Smoking Knocks Breath out of TNFi for Axial Spondyloarthritis

Neil Osterweil

February 12, 2015

Smoking may weaken the effects of tumor necrosis factor inhibitors (TNFis) in patients with axial spondyloarthritis (axSpA), Swiss investigators caution.

A study of nearly 500 patients started on a TNFi for axSpA showed that current smokers with elevated levels of C-reactive protein (CRP) at baseline had significantly smaller reductions in disease activity scores after 1 year than did nonsmokers.

"Whether quitting smoking might ameliorate the course of disease during treatment with TNFi remains to be confirmed in prospective studies," write Adrian Ciurea, MD, from the Department of Rheumatology at University Hospital Zurich, Switzerland, and colleagues.

The study was published online February 9 in the Annals of the Rheumatic Diseases.

The investigators note that smoking has been implicated in diminished response to TNFi and other disease-modifying antirheumatic drugs in patients with rheumatoid arthritis (RA), and that smokers with psoriatic arthritis have also been shown to have a poorer response to treatment with a TNFi.

"The effect is well known in rheumatoid arthritis.... [I]t's also well known in RA that smoking effects citrullination, which is important because when there is more citrullination, there is more production of cyclic citrullinated peptides antibodies.... [P]eople who have those antibodies typically tend to have more severe disease and are less likely to respond to biologic agents, including anti-TNFs," commented Prabha Ranganathan, MD, associate professor of medicine in the Division of Rheumatology at Washington University School of Medicine in St. Louis, Missouri. Dr Ranganathan was not involved in the study.

However, as Dafna D. Gladman, MD, professor of medicine at the University of Toronto, Ontario, Canada, told Medscape Medical News, patients with axSpA lack the characteristic rheumatoid factors seen in RA, suggesting a different mechanism is at play in axSpA. Dr Gladman also was not involved in the study.

Longitudinal Study

To see whether smoking might have the same effect on TNFi use in axSpA as it does in RA, Dr Ciurea and colleagues took a retrospective look at data from patients recruited into the longitudinal Swiss Clinical Quality Management Cohort for axSpA. They identified a total of 698 patients for whom data on smoking status were available and who had a baseline or follow-up Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score or Ankylosing Spondylitis Disease Activity Score (ASDAS).

In all, 38.4% of patients reported being current smokers, 23.9% were former smokers, and 37.7% reported being nonsmokers.

The investigators found that current smokers had significantly smaller reductions of BASDAI scores than nonsmokers.

The investigators also determined that for the primary outcome of response to a first TNFi in ever-smokers vs never-smokers at 1 year, smoking was associated with a 0.75-unit lower drop in BASDAI score (P = .005) and a 0.69-unit lower decline in ASDAS (P = .001) among all patients with an elevated baseline CRP. Although smokers with normal baseline CRP levels tended to have smaller reductions than nonsmokers with normal CRP on both the BASDAI and ASDAS scales, the differences were not statistically significant.

For smokers, the odds ratio (OR) for achieving at least a 50% improvement in BASDAI response criteria after 1 year compared with nonsmokers was 0.54 (P = .03). Similarly, the OR for achieving at least a 40% improvement on the ASDAS scale at 1 year among smokers was 0.43 (P = .004).

The authors also created multiple adjusted logistical models to look at potential confounders on the effects of TNFi over time on BASDAI course. They identified a total of 490 patients for whom data on all potential covariates were available. These included sex, education level as a proxy for socioeconomic status, exercise, age, disease duration, human leucocyte antigen B27 status, classification (either ankylosing spondylitis or nonradiographic axSpA), and body mass index.

Among patients with both normal and elevated baseline CRP levels, disease classification (nonradiographic axSpA vs ankylosing spondylitis) was the only consistently significant predictor, other than smoking status, of a difference in disease activity scores.

"Not Really Surprising"

Dr Ranganathan said that although the study is interesting, it is unlikely to spur a significant change in practice.

"I don't think the data are powerful enough to tell us that's what we should do," she said.

Dr Gladman noted that the study supports what clinicians already know about the harmful effects of smoking.

"The question is, is there a direct biological effect? There are a number of drugs that may be hampered by nicotine, which may inhibit whatever enzyme system is necessary to metabolize these drugs, but I don't know if anything like that has been shown with anti-TNF agents," she said.

Dr Ciurea and colleagues say the cause of the link between smoking and diminished response to TNFi is unclear.

"In addition to interference with pharmacokinetic and pharmacodynamic characteristics of TNFi, other factors might be involved. Smoking may not only raise CRP levels in a dose-dependent manner, it may also increase pain levels by influencing neurological processing of sensory information or by unspecific tissue damage due to hypoxia or vasoconstriction. Additionally, physical exercise has been often regarded as a confounder, as exercise may improve disease activity and function, and smokers may exercise less," they write.

The study was supported by grants from the Stiftung für Rheumaforschung and the Schweizerische Bechterew-Stiftung. The Swiss Clinical Quality Management Foundation, which provided data management and support, was financially supported by the Swiss Society of Rheumatology, the Balgrist Foundation, the ARCO Foundation, Abbvie, Bristol-Myers-Squibb, Merck Sharp & Dohme, Pfizer, Roche, and UCB. Dr Ciurea has received consulting and/or speaking fees from Abbvie, Merck Sharp and Dohme, Pfizer, UCB, Celgene, and Jannsen-Cilag. Dr Ranganathan and Dr Gladman have disclosed no relevant financial relationships.

Ann Rheum Dis. Published online February 9, 2015. Full text

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