Impact of Smoking in Cutaneous Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect nearly every organ system. Between 59% and 85% of patients with SLE develop dermatologic involvement, including cutaneous lupus erythematosus (CLE), although patients can frequently have CLE in the absence of SLE.¹ The specific manifestations of CLE are diverse and can be grouped into 3 major subtypes: acute, subacute, and chronic CLE.¹ In addition, patients with SLE can develop lupus-related skin disease other than CLE, referred to herein as SLE with nonspecific skin involvement. Several recent publications^{2 - 3} have looked at the impact of tobacco, specifically cigarette smoking, on CLE. In this article, we report the results of an ongoing prospective database study that looked at differences between patients with lupus who were never, past, or current smokers.

Patients with lupus presenting to the outpatient medical dermatology clinic at the University of Pennsylvania, Philadelphia, were enrolled in an ongoing database study on the prevalence and severity of lupus. All patients older than 18 years with clinical, histologic, or serologic evidence of lupus were invited to participate in the study. The study protocol was approved by the institutional review board at the University of Pennsylvania.

Data were analyzed for all the patients enrolled in the lupus database from initiation of the study on January 5, 2007, through July 30, 2010. A total of 218 individuals were enrolled during this time span. Fifteen of these individuals were not included in the analyses because they had not yet had their first study visit (consented only). Five individuals were excluded because they either gave conflicting information about their smoking habits (n  =  3) or did not complete smoking-related questions (n  =  2). One individual was excluded because of a problem with the consent form, leaving 197 patients with lupus included in the analyses. To measure the severity of lupus-specific skin disease, a validated scoring system, the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), was used.⁴

Patients in the lupus database were assessed for differences in smoking status by CLE subtype (acute, subacute, and chronic CLE) using a Fisher exact test. All the patients with lupus were then divided into 2 groups: SLE with skin involvement, which included patients with SLE and either a specific CLE subtype or lupus nonspecific skin disease, and CLE only, which consisted of individuals with CLE not meeting the criteria for SLE. Data for these groups were then analyzed for differences in smoking status using χ² tests. The results of this analysis are reported as proportions (Figure 1).

CLASI scores were used to assess for differences in disease severity in patients with CLE with active skin disease based on smoking status. Of the 197 participants with lupus, 7 did not have CLASI scores recorded at visit 1 and were subsequently excluded from this analysis. In addition, 41 individuals did not have active skin disease at enrollment (CLASI score of 0) and were also excluded. To test whether these 41 individuals differed by smoking status, a Fisher exact test was used. To compare differences in smoking status of the 149 participants with CLE with active disease at enrollment, Kruskal-Wallis and Dunn multiple comparison tests were used. Results are reported as median with interquartile range (Figure 2).

We then analyzed participant responses to the modified Skindex 29+3 questionnaire, a commonly used tool in dermatology to measure patient quality of life that can be divided into 4 subsets: function, emotion, symptoms, and photosensitivity.⁵ For analysis, we used the same initial pool of individuals as shown in Figure 2, with the exclusion of 3 never smokers, 4 past smokers, and 1 current smoker because they did not complete the questionnaire at enrollment. Results of Kruskal-Wallis and Dunn multiple comparison tests are reported as median with interquartile range (Figure 3).

Participants with CLE were divided into 2 different treatment groups: those treated with only antimalarial drugs during enrollment (AM only) and those who were also treated with at least one additional immunomodulator drug (AM + IM). Table 1 lists participant characteristics within these groups and the criteria for exclusion from this particular analysis. For this study, immunomodulators included methotrexate, azathioprine sodium, mycophenolate mofetil, rituximab, thalidomide, oral corticosteroids, dapsone, cyclophosphamide, and lenalidomide (Table 2). Participants with SLE were compared between the AM-only and AM  +  IM groups using the Fisher exact test, and the results are reported as proportions.

