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Year : 2016  |  Volume : 8  |  Issue : 1  |  Page : 1-4

Steroid-sparing medications in thyroid eye disease

1 Medical Student Research Committee, Tehran University of Medical Sciences, Tehran, Iran
2 Department of Eye, Medical Faculty of Medicine, Bu Ali-Sina Hospital, Mazandaran University of Medical Sciences, Mazandaran, Iran

Date of Web Publication17-Jun-2016

Correspondence Address:
Ahmad Ahmadzadeh-Amiri
Department of Eye, Medical Faculty of Medicine, Bu Ali-Sina Hospital, Mazandaran University of Medical Sciences, Mazandaran
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1858-540X.184241

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Thyroid eye disease (TED) is a heterogeneous autoimmune reaction typically occurring in the orbit of middle age group. The orbital inflammation of Graves' disease may parallel or remain isolated from a related inflammatory reaction in the thyroid gland. Development and severity of TED may dependent to both endogenous (genetic factors, increased age, male sex) and, or exogenous factors (smoking, thyroid dysfunction, and radioiodine treatment). Although rescue medical therapy for severe TED is often initiated with glucocorticoids, steroid-sparing medications may be an alternative area of efficient treatment.

Keywords: Graves' disease, steroid-sparing medications, thyroid eye disease

How to cite this article:
Ahmadzadeh-Amiri A, Ahmadzadeh-Amiri A. Steroid-sparing medications in thyroid eye disease. Sudanese J Ophthalmol 2016;8:1-4

How to cite this URL:
Ahmadzadeh-Amiri A, Ahmadzadeh-Amiri A. Steroid-sparing medications in thyroid eye disease. Sudanese J Ophthalmol [serial online] 2016 [cited 2023 Jun 2];8:1-4. Available from: https://www.sjopthal.net/text.asp?2016/8/1/1/184241

  Introduction Top

Lymphocytic orbital inflammation that caused by autoimmune process may lead to thyroid eye disease (TED). Although it occasionally be associated with hypothyroid or euthyroid states, it commonly noted in Graves's hyperthyroidism. The Graves's disease is more prevalent in women, with 1.9% in females and about 0.19% in males and annual incidence of 16 and 2.9 cases per 100,000 in women and men, respectively, however, severe cases occur more often in men than in women.[1] Sera of patients with Graves's disease have a powerful thyroid-stimulating factor that had a longer duration of action than that of thyrotropin, the long-acting thyroid stimulator.[2],[3],[4],[5] Antigenic cross-reactivity of orbital and thyroid tissue, lead to stimulation of proteins of the extraocular muscles and orbital fat by circulating thyroid antibodies, resulting in fibroproliferation and glycosaminoglycans production. Orbital congestion and exophthalmos, ocular dysmotility, diplopia, and rarely compressive optic neuropathy are consequent.[6] Active phase of Graves's disease, typically occurred in 6-24 months, followed by progression to plateau inactive disease. This course is often stable with rarely reactivation.

Achieving to euthyroid state is an important goal of TED treatment. Tobacco smoking is a strongest modifiable risk factors for disease progression which carries at least 7.7 time for developing TED compared to not smoking, as well as severity of active disease with up-regulates inflammatory cytokines.[6],[7],[8],[9] The mainstay of treatment for sever active TED with visual threaten or corneal exposure, is corticosteroid therapy and/or orbital decompression surgery. Investigation in the efficacy of nutritional supplements, steroid-sparing agents, orbital radiation therapy, and various surgical interventions are the new era of TED management. Rituximab as a steroid-sparing medication is a most important in this category.

The present review provides an update on steroid-sparing treatment of TED till March 2015. The literature was searched from the sources such as electronic database of PubMed, English from inception to March 2015.

