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1 Thyroid Associated Orbitopathy 10 th Asia and Oceania Thyroid Association Congress October 21-23, 2012 Yuji Hiromatsu, M.D., Ph.D. Division of Endocrinology.

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Presentation on theme: "1 Thyroid Associated Orbitopathy 10 th Asia and Oceania Thyroid Association Congress October 21-23, 2012 Yuji Hiromatsu, M.D., Ph.D. Division of Endocrinology."— Presentation transcript:

1 1 Thyroid Associated Orbitopathy 10 th Asia and Oceania Thyroid Association Congress October 21-23, 2012 Yuji Hiromatsu, M.D., Ph.D. Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume, Japan

2 2 Thyroid Associated Orbitopathy Yuji Hiromatsu, M.D., Ph.D. Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume, Japan  Pathogenesis  Role of MRI  Treatment 10 th Asia and Oceania Thyroid Association Congress October 21-23, 2012

3 外眼筋 脂肪組織 涙腺 外眼筋 上眼瞼挙筋 Proptosis Lid retraction Abnormal Secretion of Lacrimal fluid Eyelid Conj. Cornea Extra- ocular Muscle Optic Nerve Retina Primary Secondary impairment Site Müller’s muscle Lacrimal gland Extraocular Muscle Orbital connective tissue 上眼瞼挙筋 Lev palpebrae sup

4 Genetic factor Genetic factor Enviromental factor Enviromental factor TRAb HyperthyroidismGraves’ ophthalmopathyPretibial myxedema Robert James Graves (1796~1853) Graves’ disease Morbus Basedow Carl von Basedow Breakdown of immunological tolerance Breakdown of immunological tolerance (1799~1854) 80~90% 25~50% (Thyroid associated orbitopathy)

5 Enlargement of eye muscles ( mm 2 ) ー + TNFαgene expression in eye muscle tissue P < Orbital fat volume (mm 2 ) P < 0.05 IL-4IL-6IL-10 ー++ー+ P < 0.05 Cytokine gene expression in orbital fat tissue ー ( Hiromatsu et al. : JCEM 85:1194, 2000 ) Increase of orbital fat tissueEnlargement of eye muscle

6 Expression of TSH-R mRNA in the orbit TSH-R ( 1.2kb ) TSH-R (296 bp) RT-PCR In situ hybridization anti-sense sense ( Hiromatsu et al. Thyroid 6: 553, 1996)

7 Gene Array Studies GeneFoldFunction PPAR-  44.2Signal transduction Pro-platelet basic protein32.9Cell proliferaion Collagen type 1  differentiation Adiponectin25.0Metabolism IL-623.9Cell proliferation Glycogenin 222.4Glycogen biosynthesis sFRP-118.5Signal transduction (Kumar et al.: JCEM 90:4730, 2005) sFRP-1 (secreted frizzled related protein-1)

8 (Kumar, S. et al. J Clin Endocrinol Metab 2005;90: ) sFRP-1 (100 nM) induced adiponectin mRNA (A), leptin mRNA (B), and TSHr mRNA (C) expression on orbital fibroblasts sFRP-1 induces adipogenesis and expression of TSHR on orbital fibroblasts. sFRP-1 (secreted frizzled related protein-1)

9 Peroxisome Proliferator-Activated Receptor-  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 6 2

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.

11 CD34 + OF CD34 - OF IL-16 RANTES CXCL10 IGF-1R↑ IGF-1R Ab Migration of T cells T cell Macrophages Adipogenesis IL-6 IL-8 CXCR4 TSHR↑ TSHR Ab Glycosaminoglycans short chain hyaluronan long chain hyaluronan proliferation B cell activation TSHR Ab IGF-1R Ab IL-1  IL-8 COX-2 CXCL12 Cytokine Th1, Th2 IL-1 TNF  TGF  IL-6 TNF  CD40 CD40L B7 TCR HLA Th1- : Leukoregulin,TNFα, IL-1β, INFβ, INFγ, IL-2, IL-12 Th2- : IL-4, IL-5, IL-10 Antibody serum CD34+ fibrocytes Orbital fibroblasts + PPAR  TGF  TNF  _ IL-1  IFN  TGF  TNF  + Orbit preadipocytes 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. Bahn R.S: N Engl J Med 2010; 362: Myofibroblast Thy-1 + OF TGF-β Fibrosis Extraocular muscle enlargement Extraocular muscle enlargement Expanded Adipose tissues Expanded Adipose tissues Elevated TRAb Elevated TRAb

