Skip to main content

Advertisement

SpringerLink
Log in

2021 update on thyroid-associated ophthalmopathy

  • Review
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Purpose

Our understanding of thyroid-associated ophthalmopathy (TAO, A.K.A Graves’ orbitopathy, thyroid eye disease) has advanced substantially, since one of us (TJS) wrote the 2010 update on TAO, appearing in this journal.

Methods

PubMed was searched for relevant articles.

Results

Recent insights have resulted from important studies conducted by many different laboratory groups around the World. A clearer understanding of autoimmune diseases in general and TAO specifically emerged from the use of improved research methodologies. Several key concepts have matured over the past decade. Among them, those arising from the refinement of mouse models of TAO, early stage investigation into restoring immune tolerance in Graves’ disease, and a hard-won acknowledgement that the insulin-like growth factor-I receptor (IGF-IR) might play a critical role in the development of TAO, stand out as important. The therapeutic inhibition of IGF-IR has blossomed into an effective and safe medical treatment. Teprotumumab, a β-arrestin biased agonist monoclonal antibody inhibitor of IGF-IR has been studied in two multicenter, double-masked, placebo-controlled clinical trials demonstrated both effectiveness and a promising safety profile in moderate-to-severe, active TAO. Those studies led to the approval by the US FDA of teprotumumab, currently marketed as Tepezza for TAO. We have also learned far more about the putative role that CD34+ fibrocytes and their derivatives, CD34+ orbital fibroblasts, play in TAO.

Conclusion

The past decade has been filled with substantial scientific advances that should provide the necessary springboard for continually accelerating discovery over the next 10 years and beyond.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Availability of data and materials

Not applicable.

Code availability

Not applicable.

Abbreviations

Ad-TSHR A:

Adenovirus expressing the extracellular A-subunit of the human TSH receptor (TSHR)

AE:

Adverse event

AIRE:

Thymic autoimmune regulator

AKT:

Protein kinase B

AP-1:

Activator protein-1

ARID5B:

AT-rich interaction domain 5B

BAFF:

B-cell activating factor

CAAR-T cells:

Chimeric autoantibody receptor expressing T cells

cAMP:

Cyclic adenosine monophosphate

CAS:

Clinical activity score

CFZ533:

Iscalimab

CHO:

Chinese hamster ovary cell

CTLA4:

Cytotoxic T-lymphocyte-associated protein 4

COX-2:

Cyclooxygenase-2

CYR61:

Cysteine-rich angiogenic inducer 61

Dsg3:

Desmoglein-3

EGR-1:

Early growth response protein-1

ERK:

Extracellular signal-regulated kinases

ETA:

European Thyroid Association

GcgR:

Fc gamma receptor

FcgRI:

High affinity immunoglobulin gamma Fc receptor I

FcgRIIa:

Low affinity immunoglobulin gamma Fc region receptor II-a

FcRn:

Neonatal Fc receptor

FRAP:

FK506-binding protein 12-rapamycin-associated protein-1

FT3 :

Free triiodothyronine

FT4 :

Free thyroxine

GD-IgG:

Graves’ disease immunoglobulins

GD-OF:

Graves’ disease orbital fibroblasts

GO:

Graves’ orbitopathy

GO-QOL:

Graves’ ophthalmopathy quality-of-life scale

GR:

Glucocorticoid receptor

HAS1:

Hyaluronan synthase 1

HAS2:

Hyaluronan synthase 2

HLA-DRβ-Arg74:

Human leukocyte antigen-DR isotype-variant containing Arginine at position 74

HMG-CoA:

3-Hydroxy-3-methylglutaryl coenzyme

IFN-γ:

Interferon gamma

IGF-I:

Insulin-like growth factor 1

IGF-II:

Insulin-like growth factor 2

IGF-1R:

Insulin-like growth factor 1 receptor

IgG-k:

Immunoglobulin G kappa light chain

LRR:

Leucine-rich repeat

MHC class I:

Major histocompatibility complex I

MHC class II:

Major histocompatibility complex II

MMF:

Mycophenolate motefil

MPA:

Mycophenolic acid

NF-κB:

Nuclear factor-κB

NIS:

Sodium iodide symporter

OD:

Oculus dexter

OF:

Orbital fibroblast

OS:

Oculus sinister

p70s6K :

Ribosomal protein S6 kinase beta-1

PDK1:

Pyruvate dehydrogenase kinase 1

PGE2 :

Prostaglandin E2

PGHS-2:

Prostaglandin endoperoxide H synthase 2

PI3K/AKT/mTOR:

Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR)

PKC:

Protein kinase C

PKCβII:

Protein kinase C beta type 2

PMBC:

Peripheral blood mononuclear cell

PPARγ:

Peroxisome proliferator-activated receptor gamma

PTPN22:

Protein tyrosine phosphatase, non-receptor type 22

PTX-3:

Pentraxin-3

qRT-PCR:

Real-time quantitative reverse transcription PCR

RA:

Rheumatoid arthritis

RANTES:

Regulated upon activation, normal T-cell expressed and presumably secreted

RTX:

Rituximab

ROBO1:

Roundabout 1

rhSlit2:

Recombinant human slit homolog 2 protein

SAP:

Serum amyloid P

sFRP-1:

Secreted frizzled-related protein-1

SGK-1:

Serine/threonine-protein kinase Sgk1

sIL-1RA:

Secreted IL-1 receptor antagonist

SLE:

Systemic lupus erythematosus

Slit2:

Slit homolog 2 protein

SNP:

Single-nucleotide polymorphisms

STAT-3:

Signal transducer and activator of transcription 3

TAO:

Thyroid-associated ophthalmopathy

TCZ:

Tocilizumab

Tg:

Thyroglobulin

TNFα:

Tumor necrosis factor

TPO:

Thyroid peroxidase

Trab:

Thyrotropin receptor antibody

TRAFS:

TNFα receptor-associated factors

Treg:

T regulatory cells

TSH‐β:

Thyroid stimulating hormone beta protein

TSHR:

Thyrotropin receptor

TSI:

Thyroid stimulating immunoglobulin

UGDH:

UDP-glucose dehydrogenase

Wnt:

Wingless/integrated

1H7:

Murine monoclonal anti-IGF-IR inhibitory antibody

486/STOP:

Dominant-negative mutant IGF-IR

References

  1. Smith TJ, Hegedüs L (2016) Graves’ disease. N Engl J Med 375(16):1552–1565. https://doi.org/10.1056/NEJMra1510030 (PMID: 27797318)

    Article  PubMed  Google Scholar 

  2. Tellez M, Cooper J, Edmonds C (1992) Graves’ ophthalmopathy in relation to cigarette smoking and ethnic origin. Clin Endocrinol (Oxf) 36(3):291–294. https://doi.org/10.1111/j.1365-2265.1992.tb01445.x (PMID: 1563082)

    Article  CAS  Google Scholar 

  3. Khalilzadeh O, Noshad S, Rashidi A, Amirzargar A (2011) Graves’ ophthalmopathy: a review of immunogenetics. Curr Genomics 12(8):564–575. https://doi.org/10.2174/138920211798120844.PMID:22654556;PMCID:PMC3271309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Villanueva R, Greenberg DA, Davies TF, Tomer Y (2003) Sibling recurrence risk in autoimmune thyroid disease. Thyroid 13(8):761–764. https://doi.org/10.1089/105072503768499653 (PMID: 14558919)

    Article  CAS  PubMed  Google Scholar 

  5. Thomsen H, Li X, Sundquist K, Sundquist J, Försti A, Hemminki K (2020) Familial risks between Graves disease and Hashimoto thyroiditis and other autoimmune diseases in the population of Sweden. J Transl Autoimmun 1(3):100058. https://doi.org/10.1016/j.jtauto.2020.100058 (PMID:32743538;PMCID:PMC7388361)

    Article  Google Scholar 

  6. Ferrari SM, Fallahi P, Ruffilli I, Elia G, Ragusa F, Benvenga S, Antonelli A (2019) The association of other autoimmune diseases in patients with Graves’ disease (with or without ophthalmopathy): review of the literature and report of a large series. Autoimmun Rev 18(3):287–292. https://doi.org/10.1016/j.autrev.2018.10.001 (Epub 2019 11 PMID: 30639646)

    Article  PubMed  Google Scholar 

  7. Hemminki K, Li X, Sundquist J, Sundquist K (2010) The epidemiology of Graves’ disease: evidence of a genetic and an environmental contribution. J Autoimmun 34(3):J307–J313. https://doi.org/10.1016/j.jaut.2009.11.019 (Epub 2009 28 PMID: 20056533)

    Article  CAS  PubMed  Google Scholar 

  8. Tomer Y (2014) Mechanisms of autoimmune thyroid diseases: from genetics to epigenetics. Annu Rev Pathol 9:147–156. https://doi.org/10.1146/annurev-pathol-012513-104713 (PMID:24460189;PMCID:PMC4128637)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Liu YH, Chen RH, Wu HH, Liao WL, Chen WC, Tsai Y, Tsai CH, Wan L, Tsai FJ (2010) Association of interleukin-1beta (IL1B) polymorphisms with Graves’ ophthalmopathy in Taiwan Chinese patients. Invest Ophthalmol Vis Sci 51(12):6238–6246. https://doi.org/10.1167/iovs.09-4965 (Epub 2010 29 PMID: 20671275)

    Article  PubMed  Google Scholar 

  10. Liu YH, Chen CC, Liao LL, Wan L, Tsai CH, Tsai FJ (2012) Association of IL12B polymorphisms with susceptibility to Graves ophthalmopathy in a Taiwan Chinese population. J Biomed Sci 19(1):97. https://doi.org/10.1186/1423-0127-19-97 (PMID: 23164360; PMCID: PMC3514134)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Huber AK, Jacobson EM, Jazdzewski K, Concepcion ES, Tomer Y (2008) Interleukin (IL)-23 receptor is a major susceptibility gene for Graves’ ophthalmopathy: the IL-23/T-helper 17 axis extends to thyroid autoimmunity. J Clin Endocrinol Metab 93(3):1077–1081. https://doi.org/10.1210/jc.2007-2190 (PMID: 18073300; PMCID: PMC2266952)

    Article  CAS  PubMed  Google Scholar 

  12. Yin X, Latif R, Bahn R, Davies TF (2012) Genetic profiling in Graves’ disease: further evidence for lack of a distinct genetic contribution to Graves’ ophthalmopathy. Thyroid 22(7):730–736. https://doi.org/10.1089/thy.2012.0007 (PMID: 22663548; PMCID: PMC3387758)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kumar S, Leontovich A, Coenen MJ, Bahn RS (2005) Gene expression profiling of orbital adipose tissue from patients with Graves’ ophthalmopathy: a potential role for secreted frizzled-related protein-1 in orbital adipogenesis. J Clin Endocrinol Metab 90(8):4730–4735. https://doi.org/10.1210/jc.2004-2239 (PMID: 15886250; PMCID: PMC1236982)

    Article  CAS  PubMed  Google Scholar 

  14. Lantz M, Vondrichova T, Parikh H, Frenander C, Ridderstråle M, Asman P, Aberg M, Groop L, Hallengren B (2005) Overexpression of immediate early genes in active Graves’ ophthalmopathy. J Clin Endocrinol Metab 90(8):4784–4791. https://doi.org/10.1210/jc.2004-2275 (PMID: 15928252)

    Article  CAS  PubMed  Google Scholar 

  15. Ezra DG, Krell J, Rose GE, Bailly M, Stebbing J, Castellano L (2012) Transcriptome-level microarray expression profiling implicates IGF-1 and Wnt signalling dysregulation in the pathogenesis of thyroid-associated orbitopathy. J Clin Pathol 65(7):608–613. https://doi.org/10.1136/jclinpath-2012-200719 (PMID: 22554965)

