepted to be a risk factor for the development of rheumatoid arthritis (RA). Both the duration and cumulative magnitude of cigarette smoking exposure have been shown to increase the risk of developing RA (1–4). In fact, smoking alone has been shown to account for ∼20% of all new cases of RA (1), with attributable risks for autoantibody-positive disease due to smoking approaching 50% in patients homozygous for HLA–DRB1 alleles containing the shared epitope alleles (5). A significant association has been shown between smoking and the presence of disease-related autoantibodies, including anti–citrullinated protein antibody (ACPA) (2, 6, 7) and rheumatoid factor (RF) (8), both of which are associated with poor disease prognosis. Cigarette smoking is additionally associated with a higher prevalence of extraarticular disease manifestations in RA, including subcutaneous nodules (9–13) and interstitial lung disease (14). This is particularly salient since both of these disease manifestations are associated with worse long-term outcomes in RA, including higher all-cause mortality (15, 16).
There has been recent evidence suggesting that worse outcomes in RA related to smoking may be secondary to a detrimental effect on treatment response to both biologic and nonbiologic disease-modifying antirheumatic drugs (DMARDs). In a large observational cohort study, heavy smokers (defined as more than a 20 pack-year cumulative smoking history) had less improvement in disease activity over a 3-year period of observation and required DMARD combinations or biologic therapies more often when compared to those who smoked less or not at all (17). Investigators from the British Society for Rheumatology Biologics Register recently reported a lower treatment response rate for the tumor necrosis factor α (TNFα) inihibitor infliximab in RA patients reporting current smoking when compared to nonsmokers (18). However, to date, there have been no studies examining the associations of cigarette smoking with treatment response in early RA in the context of a randomized double-blind controlled trial. Knowledge of whether cigarette smoking reduces treatment efficacy is important, since smoking could represent a modifiable factor in optimizing RA treatment strategies.
Significance & Innovations
In contrast to findings from other recent studies showing that smoking may reduce treatment responses in rheumatoid arthritis (RA), smoking status does not appear to be associated with RA treatment response with either triple disease-modifying antirheumatic drug therapy (methotrexate + hydroxychloroquine + sulfasalazine) or etanercept in combination with methotrexate.
To our knowledge, this is the first study utilizing a bioassay method to measure nicotine exposure instead of patient-reported exposure to investigate the possible relationship between smoking and treatment response in patients with RA.
MATERIALS AND METHODS
Study design and participants.
The Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) study was designed to compare the effectiveness of early intensive therapy versus step-up therapy to 1 of 2 combinations of medications (methotrexate [MTX; supplied by Barr Pharmaceuticals] + etanercept [ETN; supplied by Amgen] versus MTX + hydroxychloroquine + sulfasalazine [supplied by Pharmacia] triple therapy) in early, active RA (19). This study was a 2-year, randomized, double-blind trial using a 2-by-2 factorial design in which the subjects were treated initially with either MTX alone, triple therapy (MTX + hydroxychloroquine + sulfasalazine), or MTX + ETN. At 24 weeks, participants in the MTX monotherapy group with a Disease Activity Score in 28 joints (DAS28) >3.2, reflecting moderate to severe levels of persistent disease activity, were stepped up to either oral triple therapy or MTX + ETN. The primary outcome of the TEAR study was the mean DAS28 score observed from week 48 to week 102.
The eligibility criteria for enrollment in the TEAR study included age >18 years; satisfaction of the 1987 American College of Rheumatology classification criteria for RA (20); a disease duration of <3 years from the time of formal diagnosis; having active disease defined as at least 4 swollen and 4 tender joints using the 28-joint count; positive for RF or ACPA or at least 2 erosions present on radiographs of the hands, wrists, or feet if negative for RF or ACPA; stable doses of corticosteroid therapy and <10 mg/day of prednisone (or equivalent) if taking such therapy; and, if taken, stable doses of nonsteroidal antiinflammatory drugs. The participants included in the present analysis provided additional informed consent for banking of both their DNA and serum for future ancillary studies examining biomarkers as predictors of treatment response.
