THYROID Volume 2, Number 3, 1992 Mary Ann Liebert, Inc., Publishers

Immunosuppressive Treatment of Graves' Ophthalmopathy W.M. WIERSINGA

ABSTRACT

Glucocorticoids and retrobulbar irradiation are the most employed immunosuppressive treatment modalities in Graves' ophthalmopathy. The response rate is. approximately 60%. Efficacy is good for improvement of appearance and visual acuity, moderate for correction of extraocular muscle dysfunction, and poor for reduction of proptosis. Immunosuppression seldom cures the eye disease. Its main advantage is to stabilize the eye disease by inactivating the inflammation of orbital tissues, thereby permitting corrective eye surgery to be performed at an earlier time. Future developments in immunosuppression aim at reduction of side effects and enhancement of efficacy. Alternative treatment schedules (e.g., methylprednisolone pulses, intravenous immunoglobulin) may have equal efficacy but less side effects than classic high-dose oral steroids. Efficacy can be improved by restriction of immunosuppression to patients with active eye disease who are more likely to respond. Disease activity might well be the main determinant of therapeutic outcome of immunosuppression in Graves' ophthalmopathy.

INTRODUCTION

THE

RATIONALE FOR IMMUNOSUPPRESSIVE TREATMENT of Graves' ophthalmopathy is provided by the presumed autoimmune pathogenesis of the disease (1,2). Evidence in favor of this view includes (a) its close association with the autoimmune disease par excellence. Graves' hyperthyroidism, (b) the presence of a mononuclear cell infiltrate in the extraocu¬ lar muscles characterized by activated lymphocytes, some cells and occasional macrophages (which may act as antigenpresenting cells) (2), and fibroblasts expressing HLA class II antigen, and (c) various autoimmune responses to orbital tissues (1). Definitive evidence of the autoimmune nature (identifica¬ tion of the responsible autoantigen and transfer of the disease by antibodies or activated lymphocytes) is, however, lacking. Prednisone has been used in Graves' ophthalmopathy since 1953 and appears rather effective. It has become the mainstay in the immunosuppressive treatment of this thyroid-related eye disease

(3,4). ASSESSMENT OF THERAPEUTIC OUTCOME

Immunosuppressive treatment modalities other than pred¬ applied, particularly to increase the efficacy

nisone have been

Department of Endocrinology. Academisch

Medisch Centrum,

and/or to decrease the side effects of oral glucocorticoids. A proper comparison of various treatment modalities is frequently hampered, however, fora number of reasons (5,6). First, many studies employ heterogeneous patient groups, especially with regard to previous or concomitant therapy of the eye disease. Consequently, unknown factors may affect therapeutic out¬ come. The most powerful tool to circumvent known and un¬ known bias is the randomized clinical trial: randomization will result in homogeneous patient groups. A second difficulty in interpretation of treatment results is poor knowledge of the natural history of the disease. Improvement of the eye disease may be due either to the spontaneous course or to specific treatment. Therefore, a short interval of 3-6 months is recom¬ mended between therapy and assessment of therapeutic outcome to make spontaneous improvement or worsening less likely (5,7). Third, changes in thyroid function and thyroid medication can affect the eye state (8). Consequently, euthyroidism should be preserved throughout the period of observation. Finally, there is a lack of consistency in the classification of eye symptoms and signs between various studies (5). Therapeutic outcome should be assessed in an objective and meaningful manner according to predetermined criteria at a fixed time interval after initiation of treatment (9). Objective assessment implies description of eye symptoms and signs in a reproducible manner and observer

University of Amsterdam. The Netherlands. 229

230

WIERSINGA

blindness with respect to the kind of treatment given. Meaning¬ ful assessment implies that the therapeutic outcome must have clinical relevance for the patient. If visual acuity decreases, the patient will not consider the treatment result a success despite concomitant improvement in diplopia and soft tissue involve¬ ment, for example. In view of such considerations I focus on controlled studies whenever possible in discussing the relative merits of immunosuppressive treatment modalities in Graves'

ophthalmopathy.

TREATMENT MODALITIES

Specific immunosuppression would be the ideal treatment of ophthalmopathy but has so far not materialized. Conse¬ quently, at present, nonspecific immunosuppression is given by pharmacologie or nonpharmacologic interventions (Table 1). Graves'

For the sake of convenience, steroids and irradiation are in¬ cluded as immunosuppressive treatment, although these entities also can be considered as anti-inflammatory therapy.

