Immunosuppressive agents
Immunosuppressive therapy is usually a treatment of last resort, but there is little evidence that it is beneficial for the long-term retention of vision in severe idiopathic
retinal vasculitis. The use of immunosuppressive agents in retinal vasculitis is generally reserved for patients with bilateral disease whose vision has fallen below 20/40 in the better eye. Occlusive vasculitis in patients with Behcet's syndrome is the one form of uveitis for which most authorities agree that immunosuppressive drugs are the treatment of first choice. They are best administered by an internist experienced in their use, with monitoring of treatment effect by an ophthalmologist, indicating the importance of a team approach. The ones commonly used in ocular inflammations include azathioprine, cyclophosphamide, methotrexate (MTX), mycophenolate mofetil, and cyclosporine.
Other indications of immunosuppressive therapy in retinal vasculitis may include chronic inflammation that is not responding to the primary conventional corticosteroid therapy; multiple relapses of inflammation, in the same or other eye, or both eyes; or intolerance or contraindications to systemic corticosteroids.
These agents are started after an informed consent from the patient. The clinician should discuss extensively with the patient regarding the risks of secondary malignancy and gonadal dysfunction. Before starting any immunosuppressive drug, all patients are evaluated to rule out contraindications to treatment, such as hemoglobin, blood cell counts (leucocytes and platelets) and abnormal liver or renal function tests. While receiving these medications, the patients are monitored every four weeks for laboratory tests including blood cell counts, bilirubin, liver enzymes, and serum creatinine.
Identification of non infectious systemic associations warrants initiation of specific therapy, besides the conventional corticosteroids. Management of some of the common specific causes of retinal vasculitis is discussed below.
Behcet’s disease: Behcet’s disease is a systemic immune-mediated vasculitis of unclear origin. Although the vasculitis associated with Behcet’s disease responds well to systemic corticosteroids that also delays the time to blindness in patients with posterior segment involvement, but it does not alter the long-term outcome7. Further, majority of patients with ocular Behçet’s disease present with multiple relapses of inflammation. The long-term consequences of corticosteroids are unacceptable and they are not always suitable as a monotherapy for maintaining remission of vasculitis due to adverse side effects. Often it becomes necessary to add immunosuppressive drug as a steroid-sparing agent.
Cyclosporine A (3–5 mg/kg/day) and Azathioprine (2.5 mg/kg/day) are known to effectively control intraocular inflammation, to maintain visual acuity, and to prevent onset or progression of eye disease in ocular Behcet’s disease6,8. Despite aggressive immunosuppressive treatment, the visual prognosis of ocular BD remains generally poor8. Recently, novel biologic drugs, including interferon-a and tumour necrosis factor (TNF)-a-antagonists have been introduced in the treatment of ocular Behcet’s disease with very promising results and seem for the first time to improve the prognosis of the disease9,10. Unfortunately, these new drugs are very expensive and therefore they may be not universally available in countries with a low economic status.
Sarcoidosis: Retinal vasculitis in sarcoidosis is less common than anterior uveitis and vitreitis11. Systemic corticosteroids (Prednisolone 1 mg/kg/day) are the mainstay of treatment. When associated panuveitis is also present, topical corticosteroid and cycloplegic are given. The oral corticosteroids are tapered over 8-10 weeks by 5-10 mg per week depending upon the clinical response, in consultation with the pulmonologist. Few authors have reported the use of low-dose Methotrexate (MTX) in refractory cases of panuveitis12.
Retinal vasculitis may be caused directly by various infectious agents; in the majority of such cases specific antimicrobial therapy is available. It may be an antibiotic, antiparasitic or an antiviral drug administered for appropriate duration, with or without corticosteroids.
Tuberculosis: Tuberculosis is a common cause of retinal vasculitis in our experience. Once a diagnosis of presumed tubercular vasculitis is made, 4-drug anti-tubercular therapy including Isoniazid- 5 mg/kg/day, Rifampicin-450 mg/day (if body weight < 50 kg and 600 mg/day if body weight > 50 kg), Ethambutol 15 mg/kg/day, and Pyrazinamide 25-30mg/kg/day is initiated under the supervision of an internist, and continued for 3-4 months. Oral corticosteroids are administered in the standard dose of 1 mg/kg body weight per day, to be tapered depending upon the clinical response. The patients are monitored for any liver toxicity. Thereafter, Rifampicin and Isoniazid are used for another 9-14 months. Pyridoxine supplementation is given to all patients receiving anti-tubercular therapy till cessation of therapy. Anti-tubercular therapy has shown to significantly reduce recurrence of inflammation13.
