Clinical Reviews in Allergy & Immunology

, Volume 34, Issue 1, pp 118–123

Rituximab Induces Distinct Intraorbital and Intrathyroidal Effects in One Patient Satisfactorily Treated for Graves’ Ophthalmopathy

  • P. Bonara
  • G. Vannucchi
  • I. Campi
  • S. Rossi
  • F. Cantoni
  • C. Frugoni
  • F. Sbrozzi
  • C. Guastella
  • S. Avignone
  • P. Beck-Peccoz
  • M. Salvi
Article

Abstract

Hyperthyroid Graves’ disease (GD) is a B-cell-mediated disease caused by antibodies stimulating the thyroid stimulating hormone (TSH) receptor (TRAb). A proportion of patients (40–60%) present with an associated ophthalmopathy (TAO), a progressive inflammatory autoimmune disease of the retroorbital tissue. We thought that the anti-CD20 monoclonal antibody rituximab (RTX), by inducing transient B-cell depletion, may potentially modify the active inflammatory phase of TAO. One patient with GD and TAO in its active phase and unresponsive to steroid, was treated with RTX. Whereas the ophthalmopathy responded to RTX therapy and a decrease in the clinical activity score from 5 to 2 was observed during the B-cell depletion, serum antithyroid antibodies, and in particular serum TRAb, were not affected by therapy. When the patient underwent total thyroidectomy, we found B-cells in the thyroid tissue specimens. The eye disease remained stable (clinical activity score = 2) and the patient subsequently underwent orbital decompression to correct proptosis of the eye. At that time we did not find lymphocytes in any of the orbital tissue specimens. We believe that RTX therapy in GD may cause amelioration of ophthalmopathy by depleting total lymphocyte population in the orbit, but not lymphocyte depletion in thyroid tissue with consequent unchanged serum TRAb levels.

