Therapeutic Stepladder Algorithm In Uveitis

Therapeutic Stepladder Algorithm In Uveitis

practical Update on Medical Treatment in Non-infectious Uveitis Alireza Hedayatfar MD Ocular Inflammation and Uveitis Fellowship Iran University of Medical Sciences Noor Eye Hospital 9th Annual Congress of Vitreoretinal Diseases April 2016, Kermanshah, Iran Therapeutic Stepladder Algorithm In Uveitis Systemic NSAIDs Topical Cs Periocula

r Cs Systemic Cs IMT Biologic agents Therapeutic Stepladder Algorithm In Uveitis Systemic NSAIDs Topical Cs Periocula r Cs Systemic Cs

IMT Biologic agents Systemic NSAIDs are mainly indicated in cases of Non-necrotysing Scleritis Therapeutic Stepladder Algorithm In Uveitis Systemic NSAIDs Topical Cs Periocula r Cs Systemic Cs

IMT Biologic agents To treat acute anterior uveitis always remember: Hit it fast! hit it hard! Use appropriate steroid High corneal penetration High potency Corneal Penetration For a steroid to effectively penetrate Acetate the cornea, it must be biphasic

Phosphat e Bethamethasone phosphate 0.1% Loteprednole Etabonate 0.5% Dexamethasone phosphate 0.1% Prednisolone acetate 1% Therapeutic Stepladder Algorithm In Uveitis Systemic NSAIDs Topical Cs

Periocula r Cs Systemic Cs IMT Biologic agents Periocular Steroid Injections Unilateral involvement Exacerbation of inflammation in patient already on systemic treatment Uveitic macular edema Bilateral sight-threatening disease in special cases (e.g. Pregnancy) Infective cause (Toxoplasmosis, Herpetic uveitis, ARN) Steroid responder Periocular Steroid Injections Transseptal Route

Sub-tenon's Injection Therapeutic Stepladder Algorithm In Uveitis Systemic NSAIDs Topical Cs Periocula r Cs Systemic Cs IMT Biologic agents Systemic Corticosteroids

Oral therapy used when there is failure to respond to periocular injections or in bilateral sight-threatening uveitis Start with high dose then taper to the minimum required dose to keep inflammation under control Supplementary doses of corticosteroids required during acute stress e.g. surgery Intravitreal implants Ozurdex (dexamethasone) Type of Implants

Duration of Action Disadvantage Non-ideal release kinetics Biodegradable 6 months Short duration of action Iluvien (fluocinolone acetonide) Biodegradable Retisert (fluocinolone acetonide)

Non-biodegradable I-vation (triamcinolone acetonide) Non-biodegradable 1.5 or 3 years Same as above 30 months Require explantation 2 years Same as above Sample Therapeutic Stepladder Algorithm In Uveitis

Systemic NSAIDs Topical Cs Periocula r Cs Systemic Cs IMT Biologic agents Indications for lmmunomodulatory Medications Control of inflammation require unacceptably high doses of steroid for long period of time

Inadequate control of inflammation with steroids alone Unacceptable steroid side effects (especially in children) Before initiating any immunosuppressant!!! Obtain thorough history Co-morbidities DM, hypertension, renal or liver dysfunction Social history plans to start a family, alcohol intake Discuss with patient Reason to use medication(s) Informed consent History No Yes

Remarks Investigation Peptic ulcer Hepatitis WBC FBC Hb TB Liver disease Renal failure Plt Cr. RFT

BUN Pregnant Plan to conceive Alb LFT SGOT Alcohol intake Hepatotoxic drug N SGPT CXR A Remarks

?How adverse effect will be monitored Start from minimum dosage to maximum allowed dosage Ask specifically about the expected side effects Serial follow up laboratory test / /

/ / / / / / /

/ ) ( ( / ) / / / / / ) ( Medication Dosage FBS BP Hemoglobin WBC Lymphocyte Platelets

Creatinine BUN SGOT SGPT ALP lmmunomodulatory Treatment I. Antimetabolites II.

Inhibitors of intracellular signaling III. Alkylating agents lmmunomodulatory Treatment I. Antimetabolites II. Inhibitors of intracellular signaling III. Alkylating agents It is generally safe, well tolerated, easily administered

MTX possesses a variety of anti-inflammatory effects (humeral > cellular)? Administered PO, IM or SQ, at a weekly dose of 0.2-0.3 mg/kg. Methotrexate is cleared more rapidly from children than from adults, and thus, doses must be higher on a per-mass basis in children (10 to 30 mg/m2). MTX should be supplemented by folic acid Methotraxate Azathioprine is an imidazolyl derivative of 6mercaptopurine (6-MP) which antagonizes purine metabolism and may inhibit synthesis of DNA, RNA, and proteins. Cellular immunity being suppressed to a greater degree than are antibody responses.

