Ординатура / Офтальмология / Английские материалы / Retinal Vascular Disease_Joussen, Gardner, Kirchhof_2007

one-fourth of BD patients, an affection of the optic nerve will be observed as papillitis (hyperemia of the optic disk with blurring of the margins). Papilledema is not frequent, but it may occur as a result of microvasculitis of the arterioles [97, 115].

Choroidal vascular involvement occurs as well, and choroidal infarcts are probably more common

25 III than generally suggested [97, 113, 115].

Another severe and sight threatening complication is retinal edema in 20 – 80 % of cases, especially in the macular region [51, 97, 115]. At present, one of the most widely used investigations for confirming the presence of macular edema is fluorescein angiography (FA). Today optical coherence tomography (OCT) is a new method for high-resolution crosssectional imaging of the retina. It is very useful in the objective evaluation of macular thickness and quantitative assessment of macular edema. Several studies found a specificity of 100 % and a sensitivity of 96 % on OCT when FA was taken as the reference standard. OCT is superior to FA in the quantitative evaluation of the macula and when vitreous opacity is present [5].

The most common fluorescein angiography findings are diffuse vascular leakage, hyperfluorescence of the optic disk and hyperfluorescence of the macula. These changes in the FA can occur even when eye involvement is not yet seen clinically. Hence, following patients closely, some authors recommend performing FA in all patients diagnosed as BD on a regular basis [78].

Severe posterior segment involvement with recurrent eye attacks is the most serious ocular complication of BD, leading to retinal changes, like narrowed and occluded silver-wired vessels, a variable degree of chorioretinal scars, retinal pigment epithelium alterations and optic nerve atrophy, which result in reduction of visual acuity up to blindness. Several studies indicate that more than three ocular attacks per year, and exudates within the retinal vascular arcade, are the risk and prognostic factors for a poor outcome for visual acuity in BD patients [99]. However, even in such cases, the prognosis will improve with early diagnosis and appropriate therapy [1].

25.3.5 Differential Diagnosis

The differential diagnosis of ocular BD includes various other causes of intraocular inflammation, as long as uveitis or vasculitis is the leading sign of ocular BD. Table 25.3.5 summarizes the most important disorders which may have similarities to ocular BD.

In case the clinical picture of ocular BD is not complete, multiple other systemic disorders can mimic BD. So, the combination of occlusive retinopathy with uveitis and genital and/or oral ulceration seems to be extraordinarily typical for BD.

In case of ocular vasculitis the most important differential diagnosis is intermediate uveitis (characterized by snowballs, probably associated with sarcoidosis or multiple sclerosis or without any systemic manifestations) or sarcoidosis without signs of inter-

Table 25.3.5. Most important disorders which may have similarities to ocular BD

mediate uveitis. The definite diagnosis may become very difficult, when chest X-ray and even CT scan of the lung, besides angiotensin-converting enzyme, remain unremarkable.

25.3.6 Treatment

Essentials

Due to poor prognosis, early and aggressive treatment of ocular BD is necessary

Systemic immunosuppressive drugs are usually used as first-line therapy

In case of inefficacy an early switch to novel therapeutic agents is recommended Biologicals seem to improve visual prognosis of the disease

Treatment of BD often remains a difficult task, because it should not only be effective for nearly all manifestations but should also produce few side effects while being inexpensive at the same time. In clinical practice, therapy will be provided with respect to the most serious and threatening manifestations of BD, which are usually represented by the involvement of the central nervous system and of the eyes.

Visual prognosis of ocular BD has shown to be poor. Without any treatment loss of vision will occur in more than 90 % of patients on average of 3.4 years after onset of ocular symptoms [63]. Thus, compared to other forms of intraocular inflammation, aggressive treatment should be initiated as soon as possible. This usually implies systemic immunosuppressive therapy as soon as inflammatory changes of the posterior eye segment occur. Although the introduction of modern immunosuppressive drugs doubtless initiated a great advance in the treatment of BD, these drugs have not been able to avoid the loss of useful vision in more than 50 % of patients after 5 – 10 years of disease [8]. Today, the preservation of good visual function for a long time is an adequate goal in the therapy of ocular BD, which often needs a switch to novel treatment options in time. Recently the so-called biologicals, interferon- and TNF- antagonists, have shown to be very promising in improving the visual prognosis for patients with BD.

This chapter aims to reflect the recent developments in the therapy of ocular BD.

25.3.6.1 Corticosteroids

Due to their high anti-inflammatory potential and their rapid onset of action, systemic corticosteroids, administered either orally or intravenously, are most

effective in treating acute episodes of intraocular inflammation. However, because doses to maintain remission of ocular disease would be unacceptably high, they have been shown not to be suitable as long term monotherapy in BD [51]. Therefore a steroidsparing immunosuppressive drug as described below has to be added early in most cases.

Topical corticosteroids (eyedrops and ointments) III 25 may be additionally used in case of inflammatory involvement of the anterior eye segment, but they

have to be assumed to be ineffective in the treatment of posterior eye segment lesions. Intravitreally or periocularly administered corticosteroids may be useful as a temporary option in single cases, but usually they will not be able to substitute for systemic immunosuppressive therapy in severe cases of ocular BD and should be avoided.

