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Thyroid Associated Orbitopathy

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1 Thyroid Associated Orbitopathy
10th Asia and Oceania Thyroid Association Congress October 21-23, 2012 Thyroid Associated Orbitopathy Thank you for Prof. Do-Joon Park, and Prof. Karel Pandelaki, for kind introduction! Ladies and Gentlemen! It is a great pleasure for me to have this opportunity to talk you about Thyroid associated orbitopathy. Slide on please! Yuji Hiromatsu, M.D., Ph.D. Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume, Japan   1

2 Thyroid Associated Orbitopathy
10th Asia and Oceania Thyroid Association Congress October 21-23, 2012 Thyroid Associated Orbitopathy Pathogenesis Role of MRI Treatment I will talk about the recent advances on the pathogenesis, usufellness of MRI and current problems on the therapy. Yuji Hiromatsu, M.D., Ph.D. Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume, Japan   2

3 Site Primary Secondary impairment Eyelid Conj. Extra- ocular Muscle
Müller’s muscle Eyelid Lev palpebrae sup 上眼瞼挙筋 上眼瞼挙筋 Conj. Lid retraction Abnormal Secretion of Lacrimal fluid Extra- ocular Muscle Lacrimal gland 涙腺 Cornea The impairment of Muller’s muscle and/or levator palpebrae superior cause lid retraction. The enlargement of extraocular muscle and expansion of orbital connective tissue cause proptosis. Subsequently, resulting in various clinical manifestations. Orbital connective tissue 脂肪組織 Optic Nerve Retina Proptosis Extraocular Muscle 外眼筋 外眼筋

4 immunological tolerance
Graves’ disease Morbus Basedow Genetic factor Enviromental factor Breakdown of immunological tolerance Robert James Graves (1796~1853) TRAb Carl von Basedow 25~50% (1799~1854) Graves’ ophthalmopathy is frequently associated with Graves’ disease, and is thought to be an autoimmune disorder against shared antigens between thyroid and the orbit, especially TSH receptor. However, precise mechanisms ongoing in the orbit remained unclear.  バセドウ病眼症はバセドウ病に25~50%に合併する。甲状腺と後眼窩組織との共通抗原(、特にTSH受容体)に対する自己免疫疾患と考えられている。 80~90% Hyperthyroidism Graves’ ophthalmopathy Pretibial myxedema (Thyroid associated orbitopathy) 4

5 TNFαgene expression in eye muscle tissue
Enlargement of eye muscle Increase of orbital fat tissue P < 0.05 P < 0.05 P < 0.05 1400 2500 P < 0.05 1200 2000 1000 Enlargement of eye muscles(mm2) 800 1500 Orbital fat volume (mm2) There are 2 types of ophthalmopathy: one is the increase of orbital fat tissue, the other is enlargement of eye muscle. There are significant association between TNFa gene expression and eye muscle enlargement. Orbital fat volume are significantly associated with IL-6 expression, and inversely related to the expression of IL-4 and IL-10. 600 1000 400 500 200 TNFαgene expression in eye muscle tissue IL-4 IL-6 IL-10 Cytokine gene expression in orbital fat tissue (Hiromatsu et al.: JCEM 85:1194, 2000)

6 Expression of TSH-R mRNA in the orbit
RT-PCR TSH-R (1.2kb) TSH-R (296 bp) In situ hybridization The presence of TSH receptor in the orbit has been reported from several laboratory by RT-PCR, in situ hybridization and oher methods. RT-PCRやin situ hybridization法により後眼窩脂肪組織におけるTSH受容体mRNAの発現を見たものである。甲状腺組織に比べるとその発現は少ないが、少量ながら発現していることが明らかとなった。特に培養線維芽細胞には発現率が高かった。 anti-sense sense (Hiromatsu et al. Thyroid 6: 553, 1996) 6

7 Gene Array Studies Gene Fold Function PPAR-g 44.2 Signal transduction
Pro-platelet basic protein 32.9 Cell proliferaion Collagen type 1a1 28.2 differentiation Adiponectin 25.0 Metabolism IL-6 23.9 Cell proliferation Glycogenin 2 22.4 Glycogen biosynthesis sFRP-1 18.5 活動期の眼症患者の眼窩組織における遺伝子発現をGene Array法にて解析すると、このスライドのようにPPARg, adiponectin, IL-6, sFRP-1など脂肪分化増殖に関連する遺伝子の発現が亢進しています。  sFRP-1 (secreted frizzled related protein-1) (Kumar et al.: JCEM 90:4730, 2005) 7