- Figure 1a: Tubercular retinal vasculitis in a 26-year-old man. Note exuberant perivascular infiltrates both focal and segmental with extensive superficial flame shaped hemorrhages.
- Figure 1b: Same eye as in figure 1a, 4 weeks after starting anti tubercular therapy and oral corticosteroids shows resolution of exudates and hemorrhages.
- Figure 1c: Same eye as in figure 1a and 1b, 4 months later, shows almost complete resolution of retinal vasculitis
- Figure 2a: A 40-year-old man with intraocular tuberculosis showing extensive inflammation of the upper and lower temporal vessels along with choroiditis. The lower temporal artery also shows perivascular exudates.
- Figure 2b: Same eye as in figure 2b, 4 weeks later on anti tubercular therapy with corticosteroids shows resolution of inflammation. Retinal hemorrhages have absorbed to a great extent. Note deposition of hard exudates in fovea and resolving perivascular exudates especially around retinal arterioles.
- Figure 2c: 3 months later, the eye shows resolution of all hemorrhages, and exudates. Note pigmented scar along upper temporal vessels from healing of the associated choroiditis. Healed choroiditis scars are typically seen in tubercular retinal vasculitis.
Toxoplasmosis: The most commonly used combinations are Clindamycin and corticosteroids; or Pyrimethamine, Sulfadiazine and corticosteroids. Oral corticosteroids are used to limit the damaging effects of inflammation. Recommended regimen includes tablet Clindamycin 300 mg four times daily (3-4 weeks) along with tablet Septran-DS 960 mg daily (960 mg sulfamethoxazole and 160 mg trimethoprim) for 3-4 weeks. Oral corticosteroids (1-1.5 mg/kg/day) are started 48 hours after starting antitoxoplasma therapy, and tapered according to the clinical response. Other drugs that have been used in ocular toxoplasmosis are Atovaquone and Spiramycin.
Syphilis: Penicillin remains the standard treatment for ocular syphilis. The recommended regimen for treatment of ocular syphilis is the same as that for neurosyphilis,i.e, intravenous crystal penicillin G 12–18 Million Units/day for 10–14 days, followed by supplementary intramuscular penicillin G 2.4 Million Units weekly for 3–4 weeks. If the patient is allergic to penicillin, then oral tetracycline 500 mg four times a day for 4-6 weeks is a good alternative.
Lyme disease: Lyme borreliosis greatly mimics syphilis and can cause false-positive readings on both specific and non-specific tests for syphilis. Patients with Lyme uveitis are treated as if they had neuroborreliosis. Intravenous therapy with either ceftriaxone, 2 g daily for adults (50 to 100 mg/kg/day for children) for 21 days; or penicillin G, 20 million units daily, or 0.25 to 0.5 million units/kg/daily for children. Doxycycline, 100 mg twice daily, is a good alternative in adults with less severe infection but contraindicated in children, pregnant or breastfeeding women. Some patients with severe ocular inflammation may require concomitant oral prednisone (0.5 to 1.0 mg/kg/day) because of the possibility of paradoxical worsening (Jarisch-Herxheimer reaction). But steroids should not be used without appropriate antibiotic cover.
Surgical therapies such as laser photocoagulation or vitrectomy are generally not indicated except in the management of persistent neovascularization (new vessel growth) or in cases of bleeding into the vitreous or glaucoma., epiretinal membrane, tractional retinal detachment threatening the macula, combined tractional and rhegmatogenous retinal detachment and a densely opacified vitreous.
- Figure 3a: A 19-year-old boy presenting with vitreous haze, and retinal infiltrates due to Behçet’s disease.
- Figure 3b: Fundus fluorescein angiography of the same eye as in figure 3a shows perivascular staining of tertiary vessels in the macula. Note that points of intense focal staining on the angiogram correspond to the retinal infiltrates on the fundus picture in figure 3a.
Figure 4: A 25-year-old woman with advanced changes of Behçet’s disease in the right eye. On fundus fluorescein angiography, there was extensive retinal capillary non-perfusion and dye leakage from the remaining vessels in the posterior pole.
Prognosis
The prognosis for patients with retinal vasculitis is variable, reflecting the heterogenous nature of this group of disorders.
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