uveitis unplugged: systemic therapy - conference design...uveitis unplugged: systemic therapy hobart...

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

Systemic Therapy for Uveitis

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 anti-inflammatory drugs


Inflammatory causes

of vision loss

• cystoid macular

oedema

• ischaemic retinal

vasculitis

• progressive retinitis/

choroiditis

• optic neuropathy

• vitritis

• severe anterior 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

• 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

• 190 systemic therapy

• mean age 43

• 58 (31%) steroids alone

• 132 (69%) steroids +

I/S drug

• 67/132 (51%) multiple

I/S drugs

Drugs

• 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


Systemic Regimens

• 190 systemic therapy

• mean age 43

• 58 (31%) steroids alone

• 132 (69%) steroids +

I/S drug

• 67/132 (51%) multiple

I/S drugs

Drugs

• 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

IMT: The Sydney Experience


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


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17





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…… the IMT & biologics revolution

Rheumatology Rx 1986

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

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




early and sustained uveitis control

50% increase in time to treatment failure

13 24




VISUAL I:

• significant Rx

effect across

multiple

endpoints

• no difference

in time to

OCT macular

oedema


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





epub August 16





epub August 16

early and sustained uveitis control

statistically significant increase

in time to treatment failure


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


36

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

Biologics for eye disease: early Sydney experience


Use of adalimumabin non-infectious uveitis:

real world data

Jonathan T Lee, William Yates, Sophie Rogers, Peter McCluskey, Lyndell L Lim

Active at baseline

n = 13 patients

Inactive at baseline

n = 9 patients

0

5

10

15

20

25

30

35

40

45

mg/d

ay

Follow-up


Mean Prednisolone dose

Inactive eyes

0.0

00.2

50.5

00.7

51.0

0

Failure

ra

te

18 12 8 4 2 Number at risk

0 26 52 78 104Weeks

Median TTF: 21 weeks

VISUAL I: 24 weeks

Median TTF: <50% failed

VISUAL II: <50% failed

Active eyes

0.0

00.2

50.5

00.7

51.0

0

Failure

ra

te

19 6 4 2 2 Number at risk

0 26 52 78 104Weeks

Failu

re r

ate

Failu

re r

ate

Active at baseline Inactive at baseline

Time to Treatment Failure


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


Ophthalmologist Physician

Is it working?is it causing

side effects?I/S

Drug

Who does what: The team approach


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

• systemic steroids + methotrexate / mycophenolate /

azathioprine

• aim to taper & stop oral steroids

• change to / add biologic

• consider local therapy + systemic therapy

43

relapse

relapse

“No one should go blind without

a dose of intravitreal triamcinolone”


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


uveitis unplugged: systemic therapy - conference design...uveitis unplugged: systemic therapy hobart...

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