Therapy With Different Dose Regimens of Rituximab in Patients With Active Moderate-To-Severe Graves’ Orbitopathy

Abstract

BackgroundImmunosuppressive therapy of Graves’ orbitopathy (GO) is indicated during the active phase of disease. Intravenous steroids (IVGC) are effective in about 70% of patients, although unresponsiveness or relapse are observed. In previous studies, rituximab (RTX) has been shown to be effective in inactivating moderate-to-severe GO when used early in the disease, but its optimal dosage has never been studied in randomized clinical trials. Aim of this study was to compare the efficacy and safety of different doses of RTX, based on a post-hoc analysis of two open label studies and one prospective trial randomized to IVGC.Methodsof 40 patients (35 women, 5 men), with active moderate-to-severe GO treated with RTX, 14 received a single dose of 100 mg (Group 1), 15 a single dose of 500 mg (Group 2) and 11 two 1000 mg doses, administered one week apart (Group 3). Thyroid function, TSH-receptor antibodies (TRAb) and peripheral CD19+ cells were measured. Primary endpoint was disease inactivation, measured as a decrease of the Clinical Activity Score (CAS) of at least two points. Secondary endpoints were improvement of proptosis, diplopia, quality of life and safety.ResultsBaseline CAS decreased significantly in all groups (P<0.0001), independently of GO duration or whether patients had newly occurring or relapsing GO after IVGC. Proptosis did not significantly change. There was an inverse correlation between the Gorman score for diplopia and RTX dose (P<0.01). The appearance score of the GO-QoL improved in Group 1 (P=0.015), and the visual function score, in Group 2 (P=0.04). A reduction of serum TRAb was observed in Group 1 (P=0.002) and Group 2 (P<0.0002), but not in Group 3. CD19+ cell decreased in all groups (P<0.01), independently of the dose.ConclusionsWe studied the optimal dosage of RTX in the treatment of active moderate-to-severe GO. In this analysis, we considered the efficacy of RTX in inactivating GO, in changing its natural course, its effect on disease severity and on the patients’ quality of life. Based on our clinical findings, and balancing the cost of therapy, a single 500 mg dose regimen is suggested in the majority of patients.

Management of thyroid eye disease: a Consensus Statement by the American Thyroid Association and the European Thyroid Association

“…Dosing and route of administration Among the two RCTs, 64% (18/28) patients were treated with a total dose of 2000 mg RTX, the remainder with 500 mg RTX (67,100). A post hoc analysis of three studies from a single center has examined different dosing regimens of RTX in 40 patients and found equivalent rates of disease inactivation and absence of relapse with all doses of RTX (102).…”

Rituximab in the treatment of Graves’ orbitopathy: latest updates and perspectives

“…Recently, Campi et al . compared post-hoc different doses of RTX used in patients with GO across three different trials ( 61 ). A total of 40 patients across two open-label prospective studies and one randomized study were treated with 100 mg, 500 mg, and 2 × 1000mg of RTX, respectively.…”

Management of Thyroid Eye Disease: A Consensus Statement by the American Thyroid Association and the European Thyroid Association

“… 67 , 100 A post hoc analysis of three studies from a single center has examined different dosing regimens of RTX in 40 patients and found equivalent rates of disease inactivation and absence of relapse with all doses of RTX. 102 …”

“…However, the 100 mg dose failed to lead to disease inactivation or prevent progression to DON in 14% (2/14) patients, and higher doses of RTX were associated with better diplopia outcomes, so the 500 mg was deemed to be optimal. 102 Patients in the two RCTs 67 , 100 were premedicated before receiving RTX using acetaminophen/paracetamol, intravenous hydrocortisone (100 mg) or IVMP (100 mg), and antihistamines. 67 …”