Ординатура / Офтальмология / Учебные материалы / Эндокринная офтальмопатия - мультидисциплинарный подход 2007

82 consecutive patients with active and severe GO were randomly treated with either oral prednisone (starting dose 100 mg/day; withdrawal after 5 months) or intravenous methylprednisolone (15 mg/kg for 4 cycles and then 7.5 mg/kg for 4 cycles; each cycle consisted of 2 infusions on alternate days at 2-week intervals). A significant reduction of proptosis, lid width, and diplopia grades occurred, with no differences in both groups. The clinical activity score decreased significantly more in the intravenous group. By self-assessment evaluation, 85% intravenous and 73% oral steroid patients reported an improvement of ocular conditions, and responders in the intravenous group (88%) were more than in the oral group (63%). Side effects occurred in 56% intravenous and 85% oral steroid patients; in particular, cushingoid features developed in 5 of the intravenous and 35 of the oral steroid subjects. However, one intravenous steroid patient had severe hepatitis of undetermined origin at the end of steroid treatment, followed by spontaneous recovery. Finally, similar data demonstrating the superiority of a combined Rx-steroid therapy have been reported from China [33].

From the above data it is quite evident that the combination of Rx and oral steroids is more effective than oral steroids alone. Whether this is also true for the combination of Rx and intravenous steroids as compared to intravenous steroids alone, is not clear. In view of the greater efficacy of intravenous over oral steroids, the additional benefit of Rx may not exist when steroids are given intravenously. Addition of 20 Gy to intravenous pulses of methylprednisolone had no extra benefit in a nonrandomized study in Japan [34].

What Are the Results of Randomized Trials Using

Nonsteroid Immunosuppressants?

Cyclosporine

After the completion of a course of steroids, relapses of the activity of GO frequently occur. In order to avoid these recurrences and/or to keep the steroid doses low, furthermore because of the autoimmune pathogenesis of the disease, nonsteroid immunosuppressants came into use for GO in the 1970s. The drug best studied is cyclosporine which affects both humoral and cell-mediated immune reactions. It inhibits both cytotoxic T cell activation, production of cytokines and antigen presentation by monocytes and macrophages, as well as induces activation of T suppressor cells. Foremost, this agent is specific for lymphocytes and acts at an early stage of their activation. The drug binds at the lymphocyte surface on a protein (cyclophilin) and then migrates to the cell nucleus, where it has an inhibitory action on transcription of the RNA responsible for lymphokine production including that of IL-2. At our institution, a randomized

trial was carried out in 40 patients with moderately severe GO [35–38]. Group 1 received prednisone in decreasing dosage, group 2 received prednisone at a comparable dosage plus cyclosporine (5 mg/kg/BW/day). Steroids were discontinued after 10 weeks in both groups. In group 2, cyclosporine was continued over 12 months. All signs of GO improved significantly in both groups whereas the improvement was significantly greater in group 2 according to a predefined score. After steroids were discontinued, inflammatory signs recurred in 9/20 patients in group 1 and in 1/20 of group 2. During the observation period of 12 months, relapses occurred in 8 in group 1 and in only 1 in group 2. Muscle thickness decreased in 9 patients in group 2, 6 months after beginning therapy. At this time, the results were not influenced in any of the 20 subjects in group 1. Both the TSH-receptor, the microsomal and the ocular muscle autoantibodies significantly decreased during cyclosporine therapy. In the cyclosporine group, Klebsiella pneumonia occurred 4 months after starting the immunosuppressive treatment and led to the single dropout in this trial. Prummel et al. [39] also compared the efficacy of prednisone with that of cyclosporine in 36 GO patients. During the 12-week period, 11/18 (61%) of the prednisone-treated and 4/18 (22%) of the cyclosporine-treated subjects responded. Response was manifested by decreases in eye muscle enlargement and proptosis and improvement of visual acuity, total and subjective eye scores. After 12 weeks, patients who did not respond were treated for another 12 weeks with a combination of cyclosporine and a low dose of prednisone. Among the 9 patients who initially received prednisone, the addition of cyclosporine resulted in improvement in 5 (56%), and among the 13 patients who received cyclosporine initially, 8 (62%) improved after the addition of prednisone. Combination therapy was better than prednisone treatment alone. These two studies indicated a lower efficacy of cyclosporine than prednisone as a single-agent treatment and found evidence that a combination of cyclosporine and prednisone may be more effective than either treatment alone. Thus, the use of cyclosporine might be indicated in association with steroids in patients who are resistant to steroids alone and in whom the persistent disease activity warrants continuing medical intervention. This combined treatment may be regarded as a second line alternative, especially in patients with diabetes mellitus in whom high doses of steroids and Rx should be used with caution. Side effects of cyclosporine are significant and hypertension, hepatic and nephrotoxicity may occur. Therefore, cautious dosage of this drug ( 5 mg/kg/day) and measurement of the blood trough levels are recommended.

Intravenous Immunoglobulin

Intravenous administration of immunoglobulin (Ig) resulted in decreased antibody titres and clinical improvement in many autoimmune diseases [40].