8 sFRP-1 (100 nM) induced adiponectin mRNA (A), leptin mRNA (B), and TSHr mRNA (C) expression on orbital fibroblasts sFRP-1 induces adiponectin and leptin gene expression, which are markers of adipogenesis. It also induces expression of TSHR on orbital fibroblasts. sFRP-1はadiponectinやleptinやTSH受容体の発現を誘導します。 Wntシグナルを抑制することによるといわれています。 sFRP-1 (secreted frizzled related protein-1) (Kumar, S. et al. J Clin Endocrinol Metab 2005;90: ) sFRP-1 induces adipogenesis and expression of TSHR on orbital fibroblasts. 8

9 Peroxisome Proliferator-Activated Receptor-g in Thyroid
Eye Disease: Contraindicaiton for Thiazolidinedion Use? (Starkey et al: J Clin Endocrinol Metab 88: 55-59, 2003) 57 yr-old male, 8-yr history of type 2 DM Pioglitazone 30mg/d for 3 months 6wk pre 3m on 3m stop Proptosis rt 19mm lt Conj. Redness (-) mild (-) Lid swelling Mild Severe Severe Diplopia (-) Intermittent (-) CAS Thiazolidinedione, which is a PPAR-gamma agonist, induced Graves’ ophthalmopathy. He has mild GO and diabetes. 3 months after the treatment of pioglytazone, he had exacervation of opthalmopathy. We need caution and close supervision of patients who have AITD or TED when treated with TZDs (PPARg agonist). The results suggest that PPARg antagonists could ameliorate TED by reducing orbital adipogenesis. 9

10 Thiazolidinedione induced Graves’ ophthalmopathy
Starkey K, Heufelder A, Baker G, Joba W, Evans M, Davies S, Ludgate M.: Peroxisome proliferator-activated receptor-gamma in thyroid eye disease: contraindication for thiazolidinedione use? J Clin Endocrinol Metab. 2003;88:55–9. Levin F, Kazim M, Smith TJ, Marcovici E.: Rosiglitazone-induced proptosis. Arch Ophthalmol. 2005;123:119–21. Dorkhan M, Lantz M, Frid A, Groop L, Hallengren B.: Treatment with a thiazolidinedione increases eye protrusion in a subgroup of patients with type 2 diabetes. Clin Endocrinol (Oxf). 2006;65:35–9. Lee S, et al.: Thiazolidinedione induced thyroid associated orbitopathy. BMC Ophthalmol. 2007; 7: 8. Since then there are 3 reports on this issue. Thiazolidinedione induced Graves’ ophthalmopathy. Treatment with a thiazolidinedione increases eye protrusion in a subgroup of patients with type 2 diabetes. Thiazolidinedione induced thyroid associated orbitopathy.

11 Orbital fibroblasts serum CD34+OF CD34-OF CD34+ fibrocytes TSHR↑
TSHR Ab Orbital fibroblasts IGF-1R Ab serum + IL-1b IFNg TGFb TNFa Adipogenesis Glycosaminoglycans short chain hyaluronan long chain hyaluronan IL-6 IL-8 TSHR Ab IGF-1R Ab PPARg _ TGFb TNFa TSHR↑ proliferation IGF-1R↑ CD34+OF preadipocytes CD34-OF IL-16 RANTES CXCL10 HLA B7 CD40 CD40L Orbit IL-1a IL-8 COX-2 CXCL12 T cell IL-6 TNFa T cell CXCR4 TCR Cytokine Th1, Th2 Thy1+:TGF-bの作用でmyofibroblastsへ分化 Thy1ー:adiocytesへ分化 TRAbs stimulate the subtype of OF, especially CD34+ fibrobrasts, which express more TSHR, begin to differentiate into adipocytes with increased expression of TSH-R, begin to differentiate to adipocytes with increased expression of TSHR, and proliferate and produce hyaluronan and glycosaminoglycan, which cause the edema. Proliferate and produce hyaluronana and secrete chemokines, such as IL-16, CXCL10, which promote the T cell migration into the orbit. B cell activation Migration of T cells Macrophages Th1-:Leukoregulin,TNFα, IL-1β, INFβ, INFγ, IL-2, IL-12 Th2-:IL-4, IL-5, IL-10 IL-1 TNFa TGFb Antibody TSHR Ab IGF-1R Ab

12 CD90 (Thy-1)+ orbital fibroblasts may differentiate into myofibroblasts, that participate in the development of fibrosis in late stages of the disease. Thy-1+ OF TGF-β Myofibroblast CD90 (Thy-1)+ orbital fibroblasts may differentiate into myofibroblasts in the presence of TGFb, that participate in the development of fibrosis in late stages of the disease. Expanded Adipose tissues Bahn R.S: N Engl J Med 2010; 362: Elevated TRAb Extraocular muscle enlargement Fibrosis

13 Relationships between anti-TSH receptor antibidies and GO
TRAB ( 1st generation; TBII) TRAb (2nd generation; hTRAb; TRAb-CT) TRAb (3rd generation; M22) TSAb TSI [Mc4; chimeric TSH-R (amino acid residues of human TSH-R replaced by rat LH-R) ] Are anti-TSH receptor antibodies related to the severity, course of GO? These TRAbs are measured and relationships between anti-TSH receptor antibodies and GO have investigated.