Cyclosporine A Cyclosporine effectively suppresses an ongoing immune re¬ as evidenced by the inhibition of renewed antigeninduced release of lymphokines by activated cells and by the prevention of further activation and development of effector cells. In established autoimmune diseases, cyclosporine might also be of benefit by preventing the reemergence of effector clones and stimulating the expression of suppressor cells (14). Cyclosporine (7.5 mg/kg/day in two oral divided doses for 12 weeks) is less effective than oral prednisone. Response rates in a randomized clinical trial were 22% and 61%, respectively (15). Cyclosporine, despite its substantial side effects, is better tolerated than prednisone. Whereas cyclosporine alone has minor efficacy, the combination with prednisone appears to be beneficial (15,16). After failure of high-dose steroids, 56% of the patients responded to cyclosporine + 20 mg prednisone given for 12 weeks (15). The dose of cyclosporine recom¬ mended in autoimmune diseases (3-5 mg/kg/day) is lower than has been used in Graves' ophthalmopathy (17). action,

Intravenous

Glucocorticoids

High doses of oral prednisone have stood the test of time with regard to efficacy. Treatment schedules vary. We administer daily doses of 60 mg prednisone for 2 weeks, 40 mg for 2 weeks, 30 mg for 4 weeks, 20 mg for 4 weeks, tapering down to 0 mg in 8 weeks. It is effective in approximately 60% of patients but poorly tolerated because of considerable side effects (6,10). Improvement of soft-tissue involvement (class 2) and visual acuity (class 6) is usually observed, but the response in eye muscle involvement (class 4) is moderate and in proptosis (class 3) is limited. A recrudescence of the eye disease sometimes when tapering down to zero dose. Retrobulbar administration of corticosteroids is less effective than oral prednisone, as shown in a randomized clinical trial (RCT)(11). Intravenous pulses of methylprednisolone (e.g., lg daily for 3 consecutive days) followed by oral prednisone appear to be effective in open studies (12,13).

immunoglobulin (IVIG)

Various mechanisms are postulated for the therapeutic effect of high-dose IVIG: blocking of Fc receptors, solubilization of immune complexes, and neutralizing autoantibodies by antiidiotypic antibodies in the gamma globulin preparation (18). A daily dose of 400 mg/kg intravenously infused in 3-5 h on days 1-5 of the first three cycles and on day 1 only of cycles 4-12 (every cycle consists of 21 days) was very effective, similar to the response rate observed in historical controls treated with orbital irradiation and prednisone (19). IVIG appears to be a rather safe but expensive procedure. Side effects are rare. IVIG is contraindicated in IgA deficiency, and IVIG preparations have to be screened to avoid transmission of infectious agents.

occurs

Table 1. Efficacy

and

Side Effects

of

Other

drugs

Azathioprine inhibits cell proliferation. Ciamexone sup¬ presses the early stage of the autoimmune reaction. In controlled studies, both drugs appeared ineffective in Graves' ophthalmop-

Immunosuppression

in

Graves' Ophthalmopathy

Side

Immunosuppression

Efficacy

effects

++

++ + ±

Remarks

Pharmacologie Glucocorticoids Cyclosporine A Intravenous immunoglobulin

+

Azathioprine Ciamexone

Cyclophosphamide Nonpharmacologic Acupuncture Plasmapheresis

Retrobulbar irradiation





±

+ ++

+



Mainstay of immunosuppression application Very expensive

Limited

Not indicated Not indicated Uncontrolled studies Not indicated Steroids needed to prevent rebound effect Usually applied after steroid failure (but see section Future Developments)

IMMUNOSUPPRESSIVE TREATMENT OF GRAVES' OPHTHALMOPATHY

athy (20,21). Cyclophosphamide inhibits lymphocyte prolifera¬ tion and selectively depletes antigen-reactive lymphocytes. When it is given in an oral dose of 50-150 mg daily, uncon¬ trolled studies indicate improvement of class 2 and class 4 in some patients (22,23). Acupuncture was of no benefit in a randomized clinical trial

(24).

