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Home , Anakinra, Canakinumab, Daclizumab, Gevokizumab, Secukinumab, Tocilizumab

Review Anti- 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 ticosteroids, -alpha and con- Petros P. Sfikakis, MD other than TNF. The anti-IL-17 anti- ventional immunosuppressive drugs, Please address correspondence to: body and the anti-IL-2 such as , cyclosporine-A, Petros P. Sfikakis, MD, receptor were not cyclophosphamide and , 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 of anti-TNF monoclonal in GR-11527 Athens, Greece. and and the anti-IL-6 patients with BD who were refractory E-mail: [email protected] agent 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 secukinumab anti-TNFs. However, controlled studies and the IL-2 receptor binding antibody are surely needed. daclizumab were tested for BD-associ- ated ocular . 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, ,

S-149 REVIEW Anti-cytokine treatment in Behçet’s disease / A. Arida & P.P. Sfikakis tocilizumab and , 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- . 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 (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 (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 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. Relapse at discontinuation NSAIDS and re-remission after re-introduction

Cantarini, M, 39 None Mucocutaneous , fever Anakinra 150mg/d + Partial remission of mucocutaneous 18 months 2013 Prednisolone 25mg/day manifestations; femoral vein thrombosis at 6 months responding to Cyclosporine

F, 59 Sulfasalazine, Oral and genital ulcers, Anakinra 100mg/d + Remission. At 3 months bilateral 8 months Cyclosporine, unilateral panuveitis Prednisolone 12.5mg/day panuveitis responding to Adalimumab Prednisolone, and Prednisolone 25mg/day and Methotrexate

F, 29 Azathioprine, Residual disease activity despite Anakinra 100mg/d + Remission 12 months Prednisolone treatment (oral and genital ulcers, Azathoprine+Prednisolone arthralgia, bilateral panuveitis) 7.5/d

M, 47 Sulfasalazine, Oral and genital ulcers, Anakinra 100mg/d + Remission of ocular inflammation but 17 months Cyclosporine, panuveitis Prednisolone 25mg/d persistence of oral aphtosis. Panuveitis Azathioprine relapse at 8 months partially responded to Anakinra 150mg/d +Methotrexate+ Colchicine.

M, 21 Prednisolone Mucocutaneous, arthritis, fever Anakinra 100mg/d + Remission or arthritis but not of 8 months 10mg/day Prednisolone 10mg/day mucocutaneous manifestations

