Abstract
Purpose
To assess the efficacy and safety of periocular injections of methotrexate versus triamcinolone in the management of active thyroid-associated orbitopathy.
Study design
Prospective, double-masked, randomized clinical trial.
Methods
Participants with bilateral active, moderate-to-severe thyroid-associated orbitopathy were randomly assigned to receive three periocular injections of 7.5 mg methotrexate in one orbit and three periocular injections of 20 mg triamcinolone in the contralateral orbit.
Results
Among the enrolled 25 patients, 18 patients completed the study. A statistically significant reduction of the mean clinical activity score was detected in both arms (from 5.2 ± 0.89 at baseline to 0.9 ± 1.7 at study endpoint, p-value < 0.001 in the methotrexate arm, and from 5.1 ± 0.9 at baseline to 1 ± 1.7 at study endpoint, p-value < 0.001 in the triamcinolone arm), mean proptosis also decreased in both arms (from 25.2 ± 3.4 mm at baseline to 23.8 ± 3.7 mm at study endpoint, p-value = 0.01 in the methotrexate arm, and from 24.2 ± 3.06 mm at baseline to 23.2 ± 3.3 mm at study endpoint, p-value = 0.049 in the triamcinolone arm).
Lid aperture and soft tissue signs improved significantly in both arms in comparison to baseline. A statistically significant reduction in the intraocular pressure was observed in the methotrexate arm but not in the triamcinolone arm. 88.9% of patients in both arms were overall responders at 6 months. There was no significant difference in mean CAS, proptosis, lid aperture or rate of responders between the two arms at any visit. Both drugs were found to be safe with minimal local and systemic complications.
Conclusion
Periocular injections of methotrexate represent an effective and safe alternative option for the management of active, moderate-to-severe thyroid-associated orbitopathy. Although no serious complications occurred during the 6-month follow-up, the possibility of late complications such as orbital fat atrophy cannot be ruled out.
Similar content being viewed by others
References
Bahn RS. Graves’ ophthalmopathy. N Engl J Med. 2010;362:726–38.
Taylor PN, Zhang L, Lee RW, Muller I, Ezra DG, Dayan CM, et al. New insights into the pathogenesis and nonsurgical management of Graves orbitopathy. Nat Rev Endocrinol. 2020;16:104–16.
Genere N, Stan MN. Current and emerging treatment strategies for Graves’ orbitopathy. Drugs. 2019;79:109–24.
Bagheri A, Abbaszadeh M, Yazdani S. Intraorbital steroid injection for active thyroid ophthalmopathy. J Ophthalmic Vis Res. 2020;15:69–79.
Bordaberry M, Marques DL, Pereira-Lima JC, Marcon IM, Schmid H. Repeated peribulbar injections of triamcinolone acetonide: a successful and safe treatment for moderate to severe Graves’ ophthalmopathy. Acta Ophthalmol. 2009;87:58–64.
Ebner R, Devoto MH, Weil D, Bordaberry M, Mir C, Martinez H, et al. Treatment of thyroid associated ophthalmopathy with periocular injections of triamcinolone. Br J Ophthalmol. 2004;88:1380–6.
Poonyathalang A, Preechawat P, Charoenkul W, Tangtrakul P. Retrobulbar injection of triamcinolone in thyroid associated orbitopathy. J Med Assoc Thai. 2005;88:345–9.
Alkawas AA, Hussein AM, Shahien EA. Orbital steroid injection versus oral steroid therapy in management of thyroid-related ophthalmopathy. Clin Exp Ophthalmol. 2010;38:692–7.
Rivera-Grana E, Lin P, Suhler EB, Rosenbaum JT. Methotrexate as a corticosteroid-sparing agent for thyroid eye disease. J Clin Exp Ophthalmol. 2015;6:422.
Strianese D, Iuliano A, Ferrara M, Comune C, Baronissi I, Napolitano P, et al. Methotrexate for the treatment of thyroid eye disease. J Ophthalmol. 2014;2014: 128903.
Yong K-L, Chng C-L, Sie NM, Lang S, Yang M, Looi A, et al. Methotrexate as an adjuvant in severe thyroid eye disease: does it really work as a steroid-sparing agent? Ophthalmic Plast Reconstr Surg. 2019;35:369–73.
Rubinov A, Zommer H, Aghazadeh H, Weis E. Role of methotrexate in thyroid-related orbitopathy. Can J Ophthalmol. 2018;53:34–8.
Dickinson AJ, Perros P. Controversies in the clinical evaluation of active thyroid-associated orbitopathy: use of a detailed protocol with comparative photographs for objective assessment. Clin Endocrinol (Oxf). 2001;55:283–303.