Plasmapheresis Plasmapheresis is thought to act by removing pathogenic as circulating autoantibodies. The procedure (re¬ moval of a total of 10 L of plasma in four sessions over 5-8 days, which is replaced by stable solutions of plasma proteins) is a technically demanding procedure not devoid of side effects (hemostatic disturbances, susceptibility to infection). There is a rebound effect after cessation of plasmapheresis, necessitating continuation of immunosuppression with steroids. Uncontrolled studies demonstrate that plasmapheresis can be effective. In responders, the improvement in eye signs occurs rapidly factors, such

(25-27). Retrobulbar irradiation The rationale of radiotherapy is provided by the killing of orbital lymphocytes that are extremely radiosensitive. Usually 20 Gy is delivered in 2 weeks (10 fractionated doses of 2 Gy). The overall response rate in many uncontrolled studies is approximately 60% (10,28,29). Class 2 and class 6 eye signs improve most often (as with steroids), whereas the response in class 4 is moderate and in class 3 is limited. Irradiation is also effective after a previous failure of steroids. The procedure is very well tolerated, and side effects are minimal (transient loss of hair at the temples). Errors in dosage calculations and radiotherapy techniques account for the occurrence of radiation retinopathy (30). We do not apply retrobulbar irradiation in diabetic patients or in patients on systemic chemotherapy be¬ cause both of these conditions may increase retinal vascular susceptibility to radiation (31). Long-term safety is unknown. Although no sensitive detection techniques have been applied, no serious complications have been observed after 21 years of

follow-up (29).

In a randomized clinical trial, the efficacy of radiotherapy in combination with systemic corticosteroids was greater than that of systemic steroids alone (32). Some centers apply a lower radiation dose of 6-8 Gy, which appears as effective as 20 Gy (not tested in randomized study) (28).

CURRENT ROLE OF IMMUNOSUPPRESSION One may conclude from the available treatment options listed in Table 1 that high-dose steroids have the greatest efficacy but the worst tolerability. Retrobulbar irradiation, usually applied when steroids fail, is also efficacious. It is very well tolerated and seems to be safe. Cyclosporine has limited application. It can be of benefit in combination with a low dose of prednisone if high-dose steroids and radiotherapy are contrainidicated. In general, combination therapy appears more effective than single drug therapy. Plasmapheresis might be used as the last resort.

231

The aims of treatment in patients with Graves' ophthalmopa¬ are (a) protection of visual acuity, (b) correction of extra¬ ocular muscle dysfunction, (c) reduction of proptosis, (d) improvement of appearance, and (e) relief of pain (5). The ef¬ ficacy of immunosuppression is good in relieving pain, clini¬ cally irrelevant in reducing proptosis (the mean decrease of Hertel values is only 1 mm), and moderate with regard to the re¬ maining three aims. In this respect, the subjective eye score is of interest because it reflects the patient's view on the therapeutic outcome. Although this score increased in the prednisone responders from 4.9 to 6.4 (on a scale from 1 worst to 10 best possible condition), it did not reach satisfactory values, such as 8 or 9 (15). It thus follows that immunosuppres¬ sive treatment seldom cures the eye disease. A cost-benefit analysis, taking the side effects as cost and the efficacy as benefit (33), explains why immunosuppression so far has been applied mainly in severe cases of Graves' ophthalmopathy (3-5,7). Although improvement of the eye state is obtained in approx¬ imately 60%, most patients still require corrective eye surgery after completion of immunosuppressive treatment (5,7). One may thus question the validity of immunosuppression. We believe that the main advantage of immunosuppressive treat¬ ment is to stabilize the eye disease by inactivating the inflamma¬ tion of orbital tissues, thereby permitting corrective eye surgery to be performed earlier. Rehabilitative surgery is considered more difficult in the active inflammatory stage of the disease. Surgical results may be lost postoperatively if the disease is still active, and surgeons are of the opinion that corrective eye surgery (especially on eyelids and muscles, less so in case of orbital decompression) "is best attempted in a setting of stable, inactive, quiescent phase" of the eye disease (34-36).

thy

=

=

FUTURE DEVELOPMENTS Future developments in the immunosuppressive treatment of Graves' ophthalmopathy aim at the reduction of side effects and enhancement of efficacy. Really effective immunosuppression devoid of side effects might find wider application, e.g., in early and mild eye disease to prevent development into severe forms of ophthalmopathy.

How to decrease side

effects

Alternative treatment schedules might be developed to com¬ pare their efficacy and tolerability with a classic course of high-dose oral prednisone. Promising options are high-dose IVIG. methylprednisolone pulses, the combination of cyclospo¬ rine (3-5 mg/kg/day) and low-dose oral prednisone (20 mg/ day), and radiotherapy. Preliminary results indicate a similar efficacy of retrobulbar irradiation and high-dose steroids in patients with moderately severe Graves' ophthalmopathy (37), providing a real alternative for prednisone in terms of equal efficacy but less side effects.

