Clinical Endocrinology (2014) 80, 629–632
doi: 10.1111/cen.12427
CLINICAL QUESTION
Graves’ disease following immune reconstitution or immunomodulatory treatment: should we manage it any differently? Anthony P. Weetman Department of Human Metabolism, Faculty of Medicine Dentistry and Health, The Medical School, University of Sheffield, Sheffield, UK
Background Summary Graves’ disease and other disorders of thyroid function may occur following treatment with novel anticancer agents or during periods of lymphocyte recovery after lymphopenia. There are three main settings for such lymphocyte reconstitution: recovery after a bone marrow or haematopoietic stem cell transplant, alemtuzumab treatment and the use of highly active antiretroviral therapy (HAART) for human immunodeficiency virus infection. The available evidence suggests that Graves’ disease behaves as normal in most of these cases and should be treated conventionally, but it may follow a more favourable course in those receiving alemtuzumab or HAART. As spontaneous or drug-induced remission may be more likely in these two settings, first-line treatment should usually consist of an antithyroid drug. (Received 27 January 2014; returned for revision 4 February 2014; finally revised 7 February 2014; accepted 8 February 2014)
Introduction A wide variety of thyroid abnormalities have been described in patients receiving novel drugs for cancer or for other conditions such as chronic hepatitis and in settings in which the immune system is reconstituted from a lymphopenic state. In some cases, the abnormalities are due to the underlying condition, resulting in a sick euthyroid syndrome, and in others, the effects are due to the biochemical rather than immunological action of the drug. Nonetheless, when drugs are used which concurrently affect the immune system, autoimmune thyroid diseases, including Graves’ disease, can arise.
Correspondence: Anthony P. Weetman, Department of Human Metabolism, Faculty of Medicine, Dentistry and Health, University of Sheffield, The Medical School, Beech Hill Road, Sheffield S10 2RX, UK. Tel.: 00 44 114 2712570; E-mail: [email protected] © 2014 John Wiley & Sons Ltd
Novel anticancer agents include cytokines, immune system modulators and drugs which target critical biochemical pathways in individual cancers. Thyroid disease arising as a consequence of these agents tends to be hypothyroidism, although this is often as part of a destructive thyroiditis with alternating thyrotoxicosis and hypothyroidism, which may confuse the unwary into diagnosing Graves’ disease initially. An extensive and helpful review of the relevant literature has been published recently1. Those anticancer agents which have been reported convincingly to be associated with Graves’ disease are shown in Table 1. Three types of reconstitution Graves’ disease exist2. Alemtuzumab is a humanized monoclonal antibody against CD52, expressed by lymphocytes and monocytes; administration causes a profound lymphopenia with a gradual recovery in lymphocyte number over the next 2–5 years (depending on exact subset). This agent has been used in a wide variety of conditions, including haematological malignancies and autoimmune disorders, with particularly impressive results in multiple sclerosis. Up to a third of such patients develop Graves’ disease 1–5 years after initial treatment with alemtuzumab3. Smoking increases the risk three-fold (a greater risk than for conventional Graves’ disease) but gender may have less effect than normal4. Half as frequently, patients may develop a destructive thyroiditis or hypothyroidism. Significant Graves’ eye disease is uncommon4. Alemtuzumab can also cause other autoantibody-induced disorders, such as Goodpasture’s syndrome and idiopathic thrombocytopenic purpura (ITP)5. The adverse thyroid effects of alemtuzumab have been reported when it is used in other conditions such as vasculitis and as induction treatment prior to renal transplantation6,7. However the rate seems especial high in multiple sclerosis for reasons which are unclear, but could relate to disease-specific shifts in the immunological ‘environment’ during reconstitution in this disorder, as there is no major genetic association which is shared between multiple sclerosis and Graves’ disease. Highly active antiretroviral therapy (HAART) comprises the use of a combination of at least three drugs (protease inhibitors, reverse transcriptase inhibitors or agents which prevent viral entry into T cells) and has transformed the outlook for patients 629
