2012.4.5 Case conference Lupus choroidopathy Ap. 김규섭 / R3 정현진

Case presentation (2009.11.4) F/32 c.c: blurred vision(OU) onset ) for 10 days PI : 97’ SLE Dx. at Daejeon St’ Mary’s hospital 98’ Lupus nephritis III Dx. (kidney Bx.) -> 12th cyclophosphamide(cytoxan) pulse therapy until 2001 10days ago : genenalized edema & wt. gain(5kg), serum Cr ↑ . Urine protein ↑, BP↑ ->R/O SLE flare up -> Rheumatology Admission (2009.10.31) Rheumatology consultation for DDx. of R/O hypertensive retinopathy(OU) 양안 SRF

VA OD 1.0/ OS 1.0 IOP OD 12mmHg OS 13mmHg Ant. Segments : OU WNL Fd-photo (OU) NVE(-) lens clear nl. optic disc c SSRD at fovea, multiple yellow spots deposition, vit cell(-/-)

2009.11.4 M-OCT(OU) OD OS

2009.11.1 SLEDAI (systemic lupus erythematous disease activity index)  total score 20 (hematuria, proteinuria, pyuria, rash, pericarditis, low complement, increased DNA binding) 2009.10.13 HBP => Furosemide(Lasix) 40mg, beta-blolock(Atenolol) 25mg 2009.11.1 high BP => Add Angiotensin II receptor antagonist(Valsartan) 80mg 2009.9.29~10.29 inactive disease state -> prednisolone(H-LON) 7.5mg , Myocophenolic acid(Myrept )1000mg#4 2009.10.31 Adm. & evaluation & Methylprednisolone 62.5mg iv (11/2~11/3) 5:00 11:00 17:00 23:00 10/31 160/110 150/100 11/1 150/90 100/60 130/80 11/2 140/90 11/3 Dyslipidemia : Lipitor(Atorvastatin) 20mg Cyclophosphamide(alkylating agents) 면역억제제, mycophenoleic acid(MPA)+2-morpholinoethyl ester, 루푸스신염에 사용 atacicept 임상선정 기준 제외 해당

Cue list Impression Plan Blurred vision(OU) Funduscopy & M-OCT: SSRD, SRF(OU) SLE flare up (nephritis -> Cr 1.7 spot urine protein 738mg/dl) Impression Hypertensive retinopathy(OU) Steroid induced central serous choroidoretinopathy(OU) Plan 1. BP control & systemic disease control 2. Observation & FU 1 wk later

2011.11.13 (9 days later) Symptom : stationary 2011.11.10 13th cyclophosphamide pulse theraphy (500mg iv) Methylprednisolone 62.5mg (11/2~3)-> 250mg(11/4~6)-> 62.5mg (11/7~1/13) Fd OU increased SSRD at post. Pole

2009.11.13 OCT(OU) OS OD 5:00 11:00 17:00 23:00 11/6 120/90 140/80 130/80 120/80 11/9 110/70 11/11 BP 도표그리기 BP control했는데도 오히려 증상 악화 Steroid induced CSC ? -> steroid 감량 recommand

2009.11.18(2wks later) IOP OD 16mmHg/ OS 16mmHg Fd OU decreased SSRD VA OD 0.8 /OS 0.8 IOP OD 16mmHg/ OS 16mmHg Fd OU decreased SSRD

maintain reduce d Steroid dose 2009.11.18 M-OCT(OU) OD OS OCT more decreased SRF OU small PED OD Steroid 감량 후 증상호전 Steroid induced CSC maintain reduce d Steroid dose

2010.1.26(2months 2wks later) c.c: blurred vision(OD) VA OD 0.5/OS 0.8 IOP OD 18mmHg/OS 19 mmHg OD large PED with SSRD OS RPE change with sl. serous change

왜 Steroid를 줄였는데 왜 PED가 생겼을까? 2010.1.26 M-OCT(OU) OD OS 왜 Steroid를 줄였는데 왜 PED가 생겼을까? -> ICG, FAG

2010.1.27 FAG(OD) FAG OU multiple leak + HRA OU choroidal hyperF

2010.1.27 ICG(OD)

2011.1.27 FAG & ICG(OS)

Steroid Tx. Methylpredinolone 62.5mg(11/3~11/5) -> Methylpredinolone 125mg (11/6~11/8)-> Methylpredinolone 62.5mg(11/9~11/11) -> prednisolon 60mg(11/12~11/19)> prednisolon 40mg (11/20~1/27) 2009.12.15 14th cyclophosphamide (750mg) pulse therapy 2009.12.26 15th cyclophosphamide (750mg) pulse therapy 2009.1.26 16th cyclophosphamide (750mg) pulse therapy

plan 2010.1.29 intravit. Anti-VEGF inj(OD) FRP(OS) 내과와 상의하여 steroid감량 고려 (prednisolon 40mg -> 10mg 감량)