Vitale, M, 47 Corticosteroids, Mucocutaneous, recurrent deep Anakinra 100mg/d + Remission of panuveitis but not of 18 months 2013 Sulfasalazine, venous thrombosis, panuveitis, Prednisolone up to 25mg/d mucocutaneous lesions. Cyclosporine, arthritis, fever Discontinuation due to adverse event Azathioprine Canakinumab 150 mg/6 weeks Remission 6 months Anti-IL-6 Redondo- F, 51 Corticosteroids Nephrotic syndrome due to Tocilizumab 8mg/kg/month Decrease of proteinuria 12 months Pachon, low dose for secondary amyloidosis 2013 16 years Anti- Baerveldt, F, 39 Cyclosporine, Oral and genital ulcers, skin Ustekinumab 45ng at Remission 36 months IL-12/23 2013 Steroids lesions, concomitant guttate weeks 0, 4 and every 12 psoriasis and hidradenitis weeks thereafter suppurativa (given for psoriasis) exacerbation of the disease measured amelioration of visual acuity in most initially responded to anakinra but ex- by Behçet’s disease activity form, uvei- of them (Table I). The patient in whom perienced bilateral panuveitis while on tis, and folliculitis. resolution of ocular inflammation was therapy. That patient was subsequently There were no significant differences incomplete responded to peribulbar switched to adalimumab resulting in between secukinumab treatment groups and intravitreal triamcinolone. During complete remission of manifestations and placebo regarding the rate of recur- the 98-day study period one patient (14). Anakinra was discontinued due rent ocular exacerbations in the study remained relapse-free, whereas 5 pa- to urticaria in a patient presenting with eye, however there were smaller pro- tients required a second infusion due to panuveitis, recurrent deep vein throm- portions of patients with more than exacerbation, retinitis attack or cystoid bosis, mucocutaneous manifestations, 3 exacerbations in the secukinumab macular edema, resulting again in reso- arthritis and fever, after partial remis- treatment groups. Moreover, no differ- lution of ocular inflammation (18). sion. This patient was subsequently ence was noted regarding changes from We found 3 reports on a total of 7 switched to canakinumab at a dose baseline in best corrected visual acuity anti-TNF naïve patients who received of 150mg every 6 weeks, resulting in of the study eye during study course be- Anakinra (Table II). In one patient with complete remission within days (17). tween either of the secukinumab treat- bilateral panuveitis and neurological In the remaining patients Anakinra at ment groups versus placebo. Finally, involvement, partial remission was conventional doses, even along with there was significantly greater reduc- achieved with azathioprine and cor- high-dose corticosteroids, resulted in tion in mean post-baseline concomitant ticosteroids, and anakinra was added only partial disease remission or re- immunosuppressive medication score for optimal disease control, leading to lapse (Table II). in patients of both secukinumab treat- complete remission for 12 months (14). Another patient, whose mucocutane- ment groups compared to placebo (10). In an adolescent patient with BD and ous manifestations and iridocyclitis In a small pilot study a single intra- concomitant familial Mediterranean had responded to corticosteroid treat- venous infusion of the anti-IL1β- fever with secondary amyloidosis Ana- ment for 9 years, presented with sec- regulating antibody gevokizumab was kinra led to sustained clinical remis- ondary amyloidosis and started therapy tested in patients with posterior uveitis, sion and the patient remained free of with tocilizumab in combination with panuveitis and/or retinal vasculitis. Ge- fever attacks and mucosal or skin le- colchicine. After the 2nd infusion, there vokizumab resulted in rapid resolution sions (12). Another patient with unilat- was a marked and durable improve- of inflammation in 6 of 7 patients and eral panuveitis and bipolar aphthosis, ment of blood and urine examinations

S-151 REVIEW Anti-cytokine treatment in Behçet’s disease / A. Arida & P.P. Sfikakis

Table III. Results of treatment with biologic agents targeting IL-1 or IL-6 for active Behcet’s in 18 anti-TNF treatment experienced patients.

Gender, Previous Target clinical manifestations Biologic agent and Clinical outcome Follow-up Age treatment concomitant treatment period

Anti-IL1 Botsios F, 75 Cyclosporine intolerance, Oral and genital ulcers, Anakinra 100mg/d + Remission 20 months 2008 Azathioprine+ Prednisolone, arthralgias, fever Prednisolone 5mg/d Infliximab+Methotrexate

Ugurlu F, 16 Azathioprine+ Cyclospirine+ Bilateral panuveitis, retinal Anakinra 2mg/kg/d No response 1 month 2012 Prednisolone, Interferon, vasculitis Infliximab, Adalimumab Canakinumab Remission 2 months

Emmi F, 27 Azathioprine, Prednisolone, Mucocutaneous, arthralgia, Anakinra 100mg/d Remission and restoration 12 months 2013 Infliximab intolerance, abdominal symptoms, bilateral of visual acuity Adalimumab, panuveitis (visual acuity 20/50 and 20/32)

Cantarini M, 47 , Cyclosporine, Mucocutaneous, uveitis, Anakinra 150mg/d+ Partial remission unknown 2013 Azathioprine, Etanercept, retinal vasculitis Prednisolone 25mg/d Infliximab

F, 21 Sulfasalazine, Methotrexate, Mucocutaneous, arthritis, Anakinra 100mg/d +low Remission, deep vein 28 months Cyclosporine, Azathioprine, abdominal symptom, fever dose Prednisolone thrombosis after 16 months Etanercept / Infliximab intolerance

M, 7 + Mycophenolate Mucocutaneous, abdominal Anakinra 2.5 mg/kg/d + Partial remision 7 months Mofetil + Prednisolone, symptoms, arthralgias Prednisolone 15mg/d Adalimumab

F, 41 Corticosteroids, Methotrexate, Oral and genital ulcers, Anakinra 100mg/d No response 8 weeks Azathioprine, Etanercept, arthralgias, fever, abdominal Adalimumab symptoms Canakinumab 150mg/ 8 weeks Partial remission 2 weeks