Specific antimalarial regimens for each participant included in the AM-only and AM + IM groups were assessed and compared by smoking status using a χ² test, and the results are reported as proportions (Table 3). In addition, never and past smokers were combined into 1 nonsmoking group and were compared with current smokers using the Fisher exact test. Participants with SLE were compared between the AM-only and AM + IM groups using the Fisher exact test, and the results are reported as proportions. Mean CLASI scores were compared between each group at each time point, and the results of 1-way analysis of variance with post hoc Tukey tests are reported.

To analyze treatment response, the following set of rules was followed: CLASI scores at visit 1 were recorded for each participant. CLASI scores were then recorded at a visit within 2 to 7 months of visit 1. If a participant had multiple visits in this time frame, the visit closest to 2 months was used. CLASI scores at least 8 months after visit 1 were then recorded. If an individual had multiple visits in this time frame, the visit closest to 12 months was used. For visits missing CLASI scores, the next closest visit with a recorded CLASI score was used. Per-patient CLASI activity change scores between visits were calculated, and Kruskal-Wallis tests were used to assess differences between smoking groups for each follow-up visit (visit 1 to the 2- to 7-month time point and visit 1 to the ≥8-month time point). Results are presented as median with interquartile range (Table 4).

In the lupus database, patients with acute (n  =  11), subacute (n  =  46), and chronic (n  =  116) CLE had no significant differences in smoking status (P  =  .12). The CLE-only group consisted of 34% never smokers, 27% past smokers, and 39% current smokers. Never smokers represented a much higher proportion in the SLE with skin involvement group (62% never smokers, 12% past smokers, and 26% current smokers), and differences between the SLE with skin involvement and CLE-only groups were significant (P   <  .001) (Figure 1).

Among participants with CLE with CLASI scores of 0 recorded at enrollment, there were no differences in smoking status (P  =  .13). Of the 149 participants with active disease (CLASI score >0) at enrollment, 63 (42%) were never smokers, 36 (24%) were past smokers, and 50 (34%) were current smokers. For comparison, in 2009, the percentage of adults 18 years and older who were current smokers was 20.6%.⁶ Current smokers had significantly higher median CLASI scores at enrollment: 7.0 for never smokers, 6.0 for past smokers, and 9.5 for current smokers (P  =  .02, post hoc Dunn test indicated significant differences between never and current smokers [P   <  .05] and past and current smokers [P   <  .05]) (Figure 2).

Results of the quality-of-life analysis indicated that current smokers trended toward higher scores in all 4 subsets of the Skindex 29+3 (Figure 3). Differences were significant in the symptom subset between never and current smokers (P   <  .05) and between past and current smokers (P   <  .01) and in the function subset between past and current smokers (P   <  .05).

Of the 50 patients with CLE in the AM-only group, 17 (34%) were never smokers, 14 (28%) were past smokers, and 19 (38%) were current smokers. Of the 57 individuals with CLE in the AM + IM group, 29 (51%) were never smokers, 9 (16%) were past smokers, and 19 (33%) were current smokers (Table 1). Mean CLASI scores at enrollment for never smokers were 7.8 for the AM-only group and 11.1 for the AM  +  IM group, for past smokers were 6.6 and 9.7, and for current smokers were 7.8 and 11.8 (P  =  .14, P   >  .05 for all post hoc comparisons), respectively. Oral corticosteroids were the most commonly used immunomodulator drugs, followed by mycophenolate, methotrexate, and azathioprine (Table 2). Participants with SLE were much more likely to be included in the AM + IM group (67% vs 8% in the AM-only group, P   <  .001). In addition, of the 35 individuals taking oral corticosteroids, 29 had a diagnosis of SLE (83%).

When the AM-only and AM + IM groups were combined, current smokers treated with hydroxychloroquine sulfate trended toward higher rates of quinacrine hydrochloride use than never and past smokers (P  =  .08) (Table 3). Nonsmokers had significantly lower rates of concomitant quinacrine and hydroxychloroquine use compared with current smokers (P  =  .04). Mean CLASI scores at enrollment for never smokers were 7.8 for the AM-only group and 11.1 for the AM + IM group, for past smokers were 6.6 and 9.7, and for current smokers were 7.8 and 11.8 (P  =  .14, P   >  .05 for all post hoc comparisons).