25.3.6.2Immunosuppressive and Cytotoxic Agents

Due to its rapid onset of action, cyclosporin A has been the most commonly used immunosuppressive agent for ocular BD so far. At doses of 3 – 5 mg/kg/day either as a monotherapy or in combination with low dose corticosteroids, it has been shown to be effective in controlling intraocular inflammation in ocular BD [79, 108]. However, the use of cyclosporin A often may be limited by its nephrotoxicity, particularly in doses higher than 5 mg/kg/day. It is also known that a rebound uveitis may occur after discontinuation of the drug [51]. It has been described moreover that cyclosporin A may exert neurotoxic effects in BD patients or trigger the onset of neuroBD disease, respectively [50].

Tacrolimus (FK506) may be an alternative for cyclosporin A. Exerting a comparable immunosuppressive effect at lower doses, it has shown good efficacy in small groups of BD with sight-threatening posterior uveitis in whom previous cyclosporin A therapy had to be stopped due to a lack of response or unacceptable side effects [48, 95].

In a placebo-controlled double-blind study azathioprine was shown to be effective in treating ocular BD and, if treatment started less than 2 years after onset of the disease, in improving visual prognosis [32, 110, 111]. Because azathioprine, administered in doses of 2 – 2.5 mg/kg/day, is usually well tolerated, it might be a suitable alternative to cyclosporin A. However, one has to consider that azathioprine needs 2 – 3 months to become effective and therefore in the case of an acute inflammatory attack systemic corticosteroids have to be used to close this gap.

In contrast, methotrexate, mycophenolate mofetil and colchicine have been demonstrated or are

believed to have only weak therapeutic effects on severe manifestations of BD and thus will not normally be in use for ocular involvement [2, 43, 77].

Due to their toxic side effects, cyclophosphamide, chlorambucil and thalidomide should be reserved for life-threatening manifestations of BD and should not be used any longer for ocular manifestations.

25 III Novel agents like interferon- and TNF- antagonists represent potent alternatives.

25.3.6.3Novel Medical Treatment Approaches (Biologicals)

There is increasing evidence that the so-called biologicals, a novel generation of therapeutic agents, may be superior to conventional immunosuppressive drugs in the therapy of various chronic inflammatory conditions. On the other hand, depending on the drug, biologicals may be much more expensive and so far there has been only limited experience regarding their long term side effects.

Today there are two groups of biologicals, interferon (IFN)- and TNF- antagonists, in use for the treatment of BD especially with severe ocular involvement.

Interferon- is a cytokine with strong antiviral, antiproliferative and various immunomodulatory effects. Since 1986 in open studies more than 330 BD patients have been treated with recombinant human interferon-, more than 180 of them for acute ocular disease. IFN- not only induced remission of intraocular inflammation in more than 90 % of patients who did not respond to conventional immunosuppressive treatment previously but also maintained it in more than 50 % of the patients after discontinuation of the drug [52]. IFN- showed also to be effective in the resolution of cystoid macular edema as well as in regression of retinal neovascularizations and reperfusion of occluded vessels [51, 96]. Moreover, recent data suggest that IFN- may lead to a significant improvement of visual prognosis in patients with ocular BD [19]. Although side effects will occur frequently (they are nearly all dose dependent and reversible), treatment with IFN- is usually well tolerated. However, contraindications like depression, psoriasis and some autoimmune disorders such as sarcoidosis have to be ruled out before initiation of the drug. An IFN associated retinopathy which is known from patients with hepatitis C and skin melanoma, treated with inteferon-, has not been seen yet in patients who received the drug for ocular BD or other intraocular inflammatory conditions [18]. Unfortunately there is no consensus so far on the optimal dosing schedule of IFN-. In the light of our experience we recommend an initial dose of

3 – 6 million IU per day subcutaneously tapering subsequently to a maintenance dose of 3 million IU two or three times a week before discontinuation [51]. To avoid an antagonization of IFN-, previous immunosuppressants should be stopped 1 day before initiation of IFN- and corticosteroids have to be tapered to a maximum of 10 mg prednisolone equivalent per day as soon as possible [51].

In recent years TNFantagonists have been introduced more and more in the treatment regimens of various chronic inflammatory disorders, and also for ocular BD. TNF-, a proinflammatory cytokine, is thought to play a major role in inducing such diseases. To block TNF-, three different drugs are commercially available so far: etanercept (a soluble TNF- receptor), infliximab (a mouse-human chimeric monoclonal TNF- antibody) and adalimumab (a human monoclonal TNF- antibody). In open clinical studies and in many case series, the most commonly used TNF- antagonist infliximab, administered intravenously in doses of 3 – 5 mg/kg body weight at intervals of 2 – 8 weeks, has shown to be very effective in suppressing acute inflammatory attacks as well as in maintaining remission of ocular BD in patients who showed refractory to previous conventional immunosuppressive treatment. Regression of retinal neovascularization was also seen during infliximab treatment. However, there are few data existing so far regarding remission rates after discontinuation of the drug and no data about long term visual prognosis [25, 76, 92, 102]. Although infliximab as a chimeric molecule may induce allergic reactions in some cases, the drug is usually well tolerated. As TNF- antagonists may lead to reactivation of previously existing tuberculosis, this infectious disease has to be ruled out before treatment initiation.

