Clinical science Br J Ophthalmol: first published as 10.1136/bjophthalmol-2019-314154 on 1 November 2019. Downloaded from Biologic therapy for Behçet’s uveitis: a systematic review Perpetual Uke ,1 Rachel Gorodkin,1 Nicholas Beare2

1Rheumatology, University of ABSTRACT therapy but some patients do not respond well to Manchester, Manchester, UK 2 Background Biologics are increasingly used in these conventional therapies and remission is not Ophthalmology, University of ’ Liverpool, Liverpool, UK management of Behçet s Disease (BD) including ocular achieved. BD, but the evidence base is limited, mostly from studies Biologics alone, or combined with conven- Correspondence to of uveitis and BD manifestations. tional therapies are used in refractory cases of Dr Perpetual Uke, Objective To review the evidence base for biologics in ocular BD. Biologics reported for use in ocular Rheumatology, Biomedical the treatment of ocular BD. BD include interferon alpha 2a (IFN-α 2a);89 Department, University of Methods Systematic literature search was made using anti-tumour necrosis factor (TNF) agents— Manchester, Manchester, UK; 10 11 12 13 [email protected] exploded key words—Behçet’s, ocular, biologics in infliximab and adalimumab; anti- MEDLINE, Cochrane library, Database of Abstracts interleukins (IL)—tocilizumab,14 secukinumab15 Received 5 March 2019 Reviews and Effects, Clinical Trials.gov, Science Direct and gevokizumab;16 anti-CD20—rituximab17 Revised 7 October 2019 and Google Scholar. There was no limitation on region, and anti-CD 25—daclizumab.18 In a recent Accepted 9 October 2019 language or date (Search updated 16th October 2018). update on the management of BD, European Literature retrieval was restricted to randomised League Against Rheumatisim (EULAR) recom- controlled trials (RCTs) of biologics. mends glucocorticoids should not be used alone Results Of 237 papers retrieved, eight met the inclusion in patients with posterior uveitis, but conven- criteria. RCTs on interferon alpha 2a (INF-α 2a), tional or biologic immunosuppressive therapies, 19 adalimumab, secukinumab, gevokizumab, rituximab and are the preferred treatment alternative. It also daclizumab were retrieved (two for adalimumab and recommends close collaboration between rheu- gevokizumab). The outcome measures were not met for matologists and ophthalmologists in the manage- secukinumab, daclizumab and gevokizumab. Rituximab ment of BD uveitis. and INF-α 2a showed promising preliminary results but Most reports on biologics in BD treatment are sufficiently powered RCTs are needed to provide based on uncontrolled studies with few randomised adequate evidence of efficacy. The RCTs on adalimumab controlled trials (RCTs). did not evaluate efficacy for BD uveitis specifically, hence are of limited value for this review. AIM Conclusion Some biologics show promise in treating BD This work seeks to review the RCT evidence on the fi uveitis, but more RCTs are needed for rm conclusions efficacy and safety of biologics in the treatment of fi about ef cacy. A phase IV study or, registry of ocular BD. fi adalimumab could provide data on its ef cacy in BD http://bjo.bmj.com/ uveitis compared to other forms. METHODOLOGY Keyword searches The index words (Behçet’s, ocular and biologics) used in the searches were exploded. INTRODUCTION ► Behçet’s disease, Behçet’s syndrome,

Behçet’s disease (BD) is a chronic relapsing- Adamantiades-Behçet disease, Triple Symptom on July 27, 2020 at AAO/BJO. Protected by copyright. remitting immunoinflammatory disorder with complex. diverse clinical manifestations including orogenital ► Ocular, eyes, uveitis, retinitis, visual, sight, aphthae, ocular, vascular, central nervous system, ophthalmic. articular, mucocutaneous and gastrointestinal ► Biologics, biologic treatment, ustekinumab, anti- symptoms.1 Ocular involvement in BD causes epi- TNF inhibitors (adalimumab, etanercept, inflix- sodic and recurrent uveitis with or without hypop- imab), anti-CD20 (rituximab), anti-IL-1 (ana- yon, vitritis, retinitis, occlusive retinal vasculitis, kinra, canakinumab, gevokizumab, rilonacept), retinal ischaemia and cystoid macular oedema.2 anti-IL-2 (daclizumab), anti-IL-6 (tocilizumab) There is variability in presentation and severity, and anti-IL-17 (secukinumab), Apremilast. and no gold standard in treatment.3 Searches of the Cochrane Library—Cochrane ©Author(s)(ortheir Topical corticosteroid eye drops may be used in Central Register of Controlled Trials, Cochrane 45 employer(s)) 2020. No mild attacks of anterior/intermediate uveitis. Ocular Health Group Trials register, Cochrane commercial re-use. See Systemic corticosteroids are generally the next line Database of Systematic Reviews, Database of rights and permissions. of treatment based on expert opinion and on Abstracts of Reviews of Effects, Health Published by BMJ. a prospective observational study.6 Due to corticoster- Technology Assessments and MEDLINE were To cite: Uke P, Gorodkin R, oid side effects, immunosuppressive agents are added systematically made. Non-English papers were Beare N. Br J Ophthalmol as steroid-sparing drugs.7 Immunosuppressive thera- translated with the help of institutional librarian. 2020;104:1045–1051. pies and corticosteroids are used for maintenance Additional searches were done on ClinicalTrials.

