Immunohistochemical analysis of human orbital tissue in Graves’ orbitopathy

Hai, Yuanping; Lee, A C H; Frommer, Lara; Diana, Tanja; Kahaly, George J.

doi:10.1007/s40618-019-01116-4

Cited by 38 publications

(52 citation statements)

References 57 publications

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“…Rationale and Mechanisms of Action. Apart from peripheral B cell depletion, complete (or near complete) intraorbital depletion of both B and T cells after RTX therapy has been confirmed in multiple reports [36]. Since the Eur Thyroid J 2020;9(suppl 1):17-30 DOI: 10.1159/000508789 clinical improvement of GO after RTX is not consistently correlated with the reduction in serum TSH-R-Ab, the efficacy of RTX is probably explained by elimination of other B cell functions beside autoantibody production (e.g., cytokine production, antigen presentation, B-T cell costimulation, etc.)…”

Section: Rituximabmentioning

confidence: 79%

“…Orbital fibroblasts not only proliferate and differentiate into myofibroblasts and adipocytes (de novo adipogenesis), but also produce excessive hydrophilic glycosaminoglycans. The resultant expansion of orbital tissue volume and elevated intraorbital pressure have mechanical consequences which explain the typical signs and symptoms of GO [36]. Intravenous GCs (IVGCs) are a disease modifier and the mainstay of treatment for active moderate-to-severe and/or sight-threatening GO (dysthyroid optic neuropathy [DON]) [2].…”

Section: Go: Limitations Of Current Therapymentioning

confidence: 99%

“…A subsequent joint post hoc analysis suggested that several differences in baseline characteristics (younger age, lower TSH-R-Ab, shorter duration of GO) may explain the favorable treatment outcomes in the Italian trial [63]. In fact, B cell infiltration was absent in some immunohistochemically analyzed GO orbital tissues [36], and this might explain why some patients failed to respond to RTX. A recent French retrospective series also found limited efficacy of RTX in steroid-refractory active moderate-to-severe GO with long disease duration (median 26 months) [64].…”

Section: Rituximabmentioning

confidence: 99%

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Novel Approaches for Immunosuppression in Graves’ Hyperthyroidism and Associated Orbitopathy

Lee¹,

Kahaly²

2020

Eur Thyroid J

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Background: Both Graves’ hyperthyroidism (GH) and Graves’ orbitopathy (GO) are associated with significant adverse health consequences. All conventional treatment options have limitations regarding efficacy and safety. Most importantly, they do not specifically address the underlying immunological mechanisms. We aim to review the latest development of treatment approaches in these two closely related disorders. Summary: Immunotherapies of GH have recently demonstrated clinical efficacy in preliminary studies. They include ATX-GD-59, an antigen-specific immunotherapy which restores immune tolerance to the thyrotropin receptor; iscalimab, an anti-CD40 monoclonal antibody which blocks the CD40-CD154 costimulatory pathway in B-T cell interaction; and K1-70, a thyrotropin receptor-blocking monoclonal antibody. Novel treatment strategies have also become available in GO. Mycophenolate significantly increased the overall response rate combined with standard glucocorticoid (GC) treatment compared to GC monotherapy. Tocilizumab, an anti-interleukin 6 receptor monoclonal antibody, displayed strong anti-inflammatory action in GC-resistant cases. Teprotumumab, an anti-insulin-like growth factor 1 receptor monoclonal antibody, resulted in remarkable improvement in terms of disease activity, proptosis, and diplopia. Further, rituximab appears to be useful in active disease of recent onset without impending dysthyroid optic neuropathy. Key Messages: Therapeutic advances will continue to optimize our management of GH and associated orbitopathy in an effective and safe manner.

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Section: Rituximabmentioning

confidence: 79%

Section: Go: Limitations Of Current Therapymentioning

confidence: 99%

Section: Rituximabmentioning

confidence: 99%

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Novel Approaches for Immunosuppression in Graves’ Hyperthyroidism and Associated Orbitopathy

Lee¹,

Kahaly²

2020

Eur Thyroid J

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“…Since HLA-DR and TSHR are overexpressed in orbital tissues of GO patients, immunomodulation targeting HLA-DR is also considered as a feasible approach to tackle GO [79], which can be achieved by peptides derived from TSHR [58].…”

