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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 7 2244-2247
Copyright © 1997 by The Endocrine Society

Clinical Studies

Soluble Interleukin-1 Receptor Antagonist Serum Levels in Smokers and Nonsmokers with Graves’ Ophthalmopathy Undergoing Orbital Radiotherapy1

Lorenz C. Hofbauer2, Tina Mühlberg, August König, Gabriela Heufelder, Hermann-Dieter Schworm and Armin E. Heufelder

Medizinische Klinik (L.C.H., A.K., A.E.H.) and Augenklinik (H.D.S.), Klinikum Innenstadt, Ludwig-Maximilians-Universität, Munich; Städtisches Klinikum-West (T.M.), Leipzig; and Augenpraxis Prof. Neuhann (G.H.), Munich, Germany

Address all correspondence and requests for reprints to: Armin E. Heufelder, Division of Endocrinology, Medizinische Klinik, Klinikum Innenstadt, Ludwig-Maximilians-Universität, Ziemssenstraße 1 80336 Munich Germany.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Interleukin-1 (IL-1) plays an important role in the pathogenesis of Graves’ ophthalmopathy (GO). Impaired antagonism of the proinflammatory cytokine IL-1 by the naturally occurring IL-1 receptor antagonist (IL-1RA) has been implicated in the initiation and perpetuation of various autoimmune diseases and may play a role in the evolution of GO. Cigarette smoking appears to adversely affect the course of GO. We have evaluated the course of IL-1{alpha}, IL-1ß, and soluble IL-1RA (sIL-1RA) serum levels in smokers and nonsmokers with GO undergoing orbital radiotherapy (OR). We prospectively studied the eye status of 27 randomly selected patients (mean age 47.3 ± 11.0 yr; 20 females; 18 smokers) with active, moderately severe GO before and 3 and 6 months following OR, respectively. None had received any previous treatment for GO, and all patients were kept euthyroid on carbimazole. Serum concentrations of IL-1{alpha}, IL-1ß, and sIL-1RA were measured using highly sensitive enzyme linked immunosorbent assay systems. Baseline sIL-1RA levels were negatively correlated with the number of cigarettes smoked before and following OR (P < 0.0001). Patients with no or minor therapeutic response to OR (n = 8), all of whom were smokers, revealed mean baseline sIL-1RA levels of 114 ± 85 pg/mL, which increased to 172 ± 103 pg/mL at 3 months and 149 ± 96 pg/mL at 6 months after initiation of OR, respectively. By contrast, patients with a good clinical response (n = 19, 9 nonsmokers), revealed significantly higher baseline sIL-1RA levels at 294 ± 148 pg/mL (P = 0.004), which increased to 845 ± 668 pg/mL at 3 months (P = 0.01) and 634 ± 337 pg/mL at 6 months (P < 0.001), respectively, following initiation of OR. Serum concentrations of IL-1{alpha} and IL-1ß were below 3.9 pg/mL in all patients with GO who were studied, and were not correlated with gender, age, smoking status, clinical course, or outcome. Low baseline levels and impaired surge of sIL-1RA serum levels following OR were strongly correlated with smoking status and a less favorable therapeutic outcome in patients with active, moderately severe GO. Measurement of sIL-1RA may contribute to predict the therapeutic response to OR in patients with active, moderately severe GO. Strategies designed to raise local or systemic concentrations of sIL-1RA may be of benefit to patients with GO.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
A PROMINENT role of interleukin-1 (IL-1) in the evolution of the orbital immune process in Graves’ ophthalmopathy (GO) is suggested by its capacity to stimulate orbital fibroblast proliferation, glycosaminoglycan synthesis, and prostaglandin production, as well as the expression of various adhesion molecules, immunomodulatory proteins, and metalloproteases (1, 2, 3, 4). In the orbital inflammatory reaction during the course of GO, IL-1 is produced by infiltrating mononuclear cells, activated T cells, and residential fibroblasts (5). IL-1 production may be stimulated by a variety of factors, including tissue hypoxia, complement activation, fibrin degradation, cytokines, and direct effects of tobacco glycoproteins, and is inhibited by glucocorticoids and nonsteroidal antiinflammatory drugs (6). Physiologically, proinflammatory effects of IL-1{alpha} and IL-1ß are tightly balanced by the structurally related soluble IL-1 receptor antagonist (sIL-1RA), which competitively binds to IL-1 receptors without inducing any detectable biological response (7, 8). Failure to generate sufficient amounts of IL-1RA has been implicated in the pathogenesis of various immune-mediated diseases, including rheumatoid arthritis and ulcerative colitis (9, 10, 11). Cigarette smoking has been attributed a role in the evolution of hypo- and hyperthyroidism, goitrogenesis, and autoimmune thyroid diseases (12, 13, 14, 15, 16). Mechanisms of how cigarette smoking may affect the thyroid gland have remained unclear, however, contents of cigarette smoke, hypoxia, and formation of oxygen- free radicals have been implicated (17, 18, 19). Furthermore, several studies have indicated that cigarette smoking may adversely affect GO and Graves’ disease (20, 21, 22). Moreover, stimulation of IL-1 production in vitro by a tobacco glycoprotein suggests that smoking may promote inflammatory processes via an increase in IL-1 (23). We assessed IL-1{alpha}, IL-1ß, and sIL-1RA serum concentrations and clinical response to therapy in euthyroid smokers and nonsmokers with active, moderately severe GO before and 3 and 6 months following orbital radiotherapy (OR).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