Uke P, et al. Br J Ophthalmol 2020;104:1045–1051. doi:10.1136/bjophthalmol-2019-314154 1045 Clinical science Br J Ophthalmol: first published as 10.1136/bjophthalmol-2019-314154 on 1 November 2019. Downloaded from gov, Science direct and Google Scholar. RCTs was added to the overall output.

Eligibility/Selection criteria Literature retrieval of biologics therapy was restricted to RCTs. RCTs on ocular BD comparing biologics alone or in combination with any control were eligible. Study selection was done by two authors (PU, RG) who independently identified relevant studies and evaluated each trial according to eligibility criteria. There was no limitation on region, language or date (Search updated by 16th October 2018).

Exclusion criteria Uveitis attributed to other causes.

Statistical analysis Because of the small number of RCTs and different outcome measures, results were not pooled to perform a meta-analysis. Statistical analysis was performed for each individual trial where possible to evaluate level of significance of outcome parameters. Where appropriate, number needed to treat (NNT) were calculated for efficacy, and numbers needed to harm (NNH) was calculated to make a quantitative assess- ment of the safety. Where primary outcome was not met, NNH and NNT were not calculated. NNT is defined as the Figure 1 Flow diagram showing the results of the literature search. BD, number of patients who must be treated in order to obtain Behçet’s Disease; RCT; randomised controlled trial. benefit in one patient. NNH is defined as the number of patients who received the active treatment that will lead to one additional patient being harmed relative to placebo. The Daclizumab number of patients who withdrew due to adverse events was In this study 17 BD patients aged six and above, defined accord- 20 ’ used when calculating NNH. ing to the Japanese Behçet s Disease Research Committee, were recruited.18 Patients were randomised 1:1 to either standard treatment or treatment plus 1 mg/kg daclizumab given intrave- RESULTS nously every 2 weeks for 6 weeks, then once every 4 weeks for 24 Search output months minimum. Participants continued their conventional Electronic searches of the exploded index words in MEDLINE immunosuppressive therapy from enrolment, with no dose yielded 237 papers. Applying the search criteria resulted in a total reduction for the first 6 months unless a taper was medically 15 papers retrieved with seven non-RCT and non-BD uveitis indicated. Primary outcomes were number of ocular attacks, studies excluded. Overall eight papers met the inclusion criteria. amount of immunosuppressive medication required and the abil- Figure 1 shows the literature search process. Table 1 shows ity to taper immunosuppressive medications. The occurrence and http://bjo.bmj.com/ a summary of the biologics, country of trial, number, gender resolution of ocular attacks is defined by Buggage et al.18 and age of patients among others. Secondary outcomes were degree of intraocular inflammation, the presence/absence of cystoid macular oedema, changes in VA Interferon alpha 2a (IFN-α 2a) and quality of life measures. The time to first ocular attack was not This was a single-centre double-blind RCT involving 50 patients significantly different between the two groups (p=0.620), as was α –