630 A. P. Weetman Table 1. Immunomodulatory treatments and immune reconstitution syndromes associated with Graves’ disease Treatment
Comment
Inferferon-a
Can cause Graves’ disease, destructive thyroiditis or hypothyroidism Mainly induce hypothyroidism or destructive thyroiditis; rare cases may be Graves’ disease Graves’ ophthalmopathy but not hyperthyroidism has been reported During the phase of lymphocyte recovery after depletion During the phase of lymphocyte recovery from HIV-induced lymphopenia Typically arises if the donor had Graves’ disease During reconstitution
Tyrosine kinase inhibitors (imatinib, nilotinib, dasatinib) Anti-CTLA-4 monoclonal antibody (ipilimumab) Alemtuzumab Highly active antiretroviral therapy (HAART) Bone marrow transplant Haematopoietic stem cell transfer
with human immunodeficiency virus (HIV) infection. Highly active antiretroviral therapy initially increases the memory CD4+ T-cell population and subsequently naive CD4+ T-cell numbers rise. During this latter phase of immune reconstitution, a number of autoimmune disorders can appear, including Graves’ disease, type 1 diabetes mellitus and type B insulin resistance syndrome8–10. A retrospective survey found that around 3% of women and 0.2% of men developed Graves’ disease 8– 33 months after starting HAART; 40% had soft-tissue changes of Graves’ eye disease11. The onset of Graves’ disease is associated with the appearance of na€ıve and primary thymic emigrant CD4+ T cells and multiple autoantibodies, of which those against the TSH receptor (TSHR) have clinical impact12. There is also a case report of an HIV-infected individual who developed Graves’ disease during the period of lymphocyte recovery induced by interleukin-2 therapy13. As with the other agents discussed so far, care must be taken to distinguish the cause of any thyrotoxicosis in this setting as two cases of autoimmune destructive thyroiditis have been described after HAART11,14. The third type of reconstitution Graves’ disease occurs following bone marrow or haematopoietic stem cell transplantation (HSCT)2. In the case of bone marrow transplantation, the donor has typically had evidence of Graves’ disease in the past, although this is not always the case. One donor has been reported in whom the only evidence of thyroid disease in retrospect was the presence of thyroid peroxidase (TPO) antibodies; in another, no evidence at all for thyroid disease was found15,16. In one bone marrow recipient with adrenoleukodystrophy, Graves’ disease started 3 years after transplantation and was followed by the appearance of eye signs, whereas his donor sister only developed Graves’ disease without eye signs 7 years after donation17. The idea that adoptive transfer of TSHR-reactive lymphocytes might cause Graves’ disease in a lymphocyte-depleted recipient is hardly surprising immunologically, but other cases are more
complex in terms of pathogenesis. Autologous HSCT following cytotoxic chemotherapy for systemic sclerosis led to clinical improvement in the primary disorder but Graves’ disease and severe eye signs subsequently developed18. Four cases of Graves’ disease have also been reported at a mean time of 22 months following allogeneic HSCT and chemotherapy conditioning; none of the donors had evidence of thyroid disease19. These situations seem more akin to the disordered immunoregulation arising after lymphopenia reversal with alemtuzumab or HAART13. It is also possible that immunoregulation is affected by graft-versus-host disease following bone marrow transfer or HSCT, leading to expansion of previously silent TSHR-reactive donor lymphocytes. A summary of the immunological factors involved in causing reconstitution Graves’ disease is given in Table 2.