How to increase

efficacy

Efficacy might be greatly improved by specific immunosup¬ pression, but its realization in the near future is unlikely. Until then, we must use nonspecific immunosuppression by which on

WIERSINGA

232 average 2 of every 3 patients improve. Efficacy can be increased by restriction of immunosuppression to those patients who will respond. The question thus arises if a response can be predicted. We were unable to identify any specific factor related to a favorable response. Age, sex, duration of the thyroid or of the eye disease, and the severity of the eye disease had no predictive value (10,15,37), although more severe eye disease might profit to a greater extent from immunosuppression than might milder forms of the disease. We expected an association between a short duration of the eye disease and a high response rate because long-standing eye disease conceivably results in fibrosis, ren¬ dering orbital tissues less amenable to respond. A higher response rate in patients with a short duration of the eye disease than in patients with long-standing eye disease has been re¬ ported (32,38,39), although the difference was not always significant (in one study this relationship was observed if the period of exacerbation and not the total duration of eye signs and symptoms was taken into account) (40). The observed discrep¬ ancies might be related to the difference in disease duration and disease activity. Whereas, in general, a short duration of the disease is more likely to be associated with the active (inflam¬ matory) stage and long-standing disease with the inactive (fibrotic) stage of the eye disease, this might not necessarily be true. It is not unusual for a patient with Graves' ophthalmopathy to experience several episodes of exacerbation (due to a flareup of the disease activity, a common phenomenon in autoimmune disease before entering the final inactive, burnt-out or fibrotic stage of the disease). Disease activity and not disease duration appears to be the main determinant of therapeutic outcome of

immunosuppression (Fig. 1). It is hypothesized that immunosuppression is effective in the active stage of the eye disease, whereas patients with inactive

ophthalmopathy have little to gain from immunosuppression, and in these patients, one may proceed directly with corrective

eye surgery. Thus, there exists an urgent need for a reliable parameter of disease activity. In the absence of a specific disease marker, several approaches have been taken to delineate the concept of disease activity. A clinical activity score based on the classic signs of inflammation (pain, redness, edema, and im¬ paired function) has a rather good predictive value for therapeu¬ tic outcome of immunosuppression (43), as well as a low reflectivity of eye muscles assessed by A-mode ultrasonography (44). A high urinary excretion of glycosaminoglycans (45) and a long T2-relaxation time on magnetic resonance imaging of eye muscles indicating edema (46) also are associated with a favor¬ able outcome of immunosuppression. The relative merits of these proposed indicators of disease activity in predicting the response to immunosuppression await further testing in prospec¬ tive trials.

REFERENCES 1. Perros P. Kendall-Taylor 2. 3. 4.

5.

6. 7.

normal

8.

9.

10. abnormal

11.

Therapeutic outcome of immunosuppressive treat¬ ment (interrupted lines) in relation to the natural history (contin¬ uous line) of Graves' ophthalmopathy. The natural history is represented by Rundle's curve (41,42), characterized by an initial period of rapid deterioration of the eye state (time 1-3) followed by stabilization and some degree of spontaneous recovery (time 3-5). It is hypothesized that immunosuppressive FIG. 1.

intervention in the active (inflammatory) stage of the eye disease is effective, resulting in complete or incomplete recovery. Intervening in the inactive (fibrotic) stage is ineffective. Im¬ provement (if any) is due to the natural history.

12.

13.

14.

