Long-Term Efficacy of Infliximab for Treatment of Severe Behçet ’ s Uveitis

C l i n M e d International Library Citation: Interlandi E, Leccese P, Olivieri I, Latanza L (2015) Long-Term Efficacy of Infliximab for Treatment of Severe Behçet’s Uveitis. Int J Ophthalmol Clin Res 2:014 Received: October 10, 2014: Accepted: February 23, 2015: Published: February 26, 2015 Copyright: © 2015 Interlandi E. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Interlandi et al. Int J Ophthalmol Clin Res 2015, 2:1 ISSN: 2378-346X


Introduction
Behçet's disease (BD) is a multisystem inflammatory disorder of unknown aetiology and relapsing course characterised by recurrent oral and genital ulcers, skin and eye lesions [1,2].Ocular involvement mainly consists in non-granulomatous uveitis that may interest anterior segment, posterior segment or both (panuveitis).Severe forms of Behcet's uveitis may produce serious visual impairment with potential blindness of affected patients.Main goals of Behçet's uveitis management are prompt resolution of intraocular inflammation, all patients before infliximab administration and every three months during infliximab therapy to evaluate exposure to tuberculosis.In addition, full serological assessment testing both renal and hepatic function was performed at baseline and then every three months during infliximab administration.Effects of infliximab therapy on steroidal daily dose and BCVA were statistically analysed as ratio of the last record to baseline value and tested with T-tests of the ratios.Mean number of attacks observed during infliximab therapy was compared with mean number of attacks during pre-infliximab period calculated as a span of time, before infliximab administration, correspondent to follow-up time duration for each analysed case.BCVA is expressed as the logarithm of mean angle of resolution (log MAR).All values are reported as mean value with related standard deviation (SD).T-student test was adopted to calculate p-values in this study where p-value less than 0.05 were considered statistically significant.The analysis was done with the R-Development Core Team (2011).

Results
Main characteristics of patients are reported in table 1. Study population consisted in 32 patients (56 eyes) 21 male and 11 female (M: F ratio of 2:1).Mean age of patients at the onset of disease was 33.3 years (± 13.7 SD); an association to HLA-B51 resulted in 21 patients (65.6%).Mean follow-up was 33,2 months (± 21.3 SD; range 6-72).Recurrent oral aphtae were observed in all patients, skin lesions resulted the second most common sign recurring in 71,8 % of cases, while 10 patients (31.2 %) presented neuro-Behçet pattern of disease.
Ocular inflammation occurred in 56 eyes with bilateral involvement in 75 % of cases and mainly consisted in panuveitis (46.4 % of affected eyes), while posterior uveitis and anterior uveitis occurred respectively in 42.8 and 10.7% of affected eyes (Table 1 deterioration of general and/or ocular conditions, despite maximal tolerated immunosuppressive dose, or following systemic toxicity in response to them.CS consisted in oral prednisone at starting dose of 1 mg/kg/day gradually tapered during follow-up or intravenous metilprednisolone (1 g/day for three days) then followed by oral prednisone.Azathioprine (AZA) and cyclosporine-A (CSA) dosage was respectively 100-150 mg/day and 3-5 mg/kg/day.Colchicine (Colch) and methotrexate (MTX) dose, when given, was respectively 0.5-1.5 mg/day and 7.5-20 mg/kg/week.The intravenous infusions of infliximab (5 mg/kg) were administered at weeks 0,2,4,6, and every 6-8 weeks thereafter, depending on uveitis severity, until the beginning of the study.In no case adjustment or increasing of infliximab dose was adopted over full follow-up time.No relevant adverse reactions were recorded in the study population.Nevertheless patient's n. 15 and 16 developed a mild acute bronchitis during first year of therapy as possible even uncertain infliximab-related side effect; in these patients infliximab was promptly discontinued.Patient n. 15 was definitively switched to interferon-α while patient n.16 was then retreated with infliximab and finally switched to adalimumab for loss of efficacy.