Keyword

Rituximab Graves’ disease Ophthalmopathy 

References

  1. 1.
    Zakarija M, McKenzie JM (1987) The spectrum and significance of autoantibodies reacting with the thyrotropin receptor. Endocrinol Metab Clin N Am 16:343–363Google Scholar
  2. 2.
    Rees Smith B, McLachlan SM, Furmaniak J (1988) Autoantibodies to the thyrotropin receptor. Endocr Rev 8:106–121Google Scholar
  3. 3.
    Segundo C, Rodriguez C, Garcia-Poley A, Aguilar M, Gavilan I, Bellas C, Brieva JA (2001) Thyroid-infiltrating B lymphocytes in Graves’ disease are related to marginal zone and memory B cell compartments. Thyroid 11:525–530PubMedCrossRefGoogle Scholar
  4. 4.
    Michelangeli V, Poon C, Taft J, Newnham H, Topliss D, Colman P (1998) The prognostic value of thyrotropin receptor antibody measurement in the early stages of treatment of Graves’ disease with antithyroid drugs. Thyroid 8:119–124PubMedCrossRefGoogle Scholar
  5. 5.
    Bahn RS (2003) Clinical review 157: pathophysiology of Graves’ ophthalmopathy: the cycle of disease. J Clin Endocrinol Metab 88:1939–1946PubMedCrossRefGoogle Scholar
  6. 6.
    Valyasevi RW, Harteneck DA, Dutton CM, Bahn RS (2002) Stimulation of adipogenesis, peroxisome proliferator-activated receptor-gamma (PPARgamma), and thyrotropin receptor by PPARgamma agonist in human orbital preadipocyte fibroblasts. J Clin Endocrinol Metab 87:2352–2358PubMedCrossRefGoogle Scholar
  7. 7.
    Cao HJ, Wang HS, Zhang Y, Lin HY, Phipps RP, Smith TJ (1998) Activation of human orbital fibroblasts through CD40 engagement results in a dramatic induction of hyaluronan synthesis and prostaglandin endoperoxide H synthase-2 expression: insights into potential pathogenic mechanisms of thyroid-associated ophthalmopathy. J Biol Chem 273:29615–29625PubMedCrossRefGoogle Scholar
  8. 8.
    Mikozami T, Salvi M, Wall JR (2004) Eye muscle antibodies in Graves’ ophthalmopathy: pathogenic or secondary epiphenomenon? J Endocrinol Investig 27:221Google Scholar
  9. 9.
    Gerding MN, van der Meer JW, Broenink M, Bakker O, Wiersinga WM, Prummel MF (2000) Association of thyrotrophin receptor antibodies with the clinical features of Graves’ ophthalmopathy. Clin Endocrinol 52:267–271CrossRefGoogle Scholar
  10. 10.
    De Bellis A, Bizzarro A, Conte M, Solimeno C, Perrino S, Sansone D, Guaglione M, Wall JR, Bellastella A (2003) Relationship between longitudinal behaviour of some markers of eye autoimmunity and changes in ocular findings in patients with Graves’ ophthalmopathy receiving corticosteroid therapy. Clin Endocrinol 59:388–395CrossRefGoogle Scholar
  11. 11.
    Kubota S, Ohye H, Nishihara E, Kudo T, Ito M, Fukata S, Amino N, Kuma K, Miyauchi A (2005) Effect of high dose methylprednisolone pulse therapy followed by oral prednisolone administration on the production of anti-TSH receptor antibodies and clinical outcome in Graves’ disease. Endocr J 52:735–741PubMedCrossRefGoogle Scholar
  12. 12.
    Eckstein AK, Plicht M, Hildegard L, Neuhauser M, Mann K, Lederbogen S, Heckmann C, Esser J, Morgenthaler NG (2006) TSH-receptor autoantibodies are independent risk factors for Graves’ ophthalmopathy and help to predict severity and outcome of the disease. J Clin Endocrinol Metab 91:3464–3470PubMedCrossRefGoogle Scholar
  13. 13.
    Tsokos GC (2004) B cells be gone—B-cell depletion in the treatment of rheumatoid arthritis. N Engl J Med 350:2546–2548PubMedCrossRefGoogle Scholar
  14. 14.
    Pescovitz MD (2006) Rituximab, an anti-CD20 monoclonal antibody: history and mechanism of action. American Journal of Transplantation 6:859–866PubMedCrossRefGoogle Scholar
  15. 15.
    Hasselbalch HC (2003) B-cell depletion with rituximab—a targeted therapy for Graves’ disease and autoimmune thyroiditis. Immunol Lett 88:85–86PubMedCrossRefGoogle Scholar
  16. 16.
    Salvi M, Vannucchi G, Campi I, Currò N, Dazzi D, Simonetta S, Bonara P, Rossi S, Sina C, Guastella C, Ratiglia R, Beck-Peccoz P (2007) Treatment of Graves’ disease and associated ophthalmopathy with the monoclonal antibody rituximab: an open study. Eur J Endocrinol 156:33–40PubMedCrossRefGoogle Scholar
  17. 17.
    Werner SC (1969) Classification of the eye changes of Graves’ disease. J Clin Endocrinol Metab 29:982–984PubMedCrossRefGoogle Scholar
  18. 18.
    Mourits MP, Prummel MF, Wiersinga WM, Koorneef L (1997) Clinical activity score as a guide in the management of patients with Graves’ ophthalmopathy. Clin Endocrinol 47:9–14CrossRefGoogle Scholar
  19. 19.
    El Fassi D, Nielsen CH, Hasselbalch HC, Hegedus L (2005) Successful B lymphocyte depletion in a patient with recurrent Graves’ disease and severe ophthalmopathy. Thyroid 15(Suppl 1):S28 (Abstract)Google Scholar
  20. 20.
    Male D, Cooke A, Owen M, Trowsdale J, Champion B (1996) Antigen receptor molecules. In Male D, Cooke A, Owen M, Trowsdale J, Champion B (eds) Advanced immunology. Mosby, London, pp 2.1–2.2Google Scholar
  21. 21.
    Anolik JH, Campbell D, Felgar RE, Rosenblatt J, Young F, Sanz I, Looney RJ (2002) B lymphocyte depletion in the treatment of systemic lupus erythematosus. Arthritis Rheum (Suppl 9):S717 (Abstract)Google Scholar
  22. 22.
    Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T (2004) Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 350:2572–2581PubMedCrossRefGoogle Scholar
  23. 23.
    Stasi R, Pagano A, Stipa E, Amadori S (2001) Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood 98:952–957PubMedCrossRefGoogle Scholar
  24. 24.
    Leandro MJ, Edwards JC, Cambridge G (2002) Clinical outcome in 22 patients with rheumatoid arthritis treated for B lymphocyte depletion. Ann Rheum Dis 61:883–888PubMedCrossRefGoogle Scholar
  25. 25.
    Armengol MP, Juan M, Lucas-Martin A, Fernandez-Figueras MT, Jaraquemada D, Gallart T, Pujol-Borrell R (2001) Thyroid autoimmune disease: demonstration of thyroid antigen-specific B-cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers. Am J Pathol 159:861–873PubMedGoogle Scholar
  26. 26.
    Gorman C, Leandro M, Isenberg D (2003) B-cell depletion in autoimmune disease. Arthritis Research and Therapy 5(Suppl 4):S17–S21PubMedCrossRefGoogle Scholar
  27. 27.
    Takemura S, Klimiuk PA, Braun A, Goronzy JJ, Weyand CM (2001) T cell activation in rheumatoid synovium is B-cell dependent. J Immunol 167:4710–4718PubMedGoogle Scholar
  28. 28.
    Pritchard J, Tsui S, Horst N, Cruikshank WW, Smith TJ (2004) Synovial fibroblasts from patients with rheumatoid arthritis, like fibroblasts from Graves’disease, express high levels of IL-16 when treated with Igs against insulin-like growth factor-1 receptor. J Immunol 173:3564–3569PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • P. Bonara
    • 1
  • G. Vannucchi
    • 2
  • I. Campi
    • 2
  • S. Rossi
    • 3
  • F. Cantoni
    • 1
  • C. Frugoni
    • 1
  • F. Sbrozzi
    • 4
  • C. Guastella
    • 5
  • S. Avignone
    • 6
  • P. Beck-Peccoz
    • 2
  • M. Salvi
    • 2
  1. 1.Department of Internal MedicineFondazione Ospedale Maggiore IRCCSMilanItaly
  2. 2.Department of Medical SciencesUniversity of Milan, Fondazione Ospedale Maggiore IRCCSMilanItaly
  3. 3.Pathology Unit, Department of Medicine, Surgery and DentistryOspedale San PaoloMilanItaly
  4. 4.Department of OphthalmologyFondazione Ospedale Maggiore IRCCSMilanItaly
  5. 5.Department of OtolaryngologyFondazione Ospedale Maggiore IRCCSMilanItaly
  6. 6.Department of RadiologyFondazione Ospedale Maggiore IRCCSMilanItaly

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