Vitale F, 20 Prednisolone high dose, Mucocutaneous, arthritis, Anakinra 100mg/d Partial remission; discontinuation Few weeks 2013 Sulfasalazine, Methotrexate, abdominal symptoms, fever due to adverse event Cyclosporine, Azathioprine, Canakinumab 150mg/8 weeks Remission within days. At 16 22 months Leflunomide, Etanercept/ months deep vein thrombosis. Infliximab intolerance Remission with modification of Canakinumab dosage every 6 weeks

F, 41 Corticosteroids, Methotrexate, Oral and genital ulcers, fever, Anakinra 100mg/d No response 8 weeks Azathioprine, Etanercept, abdominal symptoms, Adalimumab arthralgia Canakinumab 150mg/6 weeks Remission 12 months

Caso, M, 36 Cyclosporine, Corticosteroids, Oral and genital ulcers, Anakinra 100mg/d + Remission 6 months 2013 NSAIDs, Infliximab sacroiliitis Prednisolone 5mg/d

Caso, F, 41 Prednisolone Azathioprine, Mucocutaneous, fever, uveitis, Anakinra 100mg/d Partial remission. Relapse. 20 days 20131 Cyclosporine+, Adalimumab arthralgias, pemphigus foliaceus Methotrexate, Cyclophosphamide, Infliximab

Sfikakis, F, 56 Prednisolone Azathioprine Posterior uveitis Anakinra 100mg/d No response 4 months unpublished 2 Methotrexate, Cyclosporine, Cyclophosphamide, Infliximab, Adalimumab

Anti-IL-6 Hirano F, 47 Corticosteroids, Cyclosporine, Mucocutaneous, posterior Tocilizumab 8mg/kg/4 weeks Remission, occasionally 12 months 2012 Ifmiximab uveitis oral ulcers

Shapiro M, 35 Methotrexate, Azathioprine, Aseptic menengo- Tocilizumab 8mg/kg/4 weeks Resolution of neurological 7 months 2012 Mycophenolate, Cyclosporine, (chronic Neuro-Behçet’s with symptoms, negative MRI but Interferon, Daclizumab, positve MRI) recurrence of oral ulcers Cyclophosphamide, Infliximab

Urbaniak M,46 Azathioprine, Corticosteroids, Neuro-Behçet’s (positive MRI) Tocilizumab 8mg/kg/4 weeks Remission, stable MRI, 8 months 2012 Infliximab relapse +Prednisolone 15mg/d+ discontinuation after 4th infusion Azathioprine 150mg/d because of scrotal abscess

Diamanto- F, 55 Methotrexate, Azathioprine, Mucocutaneous Tocilizumab 8mg/kg + Deterioration 1 month poulos, Etanercept, Infliximab Azathioprine 150mg 2013

F, 26 Cyclosporine, Azathioprine, Oral and genital ulcers Tocilizumab 8mg/kg/month Partial initial remission and 3 months Methotrexate, Infliximab, relapse of genital ulcers after Adalimumab 3rd infusion

S-152 Anti-cytokine treatment in Behçet’s disease / A. Arida & P.P. Sfikakis REVIEW

Table III. (continued)

Gender, Previous Target clinical manifestations Biologic agent and Clinical outcome Follow-up Age treatment concomitant treatment period

Caso, F, 41 Prednisolone, Azathioprine, Mucocutaneous, fever, uveitis, Tocilizumab 480mg/month + Remission 14 months 2013 1 Cyclosporine+ Adalimumab, arthralgias, pemphigus Prednisolone 25mg/d Methotrexate, foliaceus Cyclophosphamide, Infliximab, Anakinra

Cantarini F, 43 Prednisolone, Cyclosporine, Mucocutaneous, knee arthritis Tocilizumab 8mg/kg/dose + Deterioration of oral and 2014 Cyclophosphamide, Prednisolone genital ulcers and 2 weeks Methotrexate, Infliximab papulopustular eruption of both arms and chest. Response to + Methylprednisolone

Sfikakis, F, 56 Prednisolone Azathioprine Posterior uveitis Tocilizumab 8mg/kg/4 No response 3 months unpublished 2 Methotrexate, Cyclosporine, weeks Cyclophosphamide, Infliximab, Adalimumab, Anakinra

1Same patient; 2Same patient.