Treatment of Graves’ disease Extensive guidelines for the treatment of conventional Graves’ disease have been published which provide background data for what follows20. The first step in management is to make an accurate diagnosis that an episode of thyrotoxicosis, especially one arising in these settings, is indeed due to Graves’ disease rather than destructive thyroiditis. A third of thyrotoxicosis following interferon-a treatment has been estimated to be due to destructive thyroiditis21. However, the prevalence may be even higher depending on the frequency of testing22. Evidence that thyrotoxicosis has persisted for more than 6 weeks strongly suggests Graves’ disease, as does the presence of eye signs. Thyroid peroxidase antibodies may be positive in both types of thyrotoxicosis, whereas the detection of TSHR antibodies in the presence of thyrotoxicosis confirms Graves’ disease. The presence of TPO antibodies prior to treatment with interferon-a or other agents is a risk factor for Graves’ disease, destructive thyroiditis and hypothyroidism. If TSHR antibodies cannot be measured, a radionuclide scan (99mTc or 123I) is useful, as destructive thyroiditis will be revealed by the absence of uptake. Colour flow
Table 2. Factors which may be responsible for the pathogenesis of reconstitution Graves’ disease
• • • • • • •
Initially low CD4+ T-helper cell count, with a subsequent increase in thymic CD4+ T cells Altered cytokine profile, with a bias towards Th2 cells Functional impairment of T regulatory cells relative to the expanding autoreactive T-cell population Relatively high B cell numbers Abnormal presentation of self-antigens by dendritic cells during and after the lymphopenic phase Adoptive transfer of donor TSHR-reactive lymphocytes in allogeneic bone marrow transplantation and HSCT Graft-versus-host disease causing immune dysregulation in allogeneic bone marrow transplantation and HSCT
HSCT, haematopoietic stem cell transplantation. © 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 80, 629–632
Immunotherapy-induced Graves’ disease 631 Doppler ultrasound can also be used to distinguish between Graves’ disease and destructive thyroiditis: absent flow on ultrasound indicates destructive thyrotoxicosis, whereas flow is enhanced in Graves’ hyperthyroidism23. Having firmly established that the patient does have Graves’ disease, the question that arises is whether in these particular settings, the disease runs a different course to conventional Graves’ disease. Unfortunately, the evidence is pretty thin as information is only available from case reports or from retrospective data collected from therapeutic trials in which there has been no standardized endocrinological input. For Graves’ disease arising after treatment with antineoplastic agents, there are no data to indicate that initial therapy should be any different to normal. We do know that even when interferon-a treatment is stopped, Graves’ disease tends to persist and therefore prompt first-line treatment with an antithyroid drug or radioiodine is reasonable, with the choice depending largely on patient preference and the presence of factors such as concurrent eye disease24. Patients starting interferon-a should have a baseline TSH and TPO antibody measurement; TSH should be checked as a minimum every 3 months subsequently in those with antibodies and every 6 months in those without. There is some circumstantial evidence that the Graves’ disease associated with alemtuzumab treatment may be less aggressive than conventional Graves’ disease. In one series of UK patients, only 28% required radioiodine treatment, which seems a low figure if this treatment was being used after failure of an antithyroid drug4. A detailed analysis of the thyroid dysfunction which occurred in the CAMMS223 trial revealed that 22% of alemtuzumab-treated patients developed Graves’ disease: of them, 23% spontaneously became euthyroid and a further 15% spontaneously developed hypothyroidism25. Only 36% of those who were treated received radioiodine or surgery, and although treatment protocols were not standardized between participating centres, these figures imply that 78% of patients had recovery from Graves’ disease, either spontaneously or after an antithyroid drug. Overall, the authors concluded that there were few serious episodes of thyroid dysfunction, although three patients did develop significant eye signs, possibly worsened by radioiodine in one. In the CARE-MS II trial, all cases of Graves’ disease were said to be managed ‘conventionally’ but it is striking that of the 28 patients diagnosed with hyperthyroidism, only one each required radioiodine or surgery26. Supporting the idea that there are real differences in the behaviour of this type of reconstitution Graves’ disease, it appears that ITP induced by alemtuzumab is also distinctive, as it responds well to conventional therapy with prolonged remission5. Mechanistically, it would seem reasonable to expect that if reconstitution autoimmunity arises from an exuberant autoreactivity at a specific point during recovery from lymphopenia, this abnormality might come readily under control as the rest of the immune system is restored. Together these data make me feel that first-line treatment in this situation should be with an antithyroid drug rather than radioiodine, as there would seem to be a good chance that euthyroidism will result. It is also important to ensure that hyperthyroidism persists at the point of © 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 80, 629–632
referral before starting treatment, given the high rate of spontaneous changes. All patients to be treated with alemtuzumab should have a baseline measurement of TSH, and the TSH should be repeated every 2–3 months for at least 3 years after initial therapy; TPO antibodies are not of predictive value. Similar principles apply to Graves’ disease occurring after HAART, although there are fewer data. In the first series of five patients8, treatment details were not given, but in a retrospective analysis of 17 patients, all but one (who refused treatment) responded to carbimazole11. Prompt responsiveness to methimazole has been noted in two further cases27. Autoimmune forms of arthritis occurring after HAART also have a better clinical response than conventional forms28. I would therefore recommend an antithyroid drug as first-line treatment in this setting too. Given the low frequency of Graves’ disease after HAART, screening is probably not worthwhile29, but clinicians should be vigilant for this and other autoimmune disorders that may develop. Clinically, severe examples of Graves’ disease have been reported after bone marrow transplantation or HSCT18,30. It is possible that the reconstitution in this setting is different in character to the previous two examples, as it will typically include an expanded TSHR-reactive memory T-cell population, leading to a conventional or even unrestrained form of Graves’ disease. I would therefore recommend either an antithyroid drug or radioiodine as first-line treatment and would expect generally similar relapse rates to normal. If the donor is known to have had Graves’ disease prior to transplantation, advice should be offered to the recipient about possible signs and symptoms of thyrotoxicosis, and TSH measurements every 3–6 months for at least 3 years would be a reasonable approach to screening in such a recipient.
