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Randomized, Single Blind Trial of Intravenous versus Oral Steroid Monotherapy in Graves’ Orbitopathy

Departments of Medicine I (G.J.K., M.D.), Biology (M.D.), Ophthalmology (S.P.), and Medical Statistics (G.H.), Gutenberg University, Mainz 55101, Germany

Address all correspondence and requests for reprints to: Dr. George J. Kahaly, University Hospital, Mainz 55101, Germany, E-mail: gkahaly{at}mail.uni-mainz.de.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Glucocorticoids are effective for severe Graves’ orbitopathy (GO), which causes substantial morbidity. The question at issue is how best to use them.

Objective: The objective of this study was to optimize glucocorticoid application in GO.

Design: The study design was a randomized trial over 12 wk with 6-month follow-up.

Setting: The study was performed at university joint thyroid and ophthalmic clinics.

Patients: Seventy euthyroid out-patients with untreated, active, and severe GO were studied.

Intervention: Patients received either once weekly iv methylprednisolone (0.5 g, then 0.25 g, 6 wk each) or oral prednisolone starting with 0.1 g/d, then tapering the dose by 0.01 g/wk.

Main Outcome Measures: At 3 months, the primary end point was a composite of improvements in proptosis, lid fissure width, and rate of diplopia in primary gaze, visual acuity, eye muscle thickness, and patient’s quality of life.

Results: Intravenous glucocorticoid therapy resulted in rapid, significant, and sustained improvement. At 3 months, 27 of 35 patients (77%) in the iv group had a treatment response compared with 18 of 35 (51%) in the oral group (P < 0.01). Improvements over baseline values for disease severity (e.g. visual acuity; P = 0.01) and activity (e.g. chemosis; P < 0.01) and for quality of life (P < 0.001) were greater in the iv group. TSH receptor antibody titers decreased during iv steroid administration (P < 0.001), and smoking had a strong impact on the therapy response (P < 0.001). Additional treatment was required less frequently in the iv group. Intravenous steroids were safe, with different rates of adverse events between the two groups (P < 0.001).