    Article  CAS  PubMed  Google Scholar 

  16. Rosenbaum JT, Choi D, Wong A, Wilson DJ, Grossniklaus HE, Harrington CA, Dailey RA, Ng JD, Steele EA, Czyz CN, Foster JA, Tse D, Alabiad C, Dubovy S, Parekh PK, Harris GJ, Kazim M, Patel PJ, White VA, Dolman PJ, Edward DP, Alkatan HM, Al Hussain H, Selva D, Yeatts RP, Korn BS, Kikkawa DO, Stauffer P, Planck SR (2015) The role of the immune response in the pathogenesis of thyroid eye disease: a reassessment. PLoS ONE 10(9):e0137654. https://doi.org/10.1371/journal.pone.0137654 (PMID: 26371757; PMCID: PMC4570801)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Limbach M, Saare M, Tserel L, Kisand K, Eglit T, Sauer S, Axelsson T, Syvänen AC, Metspalu A, Milani L, Peterson P (2016) Epigenetic profiling in CD4+ and CD8+ T cells from Graves’ disease patients reveals changes in genes associated with T cell receptor signaling. J Autoimmun 67:46–56. https://doi.org/10.1016/j.jaut.2015.09.006 (Epub 2015 PMID: 26459776)

    Article  CAS  PubMed  Google Scholar 

  18. Rotondo Dottore G, Bucci I, Lanzolla G, Dallan I, Sframeli A, Torregrossa L, Casini G, Basolo F, Figus M, Nardi M, Marcocci C, Marinò M (2021) Genetic profiling of orbital fibroblasts from patients with Graves’ orbitopathy. J Clin Endocrinol Metab 106(5):e2176–e2190. https://doi.org/10.1210/clinem/dgab035 (PMID: 33484567)

    Article  PubMed  Google Scholar 

  19. Saito Y, Saito H, Liang G, Friedman JM (2014) Epigenetic alterations and microRNA misexpression in cancer and autoimmune diseases: a critical review. Clin Rev Allergy Immunol 47(2):128–135. https://doi.org/10.1007/s12016-013-8401-z (PMID:24362548;PMCID:PMC4651002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hedrich CM, Tsokos GC (2011) Epigenetic mechanisms in systemic lupus erythematosus and other autoimmune diseases. Trends Mol Med 17(12):714–724. https://doi.org/10.1016/j.molmed.2011.07.005 (Epub 2011 PMID: 21885342; PMCID: PMC3225699)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Li K, Du Y, Jiang BL, He JF (2014) Increased microRNA-155 and decreased microRNA-146a may promote ocular inflammation and proliferation in Graves’ ophthalmopathy. Med Sci Monit 18(20):639–643. https://doi.org/10.12659/MSM.890686 (PMID:24743332;PMCID:PMC3999163)

    Article  Google Scholar 

  22. Hammond CL, Roztocil E, Gonzalez MO, Feldon SE, Woeller CF (2021) MicroRNA-130a is elevated in thyroid eye disease and increases lipid accumulation in fibroblasts through the suppression of AMPK. Invest Ophthalmol Vis Sci 62(1):29. https://doi.org/10.1167/iovs.62.1.29 (PMID: 33507228; PMCID: PMC7846950)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Liu W, Ma C, Li HY, Chen L, Yuan SS, Li KJ (2020) MicroRNA-146a downregulates the production of hyaluronic acid and collagen I in Graves’ ophthalmopathy orbital fibroblasts. Exp Ther Med 20(5):38. https://doi.org/10.3892/etm.2020.9165 (Epub 2020PMID: 32952629; PMCID: PMC7480141)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jang SY, Chae MK, Lee JH, Lee EJ, Yoon JS (2019) MicroRNA-27 inhibits adipogenic differentiation in orbital fibroblasts from patients with Graves’ orbitopathy. PLoS ONE 14(8):e0221077. https://doi.org/10.1371/journal.pone.0221077 (PMID: 31415657; PMCID: PMC6695164)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Smith TJ, Bahn RS, Gorman CA (1989) Connective tissue, glycosaminoglycans, and diseases of the thyroid. Endocr Rev 10(3):366–391. https://doi.org/10.1210/edrv-10-3-366 (PMID: 2673756)

    Article  CAS  PubMed  Google Scholar 

  26. Wang Y, Smith TJ (2014) Current concepts in the molecular pathogenesis of thyroid-associated ophthalmopathy. Invest Ophthalmol Vis Sci 55(3):1735–1748. https://doi.org/10.1167/iovs.14-14002 (PMID: 24651704; PMCID: PMC3968932)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Li B, Smith TJ (2014) Regulation of IL-1 receptor antagonist by TSH in fibrocytes and orbital fibroblasts. J Clin Endocrinol Metab 99(4):E625–E633. https://doi.org/10.1210/jc.2013-3977 (Epub 2014 PMID: 24446657; PMCID: PMC3973776)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Li B, Smith TJ (2013) Divergent expression of IL-1 receptor antagonists in CD34+ fibrocytes and orbital fibroblasts in thyroid-associated ophthalmopathy: contribution of fibrocytes to orbital inflammation. J Clin Endocrinol Metab 98(7):2783–2790. https://doi.org/10.1210/jc.2013-1245 (PMID: 23633206; PMCID: PMC3701275)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang HS, Cao HJ, Winn VD, Rezanka LJ, Frobert Y, Evans CH, Sciaky D, Young DA, Smith TJ (1996) Leukoregulin induction of prostaglandin-endoperoxide H synthase-2 in human orbital fibroblasts. An in vitro model for connective tissue inflammation. J Biol Chem 271(37):22718–22728 (PMID: 8798446)

    Article  CAS  Google Scholar 

  30. Hwang CJ, Afifiyan N, Sand D, Naik V, Said J, Pollock SJ, Chen B, Phipps RP, Goldberg RA, Smith TJ, Douglas RS (2009) Orbital fibroblasts from patients with thyroid-associated ophthalmopathy overexpress CD40: CD154 hyperinduces IL-6, IL-8, and MCP-1. Invest Ophthalmol Vis Sci 50:2262–2268

    Article  Google Scholar 

  31. Koumas L, Smith TJ, Feldon S, Blumberg N, Phipps RP (2003) Thy-1 expression in human fibroblast subsets defines myofibroblastic or lipofibroblastic phenotypes. Am J Pathol 163(4):1291–1300. https://doi.org/10.1016/S0002-9440(10)63488-8.PMID:14507638;PMCID:PMC1868289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Smith TJ (2002) Orbital fibroblasts exhibit a novel pattern of responses to proinflammatory cytokines: potential basis for the pathogenesis of thyroid-associated ophthalmopathy. Thyroid 12(3):197–203. https://doi.org/10.1089/105072502753600133 (PMID: 11952039)

    Article  CAS  PubMed  Google Scholar 

  33. Douglas RS, Afifiyan NF, Hwang CJ, Chong K, Haider U, Richards P, Gianoukakis AG, Smith TJ (2010) Increased generation of fibrocytes in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 95(1):430–438. https://doi.org/10.1210/jc.2009-1614 (PMID: 19897675; PMCID: PMC2805489)

    Article  CAS  PubMed  Google Scholar 

  34. Niedermeier M, Reich B, Rodriguez Gomez M, Denzel A, Schmidbauer K, Göbel N, Talke Y, Schweda F, Mack M (2009) CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes. Proc Natl Acad Sci USA 106(42):17892–17897. https://doi.org/10.1073/pnas.0906070106 (PMID: 19815530; PMCID: PMC2764893)

    Article  PubMed  PubMed Central  Google Scholar 

  35. Chesney J, Bacher M, Bender A, Bucala R (1997) The peripheral blood fibrocyte is a potent antigen-presenting cell capable of priming naive T cells in situ. Proc Natl Acad Sci USA 94(12):6307–6312. https://doi.org/10.1073/pnas.94.12.6307 ( PMID: 9177213; PMCID: PMC21045)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Balmelli C, Ruggli N, McCullough K, Summerfield A (2005) Fibrocytes are potent stimulators of anti-virus cytotoxic T cells. J Leukoc Biol 77(6):923–933. https://doi.org/10.1189/jlb.1204701 (Epub 2005 14 PMID: 15767291)

    Article  CAS  PubMed  Google Scholar 

  37. Fernando R, Atkins S, Raychaudhuri N, Lu Y, Li B, Douglas RS, Smith TJ (2012) Human fibrocytes coexpress thyroglobulin and thyrotropin receptor. Proc Natl Acad Sci U S A 109(19):7427–7432. https://doi.org/10.1073/pnas.1202064109 (PMID:22517745;PMCID:PMC3358913)

    Article  PubMed  PubMed Central  Google Scholar 

  38. Fernando R, Lu Y, Atkins SJ, Mester T, Branham K, Smith TJ (2014) Expression of thyrotropin receptor, thyroglobulin, sodium-iodide symporter, and thyroperoxidase by fibrocytes depends on AIRE. J Clin Endocrinol Metab 99(7):E1236–E1244. https://doi.org/10.1210/jc.2013-4271 (PMID:24708100;PMCID:PMC4079309)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lu Y, Atkins SJ, Fernando R, Trierweiler A, Mester T, Grisolia ABD, Mou P, Novaes P, Smith TJ (2018) CD34- Orbital Fibroblasts From Patients With Thyroid-Associated Ophthalmopathy Modulate TNF-α Expression in CD34+ Fibroblasts and Fibrocytes. Invest Ophthalmol Vis Sci 59(6):2615–2622. https://doi.org/10.1167/iovs.18-23951 (PMID:29847668;PMCID:PMC5968835)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Raychaudhuri N, Fernando R, Smith TJ (2013) Thyrotropin regulates IL-6 expression in CD34+ fibrocytes: clear delineation of its cAMP-independent actions. PLoS ONE 8(9):e75100. https://doi.org/10.1371/journal.pone.0075100 (PMID:24086448;PMCID:PMC3783445)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gillespie EF, Papageorgiou KI, Fernando R, Raychaudhuri N, Cockerham KP, Charara LK, Goncalves AC, Zhao SX, Ginter A, Lu Y, Smith TJ, Douglas RS (2012) Increased expression of TSH receptor by fibrocytes in thyroid-associated ophthalmopathy leads to chemokine production. J Clin Endocrinol Metab 97(5):E740–E746. https://doi.org/10.1210/jc.2011-2514 (PMID:22399514;PMCID:PMC3339887)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Fernando R, Grisolia ABD, Lu Y, Atkins S, Smith TJ (2018) Slit2 modulates the inflammatory phenotype of orbit-infiltrating fibrocytes in graves’ disease. J Immunol 200(12):3942–3949. https://doi.org/10.4049/jimmunol.1800259 (PMID:29752312;PMCID:PMC6070359)

    Article  CAS  PubMed  Google Scholar 

  43. Fernando R, Atkins SJ, Smith TJ (2020) Slit2 underlie divergent induction by thyrotropin of il-23 and il-12 in human fibrocytes. J Immunol 204(7):1724–1735. https://doi.org/10.4049/jimmunol.1900434 (PMID:32086386;PMCID:PMC7365299)

    Article  CAS  PubMed  Google Scholar 

  44. Fernando R, Smith TJ (2021) Slit2 regulates hyaluronan & cytokine synthesis in fibrocytes: potential relevance to thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 106(1):e20–e33. https://doi.org/10.1210/clinem/dgaa684 (PMID:32968816;PMCID:PMC7765649)

    Article  PubMed  Google Scholar 

  45. Kidd T, Bland KS, Goodman CS (1999) Slit is the midline repellent for the robo receptor in Drosophila. Cell 96(6):785–794. https://doi.org/10.1016/s0092-8674(00)80589-9 (PMID: 10102267)

    Article  CAS  PubMed  Google Scholar 

  46. Ypsilanti AR, Chedotal A (2014) Roundabout receptors Adv Neurobiol 8:133–164. https://doi.org/10.1007/978-1-4614-8090-7_7 (PMID: 25300136)

    Article  PubMed  Google Scholar 

  47. Pilling D, Zheng Z, Vakil V, Gomer RH (2014) Fibroblasts secrete Slit2 to inhibit fibrocyte differentiation and fibrosis. Proc Natl Acad Sci USA 111(51):18291–18296. https://doi.org/10.1073/pnas.1417426112 (PMID:25489114;PMCID:PMC4280645)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hohenester E, Hutchinson WL, Pepys MB, Wood SP (1997) Crystal structure of a decameric complex of human serum amyloid P component with bound dAMP. J Mol Biol 269(4):570–578. https://doi.org/10.1006/jmbi.1997.1075 (PMID: 9217261)