(23). Finally, in a BD patient with tolerance, 8 received initially Anakinra because of scrotal abscesses and ingui- ocular and intestinal involvement and and 6 received tocilizumab (Table III). nal condyloma accuminata after the 4th concomitant psoriasis the anti-IL12/23 Anakinra was given at a dose of 100 infusion in one patient, but no exacer- agent ustekinumab was initiated and mg/d, except for a patient to whom bation was observed for 8 months of resulted in complete remission of both dosage was adapted at 2mg/kg/d. Sus- follow-up (21). In another patient with psoriasis and BD skin manifestations tained disease remission for up to 28 mucocutaneous manifestations, poste- for 36 months without adjunctive im- months at this dosage was achieved in rior uveitis and impaired visual acuity munosuppressive treatment (26). 3of 8 patients (13-15); all had recur- tocilizumab lead to sustained remission rent oral and genital ulcerations and and vision improvement (19). In three Anti-TNF treatment experienced pseudofolliculitis, one had uveitis and patients with mucocutaneous manifes- patients anakinra therapy induced remission of tations, tocilizumab was ineffective We found reports on 17 patients with ocular inflammation and restoration of (22, 25). One of them, who had expe- primary (n=3) or secondary inefficacy visual acuity, and one presented with rienced secondary failure to Infliximab or intolerance to anti-TNF monoclo- sacroiliitis. The anakinra dose was in- given initially for bipolar apthosis and nal antibodies, who were subsequent- creased to 150mg/day in a patient with pseudofolliculatis, tocilizumab result- ly treated with anti-IL-1 or anti-IL-6 mucocutaneous and ocular involve- ed in deterioration of oral and genital agents (Table III). Anakinra was given ment, but only partial remission was ac- ulcers and development of generalised in 3 patients not responding Infliximab complished even in combination with papulopustular eruption (25). Finally, or Adalimumab and proved effective in high-dose prednisolone (14). Anakinra we also report our experience on a one with remission of all disease mani- was discontinued in 4 patients: in 3 due patient with posterior uveitis, who re- festations for 20 months of follow-up to inefficacy and in one due to diffuse lapsed despite initial response to both (11), induced partial remission of mu- pruritic urticarial lesions of increasing infliximab and adalimumab. Anakinra cocutaneous manifestations, with im- severity and was switched to canaki- and subsequently tocilizumab were provement of frequency and intensity numab. This human monoclonal anti- started, but both failed to induce remis- in the second (a 7-year-old boy) (14), body targeting -1 beta, was sion (Table III). and proved ineffective in the third found to be effective in all 4 patients, patient (24). In this latter patient, pre- but dose was modified to 150 mg every Discussion senting with ocular involvement and 6 rather than 8 weeks for long-term re- The number of biological agents, be- pemphigus foliaceus, subsequent ad- mission (17). yond anti-TNF, that target specific ministration of Tocilizumab achieved The anti-IL6 antibody tocilizumab was molecules and pathways of inflam- complete remission of clinical symp- given at the conventional dose of 8 mg/ mation constantly increases. Immune toms and normalisation of inflamma- kg/month in 6 patients. Two patients system abnormalities, with disturbed tory markers within days from admin- had neuro-Behçet’s disease and tocili- homeostasis and pro-inflamma- istration and for a follow-up period of zumab resulted in rapid amelioration of tory cytokine imbalance, are thought to 14 months (24). neurological symptoms (20, 21). Nota- be involved in BD pathogenesis (27). Of the 14 patients who initially re- bly, one of them had previously also Along this line significantly higher sponded to anti-TNF treatment but received daclizumab, with no response levels of IL-1β and IL-1 receptor an- experienced secondary failure or in- (20). Tocilizumab was discontinued tagonist have been found in the serum

