Smoking Reduces Response to Early RA Treatments

Janis C. Kelly

January 06, 2011

January 6, 2011 — Patients with early rheumatoid arthritis (RA) who smoke are likely to develop more aggressive disease progression that does not respond well to either methotrexate (MTX) or tumor necrosis factor (TNF) inhibitors, Swedish researchers reported in the January issue of Arthritis & Rheumatism.

The study, by Saedis Saevarsdottir, MD, and researchers from the Karolinska Institute in Stockholm, also found that smoking cessation before diagnosis was associated with near-normal treatment responsiveness.

Dr. Saevarsdottir told Medscape Medical News: "RA patients should be strongly encouraged to stop smoking and [be] informed that smokers had a 50% less chance of responding well to the treatment compared to nonsmokers, while the chance [of responding well to treatment] in previous smokers did not differ from that in never smokers. At our early arthritis clinic, a smoking cessation program has now been initiated."

Current smokers have more aggressive RA and are less responsive to treatment.

Past smokers responded equally well to treatment as those who had never smoked. "Whether discontinuation of smoking prior to initiating treatment is beneficial remains to be studied further. Meanwhile, the findings provide a strong impetus for clinicians to include measures against smoking as a fundamental part of the therapeutic armamentarium in RA care," Dr. Saevarsdottir said.

In this analysis, all patients who had stopped cigarette smoking before the diagnosis and treatment start — irrespective of when they stopped — were defined as past smokers. "We also evaluated whether the accumulated dose, measured by pack-years (1 pack-year equals 20 cigarettes a day for 1 year), influenced response in the groups of current or past smokers, which was not the case, so it seems to be the actual smoking status which matters," Dr. Saevarsdottir explained.

The researchers used clinical data for 1430 patients entering the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study between 1996 and 2006. EIRA is a population-based case-control study in Sweden comprising patients with RA between the ages of 18 and 70 years who were enrolled, on average, 10 months from symptom onset and within 1 year of diagnosis. Of the participants, 873 started MTX monotherapy on entering EIRA, and 535 started TNF inhibitor therapy, on average 3 years after the diagnosis.

The primary outcome was good response according to European League Against Rheumatism criteria at the 3-month visit. Smokers were less likely than never-smokers to achieve a good response after 3 months receiving MTX (27% vs 36%; P = .05) or TNF inhibitors (29% vs 43%; P = .03).

In multivariate analysis that included clinical, serologic, and genetic factors, current smoking was associated with less chance of a good response (adjusted odds ratio for 3 months, 0.61; 6 months, 0.65; 1 year, 0.78; 2 years, 0.66; 5 years, 0.61). Past smoking history did not affect the patients' response to MTX or TNF inhibitors.

"We also found that only 14% of current smokers who did not start any disease-modifying treatment at baseline reached the good response category after 3 months compared to 34% of RA patients who never smoked," Dr. Saevarsdottir said.

The new data also suggest that smoking might affect RA susceptibility and RA progression by different routes.

"Cigarette smoking is a well-known risk factor for getting RA, particularly the anti-[cyclic citrullinated peptide (CCP)]-positive subset, but anti-CCP status had no modifying effect on the association of current smoking with response. Thus, the mechanism through which smoking influences susceptibility to RA and its disease course, respectively, may differ," Dr. Saevarsdottir said.

The authors recommend further studies to determine whether discontinuation of smoking before initiating treatment would be beneficial. Dr. Saevarsdottir concluded: "Our findings provide strong evidence that clinicians should include smoking cessation programs as part of their standard therapeutic arsenal in caring for patients with RA."

The results of this study also have implications for design of clinical trials testing new RA agents.

"Smoking should be taken into account when trying to evaluate or predict response to antirheumatic agents, as the decreased likelihood of response in smokers was observed for the first- and second-line treatments today, and also in the whole group, irrespective of which treatment was used," Dr. Saevarsdottir said.

Dr. Alan Silman, professor of rheumatic disease epidemiology at the University of Manchester, United Kingdom, reviewed the study for Medscape Medical News.

He said: "This study adds to the overwhelming data to suggest if a patient develops [RA], then they should stop smoking. Not only (as we knew before) does smoking make the disease more severe, but [RA] is associated with an increased [cardiovascular disease] risk, and stopping smoking must be beneficial, and smoking may limit effectiveness of [RA] treatment."

Dr. Silman was not surprised by the results because "current cigarette smoking (more than ex-smoking) is related to onset and severity of [RA], suggesting that smoking is associated with disease activity. Thus treatment aimed at suppressing disease has a 'harder job,' given the continuing exposure to the pro-inflammatory effects of smoking." He suggested that researchers whose anti-TNF trials have been completed might analyze within their treatment groups the outcomes in those exposed or not exposed to cigarettes during the trial.

Similarly, Kenneth Saag, MD, told Medscape Medical News: "This study is based on one of the premier epidemiologic cohorts for studying RA, and the results are consistent with what others have seen in other cohorts: Smoking is associated with more severe RA and lower response to treatment. It provides more support for saying to the patient who has early RA that he or she should stop smoking or risk more aggressive disease progression."

Dr. Saag is professor of medicine in the Division of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham and director of the university's Center for Outcomes and Effectiveness Research and Education.

The EIRA study was supported by grants from the Swedish Medical Research Council, the Stockholm County Council, the Flight Attendant Medical Research Institute, the Swedish Council for Working Life and Social Research, King Gustaf V's 80-Year Foundation, the Swedish Rheumatism Association, the Swedish Combine project, and the European Community Sixth Framework Programme (project AutoCure). Dr. Saevarsdottir, Dr. Silman, and Dr. Saag have disclosed no relevant financial relationships. One study author reports receiving consulting fees, speaking fees, and/or honoraria from Wyeth and Bristol-Myers Squibb.

Arthritis Rheum. 2011;63:26-36. Abstract.

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