(23 IFN- 2a, 21 placebo), age 16 55 and mean±SD of 32.38 the number/dosages of immunosuppressive therapy (p=0.47). All on July 27, 2020 at AAO/BJO. Protected by copyright. ±7.94 years.21 Table 2 shows the demographics of the patients patients on placebo followed-up for 6 months tapered their immu- and disease manifestations. Six patients withdrew, and of the nosuppressive therapies, compared with 40% of those on daclizu- remaining 44, nine had ocular BD (6 IFN-α 2a, 3 placebo). mab (p=0.02). The outcome measures were not met. IFN-α 2a or placebo was administered subcutaneously 6×106 IU thrice/week. Outcome measures were ocular inflammatory Rituximab score, frequency of attacks and changes in visual acuity (VA). Twenty patients (13 males, 7 females) aged 16–51 years, were There was a decrease in severity and frequency of ocular randomised to rituximab group (RG) or cytotoxic combination attacks in five (83%) patients in IFN-α 2a (three complete, group (CCG).5 Rituximab was given in two 1 g courses (15 day two partial remissions) relative to one (33%) in placebo interval) plus methotrexate (15 mg/weekly) and prednisolone (NNT=2). There was also an improvement in VA in nine (0.5 mg/kg per day); cytotoxic combination therapy consisted of out of 11 eyes (82%) with IFN-α 2a (five at the end of the pulse cyclophosphamide (1 g/monthly), azathioprine (2–3 mg/kg treatment period, three at the end of the follow-up period per day) and prednisolone (0.5 mg/kg per day). Primary outcome (NNT=2.1)). Inflammatory score decreased in seven (64%) was the Total Adjusted Disease Activity Index (TADAI). TADAI eyes in IFN-α 2a and 3 (50%) in placebo (NNT=7.4). It was defined as the sum of VA and Total Inflammatory Activity was concluded that IFN-α 2a seems likely to be Index (TIAI). VA was measured on a Snellen chart with an a therapeutic option in the treatment of ocular BD. There unconventional scale (‘10 on 10’); TIAI summates the total were no adverse events-related withdrawals, hence NNH inflammatory index of both eyes with an adjustment for anterior was not calculated. uveitis (x1), posterior uveitis (PU) (x2) and retinal vasculitis (RV)

1046 Uke P, et al. Br J Ophthalmol 2020;104:1045–1051. doi:10.1136/bjophthalmol-2019-314154 Clinical science Br J Ophthalmol: first published as 10.1136/bjophthalmol-2019-314154 on 1 November 2019. Downloaded from

Table 1 Summary of medications subjected to randomised clinical trials No of Age Author patients Country/centre Drug Dosage Target, Design Criteria (years) Alpsoy 50 Turkey/SC IFN-α 2a 6×106 IU S/C injected thrice/week BD,RDM International 16–55 et al21 31M PC Study 19F Group for BD (ISGBD) Buggage 17 gender USA Daclizumab 1 mg/kg intravenously every 2 weeks for six weeks, then Ocular BD, RDM, Japan BD >6 et al18 not stated PC every four weeks while on immunosuppressives PC research Committee (JBDRC) Davatchi 20 Iran/SC Rituximab Two 1000 mg at 15-day interval+MTX 15 mg weekly Ocular BD, RSB control International 17–51 et al5 13M +PRED 0.5 mg/kg/d pilot study Criteria for BD 7F (ICBD) Dick 274 mainly Countries not Secukinumab+ISP 300 mg/week for 2 weeks, then 300 mg/2weeks BD uveitis, RDM Not stated ≥18 et al15 male stated/MC PC Tugal- 21 Turkey, S. Gevokizumab 30/60 mg per 4 BD uveitis, POL ISGBD 18≤80 Tutkun gender not Korea, Tunisia four weeks; INT or S/C RPG phase two trial et al22 stated MC, 7 centres Tugal- 83 Turkey, South Gevokizumab 60 mg/4weeks S/C BD uveitis, RDM, PC, ISGBD 18–67 Tutkun 60M Korea open label extension et al23 23F study Jaffe 217, 18 countries Adalimumab 80 mg load, 40 mg biweekly Uveitis (active) of NA 18–81 et al24 gender not MC various aetiologies, stated RDM, PC Nguyen 226 21 countries Adalimumab 80 mg load, 40 mg biweekly Uveitis (inactive) of NA 18–79 et al25 88M MC various aetiologies, 138F RDM, PC BD, Behçet’s Disease; ISP, immunosuppressive; MC, multi-centre; MTX, methotrexate; PC, placebo controlled; POL, prospective open label; PRED, prednisolone; RDM, randomised double masked; RPG, randomised parallel group; RSB, randomised single blind; S/C, subcutaneously; SC, single centre.