Conclusions: In patients with active and severe GO, iv glucocorticoids were more effective and better tolerated than oral steroids.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
IN GRAVES’ ORBITOPATHY (GO), orbital fibroblasts respond markedly to proinflammatory cytokines by increasing the expression of major histocompatibility complex class II and adhesion molecules in the orbit (1, 2, 3, 4, 5, 6). Cytokine release is directly inhibited by glucocorticoids, which are established in the management of GO in view of their antiinflammatory actions (7). During the active stage of GO, immunosuppression by glucocorticoids is used initially, and by suppressing inflammatory changes, it result in improvement of the disease. Oral glucocorticoids provide favorable responses in 60% of the cases (8). They are effective on soft tissue changes, eye muscle involvement of recent onset, and optic neuropathy, whereas proptosis and long-standing GO are poorly responsive. Recurrence of active GO is a rather common problem with oral steroid therapy, not only when the drug is withdrawn, but also when its dose is tapered. Also, chronic administrations of high doses of oral steroids and severe GO per se lead to a relevant deterioration of quality of life (QL) (9, 10, 11). Other drawbacks include the need for high doses for a long period and the frequent and potentially dangerous side effects. By comparison, positive results with iv administration of high pulse steroids have been reported in patients with various autoimmune diseases (12). The rationale for the use of pulse therapy is the observation that GO is often characterized by a single flare of the autoimmune process. In addition, there is evidence that in rapidly progressive autoimmune disorders, high dose iv steroids may achieve a more rapid and effective immune suppression. Thus, a short-term series of iv steroid pulses may be effective in slowing the progression and eventually improving the final outcome of the disease. Although iv steroids have been employed in GO for many years, in most studies oral steroids were also given during the interpulse period, or other immunosuppressive agents or orbital radiotherapy were associated with iv treatment, making it difficult to ascertain the precise role of iv therapy (13, 14, 15, 16, 17, 18). Finally, all but one (18) are uncontrolled studies, and both the benefits as well as the safety of iv steroids have been questioned in GO. Therefore, the aim of the following randomized trial was to optimize the application of steroids and to compare the efficacy and tolerability of oral prednisolone, as the classical standard monotherapy, with those of iv methylprednisolone in patients with active and severe GO.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
A prospective, randomized, single-blind, and controlled study of 70 consecutive patients with untreated, active, and moderately severe GO was performed between January 2001 and June 2003 (Table 1). Informed consent was obtained from all patients, and the ethics committee of Gutenberg University approved the study. Subjects with Graves’ hyperthyroidism were rendered euthyroid with thionamide therapy. Neither radioiodine nor surgery was used. The euthyroid patients with GO of recent onset (<6 months) were randomly assigned to receive once weekly iv methylprednisolone (0.5 g, then 0.25 g, 6 wk each) or oral prednisolone for 12 wk starting with 0.1 g/d, then tapering the dose by 0.01 g/wk (cumulative doses of 4.5 and 4.0 g, respectively). The type of therapy was not known to the ophthalmologist (S.P.). Complete ophthalmic investigation and ultrasound of the orbit were performed both before as well as 12 wk after starting therapy. Assessment of the severity and activity of GO was carried out according to the proposed criteria of the European group on GO (19, 20). At 3 months, the primary end point was a composite of improvements in measures of proptosis, lid fissure width, and rate of diplopia in primary gaze, intraocular pressure in up gaze, the sum of the ultrasonically measured rectus muscle thickness, and evaluation of QL. Specifically, the response to therapy was defined as a relevant improvement of at least three clinically objective parameters (7, 21, 22): e.g. decrease in proptosis and lid width of 2 mm each, decrease in ocular pressure in up gaze and the sum of eye muscle thickness of 3 mm each, disappearance of diplopia in primary gaze, and/or amelioration of eye muscle motility and visual acuity in one gaze of 10° and 2 decimals, respectively. Proptosis (normal range, 16–19 mm) was assessed using a Hertel exophthalmometer. Eye muscle involvement was assessed using the diplopia score: intermittent, inconstant, and constant diplopia in primary position (19). Moderately severe GO was defined as marked soft tissue swelling, proptosis greater than 25 mm, and/or inconstant diplopia, but no optic nerve involvement. Severe GO was defined as constant diplopia and/or nerve involvement. Optic neuropathy was present if there was disc swelling or pallor, a visual field defect, and/or if visual acuity was less than 0.3 in the absence of other reasons for sight loss. Assessment of GO activity was carried out using the clinical activity score (CAS), which consists of seven items: spontaneous orbital pain or on eye movement; swelling of the conjunctiva, cornea, and caruncula; and redness of conjunctiva and lids; the final score is the sum of all items present (7). Smoking was assessed as follows: none (n = 29/70; 41%), less than 20 cigarettes/d (n = 29; 41%), or more than 20 cigarettes/d (n = 12; 18%). Liver enzymes, blood glucose, and renal parameters were assessed at baseline, every 4 wk during steroid therapy, and every 3 months within the 6-month follow-up period. Commercially available kits measured thyroid related-hormones and autoantibodies.

QL was assessed with the 36-item short form (SF-36), a self-rating questionnaire to assess general health status (25, 26). The first four subscales refer to physical aspects, and the next four to psychosocial aspects. Total values were computed by averaging the eight weighted domains using the coefficients generated in the study. For the German version, an investigation was carried out on a representative sample of the general population (27). Raw T-values of the questionnaire were transformed into age- and gender-specific z-values. A z-value of 0/–1/+1 indicates that the patient’s score is identical with /1 SD below/1 SD above the age- and gender-specific general population value. The self-assessment questionnaire contained 26 questions and 90 items (28). The answers to each item were coded in four categories between 4 (minimum self-reported contentment) and 1 (maximum contentment). A total score was computed as the mean of all available answers in a patient’s questionnaire. A low score represented a high self-estimated overall satisfaction.

Statistics were calculated using the SPSS/PC software package for MS Windows, release 8.0 (SPSS, Inc., Chicago, IL). To increase precision, data were entered twice into a computer program, which minimizes the possibility of typing errors. For metric variables, median values and range were given, and for dichotomous variables, absolute and relative frequencies are shown. Patients were randomly assigned following a simple randomization scheme. For statistical tests concerning eye-specific variables, the mean values of the two eyes were computed for each patient. Comparisons between two independent samples were performed by the Mann-Whitney U test (metric variables) or Fisher’s exact test (dichotomous variables). To examine whether a change occurred between 0 and 12 wk, the Wilcoxon signed-rank test was performed for metric variables, and the McNemar test was performed for dichotomous variables. Significance was set at 0.05; effects with 0.1 < P < 0.05 were viewed as a trend.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Clinical and laboratory findings at 12 wk vs. baseline

