Basic principles of systemic therapies Uveitis Course Antalya Miles Stanford, Medical Eye Unit, St Thomas Hospital

Transcription

1 Basic principles of systemic therapies Uveitis Course Antalya 2013 Miles Stanford, Medical Eye Unit, St Thomas Hospital

2 In this talk Conventional treatments The problems with the design of current trials The way forward.

3 IVIg Drugs for Uveitis Thalidomide Chlorambucil Anti TNF inhibitors Cyclophosphamide Warfarin

4 If a lot of cures are suggested for a disease, it means that the disease is incurable Anton Chekhov

5 The Options Nothing Drops Periocular injections Intraocular injections Systemic treatment

6 When to consider doing nothing Fuch s heterochromic cyclitis Toxoplasma away from anywhere important Intermediate/posterior uveitis with few symptoms and good VA

7 Treatment of Posterior Uveitis General principles No RCTs Know what you are treating Get in control of the disease Reduce drugs in a stepwise manner until cure or relapse Monitor side effects closely Remember the patient!

8 Treatment of Posterior Uveitis Orbital steroid injections Study Tanner et al Patients (eyes) 28 (28) Increased VA 12/28(43%) Improved Inflammation 21/28 (75%) Jennings et al 10 (12) 6/12(50%0 N/A Riordan-Eva et al 28 (54) 19/47(40%) 13/51 (25%) Helm et al 20 (20) 12/18(67%) N/A Dafflon et al 53 (58) 67% N/A

9 Cystoid macular oedema

10 Resolution of cystoid macular oedema Day of injection 3 days later

11 Traditional treatments Corticosteroids Azathioprine Ciclosporin Mycophenolate Methotrexate

12 Corticosteroids Treat if VA<6/12 or systemic disease that will be chronic (eg VKH) Start high to control then tail Warn patients of side effects Add other drugs if not controlling or medically important SEs Patients will vote with their feet

13 Treatment of Uveitis Effect of steroids VA improves in 60% Improvement or stabilisation to 75% with additional immunosuppressive drug Steroid side effects in at least 90%

14 Treatment of Uveitis Azathioprine - Indications Disease relapse when prednisolone > 10 mg/day Steroids not tolerated at high dose Hazardous side-effects of steroids Beware patients with TPMT mutations or who are on allopurinol

15 Role of azathioprine in management of Behcet s ocular disease Class 1B evidence to support RCT showed that azathioprine (2.5mg/kg) v placebo - reduced the number of relapses (1/25 vs. 7/23; NNT=4) - Prevented further visual morbidity whereas those in the placebo group suffered further deterioration NEJM ;281-5

16 Role of azathioprine in management of ocular Behcet s disease - prevented onset of ocular disease in those who had not developed it (1/12 vs 8/13; NNT=2) - 7 year follow up showed the effect to be sustained with less blindness in the azathioprine treated group (NNT=4) Arthritis Rheum ;769-74

17 Role of azathioprine in management of Behcet s ocular disease 157 patients treated with steroids and azathioprine 50% complete responders 40% partial responders Patients with retinal vasculitis (2x) and severe visual loss at baseline (3x) less likely to be complete responders Arthritis Care 2010

18 Treatment of Uveitis Cyclosporin A good immunosuppressant Effective in Behcet s, VKH, sarcoid. Check kidney function Can be used in combination with others Check for other drugs eg NSAID

19 Role of cyclosporin in management of ocular Behcet s disease 3 RCTs. None placebo controlled. Evidence 1B/2B Mostly rather old and at greater doses than currently used Overall probably as effective as steroids. In severe disease added to steroid/aza combination Beware CNS toxicity

20 Excellent drug Treatment of Uveitis Methotrexate Very useful in patients with JIA, sarcoid and scleritis Given 1x/week oral or s/c Dose is 5-25 mg/wk + folic acid Needs monitoring Allow 6-8 weeks for full effect Keep going for 2 years

21 Treatment of posterior uveitis Mycophenolate mofetil Synergistic with other drugs (steroids, cyclosporin) Check blood count / renal / liver function Start 500mg bd up to 1.5g bd. Adverse effects - Diarrhoea, vomiting, leucopenia, sepsis. Occur in 15-25% Monitor indices monthly

22 What s happening now Ophthalmology has been largely overtaken by the inflammologies (eg rheum-, dermat-, etc) by lack of large RCTs Clear evidence now of increasing international collaboration but the 7 problems: Denniston and Dick BMC Ophthalmology 2013

23 Problem 1 small target population Population requiring immunosuppression is small Overcome by the SITE consortium 5 academic centres retrospectively reviewing patients patients treated with IS, 68,751 visits spanning 14,910 person years

24 Problem 2 heterogenous diseases Classification by anatomical site not aetiology Splitting defines a pure cohort but leads to small numbers Lumping leads to easier recruitment but may lead to clinically meaningless results because of the range of diseases included

25 Problem 3 poorly defined phenotypes Uveitis subtypes are imperfectly defined Criteria do carry enough sensitivity/specificity to reliably separate diseases Likely to change in the future as we understand disease aetiology better (eg specific genes, etc)

26 Problem 4 diagnostic inconsistency Variation between clinicians in classification International collaboration SUN (standardisation of uveitis nomenclature) aims to define criteria into 28 different uveitis syndromes Currently 250 cases of each syndrome are being collected to validate terms referring to the syndromes

27 Problem 5 subjective outcome measures Ophthalmologists can see inflammation but this is subjective FDA currently accepts the NEI vitreous haze score Problems include subjective, non-continuous scale, poor discrimination at low levels of inflammation, limit to entry to clinical trials where a 2 step change is usually required

28 The NEI vitreous haze scoring system

29 Problem 6 measuring visual acuity VA is a poor marker of efficacy of a drug for ocular inflammation Impact on VA by disease is dependent on activity (eg CMO, vitreous haze, etc) and damage (eg cataract, glaucoma), the latter of which may be correctable VA is also affected by patient mood, general health and compliance Role of PROMs

30 Problem 7 low commercial interest In past ocular inflammation of little interest to big pharma as small target population Now seems to be changing Recent industry sponsored trials of voclosporin and anti-il 17 (secukinumab) as well as novel routes for existing drugs eg intravitreal administration via injection or implants.

31 Hopes for the future Targetting of specific gene mutations in ocular inflammation Targeted development from animal model to clinical trial (eg secukinumab) I-SPY-2 adaptive trial design randomization is adaptive. Here the probability of being assigned to a treatment arm increases if the outcome in prior patients was good and vica versa

32 Conclusions Despite years of research, uveitis is still a blinding disease Conventional drugs have a role in resource poor settings There are new initiatives afoot that should revolutionise the treatment of the disease