1989 The pathogenesis of thyroidassociated ophthamopathy. J Endocrinol 122:619-624. Weetman AP 1991 Thyroid-associated eye disease: Pathophysiology. Lancet 338:25-28. Kendall-Taylor 1989 The management of Graves' ophthalmopa¬ thy. Clin Endocrinol 31:747-756. Fells 1991 Thyroid-associated eye disease: Clinical management. Lancet 338:29-32. Bahn RS. Gorman CA 1987 Choice of therapy and criteria for assessing treatment outcome in thyroid-associated ophthalmopa¬ thy. Endocr Metab Clin North Am 16:391-407. Gayno JP, Strauch G 1987 Ciclosporine and Graves' ophthalmop¬ athy. Hormone Res 26:190-197. Prummel MF, Wiersinga WM, Mourits MPh, Koornneef L, Berghout A, Gaag R vd 1989 Amelioration of eye changes of Graves' ophthalmopathy by achieving euthyroidism. Acta Endo¬ crinol 121(suppl 2): 185-189. Prummel MF, Wiersinga WM, Mourits MPh. Koornneef L, Berghout A, Gaag R vd 1990 Effect of abnormal thyroid function on the severity of Graves' ophthalmopathy. Arch Intern Med 150:1098-1101. Wiersinga WM, Prummel MF, Mourits MPh, Koornneef L, Buller HR 1991 Classification of eye changes of Graves' disease. Thyroid 1:357-360. Wiersinga WM, Smit T, Schuster-Uittenhoeve ALJ, Gaag R vd. Koornneef L 1988 Therapeutic outcome of prednisone medication and of orbital irradiation in patients with Graves' ophthalmopathy. Ophthalmologia 197:75-84. Marcocci C, Bartelena L, Panicucci M. et al 1987 Orbital cobalt irradiation combined with retrobulbar or systemic corticosteroids for Graves' ophthalmopathy: A comparative study. Clin Endocri¬ nol 27:33-42. Kendall-Taylor P. Crombie AL, Stephenson AM, Hardwick M, Hall 1988 Intravenous methylprednisolone in the treatment of Graves' ophthalmopathy. Br Med J 297:1574-1578. Guy JR, Fagien S, Donovan JP, Rubin ML 1989 Methylpred¬ nisolone pulse therapy in severe dysthyroid optic neuropathy. Ophthalmology 96:1048-1053. Editorial 1985 Cyclosporin in autoimmune disease. Lancet 1:909-911.

IMMUNOSUPPRESSIVE TREATMENT OF GRAVES' OPHTHALMOPATHY 15. Prummel MF, Mourits MPh, Berghout A, et al 1989 Prednisone and cyclosporine in the treatment of severe Graves' ophthalmopathy. EnglJ Med 321:1353-1359. 16. Kahaly G, Schrezenmeir J, Krause U, et al 1986 Ciclosporin and prednisone v. prednisone in treatment of Graves' ophthalmopathy: A controlled, randomized and prospective study. Eur J Clin Invest 16:415-422. 17. Dieterle A, Abeywickrama K, Graffenried 1988 Nephrotoxicity and hypertension in patients with autoimmune disease treated with cyclosporine. Transplant Proc 20(supp4):349-355. 18. Editorial 1991 Intravenous immunoglobulins. Br Med J 303:375-376. 19. Antonelli A, Saracino A. Alberti . et al 1992 High-dose intrave¬ nous immunoglobulin treatment in Graves' ophthalmopathy. Acta Endocrinol 126:13-23. 20. Perros P, Weightman DR, Crombie AL, Kendall-Taylor P 1990 Azathioprine in the treatment of thyroid-associated ophthalmopa¬ thy. Acta Endocrinol 122:8-12. 21. Kahaly G, Lieb W, Muller-Forell W, et al 1990 Ciamexone in endocrine orbitopathy. A randomized double-blind, placebo-con¬ trolled study. Acta Endocrinol 122:13-21. 22. Bigos STh, Nisula BC, Daniels GH, Eastman RC, Johnson HH, Köhler PO 1979 Cyclophosphamide in the management of ad¬ vanced Graves' ophthalmopathy. A preliminary report. Ann Intern Med 90:921-923. 23. Wall JR, Strakosch CR, Fang SL, Ingbar SH, Braverman LE 1979 Thyroid binding antibodies and other immunological abnormalities in patients with Graves' ophthalmopathy: Effect of treatment with cyclophosphamide. Clin Endocrinol 10:79-91. 24. Rogvi-Hansen Ba, Perrild H, Christensen T, Detmar SE, SierbaekNielsen K, Hansen JEM 1991 Acupuncture in the treatment of Graves' ophthalmopathy. A blinded randomized study. Acta Endo¬ crinol 124:143-145. 25. Dandona P, Marshall NJ, Bidey SP, Nathan A, Havard CWH 1979 Successful treatment of exophthalmos and pretibial myxoedema with plasmapheresis. Br Med J 1:374-376. 26. Kelly W, Longsom D, Smithard D, et al 1983 An evaluation of plasma exchange for Graves' ophthalmopathy. Clin Endocrinol 18:485-493. 27. Glinoer D, Etienne-Decerf J, Schrooyen M, et al 1988 Beneficial effects of intensive plasma exchange followed by immunosuppres¬ sive therapy in severe Graves' ophthalmopathy. Metab Pediatr Syst Ophthalmol 11:133-140. 28. Sautter-Bihl ML 1990 Orbital radiotherapy: Recent experience in Europe. In: Wall JR, How J (eds) Graves' Ophthalmopathy. Blackwall Scientific Publications, Boston, pp 145-157. 29. Petersen IA, Kriss JP, McDougall IR, Donaldson SS 1990 Prog¬ nostic factors in the radiotherapy of Graves' ophthalmopathy. Int J Radiât Oncol Biol 19:259-264. 30. Kinyoun JL, Kalina RE, Brower SA, Mills RP, Johnson RH 1984 Radiation retinopathy after orbital irradiation for Graves' ophthal¬ mopathy. Arch Ophthalmol 102:1473-1476. 31. Viebahn M, Barricks ME, Osterloh MD 1991 Synergism between diabetic and radiation retinopathy: Case report and review. Br J Ophthalmol 75:629-632.

