Ординатура / Офтальмология / Английские материалы / Essentials in Ophthalmology Uveitis and Immunological Disorders_Pleyer, Forrester_2004

12.7.2.3

Immunosuppressive and Cytotoxic Agents

12.7.2.3.1 Cyclosporine A

Cyclosporine A is the most widely used immunosuppressive drug for ocular Behçet’s disease. At dosages of 3–5 mg/kg/day or in combination with low dose corticosteroids it has proven to be a rapidly acting and effective medication not only to treat acute attacks but also to reduce recurrence rates of ocular inflammation [108, 113, 136]. However, nephrotoxicity, particularly at dosages higher than 5 mg/kg per day, and relapses after discontinuation of therapy may limit the use of cyclosporine A [77]. Moreover, there is evidence suggesting that cyclosporine A exhibits neurotoxicity in patients with Behçet’s disease or accelerates the development of neuro-Behçet’s disease [73, 66].

12.7.2.3.2 Azathioprine

Azathioprine is considered as a proven immunosuppressive drug with considerably fewer side effects. Therefore it is acceptable as an alternative to cyclosporine A for the treatment of eye involvement in Behçet’s disease. In a placebo controlled double-blind study, azathioprine (dosage of 2.5 mg/kg daily) was effective in controlling intraocular inflammation, maintaining visual acuity as well as preventing an onset or progression of eye disease [153]. Compared to those patients originally allocated to the placebo group in the previous study, long-term visual prognosis improved in the group treated with azathioprine [49]. But this beneficial effect did not extend to those patients who had eye disease for 2 years or more when they first started azathioprine treatment [155]. Using azathioprine it must be noted that the therapeutic effect of this drug usually starts with a delay of 2–3 months.To treat or prevent an acute attack, this period has to be bridged with systemic steroids.

12.7.2.3.3 Colchicine

The therapeutic effect of colchicine in Behçet’s disease seems to vary among races. Except for Japan, where it is widely used and has been reported to be very effective, colchicine has been shown to be beneficial only for mucocutaneous and articular manifestations but not for severe ocular involvement [8, 102].

12.7.2.3.4 Tacrolimus (FK506)

Tacrolimus (FK506) develops a similar immunosuppressive activity at lower dosages than cyclosporine A. In a few open studies with small cohorts of Behçet’s patients, low dose tacrolimus showed good efficacy in cases of sight-threatening posterior uveitis, in which previous treatment with cyclosporine A had to be discontinued either because of a lack of response or unacceptable side effects [69, 131].

12.7.2.3.5 Mycophenolate Mofetil

Mycophenolate mofetil is a relatively new immunosuppressive drug. It has been successfully used in several autoimmune ocular disorders, e.g. corneal transplant rejection, endogenous uveitis or atopic keratoconjunctivitis. Theoretically one should expect that mycophenolate mofetil is also beneficial for uveitis and retinal vasculitis due to Behçet’s disease. However, there are no data published yet as to whether this holds true. Interestingly a prospective clinical proof-of-principle study investigating the effectivity of mycophenolate mofetil in mucocutaneous Behçet’s disease had to be discontinued because of treatment failure [2].

12.7.2.3.6 Methotrexate

Methotrexate does not play an important role in the treatment of eye involvement. It is generally believed that this drug has only a weak effect on the manifestations of Behçet’s disease [61].

12.7.2.3.7 Others

Cytotoxic drugs such as chlorambucil or cyclophosphamide are used for very severe and life threatening manifestations of Behçet’s disease (CNS, arterial aneurysms, gastrointestinal) [110, 148]. Thalidomide is used for therapy resistant aphthous ulcers and skin lesions as well as for exceptional cases of refractory life threatening symptoms of Behçet’s disease [50]. In our opinion, for ocular disease these drugs are usually no longer indicated because of their toxic side effects.

12.7.2.4

Immunomodulating Substances

12.7.2.4.1 Interferon-a

Interferon-a is a cytokine which belongs to the so-called type-1 interferons and which can be produced by virtually all somatic cells after viral infection. It exerts antiviral, antiproliferative, antiangiogenetic and immunomodulatory effects. There are two different human recombinant a-interferons (IFN-a-2a and IFN-a-2b) in use for the treatment of viral hepatitis and myeloproliferative syndromes,as well as for certain solid tumours and lymphomas [76].

