Advances in immune-targeted therapy for Graves' ophthalmopathy

doi:10.5246/jcps.2023.08.051

Abstract

Abstract:

Graves’ ophthalmopathy (GO) is an autoimmune disease characterized by lymphocytic infiltration behind the eyes. The pathogenesis of this disease is complex, and although no definitive conclusion has been reached, immune factors are believed to play a significant role. Currently, no specific therapeutic drugs are available for GO. Glucocorticoids are recommended as first-line drugs for patients with moderate-to-severe, active GO, but they have significant side effects, and some patients are intolerant. Immune-targeted drugs offer a new treatment option with great promise for clinical application. Recent in-depth studies of the pathogenesis of GO have led to many clinical trial studies of immune-targeted drugs. This article highlights the research progress of three immune-targeted drugs, namely teprotumumab, rituximab (RTX), and tocilizumab (TCZ), with the aim of providing more therapeutic options for GO patients. It's worth noting that although these immune-targeted drugs have unique application prospects, their clinical application is currently limited due to unclear therapeutic effects or cost issues.

Key words: Graves’ ophthalmopathy, Immunotherapy, Targeted therapy, Teprotumumab, Rituximab, Tocilizumab

Supporting:

Wen Lv, Ying Fu. Advances in immune-targeted therapy for Graves' ophthalmopathy[J]. Journal of Chinese Pharmaceutical Sciences, 2023, 32(8): 616-625.