Although adalimumab as a human molecule probably will not induce allergy and can be self-adminis- tered by the patients (subcutaneous injection every 2 weeks), there is only one report which demonstrates that remission achieved with infliximab in ocular BD is able to continue by adalimumab [71]. In contrast, etanercept has not been reported in severe ocular BD.

25.3.6.4 Surgical Treatment

Ocular BD remains a domain of medical treatment. Surgery should be reserved to complications secondary to intraocular inflammation such as cataract or glaucoma in the anterior and retinal detachment or persistent vitreous hemorrhage in the posterior eye segment. As it has been shown that novel biologicals may induce regression of retinal and disk neovascularization (Fig. 25.3.6), one should be restrictive in

performing laser photocoagulation in BD patients with retinal ischemia due to occlusive retinal vasculitis.

25.3.6.5 Recommendations for the Clinician

If a patient is suspected of having BD, it is strongly recommended to refer him to a specialized tertial medical center for diagnosis and treatment by an interdisciplinary approach. As initially mentioned, treatment has to be planned with respect to the most severe manifestation. If this is ocular disease with involvement of the posterior eye segment, a combination treatment of systemic steroids and an immunosuppressive drug, e.g., azathioprine or cyclosporin A, should be started without delay. It has to be kept in mind that immunosuppressive drugs may need weeks to months to develop their full antiinflammatory effect. Therefore corticosteroids should be tapered very slowly to bridge this gap. If after adequate time a patient does not respond to or intraocular inflammation relapses under immunosuppressive treatment, a quick switch to a biological should be performed instead of trying several immunosuppressants one after another or using doubleor triple-immunosuppressive regimens. In a BD patient who presents with an acute retinal vessel occlusion or with neovascularizations of the disk or the retina, we would suggest abstaining from conventional steroid and immunosuppressive treatment but initiating a first-line therapy with a biological immediately.

References

1.Accorinti M, Pirraglia MP, Corradi R, Marino M, PivettiPezzi P (2003) Ocular lesions other than Behcet’s disease in Behcet’s disease-affected patients. In: Zouboulis CC (ed) Adamantiades-Behcet’s disease. Kluwer Academic/Plenum Publishers, New York, pp 365 – 368

2.Adler YD, Mansmann U, Zouboulis CC (2001) Mycophenolate mofetil is ineffective in the treatment of mucocutaneous Adamantiades-Beh¸cet’s disease. Dermatology 203:322 – 324

3.Ambresin A, Tran T, Spertini F, Herbort C (2002) Beh¸cet’s disease in Western Switzerland: Epidemiology and analysis of ocular involvement. Ocul Immunol Inflamm 10:53 – 63

4.Ates A, Kinikli G, Duzgun N, Duman M (2006) Lack of association of tumor necrosis factor-alpha gene polymorphisms with disease susceptibility and severity in Beh¸cet’s disease. Rheumatol Int 26:348 – 353

5.Atmaca LS, Batioglu F, Müftüoglu O (2003) Fluorescein Angiography and optical Coherence Tomography in ocular Behcet’s disease. In: Zouboulis CC (ed) Adamantiades-Beh- cet’s disease. Kluwer Academic/Plenum Publishers, New York, pp 355 – 360

6.Ayaslioglu E, Duzgun N, Erkek E, Inal A (2004) Evidence of chronic Chlamydia pneumoniae infection in patients with Behcet’s disease. Scand J Infect Dis 36:428 – 430

7.Aydintug AO, Tokgöz G, D’Cruz DP, Gürler A, Cervera R, Düzgün N, Atmaca LS, Khamashta MA, Hughes GR (1993) Antibodies to endothelial cells in patients with Beh¸cet’s disease. Clin Immunol Immunopathol 67:157 – 162

8.BenEzra D, Cohen E (1986) Treatment and visual prognosis in Beh¸cet’s disease. Br J Ophthalmol 70:589 – 592

9.Berlit P, Stueper B, Fink I, Rebmann V, Hoyer P, Kreuzfelder E, Grosse-Wilde H (2005) Beh¸cet’s disease is associated with increased concentrations of antibodies against phosphatidylserine and ribosomal phosphoproteins. Vasa 34: 176 – 180

10.Boiardi L, Salvarani C, Casali B, Olivieri I, Ciancio G, Cantini F, Salvi F, Malatesta R, Govoni M, Trotta F, Filippini D, Paolazzi G, Nicoli D, Farnetti E, Macchioni L (2001) Intercellular adhesion molecule-1 gene polymorphisms in BD. J Rheumatol 28:1283 – 1287

