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UVEITIS SYMPOSIUM Uveitis types and its associations
- 1. MANAGEMENT OF UVEITIS Dr. AbhidnyaSurve Senior Resident, unit 1
- 2. Evaluation Demographics ofpatient (Age, sex, ethnicity, residence) Type of uveitis (Anterior, Intermediate, Posterior, Kerato uveitis, Sclerouveitis, Retintal. vasculitis) Associated symptoms (ocular / systemic) and signs Nature of uveitis (Acute or chronic; Granulomatous or nongranulomatous) Unilateral or bilateral
- 3. Associated Signs Headaches– sarcoidosis, VKH N/S deafness – VKH, sarcoidosis CSF pleocytosis – VKH, sarcoidosis, APMPPE, Behcets Psychosis – VKH, sarcoidosis, Behcet’s Vitiligo, poliosis – VKH Erythema nodosum – Behcet’s Skin nodules – sarcoidosis, onchocerciasis Oral, genital ulcer – Behcet’s, Reiter’s Sinusitis, renal involvement – Wegener’s granulomatosis Sacroilitis – Ank spond, Reiter’s, IBD Arthritis – Behcet’s, Reiter, sarcoidosis, JRA, RA, IBD
- 4. Investigation Depends onthe demographic profile, history and clinical examination (systemic and ocular) Detailed investigations is not required in all cases In anterior uveitis, investigations required if Bilateral involvement Recurrent episodes Systemic association Severe disease leading to significant loss of visual function Indication: • Rule out infection • Specific therapy • Systemic disease • Whole management
- 5. Investigation Ocular Investigations FFA/ICG FAF OCT USG Rule out infection Mantoux Chest X - Ray VDRL
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- 7. Additional Investigation Hematological Immunological Radiological HLA typing Skin test
- 8. Additional Investigation Sarcoidosis– chest X-Ray, S. ACE, S. Calcium, HRCT Tuberculosis – HRCT, Sputum examination, Lymph node biopsy JRA - Rheumatoid factor, ANA Syphilis - FTA-ABS Wegeners granulomatosis - Antineutrophilic cytoplasmic Ab Toxoplasmosis - Antitoxoplasma Ab SLE – ANA Behcets disease – HLA B51 Parasitic disease - Stool examination
- 9. APPROACH TO UVEITISPATIENT Revaluate response at each follow-up Appropriate treatment and Follow-up treatment options; risk:benefit ratio; discuss with patient Definitive diagnosis Depending on it, appropriate ocular and systemic investigations Working classification and differential diagnosis Systemic and ocular examination Detailed history
- 10. Simplified Overview Infectious Etiology •Specific treatment in addition to the control of inflammation Non - specific therapy • anterior involvement - mydriatic/ cycloplegics, steroids • Intermediate uveitis - periocular steroids • Posterior involvement – regional or systemic steroids or immunosuppressive medication • Panuveitis - combination of above Treatment of complications • Glaucoma • Cataract • Exudative retinal detachment • BSK
- 11. Objective Symptomatic relief Preserve visual acuity; visual field Prevent complications Systemic management
- 12. After startof treatment, it is important to observe the cases for assessment of response Corticosteroid alone in case of infectious uveitis could lead to worsening of symptoms It is also important to take care of the inflammatory component with non-specific therapy Disease Treatment Tuberculosis ATT Syphillis Penicillin, ceftriaxone Toxoplasmosis Sulfa and pyrimethamine Lyme Disease Tetracycline ARN IV Acyclovir CMV Retinitis IV Gancicylovir Infectious Uveitis
- 13. Mydriatic/ Cycloplegics Torelieve ciliary spasm and pain associated Addition of a short acting agent prevent post. synechiae formation To break down recently formed synechiae with intensive topical mydriatics (atropine, phenylephrine) Tropicamide 3-6 hrs Cyclopentolate 18-30 hrs Homatropine 18-36 hr Atropine 10-14 days
- 14. Steroids Glucocorticoids exerta variety of immunosuppressive, anti-inflammatory and anti-allergic effects on primary and secondary immune cells and tissues Always start with higher dose and taper before stopping Sinha A, Bagga A. Pulse steroid therapy. The Indian Journal of Pediatrics. 2008 Oct;75(10):1057–66. Topical Periocular Intravitreal Oral Intravenous