References 48

[1]	Aniszewski, J.P.; Valyasevi, R.W.; Bahn, R.S. Relationship between disease duration and predominant orbital T cell subset in Graves’ ophthalmopathy. J. Clin. Endocrinol. Metab. 2000, 85, 776–780.
[2]	Łacheta, D.; Miśkiewicz, P.; Głuszko, A.; Nowicka, G.; Struga, M.; Kantor, I.; Poślednik, K.B.; Mirza, S.; Szczepański, M.J. Immunological aspects of Graves’ ophthalmopathy. Biomed. Res. Int. 2019, 2019, 7453260.
[3]	Kloprogge, S.J.; Busuttil, B.E.; Frauman, A.G. TSH receptor protein is selectively expressed in normal human extraocular muscle. Muscle Nerve. 2005, 32, 95–98.
[4]	Wakelkamp, I.M.M.J.; Bakker, O.; Baldeschi, L.; Wiersinga, W.M.; Prummel, M.F. TSH-R expression and cytokine profile in orbital tissue of active vs. inactive Graves’ ophthalmopathy patients. Clin. Endocrinol. 2003, 58, 280–287.
[5]	Tsui, S.; Naik, V.; Hoa, N.; Hwang, C.J.; Afifiyan, N.F.; Sinha Hikim, A.; Gianoukakis, A.G.; Douglas, R.S.; Smith, T.J. Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: a tale of two antigens implicated in Graves’ disease. J. Immunol. 2008, 181, 4397–4405.
[6]	Salvi, M.; Covelli, D. B cells in Graves’ Orbitopathy: more than just a source of antibodies? Eye (Lond). 2019, 33, 230–234.
[7]	Nielsen, C.H.; El Fassi, D.; Hasselbalch, H.C.; Bendtzen, K.; Hegedüs, L. B-cell depletion with rituximab in the treatment of autoimmune diseases. Expert Opin. Biol. Ther. 2007, 7, 1061–1078.
[8]	Salvi, M.; Vannucchi, G.; Beck-Peccoz, P. Potential utility of rituximab for Graves' orbitopathy. J. Clin. Endocrinol. Metab. 2013, 98, 4291–4299.
[9]	Salvi, M.; Vannucchi, G.; Campi, I.; Rossi, S.; Bonara, P.; Sbrozzi, F.; Guastella, C.; Avignone, S.; Pirola, G.; Ratiglia, R.; Beck-Peccoz, P. 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. 2006, 154, 511–517.
[10]	Karasek, D.; Cibickova, L.; Karhanova, M.; Kalitova, J.; Schovanek, J.; Frysak, Z. Clinical and immunological changes in patients with active moderate-to-severe Graves’ orbitopathy treated with very low-dose rituximab. Endokrynol. Pol. 2017, 68, 498–504.
[11]	Eid, L.; Coste-Verdier, V.; Longueville, E.; Ribeiro, E.; Nicolescu-Catargi, B.; Korobelnik, J.F. The effects of Rituximab on Graves’ orbitopathy: a retrospective study of 14 patients. Eur. J. Ophthalmol. 2020, 30, 1008–1013.
[12]	Deltour, J.B.; d'Assigny Flamen, M.; Ladsous, M.; Giovansili, L.; Cariou, B.; Caron, P.; Drui, D.; Lebranchu, P. Efficacy of rituximab in patients with Graves’ orbitopathy: a retrospective multicenter nationwide study. Graefes Arch. Clin. Exp. Ophthalmol. 2020, 258, 2013–2021.
[13]	Vannucchi, G.; Campi, I.; Covelli, D.; Currò, N.; Lazzaroni, E.; Palomba, A.; Soranna, D.; Zambon, A.; Fugazzola, L.; Muller, I.; Guastella, C.; Salvi, M. Efficacy profile and safety of very low-dose rituximab in patients with Graves’ orbitopathy. Thyroid. 2021, 31, 821–828.
[14]	Salvi, M.; Vannucchi, G.; Currò, N.; Introna, M.; Rossi, S.; Bonara, P.; Covelli, D.; Dazzi, D.; Guastella, C.; Pignataro, L.; Ratiglia, R.; Golay, J.; Beck-Peccoz, P. Small dose of rituximab for Graves orbitopathy: new insights into the mechanism of action. Arch. Ophthalmol. 2012, 130, 122–124.
[15]	Campi, I.; Vannucchi, G.; Muller, I.; Lazzaroni, E.; Currò, N.; Dainese, M.; Montacchini, B.; Covelli, D.; Guastella, C.; Pignataro, L.; Fugazzola, L.; Arosio, M.; Salvi, M. Therapy with different dose regimens of rituximab in patients with active moderate-to-severe Graves’ orbitopathy. Front. Endocrinol. (Lausanne). 2022, 12, 790246.
[16]	Salvi, M.; Vannucchi, G.; Currò, N.; Campi, I.; Covelli, D.; Dazzi, D.; Simonetta, S.; Guastella, C.; Pignataro, L.; Avignone, S.; Beck-Peccoz, P. Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Graves’ orbitopathy: a randomized controlled study. J. Clin. Endocrinol. Metab. 2015, 100, 422–431.
[17]	Stan, M.N.; Garrity, J.A.; Carranza Leon, B.G.; Prabin, T.; Bradley, E.A.; Bahn, R.S. Randomized controlled trial of rituximab in patients with Graves’ orbitopathy. J. Clin. Endocrinol. Metab. 2015, 100, 432–441.