14 Anti-TSH receptor Antibodies
At the first visit, there is no difference in the prevalence of TRAb between GO and GD without ophthalmopathy. TSH-R antibodies GO(+) GO(ー) Normal  TBII 67%    85%    0% TSAb 59%    83%    0% In GO patients there are significant correlation between TRAb and the enlargement of eye muscle. T S A Enlargement of EM b TBII Enlargement of EM (Nishikawa et al., Acta Endocrinol 129: 213, 1993) (Hiromatsu et al., Thyroid 6: 553, 1996)

15 Anti-TSH receptor antibody in GO
Mild GO Severe GO TRAK human, 2nd generation, was greater in severe GO patients compared to mild GO.

16 The novel chimeric(Mc4) TSH-R (amino acid residues 262-335 of human TSH-R replaced by rat LH-R)

17 A novel thyroid stimulating immunoglobulin assay
chimeric (Mc4) TSH-R (amino acid residues of human TSH-R replaced by rat LH-R) TSI level of GO was greater than that of Graves’ disease without ophthalmopathy. Majority of patients with GD had undergone antithyroid treatment and were rendered euthyroid at the time of blood sampling.

18 Very good correlation between TSI and clinical disease activity has been reported.
Correlation of the thyroid stimulating lgs in GO with clinical disease activity.

19 Inflammation / fibrosis
Greves’ ophthalmopathy Genetic factors Enviromental factors EM antigens Inflammation / fibrosis G2s HLA TNFa ICAM-1 NFkB1 FOXP3 CTLA-4 CD40 PTPN22 1D Anti-EM Ab smoking SDH Severe Calsequestrin Collagen XIII Th1, Th2 cytokines Breakdown of immune tolerance IGF-1R Ab IGF-1receptor↑ Mild adipogenesis TSH receptor ↑ sFRP-1, CYR61 Tg TSI Anti-TSH receptor Abs G2s TSH receptor So our working hypothesis of pathogenesisis shown in this slide. Autoimmune reaction against shared antigen between thyroid and orbit, especially TSH-R. TSH-R is present in the orbit and its expression is induced during the adipogenesis. IL-6, inflammatory cytokine, also induce the expression of TSH-R. In severe cases, autoimmune reaction against eye muscle antigens occurs. However, it remains unclear whether it may cause eye muscle dysfunction or not. It is also unclear what is the mechanism for the breakdown of immune tolerance agaist TSH receptor. 1D Hyperthyroidism (Graves’ disease) Th2 thyroiditis Tg Shared antigens Between thyroid and orbit

20 Susceptibility genes Graves’ disease GO
  Japanese  Polish  Japanese Polish TNFa No   Yes Clin Endocrinol 2000;52:759 No Yes   Hum Immunol 2004;65:632 IFNg     Yes   No Thyroid 2004;14:93 IL-6 No No   No No Autoimmunity 2004;37:223 IL-12B No   No Endocrine J 2004;51:609 IL-13 Yes   No JCEM 2005;90:296 No   No Clin Endocrinol 2003;59:519 IL-18 No   weak Thyroid 2006;16 :243 CTLA-4 Yes Yes   No No Eur J Endo 2003;148:13 JCEM 2007;92:3162 CD40    Yes (>40y)   No Endocrinol J 2005;52:471 Yes No Thyroid 2005;15:1119 ICAM-1 No Yes (<40y) weak Yes JCEM 2003; 88:4945 PTPN22 Yes   No Clin Endocrinol 2005;62:679 Yes No Thyroid. 2008;18:625 NFkB1 No Yes Yes No Genes Immun. 2007;8:532 PPARg No weak submitted Candidate Genes 遺伝因子 バセドウ病およびバセドウ病眼症の候補遺伝子に関する研究についてまとめたものです。T細胞の活性化を抑制するCTLA4遺伝子多型は人種を越えてバセドウ病の発症に関与しているようです。 一方、バセドウ病眼症に関しましてはTNFα遺伝子多型が日本人、中国人、ポーランド人で関連しているとの報告がみられます。 20