Declaration I have received consultancy fees from Genzyme.
References 1 Torino, F., Barnabei, A., Paragliola, R. et al. (2013) Thyroid dysfunction as an unintended side effect of anticancer drugs. Thyroid, 23, 1345–1366. 2 Weetman, A. (2009) Immune reconstitution syndrome and the thyroid. Best Practice & Research Clinical Endocrinology & Metabolism, 23, 693–702. 3 Coles, A.J., Wing, M., Smith, S. et al. (1999) Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet, 354, 1691–1695. 4 Cossburn, M., Pace, A.A., Jones, J. et al. (2011) Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort. Neurology, 77, 573–579. 5 Cuker, A., Coles, A.J., Sullivan, H. et al. (2011) A distinctive form of immune thrombocytopenia in a phase 2 study of alemtuzumab for the treatment of relapsing-remitting multiple sclerosis. Blood, 118, 6299–6305. 6 Walsh, M., Chaudhry, A. & Jayne, D. (2008) Long-term followup of relapsing/refractory anti-neutrophil cytoplasm antibody
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associated vasculitis treated with the lymphocyte depleting antibody alemtuzumab (CAMPATH-1H). Annals of the Rheumatic Diseases, 67, 1322–1327. Kirk, A.D., Hale, D.A., Swanson, S.J. et al. (2006) Autoimmune thyroid disease after renal transplantation using depletional induction with alemtuzumab. American Journal of Transplantation, 6, 1084–1085. Jubault, V., Penfornis, A., Schillo, F. et al. (2000) Sequential occurrence of thyroid autoantibodies and Graves’ disease after immune restoration in severely immunocompromised human immunodeficiency virus-1-infected patients. Journal of Clinical Endocrinology & Metabolism, 85, 4254–4257. Takarabe, D., Rokukawa, Y., Takahashi, Y. et al. (2010) Autoimmune diabetes in HIV-infected patients on highly active antiretroviral therapy. Journal of Clinical Endocrinology & Metabolism, 95, 4056–4060. Mohammedi, K., Roussel, R., El Dbouni, O. et al. (2011) Type B insulin resistance syndrome associated with an immune reconstitution inflammatory syndrome in an HIV-infected woman. Journal of Clinical Endocrinology & Metabolism, 96, E653–E657. Chen, F., Day, S.L., Metcalfe, R.A. et al. (2005) Characteristics of autoimmune thyroid disease occurring as a late complication of immune reconstitution in patients with advanced human immunodeficiency virus (HIV) disease. Medicine (Baltimore), 84, 98– 106. Sheikh, V., Dersimonian, R., Richterman, A.G. et al. (2014) Graves’ disease as immune reconstitution disease in HIV-positive patients is associated with naive and primary thymic emigrant CD4 T-cell recovery. AIDS, 28, 31–39. Jimenez, C., Moran, S.A., Sereti, I. et al. (2004) Graves’ disease after interleukin-2 therapy in a patient with human immunodeficiency virus infection. Thyroid, 14, 1097–1102. Visser, R., de Mast, Q., Netea-Maier, R.T. et al. (2012) Hashimoto’s thyroiditis presenting as acute painful thyroiditis and as a manifestation of an immune reconstitution inflammatory syndrome in a human immunodeficiency virus-seropositive patient. Thyroid, 22, 853–855. Takeshita, A., Shinjo, K. & Ohno, R. (1999) Graves disease after bone marrow transplantation. Annals of Internal Medicine, 131, 157. Yamamori, I., Kanie, T., Maeda, N. et al. (2004) Appearance of thyroid stimulating and blocking immunoglobulins after bone marrow transplantation: presentation of two contrasting cases. Endocrine Journal, 51, 439–443. Vardizer, Y., Lupetti, A., Vandelanotte, S. et al. (2009) Graves’ orbitopathy in a patient with adrenoleukodystrophy after bone marrow transplantation. European Journal of Endocrinology, 161, 369–373.
