Uveitis unplugged: systemic therapy

Uveitis unplugged: systemic therapy Hobart 2017 Peter McCluskey Save Sight Institute Sydney Eye Hospital Sydney Medical School University of Sydney Sydney Australia No financial or proprietary interest in any material discussed

Disappointing Conflict of Interest Disclosure Peter McCluskey, dreadful golfer ENBREL user

Financial Disclosures: Advisory Boards and/or Consultant: - AbbVie - Allergan - Santen - Servier AbbVie & Allergan relevant for today s presentation

Principles of treatment similar despite diverse aetiologies treat infectious uveitis with specific antimicrobial therapy + judicious use of corticosteroids & IMT therapy depends on presence cause & severity of a threat to vision specific therapy for non inflammatory complications treat inflammatory visual loss with antiinflammatory drugs

Inflammatory causes of vision loss cystoid macular oedema ischaemic retinal vasculitis progressive retinitis/ choroiditis optic neuropathy vitritis severe anterior uveitis Systemic Therapy for Uveitis

Principles of treatment topical corticosteroid therapy controls most anterior uveitis CME in > 40% of patients with posterior uveitis CME is a common driver of ocular therapy - usually treat unilateral CME locally - typically treat bilateral disease with systemic therapy - often combine local & systemic therapy (up to 60% in MUST)

Local Therapy topical: steroids, NSAIDs, CAIs periocular steroids intravitreal: steroids, avastin, methotrexate, infliximab, sustained release: retisert, ozudex Surgery vitrectomy Systemic Therapy NSAIDs corticoseroids immunosuppressives: methotrexate, cyclosporine, mycophenolate, azathioprine, cyclophosphamide biologics: anti-tnfs, anti-il2, anti-il17, anti-il6, anakinra, anti- CD20, interferons

Systemic Therapy systemic steroids gold standard therapy for CME & vision threatening ocular inflammation usually for bilateral disease need sufficient therapy to control inflammation & CME rapid response with high dose steroids, then combination immunotherapy in longer term minimum 6-36 month commitment to therapy

Drug Selection Systemic Therapy for Uveitis IMT immunomodulatory therapy - corticosteroids + immunosuppressive drug steroid sparing drugs must get steroids to a safe maintenance dose at least < 7.5mgs per day, preferably 5mgs/day or zero evidence that all steroid sparing drugs effective some drugs more effective for eye disease - methotrexate - mycophenolate

commonly used drugs methotrexate mycophenolate azathioprine uncommonly used drugs cyclosporine tacrolimus cyclophosphamide dapsone sulphasalazine biologics interferon 2a monoclonal antibodies - anti-tnf - anti-cd20 - others: anti-il1β, IL6, IL17, IL2, IL12/23, CD52 IVIG

IMT: The Sydney Experience Systemic Regimens Drugs 190 systemic therapy mean age 43 58 (31%) steroids alone 132 (69%) steroids + I/S drug 67/132 (51%) multiple I/S drugs Systemic Therapy for Uveitis methotrexate 69 (52%) mycophenolate 33 (25%) cyclosporine 31 (23%) azathioprine 24 (18%) other drugs 37 (28%) (cyclophosphamide, biologics, salazopyrine) Chang J, Wakefield D, McCluskey PJ. Immunosuppressive therapy in patients with non infectious uveitis. 2009 2011; Unpublished data

Joshi J, Talat L, Yaganati S et al. Outcomes of changing immunosuppressive therapy after treatment failure in patients with non infectious uveitis. Ophthalmology 2014; 121:1119-1124 15

Joshi J, Talat L, Yaganati S et al. Outcomes of changing immunosuppressive therapy after treatment failure in patients with non infectious uveitis. Ophthalmology 2014; 121:1119-1124 16

Joshi J, Talat L, Yaganati S et al. Outcomes of changing immunosuppressive therapy after treatment failure in patients with non infectious uveitis. Ophthalmology 2014; 121:1119-1124 17

Joshi J, Talat L, Yaganati S et al. Outcomes of changing immunosuppressive therapy after treatment failure in patients with non infectious uveitis. Ophthalmology 2014; 121:1119-1124 18

Joshi J, Talat L, Yaganati S et al. Outcomes of changing immunosuppressive therapy after treatment failure in patients with non infectious uveitis. Ophthalmology 2014; 121:1119-1124 19

Rheumatology Rx 1986 the IMT & biologics revolution Rheumatology Rx 2016 Images courtesy A/Prof Jane Bleasel

Uveitis responds to TNF Mab therapy (not etanercept) Not clear where else uveitis fits within this network at this time