21 TNF-α gene polymorphism (T-1031C) and GO
(日本人) genotype Allele frequency n TT TC CC    T C     OR GO GD w/o oph 62 111 28 (45.2) 81 (73.0) 29 (46.7) 30 (27.0) 5 (8.1) (0) 85 (68.5) 192 (86.5) 39* (31.5) 30 (13.5) 2.9 We showed the association of the TNF-a gene -1031T/C polymorphism with severity of GO. TNFα遺伝子プロモーター領域のT-1031C多型と眼症との関係をみると、眼症患者では眼症のないか或いは軽症の患者に比べてCアレル頻度が有意に高い。 *P=0.0001 The C allele frequency is higher in GO patients. (Kamizono et al. Clin Endocrinol 2000; 52: ) 21

22 ICAM-1 gene polymorphism
K469E (1405 A→G) Genotype frequency Allele frequency ATA class AA 46 72 (%) (49) (36) GA 36 99 (%) (39) (49) GG 11 30 (%) (12) (15)  A (%) 128(69) 243(60)   G (%)  58(31) 159(40) OR 1.44 class ⅢーⅥ class 0-Ⅱ χ2=4.925 P=0.0852 χ2=3.825 P=0.0505 AA 46 72 (%) (49) (36) GA + GG (%)  47(51) 129(64) OR 1.75 class ⅢーⅥ class 0-Ⅱ バセドウ病患者の中で、眼症を伴うものと伴わないものを比較検討したところ、AA genotypeの頻度が眼症群で有意に高かった。 χ2=4.643 P=0.0312 The AA genotype frequency is higher in severe GO .

23 NFkB1 gene polymorphism (-94del ATTG)
Genotype frequency Allele frequency ATA class N Del (%) Hetero (%) Ins (%) Del (%) Ins (%) Ⅲ~Ⅵ 123 25(20%) 59(48%) 39(32%) 109(44%) 137(56%) 0~Ⅱ 301 38(13%) 132(44%) 131(43%) 208(35%) 394(65%) -94delATTG多型の40%が重症の眼症。軽症23% χ2=6.853 P=0.0325 OR 1.76 χ2=7.103 P=0.0077 OR 1.51 The -94delATTG polymorphism of the NFkB1 gene is higher in severe GO.

24 PPARγ (Pro12Ala) gene polymorphism
Genotype Allele ATA class N CC (%) CG (%) GG (%) C (%) G (%) Ⅲ~Ⅵ 123 120(31%)  3(13%)  0(0%) 243(30%)  3(11%) 0~Ⅱ 294 271(69%) 21(87%) 2(100%) 563(70%) 25(89%) Clinical Endocrinology2009;70:464-468にPro12Ala変異は,less transcriptional activity, less active, less severeと報告されている。(オランダ) 今回の成績は合致する。 Χ2=4.439 P = Χ2=4.430 P = OR 3.39 Fisher’s exact probability test P = OR 3.59 Patients with CC genotype frequently have severe ophthalmopathy.

25 PPARγ(Pro12Ala) gene polymorphism
Genotype Allele ATA class CC (%) CG (%) GG (%) C (%) G (%)   OR N 391 24 2 806 28 5 23 95 10 24 260 VI IV III II I 4(1%) 22(6%) 94(24%) 8 (2%) 23(6%) 240(61%) 1(4%) 2(8%) 19(79%) 9(1%) 45(6%) 189(23%) 18(2%) 46(6%) 499(62%) 1(4%) 2(7%) 21(75%) 0.38 1.89 7.95 0.96 - 1) 2) PPARγ遺伝子多型と眼症の重症度についてATA class0とATA class IIIで比較したところ、有意差があり、CC genotype、C allele と眼球突出との間に関連が示唆されます。 1) Fisher’s exact probability test P=0.0197 (III vs. 0) 2) Fisher’s exact probability test P=0.0134(III vs. 0) Graves’ disease patients with CC genotype frequently have proptosis compared to those with other genotypes.

26 Summary (1) TSH receptor is a primary autoantigen in GO. Recent study suggests the presence of GO specific TRAb (Mc4)? The increase of TSH receptor expression through adipogenesis is important in the pathogenesis of GO. 3. CD34+ fibroblasts, which are derived from peripheral blood and expand in the orbit, express TSH receptor in high level. 26

27 4. The increase of IGF-1 receptor expression in the orbital fibroblasts may also be important. Activation of IGF-1R leads secretion of IL-16 and RANTES on CD34- fibroblasts, which enhance recruitment of activated T lymphocytes. CD90 (Thy-1)+ orbital fibroblasts may differentiate into myofibroblasts that participate in the development of fibrosis in late stages of the disease. Gene polymorphisms of the immunomodulator genes (such as TNFa, ICAM-1, NFkB, PPARg and FOXP3 etc) have been proposed as the susceptibility genes for GO. The significance of the presence of anti-eye muscle antibodies, such as SDH, CASQ needs to be confirmed. 27

28 Thyroid Associated Orbitopathy
Pathogenesis Role of MRI Treatment

29 NOSPECS classification of eye changes of Graves’ disease (Thyroid 2:235, 1992)
Definition No physical signs or symptoms I Only signs, no symptoms (upper lid retraction, stare, and eyelid lag) II Soft tissue involvement (symptoms and signs) III Proptosis IV Extraocular muscle involvement V Corneal involvement VI Sight loss (optic nerve involvement) This is a famous mnemonic NOSPECS classification of GO, and still useful for reminder of the features that should be assessed.