Since the early 1990s interferon-a has become more important in the treatment of severe ocular Behçet’s disease. Several open studies were performed to investigate the efficacy of in- terferon-a especially in such patients with posterior uveitis, panuveitis, retinal vasculitis or cystoid macular edema who showed to be refractory to previous conventional immunosuppressive treatment. Interferon-a-2a led to a quick response and complete remission of ocular symptoms in more than 90% of these patients [77, 79, 134, 149]. A significant increase in visual acuity,complete disappearance of cystoid macular edema without additional treatment and an only small recurrence rate even after cessation of interferon therapy were also found. Moreover interferon-a-2a led to reperfusion of occluded retinal vessels as well as to complete regression of retinal neovascularization in

some patients. Side effects of interferon-a-2a were frequent but, except for hypothyroidism, dose dependent and reversible. The development of autoimmune phenomena during treatment with interferon may be a major concern. Pre-existing depression and psoriasis may be a contraindication for interferon as well. Recently published data suggest that interferon-a-2a also leads to a better long-term visual prognosis in severe ocular Behçet’s disease than conventional immunosuppressants. None out of 15 eyes in 9 patients,who were treated with interferon-a-2a, showed a decrease of visual acuity over a followup period of at least 5 years [25].

There exists no consensus yet on the interferon dosage for treatment of Behçet’s disease. In our hands, the initial dosage necessary to achieve optimal results is 3–6 million IU daily for 4–8 weeks; a maintenance dosage amounts to 3 million IU 3¥/week, with a treatment duration of at least 6 months before cessation of the drug [76]. Previous immunosuppressive treatment should be discontinued and systemic corticosteroids reduced to a maximum of 10 mg prednisolone equivalent per day before the initiation of interferon treatment to avoid possible antagonistic effects.

Regarding published data, there may be no doubt that interferon-a-2a is very effective in the therapy of severe ocular Behçet’s disease and moreover superior to conventional immunosuppressants. Nevertheless in Germany a randomized controlled multicentre study to compare the efficacy of interferon-a-2a against cyclosporine A has been initiated.

12.7.2.4.2

TNF-a Antagonists

A promising new approach for the treatment of Behçet’s disease is the use of inhibitors of tumour necrosis factor alpha (TNF-a). This cytokine produced by Th1-lymphocytes is assumed to play an important role in Behçet’s disease as well as in other chronic inflammatory disorders. In two case series there were a total of ten patients with sight-threatening and refractory posterior uveitis or panuveitis (due to Behçet’s disease in eight). Infliximab, a soluble humanmouse chimeric monoclonal antibody to TNF-a

(intravenously in a dosage of 3–5 mg/kg at intervals of 2–8 weeks) led to rapid and effective suppression of the acute inflammatory attacks. In one patient reactivation of tuberculosis, a known adverse effect of infliximab besides the anaphylactic reaction, occurred [58, 128]. In an early phase II clinical study infliximab showed efficacy in Behçet’s patients with uveoretinitis who did not respond well to cyclosporine treatment. But approximately 2 months after completion of the study,all subjects had recurrences of uveitis. Consequently infliximab was assumed to remain effective for 2 months only, whereafter uveitis may relapse [105]. In contrast to the majority of the immunosuppressants and to interferon-a,no more data are available so far describing the long-term beneficial effects of infliximab. Whether tachyphylaxia during therapy occurs also remains unclear. On the other hand, in Behçet’s disease infliximab seems to be more effective than etanercept, a soluble TNF-a receptor [36]. For adalimumab, the latest representative of the TNF-a antagonists,no data have been published yet regarding its efficacy in ocular Behçet’s disease.

12.7.3

Surgical Treatment

In contrast to drug therapy,ocular surgery plays a secondary role in the treatment of eye involvement due to Behçet’s disease. It is usually limited to secondary complications of the ocular inflammation like cataract or glaucoma in the anterior eye segment. Complications regarding the posterior eye segment such as macular hole, retinal detachment or persisting vitreous haemorrhage are usually indications for vitreoretinal surgery.

Cataract surgery will be able to be scheduled in most cases. However, it is highly recommended to perform this procedure only when the eye has been at least 3 months free from inflammation in order to keep postoperative inflammation mild [59].

Laser photocoagulation is a widely used procedure which has been reported to be successful in preventing complications of retinal and disc neovascularization due to occlusive vasculitis

[6]. On the other hand, interferon-a-2a led to complete regression of retinal neovascularization in some cases [77, 134]. Thus a treatment attempt with this anti-angiogenetic substance may be indicated before deletion of large parts of the retina by laser photocoagulation.

12.7.4

Practical Treatment Recommendations

Treatment of Behçet’s disease has to be adapted to patients’ most severe symptoms, usually ocular or neurological manifestations. By close cooperation between physicians of different disciplines, a therapy, which should be sufficient for all present manifestations, has to be found.

