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
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis
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)
Systemic Therapy for Uveitis
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 for Uveitis
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
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis
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 Therapy for Uveitis
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
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis
19
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
Systemic Therapy for Uveitis
…… the IMT & biologics revolution
Rheumatology Rx 1986
Rheumatology Rx 2016
Images courtesy A/Prof Jane Bleasel
Systemic Therapy for Uveitis
“Uveitis” responds to TNF Mab therapy (not etanercept)
Not clear where else uveitis fits within this network at this time
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis
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
Systemic Therapy for 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
Systemic Therapy for Uveitis
Jaffe G, Dick A, Brezin A et al. Adalimumab in patients with active non
infectious uveitis. NEJM 2016; 375:932-943
Systemic Therapy for Uveitis
Jaffe G, Dick A, Brezin A et al. Adalimumab in patients with active non
infectious uveitis. NEJM 2016; 375:932-943
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis
Uveitic 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
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis
Ophthalmologist Physician
Is it working?is it causing
side effects?I/S
Drug
Who does what: The team approach
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis
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”
Systemic Therapy for Uveitis
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
Systemic Therapy for Uveitis