30.Gül A, Hajeer AH, Worthington J, Ollier WE, Silman AJ (2001) Linkage mapping of a novel susceptibility locus for Beh¸cet’s disease to chromosome 6p22 – 23. Arthritis Rheum 44:2693 – 2696

31.Gürler A, Boyvat A, Türsen Ü (1997) Clinical manifestations of Behcet’s disease: an analysis of 2147 patients. Yonsei Med J 38:423 – 427

32.Hamuryudan V, Özyazgan Y, Hizli N, Mat C, Yurdakul S, Tüzün Y, ªenocak M, Yazici H (1997) Azathioprine in Behcet’s¸ syndrome: effects on long-term prognosis. Arthritis Rheum 40:769 – 774

33.Hasan A, Fortune F, Wilson A, Warr K, Shinnick T, Mizushima Y, van der Zee R, Stanford MR, Sanderson J, Lehner T

(1996) Role of T cells in pathogenesis and diagnosis of Beh¸cet’s disease. Lancet 347:789 – 794

34.Haznedaroglu IC, Dündar SV, Kirazli S (1995) Eicosanoids in the prethrombotic state of Beh¸cet’s disease. Thromb Res 80:445 – 446

35.Hu W, Hasan A, Wilson A, Stanford MR, Li-Yang Y, Todryk S, Whiston R, Shinnick T, Mizushima Y, van der Zee R, Lehner T (1998) Experimental mucosal induction of uveitis with 60-kDa heat shock protein-derived peptide 336 – 351. Eur J Immunol 28:2444 – 2455

36.Hughes EH, Collins RW, Kondeatis E, Wallace GR, Graham EM Vaughan RW, Stanford MR (2005) Associations of major histocompatibility complex class I chain-related molecule polymorphisms with Beh¸cet’s disease in Caucasian patients. Tissue Antigens 66:195 – 199

37.Ikbal, M, Atasoy M, Pirim I, Aliagaoglu C, Karatay S, Erdem F (2006) The alteration of sister chromatid exchange frequencies in Beh¸cet’s disease with and without HLA-B51. J Eur Acad Dermatol Venereol 20:149 – 152

38.Imirzalioglu N, Dursun A, Tastan B, Soysal Y, Yakicier MC (2005) MEFV gene is a probable susceptibility gene for Beh¸cet’s disease. Scand J Rheumatol 34:56 – 58

39.International Study Group for Beh¸cet’s Disease (1990) Criteria for diagnosis of Beh¸cet’s disease. Lancet 335:1078 – 1080

40.Isogai E, Ohno S, Kotake S, Isogai H, Tsurumizu T, Fujii N, Yokota K, Syuto B, Yamaguchi M, Matsuda H (1990) Chemiluminescence of neutrophils from patients with Beh¸cet’s disease and its correlation with an increased proportion of uncommon serotypes of Streptococcus sanguis in the oral flora. Arch Oral Biol 35:43 – 48

41.Itoh Y, Inoko H, Kulski J-K, Sasaki S, Meguro A, Takiyama N, Nishida T, Yuasa T, Ohno S, Mizuki N (2006) Four digit allele genotyping of the HLA-A and HLA-B genes in Japanese patients with Beh¸cet’s disease by a PCR-SSOP-Lumi- nex method. Tissue Antigens 67:390 – 394

42.Jang WC, Park SB, Nam YH, Lee SS, Kim JW, Chang IS, Kim KT, Chang HK (2005) Interleukin-18 gene polymorphisms in Korean patients with BD. Clin Exp Rheumatol. 23:59 – 63

43.Kaklamani VG, Kaklamanis PG (2001) Treatment of Behcet’s¸ disease – an update. Semin Arthritis Rheum 30:299 – 312

44.Kaneko F, Nakamura K, Sato M, Tojo M, Zheng X, Zhang JZ (2003) Epidemiology of Behcet’s disease in Asian countries and Japan. In: Zouboulis CC (ed) Adamantiades-Behcet’s disease. Kluwer Academic/Plenum Publishers, New York, pp 25 – 29

45.Kansu E, Sahin G, Sahin F, Sivri B, Sayek I, Batman F (1986) Impaired prostacyclin synthesis by vessel walls in Beh¸cet’s disease. Lancet ii:1554

46.Karasneh J, Hajeer AH, Barrett J, Ollier WER, Thornhill M,

Gul A (2003) Association of specific interleukin 1 gene cluster polymorphisms with increased susceptibility for Behcet’s disease. Rheumatology 42:860 – 864

47.Karasneh J, Gul A, Ollier WE, Silman AJ, Worthington J (2005) Whole-genome screening for susceptibility genes in multicase families with Beh¸cet’s disease. Arthritis Rheum 52:1836 – 1842

48.Kilmartin DJ, Forrester JV, Dick AD (1998) Tacrolimus (FK506) in failed cyclosporine A therapy in endogenous posterior uveitis. Ocul Immunol Inflamm 6:101 – 109