Regarding ocular involvement exclusive local treatment is restricted to cases with only mild or moderate anterior segment inflammation. With the background of poor visual prognosis, the first onset of vitreous or posterior segment affection normally indicates the initiation of an aggressive systemic treatment. This first-line therapy usually consists of a combination of steroids and an established immunosuppressant like cyclosporine A or azathioprine. If this immunosuppressive therapy fails, not inducing remission of the disease or recurrences under treatment occur, we do not recommend adding a further immunosuppressive drug because of potentiating adverse effects but of switching to interferon-a-2a. In those cases where retinal neovascularizations are present or an acute retinal vessel occlusion occurs, inter- feron-a-2a may also be first-line therapy without previous steroid or immunosuppressive treatment. In our opinion TNF-a antagonists should be reserved for those patients who either do not respond to interferon-a-2a or in whom interferon has to be discontinued because of side effects, because interferon-a-2a shows a lower recurrence rate at a similar cost. Ocular surgery should be limited to secondary complications of eye involvement. In most patients with ocular Behçet’s disease it should be possible today, by early initiation of sufficient medical treatment,both to preserve visual acuity and to prevent secondary complications.

Summary for the Clinician

∑Treatment of Behçet’s disease is a challenge and necessitates close cooperation between different medical disciplines

∑Posterior eye segment involvement is associated with poor visual prognosis and therefore indicates early and aggressive systemic treatment

∑First-line therapy usually consists of a combination of systemic corticosteroids and an established immunosuppressant such as cyclosporine A or azathioprine

∑Novel drugs such as interferon-a-2a or TNF-a antagonists may lead to better visual prognosis of ocular Behçet’s disease because they are effective even if conventional immunosuppression fails

∑In contrast to drug therapy, ocular surgery plays an inferior role in the treatment of ocular Behçet’s disease and is limited to secondary complications of inflammation

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∑The choroid is the site of origin of posterior intraocular inflammation at least as often as the retina

∑Before indocyanine green angiography (ICGA) became available, subtle inflammatory changes in the choroid were not detectable and appraisal of choroiditis was based on clinical appearance alone, leading to an amalgamation of unrelated conditions under the term “white dot syndromes”

∑By giving imaging access to the choroid and by enabling lesions to be shown at an incipient stage, ICGA has contributed to an understanding of disease mechanisms and has helped to classify choroiditides

∑The two principal properties of the indocyanine green molecule are fluorescence in the infrared wavelengths and a macromolecular behaviour because it is nearly 100 % linked to proteins

∑Infrared fluorescence can be detected through the retinal pigment epithelium and gives imaging access to the choroid

∑The macromolecular ICG-protein complex egresses from the vascular bed only when capillaries are fenestrated (or when larger vessels are severely inflamed) and so impregnates the choroidal stroma. Absence of ICG fluorescence can mean non-perfusion of the choriocapillaris or impaired diffusion of the molecule because of the presence of inflammatory foci

∑If choroidal involvement is suspected, dual fluorescein and ICG angiography is indicated (allows complete and thorough work-up of inflammatory involvement of all struc-

tures and is essential for follow-up of choroidal inflammation)

∑Use a conventional fundus camera coupled to an image digitalizing system (easier for peripheral imaging) or a scanning laser ophthalmoscopy system

∑Use one vial of 25 mg indocyanine green diluted in 7.5 ml of physiologic saline solution (Cardiogreen, Akorn, Inc., Buffalo Grove, IL, USA). In case of iodine allergy use iodinefree Infracyanine (SERB Laboratories, Paris, France)

∑Angiographic procedure: (1) exclude autofluorescence by taking frames with the highest flash intensity previous to the dye injection; (2) perform early frames of the posterior pole up to 2–3 min (early phase);

(3) perform posterior pole and 360 degree periphery panoramic frames at 8–12 min (intermediate phase); (4) perform fluorescein angiography between intermediate and late ICGA phases; (5) perform posterior pole and 360 degree periphery panoramic frames at 28–35 min (late phase)

∑Choroidal inflammation may involve either the choriocapillaris or the choroidal stroma, two disease mechanisms that should be distinguished. In the first group, including diseases such as APMPPE, MEWDS and multifocal choroiditis, the inflammatory process causes choriocapillaris non-per- fusion, whereas in the second group, including Vogt-Koyanagi-Harada (VKH) disease and birdshot chorioretinopathy (BC), inflammatory foci develop in the choroidal stroma and are associated with inflammation of larger stromal vessels