RETROSPECTIVE STUDY OF CLINICAL PRESENTATION, COMPLICATIONS & MANAGEMENT OF UVEITIS
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1 RETROSPECTIVE STUDY OF CLINICAL PRESENTATION, COMPLICATIONS & MANAGEMENT OF UVEITIS 1
2 DR. RANA MASOOD 2
3 ABSTRACT OBJECTIVE: To evaluate the causes, clinical presentation and management of patients of acute anterior uveitis in different ages, in short term and long term, and also to evaluate the role of immunomodulators. METHODS: We have retrospectively studied 50 cases of AAU in a Private Medical Facility in Sharjah, UAE, including children. Diagnosis was made on the basis of: Clinical Ophthalmological Examination Relevant lab investigations (for example chest x-ray, ANA, HLA- B27, Tubercular antibodies, TPHA) and associated systemic problems. Complications were assessed. RESULTS: Out of 50 cases, 34/50 (68%) were male and 16/50 (32%) were female. Majority of cases were associated with SSA (21/50 42%) followed by idiopathic ( %). All ANA positive cases belonged to category of SSA (9/21 43%). 86% of cases (43/50) developed complications. Cataract (17/50 34%) optic disc edema and (11/50 22%) were commonest complications. Majority of patients required systemic treatment (47/50 94%) followed by topical steroid (41/50 82%) CONCLUSIONS: Incidence of uveitis associated with seronegative illnesses is significantly high in middle east. Methotrexate and biologics (Adalimumab) can be used in cases of Recalcitrant uveitis. Majority of patients developed complications (47/50 94%) Couple of short comings of study It is not a prospective study to provide guidelines for use of MTX and BIOLOGICS in cases of difficult uveitis. Final out come was not assessed on the basis of blindness and indications for surgery. 3
4 The term uveitis is used clinically to describe a heterogenous group of diseases characterized by inflammation of intraocular structures. Although frequently associated with systemic inflammatory or autoimmune diseases such as sarcoidosis, multiple sclerosis, Behcet s disease, and the seronegative spondyloarthropathies, a significant number of cases defy disease classification and are labelled idiopathic. In general, noninfectious cases of uveitis are thought to represent immune-mediated disease, possibly triggered by environmental stimuli and mediated primarily by T cells in patients with an immunogenetic predisposition. The implication that cell-mediated immunity is involved in the pathogenesis of uveitis has provided a rationale for treatment with immunosuppressive medications such as corticosteroids, which have been shown to be effective in improving the signs and symptoms of ocular inflammation and the prognosis for preservation of visual acuity. The well-known adverse effects of longterm corticosteroid therapy, however, have led ophthalmologists to use corticosteroid-sparing agents to reduce the side effects associated with long-term corticosteroid use. Unfortunately, each of these agents is also associated with undesirable toxicity. Efforts are under way to identify more effective therapy, which would ideally focus on targetting specific mediators of the immune response, allowing for increased efficacy and decreased adverse effects of treatment. One horizon being explored in the search for targetted immunosuppressive agents is blockade of tumor necrosis factor α (TNF- α). Tumor necrosis factor α is an inflammatory mediator that plays an important pathogenic role in inflammatory diseases such as rheumatoid arthritis, fistulizing Crohn disease, and ankylosing spondylitis. Pharmacological blockade of this mediator has demonstrated benefit in all 3 of these diseases. In addition, ample evidence from animal and human studies implicates TNF as a potentially important mediator in uveitis. With our increasing understanding of the pathogenesis of autoimmune rheumatic diseases, several biologic agents are being developed for treatment, especially for RA. These can be classified as follows: Monoclonal antibodies Against T-cell surface molecules: CD4 (anti-cd4) Against B-cell surface molecules: CD20 (anti-cd20) Activation antigents: CD25 (anti-tac) 4