S-153 REVIEW Anti-cytokine treatment in Behçet’s disease / A. Arida & P.P. Sfikakis of patients with active or inactive BD 10). One pilot study focused on the ther- Conclusion compared to control subjects (27, 28), apeutic effect of a single gevokizumab As is the case for all chronic inflamma- suggesting that IL-1 inhibitors, such infusion, administered as monotherapy tory conditions, cytokines other than as anakinra, canakinumab and gevoki- for BD uveitis and/or retinal vasculitis TNF may be involved in the pathogen- zumab could have a place in treatment. refractory to azathioprine and/or cyclo- esis of BD (27), thus, the respective bi- Also, tocilizumab inhibits IL-6 medi- sporine. The ocular result was positive ological agents could be beneficial for ated actions and IL-6 levels have been but the efficacy of this agent, which was these patients. Blockade of IL-17- and found increased in the cerebrospinal well tolerated, on other disease manifes- IL-2- mediated actions by secukinum- fluid of neuro-BD patients and perhaps tations was not studied (18). ab and daclizinumab, respectively, was correlate with long-term outcome and In the majority of case reports and not efficacious on BD ocular manifes- disease activity (27, 29). In addition small case-series anakinra was used tations in two placebo-controlled trials to the classical proinflammatory -cy for refractory or naive disease, but with (9, 10). In case reports and small case tokines, IL-1 and IL-6, IL-12 and IL-23 concomitant high-dose corticosteroids series, although a potential for bias play important roles in the inflamma- in most patients (14, 17). Its effect to report positive effects and underre- tory response by stimulating the pro- seemed better on ocular involvement port the negative cases may exist, the duction of IFN-γ and the differentia- and systematic manifestations; its effi- therapeutic blockade of IL-1 by con- tion of T cells to Th17 cells, which in cacy on mucocutaneous manifestations ventional doses of anakinra seemed turn stimulate the production of other was limited on a number of patients, partially effective. Similarly, canaki- pro-inflammatory molecules. IL-12 has whereas in many patients a relapse of numab may have beneficial results on been shown to be upregulated in BD ocular involvement often occurred (14, various disease manifestations, espe- and to prevent expression of the CD95 24). In cases of residual or relapsing cially when dosage interval is limited death receptor (27). Ustekinumab is di- disease, anakinra dosage was increased to 6 weeks (14, 16, 17). The newer rected against and inter- to 150mg/kg, but usually this only re- anti-IL-1b agent gevokizumab could leukin 23 and has been proved effective sulted in partial remission of symptoms be a promising drug for ocular inflam- in psoriasis and (30). even after addition of an immunosup- mation, based on the positive outcome Moreover, high levels of IL-17 have pressive drug. There was a report of an of 7 anti-TNF naïve patients included been found in the peripheral blood of anti-TNF naïve patient who received in a pilot study (18). Finally, in 2 anti- BD patients with active uveitis (31), Anakinra for ocular and mucocutane- TNF treatment experienced patients and secukinumab is a monoclonal anti- ous involvement and had to be switched with CNS involvement, IL-6 blockade body against IL-17 currently in clinical to a TNF inhibitor in order to achieve by tocilizumab was beneficial (20, 21). trials for plaque psoriasis (32). Finally, remission (14). Some patients received Collectively, it seems that IL-1 and since there is evidence suggesting that canakinumab after failure of anakinra IL-6 are legitimate targets in severe BD activated T cells which express IL-2 re- (14, 16, 17), resulting in long-term re- despite the limited experience. In our ceptor are involved in BD pathogenesis mission. Canakinumab dosage interval opinion, anti-IL-1 and anti-IL-6 agents (33), daclizumab, an anti-IL-2 recep- in BD was either initially or subse- can be tried in patients refractory or tor agent used in transplantation (34) quently – in cases of relapsing disease intolerant to combination regimens and studied for (35), – reduced from 8 to 6 weeks in order to which include an anti-TNF antibody, could be a candidate drug for BD. achieve better disease control. but controlled and comparative stud- Herein, we have reviewed the so far Tocilizumab seems also promising for ies are badly needed, particularly in a accumulated published experience of BD based on a limited experience de- relapsing condition like BD which has the use of biological agents which tar- riving from case reports (20, 21). Toci- a natural course of exacerbations and get cytokines beyond TNF in BD. In- lizumab was used in the same dose as remissions on its own. terferon therapy, also considered as and induced rapid biologic therapy, has been recently dis- long-lasting remission in both patients Acknowledgments cussed in detail elsewhere (36) and was with neuro-BD, but it had to be discon- We thank very much Professor Hasan not within our review’s scope. Three tinued in the one due to infections (21). Yazici for his critical review of the randomized placebo-controlled trials Tocilizumab’s effects on other disease manuscript. of anti-cytokine treatment for BD, one manifestations, particularly mucocu- testing the anti-TNF agent etanercept taneous and ocular involvement, are References (37), have been completed. The 2 other controversial. Overall, apart from a pa- 1. INTERNATIONAL STUDY GROUP FOR BEH- studies focused on the efficacy and safe- tient who developed severe diffuse pru- ÇET’S DISEASE: Criteria for diagnosis of Be- hçet’s disease. Lancet 1990; 335: 1078-80. ty of daclizumab and secukinumab for ritic urticarial lesions while on anakinra 2. HATEMI G, YAZICI Y, YAZICI H: Behçet’s syn- BD-associated ocular inflammation in (17) and one patient in whom a scro- drome. Rheum Dis Clin North Am 2013; 39: anti-TNF naïve patients. Although both tal abscess requiring surgical drainage 245-61. safe, neither agent proved to be superior occurred during treatment with Tocili- 3. KURAL-SEYAHI E, FRESKO I, SEYAHI N et al.: The long-term mortality and morbidity of Be- to placebo in reducing the rate of ocular zumab (21), no new safety signals were hçet syndrome: a 2-decade outcome survey of attacks or improving visual acuity (9, reported. 387 patients followed at a dedicated center.

