Sequential sampling was made of patients with moderatesevere GO treated in our center. The study included patients between 16-72 years old not previously subjected to immunosuppressor therapy, radiotherapy or eye surgery. We excluded patients with contraindications for MTPiv pulse therapy (heart arrhythmias, unexplained gastric pain, a history of pulmonary tuberculosis, active liver disease, HIV infection, uncontrolled hypertension). The diagnosis was based on the typical clinical characteristics of the disease, evaluating activity and severity according to the criteria established by the EUGOGO in 20086 (moderate to severe ophthalmopathy being defined by the presence of one or more of the following: palpebral retraction > 2 mm, moderate or severe soft tissue involvement, exophthalmos > 3 mm above normal for the race and sex, and inconstant or constant diplopia; sight-threatening GO like dysthyroid optic neuropathy or corneal rupture).

Two MTPiv regimens were compared. Regimen A, which is currently used in our center, involves the administration of 6 doses of 0.5 g/week followed by 6 doses of 0.25 g/week, for a cumulative dose of 4.5 g of MTPiv over 12 consecutive weeks3. Regimen B was used in our center until late 2006, and was based on the administration of four cycles of 15 mg/kg of MTPiv, followed by another four cycles of 7.5 mg/kg (each cycle consisted of two MTPiv infusions on alternate days —Monday and Wednesday— at two-week interval), with a cumulative dose of 90 mg/kg (total administered dose per patient ranged between 4.9-7.4 g) of MTPiv over a period of 16 weeks1 (fig. 1).

Fig. 1.

Distribution of the study population between the two treatment arms. Description of the treatment regimens. GO: Graves’ ophthalmopathy.

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The blood samples were collected after a 10-hour fasting period, with quantification of the following before and after treatment: blood glucose, liver cytolysis enzymes (aspartate aminotransferase [ASAT], alanine aminotransferase [ALAT]) and lipid profile (total cholesterol, LDL-cholesterol, triglycerides), based on the VisUV Coban 711® enzyme-photometric assay; and cholestasis markers (gamma-glutamyl transpeptidase [GGT], alkaline phosphatase [AP]), based on the VisUV Coban 711® kinetic-photometry technique. The determination of anti-TSH receptor antibodies (TRACK) was carried out by Medizym® TRA enzyme immunoanalysis (reference value [vr] < 14 U/l), while antiperoxidase antibodies (antiTPO) were assessed with Axsym Abbott® electro-chemiluminescence (vr < 34 U/ml).

All patients were evaluated by the same endocrinologist before and after treatment. We establish a cutoff point for repeat evaluation of 11 weeks (range, 6-24), to evaluate the primary study objective (safety). Because of such early evaluation, many patients had not yet been re-evaluated by the Service of Ophthalmology. For this reason, clinical improvement was assessed on the basis of subjective perception of both, the patient and the Endocrinologist, registered in the case history. We recorded too the cases of recurrence and the need for additional MTPiv cycles or posterior radiotherapy or eye surgery.

The study results were analyzed on an intent-to-treat (ITT) basis, using the SPSS version 15.0 statistical package. The quantitative variables were analyzed with the Mann–Whitney U-test. The quantitative variables corresponding to paired samples in turn were analyzed with the Wilcoxon test. The χ2 test was used to evaluate differences between the categorical variables in 2 × 2 contingency tables. Univariate logistic regression analysis was performed to identify the risk factors associated with the absence of treatment response and a greater probability of GO relapse. Statistical significance was considered for p < 0.05.

MTPiv was well tolerated, with no detection of immediate side effects. Blood pressure remained stable during treatment. No significant differences were seen in the biochemical parameters at baseline or after the administration of both regimens – with the exception of a decrease in GGT concentration with regimen A (table 2). There was no correlation between the cumulative dose of MTPiv and the ASAT/ALAT ratio.

Side effects were recorded in 4 patients (table 3). Two patients of regimen A presented type 2 diabetes mellitus and one of these subjects, previously treated with insulin, was the only patient that needed to suspend the treatment after two cycles due to poor blood glucose control. Two patients (one belonging to each dosing regimen) presented transaminase elevation that did not double the normal value. Two patients showed transaminase elevation to 2-3 times the normal value: the diabetic patient in whom treatment was suspended and who proved positive for hepatitis C virus infection (regimen A), and a second patient who also showed liver cholestasis enzyme elevation with no associated comorbidity (regimen B). There were no significant differences in side effects between the two treatment groups.

Repeated assessment of ocular activity following the completion of treatment was carried out after a median of 11 weeks (percentile 25, 8; percentile 75, 16). The cumulative dose in regimen A was 4.5 g of MTPiv. Percentage subjective clinical improvement in regimen A was 92% (11 out of 12 patients; 95% CI, 65-94%). There were 5 recurrences in the group of patients that responded to treatment: 3 (25%) patients required an additional MTPiv cycle; 1 (9%) patient received orbital radiotherapy; and another patient (9%) required decompressive eye surgery in the course of follow-up.

The cumulative dose in regimen B was 5.76 g (percentile 25, 5.13; percentile 75, 6.12). In regimen B all patients experienced improvement of the symptoms and ophthalmological signs. However, 7 recurrences were recorded during follow-up: 5 (45%) patients required additional MTPiv cycles, including 2 (18%) patients who received a total of three MTPiv cycles, one of them also required orbital radiotherapy (having previously received 3 MTPiv cycles, with a total MTPiv cumulative dose of 15 g), and 2 (18%) patients were referred for orbital surgery and had received a single MTPiv treatment cycle. Regimen B showed a higher recurrence risk, although without statistical significance (odds ratio [OR] = 2.78; 95% CI, 0.48-16).

The univariate logistic regression analysis did not associate success or failure of MTPiv treatment during follow-up to any of the evaluated clinical variables (i.e., age, age over 50 years, sex, severity of GO, duration of the ocular disease, TRACK antibody titer, maximum TRACK titer > 40, TPO titer, maximum TPO titer > 1000, type of treatment prior to thyroid disease, impairment of visual acuity, diplopia prior to treatment).