Section: Discussionmentioning

confidence: 99%

Modulating TSH Receptor Signaling for Therapeutic Benefit

Krause¹,

Eckstein²,

Schülein³

2020

Eur Thyroid J

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Autoimmune thyroid-stimulating antibodies are activating the thyrotropin receptor (TSHR) in both the thyroid and the eye, but different molecular mechanisms are induced in both organs, leading to Graves’ disease (GD) and Graves’ orbitopathy (GO), respectively. Therapy with anti-thyroid drugs to reduce hyperthyroidism (GD) by suppressing the biosynthesis of thyroid hormones has only an indirect effect on GO, since it does not causally address pathogenic TSHR activation itself. GO is thus very difficult to treat. The activated TSHR but also the cross-interacting insulin-like growth factor 1 receptor (IGF-1R) contribute to this issue. The TSHR is a heptahelical G-protein-coupled receptor, whereas the IGF-1R is a receptor tyrosine kinase. Despite these fundamental structural differences, both receptors are phosphorylated by G-protein receptor kinases, which enables β-arrestin binding. Arrestins mediate receptor internalization and also activate the mitogen-activated protein kinase pathway. Moreover, emerging results suggest that arrestin plays a critical role in the cross-interaction of the TSHR and the IGF-1R either in their common signaling pathway and/or during an indirect or potential TSHR/IGF-1R interaction. In this review, novel pharmacological strategies with allosteric small-molecule modulators to treat GO and GD on the level of the TSHR and/or the TSHR/IGF-1R cross-interaction will be discussed. Moreover, monoclonal antibody approaches targeting the TSHR or the IGF-1R and thereby preventing activation of either receptor will be presented. Another chapter addresses the immunomodulation to treat GO using TSHR-derived peptides targeting the human leukocyte antigen DR isotope (HLA-DR), which is a feasible approach to tackle GO, since HLA-DR and TSHR are overexpressed in orbital tissues of GO patients.

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“…[4][5][6] The pathological Therapeutic Advances in Endocrinology and Metabolism 11 2 journals.sagepub.com/home/tae processes within the orbit include inflammatory infiltration of retro-ocular tissues within the orbit, de novo adipogenesis, and increased production of hydrophilic glycosaminoglycans (GAG) by orbital fibroblasts. 7 These fibroblasts play a key role in the pathogenesis of GO. They proliferate and differentiate into myofibroblasts and adipocytes and produce excessive hydrophilic GAG, which lead to tissue edema.…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoids in Graves’ orbitopathy: mechanisms of action and clinical application

Längericht

Krämer

Kahaly

2020

Therapeutic Advances in Endocrinology

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Background: Graves’ orbitopathy (GO) is the most frequent extrathyroidal manifestation of the autoimmune Graves’ disease. GO significantly impacts quality of life and has a psycho-social morbidity. Inflammation and swelling of the orbital tissue often leads to proptosis, diplopia, and decrease of visual acuity. Due to the inflammatory background of the disease, glucocorticoids (GC) have been used as a first-line treatment for decades. Methods: PubMed and MeSH database were searched for original articles, clinical trials, reviews, and meta-analyses published between 1 January 2000 and 31 March 2020 and pertaining to both the mechanism of action and immunological effects of GC as well as to the treatment of GO by GC. The publications were evaluated according to their setting and study design. Results: GC act through genomic (trans-activation and trans-repression) and rapid non-genomic mechanisms. GC in general, and the intravenous (IV) administration of GC in particular, markedly decrease the activity and number of the most potent antigen-presenting dendritic cells. According to the internationally acknowledged European Thyroid Association Guidelines for the management of GO, weekly IVGC application over 12 weeks is recommended as first-line treatment for patients with active and severe GO. The daily and cumulative dose should be tailored according to clinical severity, for example, 4.5 g of IV methylprednisolone for the inflammatory component versus 7.5 g in the presence of diplopia and severe proptosis. Fast and significant improvements in orbital symptoms and signs are noted in 65–70% of patients. Long-term experience over decades, and worldwide availability at low cost, underline the clinical and therapeutic relevance of GC. Adverse events are rarely severe, dose-dependent, and usually reversible, hence easy to handle by medical investigators. Oral GC application on a daily basis is characterized by high bioavailability but reduced efficacy and increased toxicity. Conclusion: IVGC still represents the standard of care in active/severe GO. Innovative biologicals, like monoclonal antibodies targeting the thyrotropin/Insulin-like growth factor-1 receptors or pro-inflammatory cytokines (e.g., Interleukin-6) should be compared with standard GC treatment with respect to short- and long-term efficacy, safety, costs, and global availability.

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Immunohistochemical analysis of human orbital tissue in Graves’ orbitopathy

Cited by 38 publications

References 57 publications

Novel Approaches for Immunosuppression in Graves’ Hyperthyroidism and Associated Orbitopathy

Novel Approaches for Immunosuppression in Graves’ Hyperthyroidism and Associated Orbitopathy

Modulating TSH Receptor Signaling for Therapeutic Benefit

Glucocorticoids in Graves’ orbitopathy: mechanisms of action and clinical application

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