  Steroid-Sparing Regimens Top

The first-line treatment of moderate to severe active TED continues to be corticosteroids. The American Society of Ophthalmic Plastic and Reconstructive Surgery showed that using and preferring oral corticosteroids over intravenous (IV) in the first choice treatment of severe TED.[10] Although corticosteroid, being well known effective treatment, harbors a significant adverse effects such as hypertension, hyperglycemia, acute liver disease, weight gain, mood instability, as well as osteoporosis.[11] As such, steroid-sparing regimens have new modality evolve with a wide target to, thyroid-stimulating hormone receptor, insulin-like growth factor-1 receptor (IGF-1R), B-cells, T-cells, and other inflammatory cytokines.[12]

Marcocci et al. were shown some antioxidant supplementation such as selenium may help patients with mild Graves' orbitopathy and selenium deficiency.[13]

According to Yoon et al. study, quercetin, a natural plant extract that found in food such as capers, may inhibitory effect on proinflammatory cytokines and has been recommended for Graves' orbitopathy.[14]

Recent research focuses on biologic factors including rituximab, adalimumab, and teprotumumab.[15]

Rituximab is an engineered chimeric mouse-human monoclonal IgG1 kappa antibody directed against the CD20 antigen. It produced by mammalian cell suspension culture in a nutrient medium containing the antibiotic gentamicin that cleared in the final product. It recognized as B-cell lymphocytes inhibitor for treatment of rheumatoid arthritis and lymphoma, approved by FDA that may also have a role in the treatment of TED.[16] Clinical randomized study comparing rituximab and methylprednisolone pulse therapy in moderate-to-severe TED revealed that 32 patients received either treatment with the primary endpoint of a decrease in the clinical activity score (CAS), and with secondary endpoints of improvements in proptosis, extraocular motility, diplopia, and quality of life as assessed by a questionnaire. At 24 weeks, all patients satisfied the primary endpoint, but 100% of patients had clinical improvement compared to only 68.7% of patients treated with steroid. Furthermore, disease reactivation occurred in five patients treated with IV steroid, whereas none reactivated with rituximab.[17] Recent review of eight patients with severe orbitopathy shown that rituximab was efficient. These patients with two infusions of rituximab 2 weeks apart had CAS score improvement and reduction in the proportion of IGF-1R CD3+ T-cells.[18]

The pivotal role of rituximab in the TED management, however, remains unclear. Gess and Silkissreport a case of rituximab treatment failure with B-cell depletion from the blood and orbital fat of a TED patient who require orbital decompression for disease progression.[19] Another, randomized, placebo-controlled trial in 21 patients with TED, compared treatment with two rituximab infusions versus two saline infusions, given 2 weeks apart, found that at 24 and 52 weeks, there was no significant difference in the improvement of the primary endpoint of CAS score or in their secondary endpoints, including lagophthalmos, exophthalmos, or diplopia in the rituximab group, fail to prove any benefit of this treatment.[20] As such, the data about rituximab remain contradictory in the management of TED.

Adalimumab is a fully human monoclonal antibody and tumor necrosis factor (TNF)-α inhibitor approved for the treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease, chronic plaque psoriasis, and polyarticular juvenile idiopathic arthritis; it has also been used for reducing inflammation in the treatment of active TED. Retrospective review of Ayabe et al. in ten patients with inflammatory-stage TED demonstrated that six patients had a decrease in their orbitopathy, eight patients were found to taper steroids while on adalimumab, and significant improvement in the CAS score in 5 individuals with the most active disease.[21]

Teprotumumab is a human monoclonal anti-IGF-1R blocking antibody, which designed for the treatment of solid and hematologic tumors and is currently also undergoing phase 2 clinical trials in patients with inflammatory-stage TED. A recent study showed that fibrocytes from patients with active TED had highly expressed TSH receptor and IGF-1R. As teprotumumab-treated fibrocytes display attenuated expression of IGF-1R and TSH receptor, implies that teprotumumab could have a rationale role in future research for therapeutic efficacy in preventing TED.[22]

Tocilizumab is a humanized antihuman interleukin (IL)-6 receptor antibody which is used to treat rheumatoid arthritis. Pérez-Moreiras et al. found in prospective study that 4 of 18 steroid-resistant patients with active TED were well-treated with weekly IV tocilizumab for four cycles. They also noted that 15 patients showing improvement of extraocular motility and 13 patients showing proptosis recovery.[23]