49.Kim JU, Chang HK, Lee SS, Kim JW, Kim KT, Lee SW, Chung WT (2003) Endothelial nitric oxide synthase gene polymorphisms in Behcet’s disease and rheumatic disease with vasculitis. Ann Rheum Dis 62:1083 – 1087

50.Kotake S, Higashi K, Yoshikawa K, Sasamoto Y, Okamoto T, Matsuda H (1999) Central nervous system symptoms in patients with Beh¸cet disease receiving cyclosporine therapy. Ophthalmology 106:586 – 589

51.Kötter I, Zierhut M, Eckstein A, Vonthein R, Ness T, Günaydin I, Grimmbacher P, Blaschke S, Peter HH, Kanz L, Stübiger N (2003) Human recombinant interferon-alpha2a (rhIFN alpha2a) for the treatment of Behcet’s disease with sight-threatening retinal vasculitis. Br J Ophthalmol 87: 423 – 431

52.Kötter I, Günaydin I, Zierhut M, Stübiger N (2004) The use

of interferon in Beh¸cet disease: review of the literature. Semin Arthritis Rheum 33:320 – 335

53.Kretschmann U, Seeliger MW, Ruether K, Usui T, Apfel- stedt-Sylla E, Zrenner E (1998) Multifocal electroretinography in patients with Stargardt’s macular dystrophy. Br J Ophthalmol 82:267 – 275

54.Lee EB, Kim JY, Lee YJ, Park MH, Song YW (2003a) TNF and TNF receptor polymorphisms in Korean Beh¸cet’s disease patients. Hum Immunol 64:614 – 620

55.Lee KH, Bang D, Choi ES, Chun WH, Lee ES, Lee S (1999) Presence of circulating antibodies to a disease-specific antigen on cultured human dermal microvascular endothelial cells in patients with Beh¸cet’s disease. Arch Dermatol Res 291:374 – 381

56.Lee KH, Chung HS, Kim HS, Oh SH, Ha MK, Baik JH, Lee S, Bang D (2003b) Human alpha-enolase from endothelial cells as a target antigen of anti-endothelial cell antibody in Beh¸cet’s disease. Arthritis Rheum 48:2025 – 2035

57.Lehner T (1997) The role of heat shock protein, microbial and autoimmune agents in aetiology of Beh¸cet’s disease. Int Rev Immunol 14:21 – 32

58.Lehner T (2000) Immunopathogenesis of Beh¸cet’s disease. In: Bang D, Lee ES, Lee S (eds) Beh¸cet’s disease. Design Mecca, Seoul, pp 3 – 18

59.Lehner T, Lavery E, Smith R, von der Zee R, Mizushima Y Shinnick T (1991) Association between the 65-kilodalton heat shock protein, Streptococcus sanguis, and the corresponding antibodies in Beh¸cet’s disease. Infect Immun 59:1434 – 1441

60.Lu Y, Ye P, Chen SL, Tan EM, Chan EK (2005) Identification of kinectin as a novel Beh¸cet’s disease autoantigen. Arthritis Res Ther 7:R1133–R1139

61.Mahesh SP, Li Z, Buggage R, Mor F, Cohen IR, Chew EY, Nussenblatt RB (2005) Alpha trompomyosin as a self-anti- gen in patients with Beh¸cet’s disease. Clin Exp Immunol 140:368 – 375

62.Mammo L, Al-Dalaan A, Bahabri SS, Saour JN. (1997) Association of factor V Leiden with Beh¸cet’s disease. J Rheumatol 24:2196 – 2198

66.Mizuki N, Inoko H, Mizuki N, Tanaka H, Kera J, Tsuiji K, Ohno S (1992) Human leukocyte antigen serologic and DNA typing of Beh¸cet’s disease and its primary association with B51. Invest Ophthalmol Vis Sci 33:3332 – 3340

67.Mizuki N, Inoko H, Ohno S (1997) Molecular genetics (HLA) of BD. Yonsei Med J 38:333 – 349

68.Müftüoglu AÜ, Yazici H, Yurdakul S, Pazarli H, Ozyazgan Y, Tuzun Y, Altac M, Yalcin B (1981) Behcet’s disease: lack of correlation of clinical manifestations with HLA antigens. Tissue Antigens 17:226 – 230

69.Musabak U, Baylan O, Cetin T, Yesilova Z, Sengul A, Saglam K, Inal A, Kocar IH (2005) Lipid profile and antivardiolipin antibodies in Beh¸cet’s disease. Arch Med Res 36:387 – 392

70.Musabak U, Pay S, Erdem H, Simsek I, Pekel A, Dinc A, Sengul A (2006) Serum interleukin-18 levels in patients with Beh¸cet’s disease. Is its expression associated with disease activity or clinical presentations? Rheumatol Int 26:545 – 550

71.Mushtaq B, Saeed T, Situnayake RD, Murray PI (2006) Adalimumab for sight-threatening uveitis in Beh¸cet’s disease. Eye (Epub ahead of print)