    Article  CAS  PubMed  Google Scholar 

  49. Cox N, Pilling D, Gomer RH (2014) Distinct Fcγ receptors mediate the effect of serum amyloid p on neutrophil adhesion and fibrocyte differentiation. J Immunol 193(4):1701–1708. https://doi.org/10.4049/jimmunol.1400281 (PMID:25024390;PMCID:PMC4120242)

    Article  CAS  PubMed  Google Scholar 

  50. Alles VV, Bottazzi B, Peri G, Golay J, Introna M, Mantovani A (1994) Inducible expression of PTX3, a new member of the pentraxin family, in human mononuclear phagocytes. Blood 84(10):3483–3493 (PMID: 7949102)

    Article  CAS  Google Scholar 

  51. Scarchilli L, Camaioni A, Bottazzi B, Negri V, Doni A, Deban L, Bastone A, Salvatori G, Mantovani A, Siracusa G, Salustri A (2007) PTX3 interacts with inter-alpha-trypsin inhibitor: implications for hyaluronan organization and cumulus oophorus expansion. J Biol Chem 282(41):30161–30170. https://doi.org/10.1074/jbc.M703738200 (PMID: 17675295)

    Article  CAS  PubMed  Google Scholar 

  52. Bonacina F, Baragetti A, Catapano AL, Norata GD (2013) Long pentraxin 3: experimental and clinical relevance in cardiovascular diseases. Mediators Inflamm 2013:725102. https://doi.org/10.1155/2013/725102 (PMID:23690668;PMCID:PMC3649691)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bottazzi B, Vouret-Craviari V, Bastone A, De Gioia L, Matteucci C, Peri G, Spreafico F, Pausa M, Dttorre C, Gianazza E, Tagliabue A, Salmona M, Tedesco F, Introna M, Mantovani A (1997) Multimer formation and ligand recognition by the long pentraxin PTX3. Similarities and differences with the short pentraxins C-reactive protein and serum amyloid P component. J Biol Chem. https://doi.org/10.1074/jbc.272.52.32817

    Article  PubMed  Google Scholar 

  54. Pilling D, Cox N, Vakil V, Verbeek JS, Gomer RH (2015) The long pentraxin PTX3 promotes fibrocyte differentiation. PLoS ONE 10(3):e0119709. https://doi.org/10.1371/journal.pone.0119709 (PMID:25774777;PMCID:PMC4361553)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wang H, Atkins SJ, Fernando R, Wei RL, Smith TJ (2015) Pentraxin-3 Is a TSH-inducible protein in human fibrocytes and orbital fibroblasts. Endocrinology 156(11):4336–4344. https://doi.org/10.1210/en.2015-1399 (PMID:26287404;PMCID:PMC4606754)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Chen H, Mester T, Raychaudhuri N, Kauh CY, Gupta S, Smith TJ, Douglas RS (2014) Teprotumumab, an IGF-1R blocking monoclonal antibody inhibits TSH and IGF-1 action in fibrocytes. J Clin Endocrinol Metab 99(9):E1635–E1640. https://doi.org/10.1210/jc.2014-1580 (PMID:24878056;PMCID:PMC4154099)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Weetman AP, Cohen S, Gatter KC, Fells P, Shine B (1989) Immunohistochemical analysis of the retrobulbar tissues in Graves’ ophthalmopathy. Clin Exp Immunol 75(2):222–227

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Rotondo Dottore G, Torregrossa L, Caturegli P, Ionni I, Sframeli A, Sabini E, Menconi F, Piaggi P, Sellari-Franceschini S, Nardi M, Latrofa F, Vitti P, Marcocci C, Basolo F, Marinò M (2018) Association of T and B cells infiltrating orbital tissues with clinical features of graves orbitopathy. JAMA Ophthalmol 136(6):613–619. https://doi.org/10.1001/jamaophthalmol.2018.0806 (PMID:29710102;PMCID:PMC6583879)

    Article  PubMed  PubMed Central  Google Scholar 

  59. Pappa A, Lawson JM, Calder V, Fells P, Lightman S (2000) T cells and fibroblasts in affected extraocular muscles in early and late thyroid associated ophthalmopathy. Br J Ophthalmol 84(5):517–522. https://doi.org/10.1136/bjo.84.5.517 (PMID:10781517;PMCID:PMC1723449.5)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Grubeck-Loebenstein B, Trieb K, Sztankay A, Holter W, Anderl H, Wick G (1994) Retrobulbar T cells from patients with Graves’ ophthalmopathy are CD8+ and specifically recognize autologous fibroblasts. J Clin Invest 93(6):2738–2743. https://doi.org/10.1172/JCI117289 (PMID:8201012;PMCID:PMC294531)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Fang S, Huang Y, Zhong S, Li Y, Zhang Y, Li Y, Sun J, Liu X, Wang Y, Zhang S, Xu T, Sun X, Gu P, Li D, Zhou H, Li B, Fan X (2017) Regulation of orbital fibrosis and adipogenesis by pathogenic th17 cells in graves orbitopathy. J Clin Endocrinol Metab 102(11):4273–4283. https://doi.org/10.1210/jc.2017-01349 (PMID: 28938397)

    Article  PubMed  Google Scholar 

  62. Fang S, Huang Y, Wang N, Zhang S, Zhong S, Li Y, Sun J, Liu X, Wang Y, Gu P, Li B, Zhou H, Fan X (2020) Insights into local orbital immunity: evidence for the involvement of the Th17 cell pathway in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 105(1):1697 (PMID: 30517642)

    Google Scholar 

  63. Rapoport B, McLachlan SM (2014) Graves’ hyperthyroidism is antibody-mediated but is predominantly a Th1-type cytokine disease. J Clin Endocrinol Metab 99(11):4060–4061. https://doi.org/10.1210/jc.2014-3011 (PMID:25210884;PMCID:PMC4223433)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Peng D, Xu B, Wang Y, Guo H, Jiang Y (2013) A high frequency of circulating th22 and th17 cells in patients with new onset graves’ disease. PLoS ONE 8(7):e68446. https://doi.org/10.1371/journal.pone.0068446 (PMID:23874630;PMCID:PMC3708941)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Aniszewski JP, Valyasevi RW, Bahn RS (2000) Relationship between disease duration and predominant orbital T cell subset in Graves’ ophthalmopathy. J Clin Endocrinol Metab 85(2):776–780. https://doi.org/10.1210/jcem.85.2.6333 (PMID: 10690890)

    Article  CAS  PubMed  Google Scholar 

  66. Shen J, Li Z, Li W, Ge Y, Xie M, Lv M, Fan Y, Chen Z, Zhao D, Han Y (2015) Th1, Th2, and Th17 cytokine involvement in thyroid associated ophthalmopathy. Dis Markers 2015:609593. https://doi.org/10.1155/2015/609593 (PMID:26089587;PMCID:PMC4451372)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kahaly GJ, Shimony O, Gellman YN, Lytton SD, Eshkar-Sebban L, Rosenblum N, Refaeli E, Kassem S, Ilany J, Naor D (2011) Regulatory T-cells in Graves’ orbitopathy: baseline findings and immunomodulation by anti-T lymphocyte globulin. J Clin Endocrinol Metab 96(2):422–429. https://doi.org/10.1210/jc.2010-1424 (PMID: 21147887)

    Article  CAS  PubMed  Google Scholar 

  68. Pawlowski P, Grubczak K, Kostecki J, Ilendo-Poskrobko E, Moniuszko M, Pawlowska M, Rejdak R, Reszec J, Mysliwiec J (2017) Decreased frequencies of peripheral blood CD4+CD25+CD127-Foxp3+ in patients with graves’ disease and graves’ orbitopathy: enhancing effect of insulin growth factor-1 on treg cells. Horm Metab Res 49(3):185–191. https://doi.org/10.1055/s-0042-122780 (PMID: 28222462)

    Article  CAS  PubMed  Google Scholar 

  69. Zhao SX, Tsui S, Cheung A, Douglas RS, Smith TJ, Banga JP (2011) Orbital fibrosis in a mouse model of Graves’ disease induced by genetic immunization of thyrotropin receptor cDNA. J Endocrinol 210(3):369–377. https://doi.org/10.1530/JOE-11-0162 (PMID:21715431;PMCID:PMC3152291)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Moshkelgosha S, So PW, Deasy N, Diaz-Cano S, Banga JP (2013) Cutting edge: retrobulbar inflammation, adipogenesis, and acute orbital congestion in a preclinical female mouse model of Graves’ orbitopathy induced by thyrotropin receptor plasmid-in vivo electroporation. Endocrinology 154(9):3008–3015. https://doi.org/10.1210/en.2013-1576 (PMID: 23900776)

    Article  CAS  PubMed  Google Scholar 

  71. Zhang M, Ding X, Wu LP, He MQ, Chen ZY, Shi BY, Wang Y (2021) A promising mouse model of graves’ orbitopathy induced by adenovirus expressing thyrotropin receptor a subunit. Thyroid 31(4):638–648. https://doi.org/10.1089/thy.2020.0088 (PMID: 33076782)

    Article  CAS  PubMed  Google Scholar 

  72. Nakahara M, Johnson K, Eckstein A, Taguchi R, Yamada M, Abiru N, Nagayama Y (2012) Adoptive transfer of antithyrotropin receptor (TSHR) autoimmunity from TSHR knockout mice to athymic nude mice. Endocrinology 153(4):2034–2042. https://doi.org/10.1210/en.2011-1846 (PMID: 22334716)

    Article  CAS  PubMed  Google Scholar 

  73. Hikage F, Atkins S, Kahana A, Smith TJ, Chun TH (2019) HIF2A-LOX pathway promotes fibrotic tissue remodeling in thyroid-associated orbitopathy. Endocrinology 160(1):20–35. https://doi.org/10.1210/en.2018-00272 (PMID:30388216;PMCID:PMC6293089)

    Article  CAS  PubMed  Google Scholar 

  74. Moraes C, Labuz JM, Leung BM, Inoue M, Chun TH, Takayama S (2013) On being the right size: scaling effects in designing a human-on-a-chip. Integr Biol (Camb) 5(9):1149–1161. https://doi.org/10.1039/c3ib40040a (PMID:23925524;PMCID:PMC3787867)

    Article  CAS  Google Scholar 

  75. Yoo L, Reed J, Shin A, Kung J, Gimzewski JK, Poukens V, Goldberg RA, Mancini R, Taban M, Moy R, Demer JL (2011) Characterization of ocular tissues using microindentation and hertzian viscoelastic models. Invest Ophthalmol Vis Sci 52(6):3475–3482. https://doi.org/10.1167/iovs.10-6867 (PMID:21310907;PMCID:PMC3109037)

    Article  PubMed  PubMed Central  Google Scholar 

  76. Weetman AP (2000) Graves’ disease. N Engl J Med 343(17):1236–1248. https://doi.org/10.1056/NEJM200010263431707 (PMID: 11071676)

    Article  CAS  PubMed  Google Scholar 

  77. Bartalena L, Baldeschi L, Dickinson A, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits M, Perros P, Boboridis K, Boschi A, Currò N, Daumerie C, Kahaly GJ, Krassas GE, Lane CM, Lazarus JH, Marinò M, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM, European Group on Graves’ Orbitopathy (2008) Consensus statement of the European Group on Graves’ orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol 158(3):273–285. https://doi.org/10.1530/EJE-07-0666 (PMID: 18299459)