2010.2.9(3months later, post intravit. inj. #10 ) VA OD 0.5 OS 0.8 IOP 16/16mmHg Fd OD large with SSRD OS RPE change, nearly flat Plan : FU 1month later consider FAG (OD) or Intravit. anti VEGF inj.(OD)

2010.3.23(4months 2wks later) IOP 13/15 VA OD 0.4 OS0.8 IOP 13/15 Fd OD decreased large PED with SSRD OS RPE change, nearly flat Plan 2010.3.23 Intravit. anti VEGF inj (OD) f/u 6wks later

2010.6.9(7months later) IOP OD 15mmHg /OS 12mmHg Fd OD flat VA OD 0.5 /OS 1.0 IOP OD 15mmHg /OS 12mmHg Fd OD flat OS RPE change, nearly flat M –OCT(OD) VA OD 0.5 OS 1.0

Serum Cr f/u ds DNA antibody f/u

2011.1.13(1yr 2months later) IOP OD 15mmHg/OD 12mmHg VA OD 0.5 OS 1.0 OU RPE change, flat

2011.1.13 M-OCT(OU) OD OS

2012.2.22(2yr 3months later) VA OD 0.63/OS 1.0 IOP OD 10mmHg/OS 12mmHg Fd OU RPE change, flat

Review

Systemic lupus erythematous autoimmune disease organs and cells damage initially mediated by tissue-binding autoa ntibodies and immune complexes 90% of patients at diagnosis are women of childbearing years Prevalence in Korea : 0.05~0.1% pathogenesis Genes confirmed in more than one genome-wide association analysis in Northern European whites as increasing susceptibility to SLE or lupus nephritis are listed (reviewed in Moser KL et al, Recent insights into the genetic basis of SLE. Genes Immun 2009:10:373). Gene-environment interactions result in abnormal immune responses that generate pathogenic autoantibodies and immune complexes that deposit in tissue, activate complement, cause inflammation, and over time lead to irreversible organ damage. Ag, antigen; C1q, complement system; C3, complement component; CNS, central nervous system; DC, dendritic cell; EBV, Epstein-Barr virus; HLA, human leukocyte antigen; FcR, immunoglobulin Fc-binding receptor; IL, interleukin; MCP, monocyte chemotactic protein; PTPN, phosphotyrosine phosphatase; UV, ultraviolet

Autoantibodies in SLE

The Dx. of SLE : based on characteris tic clinical features and autoantibodie s

Tests for Following Disease Cour se SLE flares the status of organ involvement :urinalysis for hematuria and p roteinuria, Hb ↓, platelet counts ↓, Cr ↓, albumin ↓ markers of disease activity anti-DNA antibodies several components of complement (C3 is most widely availabl e) activated complement products (including those that bind to the C4d receptor on erythrocytes) IFN-inducible gene expression in peripheral blood cells soluble IL-2 levels urinary levels of TNF-like weak inducer of apoptosis (TWEAK), n eutrophil gelatinase-associated lipocalin (NGAL), or monocyte chemotactic protein 1 (MCP-1)

Treatment of serious SLE Cytotoxic/immunosuppressive agents added to glucocor ticoids are recommended apply to treatment of nephritis. cyclophosphamide (an alkylating agent) mycophenolate mofetil (a relatively lymphocyte-specific inhibitor of inosine monophosphatase and therefore of pu rine synthesis) azathioprine (a purine analogue and cycle-specific antim etabolite)

Poor prognosis (50% mortality in 10 years (at the time of diagnosis ) high serum creatinine levels [>124 mol/L (>1.4 mg/dL)] Hypertension nephrotic syndrome (24-h urine protein excretion >2.6 g) anemia [hemoglobin <124 g/L (<12.4 g/dL)] hypoalbuminemia Hypocomplementemia aPL male 000ethnicity (African American, Hispanic)

Ocular manifestations involvement of the skin of the eyelids with cutaneous disease, Keratoconjunctivitis sicca, scleritis, Retinopathy, Steroid induced cataract, optic neuropathy. Uveitis, choroidopathy Lupus retinopathy 3.3~28.1 % Rarely, significant visual loss Antiphospholipid antibody: anticardiolipin antibody, lupus anticoagulant 다른 autoantibodies SLE activity : SLEDAI score ->질병 전체 기간중에 가장 활성이 가장 심하였을때의 점수가 망막병증에서 유의하게 높음을 알 수 있습니다 -Classic retinopathy(microangiopathy)- retinal hemorrhage, CWS -Vaso-occlussive retinopathy-obstructive of large retinal artery or vein Other retinopathy “Retinal vasculitis” : misunderstood term 루프스 환자의 망막 혈관에서 면역 복합체가 발견된다는 이전 연구결과에 기초 : 면역 복합체 관여하는 혈관병증 실제로 혈관염 같은 염증반응은 드묾 thrombosis of retinal arterioles  vaso-occlusive retinopathy 10% of SLE patients : 병의 activity 와 연관됨 Mild lupus retinopathy : CWP, HE , retinal hemorrhage…..

