Abstract: INTRODUCTION : Ocular manifestations are one of the main features of Behcet’s Disease. They occur in more than half the patients. In our series they were seen in 58% of cases1. The natural course of Ocular manifestations, like other manifestations of Behcet's Disease, is a progression by repetitive attacks followed by remission. However, on the contrary of other lesions (muco-cutaneous) the remission is much slower in posterior uveitis, and practically absent in retinal vasculitis. Usually the healing process do not complete before the next attack. Therefore, lesions will accumulate during successive attacks and lead to severe loss of vision or blindness2. Ocular lesions need aggressive treatment. The treatment will have 2 goals. 1- Combat the inflammation. Prednisolone is the best choice, 1/2 to 1 mg/kg/daily is the necessary dose. 2- Control the autoimmune disorder and prevent from further attacks. There is a large choice of drugs for this purpose. Immunomodulators such as cyclosporine, many cytotoxic drugs (cyclophosphamide, chlorambucil, azathioprine, methotrexate), and recently biologic agents (Interferon-α, anti TNF drugs) can address that issue. The treatment has to start as early as possible. Any delay in the treatment will cause a drop in visual acuity which will not recover completely under the treatment. However, it is important to note that the treatment will always remain efficient even in those with a visual acuity as low as finger count, or even hand movement3-4. We have shown in several studies that cytotoxic drugs have approximately the same efficacy in ophthalmological lesions of Behcet’s Disease5-17. Biologic agents18-20 seems to work well in ocular lesions, however their data is not standardized, and it is impossible to compare them with cytotoxic drugs. Tables 1 to 7 summarize the data of different cytotoxic drugs17. DISEASE ACTIVITY INDEX: A disease activity index (DAI) has to be calculated for each section of each eye. The calculation is based upon the inflammatory state of the eye. The severity of the inflammatory indexes is graded from 0 to 4. These indexes are determined as follow: Anterior Uveitis (AU): Cells, flare, keratic precipitate and hypopion in the anterior chamber. Posterior Uveitis (PU): Cells, snow ball and snow banking in the posterior chamber. Retinal Vasculitis (RV): Periarteritis, periphlebitis, edema of disk and macula and retina, papillitis and active peripheral lesions in retina. The visual acuity (VA) as an overall index of the eye function was determined by the Snellen chart. VA is influenced by the inflammatory state of the eye as well as complications like synechia, cataracts, vitreous organization and retinal scars. For an overall patient’s inflammatory index (Total Inflammatory Activity Index) a coefficient of gravity was given to each section of the eye. For AU it was 1, for PU it was 2, and for RV it was 3. The index was calculate as follow: TIAI= Right [(AU1) + (PU2) + (RV3)] + Left [(AU1) + (PU2) + (RV3)] For an overall patient’s evaluation (Total Adjusted Disease Activity Index) was also calculated by giving an appropriate coefficient of gravity to VA, and adding them with the TIAI as follow: TADAI= TIAI + [(10 – right VA) 2] + [(10 – left VA) 2 CYTOTOXIC DRUGS: Cyclophosphamide can be used in 3 different forms. 1- The classic way is by oral administration (OCP)11. The dose is 2 to 3 mg per kilogram of body weight, to be taken every day. Blood count must be performed regularly due to suppression of bone marrow. Hemorrhagic cystitis is one of the major side effect encountered with this mode of administration. 2- Pulse cyclophosphamide (PCP)5-6. It is used by perfusion as 1 gram cyclophosphamide per square meter of body surface. Cyclophosphamide is mixed with 1000 ml serum saline and perfused slowly upon one hour. The main side effect is nausea and vomiting, which can be avoided by keeping the stomach empty and giving repeated perfusions over the first 24 hours. Tranquilizers may be of help. Hemorrhagic cystitis and dangerous suppression of bone marrow is exceptional. The pulse is repeated once monthly until the achievement of a good result. The gap between pulses is increased to 2 months and then to 3 months and finally stopped when the disease seems to be in remission. 