    Article  CAS  PubMed  Google Scholar 

  78. Bartalena L, Baldeschi L, Boboridis K, Eckstein A, Kahaly GJ, Marcocci C, Perros P, Salvi M, Wiersinga WM, European Group on Graves’ Orbitopathy (2016) The 2016 European Thyroid Association/European Group on Graves’ orbitopathy guidelines for the management of graves’ orbitopathy. Eur Thyroid J. 5(1):9–26. https://doi.org/10.1159/000443828 (PMID: 27099835; PMCID: PMC4836120)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ponto KA, Pitz S, Mann WJ, Weber MM, Pfeiffer N, Kahaly GJ (2009) Vorgehen bei endokriner Orbitopathie Evidenzbasierte Empfehlungen [Management of Graves’ orbitopathy: evidence-based recommendations]. Dtsch Med Wochenschr 134(49):2521–2524. https://doi.org/10.1055/s-0029-1243057 (PMID: 19941237)

    Article  CAS  PubMed  Google Scholar 

  80. Längericht J, Krämer I, Kahaly GJ (2020) Glucocorticoids in Graves’ orbitopathy: mechanisms of action and clinical application. Ther Adv Endocrinol Metab. https://doi.org/10.1177/2042018820958335 (PMID:33403097;PMCID:PMC7745544)

    Article  PubMed  PubMed Central  Google Scholar 

  81. Ito K, Barnes PJ, Adcock IM (2000) Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol 20(18):6891–6903. https://doi.org/10.1128/mcb.20.18.6891-6903.2000 (PMID:10958685;PMCID:PMC88765)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. John S, Sabo PJ, Johnson TA, Sung MH, Biddie SC, Lightman SL, Voss TC, Davis SR, Meltzer PS, Stamatoyannopoulos JA, Hager GL (2008) Interaction of the glucocorticoid receptor with the chromatin landscape. Mol Cell 29(5):611–624. https://doi.org/10.1016/j.molcel.2008.02.010 (PMID: 18342607)

    Article  CAS  PubMed  Google Scholar 

  83. Barnes PJ, Adcock IM, Ito K (2005) Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J 25(3):552–563. https://doi.org/10.1183/09031936.05.00117504 (PMID: 15738302)

    Article  CAS  PubMed  Google Scholar 

  84. Kahaly GJ, Pitz S, Hommel G, Dittmar M (2005) Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves’ orbitopathy. J Clin Endocrinol Metab 90(9):5234–5240. https://doi.org/10.1210/jc.2005-0148 (PMID: 15998777)

    Article  CAS  PubMed  Google Scholar 

  85. Bartalena L, Krassas GE, Wiersinga W, Marcocci C, Salvi M, Daumerie C, Bournaud C, Stahl M, Sassi L, Veronesi G, Azzolini C, Boboridis KG, Mourits MP, Soeters MR, Baldeschi L, Nardi M, Currò N, Boschi A, Bernard M, von Arx G (2012) Efficacy and safety of three different cumulative doses of intravenous methylprednisolone for moderate to severe and active Graves’ orbitopathy. J Clin Endocrinol Metab 97(12):4454–4463. https://doi.org/10.1210/jc.2012-2389 (PMID: 23038682)

    Article  CAS  PubMed  Google Scholar 

  86. Currò N, Covelli D, Vannucchi G, Campi I, Pirola G, Simonetta S, Dazzi D, Guastella C, Pignataro L, Beck-Peccoz P, Ratiglia R, Salvi M (2014) Therapeutic outcomes of high-dose intravenous steroids in the treatment of dysthyroid optic neuropathy. Thyroid 24(5):897–905. https://doi.org/10.1089/thy.2013.0445 (PMID: 24417307)

    Article  CAS  PubMed  Google Scholar 

  87. Cao HJ, Wang HS, Zhang Y, Lin HY, Phipps RP, Smith TJ (1998) Activation of human orbital fibroblasts through CD40 engagement results in a dramatic induction of hyaluronan synthesis and prostaglandin endoperoxide H synthase-2 expression. Insights into potential pathogenic mechanisms of thyroid-associated ophthalmopathy. J Biol Chem 273(45):29615–29625. https://doi.org/10.1074/jbc.273.45.29615 (PMID: 9792671)

    Article  CAS  PubMed  Google Scholar 

  88. Thorén S, Jakobsson PJ (2000) Coordinate up- and down-regulation of glutathione-dependent prostaglandin E synthase and cyclooxygenase-2 in A549 cells Inhibition by NS-398 and leukotriene C4. Eur J Biochem 267(21):6428–6434. https://doi.org/10.1046/j.1432-1327.2000.01735.x (PMID: 11029586)

    Article  PubMed  Google Scholar 

  89. Crofford LJ (1997) COX-1 and COX-2 tissue expression: implications and predictions. J Rheumatol Suppl 49:15–19 (PMID: 9249646)

    CAS  PubMed  Google Scholar 

  90. Moleti M, Giuffrida G, Sturniolo G, Squadrito G, Campennì A, Morelli S, Puxeddu E, Sisti E, Trimarchi F, Vermiglio F, Marinò M (2016) Acute liver damage following intravenous glucocorticoid treatment for Graves’ ophthalmopathy. Endocrine 54(1):259–268. https://doi.org/10.1007/s12020-016-0928-3 (PMID: 27003434)

    Article  CAS  PubMed  Google Scholar 

  91. Le Moli R, Baldeschi L, Saeed P, Regensburg N, Mourits MP, Wiersinga WM (2007) Determinants of liver damage associated with intravenous methylprednisolone pulse therapy in Graves’ ophthalmopathy. Thyroid 17(4):357–362. https://doi.org/10.1089/thy.2006.0267 (PMID: 17465867)

    Article  CAS  PubMed  Google Scholar 

  92. Marcocci C, Watt T, Altea MA, Rasmussen AK, Feldt-Rasmussen U, Orgiazzi J, Bartalena L (2012) Fatal and non-fatal adverse events of glucocorticoid therapy for Graves’ orbitopathy: a questionnaire survey among members of the European Thyroid Association. Eur J Endocrinol 166(2):247–253. https://doi.org/10.1530/EJE-11-0779 (PMID: 22058081)

    Article  CAS  PubMed  Google Scholar 

  93. Salvi M, Vannucchi G, Currò N et al (2015) 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 100(2):422–431. https://doi.org/10.1210/jc.2014-3014

    Article  CAS  PubMed  Google Scholar 

  94. Meier-Kriesche HU, Morris JA, Chu AH, Steffen BJ, Gotz VP, Gordon RD, Kaplan B (2004) Mycophenolate mofetil vs azathioprine in a large population of elderly renal transplant patients. Nephrol Dial Transplant 19(11):2864–2869. https://doi.org/10.1093/ndt/gfh445 (PMID: 15496562)

    Article  CAS  PubMed  Google Scholar 

  95. Gabardi S, Tran JL, Clarkson MR (2003) Enteric-coated mycophenolate sodium. Ann Pharmacother 37(11):1685–1693. https://doi.org/10.1345/aph.1D063 (PMID: 14565799)

    Article  CAS  PubMed  Google Scholar 

  96. Allison AC (2002) Mechanisms of action of mycophenolate mofetil in preventing chronic rejection. Transplant Proc 34(7):2863–2866. https://doi.org/10.1016/s0041-1345(02)03538-8 (PMID: 12431636)

    Article  CAS  PubMed  Google Scholar 

  97. Fujiyama N, Miura M, Kato S, Sone T, Isobe M, Satoh S (2010) Involvement of carboxylesterase 1 and 2 in the hydrolysis of mycophenolate mofetil. Drug Metab Dispos 38(12):2210–2217. https://doi.org/10.1124/dmd.110.034249 (PMID: 20823294)

    Article  CAS  PubMed  Google Scholar 

  98. Carr SF, Papp E, Wu JC, Natsumeda Y (1993) Characterization of human type I and type II IMP dehydrogenases. J Biol Chem 268(36):27286–27290 (PMID: 7903306)

    Article  CAS  Google Scholar 

  99. Mazumder AG, Patial V, Singh D (2019) Mycophenolate mofetil contributes to downregulation of the hippocampal interleukin type 2 and 1β mediated PI3K/AKT/mTOR pathway hyperactivation and attenuates neurobehavioral comorbidities in a rat model of temporal lobe epilepsy. Brain Behav Immun 75:84–93. https://doi.org/10.1016/j.bbi.2018.09.020 (PMID: 30243822)

    Article  CAS  PubMed  Google Scholar 

  100. Kahaly GJ, Riedl M, König J, Pitz S, Ponto K, Diana T, Kampmann E, Kolbe E, Eckstein A, Moeller LC, Führer D, Salvi M, Curro N, Campi I, Covelli D, Leo M, Marinò M, Menconi F, Marcocci C, Bartalena L, Perros P, Wiersinga WM (2018) Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves’ orbitopathy (MINGO): a randomised, observer-masked, multicentre trial. Lancet Diabetes Endocrinol 6(4):287–298. https://doi.org/10.1016/S2213-8587(18)30020-2 (PMID: 29396246)

    Article  CAS  PubMed  Google Scholar 

  101. Kelley WN, Rosenbloom FM, Seegmiller JE (1967) The effects of azathioprine (imuran) on purine synthesis in clinical disorders of purine metabolism. J Clin Invest 46(9):1518–1529. https://doi.org/10.1172/JCI105643 (PMID:16695929;PMCID:PMC292897)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Perros P, Weightman DR, Crombie AL, Kendall-Taylor P (1990) Azathioprine in the treatment of thyroid-associated ophthalmopathy. Acta Endocrinol (Copenh) 122(1):8–12. https://doi.org/10.1530/acta.0.1220008 (PMID: 2305608)

    Article  CAS  Google Scholar 

  103. Traullé C, Coiffier BB (2005) Evolving role of rituximab in the treatment of patients with non-Hodgkin’s lymphoma. Future Oncol 1(3):297–306. https://doi.org/10.1517/14796694.1.3.297 (PMID: 16556002)

    Article  PubMed  Google Scholar 

  104. Smith MR (2003) Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene 22(47):7359–7368. https://doi.org/10.1038/sj.onc.1206939 (PMID: 14576843)

    Article  CAS  PubMed  Google Scholar 

  105. Piro LD, White CA, Grillo-López AJ, Janakiraman N, Saven A, Beck TM, Varns C, Shuey S, Czuczman M, Lynch JW, Kolitz JE, Jain V (1999) Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol 10(6):655–661. https://doi.org/10.1023/a:1008389119525 (PMID: 10442187)

    Article  CAS  PubMed  Google Scholar 

  106. Tedder TF, Engel P (1994) CD20: a regulator of cell-cycle progression of B lymphocytes. Immunol Today 15(9):450–454. https://doi.org/10.1016/0167-5699(94)90276-3 (PMID: 7524522)

    Article  CAS  PubMed  Google Scholar 

  107. Nielsen CH, El Fassi D, Hasselbalch HC, Bendtzen K, Hegedüs L (2007) B-cell depletion with rituximab in the treatment of autoimmune diseases. Graves’ ophthalmopathy the latest addition to an expanding family. Expert Opin Biol Ther 7(7):1061–1078. https://doi.org/10.1517/14712598.7.7.1061 (PMID: 17665994)

    Article  CAS  PubMed  Google Scholar 

  108. Byrd JC, Kitada S, Flinn IW, Aron JL, Pearson M, Lucas D, Reed JC (2002) The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: evidence of caspase activation and apoptosis induction. Blood 99(3):1038–1043. https://doi.org/10.1182/blood.v99.3.1038 (PMID: 11807010)

    Article  CAS  PubMed  Google Scholar 

  109. Anderson DR, Grillo-López A, Varns C, Chambers KS, Hanna N (1997) Targeted anti-cancer therapy using rituximab, a chimaeric anti-CD20 antibody (IDEC-C2B8) in the treatment of non-Hodgkin’s B-cell lymphoma. Biochem Soc Trans 25(2):705–708. https://doi.org/10.1042/bst0250705 (PMID: 9191187)

    Article  CAS  PubMed  Google Scholar 

  110. Storz U (2014) Rituximab: how approval history is reflected by a corresponding patent filing strategy. MAbs 6(4):820–837. https://doi.org/10.4161/mabs.29105 (PMID:24866199;PMCID:PMC4171018)

    Article  PubMed  PubMed Central  Google Scholar 

  111. El Fassi D, Nielsen CH, Bonnema SJ, Hasselbalch HC, Hegedüs L (2007) B lymphocyte depletion with the monoclonal antibody rituximab in Graves’ disease: a controlled pilot study. J Clin Endocrinol Metab 92(5):1769–1772. https://doi.org/10.1210/jc.2006-2388 (PMID: 17284622)