13 Relationships between anti-TSH receptor antibidies and GO TRAB ( 1 st generation; TBII) TRAb (2 nd generation; hTRAb; TRAb-CT) TRAb (3 rd generation; M22) TSAb TSI [Mc4; chimeric TSH-R (amino acid residues of human TSH-R replaced by rat LH-R) ]

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

15 Anti-TSH receptor antibody in GO Mild GOSevere GO

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

17 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. chimeric (Mc4) TSH-R (amino acid residues of human TSH-R replaced by rat LH-R) A novel thyroid stimulating immunoglobulin assay

18 Correlation of the thyroid stimulating lgs in GO with clinical disease activity.

19 Th2 thyroiditis Shared antigens Between thyroid and orbit Tg Hyperthyroidism (Graves’ disease) Breakdown of immune tolerance Breakdown of immune tolerance Genetic factors Enviromental factors Enviromental factors Th1, Th2 cytokines Anti-TSH receptor Abs Anti-EM Ab Tg adipogenesis TSH receptor ↑ sFRP-1, CYR61 G2 s SD H 1D1D EM antigens G2s 1D Calsequestrin TSH receptor Mild Severe smoking CTLA-4 CD40 PTPN22 HLA TNF  ICAM-1 NF  B1 FOXP3 IGF-1receptor↑ Greves’ ophthalmopathy Collagen XIII IGF-1R Ab TSI Inflammation / fibrosis

20 Graves’ disease GO Japanese Polish Japanese Polish TNF  No YesClin Endocrinol 2000;52:759 No Yes Hum Immunol 2004;65:632 IFN  Yes NoThyroid 2004;14:93 IL-6NoNo NoNoAutoimmunity 2004;37:223 IL-12BNo NoEndocrine J 2004;51:609 IL-13Yes NoJCEM 2005;90:296 No NoClin Endocrinol 2003;59:519 IL-18No weakThyroid 2006;16 :243 CTLA-4YesYes NoNoEur J Endo 2003;148:13 JCEM 2007;92:3162 CD40 Yes (>40y) NoEndocrinol J 2005;52:471 Yes NoThyroid 2005;15:1119 ICAM-1No Yes (<40y) weakYesJCEM 2003; 88:4945 PTPN22 Yes NoClin Endocrinol 2005;62:679 Yes NoThyroid. 2008;18:625 NF  B1NoYesYesNoGenes Immun. 2007;8:532 PPAR  weaksubmitted Susceptibility genes Candidate Genes

21 genotypeAllele frequency TT TC CC T C OR n 28 (45.2) 81 (73.0) 29 (46.7) 30 (27.0) 5 (8.1) 0 (0) 85 (68.5) 192 (86.5) 39* (31.5) 30 (13.5) GO GD w/o oph TNF-α gene polymorphism (T-1031C) and GO * P= ( Kamizono et al. Clin Endocrinol 2000; 52: ) 2.9 (日本人) The C allele frequency is higher in GO patients.

22 ICAM-1 gene polymorphism class ⅢーⅥ class 0-Ⅱ 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) χ 2 =4.925 P= χ 2 =3.825 P= Allele frequencyGenotype frequency class ⅢーⅥ class 0-Ⅱ AA 46 72 (%) (49) (36) GA + GG (%) 47(51) 129(64) χ 2 =4.643 P= K469E (1405 A→G) The AA genotype frequency is higher in severe GO. OR 1.75 OR 1.44 ATA class

23 NF  B1 gene polymorphism ( -94del ATTG ) Genotype frequency Allele frequency Del (%)Hetero (%)Ins (%)Del (%)Ins (%)N Ⅲ~ⅥⅢ~Ⅵ 0~Ⅱ30138(1 3%) 132(4 4%) 131(4 3%) 12325(2 0%) 59(48%)39(3 2%) 109(4 4%) 137(5 6%) 208(3 5%) 394(6 5%) χ 2 =6.853 P= OR 1.76 χ 2 =7.103 P= OR 1.51 The -94delATTG polymorphism of the NF  B1 gene is higher in severe GO. ATA class

24 PPARγ ( Pro 12 Ala) gene polymorphism Genotype Allele CC (%) CG (%) GG (%) C (%) G (%) N Ⅲ~ⅥⅢ~Ⅵ 0~Ⅱ 294271(6 9%) 21(87%)2( 100 %) 123120(3 1%) 3(13%) 0(0%) 243(3 0%) 3(1 1%) 563(7 0%) 25(8 9%) Χ 2 = P = Fisher’s exact probability test P = OR 3.59 Patients with CC genotype frequently have severe ophthalmopathy. ATA class Χ 2 = P = OR 3.39

25 PPARγ ( Pro 12 Ala) gene polymorphism Genotype Allele CC (%)CG (%)GG (%)C (%) G (%) N VI IV III II I 0 4( 1% ) 22( 6% ) 94( 24% ) 8 ( 2% ) 23( 6% ) 240( 61% ) 1( 4 %) 2( 8 %) 19( 79 %) 1111 9( 1 %) 45( 6 %) 189 ( 23 %) 18( 2 %) 46( 6 %) 499 ( 62 %) 1( 4 %) 2( 7 %) 21( 75 %) 1) Fisher’s exact probability test P= 0.0197 ( III vs. 0) ATA class OR ) Fisher’s exact probability test P= 0.0134( III vs. 0) 1)1) 2) Graves’ disease patients with CC genotype frequently have proptosis compared to those with other genotypes.

