Presentation on theme: "Thyroid Associated Orbitopathy"— Presentation transcript:
1Thyroid Associated Orbitopathy 10th Asia and Oceania ThyroidAssociation CongressOctober 21-23, 2012Thyroid Associated OrbitopathyThank 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
2Thyroid Associated Orbitopathy 10th Asia and Oceania ThyroidAssociation CongressOctober 21-23, 2012Thyroid Associated OrbitopathyPathogenesisRole of MRITreatmentI 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
3Site Primary Secondary impairment Eyelid Conj. Extra- ocular Muscle Müller’s muscleEyelidLev palpebrae sup上眼瞼挙筋上眼瞼挙筋Conj.Lid retractionAbnormalSecretion ofLacrimal fluidExtra-ocularMuscleLacrimal gland涙腺CorneaThe 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OpticNerveRetinaProptosisExtraocular Muscle外眼筋外眼筋
4immunological tolerance Graves’ diseaseMorbus BasedowGeneticfactorEnviromentalfactorBreakdown ofimmunological toleranceRobert James Graves(1796~1853)TRAbCarl von Basedow25~50%(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%HyperthyroidismGraves’ ophthalmopathyPretibial myxedema(Thyroid associated orbitopathy)4
5TNFαgene expression in eye muscle tissue Enlargement of eye muscleIncrease of orbital fat tissueP < 0.05P < 0.05P < 0.0514002500P< 0.05120020001000Enlargement of eye muscles（mm2)8001500Orbital 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-10.6001000400500200ーー＋ー＋ー＋＋TNFαgene expression in eye muscle tissueIL-4IL-6IL-10Cytokine gene expression in orbital fat tissue（Hiromatsu et al.： JCEM 85:1194, 2000）
6Expression of TSH-R mRNA in the orbit RT-PCRTSH-R（1.2kb）TSH-R(296 bp)In situ hybridizationThe 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-sensesense(Hiromatsu et al. Thyroid 6: 553, 1996)6
7Gene Array Studies Gene Fold Function PPAR-g 44.2 Signal transduction Pro-platelet basic protein32.9Cell proliferaionCollagen type 1a128.2differentiationAdiponectin25.0MetabolismIL-623.9Cell proliferationGlycogenin 222.4Glycogen biosynthesissFRP-118.5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
8sFRP-1 (100 nM) induced adiponectin mRNA (A), leptin mRNA (B), and TSHr mRNA (C) expression on orbital fibroblastssFRP-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
9Peroxisome 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 DMPioglitazone 30mg/d for 3 months6wk pre 3m on 3m stopProptosis rt 19mmltConj. Redness (-) mild (-)Lid swelling Mild Severe SevereDiplopia (-) Intermittent (-)CASThiazolidinedione, 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
10Thiazolidinedione 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.
11Orbital fibroblasts serum CD34+OF CD34-OF CD34+ fibrocytes TSHR↑ TSHR AbOrbital fibroblastsIGF-1R Abserum+IL-1bIFNgTGFbTNFaAdipogenesisGlycosaminoglycansshort chainhyaluronan＋long chainhyaluronanIL-6IL-8TSHR AbIGF-1R AbPPARg_TGFbTNFaTSHR↑proliferationIGF-1R↑CD34+OFpreadipocytesCD34-OFIL-16RANTESCXCL10HLAB7CD40CD40LOrbitIL-1aIL-8COX-2CXCL12T cellIL-6TNFaT cellCXCR4TCRCytokineTh1, Th2Ｔｈｙ１＋：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 cellactivationMigration of T cellsMacrophagesTh1-：Leukoregulin,TNFα, IL-1β,INFβ, INFγ, IL-2, IL-12Th2-：IL-4, IL-5, IL-10IL-1TNFaTGFbAntibodyTSHR AbIGF-1R Ab
12CD90 (Thy-1)+ orbital fibroblasts may differentiate into myofibroblasts, that participate in the development of fibrosis in late stages of the disease.Thy-1+OFTGF-βMyofibroblastCD90 (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.ExpandedAdiposetissuesBahn R.S:N Engl J Med 2010; 362:ElevatedTRAbExtraocularmuscleenlargementFibrosis
13Relationships between anti-TSH receptor antibidies and GO TRAB ( 1st generation; TBII)TRAb (2nd generation; hTRAb; TRAb-CT)TRAb (3rd generation; M22)TSAbTSI [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.
