In this large UK cohort of axSpA participants, smoking was associated with significantly worse disease severity at initiation of TNFi therapy. However, TNFi discontinuation was not associated with baseline smoking status. Our results also did not provide evidence that smoking affected discontinuation due to infection-related or other adverse events. The results did suggest that current smokers may have higher risk of discontinuation due to inefficacy or other reasons.
The main strengths of this study are the quality of data and use of rigorous analyses. The BSRBR-AS cohort is representative of UK clinical practice, and its rich dataset allowed us to adjust for a large number of confounders. The use of inverse-probability weights allowed us to conduct improved time-to-event analysis for each cause of TNFi discontinuation (competing risk events), while accounting for baseline differences between exposure groups and time-varying disease activity within one model.
Our data did have some important limitations. While smoking has been recorded in detail, information on time since smoking cessation was not recorded. The proportion stopping due to adverse events was higher, while inefficacy was much lower, than reported elsewhere; nevertheless, the proportion of TNFi discontinuation was in keeping with existing literature. In clinical practice, there is often an overlap between how inefficacy and adverse events are defined and reported. For instance, inflammation in previously unaffected peripheral joints may be reported as an adverse event, when it would more appropriately reflect lack of disease control and efficacy; therapy is more likely to continue in the face of mild adverse events if they are highly effective for symptom control. Before 2016—that is, the majority of this study period—the UK National Institute for Health and Care Excellence stipulated that patients who did not demonstrate initial or maintained response to treatment would not be funded to use a second TNFi.[17,18] However, switching to a second TNFi was allowed if discontinuation was due to the development of a treatment-related adverse event. This may have influenced labelling of discontinuation as adverse events or other reasons. These errors would not affect analysis of all-cause discontinuation or discontinuation due to infection-related adverse events. It would have been interesting to examine the effect of changing smoking status at the individual level, but the number of such participants was too small to permit analysis. It is possible that TNFi stop dates in medical notes may be influenced by recall error; however, there is no evidence to suggest that such error differs according to smoking status, so we do not believe this will have introduced a bias. Lastly, the BSRBR-AS did not record pack-years to examine the effect of cumulative exposure. A significant effect is unlikely since none was found for ever vs never smokers.
There has been only one previous study of TNFi discontinuation and smoking in ankylosing spondylitis. Glintborg et al. reported increased risk of all-cause TNFi discontinuation in current and ex-smokers. Compared to their study, our follow-up period was short. It is possible that differences in treatment persistence only becomes apparent with longer follow-up, although separation in Kaplan-Meier curves was clear by 2 years in their study. Importantly, Glintborg et al. did not adjust for baseline differences in disease severity and BMI from their primary analysis, on account of the fact that these variables are potential mediators. Without adjusting for these known predictors of TNFi persistence,[5,19] it is difficult to attribute a causal effect of smoking on TNFi discontinuation. In DANBIO studies of psoriatic arthritis, significant differences in TNFi persistence were reported when analyses did not adjust for BMI and baseline disease severity, while analysis using essentially the same cohort but additionally adjusting for these covariates did not find such difference (see Additional file 1: Table S4 for comparison).
Our negative results may have other explanations. The prevalence of current smoking was higher in DANBIO (43%) than in the BSRBR-AS (29%). Furthermore, we did not find smoking to be associated with age of symptom onset as previously reported. It is possible that there are differences between the study cohorts. Our results are consistent with a growing body of evidence that smoking status does not independently impact TNFi treatment. In a study of obesity and TNFi response in axSpA, current smoking (as a covariate in their multivariable Cox regression model) was not associated with TNFi discontinuation (HR 0.92; 95%CI 0.66 to 1.28). Smoking status at TNFi initiation also did not affect treatment response in several studies,[2,19,22–25] including a recent analysis of the BSRBR-AS. These results should persuade clinicians to dispel any subconscious bias that smokers may not benefit as much from TNFi treatment.
We cannot exclude the possibility that smoking in early stages of the disease causes more severe disease observed at TNFi initiation. It is unknown whether smoking cessation improves disease severity irrespective of treatment. Smoking cessation remains a priority since patients with rheumatic diseases have high burdens of cardiovascular disease and the combined impact of TNFi and smoking on malignancy risk is unknown. Furthermore, smoking may be associated with greater radiographic progression.
Arthritis Res Ther. 2019;21(177) © 2019 BioMed Central, Ltd.
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