26 Summary (1) 1.TSH receptor is a primary autoantigen in GO. Recent study suggests the presence of GO specific TRAb (Mc4)? 2.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.

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. 5.CD90 (Thy-1) + orbital fibroblasts may differentiate into myofibroblasts that participate in the development of fibrosis in late stages of the disease. 6.Gene polymorphisms of the immunomodulator genes (such as TNF , ICAM-1, NF  B, PPAR  and FOXP3 etc) have been proposed as the susceptibility genes for GO. 7.The significance of the presence of anti-eye muscle antibodies, such as SDH, CASQ needs to be confirmed.

28  Pathogenesis  Role of MRI  Treatment

29 NOSPECS classification of eye changes of Graves ’ disease (Thyroid 2:235, 1992) ClassDefinition 0No physical signs or symptoms IOnly signs, no symptoms (upper lid retraction, stare, and eyelid lag) IISoft tissue involvement (symptoms and signs) IIIProptosis IVExtraocular muscle involvement VCorneal involvement VISight loss (optic nerve involvement)

30 NOSPECS classification of eye changes of Graves ’ disease (Thyroid 2:235, 1992) ClassDefinition 0No physical signs or symptoms IOnly signs, no symptoms (upper lid retraction, stare, and eyelid lag) IISoft tissue involvement (symptoms and signs) IIIProptosis IVExtraocular muscle involvement VCorneal involvement VISight loss (optic nerve involvement) MRI 70% 50~75% of patients with Graves’ disease do not have any signs or symptoms of GO.

31 Occult Thyroid Eye Disease No physical signs or symptoms Enlargement of extra-occular muscles Occult thyroid eye disease Case 1 Case 2

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

33 Dalrymple sign (lid retraction) Case 3 Case 4

34 von Graefe’s sign RLRL Case 5 Case 6

35 RL RL Unilateral lid retraction Case 7 Case 8

36 MRI IISoft tissue involvement (symptoms and signs) TotalMildModeratesevere Lid swelling 1354(67.7)958(47.9)376(18.8)20(1.0) Conjunctiva642(32.1)451(22.6)170(8.5)21(1.0) 2000 eyes (%) Inoue et al.

37 Swelling of upper and lower eyelid Case 9

38 MRI III Proptosis Male 444 eyes female 1556 eyes Japanese Untreated Graves’ disease Symptoms 24.2% Hertel exophthalmometer mild 39%total 57% moderate 1 3% severe 5% GO patients (4598 eyes) total 85% mild 39% moderate33% severe 13% Proptosis alone18.5% + lid lag46.2% + lid swelling19.0% + lid lag and lid swelling16.3%

39 Proptosis R) 13.0 mm L) 13.0 mm R) 17.0 mm L) 17.0 mm R) 19.0 mm L) 19.0 mm R) 28.5 mm L) 30.5 mm

40 Proptosis 18mm~<21mm Proptosis ≥21mm + lid swelling + lid retraction Case 11 Case 13 Case 12 Case 14

41 MRI IV Extraocular muscle involvement TotalMildModeratesevere Diplopia447(22.3)237(11.8)74(3.7)136(6.8) 2000 eyes (%) Inoue et al.

42 Diplopia Restriction of motion in upward gaze Vertical deviation of right eye Enlargement of right inferior rectus muscle Case 15

43 MRI VI Sight loss (optic nerve involvement) TotalMildModeratesevere DON168(8.4)147(7.4)13(0.6)8(0.4) 2000 eyes (%) Inoue et al. PapilledemaPapillitisOptic disc atrophy

44 He complains orbital ache and decreased visual acuity. Eyelid swelling Eyelid eythema Conjunctival redness Proptosis 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. Case 17

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.