14Anti-TSH receptor Antibodies At the first visit, there is no difference in the prevalence of TRAb between GO and GD without ophthalmopathy.TSH-R antibodiesGO（＋） GO（ー） Normal TBII67% 85% 0%TSAb59% 83% 0%In GO patients there are significant correlation between TRAb and the enlargement of eye muscle.TSAEnlargement of EMbTBIIEnlargement of EM(Nishikawa et al., Acta Endocrinol129: 213, 1993)(Hiromatsu et al., Thyroid 6: 553, 1996)
15Anti-TSH receptor antibody in GO Mild GOSevere GOTRAK human, 2nd generation, was greater in severe GO patients compared to mild GO.
16The novel chimeric(Mc4) TSH-R (amino acid residues 262-335 of human TSH-R replaced by rat LH-R)
17A 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 renderedeuthyroid at the time of blood sampling.
18Very good correlation between TSI and clinical disease activity has been reported. Correlation of the thyroid stimulating lgs in GO with clinical disease activity.
19Inflammation / fibrosis Greves’ ophthalmopathyGenetic factorsEnviromentalfactorsEM antigensInflammation / fibrosisG2sHLA TNFaICAM-1NFkB1FOXP3CTLA-4CD40PTPN221DAnti-EM AbsmokingSDHSevereCalsequestrinCollagen XIIITh1, Th2cytokinesBreakdown ofimmune toleranceIGF-1R AbIGF-1receptor↑MildadipogenesisTSH receptor ↑sFRP-1, CYR61TgTSIAnti-TSH receptor AbsG2sTSH receptorSo 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.1DHyperthyroidism(Graves’ disease)Th2 thyroiditisTgShared antigensBetween thyroid and orbit
20Susceptibility genes Graves’ disease GO Japanese Polish Japanese PolishTNFa No Yes Clin Endocrinol 2000;52:759No Yes Hum Immunol 2004;65:632IFNg Yes No Thyroid 2004;14:93IL-6 No No No No Autoimmunity 2004;37:223IL-12B No No Endocrine J 2004;51:609IL-13 Yes No JCEM 2005;90:296No No Clin Endocrinol 2003;59:519IL-18 No weak Thyroid 2006;16 :243CTLA-4 Yes Yes No No Eur J Endo 2003;148:13JCEM 2007;92:3162CD40 Yes (>40y) No Endocrinol J 2005;52:471Yes No Thyroid 2005;15:1119ICAM-1 No Yes (<40y) weak Yes JCEM 2003; 88:4945PTPN22 Yes No Clin Endocrinol 2005;62:679Yes No Thyroid. 2008;18:625NFkB1 No Yes Yes No Genes Immun. 2007;8:532PPARg No weak submittedCandidateGenes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
21TNF-α gene polymorphism (T-1031C) and GO （日本人）genotypeAllele frequencynTT TC CC T C ORGOGDw/ooph6211128(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)2.9We 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=0.0001The C allele frequency is higher in GO patients.（Kamizono et al. Clin Endocrinol 2000; 52: )21
22ICAM-1 gene polymorphism Ｋ４６９Ｅ (1405 A→G)Genotype frequencyAllele frequencyATA classＡＡ４６７２（％）（４９）（３６）ＧＡ３６９９（％）（３９）（４９）ＧＧ１１３０（％）（１２）（１５） Ａ （％）１２８（６９）２４３（６０） Ｇ （％） ５８（３１）１５９（４０）OR1.44ｃｌａｓｓ ⅢーⅥｃｌａｓｓ ０－Ⅱχ2=4.925P=0.0852χ2=3.825P=0.0505ＡＡ４６７２（％）（４９）（３６）GA + GG （％） ４７（５１）１２９（６４）OR1.75ｃｌａｓｓ ⅢーⅥｃｌａｓｓ 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=4.643P=0.0312The ＡＡ genotype frequency is higher in severe GO .
23NFkB1 gene polymorphism （-94del ATTG） Genotype frequencyAllele frequencyATA classNDel (%)Hetero (%)Ins (%)Del (%)Ins (%)Ⅲ～Ⅵ１２３２５（２０％）５９（４８％）３９（３２％）１０９（４４％）１３７（５６％）０～Ⅱ３０１３８（１３％）１３２（４４％）１３１（４３％）２０８（３５％）３９４（６５％）-94delATTG多型の40％が重症の眼症。軽症23％χ2=6.853P=0.0325OR 1.76χ2=7.103P=0.0077OR 1.51The -94delATTG polymorphism of the NFkB1 gene is higher in severe GO.