30 50~75% of patients with Graves’ disease do not have any signs or symptoms of GO.
NOSPECS classification of eye changes of Graves’ disease (Thyroid 2:235, 1992) Class Definition No physical signs or symptoms I Only signs, no symptoms (upper lid retraction, stare, and eyelid lag) II Soft tissue involvement (symptoms and signs) III Proptosis IV Extraocular muscle involvement V Corneal involvement VI Sight loss (optic nerve involvement) MRI 70% More than a half patients with Graves’ disease do not have evident ophthalmopathy. However, If we take MRI, 70% of patients with Graves’ disease have subclinical eye involvement. 30

31 Occult Thyroid Eye Disease
Case 1 Case 2 No physical signs or symptoms These 2 ladies did not have any signs or symptoms of GO. But MRI revealed the enlargement of right lower rectus muscle in the first case. The second case had left lower rectus muscle. So she has ‘occult thyroid eye disease’. Enlargement of extra-occular muscles 31

32 Only signs, no symptoms (upper lid retraction, stare, and eyelid lag)
Total Mild Moderate severe Lid retraction 1587(79.3) 792(39.6) 620(31.0) 175(8.7) 2000 eyes (%) Inoue et al. MRI

33 Dalrymple sign (lid retraction)
Case 3 Case 4 Both patients showed lid retraction. The First case showed the enlargement of levator palpebrae superioris muscles. The second case showed the enlargement of superior rectus muscle and inferior rectus muscle. 33

34 von Graefe’s sign Case 5 Case 6 Both patients showed Graefe’s sign, a dissociation of the movements of the eyelid and the globe showing sclera above the cornea in downward gaze. MRI reveals the enlargement of levator palpebrae superioris muscle and rectus muscle in those patients. 34

35 Unilateral lid retraction
Case 7 Case 8 Unilateral eye changes occur in 15% of patients with GO. In patients with unilateral lid retraction the enlargement of levator palpebrae superioris muscle and/ or superior rectus muscle are observed in the affected eye. 35

36 Soft tissue involvement (symptoms and signs) Total Mild Moderate
II Soft tissue involvement (symptoms and signs) Total Mild Moderate severe Lid swelling 1354(67.7) 958(47.9) 376(18.8) 20(1.0) Conjunctiva 642(32.1) 451(22.6) 170(8.5) 21(1.0) 2000 eyes (%) Inoue et al. MRI

37 Swelling of upper and lower eyelid
Case 9 In patients with eyelid swelling, there are accumulation of fat tissue in the upper and lower eyelid. 37

38 III Proptosis MRI Untreated Graves’ disease Symptoms 24.2%
 Hertel exophthalmometer mild  39% total 57% moderate 13% severe   5% GO patients (4598 eyes) total 85%   mild 39% moderate 33% severe 13% Proptosis alone 18.5%  + lid lag %  + lid swelling %  + lid lag and lid swelling 16.3% Male   444 eyes female eyes Japanese Proptosis is seen in 24~57% of untreated Graves’ disease and in 85% of GO, and is usually associated with lid retraction and/ or eyelid swelling. MRI 38

39 Proptosis R) 13.0 mm L) 13.0 mm R) 17.0 mm L) 17.0 mm
Proptosis is qntitqtively measured in the horizontal section of T1 image. R) 19.0 mm L) 19.0 mm R) 28.5 mm L) 30.5 mm 39

40 Proptosis 18mm~<21mm Proptosis ≥21mm + lid swelling + lid swelling
Case 11 Case 13 + lid swelling Case 12 Case 14 + lid swelling + lid retraction In patients with exophthalmos(proptosis), various rectus muscles and levator palpebrae superioris muscles are enlarged. 40

41 Extraocular muscle involvement
IV  Extraocular muscle involvement Total Mild Moderate severe Diplopia 447(22.3) 237(11.8) 74(3.7) 136(6.8) 2000 eyes (%) Inoue et al. MRI

42 Diplopia Case 15 Restriction of motion in upward gaze
Enlargement of rt) superior rectus muscle causes the restriction of motion in upward gaze and vertical deviation of rt) eye. The enlarged eye muscle is no longer able to lengthen. Restriction of motion in upward gaze Vertical deviation of right eye Enlargement of right inferior rectus muscle 42