46 Thyroid Associated Orbitopathy  Pathogenesis  Role of MRI  Treatment

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

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

49 Pulse therapy Before After 3 cycles

50 Transantral orbital decompression for Papilledema ( dysthyroid optic neuropathy) pre post Papilledema 6 months after the surgery

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

52 Severity Activity Immunosuppressive therapy Severity Activity Immunosuppressive therapy Outcome Prediction of outcome of Immunosuppressive treatment Rehabilitative therapy

53 Classical Pulse 1g/d 3days 3 cycles Irradiation 2Gy 10 times Prednisolone 20mg15mg10mg5mg Pulse therapy Oral steroid ① 1w Efficacy : 77 % ( Pulse + irradiation : 88 %) Side effects : peptic ulcer 、 glucose intolerance 、 osteoporosis Efficacy : 59 % ( 44 % in 5 RCT ) Side effects : exacerbation of inflammation 、 Cataract 、 Retinopathy, Tumorgenesis

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? ANAAIHNone8Recovery439*** CMV3.2Recovery548 steatosisHBV15.7Recovery557 None17.1Recovery306 None15Recovery455 None17.1Death474 None7.1Death633 ANAsteatosisNone7.8 wkDeath562** None4 wk after 5 cyclesDeath711* Liver diseaseVirusTime of diagnosisOutcomeAgeCase * Weissel et al. Thyroid 10: 521, 2000 ** Marino et al. Thyroid 14: 403, 2004 *** Salvi et al. Thyroid 14: 631, 2004 The cumulative dose should be <8g methylprednisolone in one course of therapy. (EUGOGO)

55 Classical Pulse 1g/d 3days 3 cycles Irradiation 2Gy 10 times Prednisolone 20mg15mg10mg5mg Pulse therapy Oral steroid ① 1w Efficacy : 77 % ( Pulse + irradiation : 88 %) Side effects : peptic ulcer 、 glucose intolerance 、 osteoporosis Efficacy : 59 % ( 44 % in 5 RCT ) Side effects : exacerbation of inflammation 、 Cataract 、 Retinopathy, Tumorgenesis Mini-pulse 0.5g/d 3days 3 cycles Irradiation 2Gy 10 times Prednisolone 20mg15mg10mg5mg Oral steroid ② 1w

56 Liver dysfunction during and 1 year period after pulse therapy (4 centers, 480 cases) 前 (ALT) 高値 (ALT) 3(ALT)6(ALT) ALT before1 month6months12 months

57 No Liver dysfunction ( ALT) > ~ 100 total Methylprednisorone 1 g/d, 3 days, 3 courses cases 12.5 % 27 cases 19.9 % 44 cases 32.4 % Methylprednisorone 0.5g/d, 3 days, 3 courses % % % Total % % % Fisher’s exact probability test P=  2 = 、 P= Liver failure and st eroid pulse therapy (4 centers )  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 223,188,149,124. -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.

59 Treatment in inactive stage Rehabilitative Surgery Orbital Decompression Eye Muscle Surgery Eyelid Surgery

60 Pre 3 months after surgery Proptosis pre Rt 22mm Lt 20mm post Rt 15mm Lt 14mm Rehabilitative Surgery Transantral Orbital Decompression Case 19

61 6months after before Deep Lateral Orbital Decompression

62 6 months afterbefore Rt 27mm Lt 28mmRt 24mm Lt 24mm Case 20

63 Rehabilitative Surgery Eye Muscle Surgery Removal of the cicatricial tissue of left inferior rectus muscle Lt upward gaze impairment (enlargement of left inferior rectus muscle) Case 21

64 Pre Post Rehabilitative Surgery Eyelid Surgery Lengthening of Levator Muscle Lenghening of Levator Muscle procedure by using polytetrafluoroethyrene as spacer. Case 22

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

66 Triamcinolone acetonide injection Rt ) lid swelling 、 lid lag 、 Graefe’s sign 2 months after the injection Case 23

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

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 CD20 Retuximab CD3 ChAglyCD3 CD28 Abatacept CD154 IDEC-131 PPAR-  Selective PPAR modulators Somatostatin receptor Octreotide-long acting release SOM230 Thyrotropin receptor NIDDK/CEB-52 TSHR antagonist (Org )

69 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 Active stageInactive stage New therapy

70

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) 0 0

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

73 Anti-CD20 monoclonal Ab (rituximab) RTXIVGCRTX v.s. IVGC CAS better TRAb not significant not significant not significant Proposis not significant significantly decreased significantly decreased Palpebra improveimprove not significant Side effecs 33 % 45 % Recurrence 0 % 10 % Salvi et al. Eur J Endocrinol 2007; 156:33-40

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) 1.Liver dysfunction (ALT>100) was more frequently found in patients with high dose of methylprednisolone (>9g) pulse therapy than in low dose (4.5g). 2.Reactivation of viral hepatitis should be considered.

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.

77 ご清聴 ありがとう ございました。 Thank you for your attention.


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