[18]	Stan, M.N.; Salvi, M. MANAGEMENT OF ENDOCRINE DISEASE: Rituximab therapy for Graves’ orbitopathy - lessons from randomized control trials. Eur. J. Endocrinol. 2017, 176, R101–R109.
[19]	Bartalena, L.; Kahaly, G.J.; Baldeschi, L.; Dayan, C.M.; Eckstein, A.; Marcocci, C.; Marinò, M.; Vaidya, B.; Wiersinga, W.M.;. The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy. Eur. J. Endocrinol. 2021, 185, G43–G67.
[20]	Tsui, S.; Naik, V.; Hoa, N.; Hwang, C.J.; Afifiyan, N.F.; Sinha Hikim, A.; Gianoukakis, A.G.; Douglas, R.S.; Smith, T.J. Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: a tale of two antigens implicated in Graves’ disease. J. Immunol. 2008, 181, 4397–4405.
[21]	Krieger, C.C.; Sui, X.L.; Kahaly, G.J.; Neumann, S.; Gershengorn, M.C. Inhibition of TSH/IGF-1 receptor crosstalk by teprotumumab as a treatment modality of thyroid eye disease. J. Clin. Endocrinol. Metab. 2022, 107, e1653–e1660.
[22]	Fernando, R.; Caldera, O.; Smith, T.J. Therapeutic IGF-I receptor inhibition alters fibrocyte immune phenotype in thyroid-associated ophthalmopathy. Proc. Natl. Acad. Sci. USA. 2021, 118, e2114244118.
[23]	Chen, H.; Mester, T.; Raychaudhuri, N.; Kauh, C.Y.; Gupta, S.; Smith, T.J.; Douglas, R.S. Teprotumumab, an IGF-1R blocking monoclonal antibody inhibits TSH and IGF-1 action in fibrocytes. J. Clin. Endocrinol. Metab. 2014, 99, E1635–E1640.
[24]	Jain, A.P.; Gellada, N.; Ugradar, S.; Kumar, A.; Kahaly, G.; Douglas, R. Teprotumumab reduces extraocular muscle and orbital fat volume in thyroid eye disease. Br. J. Ophthalmol. 2022, 106, 165–171.
[25]	Markham, A. Teprotumumab: first approval. Drugs. 2020, 80, 509–512.
[26]	Smith, T.J.; Kahaly, G.J.; Ezra, D.G.; Fleming, J.C.; Dailey, R.A.; Tang, R.A.; Harris, G.J.; Antonelli, A.; Salvi, M.; Goldberg, R.A.; Gigantelli, J.W.; Couch, S.M.; Shriver, E.M.; Hayek, B.R.; Hink, E.M.; Woodward, R.M.; Gabriel, K.; Magni, G.; Douglas, R.S. Teprotumumab for thyroid-associated ophthalmopathy. N. Engl. J. Med. 2017, 376, 1748–1761.
[27]	Douglas, R.S.; Kahaly, G.J.; Patel, A.; Sile, S.B.; Thompson, E.H.Z.; Perdok, R.; Fleming, J.C.; Fowler, B.T.; Marcocci, C.; Marinò, M.; Antonelli, A.; Dailey, R.; Harris, G.J.; Eckstein, A.; Schiffman, J.; Tang, R.; Nelson, C.; Salvi, M.; Wester, S.; Sherman, J.W.; Vescio, T.; Holt, R.J.; Smith, T.J. Teprotumumab for the treatment of active thyroid eye disease. N. Engl. J. Med. 2020, 382, 341–352.
[28]	Douglas, R.S.; Kahaly, G.J.; Ugradar, S.; Elflein, H.; Ponto, K.A.; Fowler, B.T.; Dailey, R.; Harris, G.J.; Schiffman, J.; Tang, R.; Wester, S.; Jain, A.P.; Marcocci, C.; Marinò, M.; Antonelli, A.; Eckstein, A.; Führer-Sakel, D.; Salvi, M.; Sile, S.B.; Francis-Sedlak, M.; Holt, R.J.; Smith, T.J. Teprotumumab efficacy, safety, and durability in longer-duration thyroid eye disease and re-treatment: optic-X study. Ophthalmology. 2022, 129, 438–449.
[29]	Ugradar, S.; Kang, J.L.; Kossler, A.L.; Zimmerman, E.; Braun, J.; Harrison, A.R.; Bose, S.; Cockerham, K.; Douglas, R.S. Teprotumumab for the treatment of chronic thyroid eye disease. Eye (Lond). 2022, 36, 1553–1559.
[30]	Prof, G.J.; Kahaly, M.D. Teprotumumab for patients with active thyroid eye disease: a pooled data analysis, subgroup analyses, and off-treatment follow-up results from two randomised, double-masked, placebo-controlled, multicentre trials. Lancet Diabetes Endocrinol. 2021, 9, 360–372.
[31]	Douglas, R.S; Kossler, A.L; Abrams, J; Briceño, C.A; Gay, D; Harrison, A; Lee, M; Nguyen, J; Joseph, S.S; Schlachter, D; Tan, J; Lynch, J; Oliver, L; Perry, R; Ugradar, S. Expert Consensus on the Use of Teprotumumab for the Management of Thyroid Eye Disease Using a Modified-Delphi Approach. J. Neuroophthalmol. 2022, 42, 334–339.
[32]	Strianese, D.; Rossi, F. Interruption of autoimmunity for thyroid eye disease: B-cell and T-cell strategy. Eye (Lond). 2019, 33, 191–199.