Twenty-seven randomly selected out-patients (mean age 47.3 \ 11.0 yr; 20 females) with moderately severe, active GO of recent onset (4.0 \ 1.7 months) were evaluated at baseline and 3 and 6 months following fractionated OR (10 x 2 Gy in two weeks) using a 5 meV linear accelerator. Patients had not received any previous treatment for GO, and all were euthyroid while on carbimazole. Smokers were defined as individuals who had smoked cigarettes for at least 5 yr before enrollment in this study, and nonsmokers were individuals who had never smoked. There were 9 nonsmokers and 18 smokers (mean number of cigarettes smoked: 19.4 \ 6.6 per day). Smoking was classified as mild (1–10 cigarettes/day), moderate (11–20 cigarettes/day), or heavy (>21 cigarettes/day). As part of the therapeutic intervention, all patients were strongly and repeatedly encouraged to quit or reduce smoking.

Clinical assessment

Diagnosis of GO was based on characteristic eye signs and symptoms, the presence of Graves’ hyperthyroidism, positive TSH receptor autoantibodies, and detection of enlarged extraocular muscles by orbital ultrasonography, computed tomography, or magnetic resonance imaging. Patients with Hashimoto’s thyroiditis and ophthalmopathy were not included in our study. To ensure consistency in evaluation and grading of GO, eye status was assessed on each visit by the same ophthalmologist or endocrinologist using a clinical activity score. This score was based on the sum of a GO activity score (spontaneous retrobulbar pain, pain with eye movement, eye lid erythema, eye lid edema or swelling, conjunctival injection, chemosis, caruncle swelling; 1 point per criterion) and a patient self-assessment score (appearance, visual acuity, eye discomfort, diplopia; 1 point per criterion) according to the American Thyroid Association consensus classification (24). Severity of GO was not significantly different among patients undergoing OR. None of the patients studied revealed any evidence of corneal or optic nerve involvement. Therapeutic response was assessed at 6 months following initiation of OR, and patients were classified accordingly as nonresponders (decrease of <3 points of clinical activity score) or responders (decrease >=3 points of clinical activity score). Euthyroid function was ensured by bimonthly measurements of TSH, free T4, and free T3 serum levels. Highly sensitive, commercially available enzyme linked immunosorbent assay systems (Quantikine, R & D Systems, Minneapolis, MN) were used to measure serum concentrations of IL-1{alpha} (sensitivity: 0.2 pg/mL); average normal serum level: <3.9 pg/mL), IL-1ß (sensitivity: 0.5 pg/mL; average normal serum level: <3.9 pg/mL), and sIL-1RA (sensitivity: 6.5 pg/mL; average normal serum level: 196 pg/mL), respectively. Coefficients of variance derived from intra- and interassay precision analyses were generally <7% for all assays performed.