3- Low dose pulse cyclophosphamide (LDP)7. The method is the same as for PCP, only the dosage of cyclophosphamide is half of it (0.5 gram per square meter of body surface). Methotrexate (MTX) is used as low dose weekly pulses of 7.5 mg orally9-10. MTX is given as tablets of 2.5 mg, in one day, in one intake or 3 separated intakes. MTX is well tolerated. Laboratory tests for liver function tests (SGOT, SGPT) and blood count may be performed once every 2 to 3 months. One of the advantages of MTX is that it can be continued over a long period of time without any serious side effect. Chlorambucil (CHL)15-17 is used by oral administration. It is one of the oldest cytotoxic therapies for ocular lesions of Behcet’s Disease. It is used as 0.2 mg per kilogram of body weight, and per day. Like Oral cyclophosphamide close monitoring of blood cell counts is necessary. Azathioprine (AZA)13, 17 is a well known cytotoxic drug, easy to use and manage. It is given as 2 to 3 mg/kg/day by oral root. It needs blood cell count monitoring, but less than cyclophosphamide. It is an easy cytotoxic drug to manipulate. Cyclosporine A (CyA)12, 15-17, 22-23 is an immunomodulator in use for tissue transplant and many autoimmune diseases like Rheumatoid Arthritis. In ocular lesions of BD it is used as 5 mg/kg/daily. As soon as a therapeutic response is obtained the drug must be reduced to the minimum dose, keeping the patient in remission. Side effects are important especially the nephrotoxicity which leads to renal insufficiency. In severe cases combination therapy with 2 cytotoxic drugs may be more efficient. The two combinations we have used are LDP-MTX and LDP-AZA. The doses are the same as when they are used in single therapy. TREATMENT STRATEGY: Before the treatment, a complete ophthalmological evaluation is mandatory. Different inflammatory indexes and visual acuity (VA) has to be calculated. As stated before, all the 8 methods that we evaluated in a same and standardized protocol (OCP, PCP, LDP, MTX, CHL, AZA, CyA, LDP-MTX) have approximately the same efficacy. The important factor to choose one of them is mainly the availability of the product and the ease one have to use them. Then comes the price of the drug and the price of regular controls for their side effects. Another consideration is the presence of retinal vasculitis, which responds better to PCP or LDP than to the other methods. Once the treatment protocol is selected, the patient will have at the same time prednisolone as 0.5 mg/kg/daily by oral route. Repeated and regular ophthalmological evaluation is mandatory. The first evaluation is scheduled in a month, or two months. When the inflammation is subsided prednisolone has to be tapered gradually. When prednisolone arrives to low doses (7.5 mg daily) the cytotoxic drug can be tapered to the minimum efficient dose. In case of relapse an increase of the dosage may suffice, otherwise the protocol is started from the beginning. Usually 70 to 75% of patients will respond favorably to the selected protocol. If after 3 to 6 months of treatment the patient’s eye (eyes) does not respond to the treatment (non responder), their treatment protocol has to be changed. The percentage of a favorable therapeutic response for the second protocol is the same as for the first protocol24. Non responders have to change to a third protocol. Their chance to respond favorably is about 50%. Some of the non responders may still profit from another change, although the chances are not more than 30%. REFERENCES: 1. Davatchi F, Shahram F, Akbarian M, Gharibdoost F, Nadji A, Chams C, Chams H, Jamshidi AR. Behcet’s Disease - Analysis of 3443 cases. APLAR Journal of Rheumatology 1997; 1: 2-5. 2. Davatchi F. Behcet’s Disease. In Textbook of Clinical Rheumatology. Edited by Howe HS and Feng PH. Singapore, National Arthritis Foundation, 1998: 298-315. 3. Davatch F, Shahram F, Shams H, Nadji A, Jamshidi AR, Chams C, Akbarian M, Gharibdoost F. Long-term outcome of vision in Behcet’s Disease. Arthritis Rheum 2001; 44: S1309. 4. Davatchi F, Shahram F, Chams H, Nadji A, Jamshidi AR, Chams C, Akbarian M, Gharibdoost F. The influence of the delay in aggressive treatment on the vision and its outcome in Behcet’s Disease. !0th International Conference on Behcet’s Disease. Berlin 26-29 June 2002, Abstract. 5. Davatchi F, Shahram F, Chams H, Chams C, Akbarian M, Hatef MR, Aalami-Harandi Z, Nikbin B. Pulse cyclophosphamide in ophthalmological manifestations of Behcet’s disease. In O’Duffy J.D. and Kokmen E. Behcet’s Disease Basic and Clinical Aspects. New York: Marcel Decker Inc.; 1991: 555-561. 6. Davatchi F, Shahram F, Chams H, Akbarian M, Nadji A, Gharibdoost F, Jamshidi AR. Pulse cyclophosphamide for ocular manifestations of Behcet’s Disease. Cohort study on 283 patients. Rev Rheum (Engl. Ed.) 1998; 65: 692. 