24PPARγ （Pro12Ala) gene polymorphism GenotypeAlleleATA classNＣＣ (%)ＣＧ (%)GG (%)Ｃ (%)Ｇ (%)Ⅲ～Ⅵ１２３１２０（３１％） ３（１３％） ０（０％）２４３（３０％） ３（１１％）０～Ⅱ２９４２７１（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＝4.439P =Χ２＝4.430P =OR 3.39Fisher’s exact probability testP =OR 3.59Patients with ＣＣ genotype frequently have severe ophthalmopathy.
25PPARγ（Pro12Ala) gene polymorphism GenotypeAlleleATA classCC (%)CG (%)GG (%)C (%)G (%) ORN39124280628523951024260VIIVIIIIII４（1%）２２（6%）９４（24%）８ （2%）２３（6%）２４０（61%）１（4％）２（8％）１９（79％）１９（1％）４５（6％）１８９（23％）１８（2％）４６（6％）４９９（62％）１（4％）２（7％）２１（75％）0.381.897.950.96-１)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 testP=０．０１９７ （III vs. ０）2) Fisher’s exact probability testP=０．０１３４（III vs. ０）Graves’ disease patients with CC genotype frequently have proptosis compared to those with other genotypes.
26Summary (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
274. 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
28Thyroid Associated Orbitopathy PathogenesisRole of MRITreatment
29NOSPECS classification of eye changes of Graves’ disease (Thyroid 2:235, 1992) DefinitionNo physical signs or symptomsIOnly signs, no symptoms (upper lid retraction, stare,and eyelid lag)IISoft tissue involvement (symptoms and signs)IIIProptosisIVExtraocular muscle involvementVCorneal involvementVISight 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.
3050~75% 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)ClassDefinitionNo physical signs or symptomsIOnly signs, no symptoms (upper lid retraction, stare,and eyelid lag)IISoft tissue involvement (symptoms and signs)IIIProptosisIVExtraocular muscle involvementVCorneal involvementVISight 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
31Occult Thyroid Eye Disease Case 1Case 2No physical signs or symptomsThese 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 muscles31
32Only signs, no symptoms (upper lid retraction, stare, and eyelid lag) TotalMildModeratesevereLid retraction1587(79.3)792(39.6)620(31.0)175(8.7)2000 eyes (%)Inoue et al.MRI
33Dalrymple sign (lid retraction) Case 3Case 4Both 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
34von Graefe’s signＲＬＲＬCase 5Case 6Both 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
35Unilateral lid retraction Case 7Case 8ＲＬUnilateral 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.ＲＬ35
36Soft tissue involvement (symptoms and signs) Total Mild Moderate IISoft tissue involvement (symptoms and signs)TotalMildModeratesevereLid swelling1354(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.MRI
37Swelling of upper and lower eyelid Case 9In patients with eyelid swelling, there are accumulation of fat tissue in the upper and lower eyelid.37
38III Proptosis MRI Untreated Graves’ disease Symptoms 24.2% Hertel exophthalmometermild 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 eyesfemale eyesJapaneseProptosis 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.MRI38
39Proptosis 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 mmR) 28.5 mm L) 30.5 mm39
40Proptosis 18mm~<21mm Proptosis ≥21mm + lid swelling + lid swelling Case 11Case 13+ lid swellingCase 12Case 14+ lid swelling+ lid retractionIn patients with exophthalmos(proptosis), various rectus muscles and levator palpebrae superioris muscles are enlarged.40
41 Extraocular muscle involvement IV Extraocular muscle involvementTotalMildModeratesevereDiplopia447(22.3)237(11.8)74(3.7)136(6.8)2000 eyes (%)Inoue et al.MRI
42Diplopia 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 gazeVertical deviation of right eyeEnlargement of right inferior rectus muscle42
43 Sight loss (optic nerve involvement) VI Sight loss (optic nerve involvement)PapilledemaPapillitisOptic disc atrophyTotalMildModeratesevereDON168(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.MRI43
44He complains orbital ache and decreased visual acuity. Eyelid swellingEyelid eythemaConjunctival rednessProptosisCase 17MRI: The enlargement of superior, inferior, medial and lateral rectus musclesmay compress optic nerve.T2 immage:The increased T2 relaxation time indicates that GO is in active state.