Statistical analysis

All sIL-1RA values are expressed as mean \ SD. ANOVA (25) was used to assess differences of sIL-1RA levels in patients with different sex and smoking habits at each of the three points of evaluation. Student’s paired t test was used to evaluate differences of sIL-1RA values between responders and nonresponders. Pearson’s {chi}-square test was used to evaluate differences in the outcome with respect to smoking status. A P value of <0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
In patients with moderately severe, active GO, overall mean baseline sIL-1RA levels were 240 \ 155 pg/mL before OR, 645 \ 640 pg/mL at 3 months, and 490 \ 363 pg/mL at 6 months after initiation of OR, respectively (all P < 0.0001). Mean sIL-1RA levels at baseline, as well as mean sIL-1RA levels at 3 and 6 months following initiation of OR, were significantly lower in smokers as compared with nonsmokers with GO, and showed strong dependence on the number of cigarettes smoked within the last 6 months before initiation of OR (overall P < 0.0001 by ANOVA; Table 1Go). Similarly, the number of cigarettes smoked during the 6 months following initiation of OR was inversely correlated with mean sIL-1RA levels at baseline and 3 and 6 months following initiation of OR (overall P < 0.0001 by ANOVA). Nonsmokers (n = 11): 7 women; mean age, 53.1 \ 11.9 yr; 348 \ 174 pg/mL at baseline, 1186 \ 705 pg/mL at 3 months, and 807 \ 351 pg/mL at 6 months. Mild smokers (n = 6): 5 women; mean age, 44.7 \ 8.9 yr; 214 \ 59 pg/mL at baseline, 379 \ 49 pg/mL at 3 months, and 401 \ 75 pg/mL at 6 months. Moderate smokers (n = 7): 5 women; mean age, 43.0 \ 6.6 yr; 173 \ 84 pg/mL at baseline, 267 \ 111 pg/mL at 3 months, and 247 \ 122 pg/mL at 6 months. Heavy smokers (n = 3): 3 women; mean age, 41.0 \ 13.8 yr; 56 \ 18 pg/mL at baseline, 83 \ 29 pg/mL at 3 months, and 74 \ 7 pg/mL at 6 months. At any point in time, there were no significant differences in mean sIL-1RA levels between women and men (P = 0.60) or in patients below and above 45 yr of age (P = 0.15). There was, however, a trend towards lower mean sIL-1RA serum levels at baseline in patients with higher degrees of GO (P = 0.06). Of 18 smokers at baseline, 2 (11%) quit smoking, 12 (67%) reduced the amount of cigarettes smoked, and 4 (22%) maintained their level of cigarette consumption. None of the smokers increased their level of cigarette consumption during the study period, and none of the nonsmokers started smoking.


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  		Table 1. sIL-1RA levels in smokers compared with nonsmokers

 
OR resulted in good clinical improvement (responders) in 19/27 patients (70.4%; 9 nonsmokers). Minor improvement, no change, or progression of disease (nonresponders) was noted in 8 of 27 patients (29.6%), all of whom were smokers. Nonresponders revealed mean baseline sIL-1RA levels of 114 \ 85 pg/mL, which increased to 172 \ 103 pg/mL at 3 months and 149 \ 96 pg/mL at 6 months following initiation of OR, respectively (Fig. 1Go). By contrast, responders revealed significantly higher baseline sIL-1RA levels at 294 \ 148 pg/mL (P = 0.004), which increased to 845 \ 668 pg/mL (P = 0.01) at 3 months and 634 \ 337 pg/mL (P = 0.0006) at 6 months following initiation of OR, respectively (Fig. 1Go). Heavy smoking before and following initiation of OR was significantly correlated with an unfavorable clinical outcome (each P < 0.001). Nonresponders (mean age: 42.9 \ 9.4 yr) smoked 22.5 \ 6.6 cigarettes per day before, and 19.4 \ 5.6 cigarettes per day following initiation of OR, respectively. By contrast, responders (mean age: 49.1 \ 11.3 yr; P = 0.185) smoked significantly fewer cigarettes (8.9 \ 9.7 and 3.8 \ 5.4 per day), both before (P = 0.001) and following initiation of OR (P < 0.001), respectively. In all serum samples derived from patients with GO, serum concentrations of IL-1{alpha} and IL-1ß were below or close to the lowest IL-1{alpha} and IL-1ß standards (<3.9 pg/mL) of the assays, respectively, and, where measurable, were not correlated with gender, age, smoking status, clinical course, or outcome.



