Cigarette Smoking and Treatment Outcomes in Graves Ophthalmopathy

Methods

Patients

Study 1

Study 1 included 300 patients receiving radioiodine treatment for Graves hyperthyroidism with mild or no ophthalmopathy. Mild ophthalmopathy was defined as proptosis less than 22 mm, intermittent or no diplopia, absence of optic neuropathy, and mild conjunctival and periorbital inflammation. Exclusion criteria were severe ophthalmopathy, large goiter requiring thyroidectomy, and contraindications to glucocorticoids. The 300 patients, who previously took part in a study analyzing the effect of radioiodine on ophthalmopathy [5], were assigned by computer-generated random numbers to treatment with radioiodine alone or radioiodine followed by a 3-month course of oral prednisone (initial dosage, 0.4 to 0.5 mg/kg of body weight per day) [3]. Five patients in the radioiodine plus prednisone group were lost to follow-up. Smoking habits did not differ in the two groups.

Study 2

This retrospective study included 150 consecutive patients with severe ophthalmopathy (110 women and 40 men; mean age, 41 years [range, 30 to 63 years]) treated from 1989 to 1995 with orbital radiation therapy (20 Gy per eye) and high-dose oral prednisone (initial dose, 80 to 100 mg) [9]. The prednisone dose was gradually tapered, and therapy was discontinued after 6 months. Severe ophthalmopathy was defined as proptosis of 22 mm or more, inconstant or constant diplopia, and marked inflammatory soft-tissue changes with or without optic neuropathy.

The study was approved by the institutional review board, and informed consent was obtained from patients.

Smoking Habits

The number of cigarettes smoked was measured in pack-years, expressed as x = a x b/c, where a = number of cigarettes smoked per day, b = number of years of smoking, and c = 20 cigarettes per pack. Patients who had refrained from smoking for less than 1 year were considered smokers. Smokers were subdivided into light (≤ 10 pack-years), moderate (11 to 19 pack-years), and heavy smokers (≥ 20 pack-years).

Ocular Evaluation

Ocular evaluation, performed by one examiner who was blinded to treatment and smoking groups, included assessment of soft-tissue changes; measurement of proptosis (by Hertel exophthalmometry), ocular tension, and lid width; evaluation of eye muscle function (Hess chart or computerized perimetry); and determination of visual acuity. The activity score was determined according to the method of Mourits and colleagues [10], which includes consideration of seven manifestations (spontaneous retrobulbar pain, pain with eye movements, eyelid erythema, eyelid edema, conjunctival injection, chemosis, and swelling of the caruncle); one point was given to any manifestation, for a score from 0 (no activity) to 7 (very high activity). Each patient provided a self-assessment evaluation sheet.

Appearance, progression, and alleviation of ophthalmopathy were defined according to major and minor criteria [5]. Major criteria were variations in exophthalmometer readings and lid width of 2 mm or more, diplopia (intermittent, inconstant, or constant), variations in activity score of 2 points or more, and changes in visual acuity of 1/10 or more. Minor criteria were variations in soft tissues or self-assessment. Appearance, progression, and alleviation of ophthalmopathy were defined by changes in at least two major criteria and one minor criterion [5].

Statistical Analysis

Differences in the prevalence of smokers in the two studies were analyzed by using a chi-square test with Yates correction for continuity. Exact binomial 95% CIs were calculated for all proportions. Patients in study 1 were included in an intention-to-treat analysis in which the effects of radioiodine or radioiodine plus prednisone on ophthalmopathy were evaluated according to the predefined criteria outlined above.

Role of the Study Sponsor

Neither funding source had a role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication.

Results

Study 1

Among patients who received radioiodine alone, 23 (15.3% [95% CI, 10% to 22%]) had progression of ophthalmopathy. Ocular conditions were unchanged in the remaining 127 patients [5]. Among patients who received radioiodine plus prednisone, 0 had progression and 50 of 75 (66.7% [CI, 55% to 77%]) had alleviation of eye disease [5].

In the group that received radioiodine alone, ophthalmopathy progressed in 4 of 68 nonsmokers (5.9% [CI, 3% to 9%]) and 19 of 82 smokers (23.2% [CI, 13% to 33%]) (P = 0.007). In the group that received radioiodine plus prednisone, ophthalmopathy was alleviated in 37 of 58 nonsmokers (63.8% [CI, 51% to 78%]) and 13 of 87 smokers (14.9% [CI, 10% to 22%]) (P < 0.001) (Table 1).