(x3). The secondary outcomes were VA, disease activity index for days in patients with a recent acute exacerbation of BD uveitis.22 PU and RV and TIAI. Disease activity index was evaluated at Patients had a history of posterior uveitis, on a regimen of oral baseline, 2, 4 and 6 months. The mean improvement for TADAI corticosteroids and at least one immunosuppressive drug. Patients was 7.0 for RG versus 3.6 for CCG but the difference was not continued with these drugs as background treatment, and were statistically significant (p=0.2). There were no statistically sig- randomised to one of three gevokizumab regimes. nificant differences in VA (p=0.49), PU (p=0.77), RV (p=0.24), Acute patients had a new ocular exacerbation and if they TIAI (p=0.06) and macular oedema (p=0.82) between groups. responded to gevokizumab continued receiving gevokizumab The authors concluded rituximab is an effective treatment in for up to 336 days. Whereas at-risk patients were enrolled in intractable ocular BD, at least as effective as CCG. the study if they had had one or more acute exacerbations in the http://bjo.bmj.com/ previous 18 months and findings of retinal vascular leakage Gevokizumab I documented by fundus fluorescein angiography score ≥6 (if Twenty-one (17 acute, 4 at-risk) patients were involved in this both eyes had a score ≥6, the eye with the most recent exacerba- prospective randomised parallel-group phase 2 trial consisting of tion was chosen as the index eye). At-risk patients were randomly a response-phase to evaluate response to gevokizumab for up to 21 assigned to follow-up period. Response to gevokizumab was defined as described in Tugal-Tutkun et al.22 Gevokizumab was administered every 4 weeks intravenously on July 27, 2020 at AAO/BJO. Protected by copyright. then intravenously or subcutaneously. The primary objective was α Table 2 Patients demographic data for IFN- 2a investigating the safety of gevokizumab; secondary objectives IFN-α 2a group Placebo group were treatment efficacy evaluated by VA, vitreous haze score, Characteristic (n=23) (n=21) Total (n=44) retinal infiltrates and RV. Fourteen acute patients responded Age, mean±SD, (years) 32.82±8.17 31.89±7.85 32.38±7.94 and entered follow-up. Male–Female ratio 16:07 27:17:00 Best corrected visual acuity (BCVA) improved (22±15 letters Duration of disease mean 6.54±5.70 11:10 6.44±5.70 in index eye), vitreous haze score of zero occurred in 33% of ±SD (y) patients, compared with 12% at baseline, and Disease Activity Oral ulcer 23 21 44 Index score reduced by 2.1±1.8 in index eye of 14 acute patients Genital ulcer 22 20 42 at day 14. Only four patients completed 1 year of follow-up. The Papulopustular lesions 20 21 41 authors concluded gevokizumab was well tolerated and rapidly controlled acute exacerbations of BD uveitis without need of Erythema nodosum-like 12 12 24 lesions high-dose corticosteroid on top of immunosuppressive drugs. Thrombophlebitis 5 4 9 Gevokizumab II Articular symptoms 12 14 26 This was a multi-centre (13 countries) prospective double- Ocular manifestations 6 3 9 masked placebo-controlled event-driven trial in which BD

Uke P, et al. Br J Ophthalmol 2020;104:1045–1051. doi:10.1136/bjophthalmol-2019-314154 1047 Clinical science Br J Ophthalmol: first published as 10.1136/bjophthalmol-2019-314154 on 1 November 2019. Downloaded from

Table 3 Summary of side effects and withdrawals Patients Treatment (N) Total withdrawals (N) Side effects Individual side effects (N) IFN-α 2a 6 Severe eye disease 1 IFN-α 2a; two placebo 50 Progressive mucocutaneous symptoms 1 IFN α−2a New eye/mucocutaneous disease One placebo Progressive mucocutaneous/articular disease One placebo Daclizumab* 2 For personal reasons 1 17 Non-drug related haematological malignancy 1 Rituximab 1 RG-Severe allergic reaction 1 20 Conjunctivitis 2 Rituximab; 1 CCG Pneumonia 1 Herpes zoster 1 Secukinumab† 21 Adverse event 4 300 mg/2wks; 2 300 mg/4wks 118 Lost to follow-up 1 300 mg/2wks only Protocol deviation 2 300 mg/2wks; 2 300 mg/4wks Ineffective therapeutic effect 1 300 mg/4wks; four placebo Withdrew consent 4 300 mg/4wks; one placebo Gevokizumab I‡ 3 (21 days response) Withdrew due to local regulations 2 21 Lack of efficacy 1 7 (84 days follow-up) Ocular exacerbation 7 3 (186 days follow-up) Ocular exacerbation 2 Non-medical reason 1 4 (336 days follow-up) Ocular exacerbation 2 Non-medical reason 2 Gevokizumab II 6 Hypertension Four gevokizumab; two placebo 83 45 Eye disorders 15 gevokizumab; 30 placebo 31 Infections and Infestations 21 gevokizumab; 30 placebo 9 Increased intraocular pressure Five gevokizumab; four placebo 5 Raised C reactive protein Two gevokizumab; three placebo