    Article  CAS  PubMed  Google Scholar 

  112. Salvi M, Vannucchi G, Campi I, Currò N, Dazzi D, Simonetta S, Bonara P, Rossi S, Sina C, Guastella C, Ratiglia R, Beck-Peccoz P (2007) Treatment of Graves’ disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study. Eur J Endocrinol 156(1):33–40. https://doi.org/10.1530/eje.1.02325 (PMID: 17218723)

    Article  CAS  PubMed  Google Scholar 

  113. Heemstra KA, Toes RE, Sepers J, Pereira AM, Corssmit EP, Huizinga TW, Romijn JA, Smit JW (2008) Rituximab in relapsing Graves’ disease, a phase II study. Eur J Endocrinol 159(5):609–615. https://doi.org/10.1530/EJE-08-0084 (PMID: 18628345)

    Article  CAS  PubMed  Google Scholar 

  114. Stan MN, Garrity JA, Carranza Leon BG, Prabin T, Bradley EA, Bahn RS (2015) Randomized controlled trial of rituximab in patients with Graves’ orbitopathy. J Clin Endocrinol Metab 100(2):432–441. https://doi.org/10.1210/jc.2014-2572 (PMID:25343233;PMCID:PMC4318907)

    Article  CAS  PubMed  Google Scholar 

  115. Stan MN, Salvi M (2017) MANAGEMENT OF ENDOCRINE DISEASE: Rituximab therapy for Graves’ orbitopathy - lessons from randomized control trials. Eur J Endocrinol 176(2):R101–R109. https://doi.org/10.1530/EJE-16-0552 (PMID: 27760790)

    Article  CAS  PubMed  Google Scholar 

  116. Chen D, Gallagher S, Monson NL, Herbst R, Wang Y (2016) Inebilizumab, a B cell-depleting anti-cd19 antibody for the treatment of autoimmune neurological diseases: insights from preclinical studies. J Clin Med 5(12):107. https://doi.org/10.3390/jcm5120107 (PMID: 27886126; PMCID: PMC5184780)

    Article  CAS  PubMed Central  Google Scholar 

  117. Gallagher S, Turman S, Yusuf I, Akhgar A, Wu Y, Roskos LK, Herbst R, Wang Y (2016) Pharmacological profile of MEDI-551, a novel anti-CD19 antibody, in human CD19 transgenic mice. Int Immunopharmacol 36:205–212. https://doi.org/10.1016/j.intimp.2016.04.035 (PMID: 27163209)

    Article  CAS  PubMed  Google Scholar 

  118. Herbst R, Wang Y, Gallagher S, Mittereder N, Kuta E, Damschroder M, Woods R, Rowe DC, Cheng L, Cook K, Evans K, Sims GP, Pfarr DS, Bowen MA, Dall'Acqua W, Shlomchik M, Tedder TF, Kiener P, Jallal B, Wu H, Coyle AJ. B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody. J Pharmacol Exp Ther. 2010 ;335(1):213–22. doi: https://doi.org/10.1124/jpet.110.168062. Epub 2010 6. Erratum in: J Pharmacol Exp Ther. 2011 ;336(1):294. Dall'Aqua, William [corrected to Dall'Acqua, William]. PMID: 20605905

  119. Lesley R, Xu Y, Kalled SL, Hess DM, Schwab SR, Shu HB, Cyster JG (2004) Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF. Immunity 20(4):441–453. https://doi.org/10.1016/s1074-7613(04)00079-2 (PMID: 15084273)

    Article  CAS  PubMed  Google Scholar 

  120. Lin JD, Wang YH, Fang WF, Hsiao CJ, Chagnaadorj A, Lin YF, Tang KT, Cheng CW (2016) Serum BAFF and thyroid autoantibodies in autoimmune thyroid disease. Clin Chim Acta 462:96–102. https://doi.org/10.1016/j.cca.2016.09.004 (PMID: 27616625)

    Article  CAS  PubMed  Google Scholar 

  121. Endocrine Abstracts (2020) 70 YI9 | DOI: https://doi.org/10.1530/endoabs.70.YI9

  122. Patel DD, Bussel JB (2020) Neonatal Fc receptor in human immunity: Function and role in therapeutic intervention. J Allergy Clin Immunol 146(3):467–478. https://doi.org/10.1016/j.jaci.2020.07.015 (PMID: 32896307)

    Article  CAS  PubMed  Google Scholar 

  123. Henne KR, Ason B, Howard M, Wang W, Sun J, Higbee J, Tang J, Matsuda KC, Xu R, Zhou L, Chan JC, King C, Piper DE, Ketchem RR, Michaels ML, Jackson SM, Retter MW (2015) Anti-PCSK9 antibody pharmacokinetics and low-density lipoprotein-cholesterol pharmacodynamics in nonhuman primates are antigen affinity-dependent and exhibit limited sensitivity to neonatal Fc receptor-binding enhancement. J Pharmacol Exp Ther 353(1):119–131. https://doi.org/10.1124/jpet.114.221242 (PMID: 25653417)

    Article  CAS  PubMed  Google Scholar 

  124. Newland AC, Sánchez-González B, Rejtő L, Egyed M, Romanyuk N, Godar M, Verschueren K, Gandini D, Ulrichts P, Beauchamp J, Dreier T, Ward ES, Michel M, Liebman HA, de Haard H, Leupin N, Kuter DJ (2020) Phase 2 study of efgartigimod, a novel FcRn antagonist, in adult patients with primary immune thrombocytopenia. Am J Hematol 95(2):178–187. https://doi.org/10.1002/ajh.25680 (PMID:31821591;PMCID:PMC7004056)

    Article  CAS  PubMed  Google Scholar 

  125. Howard JF Jr, Bril V, Burns TM, Mantegazza R, Bilinska M, Szczudlik A, Beydoun S, Garrido FJRR, Piehl F, Rottoli M, Van Damme P, Vu T, Evoli A, Freimer M, Mozaffar T, Ward ES, Dreier T, Ulrichts P, Verschueren K, Guglietta A, de Haard H, Leupin N, Verschuuren JJGM (2019) Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis. Neurology 92(23):e2661–e2673. https://doi.org/10.1212/WNL.0000000000007600 (PMID: 31118245; PMCID: PMC6556100)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Bril V, Benatar M, Andersen H, Vissing J, Brock M, Greve B, Kiessling P, Woltering F, Griffin L, Van den Bergh P (2021) Efficacy and safety of rozanolixizumab in moderate to severe generalized myasthenia gravis: a phase 2 randomized control trial. Neurology 96(6):e853–e865. https://doi.org/10.1212/WNL.0000000000011108 (PMID: 33219142; PMCID: PMC8105899)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Sabini E, Mazzi B, Profilo MA, Mautone T, Casini G, Rocchi R, Ionni I, Menconi F, Leo M, Nardi M, Vitti P, Marcocci C, Marinò M (2018) High serum cholesterol is a novel risk factor for graves’ orbitopathy: results of a cross-sectional study. Thyroid 28(3):386–394. https://doi.org/10.1089/thy.2017.0430 (PMID: 29336220)

    Article  CAS  PubMed  Google Scholar 

  128. Lanzolla G, Sabini E, Profilo MA, Mazzi B, Sframeli A, Rocchi R, Menconi F, Leo M, Nardi M, Vitti P, Marcocci C, Marinò M (2018) Relationship between serum cholesterol and Graves’ orbitopathy (GO): a confirmatory study. J Endocrinol Invest 41(12):1417–1423. https://doi.org/10.1007/s40618-018-0915-z (PMID: 29923059)

    Article  CAS  PubMed  Google Scholar 

  129. Moreno-Navarrete JM, Moreno M, Ortega F, Xifra G, Hong S, Asara JM, Serrano JCE, Jové M, Pissios P, Blüher M, Ricart W, Portero-Otin M, Fernández-Real JM (2017) TSHB mRNA is linked to cholesterol metabolism in adipose tissue. FASEB J 31(10):4482–4491. https://doi.org/10.1096/fj.201700161R (PMID:28646016;PMCID:PMC5602896)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Zhou Q, Liao JK (2009) Statins and cardiovascular diseases: from cholesterol lowering to pleiotropy. Curr Pharm Des 15(5):467–478. https://doi.org/10.2174/138161209787315684 (PMID:19199975;PMCID:PMC2896785)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Koushki K, Shahbaz SK, Mashayekhi K, Sadeghi M, Zayeri ZD, Taba MY, Banach M, Al-Rasadi K, Johnston TP, Sahebkar A (2021) Anti-inflammatory Action of Statins in Cardiovascular Disease: the Role of Inflammasome and Toll-Like Receptor Pathways. Clin Rev Allergy Immunol 60(2):175–199. https://doi.org/10.1007/s12016-020-08791-9 (PMID:32378144;PMCID:PMC7985098)

    Article  CAS  Google Scholar 

  132. Stein JD, Childers D, Gupta S, Talwar N, Nan B, Lee BJ, Smith TJ, Douglas R (2015) Risk factors for developing thyroid-associated ophthalmopathy among individuals with Graves disease. JAMA Ophthalmol 133(3):290–296. https://doi.org/10.1001/jamaophthalmol.2014.5103 (PMID:25502604;PMCID:PMC4495733)

    Article  PubMed  PubMed Central  Google Scholar 

  133. Nilsson A, Tsoumani K, Planck T (2021) Statins decrease the risk of orbitopathy in newly diagnosed patients with graves disease. J Clin Endocrinol Metab 106(5):1325–1332. https://doi.org/10.1210/clinem/dgab070 (PMID: 33560351)

    Article  PubMed  Google Scholar 

  134. Pinal-Fernandez I, Casal-Dominguez M, Mammen AL (2018) Statins: pros and cons. Med Clin (Barc) 150(10):398–402. https://doi.org/10.1016/j.medcli.2017.11.030 (PMID:29292104;PMCID:PMC6019636)

    Article  Google Scholar 

  135. Sempowski GD, Rozenblit J, Smith TJ, Phipps RP (1998) Human orbital fibroblasts are activated through CD40 to induce proinflammatory cytokine production. Am J Physiol 274(3):C707–C714. https://doi.org/10.1152/ajpcell.1998.274.3.C707 (PMID: 9530102)

    Article  CAS  PubMed  Google Scholar 

  136. Mester T, Raychaudhuri N, Gillespie EF, Chen H, Smith TJ, Douglas RS (2016) CD40 expression in fibrocytes is induced by tsh: potential synergistic immune activation. PLoS ONE 11(9):e0162994. https://doi.org/10.1371/journal.pone.0162994 (PMID:27631497;PMCID:PMC5025085)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Baccam M, Woo SY, Vinson C, Bishop GA (2003) CD40-mediated transcriptional regulation of the IL-6 gene in B lymphocytes: involvement of NF-kappa B, AP-1, and C/EBP. J Immunol 170(6):3099–3108. https://doi.org/10.4049/jimmunol.170.6.3099 (PMID: 12626566)

    Article  CAS  PubMed  Google Scholar 

  138. Lee HJ, Lombardi A, Stefan M, Li CW, Inabnet WB 3rd, Owen RP, Concepcion E, Tomer Y (2017) CD40 signaling in graves disease is mediated through canonical and noncanonical thyroidal nuclear factor κb activation. Endocrinology 158(2):410–418. https://doi.org/10.1210/en.2016-1609 (PMID:27929668;PMCID:PMC5413074)

    Article  CAS  PubMed  Google Scholar 

  139. Zhao LQ, Wei RL, Cheng JW, Cai JP, Li Y (2010) The expression of intercellular adhesion molecule-1 induced by CD40-CD40L ligand signaling in orbital fibroblasts in patients with Graves’ ophthalmopathy. Invest Ophthalmol Vis Sci 51(9):4652–4660. https://doi.org/10.1167/iovs.09-3789 (PMID: 20107176)