5 Against cytokines: TNF α (anti-tnf α), IL-6 (anti-il-6), IL-8 (anti IL-8) Against adhesion molecules: ICAM-I/LFA-1 interaction (anti-cd1 I α receptor) Against complement: C5 (anti-c5) Against costimulatory molecules: CD40L (anti-cd40l) Biologics targeting T/B-cell collaboration molecules CD28/B7 interaction (CTLA-4 Ig) Biologics targeting inflammatory cytokinase Cytokine receptor antagonist proteins (IL-1 Ra) Soluble receptors (TNF α receptor) Methods targeting antigent-mhc-tcr interaction Oral tolerance (Type II collagen in Ra) TcR Vβ peptide vaccine MHC peptide vaccine Others Antisense olignucleotides (against ICAM-1) T-cell vaccination Gene therapy (IL-Ra, Fas ligand) IL-10: an anti-inflammatory cytokine The following biologic agents are currently available to treat rheumatic diseases: 1. Etanercept (Enbrel) 2. Infliximab (Remicade) 3. Anakinra (Kineret) Studies are available where etanercept and infliximab only have been used to treat uveitis. In this study we have used another biologic agent that is Adalimumab (humira). Adalimumab (D2E7): fully humanized anti-tnf monoclonal antibody. Given subcutaneously every other week without having to worry about neutralizing antibodies. 5
6 There are four primary parameters used to characterize subsets of uveitis: 1. Anatomic location of inflammation (anterior, intermediate, posterior, panuveitis). 2. laterality (unilateral, bilateral) 3. onset (Acute, insidious) 4. duration (self-limited, chronic, recurrent) The location, laterality, and onset of uveitis can assist in identifying a specific etiology of the uveitis. For example, HLA-B27-associated uveitis is almost always acute, anterior, and unilateral, while the uveitis associated with sarcoidosis may be a chronic, bilateral panuveitis. PATIENTS AND METHODS: The study included 50 patients with active uveitis examined at a private clinic facility in Sharjah, UAE. Patients belonging to any age group 8 50 years were included in this study. We conducted a retrospective analysis of medical records of all patients, a special attention was paid to the relevance of diverse diagnostic procedures, the presence of systemic diseases, the necessity for treatment with systemic immunosuppressive drugs and corticosteroids, ocular complication rates and visual loss. The patients were classified by the involvement and specific diagnosis of uveitis, according to the criteria of international uveitis study group. We have made a little modification in this criteria. The uveitis was considered chronic, if the duration of active ocular inflammation was longer than 3 months. Depending on the severity of disease and clinical presentation, patients underwent a uveitis screening protocol which encompassed erythrocyte sedimentation rate, complete blood count, x-ray chest, serology for syphilis, antinuclear antibodies, HLA B27 and antibodies for tuberculosis. We have not done any test for Toxoplasma gondii, Borrelia burgdorferi, Bartonella henselae, Toxocara, Ascaris, and Epstien-Barr virus. Diagnosis of viral infections were made on the basis of medical history, clinical presentation and in some cases polymerase chain reaction and viral antibodies. Depending on medical history, clinical presentation, and results of uveitis screening, a subsequent reference to specialist followed. The diagnosis of JRA was according to criteria from the International League Against Rheumatism (ILAR). In short, JRA was defined as arthritis, starting before the age of 16 years with duration longer than 6
7 3 months and the patients had no otherwise identifiable cause for the uveitis. For the diagnosis of sarcoidosis, clinical history and chest x- ray was done. No histological examination was performed. Since the incidence of toxoplasma is minimal in this part of world, therefore we did not do any specific test to establish the diagnosis of uveitis due to T. gondii. Additional associated diseases were diagnosed according to current standard criteria. All patients underwent a complete ocular examination including measurements of corrected visual acuity, slit lamp examination, funduscopy, and tonometry. Othoptic examination, fluorescein angiography, and visual fields examination were performed in selected cases. RBS was done in all cases before starting systemic steroids. All patients were explained about the teratogenic effects of Methotrexate and during the course of treatment, monthly CBC, thee monthly LFT was done as well as three monthly chest x-ray to exclude the possibility of interstitial pneumonitis. For patients on Adalimumab treatment, PPD and Tubercular antibodies was done. 7