Retinopathy in SLE Classic retinopathy Retinal vaso-occlusive disease common cotton wool spots (m/c) retinal hemorrhages optic disc edema correlate with SLE disease activity usually associated with very good prognosis for vision : V.A is generally unaffected. rare form BRVO/ CRVO CRAO/BRAO Combined . neovascularization , Vit. Hm. independently of disease activity in SLE usually associated with very poor prognosis for vision : visual loss often Fag: non-perfusion is present in macula region

Lupus choroidopathy not common presents as multifocal serous elevations of the neurosensory retina and RPE sensitive indicator of lupus activity visual loss depend on the extent of macular involvement Mechanism (1) choroid vasculopathy => ischemia induced RPE dysfunction (2) Choroid inflammation=> RPE dysfunction (3) Corticosteroid=> RPE dysfunction # Dysfunction choroidal BV=> CNV=> breakdown outer blood-ocular barrier=> ciliochoroidal effusion=> SACG, CSCR Fluorescein angiogram demonstrates multiple "smokestack" areas of fluorescein leakage 전신성 홍반성 낭창에서 중심장액망막박리를 일으키는 원인은 다양하게 추정 전신성 홍반성 낭창이 중심장액맥락망막병증을 일으키는 원인은 명확하게 밝혀진 바는 없다. 전신성 홍반성 낭창과 연관된 장액망막박리는 전신적인 질환의 중등도와 연관되어 나타나는 매우 드문 안질환이다. 그 기전으로는 폐쇄성 맥락막혈관염에 의해 망막색소상피에 손상을 일으켜 망막아래에 장액성 삼출물이 고이는 것을 생각해 볼 수 있다. Ref.) 전신적인 고혈압이 전신성 홍반성 낭창에서 흔히 동반되는데 이는 맥락막혈관에 손상을 주고 정수압을 높여 장액망막박리를 일으키는 원인이 될 수 있다. Ref) 또한 스테로이드는 망막색소상피의 이온 수송 능력을 저하시켜 장액망막박리를 일으키거나 악화시킬 수 있다. 전신성 홍반성 낭창에서 장액망막박리가 생기는 기전은 환자들이 맥락막혈관의 염증, 신우염, 고혈압, 스테로이드 치료 등의 인자들을 이미 갖고 있었기 때문에 명확하게 규명하기는 어렵다. 이런 원인들이 복합적으로 병인이 될 것으로 생각되며 스테로이드에 의해 중심장액망막병증이 악화된다는 단순한 논리로 스테로이드 중단으로 생명을 위협할 수 있는데도 감행하는 것은 위험한 결단일 것이다. 전신성 홍반성 낭창의 중심 장액맥락망막병증에서 전신적인 스테로이드는 두 가지 상반되는 효과가 있다. 하나는 전신적인 혈관염으로 인한 염증을 감소시켜 맥락망막병증을 호전시킬 수 있다. 반면에 다른 측면에서는 혈액-망막 장벽을 무너뜨려 장액성 망막박리가 급속히 진행할 수 있다. 본 증례에서는 양쪽 측면을 볼 수 있었다. 우선 스테로이드를 지속한지 1달째 누출점 한 개가 막혔으므로 이는 전자로 해석이 된다. 반면에 한 누출점은 그 정도가 심해졌으므로 이는 후자로 해석할 수 있다. the retinal and choroidal pathology is vascular and thought to arise from autoimmune me mechanism : polcolonal B-cell activation, a phethora of autoantibodies, the circulating immune complex cause microangiopathy, The demaged vessels histopathologically show hematoxylin bodies and fibrinoid necrosis

findings Fd-photo multifocal serous RD with accumulated SRF through Bruch’s membrane and RPE affected by choroidal ischemia and inflammation FAG: multiple "smokestack" areas of fluorescein leakage ICG (1) very early phase: focal transient hypofluorescent areas (2) intermediate to late: focal clusterof pinpoint spots of choroidal hyperfluorescence (3) Late phase: poorly-defined area of choroidal hypofluorescence

ICG

Tx DDx. * multifocal CSCR most difficult to distinguish from lupus choroidopathy *hypertensive choroidopathy * VKH SD chor0idal metastasis Tx Treatment of the underlying disease with systemic corticosteroids, immunosuppressive agents if needed, and control of the hypertension 2. accelerated breakdown of the blood-retinal barrier=> lead to serous RD focal laser treatment: refractory to systemic corticosteroid therapy

Thank you for your attention !