43 Sight loss (optic nerve involvement)
VI  Sight loss (optic nerve involvement) Papilledema Papillitis Optic disc atrophy Total Mild Moderate severe DON 168(8.4) 147(7.4) 13(0.6) 8(0.4) Optic nerve involvement , socalled Dysthyroid optic neuropaty, is observed in 3-5% of GO. 2000 eyes (%) Inoue et al. MRI 43

44 He complains orbital ache and decreased visual acuity.
Eyelid swelling Eyelid eythema Conjunctival redness Proptosis Case 17 MRI: The enlargement of superior, inferior, medial and lateral rectus muscles may compress optic nerve. T2 immage: The increased T2 relaxation time indicates that GO is in active state.

45 Summary (2) MRI is useful for the assessment of GO.
useful for planning of the management of GO. We strongly recommend MRI for management of GO. 45

46 Thyroid Associated Orbitopathy
Pathogenesis Role of MRI Treatment

47 Treatment of Graves’ ophthalmopathy
Mild Moderate to severe Sight-threatening (DON) i.v. GCs (±OR)  prompt decompression Still active Iv GCs (±OR) Rehabilitative surgery Stable & inactive Active     (if needed) i.v. GCs (±OR) Rehabilitative surgery Inactive Local injection of GCs or Botulinum toxin Ophtalmological examination, CAS, QOL Local measures Wait and see MRI Poor response (2 weeks) All patients with GO NOSPECS Class 0 NOSPECS Class I~VI Restore euthyroid (avoid hypothyroidism) Urge smoking withdrawal Occult thyroid eye disease Specialized center Inflammation of Upper eyelids intractable Immuno-suppressant , Decompression eye muscles Stable & inactive Progression

48 Pulse therapy Dysthyroid optic neuropathy(DON)and/or Corneal breakdown
Sight-threating GO (DON) Sight-threating GO (DTN) MRI i.v. Glucocorticoids Pulse therapy Poor response (2 weeks) methylpredonisolone 1g/d 3days 3 cycles Prompt decompression Still active Stable and inactive 1w Dysthyroid optic neuropathy or corneal breakdown is sight-threatening and requires immediate treatment i.v. Glucocorticoids ( orbital radiation) Rehabilitative surgery

49 Pulse therapy Before After 3 cycles
Before the pulse therapy marked enlargement of left medial and inferior rectus muscles are observed and the left . Those muscles showed high signal intensity, suggesting the presence of activity 49

50 Transantral orbital decompression for
Papilledema(dysthyroid optic neuropathy) Papilledema pre 6 months after the surgery post If insufficient improvement is attained, decompressive surgery could be performed to restore visual acuity. Trasantral orbital decompression is performed for optic neuropathy in the active phase. 50

51 Moderately to severe GO
MRI active inactive i.v. Glucocorticoids ( orbital radiation) Rehabilitative surgery Stable and inactive

52 Rehabilitative therapy
Prediction of outcome of Immunosuppressive treatment Rehabilitative therapy Immunosuppressive therapy Immunosuppressive therapy Activity Activity Severity Severity If the immunosuppressive therapy is performed in the active stage, the outcome will be good. If the therapy is performed during the inactive stage, there is no favorable effects. (the outcome may be the same as natural course) Therefore, in this inactive stage, the rehabilitative therapy is indicated. Outcome Outcome 52

53 Pulse therapy Oral steroid Classical Pulse ①
Efficacy: 77% (Pulse+irradiation:88%)  Side effects:peptic ulcer、glucose intolerance、osteoporosis Pulse therapy Oral steroid Classical Pulse 1g/d 3days 3 cycles Prednisolone 20mg 15mg 10mg 5mg Efficacy: 59% ( 44% in 5 RCT ) Side effects: exacerbation of inflammation、Cataract、Retinopathy, Tumorgenesis 1w Irradiation 2Gy 10 times 53

54 Fatal liver failure Acute liver damage occurred in 0.8%, and was lethal in 0.3% of patients with GO underwent iv GC. Direct toxic effect? Precipitation of virus-induced hepatitis? AIH? Case Age Outcome Time of diagnosis Virus Liver disease 1* 71 Death 4 wk after 5 cycles None 2** 56 Death 7.8 wk None steatosis ANA 3 63 Death 7.1 None 4 47 Death 17.1 None 5 45 Recovery 15 None 6 30 Recovery 17.1 None Acute liver damage occurred in 0.8%, and was lethal in 0.3% of patients with GO underwent iv GC. Strict surveillance of possible liver toxicity is mandatory, particularly in patients with liver steatosis. EUGOGO recommends that the cumulative dose should be <8g methylprednisolone in one course of therapy. 7 55 Recovery 15.7 HBV steatosis 8 54 Recovery 3.2 CMV 9*** 43 Recovery 8 None AIH ANA The cumulative dose should be <8g methylprednisolone in one course of therapy. (EUGOGO) * Weissel et al. Thyroid 10: 521, ** Marino et al. Thyroid 14: 403, 2004 *** Salvi et al. Thyroid 14: 631, 2004 54