S-154 Anti-cytokine treatment in Behçet’s disease / A. Arida & P.P. Sfikakis REVIEW

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EULAR Expert Committee. EULAR recom- 1589-91. 28. DÜZGÜN N, AYAŞLIOĞLU E, TUTKAK H, mendations for the management of Behçet 17. VITALE A, RIGANTE D, CASO F et al.: AYDINTUĞ OT: Cytokine inhibitors: soluble disease. Ann Rheum Dis 2008; 67: 1656-62. Inhibition of interleukin-1 by canakinumab tumor necrosis factor receptor 1 and interleu- 6. SFIKAKIS PP, MARKOMICHELAKIS N, ALP- as a successful mono-drug strategy for the kin-1 receptor antagonist in Behçet’s disease. SOY E et al.: Anti-TNF therapy in the man- treatment of refractory Behçet’s disease: a Rheumatol Int 2005; 25: 1-5. agement of Behçet’s disease--review and case series. Dermatology 2014; 228: 211-4. 29. AKMAN-DEMIR G, TÜZÜN E, IÇÖZ S et al.: basis for recommendations. Rheumatology 18. GÜL A, TUGAL-TUTKUN I, DINARELLO CA Interleukin-6 in neuro-Behçet’s disease: as- (Oxford) 2007; 46: 736-41. et al.: Interleukin-1β-regulating antibody sociation with disease subsets and long-term 7. ARIDA A, FRAGIADAKI K, GIAVRI E, SFI- XOMA 052 (gevokizumab) in the treatment outcome. Cytokine. 2008; 44: 373-6. KAKIS PP: Anti-TNF agents for Behçet’s of acute exacerbations of resistant uveitis of 30. McINNES IB, KAVANAUGH A, GOTTLIEB AB disease: analysis of published data on 369 Behçet’s disease: an open-label pilot study. et al.; PSUMMIT 1 Study Group: Efficacy patients. Semin Arthritis Rheum 2011; 41: Ann Rheum Dis 2012; 71: 563-6. and safety of ustekinumab in patients with 61-70. 19. HIRANO T, OHGURO N, HOHKI S et al.: A case active psoriatic arthritis: 1 year results of the 8. OZGULER Y, HATEMI G, YAZICI H: Man- of Behçet’s disease treated with a humanized phase 3, multicentre, double-blind, placebo- agement of Behçet’s syndrome. Curr Opin anti-interleukin-6 receptor antibody, tocili- controlled PSUMMIT 1 trial. Lancet 2013; Rheumatol 2014; 26: 285-91. zumab. Mod Rheumatol 2012; 22: 298-302. 382: 780-9. 9. BUGGAGE RR, LEVY-CLARKE G, SEN HN 20. SHAPIRO LS, FARRELL J, BORHANI HAG- 31. CHI W, ZHU X, YANG P et al.: Upregulated et al.: A double-masked, randomized study HIGHI A: Tocilizumab treatment for neuro- IL-23 and IL-17 in Behçet patients with ac- to investigate the safety and efficacy of da- Behçet’s disease, the first report. Clin Neurol tive uveitis. Invest Ophthalmol Vis Sci 2008; clizumab to treat the ocular complications Neurosurg 2012; 114: 297-8. 