    Article  PubMed  Google Scholar 

  140. Douglas RS, Mester T, Ginter A, Kim DS (2014) Thyrotropin receptor and CD40 mediate interleukin-8 expression in fibrocytes: implications for thyroid-associated ophthalmopathy (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc 112:26–37

    PubMed  PubMed Central  Google Scholar 

  141. Alaaeddine N, Hassan GS, Yacoub D, Mourad W (2012) CD154: an immunoinflammatory mediator in systemic lupus erythematosus and rheumatoid arthritis. Clin Dev Immunol 2012:490148. https://doi.org/10.1155/2012/490148 (PMID:22110533;PMCID:PMC3202102)

    Article  CAS  PubMed  Google Scholar 

  142. Shock A, Burkly L, Wakefield I, Peters C, Garber E, Ferrant J, Taylor FR, Su L, Hsu YM, Hutto D, Amirkhosravi A, Meyer T, Francis J, Malcolm S, Robinson M, Brown D, Shaw S, Foulkes R, Lawson A, Harari O, Bourne T, Maloney A, Weir N (2015) CDP7657, an anti-CD40L antibody lacking an Fc domain, inhibits CD40L-dependent immune responses without thrombotic complications: an in vivo study. Arthritis Res Ther 17(1):234. https://doi.org/10.1186/s13075-015-0757-4 (PMID:26335795;PMCID:PMC4558773)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Kawai T, Andrews D, Colvin RB, Sachs DH, Cosimi AB (2000) Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand. Nat Med 6(2):114. https://doi.org/10.1038/72162 (PMID: 10655072)

    Article  CAS  PubMed  Google Scholar 

  144. Cordoba F, Wieczorek G, Audet M, Roth L, Schneider MA, Kunkler A, Stuber N, Erard M, Ceci M, Baumgartner R, Apolloni R, Cattini A, Robert G, Ristig D, Munz J, Haeberli L, Grau R, Sickert D, Heusser C, Espie P, Bruns C, Patel D, Rush JS (2015) A novel, blocking, Fc-silent anti-CD40 monoclonal antibody prolongs nonhuman primate renal allograft survival in the absence of B cell depletion. Am J Transplant 15(11):2825–2836. https://doi.org/10.1111/ajt.13377 (PMID: 26139432)

    Article  CAS  PubMed  Google Scholar 

  145. Ristov J, Espie P, Ulrich P, Sickert D, Flandre T, Dimitrova M, Müller-Ristig D, Weider D, Robert G, Schmutz P, Greutmann B, Cordoba-Castro F, Schneider MA, Warncke M, Kolbinger F, Cote S, Heusser C, Bruns C, Rush JS (2018) Characterization of the in vitro and in vivo properties of CFZ533, a blocking and non-depleting anti-CD40 monoclonal antibody. Am J Transplant 18(12):2895–2904. https://doi.org/10.1111/ajt.14872 (PMID: 29665205)

    Article  CAS  PubMed  Google Scholar 

  146. Kahaly GJ, Stan MN, Frommer L, Gergely P, Colin L, Amer A, Schuhmann I, Espie P, Rush JS, Basson C, He Y (2020) A novel anti-cd40 monoclonal antibody, iscalimab, for control of graves hyperthyroidism-a proof-of-concept trial. J Clin Endocrinol Metab. https://doi.org/10.1210/clinem/dgz013 (PMID: 31512728)

    Article  PubMed  PubMed Central  Google Scholar 

  147. Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, Jackson CG, Lange M, Burge DJ (1999) A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 340(4):253–259. https://doi.org/10.1056/NEJM199901283400401 (PMID: 9920948)

    Article  CAS  PubMed  Google Scholar 

  148. den Broeder AA, Joosten LA, Saxne T, Heinegård D, Fenner H, Miltenburg AM, Frasa WL, van Tits LJ, Buurman WA, van Riel PL, van de Putte LB, Barrera P (2002) Long term anti-tumour necrosis factor alpha monotherapy in rheumatoid arthritis: effect on radiological course and prognostic value of markers of cartilage turnover and endothelial activation. Ann Rheum Dis 61(4):311–318. https://doi.org/10.1136/ard.61.4.311 (PMID:11874832;PMCID:PMC1754066)

    Article  Google Scholar 

  149. Durrani OM, Reuser TQ, Murray PI (2005) Infliximab: a novel treatment for sight-threatening thyroid associated ophthalmopathy. Orbit 24(2):117–119. https://doi.org/10.1080/01676830590912562 (PMID: 16191800)

    Article  CAS  PubMed  Google Scholar 

  150. Paridaens D, van den Bosch WA, van der Loos TL, Krenning EP, van Hagen PM (2005) The effect of etanercept on Graves’ ophthalmopathy: a pilot study. Eye (Lond) 19(12):1286–1289. https://doi.org/10.1038/sj.eye.6701768 (PMID: 15550932)

    Article  CAS  Google Scholar 

  151. Ayabe R, Rootman DB, Hwang CJ, Ben-Artzi A, Goldberg R (2014) Adalimumab as steroid-sparing treatment of inflammatory-stage thyroid eye disease. Ophthalmic Plast Reconstr Surg 30(5):415–419. https://doi.org/10.1097/IOP.0000000000000211 (PMID: 24978425)

    Article  PubMed  Google Scholar 

  152. Wang L, Walia B, Evans J, Gewirtz AT, Merlin D, Sitaraman SV (2003) IL-6 induces NF-kappa B activation in the intestinal epithelia. J Immunol 171(6):3194–3201. https://doi.org/10.4049/jimmunol.171.6.3194 (PMID: 12960348)

    Article  CAS  PubMed  Google Scholar 

  153. Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 Cells. Annu Rev Immunol 27:485–517. https://doi.org/10.1146/annurev.immunol.021908.132710 (PMID: 19132915)

    Article  CAS  Google Scholar 

  154. Salvi M, Girasole G, Pedrazzoni M, Passeri M, Giuliani N, Minelli R, Braverman LE, Roti E (1996) Increased serum concentrations of interleukin-6 (IL-6) and soluble IL-6 receptor in patients with Graves’ disease. J Clin Endocrinol Metab 81(8):2976–2979. https://doi.org/10.1210/jcem.81.8.8768861 (PMID: 8768861)

    Article  CAS  PubMed  Google Scholar 

  155. Salvi M, Pedrazzoni M, Girasole G, Giuliani N, Minelli R, Wall JR, Roti E (2000) Serum concentrations of proinflammatory cytokines in Graves’ disease: effect of treatment, thyroid function, ophthalmopathy and cigarette smoking. Eur J Endocrinol 143(2):197–202. https://doi.org/10.1530/eje.0.1430197 (PMID: 10913938)

    Article  CAS  PubMed  Google Scholar 

  156. Molnár I, Balázs C (1997) High circulating IL-6 level in Graves’ ophthalmopathy. Autoimmunity 25(2):91–96. https://doi.org/10.3109/08916939708996275 (PMID: 9189010)

    Article  PubMed  Google Scholar 

  157. Azar AA, Michie AM, Tarafdar A, Malik N, Menon GK, Till KJ, Vlatković N, Slupsky JR (2020) A novel transgenic mouse strain expressing PKCβII demonstrates expansion of B1 and marginal zone B cell populations. Sci Rep 10(1):13156. https://doi.org/10.1038/s41598-020-70191-y (PMID: 32753714; PMCID: PMC7403146)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Decouvelaere AV, Morschhauser F, Buob D, Copin MC, Dumontet C (2007) Heterogeneity of protein kinase C beta(2) expression in lymphoid malignancies. Histopathology 50(5):561–566. https://doi.org/10.1111/j.1365-2559.2007.02666.x (PMID: 17394491)

    Article  PubMed  Google Scholar 

  159. Shetty A, Hanson R, Korsten P, Shawagfeh M, Arami S, Volkov S, Vila O, Swedler W, Shunaigat AN, Smadi S, Sawaqed R, Perkins D, Shahrara S, Sweiss NJ (2014) Tocilizumab in the treatment of rheumatoid arthritis and beyond. Drug Des Devel Ther 28(8):349–364. https://doi.org/10.2147/DDDT.S41437 (PMID:24729685;PMCID:PMC3974690)

    Article  Google Scholar 

  160. Kimura A, Kishimoto T (2010) IL-6: regulator of Treg/Th17 balance. Eur J Immunol 40(7):1830–1835. https://doi.org/10.1002/eji.201040391 (PMID: 20583029)

    Article  CAS  PubMed  Google Scholar 

  161. Pérez-Moreiras JV, Alvarez-López A, Gómez EC (2014) Treatment of active corticosteroid-resistant graves’ orbitopathy. Ophthalmic Plast Reconstr Surg 30(2):162–167. https://doi.org/10.1097/IOP.0000000000000037 (PMID: 24503568)

    Article  PubMed  Google Scholar 

  162. Perez-Moreiras JV, Gomez-Reino JJ, Maneiro JR, Perez-Pampin E, Romo Lopez A, Rodríguez Alvarez FM, Castillo Laguarta JM, Del Estad CA, Gessa Sorroche M, España Gregori E, Sales-Sanz M (2018) Efficacy of tocilizumab in patients with moderate-to-severe corticosteroid-resistant graves orbitopathy: a randomized clinical trial. Am J Ophthalmol 195:181–190. https://doi.org/10.1016/j.ajo.2018.07.038 (PMID: 30081019)

    Article  CAS  PubMed  Google Scholar 

  163. Pérez-Moreiras JV, Varela-Agra M, Prada-Sánchez MC, Prada-Ramallal G (2021) Steroid-resistant graves’ orbitopathy treated with tocilizumab in real-world clinical practice: a 9-year single-center experience. J Clin Med 10(4):706. https://doi.org/10.3390/jcm10040706 (PMID: 33670151; PMCID: PMC7916878)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Khoo DH, Eng PH, Ho SC, Tai ES, Morgenthaler NG, Seah LL, Fong KS, Chee SP, Choo CT, Aw SE (2000) Graves’ ophthalmopathy in the absence of elevated free thyroxine and triiodothyronine levels: prevalence, natural history, and thyrotropin receptor antibody levels. Thyroid 10(12):1093–1100. https://doi.org/10.1089/thy.2000.10.1093 (PMID: 11201855)

    Article  CAS  PubMed  Google Scholar 

  165. Núñez Miguel R, Sanders J, Furmaniak J, Smith BR (2017) Structure and activation of the TSH receptor transmembrane domain. Auto Immun Highlights 8(1):2. https://doi.org/10.1007/s13317-016-0090-1 (PMID:27921237;PMCID:PMC5136658)

    Article  CAS  PubMed  Google Scholar 

  166. Rapoport B, McLachlan SM (2020) TSH receptor cleavage into subunits and shedding of the a-subunit; a molecular and clinical perspective. Endocr Rev. https://doi.org/10.1210/er.2015-1098 (PMID:26799472;PMCID:PMC4823380)

    Article  Google Scholar 

  167. Chazenbalk GD, Tanaka K, Nagayama Y, Kakinuma A, Jaume JC, McLachlan SM, Rapoport B (1997) Evidence that the thyrotropin receptor ectodomain contains not one, but two, cleavage sites. Endocrinology 138(7):2893–2899. https://doi.org/10.1210/endo.138.7.5259 (PMID: 9202233)

    Article  CAS  PubMed  Google Scholar 

  168. Rapoport B, Aliesky HA, Chen CR, McLachlan SM (2015) Evidence that TSH receptor a-subunit multimers, not monomers, drive antibody affinity maturation in Graves’ disease. J Clin Endocrinol Metab 100(6):E871–E875. https://doi.org/10.1210/jc.2015-1528 (PMID:25856215;PMCID:PMC4454809)

    Article  PubMed  PubMed Central  Google Scholar 

  169. Zhang M, Phuong K, Tong T, Fremont V, Chen J, Narayan P, Puett D, Weintraub BD, Szkudlinski MW (2000) The extracellular domain suppresses constitutive activity of the transmembrane domain of the human TSH receptor: implications for hormone-receptor interaction and antagonist design. Endocrinology 141:3514–3517. https://doi.org/10.1210/en.141.9.351433

