We report a case-control study demonstrating a strong association between cigarette smoking and uveitis. After adjusting for differences in age, race, gender, and median income, we demonstrated that smoking was significantly associated with an increased odds of having any anatomical subtype of uveitis, with an overall odds ratio of 2.2 for smokers (either past or current) compared with those who had never smoked. This is comparable to the odds ratios seen in multiple retrospective case-control studies that demonstrated an association between smoking and macular degeneration, including the Eye Disease Case-Control Study and the Beaver Dam Eye Study, which reported odds ratios of 2.2 and 2.5, respectively, for developing neovascular macular degeneration in smokers.4, 14
Other inflammatory conditions of the eye as well as certain systemic autoimmune conditions have also been linked to smoking.2
A recent meta-analysis summarized studies that investigated the association between smoking and rheumatoid arthritis.15
The consensus was that there was a strong correlation between smoking and rheumatoid factor positive rheumatoid arthritis.15
Another meta-analysis reported a causal relationship between thyroid eye disease and smoking. It established that there was a positive association, with a reduced risk of thyroid eye disease in ex-smokers.7
In contrast to the latter two conditions, very little has been published regarding an association with smoking and uveitis. In a retrospective cohort study looking at the characteristics of patients with intermediate uveitis in Olmstead County, Minnesota, Donaldson et al reported that 52% of intermediate uveitis patients were smokers compared to a 16% rate of smoking in the general population (the national smoking rate is 23%).16
In a small study (37 study patients) presented at a 1970 meeting of the American Medical Association, David Knox reported a smoking prevalence of 87% among men and 54% among women with pars planitis compared with respective smoking prevalences of 27% and 14% in the general population at the time.17
In our case-control study, we find that the rate of smoking (past or current) was higher in both controls and cases compared to the smoking rate in San Francisco county (18.9%, http://www.sonoma-county.org/health/prev/pdf/regional.pdf
, accessed on May 5, 2009). This demonstrates the importance of a case-control study design.
Our data also suggest an especially strong association between smoking and infectious uveitis (OR 4.5, P<0.001). There are complex host, pathogen, and environmental factors that result in an infectious agent reaching intraocular tissues without direct inoculation. These mechanisms are not yet completely understood. We can speculate that the pro-inflammatory components of tobacco smoke which are known to cause vascular inflammation may promote not only access of organisms to intraocular tissue, but also perhaps enhance the response of inflammatory cells to the microorganism, although this would have to be tested in the appropriate models. This may partially explain why highly prevalent infections, such as herpes simplex virus-1 and toxoplasmosis, cause intraocular inflammation in only a small subset of infected individuals.
Subgroup analyses were robust for certain subgroups, but small sample size limited our ability to draw conclusions in other cases. In contrast to the strong association between smoking and uveitis, a strong association between smoking and scleritis could not be established in our study. This may be due to different pathophysiologic mechanisms underlying the development of scleritis as compared to uveitis. No conclusions could be drawn about the association between episcleritis and smoking. However, this could have been due to the small number of cases with a diagnosis of episcleritis. The relationship between smoking and uveitis was evident in both current smokers and past smokers alike, as well as in various analyses used to test the robustness of the association. This included patients over 21 and patients stratified by racial group. In certain racial groups, however, such as African Americans, the association between uveitis and smoking did not hold. Conclusions cannot be drawn in regards to our Native American and Middle Eastern patients as these subgroups had small sample sizes.
There is a biologically plausible mechanism which may explain the association between cigarette smoke exposure and uveitis. Although nicotine itself may have antiinflammatory properties, cigarette smoke has a pro-inflammatory effect primarily through the promotion of vascular inflammation related to the release of reactive oxygen species. 3, 9
It has been reported that exposure to cigarette smoke extract increases vascular H2
production, activates NF-κB, and results in the up-regulation of the proinflammatory cytokines, IL-1β, IL-6, and TNF-α3
The mechanism of smoking in the development of macular degeneration and thyroid eye disease is thought to be related to the production of reactive oxygen species.18, 19
Although we have found that there is a strong correlation between smoking and uveitis in patients seen at the Proctor Foundation, we have not proven that smoking causes uveitis, nor can we determine that smoking exacerbates uveitis, although both scenarios are biologically plausible.