Studies on anti-inflammatory agents to cytokines inhibition that influence the pathogenesis of TED focuses on studies of IL-6, IL-8, TNF, and interferon-γ (IFN-γ). Tanshinone, a molecule isolated from the Chinese plant salvia miltiorrhiza, carried anti-inflammatory and antioxidative properties. Tanshinone IIA is available in the form of purified sulfonate salts can reduce expression of IL-6 and IL-8 in orbital fibroblasts, amount of reactive oxygen species, and degree of adipogenesis on orbital tissue obtained from orbital decompression surgeries from patients with TED.[24]

Active TED associated with elevation of IFN-γ, a potent cytokine that can induce the secretion of proteins such as the alpha chemokine IFN-γ-induced protein (IP-10). Levels of IP-10 are reduced after treatment with steroids and radiation in inflammatory TED cause IP-10 level reduction.[25] Lee et al. study revealed that benzylidene acetophenone derivatives can decrease IPs, such as IP-10, in orbital fibroblasts of TED.[26]

Octreotide, a synthetic somatostatin analog, is thought a beneficial effect on some cases of TED. Lanreotide is a longer-acting somatostatin analog, has a good response. Pentoxifylline and nicotinamide thought to inhibit cytokine-induced glycosaminoglycan synthesis in retro-orbital fibroblasts may also be useful. Plasmapheresis and IV immunoglobulin in treatment of active TED is not well specified. Kahaly et al. explored randomized trial of IV immunoglobulin versus oral prednisolone, both treatments had equal effect in management of active TED.[27]