8 RESULTS TABLE I CAUSES, DEMOGRAPHICS, AND LOCATION OF UVEITIS Sl. No. CAUSES NO. OF PATIENTS (%) 1 Idiopathic 19/50 (38%) MALE FEMALE LOCATION OF UVEITIS 10/19 9/19 Anterior/Intermediate (53%) (47%) 2 Infective A. Viral (Herpes Simplex and Herpes Zoster) B. Bacterial TB - Syphilis 9/50 (18%) /9 (89%) /9 (11%) Anterior Anterior/Intermediate Anterior/Intermediate 3 Associated with seronegative spondyloarthropathies a. ankylosing spondylitis b. Reiter s Syndrome c. Reactive d. JRA e. Psoriasis 21/50 (42%) /21 (76%) /21 (24%) 4 Sarcoidosis 1/50 (2%) 0 1 (100%) TOTAL (68%) (32%) Anterior Panuveitis Anterior uveitis, patients usually present with complaints of pain, redness, and photophobia. Most cases are unilateral, but bilateral disease can be seen in patients with interstitial nephritis or Sjogren s syndrome. Intermediate uveitis, patients usually complain of insidious onset of floaters or mild haziness of vision. Typically, the external eye is quiet, and there is no pain or photophobia. Although initial complaints are usually limited to one eye, evidence of mild inflammation in the contralateral eye is common. 8
9 Posterior uveitis, patients usually complain of insidious onset of blurred vision, floaters, and scotomata. As in intermediate uveitis, the external eye is quiet and there is no pain or photophobia. This series consisted of 50 patients and majority of them were male (34/50-68%). Majority of the patients belonged to the category - Associated with SSA i.e. 21/50, 42%. Out of all the cases of seronegative spondyloarthropathies, majority belonged to the category of reactive arthritis. Only one female patient of sarcoidosis was registered for this study. In infective category, majority of patients were viral, only 2 cases of tuberculosis and 1 case of syphilis was registered. In all groups, majority of patients had anterior uveitis. Only sarcoidosis had panuveitis. We did not find any case of toxoplasmosis, cytomegalovirus retinitis, histoplasmosis, etc. 9
10 TABLE 2 INVESTIGATIONS (SPECIFIC) Sl. No. CAUSES X-RAY CHEST TPHA ANA HLA- B27 TB ANTIBODIES 1gG/1 gm 1 Idiopathic 2 Infective a. Viral (Herpes simplex and Herpes Zoster) b. Bacterial - TB + 2/2 (100%) - Syphillis + 1/2 (50%) 3 Associated with SSA 21/50 a. Ankylosing spondylitis b. Reiter s syndrome c. Reactive arthropathy d. JRA e. Psoriasis + 1/1 (100%) + 3/3 (100%) 9/21 (43%) 4 Sarcoidosis + 1/1 (100%) TB Immunochromatographic assay TB 1 gg/ 1 gm: One step syphilis Anti TP test. 10
11 LABORATORY TESTS ARE OF DIAGNOSTIC VALUE FOR PATIENT WITH UNCLASSIFIED UVEITIS Chest roentgenogram and fluorescent treponomal antibody absorption (FTA-ABS) because sarcoidosis and syphilis may have ocular inflammation without clinically apparent systemic disease, tests for these two entities are indicated in all patients with uveitis of unknown etiology. Specifically, one should obtain a serologic test for syphilis (FTA) and a chest roentgenogram to screen for sarcoidosis. Other laboratory tests should be ordered depending on the nature and setting of the uveitis. Antinuclear antibody (ANA) testing is indicated only in the evaluation of pediatric patients with bilateral, chronic iritis, as this test is positive in up to 88% of patients with juvenile rheumatoid arthritis and iritis. It is not indicated for a routine screening of adult patients with unclassified uveitis, because a patient with uveitis and a positive ANA has a <1% chance of having systemic lupus erythematosus. Similarly, a patient with uveitis and a positive purified protein derivative (PPD) test has only a 1% likelihood of having tuberculosis. PPD testing in uveitis should be limited to patients having an appropriate exposure history or an abnormal chest roentgenogram suggestive of tuberculosis. HLA-B27 testing is only appropriate for patients presenting with acute, anterior uveitis. It is not helpful in the evaluation of patients with chronic, intermediate or posterior uveitis. In a white population, AAU is associated with HLA-B27 in 50% of cases. Of patients with HLA-B27-positive AAU, more than half suffer from an associated seronegative spondyloarthropathy (ankylosing spnodylitis, Reiter s syndrome, psoriatic arthritis, or infilammatory bowel disease). Patients positive for HLA-B27 are often younger, are predominantly men, and have more frequent recurrences of AAU than patients negative for HLA-B27. Majority of HLA-B27 positive patients belong to category of associated with SSA i.e. 9/50 (43%). Out of SSA group, all 3 cases of JRA were ANA positive. Out of 2 cases of tuberculosis, only one case revealed tuberculosis of lungs. 11
