Author reply
Authors: Raymond S. Douglas, Terry J. Smith
Journal: Ophthalmology (2010)

We appreciate the authors' enthusiasm for the introduction of new treatment strategies directed at thyroid associated orbitopathy (TAO). We share their concerns regarding rational use of anti-B cell therapies and heartily agree that their use warrants further discussion. This dialogue must focus on specific indications for treatment and identifying clinical and laboratory end points of effectiveness.In our manuscript, the use of anti-B cell therapy (Rituximab) in TAO patients was based upon therapeutic efficacy and the side effect profile established in related autoimmune disorders.1Abbott J.D. Moreland L.W. Rheumatoid arthritis: developing pharmacological therapies.Expert Opin Investig Drugs. 2004; 13: 1007-1018Crossref PubMed Scopus (25) Google Scholar Auto-antibodies generated against the thyrotropin receptor are the proximate cause of thyroid glandular manifestations in Graves' disease. Since B cells produce antibodies, eliminating these cells via anti-B cell therapy appears to represent a straightforward, albeit simplistic rationale for treatment. However, given the multifaceted role of B cells in immune responses, the therapeutic mechanism of anti-B cell depletion is likely to prove considerably more complex.2Dorner T. Crossroads of B cell activation in autoimmunity: rationale of targeting B cells.J Rheumatol Suppl. 2006; 77: 3-11PubMed Google Scholar B lymphocytes are efficient antigen-presenting cells and produce abundant cytokines, both of which are required for robust immune responses. Thus, anti-B cell therapy for autoimmune diseases, including rheumatoid arthritis, has been more efficacious than initially anticipated. The treatment paradigms established in other autoimmune processes has reinforced the rationale for its use in Graves' disease and TAO.The short- and long-term side effect profile of Rituximab has been evaluated in patients with B cell malignancies and more recently in patients with autoimmune disease. This drug can cause serious side effects, as discussed in the editorial and in our article. It is important to consider that many of the reported life-threatening complications occurred using higher dosing regimens.3Keystone E.C. Safety issues related to emerging therapies for rheumatoid arthritis.Clin Exp Rheumatol. 2004; 22: S148-S150PubMed Google Scholar Furthermore, long-term steroid use (intravenous and/or oral) has been the standard of care for TAO for decades, even though its side effect profile can be substantial and includes liver toxity and death. Moreover, the side effect profile of steroids is concerning, since its use may offer only marginal benefit. A recent study comparing the side effects of Rituximab and intravenous steroids in the treatment of TAO, overwhelmingly demonstrated better tolerability of Rituximab.4Salvi M. Vannucchi G. Campi I. et al.Treatment of Graves' disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study.Eur J Endocrinol. 2007; 156: 33-40Crossref PubMed Scopus (202) Google ScholarWe agree with the authors of this editorial comment that administration of immunomodulatory agents, including Rituximab, is outside the expertise of most ophthalmologists. We subscribe to the philosophy that patients with TAO require multidisciplinary approaches, which include input from orbital specialists, thyroid surgeons, endocrinologists, rheumatologists, and strabismus specialists. These sub-specialists evaluate patients in tandem and participate in the generation of a treatment plan. However, orbital specialists are best positioned to assess TAO activity and severity and to initiate treatment. The multidisciplinary approach can be inferred from our manuscript.The editorial raises an important issue regarding risk vs. benefit associated with treatment of TAO. The introduction and evaluation of novel therapies must be predicated on clearly defined indications and end points. In previous studies, Rituximab was administered to patients with hyperthyroidism but few patients manifested clinically significant TAO.5El Fassi D. Nielsen C.H. Bonnema S.J. et al.B lymphocyte depletion with the monoclonal antibody rituximab in Graves' disease: a controlled pilot study.J Clin Endocrinol Metab. 2007; 92: 1769-1772Crossref PubMed Scopus (120) Google Scholar While B cell depletion might sustain euthyroid function, treatments for hyperthyroidism already exist and have far less risk. Thus, in our opinion, treatment with Rituximab in patients with uncomplicated Graves' disease appears unwarranted.Currently, there are few effective medical treatments for active TAO. Intravenous steroid administered over the course of several months may marginally improve long-term disease outcome. These regimens are typically reserved for patients with moderate to severe disease, given their potential risks. As new agents become available and are evaluated, their benefit must clearly outweigh potential risks. For example, if immunomodulatory treatment prevents progression of TAO and obviates the need for surgical decompression, the benefit may outweigh the risks of therapy. In our manuscript, patients with intractable TAO, including optic neuropathy, improved after Rituximab administration. The treatment obviated the need for urgent decompression surgery in most patients.It remains to define specific indications for treatment of TAO and to identify the clinical and laboratory end points required for evaluation of each agent. Overcoming these hurdles has been the focus of the International Thyroid Eye Disease Society (ITEDS). The goals of studies initiated by ITEDS are to establish valid clinical end points that define disease stage, activity, and signal disease remission. Accomplishing these goals should provide the necessary tools for conducting multicenter treatment trials. We appreciate the authors' enthusiasm for the introduction of new treatment strategies directed at thyroid associated orbitopathy (TAO). We share their concerns regarding rational use of anti-B cell therapies and heartily agree that their use warrants further discussion. This dialogue must focus on specific indications for treatment and identifying clinical and laboratory end points of effectiveness. In our manuscript, the use of anti-B cell therapy (Rituximab) in TAO patients was based upon therapeutic efficacy and the side effect profile established in related autoimmune disorders.1Abbott J.D. Moreland L.W. Rheumatoid arthritis: developing pharmacological therapies.Expert Opin Investig Drugs. 