Biologic therapy Systemic Therapy for Uveitis monoclonal antibodies TNF antibodies effective: sarcoid, JIA, IBD uveitis compelling evidence in Behcets 80% plus response rates no long term remission increasing range of drugs variable experience as most new drugs Yamada Y, Sugita S, Tanaka H et al. Comparison of infliximab versus ciclosporin during the initial 6 month treatment period in Behcet disease. Brit J Ophthalmol 2010; 94:284-88

Adalimumab Clinical trials: clinical case series: - several open label studies - retrospective & prospective case series - 38% at 12 weeks; 57% at 1 year - 50 70% treatment effect across studies - French TNF study 93% at 1 year randomised prospective studies: - VISUAL I active uveitis - VISUAL II inactive uveitis

VISUAL I: RCT: active intermediate, posterior or pan uveitis (NINA uveitis) 217 patients steroid sparing effect of adalimumab Vs placebo 1 endpoint: time to treatment failure multiple endpoints for Rx failure: AC cells, vitreous flare, new lesions, >15 letter V/A loss, OCT CMT Jaffe G, Dick A, Brezin A et al. Adalimumab in patients with active non infectious uveitis. NEJM 2016; 375:932-943

Jaffe G, Dick A, Brezin A et al. Adalimumab in patients with active non infectious uveitis. NEJM 2016; 375:932-943

early and sustained uveitis control 50% increase in time to treatment failure 13 24 Jaffe G, Dick A, Brezin A et al. Adalimumab in patients with active non infectious uveitis. NEJM 2016; 375:932-943

VISUAL I: significant Rx effect across multiple endpoints no difference in time to OCT macular oedema Jaffe G, Dick A, Brezin A et al. Adalimumab in patients with active non infectious uveitis. NEJM 2016; 375:932-943

Uveitic Macular Oedema

VISUAL II: RCT: inactive intermediate, posterior or pan uveitis (NINA uveitis) 229 patients steroid sparing effect of adalimumab Vs placebo 1 endpoint: time to treatment failure multiple endpoints for Rx failure: AC cells, vitreous flare, new lesions, >15 letter V/A loss, OCT CMT Nguyen Q, Merrel P, Jaffe G et al. Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial. Lancet 2016; epub August 16

Nguyen Q, Merrel P, Jaffe G et al. Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial. Lancet 2016; epub August 16

early and sustained uveitis control statistically significant increase in time to treatment failure Nguyen Q, Merrel P, Jaffe G et al. Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial. Lancet 2016; epub August 16

VISUAL I & II: drug safety > 10 years of adalimumab use in other diseases side effects: - injection site reactions - infection no new safety signals esp malignancy & infection must exclude latent TB intermediate uveitis: must have MRI to exclude demyelinating disorder

Biologics for eye disease: early Sydney experience Behcet s 6 interferon 1 poor responder JIA uveitis 11 adalimumab 8 infliximab 3 3 poor responders => multiple TNFs + IL-6 SpA + RAAU/CAU 13 adalimumab 1 poor responder => multiple TNFs sarcoid uveitis 2 adalimumab scleritis 3 adalimumab 1 infliximab 1 rituximab 1 36

Use of adalimumab in non-infectious uveitis: real world data Jonathan T Lee, William Yates, Sophie Rogers, Peter McCluskey, Lyndell L Lim

mg/day Systemic Therapy for Uveitis Mean Prednisolone dose 45 40 35 Active at baseline n = 13 patients Inactive at baseline n = 9 patients 30 25 20 15 10 5 0 Follow-up

Failure rate Failure rate 0.00 0.25 0.50 0.75 1.00 Failure rate Failure rate 0.00 0.25 0.50 0.75 1.00 Systemic Therapy for Uveitis Time to Treatment Failure Active at baseline Inactive at baseline Active eyes Inactive eyes Number at risk 0 26 52 78 104 Weeks 19 6 4 2 2 Number at risk 0 26 52 78 104 Weeks 18 12 8 4 2 Median TTF: 21 weeks VISUAL I: 24 weeks Median TTF: <50% failed VISUAL II: <50% failed

The challenge TNF blockers are very useful therapy for patients with vision threatening uveitis often challenging co-morbidities Ophthalmologists do not have the skills to manage patients on TNF blockers in isolation significant potential for systemic complications will require new team management paradigm 40

Who does what: The team approach Ophthalmologist Physician Is it working? I/S Drug is it causing side effects?

The challenge when are biologics contra-indicated???? - infective uveitis - demyelinating disease - infective co-morbidities what are the risks????? - infection - latent TB - demyelinating disease in IU patients - non lethal malignancy 42

Emerging Treatment Paradigm relapse relapse systemic steroids + methotrexate / mycophenolate / azathioprine aim to taper & stop oral steroids change to / add biologic consider local therapy + systemic therapy No one should go blind without a dose of intravitreal triamcinolone 43

Take Home Messages: long term commitment by both patient and ophthalmologist get help team approach for systemic therapy defining role of biologics about to start biologics revolution in uveitis