- 15. Steroids Especially usefulin anterior segment inflammation Various preparations available Action – ability to penetrate cornea; relative anti-infl potency; duration of action; dosage and frequency; SE profile Taper drug according to the response Slow tapering especially with recurrent attacks IOP, HSV reactivation Topical
- 16. Steroids Posterior involvement Severe inflammation, unilateral disease Especially in cases with CME max dose to eye; minimal in systemic Superotemporal area preferred SE – perforation, proptosis, fibrosis, severe intractable glaucoma Effect last for 4-6 weeks Avoided in steroid responders, glaucoma Periocular
- 17. Steroids Intravitreal Bypass blood-ocularbarrier; high intraocular concentrations Especially in cases with frequent recurrence April 2005 – Fuocinolone acetonide – FDA appr chronic NI intermediate and posterior uveitis Ozurdex – Dexamethasone 700 ug implant - FDA appr drug for NI posterior uveitis Effect last for 3-6 months
- 18. Steroids Bilateral intermediateuveitis Unilateral intermediate uveitis not responding to PST Posterior involvement and panuveitis with Severe inflammation Exudative retinal detachment Rapid loss of vision Lesion threatening macula, papillomacular bundle or optic nerve Systemic
- 19. cataract glaucoma obesity Fluid retention, weightgain hypertension Diabetes Peptic ulcer osteoporesis Adverse effects
- 20. Syphillis – responseto ceftriaxone in 20 days
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- 22. VKH – treatmentwith steroids and started on methotrexate
- 24. IMMUNOSUPPRESSION Before consideringimmunosuppression, one should Patients adherence to treatment reconsider diagnosis Rule out tuberculosis, infections Rule out liver, renal or hematological abnormalities Meticulous follow-up available Informed consent Adverse reaction can be severe and life threatening Delay in therapeutic response for weeks to months; therefore, need to be maintained on corticosteroids until the immunomodulatory agent begins to take effect
- 25. IMMUNOSUPPRESSION INDICATION – CS resistantor intolerant cases Increase in inflammation when dose > 0.5mg/kg/day (30 mg/day) or recurrence when the dose is decreased to < 7-10 mg/ day In vision threatening inflammation, can be started as first line Specific cases Behcet disease Sympathetic Ophthalmia VKH Syndrome Necrotizing sclerouveitis
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- 28. Anti-Metabolites Antimetabolites areoften the first immunomodulatory therapies used when corticosteroid sparing is desired. Azathioprine - Purine analogue – prodrug of 6-mercaptopurine Dose dependent, slow and persist after discontinuation Dose start 1 mg/kg and then can be increased to 2.5 mg/kg Effect start 2-4 weeks slightly higher incidence of adverse effects Complete blood counts and liver function tests must be closely monitored. effective - Behcet disease, VKH, SO, Necrotizing uveitis Myelosuppression, GIT upset, hepatotoxicity, hepatic veno-occlusive disease, hypersensitivity pancreatitis
- 29. Anti-Metabolites Methotrexate Folicacid antagonist – inhibit dihydrofolate reductase 10-25mg/week PO, SC, IM Effective – JIA associated anterior uveitis, sarcoidosis, panuveitis, and scleritis. up to 6 months to produce its full effect in controlling intraocular inflammation Gastrointestinal symptoms, hepatotoxicity, interstitial pneumonitis, pulmonary fibrosis teratogenic, and complete blood counts and liver function tests (6-8 week) should be conducted regularly.
- 30. Anti-Metabolites Mycophenolate mofetil IMP dehydrogenase inhibitor (pyrimidine) 500 mg BD initially; max 1.5 mg work rapidly - has a significantly shorter time to treatment success. Costly Less than 20% of patients have adverse effect; Diarrhoea, nausea, neutropenia Regular laboratory monitoring required Effective corticosteroid-sparing agent in up to 85% of patients with chronic uveitis. Safe alternative to methotrexate in patients with pediatric uveitis.