18 Tailor, I.K., Akil, M., Rennie, I. et al. (2012) Reconstitution Graves’ disease following autologous haematopoietic stem cell transplantation for severe diffuse systemic sclerosis. Quarterly Journal of Medicine, 105, 369–371. 19 Sinha, A., Abinun, M., Gennery, A.R. et al. (2013) Graves’ immune reconstitution inflammatory syndrome in childhood. Thyroid, 23, 1010–1014. 20 Bahn, R.S., Burch, H.B., Cooper, D.S. et al. (2011) Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Endocrine Practice, 17, 456–520. 21 Prummel, M.F. & Laurberg, P. (2003) Interferon-alpha and autoimmune thyroid disease. Thyroid, 13, 547–551. 22 Mammen, J.S., Ghazarian, S.R., Rosen, A. et al. (2013) Patterns of interferon-alpha-induced thyroid dysfunction vary with ethnicity, sex, smoking status, and pretreatment thyrotropin in an international cohort of patients treated for hepatitis C. Thyroid, 23, 1151–1158. 23 Hiraiwa, T., Tsujimoto, N., Tanimoto, K. et al. (2013) Use of Color Doppler Ultrasonography to Measure Thyroid Blood Flow and Differentiate Graves’ Disease from Painless Thyroiditis. European Thyroid Journal, 2, 120–126. 24 Wong, V., Fu, A.X., George, J. et al. (2002) Thyrotoxicosis induced by alpha-interferon therapy in chronic viral hepatitis. Clinical Endocrinology, 56, 793–798. 25 Daniels, G.H., Vladic, A., Brinar, V. et al. (2014) Alemtuzumabrelated thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis. Journal of Clinical Endocrinology & Metabolism, 99, 80–89. 26 Cohen, J.A., Coles, A.J., Arnold, D.L. et al. (2012) Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet, 380, 1819–1828. 27 Honda, A., Kashiwazaki, K., Tsunoda, T. et al. (2012) Short communication: CD4 cell count increases during successful treatment of Graves’ disease with methimazole in HIV-infected patients on antiretroviral therapy. AIDS Research and Human Retroviruses, 28, 1627–1629. 28 Yang, J.J., Tsai, M.S., Sun, H.Y. et al. (2013) Autoimmune diseases-related arthritis in HIV-infected patients in the era of highly active antiretroviral therapy. Journal of Microbiology, Immunology and Infection. pii, S1684-1182(13)00147-3. [Epub ahead of print] 29 Madge, S., Smith, C.J., Lampe, F.C. et al. (2007) No association between HIV disease and its treatment and thyroid function. HIV Medicine, 8, 22–27. 30 Karthaus, M., Gabrysiak, T., Brabant, G. et al. (1997) Immune thyroiditis after transplantation of allogeneic CD34 + selected peripheral blood cells. Bone Marrow Transplantation, 20, 697–699.
© 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 80, 629–632
doi: 10.1111/cen.12427
CLINICAL QUESTION
Graves’ disease following immune reconstitution or immunomodulatory treatment: should we manage it any differently? Anthony P. Weetman Department of Human Metabolism, Faculty of Medicine Dentistry and Health, The Medical School, University of Sheffield, Sheffield, UK
Background Summary Graves’ disease and other disorders of thyroid function may occur following treatment with novel anticancer agents or during periods of lymphocyte recovery after lymphopenia. There are three main settings for such lymphocyte reconstitution: recovery after a bone marrow or haematopoietic stem cell transplant, alemtuzumab treatment and the use of highly active antiretroviral therapy (HAART) for human immunodeficiency virus infection. The available evidence suggests that Graves’ disease behaves as normal in most of these cases and should be treated conventionally, but it may follow a more favourable course in those receiving alemtuzumab or HAART. As spontaneous or drug-induced remission may be more likely in these two settings, first-line treatment should usually consist of an antithyroid drug. (Received 27 January 2014; returned for revision 4 February 2014; finally revised 7 February 2014; accepted 8 February 2014)
Introduction A wide variety of thyroid abnormalities have been described in patients receiving novel drugs for cancer or for other conditions such as chronic hepatitis and in settings in which the immune system is reconstituted from a lymphopenic state. In some cases, the abnormalities are due to the underlying condition, resulting in a sick euthyroid syndrome, and in others, the effects are due to the biochemical rather than immunological action of the drug. Nonetheless, when drugs are used which concurrently affect the immune system, autoimmune thyroid diseases, including Graves’ disease, can arise.