5 Mycobacterium tuberculosis test positive Two gevokizumab; three placebo http://bjo.bmj.com/ 4 Raised triglycerides One gevokizumab; three placebo 3 Weight loss3 gevokizumab 29 Gastrointestinal disorder 15 gevokizumab; 30 placebo 24 Musculoskeletal/connective tissue disorders 24 Nervous system disorders 11 gevokizumab; 13 placebo

9 Fatigue/asthenia Nine placebo on July 27, 2020 at AAO/BJO. Protected by copyright. 12 Skin/subcutaneous tissue disorders Five gevokizumab; seven placebo 9 Respiratory/thoracic/mediastinal disorders Four gevokizumab; five placebo *Withdrawals in daclizumab not due to side effects. †All withdrawals in secukinumab not due to side effects. ‡All reported withdrawals in gevokizumab I not due to side effects. CCG, cytotoxic combination group; RG, rituximab group. and other non-infectious uveitis patients were randomly non-infectious uveitis. Details of Part 1 and Part 2 are given assigned 60 mg gevokizumab or placebo every 4 weeks in Tu g a l -Tu t ku n et al23 along with standard corticosteroid tapering.23 It consisted of For Part 1, the primary endpoint was not met; the superiority two parts, a double-masked (Part 1) and an open-label of gevokizumab over placebo in delaying time to first acute ocular (Part 2) with all BD patients diagnosed according to the exacerbation was not demonstrated (p=0.661). There were no ISGBD criteria except one. Part 1 was designed to evaluate statistically significant differences in the secondary outcome the efficacy of gevokizumab in reducing the risk of exacerba- parameters except VA that remained stable in gevokizumab and tions relative to placebo in addition to current standard care. deteriorated in the placebo group (p=0.035). The proportion of Part 2 consisted of an open label extension study to evaluate patients with VA worsening (≥10 letters) was significantly lower the long-term safety of gevokizumab in patients with chronic in the gevokizumab group relative to the placebo group

1048 Uke P, et al. Br J Ophthalmol 2020;104:1045–1051. doi:10.1136/bjophthalmol-2019-314154 Clinical science Br J Ophthalmol: first published as 10.1136/bjophthalmol-2019-314154 on 1 November 2019. Downloaded from