Therefore, a randomized trial was done in which 19 patients with active and severe GO were treated with oral prednisolone (starting dose 100 mg/day) and 21 received 1 g Ig/kg/BW for two consecutive days every 3 weeks. The Ig course was repeated 6 times. A successful outcome was observed in 13 (62%) Ig and in 12 (63%) steroid treated patients [41]. Overall, there were no marked differences in degree of clinical improvement between the two groups. Among the patients treated with Ig, there was a marked decrease of the TSH-receptor, microsomal, and thyroglobulin autoantibodies as well as of the CD4/CD8 ratio. The significant decrease of thyroid autoantibodies in the Ig group may be viewed as a direct and local immunosuppressive effect of the drug on the intrathyroid lymphocytes. Adverse events were more frequent and severe during prednisolone than during Ig therapy. Antonelli and co-workers [42, 43] also compared the effectiveness of steroids with high-dose intravenous Ig in active GO. Response rates were 65% (n 34) and 62% (n 27) in patients receiving either Ig or prednisone, respectively. Soft tissue involvement improved or disappeared in 90 and 92.5% of the Ig and steroid-treated subjects, respectively. Also, the degree of diplopia decreased or diplopia disappeared in 75 and 80% in the Ig and steroid groups. Finally, proptosis decreased in 65 and 62% of the Ig and steroid patients. Orbital CT confirmed a significant reduction of eye muscle thickness in the Ig group. In both studies, intravenous Ig was safe and no major adverse events were noted. Thus, prednisolone and Ig appeared to be equally effective in treatment of severe and active GO. Nevertheless, high costs, the need for intravenous administration, and its small potential risk for transmitting infectious agents limit the routine application of Ig making them unable to replace the standard treatment with glucocorticoids (table 5).

Azathioprine and Ciamexone

Azathioprine competitively inhibits the incorporation of adenosine into deoxyribonucleic acid. The preparation possesses a low therapeutic index, and the dose required to inhibit T cell proliferation is almost as high as that which induces myelosuppression. Perros et al. [44] recruited 20 patients with moderately severe GO. Ten patients received azathioprine and 10 randomly matched patients served as controls. During the treatment period of one year and subsequently during a following observation year, no changes were detected in proptosis readings, visual acuity or measurement of palpebral aperture.

Ciamexone has immunomodulatory properties and inhibits antibody production in experimental models of autoimmune diseases. 51 patients with active GO were randomly allocated to two groups. Over a period of 6 months 26 patients received ciamexone 300 mg daily and 25 patients placebo [45]. All subjects additionally took prednisone in the first 4 weeks. Detailed examination did not reveal any preferential action of ciamexone on individual ophthalmic

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parameters. Orbital CT showed no significant alterations of the ocular muscle thickness.

In summary, due to the appreciable adverse effects of the agents mentioned, non-steroidal immunosuppressants should be viewed as supplementary to steroids only in active and severe GO. They should not be administered on their own. The rationale for their use is the complementary action with glucocorticoids in the acute phase of the disease and the possibility of reducing the dose of steroids (steroid-sparing effect).

What Are the Results of Randomized Trials Using

Somatostatin Analogs?

Somatostatin (SS) analogs interact with the SS receptors located on the surface of different cell types in the orbit and might inhibit the local release of IgF-1 or cytokines, which may be relevant in triggering and/or maintaining the ongoing reactions in the orbital tissue of patients with GO. In the first comparative open study [46], 18 patients with active and severe GO randomly received either Octreotide® 200 g q8h subcutaneously (n 8) or prednisone 1 mg/kg/day in decreasing doses (n 10). Both Octreotide and prednisone therapy significantly decreased the palpebral aperture and activity score after 3 months, but those treated with prednisone had a lower activity score after treatment when compared to Octreotide. Only prednisone, but not Octreotide, was able to reduce intraocular pressure and muscle size as documented by MRI. Both groups showed significant elevation of urinary glycosaminoglycan excretion before therapy which was reduced after treatment. In summary, Octreotide was not as effective as prednisone in the treatment of severe GO (table 6).

Recently, four double-blind randomized studies were published. In the first trial conducted by Dickinson et al. [47], 50 euthyroid patients with active GO (median age 50 years, 39 females, NOSPECS 2–5, median duration of GO 0.9 years) received either 30 mg of the SS analog Octreotide LAR® intramuscularly or placebo every 4 weeks for 16 weeks. Both groups then received 30 mg Octreotide LAR for week 16–32 and were followed-up without treatment for a further 24 weeks. Objective assessments included all individual parameters of GO, CAS, and derived scores for soft tissue inflammation and ophthalmopathy index. During weeks 0–16 there was a significant reduction of CAS, soft tissue inflammation and subjective diplopia in the Octreotide-treated patients but the CAS and soft tissue inflammation were also reduced with placebo. During weeks 16–32 there was no significant change in the GO index in either group. Overall results (weeks 0–32) showed a slight reduction in the CAS and soft tissue inflammation in both groups, only. Thus, in this trial no significant