    Article  CAS  PubMed  Google Scholar 

  170. Wu T, Mester T, Gupta S, Sun F, Smith TJ, Douglas RS (2016) Thyrotropin and CD40L stimulate interleukin-12 expression in fibrocytes: implications for pathogenesis of thyroid-associated ophthalmopathy. Thyroid 26(12):1768–1777. https://doi.org/10.1089/thy.2016.0243 (PMID:27612658;PMCID:PMC5175425)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Evans M, Sanders J, Tagami T, Sanders P, Young S, Roberts E, Wilmot J, Hu X, Kabelis K, Clark J, Holl S, Richards T, Collyer A, Furmaniak J, Smith BR (2010) Monoclonal autoantibodies to the TSH receptor, one with stimulating activity and one with blocking activity, obtained from the same blood sample. Clin Endocrinol (Oxf) 73(3):404–412. https://doi.org/10.1111/j.1365-2265.2010.03831.x (PMID: 20550534)

    Article  CAS  Google Scholar 

  172. Rees Smith B, Sanders J, Evans M, Tagami T, Furmaniak J (2009) TSH receptor - autoantibody interactions. Horm Metab Res 41(6):448–455. https://doi.org/10.1055/s-0029-1220913 (PMID: 19530271)

    Article  CAS  PubMed  Google Scholar 

  173. Sanders J, Evans M, Premawardhana LD, Depraetere H, Jeffreys J, Richards T, Furmaniak J, Rees SB (2003) Human monoclonal thyroid stimulating autoantibody. Lancet 362(9378):126–128. https://doi.org/10.1016/s0140-6736(03)13866-4 (PMID: 12867115)

    Article  CAS  PubMed  Google Scholar 

  174. Sanders J, Jeffreys J, Depraetere H, Evans M, Richards T, Kiddie A, Brereton K, Premawardhana LD, Chirgadze DY, Núñez Miguel R, Blundell TL, Furmaniak J, Rees SB (2004) Characteristics of a human monoclonal autoantibody to the thyrotropin receptor: sequence structure and function. Thyroid 14(8):560–570. https://doi.org/10.1089/1050725041692918 (PMID: 15320966)

    Article  CAS  PubMed  Google Scholar 

  175. Sanders J, Evans M, Betterle C, Sanders P, Bhardwaja A, Young S, Roberts E, Wilmot J, Richards T, Kiddie A, Small K, Platt H, Summerhayes S, Harris R, Reeve M, Coco G, Zanchetta R, Chen S, Furmaniak J, Smith BR (2008) A human monoclonal autoantibody to the thyrotropin receptor with thyroid-stimulating blocking activity. Thyroid 18(7):735–746. https://doi.org/10.1089/thy.2007.0327 (PMID: 18631002)

    Article  CAS  PubMed  Google Scholar 

  176. Furmaniak J, Sanders J, Young S, Kabelis K, Sanders P, Evans M, Clark J, Wilmot J, Rees SB (2011) In vivo effects of a human thyroid-stimulating monoclonal autoantibody (M22) and a human thyroid-blocking autoantibody (K1–70). Auto Immun Highlights 3(1):19–25. https://doi.org/10.1007/s13317-011-0025-9 (PMID:26000124;PMCID:PMC4389019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Sanders P, Young S, Sanders J, Kabelis K, Baker S, Sullivan A, Evans M, Clark J, Wilmot J, Hu X, Roberts E, Powell M, Núñez Miguel R, Furmaniak J, Rees SB (2011) Crystal structure of the TSH receptor (TSHR) bound to a blocking-type TSHR autoantibody. J Mol Endocrinol 46(2):81–99. https://doi.org/10.1530/JME-10-0127 (PMID: 21247981)

    Article  CAS  PubMed  Google Scholar 

  178. Marcinkowski P, Hoyer I, Specker E, Furkert J, Rutz C, Neuenschwander M, Sobottka S, Sun H, Nazare M, Berchner-Pfannschmidt U, von Kries JP, Eckstein A, Schülein R, Krause G (2019) A new highly thyrotropin receptor-selective small-molecule antagonist with potential for the treatment of graves’ orbitopathy. Thyroid 29(1):111–123. https://doi.org/10.1089/thy.2018.0349 (PMID: 30351237)

    Article  CAS  PubMed  Google Scholar 

  179. Latif R, Ali MR, Ma R, David M, Morshed SA, Ohlmeyer M, Felsenfeld DP, Lau Z, Mezei M, Davies TF (2015) New small molecule agonists to the thyrotropin receptor. Thyroid 25(1):51–62. https://doi.org/10.1089/thy.2014.0119 (PMID:25333622;PMCID:PMC4291085)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Neumann S, Eliseeva E, McCoy JG, Napolitano G, Giuliani C, Monaco F, Huang W, Gershengorn MC (2011) A new small-molecule antagonist inhibits Graves’ disease antibody activation of the TSH receptor. J Clin Endocrinol Metab 96(2):548–554. https://doi.org/10.1210/jc.2010-1935 (PMID:21123444;PMCID:PMC3048317)

    Article  CAS  PubMed  Google Scholar 

  181. Neumann S, Nir EA, Eliseeva E, Huang W, Marugan J, Xiao J, Dulcey AE, Gershengorn MC (2014) A selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice. Endocrinology 155(1):310–314. https://doi.org/10.1210/en.2013-1835 (PMID:24169564;PMCID:PMC3868809)

    Article  CAS  PubMed  Google Scholar 

  182. Tabasum A, Khan I, Taylor P, Das G, Okosieme OE (2016) Thyroid antibody-negative euthyroid Graves’ ophthalmopathy. Endocrinol Diabetes Metab Case Rep 2016:160008. https://doi.org/10.1530/EDM-16-0008 (PMID:27284451;PMCID:PMC4898069)

    Article  PubMed  PubMed Central  Google Scholar 

  183. Wall JR, Lahooti H, El Kochairi I, Lytton SD, Champion B (2014) Thyroid-stimulating immunoglobulins as measured in a reporter bioassay are not detected in patients with Hashimoto’s thyroiditis and ophthalmopathy or isolated upper eyelid retraction. Clin Ophthalmol 8:2071–2076. https://doi.org/10.2147/OPTH.S67098 (PMID:25336908;PMCID:PMC4199859)

    Article  PubMed  PubMed Central  Google Scholar 

  184. Pritchard J, Horst N, Cruikshank W, Smith TJ (2002) Igs from patients with Graves’ disease induce the expression of T cell chemoattractants in their fibroblasts. J Immunol 168(2):942–950. https://doi.org/10.4049/jimmunol.168.2.942 (PMID: 11777993)

    Article  CAS  PubMed  Google Scholar 

  185. Pritchard J, Han R, Horst N, Cruikshank WW, Smith TJ (2003) Immunoglobulin activation of T cell chemoattractant expression in fibroblasts from patients with Graves’ disease is mediated through the insulin-like growth factor I receptor pathway. J Immunol 170(12):6348–6354. https://doi.org/10.4049/jimmunol.170.12.6348 (PMID: 12794168)

    Article  CAS  PubMed  Google Scholar 

  186. Crudden C, Girnita A, Girnita L (2015) Targeting the IGF-1R: The Tale of the Tortoise and the Hare. Front Endocrinol (Lausanne) 6:64. https://doi.org/10.3389/fendo.2015.00064 (PMID:25964779;PMCID:PMC4410616)

    Article  Google Scholar 

  187. Reiter E, Ayoub MA, Pellissier LP, Landomiel F, Musnier A, Tréfier A, Gandia J, De Pascali F, Tahir S, Yvinec R, Bruneau G, Poupon A, Crépieux P (2017) β-arrestin signalling and bias in hormone-responsive GPCRs. Mol Cell Endocrinol 449:28–41. https://doi.org/10.1016/j.mce.2017.01.052 (PMID: 28174117)

    Article  CAS  PubMed  Google Scholar 

  188. Kenakin T, Christopoulos A (2013) Signalling bias in new drug discovery: detection, quantification and therapeutic impact. Nat Rev Drug Discov 12(3):205–216. https://doi.org/10.1038/nrd3954 (PMID: 23411724)

    Article  CAS  PubMed  Google Scholar 

  189. Kim J, Ahn S, Rajagopal K, Lefkowitz RJ (2009) Independent beta-arrestin2 and Gq/protein kinase Czeta pathways for ERK stimulated by angiotensin type 1A receptors in vascular smooth muscle cells converge on transactivation of the epidermal growth factor receptor. J Biol Chem 284(18):11953–11962. https://doi.org/10.1074/jbc.M808176200 (PMID:19254952;PMCID:PMC2673264)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Lin FT, Daaka Y, Lefkowitz RJ (1998) beta-arrestins regulate mitogenic signaling and clathrin-mediated endocytosis of the insulin-like growth factor I receptor. J Biol Chem 273(48):31640–31643. https://doi.org/10.1074/jbc.273.48.31640 (PMID: 9822622)

    Article  CAS  PubMed  Google Scholar 

  191. Girnita L, Shenoy SK, Sehat B, Vasilcanu R, Girnita A, Lefkowitz RJ, Larsson O (2005) {beta}-Arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase. J Biol Chem 280(26):24412–24419. https://doi.org/10.1074/jbc.M501129200 (PMID: 15878855)

    Article  CAS  Google Scholar 

  192. Girnita L, Shenoy SK, Sehat B, Vasilcanu R, Vasilcanu D, Girnita A, Lefkowitz RJ, Larsson O (2007) Beta-arrestin and Mdm2 mediate IGF-1 receptor-stimulated ERK activation and cell cycle progression. J Biol Chem 282(15):11329–11338. https://doi.org/10.1074/jbc.M611526200 (PMID: 17303558)

    Article  CAS  Google Scholar 

  193. Zheng H, Shen H, Oprea I, Worrall C, Stefanescu R, Girnita A, Girnita L (2012) β-Arrestin-biased agonism as the central mechanism of action for insulin-like growth factor 1 receptor-targeting antibodies in Ewing’s sarcoma. Proc Natl Acad Sci USA 109(50):20620–20625. https://doi.org/10.1073/pnas.1216348110 (PMID:23188799;PMCID:PMC3528604)

    Article  PubMed  PubMed Central  Google Scholar 

  194. Weightman DR, Perros P, Sherif IH, Kendall-Taylor P (1993) Autoantibodies to IGF-1 binding sites in thyroid associated ophthalmopathy. Autoimmunity 16(4):251–257. https://doi.org/10.3109/08916939309014643 (PMID: 7517705)

    Article  CAS  PubMed  Google Scholar 

  195. Reiss K, Tu X, Romano G, Peruzzi F, Wang JY, Baserga R (2001) Intracellular association of a mutant insulin-like growth factor receptor with endogenous receptors. Clin Cancer Res 7(7):2134–2144 (PMID: 11448933)

    CAS  PubMed  Google Scholar 

  196. Smith TJ, Hoa N (2004) Immunoglobulins from patients with Graves’ disease induce hyaluronan synthesis in their orbital fibroblasts through the self-antigen, insulin-like growth factor-I receptor. J Clin Endocrinol Metab 89(10):5076–5080. https://doi.org/10.1210/jc.2004-0716 (PMID: 15472208)

    Article  CAS  PubMed  Google Scholar 

  197. Douglas RS, Gianoukakis AG, Kamat S, Smith TJ (2007) Aberrant expression of the insulin-like growth factor-1 receptor by T cells from patients with Graves’ disease may carry functional consequences for disease pathogenesis. J Immunol 178(5):3281–3287. https://doi.org/10.4049/jimmunol.178.5.3281 (PMID: 17312178)

    Article  CAS  PubMed  Google Scholar 

  198. Douglas RS, Naik V, Hwang CJ, Afifiyan NF, Gianoukakis AG, Sand D, Kamat S, Smith TJ (2008) B cells from patients with Graves’ disease aberrantly express the IGF-1 receptor: implications for disease pathogenesis. J Immunol 181(8):5768–5774. https://doi.org/10.4049/jimmunol.181.8.5768 (PMID: 18832736)