Administered at a dose of 2mg/kg/day. Many clinicians start the drug at 50mg/day for 1 week to see if the patient develops any gastrointestinal side effect . Azathioprine (Immuran, Azaram) Mycophenolate mofetil Mycophenolate mofetil is a reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) It blocks de novo biosynthesis of guanosine nucleotides by inhibition of the enzyme inosine monophosphate dehydrogenase. MPM has good oral bioavailability and is given at a dose of 1gm twice daily lmmunomodulatory Treatment I.

Antimetabolites II. Inhibitors of intracellular signaling III. Alkylating agents Cyclosporine As a calcineurin inhibitors, inhibits T-lymphocyte proliferation by blocking the production and release of various cytokines, especially interleukin-2. Cyclosporine preferentially inhibits the T1 helper and cytotoxic subsets, with minimal effects on regulatory (suppressor) T lymphocytes.

Monthly blood pressure, serum creatinine levels, and complete blood counts are used to monitor patients . Tacrolimus Tacrolimus is a macrolide antibiotic and calcineurin inhibitors. Tacrolimus interacts with and inhibits calcineurin thus inhibiting both T-lymphocyte signal transduction and IL-2 transcription and therefore, directly interferes with helper Tlymphocyte proliferation. Its main side effect, nephrotoxicity, is less common than it is with cyclosporine. Serum creatinine and complete blood counts are monitored monthly. Sirolimus A macrolide compound obtained from Streptomyces hygroscopicus that possesses both antifungal and antineoplastic properties. Despite its similarities to tacrolimus, its mechanism of

action is different. Sirolimus blunts the responses of both T Lymphocytes and B lymphocytes to specific lymphokines (Interleukin IL-2, IL-4, and IL-15) in the G1 phase of the cell cycle rather than inhibiting their production. lmmunomodulatory Treatment I. Antimetabolites II. Inhibitors of intracellular signaling III. Alkylating agents Cyclophosphamide Cytotoxic to resting and actively dividing lymphocytes.

Administered orally (2mg/kg/day) or monthly intravenous pulses Cyclophosphamide has been shown to be effective in treating necrotizing scleritis associated with systemic vasculitides such as Wegener granulomatosis or relapsing polychondritis and severe retinal vasculitis including Behcet disease. Therapeutic Stepladder Algorithm In Uveitis Systemic NSAIDs Topical Cs Periocula r Cs Systemic Cs IMT

Biologic agents Biologic response modifiers Target pro-inflammatory cytokines or their receptors monoclonal antibodies Biologic response modifiers fusion proteins When to Use Biologics in Uveitis? Biologics are useful when Standard immunosuppression has failed to control inflammation Standard immunosuppression has poorly been tolerated Patients with concomitant ocular and systemic inflammation that might benefit from these medications e.g.. JIA Generic names Trade names

Specific target Route Dosage Potential side effects TNF inhibitors Infliximab Remicade TNF- IV 35 mg/kg loading at weeks 0, 2, and 6, then maintenance 310 mg/kg

every 48 weeks; maximal dose 20 mg/kg in children 40 mg every 12 weeks (if bodyweight <30 kg; 20 mg every 2 weeks); loading doses of 80160 mg are recommended for CD and PsO Adalimumab Humira TNF- SQ Etanercept Enbrel TNF-,- SQ

Golimumab Simponi TNF- SQ Certolizumab Cimzia TNF- SQ Susceptibility to infections, including: reactivation of tuberculosis, histoplasmosis, hepatitis B, and fungal infection;

Adults 50 mg weekly (may be given hypersensitivity 50 mg twice weekly for first 3 reactions; demyelinating months for PsO); children 0.8 mg/kg/ disease; lupus-like week (max 50 mg/week) syndrome; malignancy; thromboembolic events; congestive heart failure 50 mg SQ monthly; except for UC 200 mg at week 0, 100 mg at week 2, then 100 mg every 4 weeks 400 mg SQ at weeks 0, 2, and 4, then 200 mg every 2 weeks or 400 mg every 4 weeks Infliximab (Remicade) is a chimeric anti-TNF

Concomitant administration of infliximab with methotrexate (5-7.5 mg/week) has been associated with a decrease in the formation of human anti-chimeric antibodies Administered in the form of IV on day 0, at 2 weeks ,at 6 weeks and then every 6-8 weeks May cause reactivation of TB to disseminated form so use in patients with positive PPD test is contraindicated Besides BD and JIA, infliximab may also be effective to treat Recalcitrant uveitic CME HLA-B27-related anterior uveitis Pars planitis Infliximab (Remicade)