In addition to the association between smoking and all anatomical subtypes of uveitis, we also found a correlation of smoking with CME in intermediate and panuveitis patients, but not in anterior or posterior uveitis. Among the latter two types of uveitis, anterior uveitis patients had low rates of CME, and we had small numbers of posterior uveitis patients compared with the other types of uveitis. The notion of smoking increasing the risk of CME in intermediate uveitis is not novel. In a cross sectional study Thorne et al demonstrated that smoking was a risk factor in the development of CME in intermediate uveitis patients.11
This result corroborated unpublished data reported by Cunningham and colleagues (Invest Ophthalmol Vis Sci 2001[Suppl]:708). Here we show that smoking was associated with CME in patients with both panuveitis and intermediate uveitis. We hypothesize that smoking not only plays a role in the development of uveitis, but also contributes to the severity of inflammation resulting in the development of a sight-threatening complication such as CME. An issue that deserves discussion is whether smoking causes CME, regardless of its etiology, or if it exacerbates inflammation resulting in a complication such as CME. We propose that it is the latter, given that in our study, we have shown that smoking is associated with uveitis, even in the absence of CME. Furthermore, studies looking at other causes of CME, such as diabetic retinopathy, have shown that there is no relationship between smoking and the incidence or progression of diabetic macular edema.20–24
This implies that the primary mechanism of uveitic CME may be different than that of diabetic CME, although there is likely some overlap.
There are many strengths of our study, including the large size and the case-control design. However, the results should be interpreted conservatively given its retrospective nature. We did not have information on the timing of onset of smoking in relation to the onset of uveitis, nor did we have information regarding the dosage in pack-years of smoking, given that patients did not routinely self-report (nor did we routinely collect) this particular type of information. Relying on patient self-report may also introduce underestimation of the smoking prevalence in our study although this would be expected to have an effect on both the study and control groups.25
We also did not have specific information on the type of smoke exposure (cigar, cigarette, filtered, non-filtered, environmental cigarette smoke, etc.). Despite these limitations, both current and past smoking had a significant association with uveitis, although we cannot do anymore than conjecture why past smoking had a slightly higher odds ratio than current smoking. One possibility is that ex-smokers have a particularly high rate of misclassification of current smoking status according to serum biomarker measurements, as one study suggests.26
Another possibility is that non-incident cases of uveitis seen in our clinic that classify themselves as ex-smokers may have been smoking prior to the onset of their uveitis but quit smoking for a variety of unknown reasons before they were seen in our clinic.
Although we adjusted for many significant confounders including age, gender, race, and median income, there remains the possibility of other unknown factors (e.g., systemic cardiovascular disease) that may inherently differ between our cases and controls. We chose to adjust for median household income by zip code as a surrogate for socioeconomic status, but this method has its limitations. In choosing our controls, we used comprehensive eye clinic patients rather than retina or other subspecialty patients given that common retinal diseases have been associated with smoking. In regards to the relationship between CME and smoking, careful prospective studies looking at complication rates and severity of inflammation in relation to smoking would need to be conducted to test the hypothesis that smoking increases the severity of inflammation in uveitis, although even then, causality would not necessarily be established.
Our data suggest that smoking is a significant risk factor for all anatomic types of uveitis as well as infectious uveitis. We also show a particularly strong relationship with smoking in inflammatory CME in intermediate and panuveitis patients. Whether or not this information is applied broadly towards a change in counseling uveitis patients will depend on results borne out over multiple independent studies. However, we do feel that the strength of the association is substantial and warrants further investigation.