55 Pulse therapy Oral steroid Classical Pulse ① Oral steroid Mini-pulse ②
Efficacy: 77% (Pulse+irradiation:88%)  Side effects:peptic ulcer、glucose intolerance、osteoporosis Pulse therapy Oral steroid Classical Pulse 1g/d 3days 3 cycles Prednisolone 20mg 15mg 10mg 5mg Efficacy: 59% ( 44% in 5 RCT ) Side effects: exacerbation of inflammation、Cataract、Retinopathy, Tumorgenesis 1w Irradiation 2Gy 10 times Mini-pulse 0.5g/d 3days 3 cycles Oral steroid Prednisolone 20mg 15mg 10mg 5mg We comared the incidence of the liver dysfunctions during and 1 year period after the pulse therapy between 0.5g and 1g of methylprednisolone pulse theray. 1w Irradiation 2Gy 10 times 55

56 Liver dysfunction during and 1 year period after
pulse therapy (4 centers, 480 cases) ALT 540 520 500 480 460 440 420 400 380 360 340 320 300 280 260 240 220 200 180 160 140 120 100 80 60 40 20 before 1 month 6months 12 months 前(ALT) 高値(ALT) 3(ALT) 6(ALT)

57 Liver dysfunction (ALT)
Liver failure and steroid pulse therapy (4 centers) No Liver dysfunction (ALT) >100 50~100 total Methylprednisorone  1g/d, 3 days, 3 courses 136    17 cases 12.5% 27 19.9% 44 32.4% Methylprednisorone 0.5g/d, 3 days, 3 courses 97  3 3.1% 17.5% 20 20.6% Total 233 8.6% 18.9% 64 27.5% Fisher’s exact probability test P=0.0115 c2=3.913、P=0.0479 Liver dysfunction (ALT>100) was more frequently found in patients with high dose of methylprednisolone (>9g) pulse therapy than in low dose (4.5g). -Dose dependency- Out of 20 cases with increase of ALT>100, Two cases were HBcAb+, their ALT increased to 639、326. Four cases were were HCVAb positive, and their ALT elevated to 223,188,149, Reactivation of hepatitis virus infection – In 7 out of 11 cases, who were HCVAB positive before pulse therapy, the increase of ALT was observed.

58 HBV carrier and patietns with past history of HBV infection.
Check HBV-DNA. Avoid pulse therapy. If ophthalmopathy needs pulse therapy, consult with hepatologists for the use of entecavir. Check liver function and HBV-DNA every month during and 1 year-period after pulse therapy. We usually check HBsAg, HBsAb, HBcAb. If it is positive, we recommend to measure HBV-DNA and avoid pulse therapy. If ophthalmopathy needs pulse therapy, consult with hepatologists for the use of entecavir. Check liver function and HBV-DNA every month during and 1 year-period after pulse therapy.

59 Treatment in inactive stage
Rehabilitative Surgery Orbital Decompression Eye Muscle Surgery Eyelid Surgery In inactive stage, rehabilitative surgery is indicated. 59

60 Rehabilitative Surgery Transantral Orbital Decompression
Case 19 Pre 3 months after surgery Proptosis pre Rt 22mm Lt 20mm post Rt 15mm Lt 14mm Severe proposis, lower lid retraction, eyelid edema: were observed in this patient. Proptosis was markedly improved by bilateral transantral orbital decompression 60

61 Deep Lateral Orbital Decompression
before 6months after

62 before 6 months after Case 20 Rt 27mm Lt 28mm Rt 24mm Lt 24mm

63 Rehabilitative Surgery
Eye Muscle Surgery Case 21 パルス療法や放射線照射療法後も複視が残存した場合、非活動期に行われます。Extraocular Muscle Surgery: The enlargement of left inferior rectus muscle caused lt upward gaze impairment. The cicatricial tissue was removed. And inferior rectus muscle was detached from the globe, moved posteriorly (recessed) and reattached to the globe. Lt upward gaze impairment (enlargement of left inferior rectus muscle) Removal of the cicatricial tissue of left inferior rectus muscle 63

