Rituximab treatment in patients with active Graves' orbitopathy: effects on proinflammatory and humoral immune reactions

Abstract

In active Graves' orbitopathy (GO), proinflammatory cytokines predominate. Circulating thyroid stimulating hormone (TSH)-receptor antibodies (TRAb) have been correlated with GO clinical activity and severity. In preliminary studies rituximab (RTX), an anti-CD 20 monoclonal antibody, has induced clinical improvement of active GO without a change in serum anti-thyroid antibodies. We have studied whether RTX in GO acts by affecting proinflammatory cytokines and thyroid and orbital-directed antibodies. Ten patients with GO were treated with RTX, administered twice intravenously (i.v.) (1000 mg) at days 1 and 15, and 20 with methylprednisolone, administered weekly i.v. (500 mg), for 16 weeks. Patients were studied before treatment, at B cell depletion and at 4, 8, 16, 20, 30 and 50 weeks. Peripheral lymphocytes, serum interleukin (sIL)-6, sIL-6r, chemokine (C-X-C motif) ligand 10 (CXCL10), TRAb and stimulating antibodies (TSAb) and autoantibodies against orbital calsequestrin, collagen XIII and flavoprotein subunit of succinate dehydrogenase (FP-SDH) were measured at baseline and after treatment. Serum IL-6 and sIL-6R concentrations did not change after RTX [P = not significant (n.s.)]. Serum CXCL10 increased after RTX at B cell depletion and at 30 weeks (P < 0·003). Serum TSAb did not change in relation to TRAb, nor did antibodies against orbital antigens (P = n.s.). In conclusion, this study shows that RTX in GO does not affect humoral reactions. The observed increase of serum CXCL10 concentrations at B cell depletion may result from cell lysis. We suggest that RTX may exert its effect in GO by inhibiting B cell antigen presentation.

© 2010 British Society for Immunology.

Figures

Fig. 2

Effects of intravenous glucocorticoids on thyroid stimulating hormone (TSH)-receptor antibodies, TBII and TSAb (a), interleukin (IL)-6 (b), serum interleukin (sIL)-6-R (c) and chemokine (C-X-C motif) ligand 10 (CXCL10) (d) at baseline and at 20 weeks after treatment. Data are shown as mean ± standard error.

Fig. 1

Effects of RTX on peripheral CD 20+ () and CD 19+ () cells (a), serum IL-6 (b), sIL-6R (c) and chemokine (C-X-C motif) ligand 10 (CXCL10) (d) concentrations in basal condition, at B cell depletion, at 30 and 50 weeks of follow-up. Data are shown as mean ± standard error.

Fig. 3

Effect of rituximab (RTX) on thyroid stimulating hormone (TSH)-receptor antibodies, TRAb (a) and TSAb (c) at baseline (), at CD20 B cell depletion (), at 30 () and 50 (□) weeks of follow-up in each treated patient. In (b) mean serum TRAb were analyzed by analysis of variance (P = not significant) at the same time-points of the study.

Fig. 4

Effects of rituximab (RTX) on antibodies against orbital antigens: collagen XIII (), calsequestrin () and flavoprotein subunit of succinate dehydrogenase (FP-DSH) () at baseline, at CD20 B cell depletion, at 30 and 50 weeks of follow-up. No significant changes were observed. Data are shown as mean ± standard error.