45Summary (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
46Thyroid Associated Orbitopathy PathogenesisRole of MRITreatment
47Treatment of Graves’ ophthalmopathy MildModerate to severeSight-threatening (DON）i.v. GCs (±OR) prompt decompressionStill activeIv GCs(±OR)RehabilitativesurgeryStable & inactiveActive (if needed)i.v. GCs (±OR)Rehabilitative surgeryInactiveLocal injection of GCs or Botulinum toxinOphtalmological examination, CAS, QOLLocal measuresWait and seeMRIPoor response (2 weeks)All patients with GONOSPECS Class 0NOSPECS Class I~VIRestore euthyroid (avoid hypothyroidism)Urge smoking withdrawalOccult thyroid eye diseaseSpecialized centerInflammation ofUpper eyelidsintractableImmuno-suppressant ,Decompressioneye musclesStable &inactiveProgression
48Pulse therapy Dysthyroid optic neuropathy（DON）and/or Corneal breakdown Sight-threating GO (DON)Sight-threating GO (DTN)MRIi.v. GlucocorticoidsPulse therapyPoor response(2 weeks)methylpredonisolone1g/d 3days 3 cyclesPrompt decompressionStill activeStable and inactive1wDysthyroid optic neuropathy or corneal breakdown is sight-threatening and requires immediate treatmenti.v. Glucocorticoids( orbital radiation)Rehabilitativesurgery
49Pulse 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 activity49
50Transantral orbital decompression for Papilledema（dysthyroid optic neuropathy)Papilledemapre6 months after the surgerypostIf 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
51Moderately to severe GO MRIactiveinactivei.v. Glucocorticoids( orbital radiation)RehabilitativesurgeryStable and inactive
52Rehabilitative therapy Prediction of outcome ofImmunosuppressive treatmentRehabilitative therapyImmunosuppressive therapyImmunosuppressive therapyActivityActivitySeveritySeverityIf 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.OutcomeOutcome52
53Pulse therapy Oral steroid Classical Pulse ① Efficacy： 77％ （Pulse＋irradiation：88％） Side effects：peptic ulcer、glucose intolerance、osteoporosisPulse therapyOral steroidClassical Pulse1g/d 3days 3 cyclesPrednisolone 20mg15mg10mg5mg①Efficacy： 59％ ( 44％ in 5 RCT )Side effects： exacerbation of inflammation、Cataract、Retinopathy, Tumorgenesis1wIrradiation2Gy 10 times53
54Fatal liver failureAcute 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?CaseAgeOutcomeTime of diagnosisVirusLiver disease1*71Death4 wk after 5 cyclesNone2**56Death7.8 wkNonesteatosisANA363Death7.1None447Death17.1None545Recovery15None630Recovery17.1NoneAcute 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 methylprednisolonein one course of therapy.755Recovery15.7HBVsteatosis854Recovery3.2CMV9***43Recovery8NoneAIHANAThe cumulative dose should be <8g methylprednisolonein one course of therapy. (EUGOGO)* Weissel et al. Thyroid 10: 521, ** Marino et al. Thyroid 14: 403, 2004*** Salvi et al. Thyroid 14: 631, 200454
55Pulse therapy Oral steroid Classical Pulse ① Oral steroid Mini-pulse ② Efficacy： 77％ （Pulse＋irradiation：88％） Side effects：peptic ulcer、glucose intolerance、osteoporosisPulse therapyOral steroidClassical Pulse1g/d 3days 3 cyclesPrednisolone 20mg15mg10mg5mg①Efficacy： 59％ ( 44％ in 5 RCT )Side effects： exacerbation of inflammation、Cataract、Retinopathy, Tumorgenesis1wIrradiation2Gy 10 timesMini-pulse0.5g/d 3days 3 cyclesOral steroidPrednisolone 20mg15mg10mg5mgWe 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.②1wIrradiation2Gy 10 times55
56Liver dysfunction during and 1 year period after pulse therapy (4 centers, 480 cases)ALT54052050048046044042040038036034032030028026024022020018016014012010080604020before1 month6months12 months前(ALT)高値(ALT)3(ALT)6(ALT)
57Liver dysfunction （ALT) Ｌｉｖｅｒ ｆａｉｌｕｒｅ ａｎｄ ｓｔｅｒｏｉｄ ｐｕｌｓｅ ｔｈｅｒａｐｙ（４ centers）NoLiver dysfunction （ALT)＞10050～100totalMethylprednisorone １g/d, 3 days, 3 courses136 17cases12.5％2719.9％4432.4％Methylprednisorone0.5g/d, 3 days, 3 courses97 33.1％17.5％2020.6％Total2338.6％18.9％6427.5％Fisher’s exact probability testP=0.0115c２＝3.913、P=0.0479Liver dysfunction (ALT>100) was more frequently found in patients with high dose ofmethylprednisolone (>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.