Treatment with iv glucocorticoids resulted in rapid, significant, and sustained improvement (Tables 2 and 3). According to the predefined criteria, 27 of 35 patients (77%) in the iv group had a treatment response at 3 months compared with 18 (51%) in the oral group (P < 0.01). Improvements over baseline values for various measures of disease severity were significantly greater in the iv group. More specifically, the rate of constant diplopia in primary gaze and the number of cases with optic neuropathy markedly declined after iv treatment. In the iv group, diplopia disappeared in six (17%; three constant and three inconstant), improved in 10 (29%; from constant to inconstant in seven and from constant to intermittent in three), and did not change in 10 (29%). In the oral group, diplopia disappeared in four of 35 subjects (one constant, two inconstant, and one intermittent), but newly appeared in two of 35, improved in six (17%; from constant to inconstant), and did not change in 14 (40%). Improvement of eye muscle motility in one gaze of 10° was noted in 16 (46%) and nine (26%) patients of the iv and oral groups, respectively (P < 0.01). In contrast to the oral route, a significant decrease in proptosis, rectus muscle thickness, and intraocular pressure in up gaze was noted in the iv group. Twenty-one (60%) and 14 (40%) patients in the iv and oral groups, respectively, had a decrease in proptosis of at least 2 mm (P < 0.02). Also, 22 (63%) and 14 (40%) subjects in the iv and oral groups, respectively, showed a decrease in lid width of 2 mm (P < 0.01). The number of subjects with chemosis, conjunctivitis, and orbital pain markedly decreased after iv therapy. In this group, the CAS and the titer of the TSH receptor (TSH-R) autoantibodies declined significantly more than in the oral group. Twenty-seven (77%) and 18 patients (51%) in the iv and oral groups, respectively, had a CAS decrease of 3 points (P < 0.01)

In contrast to nonsmokers, patients smoking more than 20 cigarettes daily (n = 12; 18%) showed a deterioration of various ophthalmic signs (Fig. 1) and increased TSH-R antibody titers during therapy (median value, 25 vs. 6 IU/liter; P = 0.003, by U test). Lid width (median decrease, –1; median increment, +1 mm; P = 0.01), proptosis (–1 vs. +0.5 mm; P = 0.04), and rectus muscle thickness (–2 vs. +1.5 mm; P = 0.03) decreased more in females than in males. Also, the CAS (–3.25 vs. –1.25; P = 0.0014), ocular pressure in up gaze (–3 vs. +1 mm Hg; P = 0.01), and lid width (–1 vs. +2 mm; P = 0.030) declined more, and visual acuity improved (+0.05 vs. –0.15; P = 0.0001) in patients younger than 50 yr of age (n = 39; 56%) in contrast to those older than 50 yr.

View larger version (11K): [in this window] [in a new window]   FIG. 1. Effect of smoking: none (n = 29/70; 41%), less than 20 cigarettes/d (n = 29; 41%), or more than 20 cigarettes/d (n = 12; 18%) on the response to glucocorticoid therapy. The increment and/or decline (median value) in clinically relevant and objective ophthalmic parameters (e.g. lid fissure width, proptosis, and intraocular pressure in up gaze) during steroid therapy are shown in the three panels.

The iv therapy markedly improved the physical and psychosocial components of QL (P < 0.001). In contrast, oral treatment led to slight changes only (Fig. 2). Nine percent (n = 3) and 11% (n = 4) only in the iv and oral groups, respectively, estimated their QL to be good and/or excellent before steroid treatment. The satisfaction rate increased to 80% (n = 28) and 54% (n = 19), respectively, after therapy, corresponding to an intraindividual gain in patient contentment in 25 and 15 GO patients of the iv and oral groups, respectively (P < 0.007). Seventy-seven percent (n = 27) considered their QL as "bad" before steroids, but only 11% (n = 4) did so after iv therapy (by McNemar test, P < 0.001). In the iv group, five patients (14%) did not notice substantial changes, and two had the impression of a progression of eye signs. By comparison, in the oral group, 11 (32%) reported no changes, and five (14%) subjects reported a progression of GO. The self-assessment score decreased from 3.1 (2.3–3.6) to 2.2 (1.6–2.8; P = 0.0001) and from 3.0 (2.2–3.6) to 2.6 (1.9–3.2; P = 0.564) in the iv and oral groups, respectively.