    Article  CAS  PubMed  Google Scholar 

  199. Tsui S, Naik V, Hoa N, Hwang CJ, Afifiyan NF, Sinha Hikim A, Gianoukakis AG, Douglas RS, Smith TJ (2008) 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 181(6):4397–4405. https://doi.org/10.4049/jimmunol.181.6.4397 (PMID: 18768899)

    Article  CAS  PubMed  Google Scholar 

  200. Varewijck AJ, Boelen A, Lamberts SW, Fliers E, Hofland LJ, Wiersinga WM, Janssen JA (2013) Circulating IgGs may modulate IGF-I receptor stimulating activity in a subset of patients with Graves’ ophthalmopathy. J Clin Endocrinol Metab 98(2):769–776. https://doi.org/10.1210/jc.2012-2270 (PMID: 23295466)

    Article  CAS  PubMed  Google Scholar 

  201. Minich WB, Dehina N, Welsink T, Schwiebert C, Morgenthaler NG, Köhrle J, Eckstein A, Schomburg L (2013) Autoantibodies to the IGF1 receptor in Graves’ orbitopathy. J Clin Endocrinol Metab 98(2):752–760. https://doi.org/10.1210/jc.2012-1771 (PMID: 23264397)

    Article  CAS  PubMed  Google Scholar 

  202. Yee D, Cullen KJ, Paik S, Lippman ME, Rosen N (1989) Growth regulation of human breast cancer by insulin-like growth factors. In: LeRoith D, Raizada MK (eds) Molecular and cellular biology of insulin-like growth factors and their receptors. Springer, Boston

    Google Scholar 

  203. Krieger CC, Place RF, Bevilacqua C, Marcus-Samuels B, Abel BS, Skarulis MC, Kahaly GJ, Neumann S, Gershengorn MC (2016) TSH/IGF-1 receptor cross talk in graves’ ophthalmopathy pathogenesis. J Clin Endocrinol Metab 101(6):2340–2347. https://doi.org/10.1210/jc.2016-1315 (PMID:27043163;PMCID:PMC4891793)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Chaplin R, Thach L, Hollenberg MD, Cao Y, Little PJ, Kamato D (2017) Insights into cellular signalling by G protein coupled receptor transactivation of cell surface protein kinase receptors. J Cell Commun Signal 11(2):117–125. https://doi.org/10.1007/s12079-017-0375-9 (PMID:28168348;PMCID:PMC5440347)

    Article  PubMed  PubMed Central  Google Scholar 

  205. Gavi S, Shumay E, Wang HY, Malbon CC (2006) G-protein-coupled receptors and tyrosine kinases: crossroads in cell signaling and regulation. Trends Endocrinol Metab 17(2):48–54. https://doi.org/10.1016/j.tem.2006.01.006 (PMID: 16460957)

    Article  CAS  PubMed  Google Scholar 

  206. Krieger CC, Boutin A, Jang D, Morgan SJ, Banga JP, Kahaly GJ, Klubo-Gwiezdzinska J, Neumann S, Gershengorn MC (2019) Arrestin-β-1 physically scaffolds tsh and igf1 receptors to enable crosstalk. Endocrinology 160(6):1468–1479. https://doi.org/10.1210/en.2019-00055 (PMID:31127272;PMCID:PMC6542485)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Smith TJ (2019) Challenges in orphan drug development: identification of effective therapy for thyroid-associated ophthalmopathy. Annu Rev Pharmacol Toxicol 6(59):129–148. https://doi.org/10.1146/annurev-pharmtox-010617-052509 (Epub 2018 25 PMID: 30044728)

    Article  CAS  Google Scholar 

  208. Gong Y, Yao E, Shen R, Goel A, Arcila M, Teruya-Feldstein J, Zakowski MF, Frankel S, Peifer M, Thomas RK, Ladanyi M, Pao W (2009) High expression levels of total IGF-1R and sensitivity of NSCLC cells in vitro to an anti-IGF-1R antibody (R1507). PLoS ONE 4(10):e7273. https://doi.org/10.1371/journal.pone.0007273 (PMID:19806209;PMCID:PMC2752171)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Kurzrock R, Patnaik A, Aisner J, Warren T, Leong S, Benjamin R, Eckhardt SG, Eid JE, Greig G, Habben K, McCarthy CD, Gore L (2010) A phase I study of weekly R1507, a human monoclonal antibody insulin-like growth factor-I receptor antagonist, in patients with advanced solid tumors. Clin Cancer Res 16(8):2458–2465. https://doi.org/10.1158/1078-0432.CCR-09-3220 (PMID: 20371689)

    Article  CAS  PubMed  Google Scholar 

  210. Hua H, Kong Q, Yin J, Zhang J, Jiang Y (2020) Insulin-like growth factor receptor signaling in tumorigenesis and drug resistance: a challenge for cancer therapy. J Hematol Oncol 13(1):64. https://doi.org/10.1186/s13045-020-00904-3 (PMID:32493414;PMCID:PMC7268628)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Sarfstein R, Belfiore A, Werner H (2010) Identification of insulin-like growth factor-i receptor (igf-ir) gene promoter-binding proteins in estrogen receptor (er)-positive and er-depleted breast cancer cells. Cancers (Basel) 2(2):233–261. https://doi.org/10.3390/cancers2020233 (PMID:24281069;PMCID:PMC3835077)

    Article  CAS  Google Scholar 

  212. Qu X, Wu Z, Dong W, Zhang T, Wang L, Pang Z, Ma W, Du J (2017) Update of IGF-1 receptor inhibitor (ganitumab, dalotuzumab, cixutumumab, teprotumumab and figitumumab) effects on cancer therapy. Oncotarget 8(17):29501–29518. https://doi.org/10.18632/oncotarget.15704 (PMID:28427155;PMCID:PMC5438747)

    Article  PubMed  PubMed Central  Google Scholar 

  213. Smith TJ, Kahaly GJ, Ezra DG, Fleming JC, Dailey RA, Tang RA, Harris GJ, Antonelli A, Salvi M, Goldberg RA, Gigantelli JW, Couch SM, Shriver EM, Hayek BR, Hink EM, Woodward RM, Gabriel K, Magni G, Douglas RS (2017) Teprotumumab for thyroid-associated ophthalmopathy. N Engl J Med 376(18):1748–1761. https://doi.org/10.1056/NEJMoa1614949 (PMID:28467880;PMCID:PMC5718164)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Terwee CB, Gerding MN, Dekker FW, Prummel MF, Wiersinga WM (1998) Development of a disease specific quality of life questionnaire for patients with Graves’ ophthalmopathy: the GO-QOL. Br J Ophthalmol 82(7):773–779. https://doi.org/10.1136/bjo.82.7.773 (PMID:9924370;PMCID:PMC1722683)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Douglas RS, Kahaly GJ, Patel A, Sile S, Thompson EHZ, Perdok R, Fleming JC, Fowler BT, Marcocci C, Marinò M, Antonelli A, Dailey R, Harris GJ, Eckstein A, Schiffman J, Tang R, Nelson C, Salvi M, Wester S, Sherman JW, Vescio T, Holt RJ, Smith TJ (2020) Teprotumumab for the treatment of active thyroid eye disease. N Engl J Med 382(4):341–352. https://doi.org/10.1056/NEJMoa1910434 (PMID: 31971679)

    Article  CAS  PubMed  Google Scholar 

  216. Kahaly GJ, Douglas RS, Holt RJ, Sile S, Smith TJ (2021) 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. https://doi.org/10.1016/S2213-8587(21)00056-5 (PMID: 33865501)

    Article  PubMed  Google Scholar 

  217. Okuyama T, Kyohara M, Terauchi Y, Shirakawa J (2021) The Roles of the IGF axis in the regulation of the metabolism: interaction and difference between insulin receptor signaling and igf-i receptor signaling. Int J Mol Sci 22(13):6817. https://doi.org/10.3390/ijms22136817 (PMID: 34202916)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Markham A (2020) Teprotumumab: first approval. Drugs 80(5):509–512. https://doi.org/10.1007/s40265-020-01287-y (PMID: 32157641)

    Article  CAS  PubMed  Google Scholar 

  219. Sears CM, Azad AD, Dosiou C, Kossler AL (2020) Teprotumumab for dysthyroid optic neuropathy: early response to therapy. Ophthalmic Plast Reconstr Surg. https://doi.org/10.1097/IOP.0000000000001831 (PMID: 32976335)

    Article  Google Scholar 

  220. Slentz DH, Smith TJ, Kim DS, Joseph SS (2021) Teprotumumab for optic neuropathy in thyroid eye disease. JAMA Ophthalmol 139(2):244–247. https://doi.org/10.1001/jamaophthalmol.2020.5296 (PMID: 33270090)

    Article  PubMed  Google Scholar 

  221. Hwang CJ, Nichols EE, Chon BH, Perry JD (2021) Bilateral dysthyroid compressive optic neuropathy responsive to teprotumumab. Eur J Ophthalmol. https://doi.org/10.1177/1120672121991042 (PMID: 33525898)

    Article  PubMed  Google Scholar 

  222. Ozzello DJ, Kikkawa DO, Korn BS (2020) Early experience with teprotumumab for chronic thyroid eye disease. Am J Ophthalmol Case Rep 19:100744. https://doi.org/10.1016/j.ajoc.2020.100744 (PMID:32462101;PMCID:PMC7243051)

    Article  PubMed  PubMed Central  Google Scholar 

  223. Ozzello DJ, Dallalzadeh LO, Liu CY (2021) Teprotumumab for chronic thyroid eye disease. Orbit 1:1–8. https://doi.org/10.1080/01676830.2021.1933081 (PMID: 34060414)

    Article  Google Scholar 

  224. Larché M, Wraith DC (2005) Peptide-based therapeutic vaccines for allergic and autoimmune diseases. Nat Med 11(4 Suppl):S69-76. https://doi.org/10.1038/nm1226 (PMID: 15812493)

    Article  CAS  PubMed  Google Scholar 

  225. Anderton SM, Viner NJ, Matharu P, Lowrey PA, Wraith DC (2002) Influence of a dominant cryptic epitope on autoimmune T cell tolerance. Nat Immunol 3(2):175–181. https://doi.org/10.1038/ni756 (PMID: 11812995)

    Article  CAS  PubMed  Google Scholar 

  226. Payne AS, Ishii K, Kacir S, Lin C, Li H, Hanakawa Y, Tsunoda K, Amagai M, Stanley JR, Siegel DL (2005) Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display. J Clin Invest 115(4):888–899. https://doi.org/10.1172/JCI24185 (PMID:15841178;PMCID:PMC1070425)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Ellebrecht CT, Bhoj VG, Nace A, Choi EJ, Mao X, Cho MJ, Di Zenzo G, Lanzavecchia A, Seykora JT, Cotsarelis G, Milone MC, Payne AS (2016) Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 353(6295):179–184. https://doi.org/10.1126/science.aaf6756.PMID:27365313;PMCID:PMC5343513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

National Institutes of Health Grants EY008976,

Author information

Author notes

  1. E. J. Neag

    Present address: Michigan State University College of Osteopathic Medicine, East Lansing, MI, USA

Authors and Affiliations

  1. Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, Brehm Tower, 1000 Wall Street, Ann Arbor, MI, 48105, USA

    E. J. Neag & T. J. Smith

  2. Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical School, Ann Arbor, MI, 48105, USA

    E. J. Neag & T. J. Smith

Authors
  1. E. J. Neag
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. J. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors participated in the writing of the manuscript.

Corresponding author

Correspondence to T. J. Smith.

Ethics declarations

Conflict of interest

TJS was issued US patents for the use of IGF-I receptor inhibition in the treatment of autoimmune diseases. These are held by UCLA and the Lundquist Institute. He is a paid consultant for Horizon Therapeutics.

Ethics approval

Not applicable.

Informed consent

Not applicable.

Research involving human or animal participants

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Neag, E.J., Smith, T.J. 2021 update on thyroid-associated ophthalmopathy. J Endocrinol Invest 45, 235–259 (2022). https://doi.org/10.1007/s40618-021-01663-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-021-01663-9

Keywords

Search

Navigation