58HBV 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.
59Treatment in inactive stage Rehabilitative SurgeryOrbital DecompressionEye Muscle SurgeryEyelid SurgeryIn inactive stage, rehabilitative surgery is indicated.59
60Rehabilitative Surgery Transantral Orbital Decompression Case 19Pre3 months after surgeryProptosispreRt 22mmLt 20mmpostRt 15mmLt 14mmSevere proposis, lower lid retraction, eyelid edema: were observed in this patient.Proptosis was markedly improved by bilateral transantral orbital decompression60
61Deep Lateral Orbital Decompression before6months after
63Rehabilitative Surgery Eye Muscle SurgeryCase 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 inferiorrectus muscle)Removal of the cicatricial tissueof left inferior rectus muscle63
64Rehabilitative Surgery Eyelid SurgeryLengthening of Levator MuscleCase 22PreFor 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。PostLenghening of Levator Muscle procedure by using polytetrafluoroethyrene as spacer.64
65Mild GO MRI Local measures progression active Wait and see Inflammation ofeyelidInflammation ofEM and fat tissuesStable andinactiveLocal injection of triamcinolone acetonide and botulinum A toxini.v. glucocorticoids(±orbital radiationRehabilitativesurgery (if needed)Stable andinactive
66Triamcinolone acetonide injection Case 23This 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 sign2 months after the injection66
67Botulinum toxin therapy Case 24Botulinum 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
68Potential Therapeutic Targets in Graves’ ophthalmopathy Target Current AgentTNF InfliximabTNF receptor EtanerceptIL-1 receptor AnakinraIL-6 receptor TocilizumabTGF-b LerdelimumabOxygen free radicals SeleniumCD RetuximabCD ChAglyCD3CD AbataceptCD IDEC-131PPAR-g Selective PPAR modulatorsSomatostatin receptor Octreotide-long acting release SOM230Thyrotropin receptor NIDDK/CEB-52TSHR antagonist (Org )Potential therapeutic targets are shown in this slide. Studies on these agents are currently ongoing.
69Somatostatin analogues New therapySomatostatin analoguesSomatostatin receptor orbital fibroblasts, activated lymphocytes express SSROctreoscan octreotide accumulates in the orbitOctreotide(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 effectof octreotide-LAR in 2 RCT.ＳＯＭ２３０Since orbital fibroblasts and activated lymphocytes express somatostatin receptor. And octreotide accumulates in the orbitIn active phase of ophthalmopathy.Active stageInactive stage69
70Metaanalysis showed that somatostatin analogs are effective for ophthalmopathy.
71Anti-CD20 monoclonal Ab (rituximab) Open study： 9 caces RTX 1000mg iv twice at 2wk interval20 cases IVGC methylprednisolone 500mg iv for 16 weeksSalvi et al. Eur J Endocrinol 2007; 156:33-40Rituximab (1000mg)０００The administration of retuximab 1000 mg twice at 2 weeks interval
72Anti-CD20 monoclonal Ab (rituximab) B cellCD20B cellCD20Peripheral depletion of CD20+ cellsSalvi et al. Eur J Endocrinol 2007; 156:33-40
73Anti-CD20 monoclonal Ab (rituximab) ＲＴＸ ＩＶＧＣ ＲＴＸ v.s. ＩＶＧＣＣＡＳ 4.7 2.0 betterＴＲＡｂ 19.3 not significant not significant not significantProposis 22.4 not significantsignificantly decreased significantly decreasedPalpebra improve improve not significantSide effecs 33％ 45％Recurrence 0％ 10％And improve CAS , proptosis and appearance.Salvi et al. Eur J Endocrinol 2007; 156:33-4073
74Complete Inhibition of rhTSH-, Graves’ Disease IgG-, and M22-Induced cAMP Production in Differentiated Orbital Fibroblasts by a Low-Molecular-Weight TSHR AntagonistClementine 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)
75Summary (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
76ConclusionSignificant 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