Rituximab treatment in patients with active Graves' orbitopathy: effects on proinflammatory and humoral immune reactions.
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.
Department of Medical Sciences, University of Milan, Milan, Italy.
G
G
Vannucchi
I
I
Campi
M
M
Bonomi
D
D
Covelli
D
D
Dazzi
N
N
Currò
S
S
Simonetta
P
P
Bonara
L
L
Persani
C
C
Guastella
J
J
Wall
P
P
Beck-Peccoz
M
M
Salvi
D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D001323:Autoantibodies / Q000097:blood; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002155:Calsequestrin / Q000276:immunology; D054357:Chemokine CXCL10 / Q000097:blood; D016207:Cytokines / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D049970:Graves Ophthalmopathy / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral / Q000187:drug effects*; D007155:Immunologic Factors / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D019947:Receptors, Interleukin-6 / Q000097:blood; D011989:Receptors, Thyrotropin / Q000276:immunology; D000069283:Rituximab; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013972:Thyrotropin / Q000097:blood
D058846:Antibodies, Monoclonal, Murine-Derived; D001323:Autoantibodies; D002155:Calsequestrin; D054357:Chemokine CXCL10; D016207:Cytokines; D007155:Immunologic Factors; D018836:Inflammation Mediators; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D011989:Receptors, Thyrotropin; D000069283:Rituximab; D013972:Thyrotropin