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  		Figure 1. Soluble IL-1RA levels in patients with GO with and without response to OR. sIL-1RA serum levels (mean ± SD) in responders (black bars) vs. nonresponders (grey bars) to OR (baseline: P = 0.004; 3 months: P = 0.01; 6 months: P < 0.001 by Student’s paired t test). See Subjects and Methods for definition of responders and nonresponders, respectively.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
IL-1 is a potent proinflammatory mediator that plays an important role in the orbital inflammatory process in GO. IL-1 acts on orbital fibroblasts to induce cell proliferation, expression of immunomodulatory molecules, and production of several inflammatory mediators (1, 2, 3, 4). The concept of competition between IL-1 and sIL-1RA for occupation of IL-1 receptors has recently generated the hypothesis that an imbalance between IL-1 and IL-1-RA may play a role in the pathogenesis of various inflammatory diseases (7, 8, 9, 10, 11). Although cigarette smoking appears to be associated with a higher incidence of GO in patients with Graves’ disease, and with a more severe course of GO (20, 21, 22), mechanisms of how smoking may affect or modulate the orbital immune process have remained uncertain. Possible adverse effects of smoking may be mediated by contents of cigarette smoke such as thiocyanate and 3-methylcholanthrene, generation of oxygen-free radicals, hypoxia, and production and release of various inflammatory cytokines, as well as more generalized effects on the immune system (16, 17, 18). Our study examined the therapeutic outcome and the course of IL-1{alpha}, IL-1ß, and sIL-1RA serum levels in untreated, euthyroid patients undergoing OR for active, moderately severe GO. In responders, administration of OR resulted in a 3-fold increase of sIL-1RA levels at 3 months and a 2-fold increase at 6 months, respectively, compared with sIL-1RA levels at baseline. This suggests that an increase of sIL-1RA levels in response to OR may account for at least some of the antiinflammatory effects conferred by OR. The number of cigarettes smoked before and following OR showed a significant inverse correlation with sIL-1RA levels at baseline and with a blunted sIL-1RA surge following OR, suggesting that smoking may adversely influence the immunomodulatory effects of OR. In fact, all patients with GO and a clinical response to OR, most of whom were nonsmokers or mild smokers, revealed significantly higher sIL-1RA levels at baseline and a greater and more sustained sIL-1RA surge following OR. In contrast, failure of OR to improve the clinical course of GO correlated significantly with lower sIL-1RA levels at baseline and with a blunted increase of sIL-1RA levels in response to OR.

Several limitations of our study should be noted. First, drainage into the systemic circulation of sIL-1RA that is produced locally within the orbital tissues may vary substantially within and between individuals. Thus, sIL-1RA levels measured in the serum may not adequately reflect sIL-1RA concentrations present locally in the affected orbital tissues. Of note, alveolar macrophages from smokers with interstitial lung disease have been shown to produce lower levels of IL-1RA than those obtained from nonsmokers (26). Although similar effects may have to be considered in smokers with GO, recent data obtained in vitro suggested that exposure of orbital fibroblasts to low doses of ultraviolet irradiation enhances their capacity to produce and release sIL-1RA (27). Second, the natural course of GO has to be considered as a confounding factor. However, the close temporal link between OR and changes in sIL-1RA serum levels, the consistency of the effects observed, and our in vitro results (27) argue against this possibility. Third, correlation of changes in sIL-1RA and therapeutic response to OR does not prove an etiologic relationship. Finally, because our study population was nonrandomized and of small number, conclusions must be drawn with caution.

Our data suggest that endogenous sIL-1RA may play an important role in regulating the orbital inflammatory response, most probably by counteracting the proinflammatory and fibrogenic effects of IL-1 produced locally during the active stages of GO. Antiinflammatory effects of OR may be mediated, at least in part, by local stimulation of sIL-1RA levels. Conversely, failure to generate sufficient quantities of sIL-1RA levels in response to OR, a prominent feature in active smokers who failed to reduce their cigarette consumption and who responded poorly to OR, may act to sustain or promote IL-1-mediated adverse effects. If confirmed in a larger series of patients, assessment of sIL-1RA serum levels may prove as a readily accessible marker of disease activity, and perhaps could yield important prognostic information in patients with active GO. For instance, low IL-1RA levels in bronchoalveolar lavage fluid have been demonstrated in patients with a more severe course of the adult respiratory distress syndrome, and are associated with a poor prognosis (28). Recently, it has been demonstrated that IL-1-induced glycosaminoglycan production by human orbital fibroblasts in vitro is effectively inhibited by the administration of IL-1RA and soluble IL-1 receptor (29). Together with our present data, these results provide a rationale for the development and clinical evaluation of strategies designed to raise sIL-1RA concentrations either systemically or locally within the orbital tissues in GO (29, 30). Finally, our results clearly support the notion that smoking negatively affects the clinical course of patients with active GO and their response to OR. Thus, studies designed to assess the effect of cessation of smoking, a noninvasive and cost-effective intervention, on the clinical course and response to therapy in patients with active, moderately severe GO will be worthwhile.


   Footnotes
 
1 This work was supported by grants from Friedrich-Baur-Foundation (to A.E.H. and L.C.H.) and Deutsche Forschungsgemeinschaft (to A.E.H.) (He 1485/5–1), Bonn, and Forum Schilddrüse e.V., Hamburg, Germany. Parts of this study were presented in abstract form at the 69th Annual Meeting of the American Thyroid Association in San Diego, California, 1996. Back

2 Current address: Endocrine Research Unit, Joseph 5–164, Mayo Clinic, Rochester, Minnesota. Back

Received January 27, 1997.

Revised March 28, 1997.

Accepted April 9, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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