12 Tubercular antibodies were positive in all cases of tuberculosis. Sarcoidosis was diagnosed on the basis of history, clinical examination, and classical findings on chest x-ray. No histopathological examination was done to confirm the diagnosis of sarcoidosis. TABLE 3 COMPLICATIONS SL. NO. COMPLICATIONS NO. OF PATIENTS PERCENTAGE 1 Cataract 17/50 34% 2 Glaucoma 9/50 18% 3 Optic Disc Edema 11/50 22% 4 Cystoid macular Edema (CME) 9/50 18% 5 Hypotony 4/50 8% 6 Retinal Detachment 1/50 2% 7 Band Keratopathy 3/50 6% 8 Iris Atrophy 3/50 6% Patients can have more than 1 complications Total no. of complications 43/50 (86%) Complications of uveitis developed in 43/50 (86%) of cases. The most frequent complications were cataract 17/50 (34%) and glaucoma 9/50 (18%). Optic disc edema was noted in 22% cases. 12
13 CME was detected in 18% cases. Complications like retinal detachment, band keratopathy, and iris atrophy were less. We do not know in how many cases intraocular surgery was required. In this study, we did not assess the role of surgery in complications of uveitis and the visual outcome. The ocular complication responsible for legal blindness (visual acuity <0.1) were not assessed in this study. TABLE 4 MEDICAL TREATMENT OF UVEITIS SL. NO. MEDICATIONS 1 Corticosteroid eye drops 2 Periocular corticosteroid injections 3 Systemic a. NSAIDS. b. Steroid prednisolone 1 mg/kg/day c. MTX 5-15 mg/wk/p.o. d. Adalimumab Humira 40 mg/0.8 ml, SC every 2 nd week e. Antiviral f. Antibiotics NO. OF PERCENTAGE PATIENTS 41/50 82% 5/50 10% 7/50 14/50 4/50 2/50 14% 28% 8% 4% 4 Miscellaneous Mydriatics Cycloplegies Acetazolamide 4/50 16/50 43/50 45/50 10/50 8% 32% 86% 90% 20% 13
14 Topical corticosteroids were used in majority of patients i.e. 82%. Periocular corticosteroid injections were given to less number of patients i.e. 10%. In other series, majority of the studies shows higher percentage of use of these injections. Systemic treatment was required in more cases i.e. 94%. Majority of the patients needed oral prednisolone and antibiotics. Adalimumab (Humira) was given to only 2 patients of ankylosing spondylitis for their rheumatological problems and was effective to treat uveitis. Methotrexate was given to only 8% of patients though the use of methotrexate was found to be very safe even in children in most of the studies published. Antiviral agents were prescribed to cases of herpes simplex and herpes zoster. Majority of the patients who were on antibiotics belonged to the category of SSA. Majority of patients required cycloplegics to prevent synechia. DISCUSSION: The incidence of uveitis could be very high in other parts of the globe, but we could study only 50 cases of uveitis at private facility from Majority of our patients were male belonging to category of SSA. Only 16 cases were female i.e. 32%. Majority of our patients had anterior uveitis. First we present differential diagnosis of uveitis as described in literature and the commonest cause. Idiopathic 52% HLA-B27 (ocular only) 36% Ankylosing Spondylitis 8% Reiter s Syndrome 3% Juvenile rheumatoid arthritis <1% 14
15 Fuchs iridocyclitis <1% Psoriatic arthritis <1% Inflammatory bowel disease <1% Acute intersistial nephritis <1% Kawasaki s disease <1% Posner-Schlossman syndrome (glaucomatocyclic crisis) <1% Idiopathic anterior uveitis is probably the most common form of anterior segment inflammation, accounting for > 50% of cases. Majority of patients in our study belonged to category of SSA and the next common cause is idiopathic. In other studies although most cases are idiopathic, underlying systemic disease may occasionally be found to include sarcoidosis (2-10%), multiple sclerosis (10%), or infection (syphilis, Lyme disease, tuberculosis). Though we have not compared in the category of SSA, the onset, laterality, and location in our study, but we present the commonest pattern in rheumatic diseases observed in other studies. 15