Wiersinga W, Perros P, Kahaly G, Mourits M, Baldeschi L, Boboridis K, et al. Clinical assessment of patients with Graves’ orbitopathy: the European Group on Graves’ Orbitopathy recommendations to generalists, specialists and clinical researchers. Eur J Endocrinol. 2006;155:387–9.
Cipriani P, Ruscitti P, Carubbi F, Liakouli V, Giacomelli R. Methotrexate: an old new drug in autoimmune disease. Expert Rev Clin Immunol. 2014;10:1519–30.
Bartalena L, Tanda ML, Medea A, Marcocci C, Pinchera A. Novel approaches to the management of graves’ ophthalmopathy. Hormones (Athens). 2002;1:76–90.
Khalil HEDM, El Gendy HA, Youssef HAR, Haroun HE, Gheita TA, Bakir HM. The effectiveness of intraocular methotrexate in the treatment of posterior uveitis in Behçet’s disease patients compared to retrobulbar steroids injection. J Ophthalmol. 2016;2016: 1678495.
Benner JD, Dao D, Butler JW, Hamill KI. Intravitreal methotrexate for the treatment of proliferative vitreoretinopathy. BMJ Open Ophthalmol. 2019;4: e000293.
Smith JR, Rosenbaum JT, Wilson DJ, Doolittle ND, Siegal T, Neuwelt EA, et al. Role of intravitreal methotrexate in the management of primary central nervous system lymphoma with ocular involvement. Ophthalmology. 2002;109:1709–16.
Mittal J, Mahajan B. Intramatricial injections for nail psoriasis: an open-label comparative study of triamcinolone, methotrexate, and cyclosporine. Indian J Dermatol Venereol Leprol. 2018;84:419–23.
Ustuner P, Balevi A, Ozdemir M. The comparison of the efficacy and safety of intralesional triamcinolone acetonide and methotrexate injections for the treatment of fingernail psoriasis. J Ankara Univ Fac Med. 2018;71:145–51.
Carriere C, Baier S, Campana LG, Puviani M, Eisendle K. Palliative intralesional tumescent methotrexate for recurrent locally advanced periocular cutaneous squamous cell carcinoma. J Dtsch Dermatol Ges. 2020;18:1063–6.
Searle T, Ali FR, Al-Niaimi F. Intralesional methotrexate in dermatology: diverse indications and practical considerations. Dermatol Ther. 2021;34: e14404.
Lee SJ, Rim THT, Jang SY, Kim CY, Shin DY, Lee EJ, et al. Treatment of upper eyelid retraction related to thyroid-associated ophthalmopathy using subconjunctival triamcinolone injections. Graefes Arch Clin Exp Ophthalmol. 2013;251:261–70.
Xu D, Liu Y, Xu H, Li H. Repeated triamcinolone acetonide injection in the treatment of upper-lid retraction in patients with thyroid-associated ophthalmopathy. Can J Ophthalmol. 2012;47:34–41.
Yakopson V, Carrasco J, Sharma P, Rabinowitz M, Stefanyszyn M. Effect of intraorbital steroid injections on intraocular pressure in thyroid eye disease. J Thyroid Disord Ther. 2015;4:173.
Chee E, Chee S. Subconjunctival injection of triamcinolone in the treatment of lid retraction of patients with thyroid eye disease: a case series. Eye. 2008;22:311–5.
Wang Y, Du B, Yang M, Zhu Y, He W. Peribulbar injection of glucocorticoids for thyroid-associated ophthalmopathy and factors affecting therapeutic effectiveness: a retrospective cohort study of 386 cases. Exp Ther Med. 2020;20:2031–8.
Razeghinejad MR, Katz LJ. Steroid-induced iatrogenic glaucoma. Ophthalmic Res. 2012;47:66–80.
Modjtahedi SP, Modjtahedi BS, Mansury AM, Selva D, Douglas RS, Goldberg RA, et al. Pharmacological treatments for thyroid eye disease. Drugs. 2006;66:1685–700.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
I. Y. Swaify, None; H. E. Nasr, None; R. A. El Essawy, None; K. B. Elessawy, None.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Corresponding Author: Islam Y. Swaify
About this article
Cite this article
Swaify, I.Y., Nasr, H.E., El Essawy, R.A. et al. Periocular methotrexate versus periocular triamcinolone injections for active thyroid-associated orbitopathy: a randomized clinical trial. Jpn J Ophthalmol 67, 699–710 (2023). https://doi.org/10.1007/s10384-023-01016-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10384-023-01016-4