- 31. T-cell inhibitors Cyclosporineand tacrolimus fungus derivative - calcineurin inhibitors Nephrotoxic, HTN, hyperkalemia, tremor, hirsuitism, gum hyperplasia Patients with psoriasis - greater risk of primary skin cancers Sirolimus noncalcineurin inhibitor inhibits antibody production and B lymphocytes Effective – Behcet, posterior uveitis including VKH
- 32. Alkylating agents Cyclophosphamide,Chlorambucil used only if other immunomodulators fail to control uveitis; Considered for necrotizing scleritis associated with systemic vasculitides such as granulomatosis with polyangiitis (formerly, Wegener granulomatosis) or relapsing polychondritis. Effective - Intermediate uveitis, VKH syndrome, sympathetic ophthalmia, and Behçet disease. BM suppression, hemorrhagic cystitis, malignancy, infection, infertility high rate of sterility
- 33. Biologics TNF blocker Infliximab Adalimumab Etanercept IL receptor antagonist IL1- Anakinra IL2 - blocker Lymphocyte antagonist anti CD52 - Alemtuzumab CD 20 blocker - Rituximab CD 2 blocker - Alefacept CD 11a blocker - Efalizumab Others Interferon alpha IVIG
- 34. Adalimumab NI Inetrmediate,posterior and panuveitis 40mg SC Reduces risk of treatment failure in both active and non-active disease VISUAL study Nasopharyngitis, arthralgia, fatigue
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Editor's Notes
- #5 ROUTINE - Cbc esr dlc not of much help as they are non-specific and do not contribute much to the diagnosis While they are imp in case of starting antimetabole for baseline and folllowup to detect bm suppression In HIV cd4/cd8 ratio is imp Suspicion of parasitic infection – raised esosinophils
- #7 Active toxo; aids; cvd RF – one must know it is seronegative arthritis like JRA and ankylosing spondylitis which are usually associated with uveitis compared to RF pos Anterior uveitis in children get ANA titres as pauciarticular jra have iridocyc and 90% of these cases ANA associ ANA – 99% SLE Anti ds-dna; ANCA; ACE Toxoplasmosis – strong clinical susp based on morphology……any positive titre with strong clinical susp indicate treatment while neg excludes the diag but if healed not of much use of such test Ant seg exam S ace level monitor disease activity and response ; pos 85% cases active X ray; sacroiliac joint; skull( calcific in cong toxo) Hla b27; b5; a29 Skin - tb histoplasmosis, anergy in sarcoidosis Histoplasmin test - POHS, may reactivate older lesions. Kveim test Sarcoidosis, No longer used
- #8 RF – one must know it is seronegative arthritis like JRA and ankylosing spondylitis which are usually associated with uveitis compared to RF pos ANA titres must be done as 90% of these cases are Histoplasmin test - POHS, may reactivate older lesions. Kveim test Sarcoidosis, No longer used
- #10 The goal of medical management of uveitis is to effectively control inflammation so as to eliminate or reduce the risk of vision loss from structural and functional complications that result from uncontrolled inflammation—cataracts, glaucoma, CME, and hypotony
- #11 The goal of medical management of uveitis is to effectively control inflammation so as to eliminate or reduce the risk of vision loss from structural and functional complications that result from uncontrolled inflammation—cataracts, glaucoma, CME, and hypotony
- #14 Greter the severity of inflamm; greater threat to vision; more intense and rapid resolution
- #15 GC pass through cytoplasmic membrane to bind to the cytosolic glucocorticoid receptor (cGCR), displacing several associated proteins (heat shock proteins hsp, kinases like mitogen activated protein kinase/MAPK and co-chaperones like src) that mediate nongenomic effects. The GC-cGCR complex moves into the nucleus to affect transcription by ways depicted above. (i) and (ii) involve binding of cGCR to positive and negative glucocorticoid responsive elements (GRE and nGRE); in (iii) binding of cGCR is prevented by competition for nuclear coactivators between the cGCR and transcription factors like activator protein 1 (AP1); (iv) involves transrepression due to direct or indirect interaction of the cGCR with transcription factors such as nuclear factor-kB (NF-kB) at its binding site (kB site). Non-genomic effects are also suggested to be mediated through membrane bound GCR (mGCR) and by interactions with cellular membranes.