64 Rehabilitative Surgery
Eyelid Surgery Lengthening of Levator Muscle Case 22 Pre For severe lid retraction: Lenghening of Levator Muscle procedure by using polytetrafluoroethyrene as spacer. 重症の上眼瞼後退に対して、上眼瞼挙筋の延長術を施行します。 polytetrafluoroethyrene が spacerとして使用されています。 Post Lenghening of Levator Muscle procedure by using polytetrafluoroethyrene as spacer. 64

65 Mild GO MRI Local measures progression active Wait and see
Inflammation of eyelid Inflammation of EM and fat tissues Stable and inactive Local injection of triamcinolone acetonide and botulinum A toxin i.v. glucocorticoids (±orbital radiation Rehabilitative surgery (if needed) Stable and inactive

66 Triamcinolone acetonide injection
Case 23 This patient had right eyelid retraction and lid swelling. Grafe’s sign. MRI reveals the enlargement of levator palpebrae superioris muscle. 2 months after the triamcinolone injection lid retraction and lid swelling are improved. Rt)lid swelling、 lid lag 、Graefe’s sign 2 months after the injection 66

67 Botulinum toxin therapy
Case 24 Botulinum toxin injection is also effective against upper lid retraction. Full effect is evident after 2-3 days and persists for 4-6 weeks. Indication: upper lid retraction

68 Potential Therapeutic Targets in Graves’ ophthalmopathy
Target Current Agent TNF Infliximab TNF receptor Etanercept IL-1 receptor Anakinra IL-6 receptor Tocilizumab TGF-b Lerdelimumab Oxygen free radicals Selenium CD Retuximab CD ChAglyCD3 CD Abatacept CD IDEC-131 PPAR-g Selective PPAR modulators Somatostatin receptor Octreotide-long acting release SOM230 Thyrotropin receptor NIDDK/CEB-52 TSHR antagonist (Org ) Potential therapeutic targets are shown in this slide. Studies on these agents are currently ongoing.

69 Somatostatin analogues
New therapy Somatostatin analogues Somatostatin receptor  orbital fibroblasts, activated lymphocytes express SSR Octreoscan  octreotide accumulates in the orbit Octreotide (0.3~0.6mg x 3/day for 3months) Efficacy 66% Lanreotide (40mg/2w for 3 months) Efficacy 80%   Not useful in RCT (GO 30、placebo 30) Octreotide-long acting rlease (LAR) (30 mg at 4 wk intervals over 4 months) No significant therapeutic effect of octreotide-LAR in 2 RCT. SOM230 Since orbital fibroblasts and activated lymphocytes express somatostatin receptor. And octreotide accumulates in the orbit In active phase of ophthalmopathy. Active stage Inactive stage 69

70 Metaanalysis showed that somatostatin analogs are effective for ophthalmopathy.

71 Anti-CD20 monoclonal Ab (rituximab)
Open study: 9 caces RTX 1000mg iv twice at 2wk interval 20 cases IVGC methylprednisolone 500mg iv for 16 weeks Salvi et al. Eur J Endocrinol 2007; 156:33-40 Rituximab (1000mg) 00 The administration of retuximab 1000 mg twice at 2 weeks interval

72 Anti-CD20 monoclonal Ab (rituximab)
B cell CD20 B cell CD20 Peripheral depletion of CD20+ cells Salvi et al. Eur J Endocrinol 2007; 156:33-40

73 Anti-CD20 monoclonal Ab (rituximab)
    RTX IVGC RTX v.s. IVGC CAS  4.7       2.0   better TRAb  19.3      not significant   not significant not significant    Proposis    22.4      not significant significantly decreased significantly decreased Palpebra    improve improve not significant Side effecs  33% 45% Recurrence  0% 10% And improve CAS , proptosis and appearance. Salvi et al. Eur J Endocrinol 2007; 156:33-40 73

74 Complete Inhibition of rhTSH-, Graves’ Disease IgG-, and M22-Induced cAMP Production in Differentiated Orbital Fibroblasts by a Low-Molecular-Weight TSHR Antagonist Clementine J. J. van Zeijl, Chris J. van Koppen, Olga V. Surovtseva, et al. (J Clin Endocrinol Metab 97: E781–E785, 2012) Clementine J. J. van Zeijl, Chris J. van Koppen, Olga V. Surovtseva, et al. (J Clin Endocrinol Metab 97: E781–E785, 2012)

75 Summary (3) Liver dysfunction (ALT>100) was more frequently found in patients with high dose of methylprednisolone (>9g) pulse therapy than in low dose (4.5g). Reactivation of viral hepatitis should be considered. 75

76 Conclusion Significant progress has been made in our understanding of the immunogenetic mechanisms leading to GO.   We hope that these findings may be translated into new therapies and prevention strategies in GO.  All the patients with GO should benefit from these efforts in near future. 76

77 Thank you for your attention.
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