Self-reported smoking status was not collected as part of the TEAR study. Recognizing that the association of smoking with treatment response was not a primary objective of the parent study, participants were categorized as current smokers or nonsmokers based on their serum cotinine status. Serum cotinine is a metabolite of nicotine and is widely used in epidemiologic research as an objective measure of recent tobacco use (21, 22). Circulating cotinine was measured using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (Calbiotech) and banked serum from baseline and week 48 of followup. Of the 755 participants enrolled in the TEAR study, 148 did not participate in the serum and DNA banking substudies and were subsequently excluded from this analysis. Of the 607 participants with serum available, 161 were excluded from the primary analyses due to serum being available only at baseline (n = 150) or only at 48 weeks (n = 11). Participants with discordant values at baseline and week 48 were excluded (n = 34), resulting in a total of 412 study participants included in the primary analyses. Study participants with detectable cotinine concentrations (>5 ng/ml) at both visits were categorized as current smokers, and those with undetectable cotinine levels at both the baseline and 48 week visits were classified as nonsmokers (Figure 1).
The approach of classifying smoking status based on serum cotinine was examined in an independent population that included 691 RA patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry (23, 24). The VARA participants examined were primarily men (93%), had a mean ± SD age of 68 ± 11 years, and 26% (n = 180) had self-reported current smoking status concurrent with the blood draw. The information specific to other forms of tobacco use or nicotine replacement therapy was not routinely available for VARA participants. There was excellent concordance of any detectable serum cotinine (sensitivity 0.94, specificity 0.85) with self-reported current smoking status. The corresponding area under the receiver operating curve was 0.90. Serum cotinine has a circulating half-life of ∼20 hours and may be detectable for several days following exposure to tobacco (25). Additionally, the manufacturer of the ELISA kit used for the cotinine analysis reports performance characteristics, including the ability to detect cotinine in samples taken from nonsmokers exposed to passive inhalation for over 30 days.
Demographic and RA-related characteristics were compared between the current smokers and nonsmokers using the Student's t-test for continuous values and the chi-square test for categorical values. To assess for the possibility of participation bias, we also compared the same characteristics between those with available cotinine values at any time point (n = 607) and those not participating in the DNA banking substudy (n = 148) (Figure 1). The association of smoking status with the mean DAS28 scores from week 48 and week 102 was examined using analysis of covariance, adjusting for the baseline DAS28 score. In secondary analyses using the chi-square test, we also examined the association of smoking status with treatment response based on the European League Against Rheumatism (EULAR) improvement criteria (26), including the frequency of those attaining a good response or remission. These analyses were done in the overall trial group as well as in the different treatment arms included in the TEAR study. Based on reports that smoking may be a risk factor for treatment-related infection (27, 28), we also explored whether smoking was associated with the occurrence of serious adverse events (AEs), study withdrawal, and serious infections (categorized as any serious infection or a serious respiratory infection, including bronchitis and/or pneumonia). Given the relatively low frequency of serious AEs in the TEAR study and resulting modest study power, these analyses were considered exploratory. Recognizing that randomization was not stratified by smoking status for the parent study, we also examined whether the primary results changed after adjustments for factors, including age, sex, race, disease duration, patient global assessment, Health Assessment Questionnaire (HAQ) score, functional status, and comorbidities (including self-reported cardiovascular or respiratory conditions). An additional subanalysis included the evaluation of the primary outcome limited to women. To further examine the possibility that the results may have been impacted by differential dropout/withdrawal between smokers and nonsmokers, we performed a sensitivity analysis including all participants with available serum (n = 607) using a last observation carried forward (LOCF) imputation. We also examined whether heavy smoking, defined as a serum cotinine concentration >100 ng/ml, was associated with treatment response using the approach defined above. All analyses were completed using SAS, version 9.2.
Of the 607 participants with cotinine values available at baseline or week 48, a total of 412 participants were included in the primary analysis, with 293 (71%) categorized as nonsmokers and 119 (29%) categorized as current smokers. Of these, 94 were classified as heavy smokers at baseline, defined as a serum cotinine concentration >100 ng/ml. There were no differences in age, sex, and other RA-related factors between the 607 participants with serum available and the 148 participants randomized but not participating in the DNA/serum banking substudy. A summary of the participant baseline characteristics is shown in Table 1. The patient characteristics were similar between the 2 groups, including age, sex, race, disease duration, body mass index, and cardiovascular disease at baseline, with the exception that current smokers had higher baseline patient and physician global assessment scores (P < 0.001 and P = 0.030, respectively) and were more likely to have a history of respiratory disease (P = 0.017). Additionally, a significantly higher proportion of current smokers had worse functional status compared to nonsmokers, since current smokers were more likely to be in functional class II or III. There was no significant difference in the number of participants withdrawing from the study during the 2-year trial based on smoking status (data not shown).