- #16 Response to treatment - improvement/ stabilization of va; media clarity; cells ; decrease in symptoms; regression of lesion Steroid resist – when no clinical resp on 2 weeks of max dosage of oral steroids
- #17 Retisert – 2.5 years 0.59 mg high rates of glaucoma and cataract
- #18 Retisert – 2.5 years 0.59 mg high rates of glaucoma and cataract
- #19 Tapering
- #21 Cushing syndrome is an an absolute ci
- #28 Primary immunological abnormality leading to inflamm Immunosprresive act on all immune cells non-specifically Thus suppress activity of normal cells as well Thus importance of risk benefit ratio
- #29 The use of IMT in uveitis is warranted for consideration in the following settings: vision-threatening intraocular inflammation disease process that is likely reversible corticosteroids contraindicated because of systemic problems or intolerable adverse effects unacceptable corticosteroid adverse effects long-term corticosteroid dependence these drugs should also be considered in patients who require long-term corticosteroid therapy (longer than 3 months) at doses greater than 5–10 mg/day.
- #33 Many clinicians start administering azathioprine at 50 mg/day for 1 week to watch for development of any gastrointestinal adverse effects (nausea, upset stomach, and vomiting) before escalating the dose. These symptoms are common and may occur in up to 25% of patients, necessitating discontinuation. Bone marrow suppression is unusual at the doses of azathioprine used to treat uveitis. However, patients taking allopurinol and azathioprine concomitantly are at higher risk for bone marrow suppression. Reversible hepatic toxicity occurs in less than 2% of patients, and dose reduction may remedy mild hepatotoxicity. MYELOSUPPRESION – early (idiosyncratic) and delayed response (dose- dependent)… weekly * 1m twice a month for 3 m then monthly
- #34 Affect humoral immunity mainly and minim on CMI. Also releases adenosine which has anti-inflammatory actions Any pt with cough dyspnea - get a chest x ray to rule out interstitial pneumonitis
- #35 Many clinicians start administering azathioprine at 50 mg/day for 1 week to watch for development of any gastrointestinal adverse effects (nausea, upset stomach, and vomiting) before escalating the dose. These symptoms are common and may occur in up to 25% of patients, necessitating discontinuation. Bone marrow suppression is unusual at the doses of azathioprine used to treat uveitis. However, patients taking allopurinol and azathioprine concomitantly are at higher risk for bone marrow suppression. Reversible hepatic toxicity occurs in less than 2% of patients, and dose reduction may remedy mild hepatotoxicity.
- #36 that eliminate T-cell receptor signal transduction and downregulate interleukin-2 (IL-2) gene transcription and receptor expression of CD4+ T lymphocytes.
- #37 The most worrisome adverse effect of alkylating agents is an increased risk of malignancy Cyclophosphamide Lymphotoxicity Chlorambucil Dna crosslinking Patients with polycythemia rubra vera - chlorambucil - 13.5-fold greater risk of leukemia. Patients with granulomatosis with polyangiitis - cyclophosphamide - 2.4-fold increased risk of cancer and a 33-fold increased risk of bladder cancer
- #39 recombinant human immunoglobulin G1 monoclonal antibody that binds specifically to TNF-a (a proinflammatory cytokine produced predominantly by macrophages and T cells inhibits (with a half-maximal inhibitory concentration of 0.1–0.2 nmol/L) the adhesion molecules responsible for leukocyte migration (endothelial-leukocyte adhesion molecule-1, intracellular adhesion molecule-1 and vascular cell adhesion molecule-1) therapy with adalimumab was associated with significant reductions in plasma vascular endothelial growth factor (VEGF) levels Two double-blind, placebo-controlled, multinational, phase III studies evaluated the therapeutic efficacy of subcutaneous adalimumab in adults (aged C18 years) with active (VISUAL I [11]) or inactive (VISUAL II [12]) non-infectious, intermediate, posterior or panuveitis (Sect. 4.1). Patients with isolated anterior uveitis were excluded [11, 12]. Longer-term efficacy data (derived from an abstract [13]) from an open-label extension of these studies (VISUAL III), which was primarily designed to evaluate the safety and tolerability of adalimumab, are also reviewed