placebo) all 18 years or older. All causes of uveitis were enrolled Table 4 Summary of serious adverse events for Adalimumab and in both trials 16 patients (7%) had BD uveitis. Side effects/adverse Events (N) VISUAL I and II The primary outcome in VISUAL I was the time to treatment Adalimumab Placebo failure (TF) after week 6. TF was active uveitis defined by para- Infections 7 (Upper respiratory, urinary, Abortion induced 1 meters described in detail in Jaffe et al.24 In VISUAL II patients tract) were initially inactive, and assessed at intervals until TF Tuberculosis, Pneumonia (2), legionella Acute hepatitis 1 occurred.25 Tables 3 and 4 show side effects/withdrawals of Accidental overdose 1 Infections (Acute pyelonephritis, VISUAL I and II respectively. Sepsis, In VISUAL I, efficacy results for individual causes of uveitis Anaphylactic reaction 1 viral gastroenteritis) were analysed for 20 or more patients within each group; only Angle closure glaucoma 1 Wrist fracture 1 idiopathic uveitis and birdshot choroidopathy met the criterion. Carcinoid tumour of the intestinal tract 1 Choroidal neovascularisation 1 The efficacy of adalimumab in BD uveitis was not evaluated. In Chronic renal failure and fluid overload 2 Retinal detachment 1 VISUAL II, the primary outcome was not reported by aetiology; Demyelination 1 Meningitis aseptic 1 this limits the relevance of these trials for this review. Glioblastoma multiforme 1 Tonsillitis 1 Ligament rupture 1 Humerus fracture 1 DISCUSSION α Lupus-like syndrome 1 Arthritis 1 IFN- 2a Interferons are a group of signalling proteins that activate Neovascularisation 1 Osteonecrosis 1 immune cells and increase expression of major histocompatibility Pilonidal cyst 1 Deep vein thrombosis 2 complex antigens to eradicate pathogens and regulate immune Pleurisy 1 Hypertensive crisis 1 function.26 IFN-α 2a is recommended in refractory cases of BD Tendon rupture 1 uveitis, in selected cases of mucocutaneous and chronic joint Urticaria 1 involvement.19 In the interpretation of the result of this trial, Neutropenia 1 caution needs to be exercised as the RCT was not targeted at Cardiac tamponade 1 eye involvement, hence is not a proper evaluation of IFN-α 2a 9 Blindness transient 1 for BD uveitis. Second the number of uveitis patients were small ; α Dysphagia 1 (6 IFN- 2a, three placebo) hence, no firm conclusions can be Fibula fracture 1 drawn. Various non-RCT studies have demonstrated that IFN-α 2a is Lung Adenocarcinoma stage IV 1 – effective in the treatment of BD uveitis,27 34 but there is no Dysarthria 1 consensus dosage or therapy duration.8 More RCTs are required Status migrainosus 1 to establish efficacy, optimal dosage and therapy duration. Epistaxis 1 Adverse effects are significant, particularly flu-like symptoms, Aortic dissection 1 reversible alopecia, leucopenia and diarrhoea, and higher doses 34 Total withdrawals; 21—adalimumab, 17—placebo. In VISUAL I—10 adalimumab and three may make patients susceptible to more adverse effects. placebo patients withdrew, in VISUAL II 11 adalimumab and seven placebo patients with- drew due to adverse events. Daclizumab Daclizumab is a recombinant monoclonal immunoglobulin of the

human IgG-1 isotype that inhibits IL-2 mediated responses.18 http://bjo.bmj.com/ (p=0.048). The authors suggested gevokizumab could reduce the However, there is no agreement on the exact role of IL-2 in BD severity of uveitis attacks and hence improve VA. or BD uveitis. Yang et al reported high serum levels of IL-2 in 24 patients.35 Alayli et al genotyped 80 BD patients and 105 healthy Secukinumab controls and reported no significant difference for IL-2 (T/G– Secukinumab was studied in three linked multi-centre double- 330) polymorphism in both.36 This suggests more studies are masked RCTs against placebo over 24 weeks enrolling 274 15 needed for better understanding of the role of IL-2 in BD and patients. Each study had a different regime of secukinumab, on July 27, 2020 at AAO/BJO. Protected by copyright. BD uveitis. In this study daclizumab was not shown to be effective and this was in addition to standard-of-care immunosuppressive in the treatment of ocular complications of BD. therapy, with the option to taper concomitant therapy in a stepwise fashion.15 Outcomes were reduction of uveitis recur- rences or vitreous haze score during withdrawal of concomitant Rituximab immunosuppressive medication, VA, immunosuppressive use and Rituximab is a chimeric monoclonal antibody that acts against the safety. CD20 protein found primarily on B cells and when it binds to 26 There were no statistical differences in changes in VA, vitreous B lymphocytes, it leads to apoptosis and a reduction in B cells. haze score and rate of uveitis recurrences in between secukinu- This was a small pilot RCT, with no statistically significant differ- mab and placebo. The authors concluded that the primary effi- ence between the RG and CCG treatment groups, but the number cacy end points were not met. of patients involved in the study were too small to determine equivalence or superiority. The evidence provided from this work Adalimumab is insufficient to determine efficacy but supports a larger RCT The efficacy and safety of adalimumab was evaluated in patients with an appropriate number of patients. with active (VISUAL I24), and inactive (VISUAL II25) non- infectious uveitis in a multi-centre RCT against placebo. Gevokizumab VISUAL 1 was carried out in 18 countries involving 217 patients Gevokizumab is recombinant humanised antibody that modu- (110 adalimumab, 107 placebo) while VISUAL II was conducted lates anti-IL-1β activity.16 In the first randomised dose ranging in 21 countries involving 226 patients (115 adalimumab, 111 study, a rapid and durable effect on clinical activity with complete

