Review Anti-cytokine biologic treatment beyond anti-TNF in Behçet’s disease A. Arida, P.P. Sfikakis First Department of Propedeutic Internal ABSTRACT and thrombotic complications (1-3). Medicine Laikon Hospital, Athens, Unmet therapeutic needs in Behçet’s Treatment varies according to type and University Medical School, Greece. disease have drawn recent attention to severity of disease manifestations. Cor- Aikaterini Arida, MD biological agents targeting cytokines ticosteroids, interferon-alpha and con- Petros P. Sfikakis, MD other than TNF. The anti-IL-17 anti- ventional immunosuppressive drugs, Please address correspondence to: body secukinumab and the anti-IL-2 such as azathioprine, cyclosporine-A, Petros P. Sfikakis, MD, receptor antibody daclizumab were not cyclophosphamide and methotrexate, First Department of Propedeutic superior to placebo for ocular Behçet’s and Internal Medicine, are used either alone or in combination Laikon Hospital, in randomised controlled trials, com- for vital organ involvement. During the Athens University Medical School, prising 118 and 17 patients, respec- last decade there has been increased use Ag Thoma, 17, tively. The anti-IL-1 agents anakinra of anti-TNF monoclonal antibodies in GR-11527 Athens, Greece. and canakinumab and the anti-IL-6 patients with BD who were refractory E-mail: [email protected] agent tocilizumab were given to iso- to conventional treatment or developed Received on June 7, 2014; accepted in lated refractory disease patients, who life-threatening complications (4, 5). revised form on September 17, 2014. were either anti-TNF naïve (n=9) or Anti-TNF treatment has been shown to Clin Exp Rheumatol 2014; 32 (Suppl. 84): experienced (n=18). No new safety be beneficial for the majority of these S149-S155. signals were reported. Although a po- patients (6, 7) but since unmet needs © Copyright CLINICAL AND tential for bias to report positive effects still exist reports on patients who have EXPERIMENTAL RHEUMATOLOGY 2014. and underreport negative cases may been treated with biologic agents tar- exist, Anakinra was partially effective, geting other cytokines are increasingly Key words: Behçet’s disease, whereas disease remission was noted appearing in the literature (8). biological treatment, anti-TNF agents, after canakinumab in some anti-TNF Herein, we critically discuss the po- cytokines, IL-1, IL-6, IL-17, IL-2 resistant patients. Tocilizumab ap- tential usefulness of the IL-1 receptor peared effective for neuro-Behçet’s, but antagonist anakinra, the anti-IL-1β an- not for mucocutaneous manifestations. tibodies canakinumab and gevokizum- Finally, in a pilot study of 7 patients ab and the anti-IL-6 receptor antibody with relapsing posterior uveitis re- Tocilizumab, which were given in the fractory to azathioprine and/or cyclo- first 33 patients with BD refractory to sporine, the anti-IL-1β antibody Ge- currently available treatment regimens. vokizumab was beneficial. Collectively, We also summarise the negative results it seems that IL-1 and IL-6 are prom- of the 2 randomised placebo-controlled ising targets in patients refractory or trials performed so far, in which the IL- intolerant to other regimens including 17 monoclonal antibody secukinumab anti-TNFs. However, controlled studies and the IL-2 receptor binding antibody are surely needed. daclizumab were tested for BD-associ- ated ocular inflammation. Introduction Behçet’s disease (BD) is a chronic im- Materials and methods mune-mediated systemic vasculitis with We searched the Medline/Pubmed da- severe morbidity and increased mortal- tabase for primary articles published ity. Although clinical manifestations of trough April 2014 reporting on the the disease may have great individual therapeutic use of biological agents variability, BD is characterised by re- targeting cytokines other than TNF in current oral and genital ulcers, pustular BD. Search terms included: Behçet’s skin lesions, arthritis, posterior uveitis in combination with cytokine, inter- attacks which lead to significant visual leukin, IL-1, IL-6, IL-17, IL-12/23, impairment or visual loss, neurologi- IL-2 biologics, monoclonal antibody, Competing interests: none declared. cal and gastrointestinal manifestations anakinra, canakinumab, gevokizumab, S-149 REVIEW Anti-cytokine treatment in Behçet’s disease / A. Arida & P.P. Sfikakis tocilizumab and ustekinumab, secuki- 5 of whom were subsequently treated endpoints in the secukinumab study numab, daclizumab. We included case also with canakinumab. Of the remain- were reduction of uveitis recurrence or reports, case series and research stud- ing 10 anti-TNF experienced patients, vitreous haze score during withdrawal ies, whereas systematic reviews, meta- 5 had been previously treated with In- of concomitant immunosuppressive analyses, comments and duplicate stud- fliximab (11, 14, 15, 17), 3 with adali- medication. Daclizumab was not found ies were excluded. Abstracts presented mumab (14, 17) and 2 with both these to be beneficial in comparison with in conferences were not considered. anti-TNF agents (13, 16). placebo for ocular