72.Nagafuchi H, Takeno M, Yoshikawa H, Kurokawa MS, Nara K, Takada E, Masuda C, Mizoguchi M, Suzuki N (2005) Excessive expression of Txk, a member of the Tec family of tyrosine kinases, contributes to excessive Th1 cytokine production by T lymphocytes in patients with Beh¸cet’s disease (2005). Clin Exp Immunol 139:363 – 370

73.Nakae K, Masaki F, Hashimoto T (1993) Behcet’s disease. In: Wechsler B, Godeau P (eds) International congress series 1037. Excerpta Medica, Amsterdam, pp145 – 151

74.Niwa Y, Mizushima Y (1990) Neutrophil-potentiating factors released from stimulated lymphocytes; special reference to the increase in neutrophil-potentiating factors from streptococcus-stimulated lymphocytes of patients with Beh¸cet’s disease. Clin Exp Immunol 79:353 – 360

75.Ohno S, Ohguchi M, Hirose S, Matsuda H, Wakisaka A, Aizawa M (1982) Close association of HLA-Bw51 with Behcet’s disease. Arch Ophthalmol 100:1455 – 1458

76.Ohno S, Nakamura S, Hori S, Shimakawa M, Kawashima H, Mochizuki M, Sugita S, Ueno S, Yoshizaki K, Inaba G (2004) Efficacy, safety, and pharmacokinetics of multiple administration of infliximab in Beh¸cet’s disease with refractory uveoretinitis. J Rheumatol 31:1362 – 1368

77.Okada AA (2000) Drug therapy in Beh¸cet’s disease. Ocul Immunol Inflamm 8:85 – 91

78.Özdal PC, Ortac S, Taskintuna I, Firat E (2002a) Posterior segment involvement in ocular Beh¸cet’s disease. Eur J Ophthalmol 12:424 – 431

79.Özdal PC,¸ Orta¸c S, Taskintuna I, Firat E (2002b) Long-term therapy with low dose cyclosporine A in ocular Beh¸cet’s disease. Doc Ophthalmol 105:301 – 312

80.Oztas MO, Onder M, Gurer MA, Bukan N, Sancak B (2005) Serum interleukin 18 an tumor necrosis factor-alpha levels are increased in Beh¸cet’s disease. Clin Exp Dermatol 30:61 – 63

99.Takeuchi M, Hokama H, Tsukahara R, Kezuka T, Goto H, Sakai J, Usui M (2005) Risk and prognostic factors of poor visual outcome in Beh¸cet’s disease with ocular involvement. Graefes Arch Clin Exp Ophthalmol 243(11):1147 – 1152

100.Todaro M, Zerilli M, Triolo G, Iovino F, Patti M, AccardoPalumbo A, di Gaudio F, Turco MC, Petrella A, de Maria R, Stassi G 2005 (2005) NF-kappaB protects BD T cells against CD95-induced apoptosis up-regulating antiapoptotic proteins. Arthritis Rheum 52:2179 – 2191

101.Tokay S, Direskeneli H, Yurdakul S, Akoglu T (2001) Anticardiolipin antibodies in Beh¸cet’s disease: a reassessment. Rheumatology (Oxford) 40:192 – 195

102.Tugal-Tutkun I, Mudun A, Urgancioglu M, Kamali S, Kasapoglu E, Inanc M, Gül A (2005) Efficacy of infliximab in the treatment of uveitis that is resistant to treatment with the combination of azathioprine, cyclosporine, and corticosteroids in Beh¸cet’s disease. Arthritis Rheum 52:2478 – 2484

103.Ureten K, Ertenli I, Ozturk MA, Kiraz S, Onat AM, Tuncer M, Okur H, Akdogan A, Apras S, Calguneri M (2005) Neutrophil CD 64 expression in Beh¸cet’s disease. J Rheumatol 32:849 – 852

104.Verity DH, Marr JE, Ohno S, Wallace GR, Stanford MR (1999a) BD, the Silk Road and HLA-B51: historical and geographical perspectives. Tissue Antigens 54:213 – 220

105.Verity DH, Vaughan RW, Madanat W, Kondeatis E, Zureikat H, Fayyad F, Kanawati CA, Ayesh I, Stanford MR, Wallace GR (1999b) Factor V Leiden mutation is associated with ocular involvement in Beh¸cet’s disease. Am J Ophthalmol 128:352 – 356

106.Verjans GM, van Hagen PM, van der Kooi A, Osterhaus AD, Baarsma GS (2002) Vgamma9Vdelta2 T cells recovered from eyes of patients with Beh¸cet’s disease recognize non-peptide prenyl pyrophosphate antigens. J Neuroimmunol 130:46 – 54

107.Wakisaka S, Takeba Y, Mihara S, Takeno M, Yamamoto S, Sakane T, Suzuki N (2002) Aberrant Fas ligand expression in lymphocytes in patients with BD. Int Arch Allergy Immunol 129:175 – 180

108.Whitcup SM, Salvo EC, Nussenblatt RB (1994) Combined cyclosporine and corticosteroid therapy for sight-threat- ening uveitis in Beh¸cet’s disease. Am J Ophthalmol 118: 39 – 45