49: 3058-64. related to Behçet’s disease. Ocul Immunol 21. URBANIAK P, HASLER P, KRETZSCHMAR 32. NWE SM, CHAMPLAIN AH, GORDON KB: Inflamm 2007; 15: 63-70. S: Refractory neuro-Behçet treated by toci- Rationale and early clinical data on IL-17 10. DICK AD, TUGAL-TUTKUN I, FOSTER S et lizumab: a case report. Clin Exp Rheumatol blockade in psoriasis. Expert Rev Clin Immu- al.: Secukinumab in the treatment of nonin- 2012; 30 (Suppl. 72): S73-5. nol 2013; 9: 677-82. fectious uveitis: results of three randomized, 22. DIAMANTOPOULOS AP, HATEMI G: Lack 33. LI B, YANG P, ZHOU H et al.: T-bet expression controlled clinical trials. Ophthalmology of efficacy of tocilizumab in mucocutane- is upregulated in active Behçet’s disease. 2013; 120: 777-87. ous Behçet’s syndrome: report of two cases. Br J Ophthalmol 2003; 87: 1264-7. 11. BOTSIOS C, SFRISO P, FURLAN A, PUNZI L, Rheumatology (Oxford) 2013; 52: 1923-4. 34. HAO WJ, ZONG HT, CUI YS, ZHANG Y: DINARELLO CA: Resistant Behçet disease re- 23. REDONDO-PACHÓN MD, ENRÍQUEZ R, SIR- The efficacy and safety of and sponsive to anakinra. Ann Intern Med 2008; VENT AE et al.: Tocilizumab treatment for daclizumab versus antithymocyte globulin 149: 284-6. nephrotic syndrome due to amyloidosis in during organ transplantation: a meta-analy- 12. BILGINER Y, AYAZ NA, OZEN S: Anti-IL-1 Behçet’s disease. Ren Fail 2013; 35: 547-50. sis. Transplant Proc 2012; 44: 2955-60. treatment for secondary amyloidosis in an 24. CASO F, IACCARINO L, BETTIO S et al.: 35. PFENDER N, MARTIN R: Daclizumab (anti- adolescent with FMF and Behçet’s disease. Refractory pemphigus foliaceus and Be- CD25) in multiple sclerosis. Exp Neurol Clin Rheumatol 2010; 29: 209-10. hçet’s disease successfully treated with toci- 2014 Apr 24 [Epub ahead of print]. 13. EMMI G, SILVESTRI E, CAMELI AM et al.: lizumab. Immunol Res 2013; 56: 390-7. 36. KÖTTER I, HAMURYUDAN V, OZTÜRK ZE, Anakinra for resistant Behçet uveitis: why 25. CANTARINI L, LOPALCO G, VITALE A et al.: YAZICI H: Interferon therapy in rheumatic not? Clin Exp Rheumatol 2013; 31 (Suppl. Paradoxical mucocutaneous flare in a case of diseases: state-of-the-art 2010. Curr Opin 77): S152-3. Behçet’s disease treated with tocilizumab. Rheumatol 2010; 22: 278-83. 14. CANTARINI L, VITALE A, SCALINI P et al.: Clin Rheumatol 2014 Apr 15. [Epub ahead of 37. MELIKOGLU M, FRESKO I, MAT C et al.: Anakinra treatment in drug-resistant Be- print] Short-term trial of etanercept in Behçet’s hçet’s disease: a case series. 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