Table 1. Baseline participant characteristics for those with concordant cotinine values at baseline and at 48 weeks (n = 412)*
Total (n = 412)
Nonsmokers (n = 293)
Current smokers (n = 119)
Current vs. nonsmokers, P
Values are the mean ± SD unless otherwise indicated. BMI = body mass index; CV = cardiovascular; RA = rheumatoid arthritis; DAS28 = Disease Activity Score in 28 joints; ESR = erythrocyte sedimentation rate; HAQ = Health Assessment Questionnaire.
There was no significant difference in the primary outcome (mean DAS28 score at weeks 48 and 102) based on smoking status among overall study participants (P = 0.881). Likewise, there were also no differences in outcomes when stratified by the TEAR study treatment groups (Figure 2 and Table 2) or when a multivariate analysis was performed adjusting for age, sex, race, disease duration, patient global assessment, HAQ score, functional status, cardiovascular disease, and respiratory disease (P = 0.755). An additional subanalysis of the primary outcome after limiting to women again showed no significant difference in treatment response based on smoking status (P = 0.962). Figure 2 shows the DAS28 values over time for participants assigned to receive ETN + MTX as either immediate combination or as step-up therapy, participants assigned to receive triple therapy as either immediate combination or as step-up therapy, participants assigned to receive initial MTX monotherapy followed by step-up therapy as needed, and participants assigned to receive initial combination therapy, either ETN + MTX or triple therapy. Table 2 shows a summary of the treatment results for the overall study population in addition to the treatment results for participants specifically assigned to an immediate combination of ETN + MTX, participants assigned to immediate triple therapy, participants assigned to initial MTX monotherapy with the addition of ETN if needed, and participants assigned to initial MTX monotherapy with escalation to triple therapy if needed. There were no differences in DAS28 outcomes by smoking status using the earlier time points of 24 and 48 weeks. Using the secondary outcomes of good response or remission as defined by the EULAR response criteria, there was again no difference based on smoking status overall or by treatment group at any time point. Good response as defined by the EULAR response criteria was observed in 62.5% of current smokers and 56.3% of nonsmokers at 48 weeks (P = 0.552). Remission was reached by 35% and 32.6% of current smokers and nonsmokers at 48 weeks, respectively (P = 0.642). The LOCF imputation method was used for the sensitivity analysis of all subjects with serum available (n = 607), with no significant difference of change in DAS28 scores observed between current smokers and nonsmokers (data not shown). The number of participants initially receiving MTX monotherapy and not reaching a DAS28 score of ≤3.2 at 6 months whose therapy was subsequently stepped up per study protocol was not significantly different based on smoking status (74% of current smokers received treatment escalation versus 77% of nonsmokers; P = 0.649). We also found no difference between heavy smokers, defined as having a serum cotinine concentration >100 ng/ml, and nonsmokers in treatment response (P = 0.446).
Table 2. Mean ± SD DAS28 scores in the overall and treatment groups among current smokers and nonsmokers (n = 412)*
P value represents the difference (current smokers versus nonsmokers) in the mean DAS28 score at weeks 48–102 after adjusting for the baseline value. The numbers of participants by treatment arm are active etanercept + MTX (n = 143), active triple therapy (n = 69), step-up etanercept (n = 136), and step-up triple therapy (n = 64).
5.8 ± 1.0
5.8 ± 1.1
3.17 ± 1.3
3.14 ± 1.3
Active etanercept + MTX
5.9 ± 1.1
5.7 ± 1.0
3.01 ± 1.3
3.07 ± 1.2
Active triple therapy
5.7 ± 1.0
5.7 ± 1.3
3.24 ± 1.3
3.15 ± 1.9
5.6 ± 1.1
6.1 ± 1.1
3.31 ± 1.3
3.20 ± 1.4
Step-up triple therapy
5.8 ± 0.9
5.9 ± 1.0
3.07 ± 1.4
3.23 ± 1.1
In further exploratory analyses, we found no significant differences between current smokers and nonsmokers in the frequency of serious AEs both overall and based on the treatment group (Table 3). Additional subanalyses of infectious AEs and respiratory infections (serious and nonserious) again showed no differences based on smoking status.