Study 2

Of 150 consecutive patients, 85 (57%) were smokers. Sixty patients (40%) had an excellent or good response to therapy and 59 (39.3%) had a moderate response. Ophthalmopathy remained unchanged in 26 patients (17.3%) and progressed in 5 (4.3%). Duration of ophthalmopathy did not differ among groups.

Sixty-one of 65 nonsmokers (93.8% [CI, 90% to 98%]) and 58 of 85 smokers (68.2% [CI, 57% to 78%]) (P < 0.001) responded to therapy (Table 2). Thirty-three of the 58 smokers who responded to therapy (56.9% [CI, 45% to 68%]) and 5 of 27 nonresponders (18.5% [CI, 9% to 29%]) were light smokers (P = 0.01).

Discussion

The results of our randomized study showed that cigarette smoking was associated with progression of mild ophthalmopathy, seen in 15% of patients after radioiodine therapy. In addition, smoking was associated with reduced efficacy of glucocorticoids given concomitantly with radioiodine. In the retrospective study, smoking and degree of smoking seemed to adversely affect the outcome of orbital radiation therapy and high-dose glucocorticoid treatment in patients with severe ophthalmopathy.

Cigarette smoking is a risk factor for Graves ophthalmopathy. The prevalence of smoking is higher in patients with Graves disease who have ophthalmopathy than in those who do not have ophthalmopathy [1], and some [2, 11, 12] but not all [13] studies show a relation between degree and duration of smoking and severity of ophthalmopathy. Tallstedt and associates [4] reported that progression of ophthalmopathy after radioiodine therapy was more frequent in smokers than in nonsmokers, although differences were not statistically significant. Similarly, in a small series of Chinese women, Kung and coworkers [14] found no differences between smokers and nonsmokers in the progression of ophthalmopathy after radioiodine therapy. The differences between our results and those of previous studies may be explained by the larger number of patients and the consequent greater power of our study. Ethnic factors may also be important: Asian patients have a lower risk for ophthalmopathy, and the prevalence of smoking among Asian women is low [11].

Medical management of severe ophthalmopathy mostly relies on orbital radiation therapy or treatment with high-dose steroids, but results are not always favorable [8]. This may be related to several factors, including the long duration or limited activity of ophthalmopathy [8]. Our results suggest that smoking also negatively affects treatment outcome.

Of note, several smokers in study 1 had no progression of ophthalmopathy after radioiodine therapy, and the condition improved with concomitant prednisone treatment. Similarly, in study 2, several smokers had excellent or good responses to orbital radiation therapy and high-dose glucocorticoid therapy. This implies that cigarette smoking is only one of many risk factors involved in the progression of ophthalmopathy. Identification of such risk factors should be a goal of future research so that treatment may be improved and disease may be prevented.

The mechanisms by which cigarette smoking may affect the course of Graves ophthalmopathy and its response to treatment are largely unknown [1]. Besides having direct irritative effects, smoking may affect immune reactions occurring in the retro-orbital space [15]. Cytokines present in the retro-orbital tissues of patients with Graves ophthalmopathy [16] exert several actions relevant to the pathogenesis of the disease, including induction of expression of MHC class II molecules, heat-shock proteins, and adhesion molecules [16]. Cytokines also stimulate orbital fibroblasts to proliferate and to secrete glycosaminoglycans; the latter are responsible for most manifestations of the disease [15]. Smoking may intervene in cytokine-mediated paracrine and autocrine actions because smoking-induced hypoxia in the retrobulbar space stimulates the release of cytokines [17]. Interleukin-1 may play a pivotal role in this context, and interleukin-1 receptor antagonist was shown to inhibit interleukin-1-induced glycosaminoglycan production by orbital fibroblasts in vitro [18]. Of interest, smokers had lower serum levels of interleukin-1 receptor antagonist than nonsmokers did, and unfavorable responses of ophthalmopathy to orbital radiation therapy were associated with a lower serum interleukin-1 receptor antagonist surge in smokers [19].

In conclusion, our results suggest that cigarette smoking increases the risk for progression of ophthalmopathy after radioiodine therapy and decreases the efficacy of orbital irradiation and steroids. Thus, patients with Graves ophthalmopathy should be strongly encouraged to refrain from smoking. Whether cessation of smoking may favorably influence the course of ophthalmopathy remains to be established.

Drs. Bartolomei and Nardi: Dipartimento di Neuroscienze, University of Pisa, Ospedale S. Chiara, via Roma, 67, 56122 Pisa, Italy.