View larger version (15K): [in this window] [in a new window]   FIG. 2. Physical and psychosocial components of the SF-36 questionnaire evaluating health-related QL both at baseline as well as after completion of glucocorticoid therapy in the two iv and oral study groups (A and B). Age- and gender-adapted and transformed z-values (median) are shown.

Intravenous glucocorticoids were fairly well tolerated, with significant differences in rates of adverse events between the groups (Table 4). Both the total number of patients with side effects as well as the number of major adverse events (depression or severe hypertension) were higher in the oral group. Fasting blood glucose and all liver and renal parameters were normal in the two groups both during steroid treatment as well as after completion of therapy. These laboratory values also stayed within the normal range during the 6-month follow-up. At 12 wk and in contrast to the iv scheme (baseline, 1.15 g/cm²; 12 wk, 1.12 g/cm²), a significant decrease in bone mineral density of the lumbar spine, but not of the femur neck, was noted in the oral group only (baseline, 1.1 g/cm²; range, 0.8–1.3; 12 wk, 0.95 g/cm²; range, 0.6–1.2; P < 0.05).

Additional forms of treatment were required less frequently in the iv group. After completion of glucocorticoid therapy, four of 35 patients in the oral group developed optic neuropathy within a follow-up period of 6 months vs. none in the iv group (P = 0.01). Also, 11 (32%) and five (14%) subjects in the oral and iv groups, respectively, had orbital decompression surgery (P = 0.003). Finally, squint surgery was necessary in 12 (35%) vs. seven (20%, P = 0.02) in the oral and iv groups, respectively.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This is a randomized, single-blind trial comparing two forms of glucocorticoid monotherapies in euthyroid patients with untreated and active GO. This prospective study evaluates the effects of smoking, gender, and age on the response to glucocorticoids in subjects with GO of recent onset. This controlled trial also evaluates the effects of two steroid monotherapies on the physical and psychosocial components of QL in severe GO. In this trial, iv methylprednisolone pulses were safe, more effective, and better tolerated than oral prednisolone treatment, resulting in rapid, significant, and sustained clinical improvement.

Efficacy of iv glucocorticoids

As previously stated, with the exception of one, all published studies dealing with iv steroids in GO were not randomized, the patients received one or many treatments either between or after the steroid pulses, and the study protocols included a small number of GO patients (13, 14, 15, 16, 17). Thus, to compare our findings with those reported in the literature, we mainly relied on the only randomized trial of oral vs. iv steroids in a large number of patients with severe GO (18). In this paper and in contrast with our study, all GO subjects were also treated with orbital irradiation (total dose, 20 Gy), and the cumulative dose of iv steroids was 2- to 3-fold higher (9–12 vs. 4.5 g). Patients were treated with either oral prednisone (initial dose, 0.1 g/daily; with gradual tapering and withdrawal after 5 months; total dose, 6 g) or iv methylprednisolone (15 mg/kg body weight for four cycles, then 7.5 mg/kg for four cycles; each cycle consisted of two infusions on alternate days at 2-wk intervals; total dose, 9–12 g). No oral steroids were given during the interpulse period. Comparison of the iv and oral routes showed an overall greater effectiveness of iv steroids, because 83% of patients treated with this form had a favorable outcome compared with 63% of those treated orally. However, the difference in efficacy between oral and iv steroids in the Italian trial might have been due to the higher cumulative dose of iv steroids. In our and Marcocci’s studies (18), optic neuropathy and inflammatory changes were the ocular manifestations that responded to a greater extent to iv steroids, even though there was a tendency toward a greater effectiveness also for diplopia. The self-assessment of ocular changes was in good agreement with the clinical response, pointing to a more favorable outcome of iv treatment. In this respect, the positive evaluation was comparable to that recently observed after orbital decompression in patients with severe GO (28). Also, the SF-36 questionnaire demonstrated the marked improvement in psychosocial components of QL after iv glucocorticoid treatment.

In our collective, patients younger than 50 yr of age and female subjects responded better to steroid therapy, be it iv or oral. These findings confirm previous work that old subjects and male subjects show severe forms of GO (7). However, our results also add clinically relevant information regarding the outcome of steroid therapy; namely, these patients also seem to respond poorly to antiinflammatory treatment. Nevertheless, the most impressive factor was smoking. Even during steroid therapy, deterioration of relevant ophthalmic signs was noted in the heavy smokers. In contrast to nonsmokers, TSH-R antibodies increased in those subjects, possibly stimulating the activity and growth of orbital target cells. These data also emphasize the recently published statements of a causal role of smoking in GO (29).