complications of The use of IL-6 inhibitor tocilizumab BD in a total of 17 patients (9). From Results was described in 7 reports including 8 9 patients assigned to receive the study Two randomised double-blind placebo- patients (19-25), of whom only one was drug, none experienced a safety end- controlled trials were found, as well anti-TNF therapy naive (23), 4 had been point, but 2 discontinued prior to the as one open-label research pilot study treated with infliximab (19-22, 25), end of the study due to personal rea- (Table I) and 15 primary case reports or one had previously received both Inf- sons. Visual acuity remained stable in case-series (Tables II and III). The first liximab and adalimumab (22) and one all participants. Six daclizumab-treated randomised study, involving a total of – apart from anti-TNF antibodies – had patients experienced ocular attacks dur- 17 patients, focused on the efficacy and also been treated with anakinra (24). ing the study period requiring therapy, safety of daclizumab for ocular mani- We found only one report on the use of versus 4 receiving placebo, and the me- festations of BD (9). The second study ustekinumab (anti-IL12/23 antibody) in dian ocular attack rate was greater in the included 118 BD patients assigned to one psoriasis patient with concomitant daclizumab treatment group compared 3 treatment arms and aimed to explore BD who had not previously received to placebo. Moreover, there was greater the therapeutic effect and safety of any biological treatment (26). reduction of concomitant immunosup- secukinumab for posterior uveitis and pressants in patients receiving placebo panuveitis (10). Anti-TNF treatment naïve patients than daclizumab. There were 8 reports on the use of Both randomised controlled studies In the secukinumab trial 39 patients anti-IL-1 agents; 12 patients were involved patients with relapsing ocu- received 300mg/2 weeks, 40 received treated with anakinra (11-15), 5 were lar inflammation despite conventional 300mg/4 weeks and 39 patients re- treated with canakinumab after having treatment. Primary efficacy outcomes ceived placebo; there were more dis- received anakinra (14, 16, 17), and 7 in the daclizumab study were the num- continuations due to adverse events in patients described in the pilot study, ber of ocular attacks and an assessment the secukinumab treatment groups com- were treated with gevokizumab (18). of systemic immunosuppressive medi- pared to placebo group. Overall, 9% of All patients included in the pilot study cations required during the study, in- patients discontinued secukinumab be- were anti-TNF treatment naïve, as cluding the ability to taper concomitant cause of serious adverse events and the were 7 patients treated with anakinra, immunosuppressive therapy. Primary 3 most frequently reported events were Table I. Therapeutic results of a single infusion of the anti-IL1beta monoclonal antibody gevokizumab given for a unilateral relapse of posterior uveitis despite treatment with azathioprine and/or cyclosporine in 7 patients with Behçet’s disease, 4 of whom received a second injection (18). Gender, Previous treatment Concomitant Clinical outcome and maximum visual acuity (VA) change Outcome on follow-up to day 95 Age suspended at day 0 prednisolone after a single gevokizumab intravenous infusion (0.3mg/kg) dose (mg/d) M, 25 Azathioprine, 10 Almost complete resolution of hypopyon at day 1, Exacerbation at day 56 requiring Cyclosporine VA improvement at day 21 (20/20 from 20/63) a second infusion and response M, 37 Cyclosporine 7.5 Resolution of intraocular inflammation, VA stable (20/20) Exacerbation at day 56 requiring a second infusion and response F, 33 Azathioprine, 10 VA improvement at day 56 (20/100 from counting fingers 2m) Sustained response. Cyclosporine M, 37 Azathioprine, 5 Resolution of inflammation, VA improvement at day 4 Retinitis attack at day 25 requiring Cyclosporine (20/25 from 20/63) increased doses of prednisolone. M, 26 Azathioprine 5 Resolution of intraocular inflammation within 1 week. Cystoid macular edema at day 28 VA improvement at day 14 (20/25 from counting fingers 0.2m) requiring a second infusion and response M, 29 Azathioprine 20 Resolution of intraocular inflammation, VA improvement Exacerbation on day 49 requiring a at day 28 (20/20 from 20/32) second infusion and response. Another exacerbation at day 96 treated with corticosteroids M, 25 Azathioprine, 10 Incomplete resolution of cystoid macular edema, Beribulbar and intravitreal Cyclosporine VA stable at day 7 (20/100) triamcinolone at days 7 and 22. S-150 Anti-cytokine treatment in Behçet’s disease / A. Arida & P.P. Sfikakis REVIEW Table II. Results of treatment with biologic agents targeting IL-1, IL-6, or IL-12/23 for active Behçet’s in 9 anti-TNF treatment naïve patients. Gender, Previous Target clinical manifestations Biologic agent and Clinical outcome Follow up Age treatment concomitant treatment period Anti-IL1 Bilginer, F,17 Methotrexate, Mucocutaneous, arthritis, Anakinra 1mg/kg/d Remission for 6 months under 1 year 2010 Corticosteroids, secondary amyloidosis treatment.