  Conclusion Top

TED is a devastating condition that troubles for both patients and its providers. Abundance of present report in this review illustrates efforts for treatment of TED continues by clinicians and scientists. However, the majority had limited due to weaknesses in several item including Relatively low case numbers, absence of proper controls, disparate method, and distinct grading designs. Spontaneous recovery of inflammation over time as a natural history of TED is another confounding factor that is difficult to control in studies. Nevertheless, there have been some actual improvements with expansion of steroid-sparing agents in a number of patients who have failed corticosteroid treatment.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Bartley GB, Fatourechi V, Kadrmas EF, Jacobsen SJ, Ilstrup DM, Garrity JA, et al. The incidence of Graves' ophthalmopathy in Olmsted County, Minnesota. Am J Ophthalmol 1995;120:511-7.  Back to cited text no. 1
Mcgiven AR, Adams DD, Purves HD. A comparison of the heat stability of long-acting thyroid stimulator and human thyroid-stimulating hormone. J Endocrinol 1965;32:29-33.  Back to cited text no. 2
Adams DD, Kennedy TH, Purves HD, Siret NE. Failure of TSH antisera to neutralize long-acting thyroid stimulator. Endocrinology 1962;70:801-5.  Back to cited text no. 3
Adams DD. The presence of an abnormal thyroid-stimulating hormone in the serum of some thyrotoxic patients. J Clin Endocrinol Metab 1958;18:699-712.  Back to cited text no. 4
Adams DD. The pathogenesis of thyrotoxicosis the discovery of LATS. N Z Med J 1975;81:15-7.  Back to cited text no. 5
Prummel MF, Wiersinga WM. Smoking and risk of Graves' disease. JAMA 1993;269:479-82.  Back to cited text no. 6
Bartalena L, Pinchera A, Marcocci C. Management of Graves' ophthalmopathy: Reality and perspectives. Endocr Rev 2000;21:168-99.  Back to cited text no. 7
Planck T, Shahida B, Parikh H, Ström K, Åsman P, Brorson H, et al. Smoking induces overexpression of immediate early genes in active Graves' ophthalmopathy. Thyroid 2014;24:1524-32.  Back to cited text no. 8
Kahaly GJ, Pitz S, Hommel G, Dittmar M. Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves' orbitopathy. J Clin Endocrinol Metab 2005;90:5234-40.  Back to cited text no. 9
Perumal B, Meyer DR. Treatment of severe thyroid eye disease: A survey of the American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS). Ophthal Plast Reconstr Surg 2015;31:127-31.  Back to cited text no. 10
Sisti E, Coco B, Menconi F, Leo M, Rocchi R, Latrofa F, et al. Intravenous glucocorticoid therapy for Graves' ophthalmopathy and acute liver damage: An epidemiological study. Eur J Endocrinol 2015;172:269-76.  Back to cited text no. 11
Salvi M. Immunotherapy for Graves' ophthalmopathy. Curr Opin Endocrinol Diabetes Obes 2014;21:409-14.  Back to cited text no. 12
Marcocci C, Kahaly GJ, Krassas GE, Bartalena L, Prummel M, Stahl M, et al. Selenium and the course of mild Graves' orbitopathy. N Engl J Med 2011;364:1920-31.  Back to cited text no. 13
Yoon JS, Chae MK, Jang SY, Lee SY, Lee EJ. Antifibrotic effects of quercetin in primary orbital fibroblasts and orbital fat tissue cultures of Graves' orbitopathy. Invest Ophthalmol Vis Sci 2012;53:5921-9.  Back to cited text no. 14
Bartalena L. Commentary: Rituximab, adalimumab, etanercept, tocilizumab — Are biologics the future for Graves' orbitopathy? Ophthal Plast Reconstr Surg 2014;30:420-3.  Back to cited text no. 15
Khanna D, Chong KK, Afifiyan NF, Hwang CJ, Lee DK, Garneau HC, et al. Rituximab treatment of patients with severe, corticosteroid-resistant thyroid-associated ophthalmopathy. Ophthalmology 2010;117:133-9.e2.  Back to cited text no. 16
Salvi M, Vannucchi G, Currò N, Campi I, Covelli D, Dazzi D, et al. 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;100:422-31.  Back to cited text no. 17
McCoy AN, Kim DS, Gillespie EF, Atkins SJ, Smith TJ, Douglas RS. Rituximab (Rituxan) therapy for severe thyroid-associated ophthalmopathy diminishes IGF-1R(+) T cells. J Clin Endocrinol Metab 2014;99:E1294-9.  Back to cited text no. 18
Gess AJ, Silkiss RZ. Orbital B-lymphocyte depletion in a treatment failure of rituximab for thyroid eye disease. Ophthal Plast Reconstr Surg 2014;30:e11-3.  Back to cited text no. 19
Stan MN, Garrity JA, Carranza Leon BG, Prabin T, Bradley EA, Bahn RS. Randomized controlled trial of rituximab in patients with Graves' orbitopathy. J Clin Endocrinol Metab 2015;100:432-41.  Back to cited text no. 20
Ayabe R, Rootman DB, Hwang CJ, Ben-Artzi A, Goldberg R. Adalimumab as steroid-sparing treatment of inflammatory-stage thyroid eye disease. Ophthal Plast Reconstr Surg 2014;30:415-9.  Back to cited text no. 21
Chen H, Mester T, Raychaudhuri N, Kauh CY, Gupta S, Smith TJ, et al. Teprotumumab, an IGF-1R blocking monoclonal antibody inhibits TSH and IGF-1 action in fibrocytes. J Clin Endocrinol Metab 2014;99:E1635-40.  Back to cited text no. 22
Pérez-Moreiras JV, Alvarez-López A, Gómez EC. Treatment of active corticosteroid-resistant Graves' orbitopathy. Ophthal Plast Reconstr Surg 2014;30:162-7.  Back to cited text no. 23
Rhiu S, Chae MK, Lee EJ, Lee JB, Yoon JS. Effect of tanshinone IIA in an in vitro model of Graves' orbitopathy. Invest Ophthalmol Vis Sci 2014;55:5900-10.  Back to cited text no. 24
Mancusi C, Di Domenicantonio A, Politti U, Giuggioli D, Antonelli A, Ferri C, et al. The alpha chemokine “Interferon gamma-induced protein 10” (IP-10) in Graves' disease. Clin Ter 2014;165:e174-80.  Back to cited text no. 25
Lee SH, Lim SY, Choi JH, Jung JC, Oh S, Kook KH, et al. Benzylideneacetophenone derivatives attenuate IFN-γ-induced IP-10/CXCL10 production in orbital fibroblasts of patients with thyroid-associated ophthalmopathy through STAT-1 inhibition. Exp Mol Med 2014;46:e100.  Back to cited text no. 26
Kahaly G, Pitz S, Müller-Forell W, Hommel G. Randomized trial of intravenous immunoglobulins versus prednisolone in Graves' ophthalmopathy. Clin Exp Immunol 1996;106:197-202.  Back to cited text no. 27

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