Uke P, et al. Br J Ophthalmol 2020;104:1045–1051. doi:10.1136/bjophthalmol-2019-314154 1049 Clinical science Br J Ophthalmol: first published as 10.1136/bjophthalmol-2019-314154 on 1 November 2019. Downloaded from resolution of acute exacerbations was reported; no safety con- Funding The authors have not declared a specific grant for this research from any fi cerns or need for increase in corticosteroid dose. However, funding agency in the public, commercial or not-for-pro t sectors. patients’ withdrawal rate was very high; four completed the Competing interests Nicholas Beare—Advisory Board for Alimera Sciences, study. This negates any conclusions. The second RCT was con- Consultancy for Abbvie, Expert Advisor for The Wellcome Trust on Research Supervisory Group for uveitis related grant. ducted as a phase III follow-up to evaluate gevokizumab com- pared with placebo on top of current standard of care in reducing Patient consent for publication Not required. risk of BD uveitis exacerbations and assess safety.23 The primary Provenance and peer review Not commissioned; externally peer reviewed. endpoint was not met. The safety profile was similar in both Data availability statement All data relevant to the study are included in the RCTs; the number of withdrawals were unusually high and it article or uploaded as supplementary information. becomes difficult not to ascribe these to either a sign of the ORCID iD drugs ineffectiveness or an inadequate assessment of side effects. Perpetual Uke http://orcid.org/0000-0002-9049-1397