Adalimumab (Humira) Adalimumab (Humira) is a fully human monoclonal antibody against TNF-. Due to its promising results and subcutaneous route of administration, experience in both rheumatologic and ocular indications is growing. Several clinical studies have shown its potential efficacy for the treatment of juvenile uveitis (mainly JIA) and BD uveitis . Generic names Trade names Specific target Route Dosage

Potential side effects Lymphocyte inhibitors Daclizumab Rituximab Abatacept Basiliximab Zenapax Rituxan Orencia Simulect T-cells (IL-2R)

B-cells (CD20) T-cells (CTLA-4) T-cells (IL-2R; CD25) IV, SQ IV IV, SQ IV Hypersensitivity reactions, 12 mg/kg every 2 or 4 headache, and weeks gastrointestinal disturbance Susceptibility to 500 or 1,000 mg at week infections, infusion

0 and 2; may repeat at 6 reactions, gastrointestinal 12 months thereafter disturbance, (different regimen for cardiovascular events, hematologic muscle spasm, and malignancies) headache Adult RA 5001,000 mg IV loading, then 125 mg SQ weekly; JIA 10 mg/kg, max 1,000 mg IV at weeks 0, 2, and 4, then every 4 weeks Susceptibility to infections, allergic reactions, headache, nausea, and malignancy Gastrointestinal

disturbance, headache, 40 mg IV at weeks 0, 2, susceptibility to infections, 4, 8, and 12 and hypersensitivity reactions It functions as an IL-2 receptor antagonist It is indicated for the prophylaxis of acute organ rejection Daclizumab: Anti IL-2 in patients receiving renal transplants Daclizumab has been demonstrated effective for refractory birdshot retinochoroidopathy and some non-infectious

uveitis However, daclizumab failed to demonstrate effectiveness in BD-associated uveitis in a randomized trial Rituximab: Anti CD-20 Rituximab (Rituxan) is a chimeric anti-CD20 monoclonal antibody Acts by causing B cell apoptosis used in B cell lymphomas It has shown promising results in the treatment of: Orbital inflammation from Graves disease Refractory scleritis JIA associated uveitis

Generic names Trade names Specific target Route Dosage Potential side effects Specific receptor antagonists Anakinra Canakinumab Tocilizumab Alemtuzumab Efalizumab

Kineret Ilaris Actemra Campath Raptiva IL-1 receptor IL-1 IL-6 receptor CD52 CD11a SQ

100 mg SQ daily; children, Injection-site reaction, starting 12 mg/kg to max 8 infections, headache, mg/kg daily (dose adjustment gastrointestinal disturbance, for renal insufficiency) and fever IV, SQ Systemic JIA: 4 mg/kg (max Susceptibility to infections, 300 mg) SQ every 4 weeks; headache, nausea, and CAPS, 23 mg/kg SQ every 8 abdominal pain weeks Serious infections, hypersensitivity reactions, and gastrointestinal perforation IV

Initial 4 mg/kg IV every 4 weeks, then increase to 812 mg/kg every 24 weeks IV Cytopenias, infusion 30 mg IV, 3 days per week for reactions, infections, 12 weeks gastrointestinal disturbance, and insomnia SQ 0.7 mg/kg first dose, then 1 mg/kg weekly (max 200 mg/dose) Infections, progressive multifocal leukoencephalopathy,

malignancy, arthritis, and thrombocytopenia Generic names Trade names Specific target Route Dosage Potential side effects Interferons Interferon -2aa Roferon-A Nonspecific

SQ Injection-site 36 million units SQ reactions, flu-like daily, tapering over 6 symptoms, and bone months marrow suppression Interferon INFs have antiviral, immunomodulatory, and antiangiogenic effects Different interferons are used for different conditions. INF alphas are used for treating cancers and viral infections INF betas are used for treating multiple sclerosis INF gamma is used for treating chronic granulomatous

disease. Main indications in uveitis is for treatment of BD and MS associated uveitis. Chronic intraocular inflammation is associated with increased production of inflammatory mediators, including VEGF, which are hypothesized to disrupt the blood-retinal barrier on the endothelium of retinal vessels, resulting in subsequent macular edema. Bevacizumab and ranibizumab have been used to treat and stabilize secondary complications of uveitis, which include Uveitic macular edema, CNV related to inflammatory diseases

Their use for primary suppression of inflammation has not been established Anti VEGF Thank You For Your Attention

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