773 CLINICAL SCIENCE Br J Ophthalmol: first published as 10.1136/bjo.87.6.773 on 1 June 2003. Downloaded from Impact of smoking on the response to treatment of thyroid associated ophthalmopathy A Eckstein, B Quadbeck, G Mueller, A W Rettenmeier, R Hoermann, K Mann, P Steuhl, J Esser ............................................................................................................................. Br J Ophthalmol 2003;87:773–776 Background: In patients with Graves’ disease, smoking considerably increases the incidence and severity of thyroid associated ophthalmopathy (TAO). The authors sought to determine if smoking also influences the course of TAO during treatment, and the efficacy of therapy. Methods: 41 smokers and 19 non-smokers with moderate untreated TAO were included in this prospective study. All patients were treated with steroids and, 6 weeks after the beginning of drug therapy, with orbital irradiation. Follow up was performed 1.5, 4.5, 7.5, and 12 months after the See end of article for beginning of the study. Proptosis, clinical activity score (CAS), and motility were evaluated. The extent authors’ affiliations of smoking was derived from the concentration of the haemoglobin adduct N-2-hydroxyethylvaline ....................... (HEV), a parameter of long term smoking. Correspondence to: Results: There was no difference in the clinical manifestations of TAO between smokers and Anja Eckstein, MD, non-smokers at the beginning of treatment. However, CAS decreased (p<0.05) and motility improved University Essen, (p<0.02) significantly faster and to a greater extent in non-smokers than smokers. Inverse correlations Department of between the CAS decrease and the HEV levels observed 4.5 and 7.5 months after the beginning of Ophthalmology, Hufelandstrasse 55, treatment and between the improvement of motility and the HEV levels after 1.5, 4.5, and 7.5 months 45122 Germany; indicated a dose dependence. Mean HEV levels did not vary much during the follow up period and [email protected] were significantly different in smokers (mean 5.4 (SD 2.7) µg/l) and non-smokers (mean 1.8 (1.3) µg/l; Accepted for publication p<0.01). 7 October 2002 Conclusion: Smoking influences the course of TAO during treatment in a dose dependent manner. The ....................... response to treatment is delayed and considerably poorer in smokers. hyroid associated ophthalmopathy (TAO) occurs more were excluded because of radioiodine therapy. Among the frequently and tends to be more severe in smokers than patients who completed the study, 41 were smokers (11 men http://bjo.bmj.com/ non-smokers.1–8 Current but not lifetime tobacco use cor- and 30 women, mean age 46 (18–70) years) and 19 T 8 relates with the severity of TAO. A prospective study revealed non-smokers (four men and 15 women, mean age 47 (30–69) that smoking increases the risk of ophthalmopathy progres- years). sion after radioiodine therapy.9 A retrospective study showed Thyroid status of the patients was mainly euthyroid with that smoking decreases the efficacy of orbital irradiation and thyrosis stimulating hormone (TSH) still being suppressed of glucocorticoid therapy.9 According to another retrospective under antithyroid therapy except for a few patients presenting investigation, however, the final outcome does not seem to be with overt hyperthyroidism or hypothyroidism (because of influenced by smoking habits.10 overtreatment). Thyroidal function was not significantly on September 23, 2021 by guest. Protected copyright. In this prospective study, we investigated the influence of different in smokers and non-smokers at the time of the initial smoking on the response to treatment during the course of presentation (Table 1) and during the course of the study (data TAO. Tobacco use was evaluated by quantitative analysis of the not shown). TSH receptor antibodies were elevated in the haemoglobin adduct N-2-hydroxyethylvaline (HEV). This majority of patients (n=58) with no significant difference in approach allows us to evaluate the dose dependence of the titre between the groups (Table 1). Two smokers and one non- therapeutic response from tobacco consumption. HEV is smoker underwent thyroidectomy, two patients received formed from hydroxyethylating agents of cigarette smoke and radioiodine treatment. reflects the integrated “smoking dose” over the lifetime of All patients were treated with steroids (fluorocortolone 100 erythrocytes. Although other sources of ethylene oxide (that mg reduced by 10 mg every 4 days) for 6 weeks and, after that, is, exhaust fumes, endogenous ethylene production11) influ- with orbital irradiation (12 Gy). They were examined at the ence the HEV concentration, a linear relation between the beginning of the study and after 6 weeks, 4.5, 7.5, and 12 number of cigarettes smoked per day and the HEV levels has