Table 4 summarizes the median CLASI change at each follow-up visit for both treatment groups. Current smokers in the AM-only group had greater improvement than did never or past smokers at the 2- to 7-month (P  =  .02) and 8-month and longer (P  =  .24) follow-up visits. In the AM + IM group, never smokers had greater improvement than past or current smokers at the 2- to 7-month (P  =  .07) and 8-month and longer (P  =  .04) follow-up visits.

Results of previous studies have suggested that smoking is associated with CLE in general⁷ and with discoid lupus erythematosus,^{8 - 9} tumid lupus,³ and subacute CLE¹⁰ in particular. Although the present data indicate that the acute, subacute, and chronic CLE groups were not statistically significantly different from each other in terms of smoking status, the fact that individuals in the CLE-only group had a higher percentage of current smokers than did the SLE with skin involvement group is of interest. A similar difference was also noted in a recently published prospective study² in which the authors found that 53.5% of individuals with CLE with 4 or more American College of Rheumatology criteria for SLE were current smokers vs 84.6% with fewer than 4 American College of Rheumatology criteria.² Additional studies^{11 - 12} have shown that smoking may be associated with SLE, and the present data seem to suggest an even greater association with CLE.

Data presented in Figure 2 support several recent studies^{3 ,13} that have suggested that current smokers with CLE tend to have greater disease activity than do nonsmokers. Although a pathophysiologic mechanism for this difference has not been determined, several leading hypotheses were recently summarized by Kreuter et al.³ Briefly, tobacco smoke has been shown to increase inflammatory cytokines, apoptosis, certain autoantibodies, the development of free radicals, and microparticles and is known to be phototoxic.^{14 - 20} Many of these same factors are associated with lupus, and they may be working separately or in tandem to increase CLE disease activity in current smokers compared with nonsmokers.

Current smokers with CLE also have worse quality of life than do never or past smokers. Although not all differences were statistically significant, current smokers had higher median scores in all Skindex 29+3 subsets, suggesting that the statistically significant increase in CLASI scores in current smokers also has clinical relevance because these participants also had worse quality of life.

Participants in the AM + IM treatment group were more likely to have SLE than were those in the AM-only group, and, thus, the additional immunomodulators may have been added for increased systemic lupus activity and not necessarily for skin activity specifically. However, by using the CLASI, it was possible to assess for cutaneous improvement irrespective of why patients with lupus were taking additional medications. Furthermore, 38% of participants in the AM-only group were current smokers compared with 33% in the AM + IM group. This difference suggests that current smokers were not any more likely to be treated with additional immunomodulators, despite the fact that they were more often treated with hydroxychloroquine and quinacrine rather than with hydroxychloroquine alone.

Previous studies have shown that current smokers are more likely to have refractory disease than are nonsmokers⁵ and that antimalarial agents may be less effective in patients with CLE who smoke.^{3 ,21 - 23} In contrast, a small prospective study²⁴ in France examined 26 patients with CLE treated with antimalarial drugs and found similar rates of smoking in responders and nonresponders. The present results showed that current smokers did worse when treated with a combination of antimalarial drugs and immunomodulators but when treated with antimalarial drugs alone actually responded better than nonsmokers. One possible explanation for this difference centers on the fact that mean CLASI scores at enrollment trended higher in the AM + IM group than in the AM-only group regardless of smoking status. It is possible that response to antimalarial therapy is worse in current smokers with higher CLE activity but not necessarily when activity is lower. Further studies are necessary to test this hypothesis. Another possible explanation is that quantity of smoking has an effect on antimalarial response. A weakness of the study presented herein is that the number of cigarettes smoked was not initially requested. Perhaps there is a threshold number of cigarettes that need to be smoked during a given period before differences in antimalarial response between smokers and nonsmokers are manifested.

Data presented herein enhance the current literature by showing in a prospective cohort study that current smokers with lupus have worse disease, have worse quality of life, and respond worse to treatment when requiring both antimalarials and immunomodulators. Together, these data further strengthen the need for smoking cessation in the CLE population.