[33]	Slowik, M.; Urbaniak-Kujda, D.; Bohdanowicz-Pawlak, A.; Kapelko-Slowik, K.; Dybko, J.; Wolowiec, D.; Jazwiec, B.; Daroszewski, J. CD8+CD28− lymphocytes in peripheral blood and serum concentrations of soluble interleukin 6 receptor are increased in patients with Graves’ orbitopathy and correlate with disease activity. Endocr. Res. 2012, 37, 89–95.
[34]	Kumar, S.; Bahn, R.S. Relative overexpression of macrophage-derived cytokines in orbital adipose tissue from patients with Graves’ ophthalmopathy. J. Clin. Endocrinol. Metab. 2003, 88, 4246–4250.
[35]	Jyonouchi, S.C.; Valyasevi, R.W.; Harteneck, D.A.; Dutton, C.M.; Bahn, R.S. Interleukin-6 stimulates thyrotropin receptor expression in human orbital preadipocyte fibroblasts from patients with Graves’ ophthalmopathy. Thyroid. 2001, 11, 929–934.
[36]	Mihara, M.; Hashizume, M.; Yoshida, H.; Suzuki, M.; Shiina, M. IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin. Sci. (Lond). 2012, 122, 143–159.
[37]	Pérez-Moreiras, J.V.; Alvarez-López, A.; Gómez, E.C. Treatment of active corticosteroid-resistant Graves’ orbitopathy. Ophthalmic Plast. Reconstr. Surg. 2014, 30, 162–167.
[38]	Perez-Moreiras, J.V.; Gomez-Reino, J.J.; Maneiro, J.R.; Perez-Pampin, E.; Lopez, A.R.; Rodríguez Alvarez, F.M.; Castillo Laguarta, J.M.; Del Estad Cabello, A.; Sorroche, M.G.; Gregori, E.E.; Sales-Sanz, M.; Tocilizumab in Graves Orbitopathy Study Group. Efficacy of tocilizumab in patients with moderate-to-severe corticosteroid-resistant Graves orbitopathy: a randomized clinical trial. Am. J. Ophthalmol. 2018, 195, 181–190.
[39]	Sánchez-Bilbao, L.; Martínez-López, D.; Revenga, M.; López-Vázquez, Á.; Valls-Pascual, E.; Atienza-Mateo, B.; Valls-Espinosa, B.; Maiz-Alonso, O.; Blanco, A.; Torre-Salaberri, I.; Rodríguez-Méndez, V.; García-Aparicio, Á.; Veroz-González, R.; Jovaní, V.; Peiteado, D.; Sánchez-Orgaz, M.; Tomero, E.; de Miera, F.J.T.S.; Pinillos, V.; Aurrecoechea, E.; Mora, Á.; Conesa, A.; Fernández-Prada, M.; Troyano, J.A.; Calvo-Río, V.; Demetrio-Pablo, R.; González-Mazón, Í.; Hernández, J.L.; Castañeda, S.; González-Gay, M.Á.; Blanco, R. Anti-IL-6 receptor tocilizumab in refractory Graves' orbitopathy: national multicenter observational study of 48 patients. J. Clin. Med. 2020, 9, 2816.
[40]	Pérez-Moreiras, J.V.; Varela-Agra, M.; Prada-Sánchez, M.C.; Prada-Ramallal, G. Steroid-resistant Graves’ orbitopathy treated with tocilizumab in real-world clinical practice: a 9-year single-center experience. J. Clin. Med. 2021, 10, 706.
[41]	Dorado Cortez, O.; Grivet, D.; Perrillat, N.; Gain, P.; Thuret, G. Treatment of corticosteroid-resistant Graves’ orbitopathy with tocilizumab: a single-centre prospective study. Orbit. 2022, 1–7.
[42]	Moi, L.; Hamedani, M.; Ribi, C. Long-term outcomes in corticosteroid-refractory Graves’ orbitopathy treated with tocilizumab. Clin. Endocrinol. 2022, 97, 363–370.
[43]	Copperman, T.; Idowu, O.O.; Kersten, R.C.; Vagefi, M.R. Subcutaneous tocilizumab for thyroid eye disease: simplified dosing and delivery. Ophthalmic Plast. Reconstr. Surg. 2019, 35, e64–e66.
[44]	Silkiss, R.Z.; Paap, M.K.; Roelofs, K.A.; Agi, J.; Weis, E. Treatment of corticosteroid-resistant thyroid eye disease with subcutaneous tocilizumab. Can. J. Ophthalmol. 2021, 56, 66–70.
[45]	Mejía González, M.A.; Carbone, J. How suitable is intravenous tocilizumab for the treatment of Graves’ ophthalmopathy? Expert Rev. Clin. Immunol. 2021, 17, 1151–1153.
[46]	Paridaens, D.; van den Bosch, W.A.; van der Loos, T.L.; Krenning, E.P.; van Hagen, P.M. The effect of etanercept on Graves’ ophthalmopathy: a pilot study. Eye (Lond). 2005, 19, 1286–1289.
[47]	Ayabe, R.; Rootman, D.B.; Hwang, C.J.; Ben-Artzi, A.; Goldberg, R. Adalimumab as steroid-sparing treatment of inflammatory-stage thyroid eye disease. Ophthalmic Plast. Reconstr. Surg. 2014, 30, 415–419.
[48]	Durrani, O.M.; Reuser, T.Q.; Murray, P.I. Infliximab: a novel treatment for sight-threatening thyroid associated ophthalmopathy. Orbit. 2005, 24, 117–119.