109.Yazici H, Basaran G, Hamuryudan V, Hizli N, Yurdakul S, Mat C, Tuzun Y, Ozyazgan Y, Dimitriyadis I (1996) The ten-year mortality in Behcet’s syndrome. Br J Rheumatol 35:139 – 141

110.Yazici H, Ozyagan Y (1999) Medical management of Behcet’s¸ syndrome. Dev Ophthalmol 31:118 – 131

111.Yazici H, Pazarli H, Barnes CG, Tüzün Y, Özyazgan Y, Silman A, Serdaroðlu S, Oðuz V, Yurdakul S, Lovatt GE, Yazici B, Somani S, Müftüoðlu A (1990) A controlled trial of azathioprine in Beh¸cet’s syndrome. N Engl J Med 322: 281 – 285

112.Yurdakul S, Günaydin I, Tuzkun Y, Tankurt N, Pazarli H, Ozyazgan Y, Yasici H (1988) The prevalence of Behcet’s syndrome in a rural area in northern Turkey. J Rheumatol 15:820 – 822

113.Zafirakis P, Foster CS (2002) Adamantiades-Behcet’s disease. In: Foster CS, Vitale AT (eds) Diagnosis and treatment of uveitis. Saunders, Philadelphia, pp 632 – 652

114.Zierhut M, Mizuki N, Ohno S, Inoko H, Gul A, Onoe K, Isogai E (2003) Immunology and functional genomics of BD. Cell Mol Life Sci 60:1903 – 1922

115.Zierhut M, Stübiger N, Deuter CME (2004): Beh¸cet’s disease. In: Pleyer U, Mondino B (eds) Essentials in ophthalmology: uveitis and immunological disorders. Springer, Berlin Heidelberg New York, pp 173 – 195

116.Zouboulis CC (1999) Epidemiology of AdamantiadesBehcet’s disease. Ann Med Interne (Paris) 150:488 – 498

117.Zouboulis CC (2003) Epidemiology of AdamantiadesBehcet’s disease. In: Zierhut M, Ohno S (eds) Immunology

of Beh¸cet’s disease. Swets and Zeitlinger, Lisse, Tokyo, pp 1 – 16

118. Zouboulis CC, Kötter I, Djawari D, Kirch W, Kohl PK, Ochsendorf FR, Keitel W, Stadler R, Wollina Uproksch E, Sohnchen R, Weber H, Gollnick HP, Holzle E, Fritz K, Licht T, Orfanos CE (1997) Epidemiological features of Ada- mantiades-Behcet’s disease in Germany and in Europe.

Yonsei Med J 38:411 – 422

III 25

Core Messages

In addition to optic neuritis, multiple sclerosis (MS) can affect the eye with intraocular inflammation termed “uveitis.” Uveitis in patients with MS is often a bilateral disease and manifests with vitritis and retinal vasculitis (called intermediate uveitis)

Prognosis of visual acuity is often determined by optic atrophy or cystoid macular edema (CME) and the formation of retinal neovascularization In addition to treatment with high-dose corticosteroids and immunosuppressive drugs, therapy with interferon- is evolving as a new treatment option for this condition

25.4.1 History

The association between MS and optic neuritis has been known since the late 19th century. However, intraocular inflammation (uveitis) was originally described in 1945 by Rucker [30].

25.4.2 Epidemiology

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system mostly affecting young adults. The clinical picture is determined by the location of foci of demyelination within the CNS. The eyes are frequently affected with optic neuritis, extraocular muscle disturbances, and intraocular inflammation. In cooperation with consulting neurologists, the diagnosis of MS must be made based upon neurological examination and MRI imaging according to the guidelines described by Poser et al. [26]. The occurrence of the association of MS and uveitis varies widely, ranging from 0.4 % to 26.9 % in patients with MS [4, 9, 25] and from 0.8 % to 14 % in patients with uveitis [17, 20, 29]. These differences between reports are attributable to varying patient populations, examination techniques, and criteria for diagnosis. The longer the follow-up in these studies the higher the prevalence. The prevalence of MS in the uveitic population has been reported to be 1 – 2 % [7, 29], with a higher prevalence among patients with intermediate uveitis, ranging from 7.8 % to 14.8 % [41]. In the database of the Interdisciplinary Uveitis Center Heidelberg (tertiary referral center), 50 out of 1,430 total uveitis patients (3 %) had an association with MS. Seventy-

six percent of these patients were female with an age median of 43.5 years, and 72 % had bilateral disease, with 54 % patients having a chronic disease course, 68 % intermediate uveitis, and 50 % associated optic neuritis (papillitis, retrobulbar neuritis). Anterior uveitis is rare in patients with MS [19, 21]. It occurred in only 14 % of MS patients in our database. Conversely, the prevalence of MS in patients with intermediate uveitis at the Interdisciplinary Uveitis Center in Heidelberg was 13 %.