16 Rheumatic Disease Onset Laterality Location Ankylosing spondylitis Juvenile rheumatoid arthritis Psoriatic arthritis Acute Unilateral Anterior Insidious Bilateral Anterior Acute Unilateral Anterior Reiter s Acute Unilateral Anterior syndrome Sjogren s syndrome Insidious Bilateral Panuveitis Unlike patients with almost all other causes of anterior uveitis, JRA patients with anterior uveitis usually are asymptomatic, and the involved eye is often white, without obvious evidence of inflammation. As a result, complications of uveitis may develop before the inflammation is detected. It is typically seen in ANA positive young girls with pauciarticular JRA. In this study, we could not include posterior uveitis because of 2 reasons: 1. It is a retrospective study. 2. We did not get cases of posterior uveitis or may be they could not be diagnosed properly. Therefore, we simply mentioned differential diagnosis of posterior uveitis given in literature. 16
17 DIFFERENTIAL DIAGNOSES OF POSTERIOR UVEITIS Idiopathic retinal vasculitis (Eale s disease) Acute posterior multifocal placoid pigment epithelipathy Sarcoidosis Infectious posterior uveitis Birdshot choroidoretinopathy Behcet s disease Herpes simplex induced acute retinal necrosis Cytomegalovirus retinitis Vogt-Koyanagi-Harada syndrome Toxoplasmosis retinochoroiditis Sympathetic ophthalmia Syphilis Serpiginous chroidoitis Histoplasmosis Tuberculosis Regarding management of uveitis, bilateral moderate-to-severe ocular inflammation or vision-threatening anterior or posterior segment inflammation unresponsive to topically or periocularly administered corticosteroids. Systemic therapy is generally reserved for patients whose visual acuity has declined to 20/40 or worse because of an inflammatory condition and in whom recovery of vision is thought to be possible. Usually the initial dosage is 60 mg or mg/kg/day, which is subsequently tapered slowly. A good approach is to taper the dosage to mg over 3 4 weeks and to be observe the patient carefully for any recurrence of symptoms. If the patient s condition remains stable, a slow taper off the medication may then be attempted. 17
18 CONCLUSION: Majority of patients of uveitis in this study belonged to the category of SSA. Out of this category majority of patients were suffering from reactive arthritis. Reactive arthritis (ReA) is a sterile inflammatory synovitis following an infection by organisms that infect mucosal surfaces, especially urogenital or enteric infections. The clinical features of reactive arthritis among HLA-B27 positive patients are similar to those found in other seronegative spondyloarthropathies, whereas HLA-B27 negative patients usually resemble patients presenting with an undifferentiated oligoarthritis. ReA patients commonly exhibit systemic symptoms with unique extra-articular manifestations including skin, eye, and enthesopathy features. Susceptibility to reactive arthritis may be conferred by specific class I major histocompatability antigens (e.g. HLA-B27). However, its acquisition is strictly depending on infection with certain gastrointestinal (enterogenic) or genitourinary (urogenital) pathogens. The most common organisms associated with disease among HLA-B27 patients include Salmonella, Shigella, Yersinia, Chlamydia, Campylobacter and Clostridium. Many studies using electron microscopy, molecular amplification and immunofluorescence techniques have identified microbacterial products including nucleic acids within the synovium of these patients. Urogenital Enterogenic Others Chlamydia trachomatis, Ureoplasma urealyticum Salmonella typhimurium, S. Enteritidis, S. Heidelberg, S. chloerae-suis, Shigella flexneri, S. sonnei, Yersinia enterocolitica, Y. pseudotuberculosis, Campylobacter jejuni Clostrdium difficile Chlamydia pneumoniae Vibrio parahaemolyticus Borrelia burgdorferi Neisseria gonorrhoeae Streptococcus (post-streptococcal reactive arthritis) Hepatitis C Giardia lamblia Mycoplasma 18
19 As the incidence of SSA is on the increase in Middle East, our study indicates that most of the patients of AAU were associated with this disease entity. Methotrexate has been widely used for management of JRA globally and enough research evidence is present in the literature to prove its safety in children, but we have not used Methotrexate indiscriminately in children. In our study, we have used Methotrexate as corticosteroid sparing agent in the management of difficult uveitis associated with SSA. Adalimumab is a very expensive drug, it was used only in AS with musculoskeletal problems as well as AAU. Being a retrospective study, few short comings were present Eg. End result of AAU, Eg. Blindness, number of patients requiring surgery were not mentioned in this study. Majority of patients developed complication Eg. Cataract and glaucoma. RECOMMENDATIONS Role of biologics should be investigated in difficult or recurrent AAU. We propose a proper prospective study to investigate the safety of Methotrexate and biologics in different age groups. As we used Adalimumab in only 2 cases of AS, we cannot recommend its use in all AAU cases in general. 19