Correspondence: Anthony P. Weetman, Department of Human Metabolism, Faculty of Medicine, Dentistry and Health, University of Sheffield, The Medical School, Beech Hill Road, Sheffield S10 2RX, UK. Tel.: 00 44 114 2712570; E-mail: [email protected] © 2014 John Wiley & Sons Ltd
Novel anticancer agents include cytokines, immune system modulators and drugs which target critical biochemical pathways in individual cancers. Thyroid disease arising as a consequence of these agents tends to be hypothyroidism, although this is often as part of a destructive thyroiditis with alternating thyrotoxicosis and hypothyroidism, which may confuse the unwary into diagnosing Graves’ disease initially. An extensive and helpful review of the relevant literature has been published recently1. Those anticancer agents which have been reported convincingly to be associated with Graves’ disease are shown in Table 1. Three types of reconstitution Graves’ disease exist2. Alemtuzumab is a humanized monoclonal antibody against CD52, expressed by lymphocytes and monocytes; administration causes a profound lymphopenia with a gradual recovery in lymphocyte number over the next 2–5 years (depending on exact subset). This agent has been used in a wide variety of conditions, including haematological malignancies and autoimmune disorders, with particularly impressive results in multiple sclerosis. Up to a third of such patients develop Graves’ disease 1–5 years after initial treatment with alemtuzumab3. Smoking increases the risk three-fold (a greater risk than for conventional Graves’ disease) but gender may have less effect than normal4. Half as frequently, patients may develop a destructive thyroiditis or hypothyroidism. Significant Graves’ eye disease is uncommon4. Alemtuzumab can also cause other autoantibody-induced disorders, such as Goodpasture’s syndrome and idiopathic thrombocytopenic purpura (ITP)5. The adverse thyroid effects of alemtuzumab have been reported when it is used in other conditions such as vasculitis and as induction treatment prior to renal transplantation6,7. However the rate seems especial high in multiple sclerosis for reasons which are unclear, but could relate to disease-specific shifts in the immunological ‘environment’ during reconstitution in this disorder, as there is no major genetic association which is shared between multiple sclerosis and Graves’ disease. Highly active antiretroviral therapy (HAART) comprises the use of a combination of at least three drugs (protease inhibitors, reverse transcriptase inhibitors or agents which prevent viral entry into T cells) and has transformed the outlook for patients 629
630 A. P. Weetman Table 1. Immunomodulatory treatments and immune reconstitution syndromes associated with Graves’ disease Treatment
Comment
Inferferon-a
Can cause Graves’ disease, destructive thyroiditis or hypothyroidism Mainly induce hypothyroidism or destructive thyroiditis; rare cases may be Graves’ disease Graves’ ophthalmopathy but not hyperthyroidism has been reported During the phase of lymphocyte recovery after depletion During the phase of lymphocyte recovery from HIV-induced lymphopenia Typically arises if the donor had Graves’ disease During reconstitution
Tyrosine kinase inhibitors (imatinib, nilotinib, dasatinib) Anti-CTLA-4 monoclonal antibody (ipilimumab) Alemtuzumab Highly active antiretroviral therapy (HAART) Bone marrow transplant Haematopoietic stem cell transfer
with human immunodeficiency virus (HIV) infection. Highly active antiretroviral therapy initially increases the memory CD4+ T-cell population and subsequently naive CD4+ T-cell numbers rise. During this latter phase of immune reconstitution, a number of autoimmune disorders can appear, including Graves’ disease, type 1 diabetes mellitus and type B insulin resistance syndrome8–10. A retrospective survey found that around 3% of women and 0.2% of men developed Graves’ disease 8– 33 months after starting HAART; 40% had soft-tissue changes of Graves’ eye disease11. The onset of Graves’ disease is associated with the appearance of na€ıve and primary thymic emigrant CD4+ T cells and multiple autoantibodies, of which those against the TSH receptor (TSHR) have clinical impact12. There is also a case report of an HIV-infected individual who developed Graves’ disease during the period of lymphocyte recovery induced by interleukin-2 therapy13. As with the other agents discussed so far, care must be taken to distinguish the cause of any thyrotoxicosis in this setting as two cases of autoimmune destructive thyroiditis have been described after HAART11,14. The third type of reconstitution Graves’ disease