25.4.3 Pathogenesis

Experimental autoimmune encephalomyelitis (EAE) is a well-established rodent model of CNS-specific inflammatory disease and is known to be the best animal model for studying the etiology and pathogenesis of MS. It is mediated by T cells and results in progressive demyelination and paralysis. Anterior uveitis (AU) has been found to coincide with EAE in rabbits, monkeys, in the Lewis rat [2, 36] and more recently in (PL/J×SJL/J) F1 mice [11]. The encephalogenic T cells are specific for the antigen myelin basic protein (MBP), which is a component of the myelinated sheath surrounding nerve bundles. These myelinated nerve bundles are abundant in the spinal cord and in the iris; thus this “autoantigen” is located at sites of inflammation. This suggests shared antigenic determinants between neurological and ophthalmological manifestations of the disease with similar pathomechanisms [2]. In the rodent models of EAE, AU generally persists after the paralysis has subsided. EAE and AU can be induced actively by immunizing with MBP in the presence of adjuvant, or passive-

ly by using adoptive transfer of MBP-specific T cells that have been generated against the whole antigen or encephalogenic peptides. Treatment with IFN- reduced ocular inflammation in this model [23].

Despite these findings, most EAE studies have focused on the problems of spinal cord and brain disease and there is little information on ocular pathologic events in the course of this experimental illness. As in MS, EAE is characterized by a breakdown of the blood-brain barrier. The inflammatory response is characterized by mononuclear infiltrates located around vessels of the CNS white matter, by activation of local microglia and astrocytes, and in the most severe cases it may be eventually followed by demyelination. Recently, several authors have examined the ophthalmologic manifestations of EAE in Lewis rats and all described the induction of anterior uveitis [2, 33, 36]. More recently, Hu et al. [14, 15] investigated the cellular responses in the optic nerve and retina of Lewis rats with MBPinduced EAE. Villarroya et al. induced relapsing EAE in rats to determine the phenotype and localization of immunocompetent cells as well as the MHC class I and class II antigen expression in various structures of the visual system [37]. Their findings suggest that ocular structures and optic pathways, in particular optic chiasma, are important targets in relapsing EAE, and the development of ocular findings shares similar pathogenic mechanisms with neurologic disease. Disruption of the cerebral endothelial barrier and transendothelial migration of inflammatory cells into the brain plays a significant role in the pathogenesis of MS.

25.4.4Intermediate Uveitis and Retinal Vasculitis as the Clinical Manifestations in MS-Associated Uveitis

Optic neuritis (ON) is the most common ocular manifestation of MS, occurring in an estimated 30 % of patients [24]; however, intraocular inflammation (uveitis) also occurs. Conversely, 30 % of patients with ON will develop clinically definite MS, as reported by the Optic Neuritis Study Group [24]. The classic manifestation of ON includes unilateral, sudden onset reduction of visual acuity, relative afferent pupillary defect, and paracentral or centrocecal scotoma in a young female patient. In a recent retrospective multicenter case observational study [6] with 13 patients, in 7 patients MS started a median of 8.2 years (range 2.8 – 24.2 years) before uveitis, and in 6 patients uveitis was diagnosed a median of 5.5 years (0.3 – 20.6 years) before MS. Seven patients had suffered from ON in at least one eye during the previous course of their disease. In all 13 patients ON occurred before the onset of uveitis.

III 25

Fig. 25.4.1. Granulomatous “mutton-fat” keratic precipitates in a patient with MS-associated uveitis. The white pupil indicates the presence of cataract

The most common type of uveitis is intermediate uveitis (according to Bloch-Michel and Nussenblatt [8]) with characteristic changes (iritis, pars planitis, vitritis, periphlebitis with or without neovascularization) and may present with “granulomatous changes” [1, 4, 7, 35]. Granulomatous changes in the anterior segment include large, “mutton-fat” keratic precipitates located on the corneal endothelium (Fig. 25.4.1), iris nodules (Koeppe nodules at the pupillary border, Bussacca nodules in the iris stroma). These changes are not only typical for histologically granulomatous diseases like sarcoid or tuberculosis but can also be seen in ocular structures in histologically non-granuloma- tous diseases like MS. In patients with this type of uveitis, secondary changes like the formation of CME or occlusive vasculitis with vasoproliferations often develop. These changes have a profound effect on visual prognosis. If they occur, the disease is often difficult to manage and requires high dosages of corticosteroids [38] or laser treatment, and often remains refractory to these standard therapies.

Retinal vasculitis in MS uveitis patients is considered to affect exclusively veins (“periphlebitis,” retinal venous “sheathing”). It encompasses both active periphlebitis and chronic venous sclerosis [3]. The chronic form of sheathing appears typically as dense, white linear stripes following the course of several generations of the venous tree. In our MS patients vasculitis usually manifested in a continuous fashion over several branches of the vascular tree in contrast to sarcoidosis, which shows a multifocal pattern (“candle wax drippings”). There may be associated constriction and dilation of the veins, with occasional retinal hemorrhage. However, there are also focal lesions in MS-associated uveitis, especially in the acute phase. Venous sclerosis seems to be the result of persistent inflammation (Fig. 25.4.2). Retinal arteriolar involvement in MS-associated uveitis has not been described to our knowledge.