2004; 13: 1007-1018Crossref PubMed Scopus (25) Google Scholar Auto-antibodies generated against the thyrotropin receptor are the proximate cause of thyroid glandular manifestations in Graves' disease. Since B cells produce antibodies, eliminating these cells via anti-B cell therapy appears to represent a straightforward, albeit simplistic rationale for treatment. However, given the multifaceted role of B cells in immune responses, the therapeutic mechanism of anti-B cell depletion is likely to prove considerably more complex.2Dorner T. Crossroads of B cell activation in autoimmunity: rationale of targeting B cells.J Rheumatol Suppl. 2006; 77: 3-11PubMed Google Scholar B lymphocytes are efficient antigen-presenting cells and produce abundant cytokines, both of which are required for robust immune responses. Thus, anti-B cell therapy for autoimmune diseases, including rheumatoid arthritis, has been more efficacious than initially anticipated. The treatment paradigms established in other autoimmune processes has reinforced the rationale for its use in Graves' disease and TAO. The short- and long-term side effect profile of Rituximab has been evaluated in patients with B cell malignancies and more recently in patients with autoimmune disease. This drug can cause serious side effects, as discussed in the editorial and in our article. It is important to consider that many of the reported life-threatening complications occurred using higher dosing regimens.3Keystone E.C. Safety issues related to emerging therapies for rheumatoid arthritis.Clin Exp Rheumatol. 2004; 22: S148-S150PubMed Google Scholar Furthermore, long-term steroid use (intravenous and/or oral) has been the standard of care for TAO for decades, even though its side effect profile can be substantial and includes liver toxity and death. Moreover, the side effect profile of steroids is concerning, since its use may offer only marginal benefit. A recent study comparing the side effects of Rituximab and intravenous steroids in the treatment of TAO, overwhelmingly demonstrated better tolerability of Rituximab.4Salvi M. Vannucchi G. Campi I. et al.Treatment of Graves' disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study.Eur J Endocrinol. 2007; 156: 33-40Crossref PubMed Scopus (202) Google Scholar We agree with the authors of this editorial comment that administration of immunomodulatory agents, including Rituximab, is outside the expertise of most ophthalmologists. We subscribe to the philosophy that patients with TAO require multidisciplinary approaches, which include input from orbital specialists, thyroid surgeons, endocrinologists, rheumatologists, and strabismus specialists. These sub-specialists evaluate patients in tandem and participate in the generation of a treatment plan. However, orbital specialists are best positioned to assess TAO activity and severity and to initiate treatment. The multidisciplinary approach can be inferred from our manuscript. The editorial raises an important issue regarding risk vs. benefit associated with treatment of TAO. The introduction and evaluation of novel therapies must be predicated on clearly defined indications and end points. In previous studies, Rituximab was administered to patients with hyperthyroidism but few patients manifested clinically significant TAO.5El Fassi D. Nielsen C.H. Bonnema S.J. et al.B lymphocyte depletion with the monoclonal antibody rituximab in Graves' disease: a controlled pilot study.J Clin Endocrinol Metab. 2007; 92: 1769-1772Crossref PubMed Scopus (120) Google Scholar While B cell depletion might sustain euthyroid function, treatments for hyperthyroidism already exist and have far less risk. Thus, in our opinion, treatment with Rituximab in patients with uncomplicated Graves' disease appears unwarranted. Currently, there are few effective medical treatments for active TAO. Intravenous steroid administered over the course of several months may marginally improve long-term disease outcome. These regimens are typically reserved for patients with moderate to severe disease, given their potential risks. As new agents become available and are evaluated, their benefit must clearly outweigh potential risks. For example, if immunomodulatory treatment prevents progression of TAO and obviates the need for surgical decompression, the benefit may outweigh the risks of therapy. In our manuscript, patients with intractable TAO, including optic neuropathy, improved after Rituximab administration. The treatment obviated the need for urgent decompression surgery in most patients. It remains to define specific indications for treatment of TAO and to identify the clinical and laboratory end points required for evaluation of each agent. Overcoming these hurdles has been the focus of the International Thyroid Eye Disease Society (ITEDS). The goals of studies initiated by ITEDS are to establish valid clinical end points that define disease stage, activity, and signal disease remission. Accomplishing these goals should provide the necessary tools for conducting multicenter treatment trials. Thyroid-Associated OrbitopathyOphthalmologyVol. 117Issue 9PreviewWe would like to thank Khanna et al.1 for sharing their results using rituximab (RTX) for severe thyroid-associated ophthalmopathy (TAO). We agree that current treatment options do not alter the ultimate course of TAO, and we applaud their efforts to study a newer biologic therapy. The authors correctly point out that the safety profile of RTX compares favorably with that of corticosteroids and treatment guidelines for autoimmune disease call for substantially lower doses and frequencies than those for lymphoma. Full-Text PDF