Treatment of Graves’ disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study

Abstract

Introduction: Hyperthyroid Graves' disease (GD) is a B-cell-mediated condition caused by TSH receptor antibodies (TRAb), which decline when GD remits. Anti-CD20 monoclonal antibody rituximab (RTX) induces transient B-cell depletion that may potentially modify the active inflammatory phase of thyroid-associated ophthalmopathy (TAO). Methods: Nine patients with GD, (seven with active TAO, two with mild lid signs) were studied. The trial was only approved as an open pilot study; thus we compared the effect of RTX therapy to that of i.v. glucocorticoids (IVGC) in 20 consecutive patients. Patients were treated with RTX (1000 mg i.v. twice at 2-week interval) or with IVGC (500 mg i.v. for 16 weeks). TAO was assessed by the clinical activity score (CAS) and severity was classified using NOSPECS (No signs or symptoms; Only signs (lid); Soft tissue involvement; Proptosis, Extraocular muscle involvement; Corneal involvement; Sight loss). Thyroid function and lymphocyte count were measured by standardized methods. Results: All patients attained peripheral B-cell depletion with the first RTX infusion. Minor side effects were reported in three patients. Thyroid function was not affected by RTX therapy and hyperthyroid patients required therapy with methimazole. After RTX, the changes in the levels of thyroglobulin antibodies, thyroperoxidase antibodies and TRAb were neither significant nor correlated with CD20C depletion (PZNS). CAS values before RTX were 4.7G0.5 and decreased to 1.8G0.8 at the end of follow-up (P!0.0001) and more significantly compared with IVGC (P!0.05). Proptosis decreased significantly after RTX both in patients with active TAO (ANOVA; P!0.0001) and those with lid signs (ANOVA; P!0.003). The degree of inflammation (class 2) decreased significantly in response to RTX (ANOVA; P!0.001). Relapse of active TAO was not observed in patients treated with RTX, but occurred in 10% of those treated with IVGC, who also experienced adverse effects more frequently (45 vs 33% of patients). Conclusions: RTX positively affects the clinical course of TAO, independently of either thyroid function or circulating antithyroid antibodies, including TRAb. If our findings are confirmed in large controlled studies, RTX may represent a useful therapeutic tool in patients with active TAO.

Rituximab in relapsing Graves' disease, a phase II study

“…In addition, no correlation was found between proportions of CD-20C lymphocytes and TBII levels. This is in agreement with the study of Salvi et al (24) and El Fassi et al (23). In fact, it is well documented that there is no linear relationship between serum TBII concentrations and serum FT 4 levels in patients with Graves' disease (1), as TBII are a heterogeneous pool of both stimulating and blocking antibodies.…”

“…We therefore believe that the effects observed can be attributed to rituximab. These findings are in agreement with the conclusions of El Fassi et al (23) who found a beneficial effects of rituximab in patients who in the majority had a first episode of Graves' disease, but differs from the observations in patients with Graves' ophthalmopathy, where no effect on hyperthyroidism was found (22,24).…”

“…In addition, a fraction of plasma cells have a very slow turnover (28). In addition, B cell depletion may be less pronounced in lymphoid cells in germinal centres in the thyroid (29) as discussed by El Fassi and Salvi (23,24). However, El Fassi found complete intrathyroidal B-lymphocyte depletion (30).…”

“…In our study, the proportion of CD-20 positive lymphocytes was not associated with TBII levels. As discussed by Salvi et al (24) and El Fassi et al (23) synthesis of new antibodies occurs after rituximab treatment given that the half life of human IgG is w3 weeks. This and the absence of a beneficial effect of rituximab in some patients may be related to the fact that an important source of auto antibodies is plasma cells that do not express MS4A1.…”

“…Recently, a few papers have been published on the effectiveness of rituximab in Graves' ophthalmopathy and hyperthyroidism (22)(23)(24). In a study of nine patients with Graves' ophthalmopathy, rituximab positively affected the clinical course without influencing thyroid function (22).…”