occurs following bone marrow or haematopoietic stem cell transplantation (HSCT)2. In the case of bone marrow transplantation, the donor has typically had evidence of Graves’ disease in the past, although this is not always the case. One donor has been reported in whom the only evidence of thyroid disease in retrospect was the presence of thyroid peroxidase (TPO) antibodies; in another, no evidence at all for thyroid disease was found15,16. In one bone marrow recipient with adrenoleukodystrophy, Graves’ disease started 3 years after transplantation and was followed by the appearance of eye signs, whereas his donor sister only developed Graves’ disease without eye signs 7 years after donation17. The idea that adoptive transfer of TSHR-reactive lymphocytes might cause Graves’ disease in a lymphocyte-depleted recipient is hardly surprising immunologically, but other cases are more
complex in terms of pathogenesis. Autologous HSCT following cytotoxic chemotherapy for systemic sclerosis led to clinical improvement in the primary disorder but Graves’ disease and severe eye signs subsequently developed18. Four cases of Graves’ disease have also been reported at a mean time of 22 months following allogeneic HSCT and chemotherapy conditioning; none of the donors had evidence of thyroid disease19. These situations seem more akin to the disordered immunoregulation arising after lymphopenia reversal with alemtuzumab or HAART13. It is also possible that immunoregulation is affected by graft-versus-host disease following bone marrow transfer or HSCT, leading to expansion of previously silent TSHR-reactive donor lymphocytes. A summary of the immunological factors involved in causing reconstitution Graves’ disease is given in Table 2.
Treatment of Graves’ disease Extensive guidelines for the treatment of conventional Graves’ disease have been published which provide background data for what follows20. The first step in management is to make an accurate diagnosis that an episode of thyrotoxicosis, especially one arising in these settings, is indeed due to Graves’ disease rather than destructive thyroiditis. A third of thyrotoxicosis following interferon-a treatment has been estimated to be due to destructive thyroiditis21. However, the prevalence may be even higher depending on the frequency of testing22. Evidence that thyrotoxicosis has persisted for more than 6 weeks strongly suggests Graves’ disease, as does the presence of eye signs. Thyroid peroxidase antibodies may be positive in both types of thyrotoxicosis, whereas the detection of TSHR antibodies in the presence of thyrotoxicosis confirms Graves’ disease. The presence of TPO antibodies prior to treatment with interferon-a or other agents is a risk factor for Graves’ disease, destructive thyroiditis and hypothyroidism. If TSHR antibodies cannot be measured, a radionuclide scan (99mTc or 123I) is useful, as destructive thyroiditis will be revealed by the absence of uptake. Colour flow
Table 2. Factors which may be responsible for the pathogenesis of reconstitution Graves’ disease
• • • • • • •
Initially low CD4+ T-helper cell count, with a subsequent increase in thymic CD4+ T cells Altered cytokine profile, with a bias towards Th2 cells Functional impairment of T regulatory cells relative to the expanding autoreactive T-cell population Relatively high B cell numbers Abnormal presentation of self-antigens by dendritic cells during and after the lymphopenic phase Adoptive transfer of donor TSHR-reactive lymphocytes in allogeneic bone marrow transplantation and HSCT Graft-versus-host disease causing immune dysregulation in allogeneic bone marrow transplantation and HSCT
HSCT, haematopoietic stem cell transplantation. © 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 80, 629–632
Immunotherapy-induced Graves’ disease 631 Doppler ultrasound can also be used to distinguish between Graves’ disease and destructive thyroiditis: absent flow on ultrasound indicates destructive thyrotoxicosis, whereas flow is enhanced in Graves’ hyperthyroidism23. Having firmly established that the patient does have Graves’ disease, the question that arises is whether in these particular settings, the disease runs a different course to conventional Graves’ disease. Unfortunately, the evidence is pretty thin as information is only available from case reports or from retrospective data collected from therapeutic trials in which there has been no standardized endocrinological input. For Graves’ disease arising after treatment with antineoplastic agents, there are no data to indicate that initial therapy should be any different to normal. We do know that even when