7. Shahram F, Davatchi F, Chams H, Akbarian M, Gharibdoost F. Low dose pulse cyclophosphamide (LDP) in ophthalmologic lesions of Behcet’s Disease. In Behcet’s Disease. Edited by P Godeau and B Wechsler. Amsterdam, Elsevier Science Publishers B.V., 1993: 683-686. 8. Shahram F, Davatchi F, Chams H, Akbarian M, Chams C. Pulse Cyclophosphamide versus Pulse Methotrexate in Ophthalmological Manifestations of Behcet's Disease. In: Nasution AR. and Darmawan J. and Isbagio H. ( ed. ). APLAR Rheumatology 1992, Tokyo: Churchill Livingstone, Sept. 1992: p. 119-122. 9. Shahram F, Davatchi F, Chams H, Akbarian M, Chams C, Tebbi ME. Methotrexate in ocular Behcet. Preliminary report. Disease. First APLAR Symposium on the Therapy of Rheumatic Diseases, November 1990, Seoul, Korea. Abstract FP-23. 10. Davatchi F, Shahram F, Chams H, Akbarian M, Nadji A, Gharibdoost F, Chams C, Jamshidi AR, Soroosh S. Methotrexate for ocular lesions of Behcet’s Disease. Cohort study on 262 patients. Arthritis Rheum 1998; 41: S356. 11. Shahram F, Davatchi F, Chams H, Akbarian, Gharibdoost F. Comparing 3 methods of Cytotoxic therapy in ophthalmologic lesions of Behcet’s Disease. In Behcet’s Disease. Edited by P Godeau and B Wechsler. Amsterdam, Elsevier Science Publishers B.V., 1993: 635-640. 12. Shahram F, Davatchi F, Chams H, Akbarian M. Cyclosporin in sever ocular lesions of Behcet’s Disease. In Hamza M Behcet’s Disease. Tunis: Pub Adhoua; 1997: 421-423. 13. Davatchi F, Shahram F, Chams H, Akbarian M, Nadji A, Chams C, Gharibdoost F, Janmshidi A, Soroosh S. Azathioprine for the treatment of ophthalmological lesions of Behcet’s Disease. In Behcet’s Disease. Edited by D. Bang, E.S. Lee, S. Lee. Seoul, Korea,, Design Mecca Publishing Co., 2000: 898-900. 14. Shahram F, Chams H, Davatchi F, Nadji A, Akbarian M. Combination therapy with low dose pulse cyclophosphamide and methotrexate in ocular lesions of Behcet’s Disease. In Behcet’s Disease. Edited by D. Bang, E.S. Lee, S. Lee. Seoul, Korea,, Design Mecca Publishing Co., 2000: 898-900. 15. Davatchi F, Shahram F, Gharibdoost F, Akbarian M, Nadji A, Chams H, Chams C. Outcome analysis of ocular lesions in Behcet’s Disease with 6 different therapeutic methods. Arthritis Rheum 1996; 39: S217. 16. Davatchi F. Neuro-ophthalmic Behcet’s. In: Torralba TP, Amante CM, and Victorio-Navarra STG ( Eds. ) APLAR 3rd. Symposium On The Therapy Of Rheumatic Diseases. 1998, Hong Kong: Excerpta Medica Asia Ltd, 1997: p. 16-17. 17. Davatchi F. Treatment of ocular manifestations of Behcet’s Disease. Proceedings, 9th Asia Pacific League of Associations for Rheumatology Congress. Beijing, China. May 21-26, 2000: 174-176. 18. Adler YD, Krause L, Foerster MH, Orfanos CE, Zouboulis CC. Treatment of ocular Adamantiades-Behcet’s disease with interferon-alpha. Behcet’s Disease. In Behcet’s Disease. Edited by D. Bang, E.S. Lee, S. Lee. Seoul, Korea,, Design Mecca Publishing Co., 2000: 446-447. 19. Wechsler B, Huong-Boutin LTD, Amoura Z, Fardeau C, Cassoux N, Bodaghi B, Le Hoang P, Piette JC. Efficacy of alpha interferon in severe and refractory uveitis of Behcet’s Disease. Behcet’s Disease. In Behcet’s Disease. Edited by D. Bang, E.S. Lee, S. Lee. Seoul, Korea,, Design Mecca Publishing Co., 2000: 483-488. 20. Kotter I, Stubiger N, Eckstein AK, Heiligenhaus A, Gunaydin I, Jacki SH, Grimbacher B, Ness TH, Peter HH, Kanz L, Zierhut M. Recmbinant human interferon-α2A (IFNα2A) in the treatment of ocular Behcet’s Disease (BD). In Behcet’s Disease. Edited by D. Bang, E.S. Lee, S. Lee. Seoul, Korea,, Design Mecca Publishing Co., 2000: 491-493. 21. Davatchi F, Shahram F, Gharibdoost F, Akbarian M, Nadji A, Chams H, Chams C. Outcome of patients with ocular lesions of Behcet’s Disease non responding to classical treatments. Arthritis Rheum 1997; 40: S66. 22. Nussenblatt RB, Palestine AG, Clan CC. Effectiveness of cyclosporin therapy for Behcet’s disease. Arthritis Rheum 1985; 28: 671-679. 23. Whitcup SM, Salvo EC Jr, Nussenblatt RB. Combined cyclosporine and corticosteroid therapy for sight-threatening uveitis in Behcet’s disease. Am J Ophthalmol 1994; 118: 39-45. 24. Davatchi F, Shahram F, Gharibdoost F, Akbarian M, Nadji A, Chams H, Chams C. Outcome of patients with ocular lesions of Behcet’s Disease non responding to classical treatments. Arthritis Rheum 1997; 40: S66. Table 1: The mean follow-up time and the mean duration of the disease in months Table 2: Anterior Uveitis Table 3: Posterior Uveitis Table 4: Retinal Vasculitis Table 5: Visual Acuity Table 6: Total Inflammatory Activity Index Table 7: Total Adjusted Disease Activity Index