20 BIBLIOGRAPHY: 1. Nussenblatt RB. The natural history of uveitis. Int Ophthalmol. 1990;14: Nussenblatt RB, Whitcup SM. Uveitis: Fundamentals and Clinical Practice. 3rd ed. St Louis, Mo: Mosby Year Book; Dana MR, Merayo-Lloves J, Schaumberg DA, Foster CS. Prognosticators for visual outcome in sarcoid uveitis. Ophthalmology. 1996;103: Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. 2000;130: Maini R, St. Clair WE, Breedveld F, et al. Infliximab (chimeric antitumour necrosis factor monocolonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomized phase III trial. Lancet. 1999;354: Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn s disease. N Engl J Med. 2004;350: Braun J, de Keyser F, Brandt J, et al. New treatment options in spondyloarthropathies: increasing evidence for significant efficacy of anti-tumor necrosis factor therapy. Curr Opin Rheumatol. 2001;13: Martin TM, Smith JR, Rosenbaum JT. Anterior uveitis: current concepts of pathogenesis and interactions with the spondyloarthropathies. Curr Opin Rheumatol. 2002;14: Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor neutralizing agent. N Engl J Med. 2001;345: Gomez-Reino JJ, Carmona L, Valverde VR, et al. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk. Arthritis Rheum. 2003;48: Raja SC, Jabs DA, Dunn JP, et al. Pars planitis: clinical features and class II associations. Ophthalmology. 1999;106: Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology. 1999;53: Nussenblatt R, Fortin E, Schiffman R, et al. Treatment of noninfectious intermediate and posterior uveitis with the humanized anti-tac mab: a phase I/II clinical trial. Proc Natl Acad Sci U S A. 1999;96:
21 14. Smith JA, Thompson DJS, Whitcup SM, et al. A randomized, placebo-controlled, double-masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis. Arthritis Rheum. 2005;53: Bloch-Michel E, Nussenblatt RB. International Uveitis Study Group recommendations for the evaluation of intraocular inflammatory disease. Am J Ophthalmol. 1987;103: Nussenblatt RB. The natural course of uveitis. Int Ophthalmol 1990;141: Rothova A, Suttorp-Schulten MSA, Treffers WF, et al. Causes and frequency of blindness in patients with intraocular inflammatory disease. Br J Ophthalmol 1996;80: Rothova A, Buitenhuis HJ, Meenken C, et al. Uveitis and systemic disease. Br J Ophthalmol 1992;76: McCannel CA, Holland G N, Helm CJ, et al. Causes of uveitis in the general practice of ophthalmology. Am J Ophthalmol 1996;121: Perkins ES. Patterns of uveitis in children. Br J Ophthalmol 1966;50: Kimura SJ, Hogan MJ, Thygeson P. Uveitis in children. Arch Ophthalmol 1954;51: Kanski JJ, Shun-Shin A. Systematic uveitis syndromes in childhood; an analysis of 340 cases. Ophthalmology 1984;91: Tugal-Tutkun I, Harvlikova K, Power WJ, et al. Changing patterns in uveitis of childhood. Ophthalmology 1996;103: Tamesis RR, Rodriguez A, Christen WG, et al. Systemic drug toxicity trends in immunosuppressive therapy of immune and inflammatory ocular disease. Ophthalmology 1996;103: Santamaria JII. Steroidal agents : their systemic and ocular complication. Ocular Inflamm Ther 1983;1: Kilmartin DJ, Forrester JV, Dick AD. Cyclosporin A therapy in refractory non-infectious childhood uveitis. Br J Ophthalmol 1998;82: Hemady RK, Baer JC, Foster CS. Immunosuppressive drugs in the management of progressive corticosteroid-resistant uveitis associated with juvenile rheumatoid arthritis. Int Ophthalmol Clin 1992;32: Ramadan A, Nussenblatt R. Cytotoxic agents in ocular inflammation. Ophthalmol Clin North Am 1997;10: Giannini EH, Brewer EJ, Kuzmina N, et al. Methotrexate in resistant juvenile rheumatoid arthritis. N Engl J Med 1992;326: Gerloni V, Cimaz R, Gattinara M. Efficacy and safety profile of cyclosporin A in the treatment of juvenile chronic (idiopathic) arthritis. Results of a 10-year prospective study. Rheumatology 2001;40:
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