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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 10 3762-3763
Copyright © 2007 by The Endocrine Society

IMAGE IN ENDOCRINOLOGY

Evidence of Intrathyroidal B-Lymphocyte Depletion after rituximab Therapy in a Patient with Graves’ Disease

Daniel El Fassi, Ole Clemmensen, Claus H. Nielsen, Rona Z. Silkiss and Laszlo Hegedüs

Departments of Endocrinology and Metabolism (D.E.F., L.H.) and Clinical Pathology (O.C.), Odense University Hospital, 5000 Odense, Denmark; Department of Clinical Immunology Section 7631 (C.H.N.), Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark; and Division of Ophthalmic Plastic, Reconstructive and Orbital Surgery (R.Z.S.), California Pacific Medical Center, San Francisco, California 94115

Address all correspondence and requests for reprints to: Laszlo Hegedüs, Department of Endocrinology and Metabolism, Odense University Hospital, 5000 Odense C, Denmark. E-mail: Laszlo.hegedus{at}ouh.regionsyddanmark.dk.

B lymphocytes usually comprise around 9% of lymphocytes found in the thyroid gland from patients with Graves’ disease (GD) (Fig. 1AGo) (1). Here, we demonstrate that 7 d after iv administration of 1000 mg of the B-lymphocyte depleting monoclonal anti-CD20 antibody rituximab (RTX), B lymphocytes were completely absent from the thyroid of a patient with GD and Graves’ ophthalmopathy (Fig. 1BGo). The RTX therapy was given on a compassionate use, off-label basis. T lymphocytes and plasma cells remained in the sample after RTX therapy (Fig. 1Go, C and D).


Figure 1
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  		FIG. 1. Thyroids from two patients with GD treated without RTX (A), or 7 d after RTX therapy (B–D). A, A germinal center is present. A and B, Stained for mature and immature B lymphocytes (CD20). C, Stained for T lymphocytes (CD3). D, Staining of plasma cells (CD79a). Magnification, x100.

 
RTX depletes circulating B lymphocytes efficiently (2). However, less is known about its effect on noncirculating lymphocytes in autoimmune disorders.

B lymphocytes were absent from the appendix 2 months after RTX/cyclophosphamide therapy in a patient with systemic lupus erythematosus (3) and from the spleen of a patient with immune thrombocytopenic purpura 3 months after RTX monotherapy (4). Complete or near-complete B-lymphocyte depletion has been reported in bone marrow aspirates from seven patients with autoimmune disorders, 3 months post RTX (2). Seven months post RTX, one GD/Graves’ ophthalmopathy patient had normal peripheral and intrathyroidal B-lymphocyte counts, whereas a retro-orbital fat biopsy was devoid of lymphocytes 3 months later (5).

To our knowledge, this is the first description of RTX-mediated B-lymphocyte depletion in an otherwise invariably B-lymphocyte infiltrated target organ of an autoimmune disease.

It is relevant to evaluate the effect of RTX on noncirculating lymphocytes because clinical benefits of RTX therapy in autoimmune diseases depend primarily upon decreasing aberrant B-lymphocyte antigen presentation and autoantibody production (2).


   Footnotes
 
Disclosure Statement: D.E.F., C.H.N., R.Z.S., and L.H. have conducted, or are conducting, clinical trials of rituximab that were supported by Roche A/S Denmark (D.E.F., C.H.N., L.H.) or Genentech (R.Z.S.). C.H.N. has received lecture fees from Roche A/S Denmark. R.Z.S. has equity interest in Genentech. O.C. has nothing to declare.

Abbreviations: GD, Graves’ disease; RTX, rituximab.

Received June 4, 2007.

Accepted June 18, 2007.


   References
Top
 References
 

  1. Segundo C, Rodriguez C, Aguilar M, Garcia-Poley A, Gavilan I, Belleas C, Brieva JA 2004 Differences in thyroid-infiltrating B lymphocytes in patients with Graves’ disease: relationship to autoantibody detection. Thyroid 14:337–344[CrossRef][Medline]
  2. Nielsen CH, El Fassi D, Hasselbalch HC, Bendtzen K, Hegedüs L 2007 B-cell depletion with rituximab in the treatment of autoimmune diseases: Graves’ ophthalmopathy the latest addition to an expanding family. Expert Opin Biol Ther 7:1061–1078[CrossRef][Medline]
  3. Paran D, Trej’o L, Caspi D 2006 Clinical images: B cell depletion in the appendix following rituximab treatment. Arthritis Rheum 54:2151
  4. Kneitz C, Wilhelm M, Tony HP 2002 Effective B cell depletion with rituximab in the treatment of autoimmune diseases. Immunobiology 206:519–527[CrossRef][Medline]
  5. Salvi M, Vannucchi G, Campi I, Rossi S, Bonara P, Sbrozzi F, Guastella C, Avignone S, Pirola G, Ratiglia R, Beck-Peccoz P 2006 Efficacy of rituximab treatment for thyroid-associated ophthalmopathy as a result of intraorbital B-cell depletion in one patient unresponsive to steroid immunosuppression. Eur J Endocrinol 154:511–517[Abstract/Free Full Text]



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