Table 3. Frequency of serious adverse events among nonsmokers and current smokers overall and based on treatment group
Etanercept + methotrexate
The TEAR study provides the only randomized, double-blind, placebo-controlled trial comparing oral triple therapy to combination therapy with ETN + MTX for the treatment of early RA with poor prognostic factors, and therefore supplies an ideal context to investigate the potential relationships between important environmental factors, such as tobacco use, on the treatment response to these therapies. We observed no significant differences in the primary outcome, the mean DAS28 score between weeks 48 and 102, between participants identified as current smokers and nonsmokers. Although few studies to date have investigated smoking as a predictor of treatment response, our results conflict with the currently available evidence (18, 29–32). Saevarsdottir et al observed significantly lower rates of RA treatment response with MTX or TNF inhibition among current smokers compared to those reporting a never smoking status, although the primary outcome measured was response to treatment after only 3 months of therapy (32). Hyrich et al specifically reported on the predictors of response to selective anti-TNFα therapy in RA and showed that current smoking was associated with a lower response rate with infliximab, although this was only significant on multivariate analysis (18). Similar results were not observed in relation to the use of other anti-TNFα agents, including ETN (18).
To date, all reported analyses of a potential relationship between smoking status and response to either DMARD or biologic therapy have come from observational or other open-label studies (17, 18, 29–32). The present analysis is unique for its use of data generated from a randomized, double-blind, placebo-controlled trial design. In addition to the difference in study design of the parent studies, the reasons underpinning the discrepant results of our study might include differences in patient populations, outcome assessments, and exposure measurements. For example, prior studies have used self-reported smoking history, while the present study used an indirect measure of smoking by measuring circulating cotinine. Regardless, the ability to identify which patients will be most likely to respond to specific therapies could be beneficial by theoretically allowing more targeted therapy to minimize unnecessary toxicities and to maximize beneficial effects. However, based on our findings, smoking status may not be a targetable environmental factor in the optimization of RA treatment responses.
The limitations to this study include the number of participants lost to analysis due to the unavailability of serum for the cotinine analysis related to either study withdrawal (prior to the 48-week assessment) or not participating in the biospecimen banking protocol. However, even when using the LOCF imputation method in the sensitivity analysis that included all subjects for whom any serum measure was available, still no significant difference in treatment response among current smokers compared to nonsmokers was found. Although we cannot definitively exclude the possibility of a participation bias, the similarities between those included and those not included in the analyses suggest that this does not serve as a major source of study bias. It is also important to recognize the possibility of exposure misclassification caused by our definitions of current smoking and nonsmoking that were based entirely on the presence of circulating cotinine. Although we found this measure to have excellent discrimination in an independent RA cohort, it is possible that other forms of tobacco (e.g., chewing tobacco) or nicotine replacement therapy could serve as sources of misclassification. It is possible that the individuals in this study with a history of biologically irrelevant secondhand exposure to cigarette smoke could have been misclassified as current smokers. None of the previous studies used a biologic method to determine smoking status, such as serum cotinine; they instead depended on self-reported smoking status. Additionally, because the TEAR cohort included patients with a more severe disease phenotype treated with a finite list of disease-remitting therapies, the results may not be generalizable to patients with less active RA or those receiving alternative therapies.
Although these results do not support an association of tobacco exposure with treatment response, this does not diminish the paramount importance of smoking cessation in patients with RA. Among RA patients who smoke, effective cessation strategies remain essential for general health considerations, including risk modification of cardiovascular disease, a major cause of morbidity and excess mortality in this patient population. However, our data would suggest smoking cessation alone may not be an important adjunct in lessening disease activity or modifying therapeutic response to commonly used disease-remitting treatments in RA. Additional studies will be needed in the context of randomized controlled trials to replicate these findings, as well as to examine the potential impact of therapies not investigated in the TEAR study.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Mikuls had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. O'Dell, Moreland.
Acquisition of data. O'Dell, Curtis, Moreland.
Analysis and interpretation of data. Maska, Sayles, O'Dell, Curtis, Bridges, Moreland, Cofield, Mikuls.
ROLE OF THE STUDY SPONSOR
Amgen, Pharmacia, and Barr Pharmaceuticals had no role in the study design or in the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit the manuscript for publication. Publication of this article was not contingent upon approval by Amgen, Pharmacia, or Barr Pharmaceuticals.
We thank the TEAR Data and Safety Monitoring Board (Michael Weinblatt, MD, David Wofsy, MD, Mark Genovese, MD, and Barbara Tilley, MD) and the external medical safety monitor (Dr. Gene Ball). We appreciate the support of all the clinical investigators, their staff, and all of the patient participants.