233

32. Bartalena L, Marcocci C, Chiovato L, et al 1983 Orbital cobalt irradiation combined with systemic corticosteroids for Graves' ophthalmopathy: Comparison with systemic corticosteroids alone. J Clin Endocrinol Metab 56:1139-1144. 33. Prummel MF 1992 Medical management of Graves' ophthalmopa¬ thy. Ph.D. Thesis. Rodopi, Amsterdam. 34. Sergott RC, Glaser JS 1981 Graves' ophthalmopathy. A clinical and immunological review. Surv Ophthalmol 26:1-21. 35. Metz HS 1984 Complications following surgery for thyroid oph¬ thalmopathy. J Pediatr Ophthalmol Strabismus 21:220-222. 36. Dresner SC, Kennerdell JS 1985 Dysthyroid orbitopathy. Neurol¬

ogy 35:1628-1634. 37. Prummel MF, Mourits MPh, Wiersinga WM, et al 1991 A random¬ ized double-blind comparison of oral prednisone and retrobulbar

radiotherapy (Abstract). Thyroid Ksuppl l):S-26. 38. Hurbi T, Char DH, Harris J, Weaver K, Greenspan F, Shelsine G 1985 Radiation therapy for thyroid eye disease. Am J Ophthalmol 99:633-637. 39. Teng LA, Crombie AL, Hall R, Ross WM 1980 An evaluation of supervoltage orbital irradiation for Graves' ophthalmopathy. Clin Endocrinol 13:545-551. 40. Donaldson SS, Bagshaw MA, Kriss JP 1973 Supervoltage orbital radiotherapy for Graves' ophthalmopathy. J Clin Endocrinol Metab 37:276-285. 41. Rundle FF, Wilson CW 1945 Development and course of exoph¬ thalmos and ophthalmoplegia in Graves' disease with special reference to the effect of thyroidectomy. Clin Sci 5:177-194. 42. Hales IB. Rundle FF 1960 Ocular changes in Graves' disease: A long-term follow-up study. QJ Med 29:113-126. 43. Mourits MPh, Koornneef L, Wiersinga WM, Prummel MF, Berghout A, Gaag R vd 1989 Clinical criteria for the assessment of disease activity inGraves'ophthalmopathy: A novel approach. BrJ Ophthalmol 73:639-644. 44. Suttorp-Schulten MSA. Prummel MF, Wiersinga WM, Verkerk NM, Koornneef L, Mourits MPh 1991 A-mode ultrasonography to measure disease activity in Graves' ophthalmopathy (Abstract). Ann Endocrinol 52:44. 45. Kahaly G, Schüler M, Sewell AC, Bernhard G, Beyer J, Krause U 1990 Urinary glycosaminoglycans in Graves' ophthalmopathy. Clin Endocrinol 33:35-44. 46. Kahaly G, Just M, Rosier HP, Stover C 1991 Magnetic resonance imaging in radiotherapy of Graves' ophthalmopathy. In: Interna¬ tional Symposium on Graves' Ophthalmopathy, Amsterdam, Ab¬ stract 27.

Address reprint requests to: W.M. Wiersinga, M.D.

Department of Endocrinology Academisch Medisch Centrum, F5-258 Meibergdreef 9 1105 A2 Amsterdam The Netherlands

Immunosuppressive treatment of Graves' ophthalmopathy.

Glucocorticoids and retrobulbar irradiation are the most employed immunosuppressive treatment modalities in Graves' ophthalmopathy. The response rate ...
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