Secukinumab REFERENCES et al Chi reported significantly elevated IL-17A in the peripheral 1 Namba K, Sonoda K-H, Kitamei H, et al. Granulocytapheresis in patients with refractory blood samples of 23 BD patients with active uveitis relative to ocular Behcet's disease. J Clin Apher 2006;21:121–8. healthy controls,37 leading to suggestions that IL-17A may be 2 Evereklioglu C. Ocular Behçet disease. Curr Opin Ophthalmol 2011;22:508–16. a therapeutic target in T-cell driven disorders.38 Secukinumab is 3 McNally TW, Damato EM, Murray PI, et al. An update on the use of biologic therapies in the management of uveitis in Behçet’s disease: a comprehensive review. Orphanet a selective high-affinity, fully human monoclonal antibody that J Rare Dis 2017;12:130. 15 binds and neutralises IL-17A. In an earlier open-label study, 4 Alpsoy E. New evidence-based treatment approach in Behçet's disease. Patholog Res secukinumab was reported to demonstrate efficacy and safety in Int 2012;2012:871019. the treatment of non-infectious uveitis.38 In this trial, secukinu- 5 Davatchi F, Shams H, Rezaipoor M, et al. Rituximab in intractable ocular lesions of mab has not shown any promise in BD uveitis. Behcet's disease; randomized single-blind control study (pilot study). Int J Rheum Dis 2010;13:246–52. 6 Markomichelakis N, Delicha E, Masselos S, et al. A single infliximab infusion vs Adalimumab corticosteroids for acute panuveitis attacks in Behçet's disease: a comparative 4-week TNF-α is a pro-inflammatory cytokine produced by Th1- study. Rheumatology 2011;50:593–7. lymphocytes and macrophages39; significantly higher levels 7 Mesquida M, Molins B, Llorenç V, et al. Current and future treatments for Behçet's 40 uveitis: road to remission. Int Ophthalmol 2014;34:365–81. have been reported in BD patients relative to placebo. 8 Yalçindağ FN, Uzun A. Results of interferon alpha-2a therapy in patients with Behcet's Various uncontrolled studies reported adalimumab as an disease. J Ocul Pharmacol Ther 2012;28:439–43. effective anti-TNF agent in patients with uveitis of various 9 Sobacı G, Erdem U, Durukan AH, et al. Safety and effectiveness of interferon alpha-2a – aetiologies.12 41 45 VISUAL I and VISUAL II were well- in treatment of patients with Behçet's uveitis refractory to conventional treatments. – designed RCTs enrolling non-infectious uveitis of any cause; Ophthalmology 2010;117:1430 5. 10 Okada AA, Goto H, Ohno S, et al. Multicenter study of infliximab for refractory unfortunately, the number with BD was too small to analyse uveoretinitis in Behçet disease. Arch Ophthalmol 2012;130:592–8. specifically, notwithstanding the number with BD was similar 11 Takeuchi M, Kezuka T, Sugita S, et al. Evaluation of the long-term efficacy and safety of to other studies reviewed here. However, this limits the rele- infliximab treatment for uveitis in Behçet's disease: a multicenter study. Ophthalmology – vance of these trials for this review. 2014;121:1877 84. 12 Vitale A, Emmi G, Lopalco G, et al. Adalimumab effectiveness in Behçet's disease: short and long-term data from a multicenter retrospective observational study. Clin CONCLUSION Rheumatol 2017;36:451–5. The use of biologic agents for ocular BD has in part been 13 Bawazeer A, Raffa LH, Nizamuddin SHM. Clinical experience with adalimumab in the treatment of ocular Behçet disease. Ocul Immunol Inflamm informed by immuno-pathogenesis of BD. While abnormal pro- – http://bjo.bmj.com/ α 2010;18:226 32. duction of some cytokines, (TNF- , interleukins and chemo- 14 Beltrán-Catalán E, Fernandez C, Blanco R, et al. FRI0486 Tocilizumab Treatment for kines) has been documented, it is not clear how they act Uveitic Cystoid Macular Edema Refractory To Other Synthetic and Biological separately or in combination to determine the disease course. Immunosuppressive Drugs. Multicentre Study of 23 Patients. Ann Rheum Dis Identification of offending cytokine(s) would help to direct the 2016;75:614.2–5. 15 Dick AD, Tugal-Tutkun I, Foster S, et al. Secukinumab in the treatment of noninfectious investigation of biologics in the search for an effective and safe uveitis: results of three randomized, controlled clinical trials. Ophthalmology treatment for ocular BD. At present there are no adequate RCTs 2013;120:777–87. which indicate an effective therapy for ocular BD. Although also 16 Gül A, Tugal-Tutkun I, Dinarello CA, et al. Interleukin-1β-regulating antibody on July 27, 2020 at AAO/BJO. Protected by copyright. including non-randomised retrospective studies, Urruticoechea- XOMA 052 (gevokizumab) in the treatment of acute exacerbations of resistant Arana et al46 reached similar conclusions uveitis of Behcet's disease: an open-label pilot study. Ann Rheum Dis 2012;71:563–6. Current EULAR guidelines on BD management recom- 17 Sadreddini S, Noshad H, Molaeefard M, et al. Treatment of retinal vasculitis in Behçet's mends the use of IFN-α and anti-TNF-α agents as first line disease with rituximab. Mod Rheumatol 2008;18:306–8. treatment for eye involvement depending on severity, and for 18 Buggage RR, Levy-Clarke G, Sen HN, et al. A double-masked, randomized study to recurrent episodes of acute sight-threatening BD uveitis.19 In investigate the safety and efficacy of daclizumab to treat the ocular complications fl – the UK, NICE recommends the use of adalimumab for the related to Behçet's disease. Ocul Immunol In amm 2007;15:63 70. 19 Hatemi G, Christensen R, Bang D, et al. 2018 update of the EULAR recom- treatment of non-infectious uveitis including BD. However, mendations for the management of Behçet's syndrome. Ann Rheum Dis recommendations specifically for BD uveitis are not able to 2018;77:808–18. be based on robust RCTs. Adequately powered RCTs are 20 Hatemi G, Silman A, Bang D, et al. Management of Behçet disease: a systematic needed to evaluate the efficacy and safety profile of biologic literature review for the European League against rheumatism evidence-based recommendations for the management of Behçet disease. Ann Rheum Dis therapies in ocular BD. 2009;68:1528–34. 21 Alpsoy E, Durusoy C, Yilmaz E, et al. Interferon alfa-2a in the treatment of Behçet disease: a randomized placebo-controlled and double-blind study. Arch Dermatol Collaborators Nicholas Beare; Rachel Gorodkin. 2002;138:467–71. Contributors Conception or design of the work—PU and RG. Data collection—PU. 22 Tugal-Tutkun I, Kadayifcilar S, Khairallah M, et al. Safety and efficacy of Gevokizumab Data analysis and interpretation—PU. Drafting the article—PU. Critical revision of the in patients with Behçet's disease uveitis: results of an exploratory phase 2 study. Ocul article—NB. Final approval of the version to be published—PU, RG and NB. Immunol Inflamm 2017;25:62–70.

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