Discussion
Ocular inflammation is one of the most serious clinical manifestations in course of BD.Despite an appropriate therapy many patients may suffer uveitis sight-threatening relapses with consequent irreversible visual loss.Experimental data suggest the possible role of TNFα in Behçet's uveitis pathogenesis demonstrating a higher concentration of this cytokine in aqueous humour and serum of affected patients or an increased number of cells producing TNFα during the active phases of disease [3][4].The documented efficacy of infliximab for treatment of many systemic inflammatory and autoimmune diseases induced experimental use of this drug for treatment of BD and severe Behçet's uveitis [5][6][7][8][9][10][11][12][13][14].
The present study retrospectively analyses long-term clinical course of a large cohort of patients affected by severe Behçet's uveitis treated with infliximab in addition to conventional immunosuppressive therapy.S. Al Rashidi et al. have recently reported favourable results of infliximab in 19 patients with Behcet's uveitis retrospectively analysed [14].In their study 47% of patients achieved complete remission associated to a BCVA ≥ 20/40 in 71% of  [13].
After 12-month follow-up the authors report improvement in ocular inflammation in 69% of cases associated to reduction of mean number of uveitis attacks from 2.66 at baseline to 0.79.Adverse reactions occurred in 56% of patients but none of them was evaluated as serious.Although steroid-sparing effect is not evaluated and despite a shorter follow-up time, their final outcomes are quite similar to ours.In 2008 K. F. Tabbara conduced an interesting retrospective study where efficacy of infliximab (Group 2 including 10 patients) is compared with conventional immunosuppressants (Group 1 including 33 patients) on overall 43 patients with Behçet's uveitis [12].
After two-year follow-up, mean overall attacks resulted 1.2 in Group 2 compared to 6.3 in Group 1 while BCVA resulted ≥ 20/50 in 50% of patients treated with infliximab respect to 6% of patients treated with conventional therapy.Also in this study safety of infliximab was good with mild infusion reactions observed in two patients.
Despite differences in study design, inclusion criteria and time of follow-up our results on infliximab efficacy are quite consistent with previously mentioned studies [12][13][14].
In our study infliximab therapy induced uveitis remission in 81.2% of treated patients associated to an improvement of BCVA, at least in one eye, in 14 patients (43.7%).A statistically significant decreasing of uveitis attacks (p<0.001) was moreover observed as well as a considerable steroid-sparing effect up to complete suspension of systemic CS in ten patients (31.2%).Improving of BCVA in the worse eye was moreover observed even though no statistically significant (p=0.2).This could be probably due to development, in many of our patient, of irreversible structural changes of retina like optic or macular atrophy as consequence of a long-lasting relapsing uveitis.BCVA improvement, indeed, appeared less evident in patients with longer uveitis duration.In our study uveitis duration, as well as panuveitis subtype, moreover influenced steroid-sparing effect of infliximab that was less significant in patients with longer uveitis duration and panuveitis.In six of our patients infliximab was suspended after loss of therapeutic effect.This phenomenon could be investigated in particular genetic configuration of patients so to influence duration of therapeutic response to infliximab.Moreover, even antibodies measurement was not performed in our patients, it could be hypothesized human anti-chimeric antibodies to be implicated in progressive decline of therapeutic effect of infliximab in these patients [18].Infliximab demonstrated to be quite well tolerated in our patients unless long-term administration equal or more than 12 months in 87.5% of cases and up to 60 months or more in 43.75% of them and only two patients developed a mild acute bronchitis during infliximab administration.Unlike of what described in literature [19,20] we didn't observe cases of tuberculosis and/or severe infective pneumonia and this might probably correlate with relative young age of our cohort.Thus far severe uveitis associated to Behçet's disease represents a serious sight-threatening condition whose prognosis depends on a prompt diagnosis and adequate treatment.In our patients infliximab therapy permitted a good control of ocular inflammation and relapses, stabilizing clinical course and improving visual prognosis of treated patients.
This study represents one the best-detailed research examining efficacy of infliximab in patients affected by long lasting, severe and various forms of uveitis in course of BD including moreover 10 patients with neuro-Behçet.Ocular findings of patients are accurately described and effectiveness of infliximab is assessed through a meticulous statistical elaboration of many primary and secondary parameters.
Nevertheless randomized, controlled trials including a larger number of patients for a longer follow-up are strongly desirable to better delineate safety and efficacy of infliximab for treatment of severe Behçet's uveitis.

Table 1 :
).All patients received infliximab in addition to DMARDs after case and included BCVA evaluation, full slit-lamp examination, tonometry and FAG and/or OCT.Any uveitis reactivation requiring therapy adjustment, independently from ocular specific localization and visual function, was considered as uveitis attack.Ocular clinical remission was defined by the absence of active uveitis assessed by full ophthalmic evaluation, FAG and OCT analysis, independently from visual outcome and therapy in course.QuantiFERON-TB test (Cellestis Inc Carneige, Victoria, and Australia) was performed in Main characteristics of patients at baseline
Table2resumes main outcomes of the study.Clinical remission was observed in 26 out 32 patients (81.25%).Mean number of uveitis attacks decreased from 2.56 during pre-infliximab period to 0.65 during infliximab therapy (p<0.001).During infliximab therapy uveitis attacks decreased in 81.2% of patients and almost 60% of them had no uveitis relapses while 12.5% had no variation between pre-infliximab and infliximab period.Systemic CS were gradually tapered in 17 patients (53%) and even suspended in 10 (31.2%) of them while mean daily dose decreased from 31.25 to 8.91 mg (p<0.001).Secondary endpoints of the study are listed in Table3.Mean BCVA of worse eye improved from 0.52 log MAR at baseline to 0.47 log MAR (p=0.2) during infliximab therapy.This parameter resulted stable in 48.2% of affected eyes (27 eyes) while improved and worsened respectively in 26.8% and 25% of the eyes.Therapy with DMARDs was discontinued in nine patients (28%) and tapered from two to one medication in three patients (9.4%).Six patients (case n. 1,6,13,16,29 and 31) were switched to adalimumab following loss of efficacy of infliximab while patient n. 17 was switched to interferon-α (3.000.000UI per 3/week) due to lack of effect after 6 months of infliximab therapy with consequent deterioration of ocular conditions.Patient n.10 discontinued infliximab, along with any other systemic therapy, as a consequence of sustained clinical remission.