interferon-a treatment is stopped, Graves’ disease tends to persist and therefore prompt first-line treatment with an antithyroid drug or radioiodine is reasonable, with the choice depending largely on patient preference and the presence of factors such as concurrent eye disease24. Patients starting interferon-a should have a baseline TSH and TPO antibody measurement; TSH should be checked as a minimum every 3 months subsequently in those with antibodies and every 6 months in those without. There is some circumstantial evidence that the Graves’ disease associated with alemtuzumab treatment may be less aggressive than conventional Graves’ disease. In one series of UK patients, only 28% required radioiodine treatment, which seems a low figure if this treatment was being used after failure of an antithyroid drug4. A detailed analysis of the thyroid dysfunction which occurred in the CAMMS223 trial revealed that 22% of alemtuzumab-treated patients developed Graves’ disease: of them, 23% spontaneously became euthyroid and a further 15% spontaneously developed hypothyroidism25. Only 36% of those who were treated received radioiodine or surgery, and although treatment protocols were not standardized between participating centres, these figures imply that 78% of patients had recovery from Graves’ disease, either spontaneously or after an antithyroid drug. Overall, the authors concluded that there were few serious episodes of thyroid dysfunction, although three patients did develop significant eye signs, possibly worsened by radioiodine in one. In the CARE-MS II trial, all cases of Graves’ disease were said to be managed ‘conventionally’ but it is striking that of the 28 patients diagnosed with hyperthyroidism, only one each required radioiodine or surgery26. Supporting the idea that there are real differences in the behaviour of this type of reconstitution Graves’ disease, it appears that ITP induced by alemtuzumab is also distinctive, as it responds well to conventional therapy with prolonged remission5. Mechanistically, it would seem reasonable to expect that if reconstitution autoimmunity arises from an exuberant autoreactivity at a specific point during recovery from lymphopenia, this abnormality might come readily under control as the rest of the immune system is restored. Together these data make me feel that first-line treatment in this situation should be with an antithyroid drug rather than radioiodine, as there would seem to be a good chance that euthyroidism will result. It is also important to ensure that hyperthyroidism persists at the point of © 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 80, 629–632
referral before starting treatment, given the high rate of spontaneous changes. All patients to be treated with alemtuzumab should have a baseline measurement of TSH, and the TSH should be repeated every 2–3 months for at least 3 years after initial therapy; TPO antibodies are not of predictive value. Similar principles apply to Graves’ disease occurring after HAART, although there are fewer data. In the first series of five patients8, treatment details were not given, but in a retrospective analysis of 17 patients, all but one (who refused treatment) responded to carbimazole11. Prompt responsiveness to methimazole has been noted in two further cases27. Autoimmune forms of arthritis occurring after HAART also have a better clinical response than conventional forms28. I would therefore recommend an antithyroid drug as first-line treatment in this setting too. Given the low frequency of Graves’ disease after HAART, screening is probably not worthwhile29, but clinicians should be vigilant for this and other autoimmune disorders that may develop. Clinically, severe examples of Graves’ disease have been reported after bone marrow transplantation or HSCT18,30. It is possible that the reconstitution in this setting is different in character to the previous two examples, as it will typically include an expanded TSHR-reactive memory T-cell population, leading to a conventional or even unrestrained form of Graves’ disease. I would therefore recommend either an antithyroid drug or radioiodine as first-line treatment and would expect generally similar relapse rates to normal. If the donor is known to have had Graves’ disease prior to transplantation, advice should be offered to the recipient about possible signs and symptoms of thyrotoxicosis, and TSH measurements every 3–6 months for at least 3 years would be a reasonable approach to screening in such a recipient.
Declaration I have received consultancy fees from Genzyme.
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