Efficacy Profile and Safety of Very Low-Dose Rituximab in Patients with Graves' Orbitopathy

Abstract

Background: Rituximab (RTX), a chimeric human-murine anti-CD20 monoclonal antibody, has been used for treatment of active moderate-severe Graves' orbitopathy (GO) since 2004 as second line therapy in patients unresponsive to intravenous steroids. We conducted an open label, prospective study (EUDRACT 2012-001980-53) in which patients were treated with a single infusion of only 100 mg RTX to analyze the efficacy and safety of this low dose.Methods: Seventeen patients, of whom nine had disease that was unresponsive to intravenous methylprednisolone, and eight with newly diagnosed GO were enrolled.Disease activity was assessed with the clinical activity score (CAS) and severity with a composite ophthalmic score. Long term surgical treatment and quality of life were also assessed, as well as treatment-related adverse events.Results: Mean baseline CAS was 4.56±0.96 and decreased to 1.25±1.14 at 24 weeks (P=0.001). Disease inactivation occurred within 24 weeks in >90% of patients and was unrelated to disease duration. Severity improved in about 60% of patients, with no relapses. All patients showed peripheral depletion of CD20 + and CD19 + cells at the end of the RTX infusion (60 minutes). Two patients required surgical orbital decompression because of optic neuropathy (ON). Among adverse events observed, there was one patient who developed a cytokine release syndrome.Conclusions: A dose of 100 mg RTX is effective in patients with active moderate-severe GO. Low doses are better tolerated, expose patients to immune suppression for a shorter period of time and are extremely cost effective, compared to higher doses. This dose, consistently with all other immunosuppressants, does not prevent the progression of GO to dysthyroid optic neuropathy.

The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy

“…Over 90% of these patients showed disease inactivation by 12 weeks, and no patient had reactivation after a 76-week follow-up. Mild infusion related AEs frequently seen with the higher dose of rituximab were rare; nevertheless, one patient developed a cytokine release syndrome (146).…”

“…A severe cytokine release syndrome presenting with marked periorbital edema and decrease of vision, then controlled with glucocorticoids, occurred in two patients (145). A recent nonrandomized prospective study of 17 patients (8 steroid naive, 9 unresponsive to iv glucocorticoids) has suggested an efficacy of a low dose (100-mg single infusion) of rituximab in moderate-to-severe and active GO (146). Over 90% of these patients showed disease inactivation by 12 weeks, and no patient had reactivation after a 76-week follow-up.…”

The Role of the Microbiota in Graves’ Disease and Graves’ Orbitopathy

“…Even though there were very few studies regarding the effects of these agents on gut microbiota, their underlying pathways can interact with gut microbiota. For example, rituximab (RTX), a chimeric human-murine anti-CD20 monoclonal antibody, has been used to treat active moderate–severe GO for more than 15 years ( Vannucchi et al., 2021 ). RTX eliminates orbital and peripheral B cells, therefore, reducing the production of antibodies.…”

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

“…methylprednisolone ( 6 ). Later observation that in GO total peripheral (and orbital) B cell depletion was occurring even after low doses of RTX (100 mg) ( 9 ), has allowed us to reduce the therapeutic dose to a single infusion of 100 mg RTX ( 14 ).…”

“…Aim of the present study was to compare the efficacy and safety of different doses of RTX, employed prospectively in two open label studies ( 14 , 15 ) and in one trial in which RTX was randomized to i.v. steroid therapy ( 6 ), in active GO.…”