A possible explanation of the therapeutically success of the iv form is a reported complete abolition of circulating dendritic cells (DC) after pulse therapy (30). DC are the most potent antigen-presenting cells and play a central role in initiating the primary immune response (31). Intravenous methylprednisolone (1 g/d) completely abrogated blood DC, and the two DC subsets (myeloid and plasmacytoid cells) disappeared in the peripheral blood. Six days after the steroid pulse, the numbers of circulating DC were still significantly lower than those before treatment. The mechanism by which iv steroids abrogate circulating DC may be accounted for in several ways. First, the redistribution of circulating DC, such as homing to lymphoid organs or peripheral tissues, may cause the loss of blood DC. Second, a decreased production or differentiation of DC from bone marrow CD34⁺ progenitors may be responsible for the depletion of circulating DC (32). Finally, DC may be eradicated from the blood by apoptosis. Indeed, in vitro studies have demonstrated that glucocorticoids directly induce apoptosis of CD34⁺ precursor-derived DC (33, 34).

Safety of iv glucocorticoids

In our hands, side effects were more prevalent in the oral group, possibly because a continuous and more prolonged administration of steroids may have pronounced untoward metabolic effects (8, 12). Also, in the oral group, a decrease in bone mineral density was noted in the lumbar spine only, whereas no differences were noted in the femur neck. Because no follow-up data are available, we are cautious when interpreting these findings. The data also confirm the results of our own randomized trial (35), in which 19 patients with active GO were treated with a 20-wk course of oral prednisolone starting with a dose of 0.1 g/d. Side effects occurred in 16 subjects (84%), whereas two of 19 (11%) had major complications, e.g. severe hypertension or psychic disorders. In Marcocci’s trial (18), patients treated with iv steroids also had a lower rate of side effects; they occurred in 56% and 85% in the iv and oral groups, respectively (P < 0.01). In particular, Cushingoid features were observed in a low proportion of iv-treated patients, whereas they were present in the vast majority of patients treated with oral steroids.

Using moderate cumulative doses of oral prednisolone (4 g) and iv methylprednisolone (4.5 g), we did not register a single case of increased liver enzymes. By comparison, there have been a few case reports of fatal liver damage associated with iv steroids: four in GO patients (36, 37) and two in patients with various autoimmune diseases (38, 39). In the patients treated by Marcocci, the rise in liver enzymes was observed either after completion of iv treatment or before the last cycle; it reached a peak at 1.5–3 months and progressively returned to the normal range after 4–5 months. In their three cases of lethal liver failure after iv steroid treatment, cumulative doses of iv methylprednisolone were 24 and 10–15 g. Thus, iv steroids may exert direct damage on liver cells, and there seems to be a dose dependence of the extent and outcome of severe liver damage. Also, iv steroid-induced immune suppression might have precipitated virus-induced hepatitis. Finally, a possible reactivation of the immune system after completion of iv steroid treatment might have precipitated immunohepatitis.

Although a direct relation between iv steroids and severe liver damage has yet to be proven, these individual reports prompt strict selection and careful monitoring of patients who are to be subjected to iv therapy. Based on their large experience with the steroid treatment of GO patients, Marcocci et al. (8, 37) estimate the total morbidity and mortality of high doses of iv methylprednisolone to 0.9% and 0.4%, respectively. In contrast, cases of hepatitis and liver failure have not been reported in patients treated with high doses of oral steroids, which may be related to the gradual withdrawal of the oral dose. Thus, the abrupt withdrawal of iv steroids may cause a reexacerbation of an underlying liver autoimmune process after a prolonged immunosuppression, which may result in liver damage. Accordingly, restrictive measures have been recommended, e.g. limiting the cumulative dose of iv methylprednisolone to 6–8 g; assessment of liver morphology, virus markers, and autoantibodies before iv treatment; and exclusion of patients at risk. Finally, monitoring liver function and morphology before, during, and after iv treatment is warranted.

	Footnotes

 
First Published Online July 5, 2005

Abbreviations: CAS, Clinical activity score; DC, dendritic cell; GO, Graves’ orbitopathy; QL, quality of life; TSH-R, TSH receptor.

Received January 24, 2005.

Accepted June 28, 2005.

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