months, respectively. Patients with mild TAO (clinical activity been observed (correlation coefficient r = 0.54) indicating that score <2), severe TAO (proptosis >24 mm, reduced visual HEV is a suitable biomarker for active and passive smoking.12 acuity due to optic nerve compression), a TAO duration of more than 12 months, former anti-inflammatory treatment, and radioiodine therapy during the follow up period were PATIENTS AND METHODS excluded from the study. Patients All follow ups were carried out by the same investigator The prospective study included 67 patients with active TAO of who assessed the following ophthalmological parameters: moderate severity (manifestation less than 12 months before the beginning of the study). Sixty patients completeda1year (1) Proptosis (mm) was measured, using the Hertel method. follow up period. The data of these patients were statistically (2) The CAS was assessed as follows (we modified the scheme evaluated. Five patients were lost during the follow up period of Mourits13): pain during eye movements (0–1), painful owing to a lack of compliance or a change of residence. Two oppressive feeling on or behind the eye (0–1); lower (0–2) and www.bjophthalmol.com 774 Eckstein, Quadbeck, Mueller, et al Table 1 Baseline characteristics of the smokers (HEV >2.9 µg/l) and non-smokers Br J Ophthalmol: first published as 10.1136/bjo.87.6.773 on 1 June 2003. Downloaded from (HEV <2,9 µg/l) obtained in the initial examination Feature Non-smokers (n=19) Smokers (n=41) p Value GD since (months) 14 (0–60) 16 (3–75) NS TAO since (months) 5 (0–12) 6 (3–12) NS CAS score 3.6 (2–6) 3.8 (2–6) NS Motility score 0.9 (0–3) 1.2 (0–3) NS Proptosis (mm) 17.4 (11–22) 17.6 (11–24) NS HEV level (µg/l) 1.5 (0.4–2.7) 5.6 (2.8–13.9) p<0.001 TSH (mU/l) 0.1 (<0.1–19.8) 0.08 (<0.1–6.7) NS free T4 (pmol/l) 16.5 (10.2–23.2) 16.0 (8.8–27.5) NS T3 (nmol/l) 2.0 (1.4–2.6) 2.4 (1.5–5.9) NS T4 (nmol/l) 103.5 (73.2–163.2) 112.0 (61.4–190.7) NS TSHRAb (U/l) 14.0 (<5–145) 14.0 (<5.0–141) NS GD = Graves’ hyperthyoidism, TAO = thyroid associated ophthalmopathy, CAS = clinical activity score, HEV = N-2-hydroxyethylvaline, TSH = thyroid stimulating hormone, T4 = L-thyroxine, T3 = tri-iodothyronine, THS-R-Ab = TSH receptor antibodies). Median values, 5% and 95% confidence intervals are presented. upper eyelid oedema (0–2); conjunctival injection (0–1); con- Statistical analysis junctival chemosis (0–1). This resulted in a maximal score of Differences between features of patients with HEV levels 8. above 2.9 µg/l (smokers) and those of patients with levels µ (3) Eye motility (score 0–3) was evaluated by measuring below 2.9 g/l (non-smokers) at the beginning of treatment monocular excursion at the Goldmann perimeter: no impair- were calculated with the unpaired two tailed t test. The ment (0), impaired monocular elevation to 25°–35° and/or response to treatment is presented via life table analysis impaired monocular abduction to 35°–40° (1), impaired according to Kaplan-Meier. The differences between smokers monocular elevation to 15°–24° and/or impaired monocular and non-smokers were tested with the log rank test 12 abduction to 30°–34° (2), impaired monocular elevation below months after the beginning of the study. We calculated Spear- 15° and/or impaired monocular abduction below 30° (3). man’s correlation coefficients for the relation between the improvement of symptoms and the HEV levels measured at Improvement upon treatment was presumed, if the CAS the time of the consecutive examinations. The difference was less than 2 (mean of both eyes), and/or proptosis was between the score at the beginning of the treatment and the reduced by more than 2 mm (mean of both eyes), and/or score assessed in each follow up examination indicated the motility improved from score 2 or 3 to score 0 or 1. improvement of symptoms. A p<0.05 was considered signifi- The characteristics of the patients at the beginning of the cant. study are given in Table 1. All patients had a CAS >2 at the first visit. According to the patients, the first TAO symptoms Medical ethics committee (increase of lid width, a proptosis of eye balls, and oedema) The study was approved by the medical ethics committee of http://bjo.bmj.com/ appeared not earlier than 12 months before the initial exam- the University of Essen, Germany. ination. 27 patients had an impaired motility judged as grade 2or3. RESULTS Biochemical measurements Clinical assessment before treatment Biochemical parameters were determined by an immunomet- Owing to the exclusion of patients with mild and severe TAO, ric assay (ACS, 180 Cheiron, Fernwald, Germany) with refer- there was no significant difference between the clinical mani- ence ranges for TSH of 0.3–4 mIU/l, for serum FT4 of 10–25 festations in smokers and non-smokers observed in the first on September 23, 2021 by guest.