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  INFLIXIMAB THERAPY IN PATIENTSWITH NONINFECTIOUS INTERMEDIATEUVEITIS RESISTANT TO CONVENTIONALIMMUNOMODULATORY THERAPY  ARASH MALEKI, MD,* †  HAITHAM F. SAHAWNEH, MD,* †  LINA MA, MD,* †  HALEA MEESE, MS,* † YUCHEN HE, MA, ‡  C. STEPHEN FOSTER, MD, FACR, FACS* † § Purpose:  To examine the ef  󿬁 cacy and safety of in 󿬂 iximab therapy in the treatment for noninfectious intermediate uveitis resistant to conventional immunomodulatory therapy. Methods:  Forty-four eyes of 23 patients with resistant noninfectious intermediate uveitiswho were treated with in 󿬂 iximab infusions for a minimum period of 3 months were included.Demographic data, clinical data, and  󿬂 uorescein angiography and optical coherencetomography  󿬁 ndings were collected from the Massachusetts Eye Research and SurgeryInstitution database between August 2005 and February 2014. Clinical response, improve-ment in ancillary test  󿬁 ndings, and major side effects were evaluated. Results:  Nineteen patients (82.6%) achieved remission. The mean duration of treatmentto induce remission was 3.99 ± 3.06 months (range, 2 – 14.7). Cystoid macular edema wasthe only complication observed during the course of the treatment in 1 eye (2.27%). Onepatient (4.3%) developed major side effects. None of the patients developed central or peripheral demyelinating neuropathies or multiple sclerosis. At 6 months after remission,logarithm of the minimum angle of resolution visual acuity (  P   = 0.006) and central macular thickness (  P   = 0.03) showed signi 󿬁 cant improvement in patients who achieved remission. Conclusion:  A signi 󿬁 cant number of patients achieved remission on in 󿬂 iximab therapy.The incidence of major side effects in our cohort was low. RETINA  37:836 – 843, 2017 I ntermediate uveitis is a chronic form of intraocular in 󿬂 ammation with indolent course that affects thevitreous, pars plana, and peripheral retina. 1 It can beidiopathic or associated with a variety of infectious andnoninfectious systemic diseases. Intermediate uveitis ac-counts for 1.4% to 25% of all cases of uveitis. 2 – 5 All agegroups are affected; however, it is most common in the 󿬁 rst three decades of life. 3 – 6 Moreover, it is the secondmost common form of uveitis in childhood. 7 Althoughintermediate uveitis usually has a benign course, com-plications can happen because of the chronicity of thedisease, which can lead to blindness if left untreated.Peripheral retinal vasculitis and cystoid macular edema (CME) are frequently associated with intermediate uve-itis. 8,9 Cystoid macular edema, with an incidence of 12% to 51%, can cause visual acuity and visual  󿬁 eldimpairment. 8,9 Cataract, glaucoma, vitreous hemorrhage,choroidal neovascularization, retinal detachment, andband keratopathy are other complications of intermedi-ate uveitis. 10 – 12 Treatment for intermediate uveitis depends on theetiology of the disease and associated complications.Medical and surgical management are used in the From the *Massachusetts Eye Research and Surgery Institution(MERSI), Waltham, Massachusetts;  † Ocular Immunology and UveitisFoundation (OIUF), Weston, Massachusetts;  ‡ Columbia University,Department of Statistics, New York, New York; and §Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.C. S. Foster declares the following: consultancies with Aldeyra Ther-apeutics (Lexington, MA), Bausch & Lomb Surgical, Inc (RanchoCucamonga, CA), Eyegate Pharma (Waltham, MA), Novartis (Cam-bridge, MA), pSivida (Watertown, MA), and Xoma (Berkeley, CA);grants or grants pending with Alcon (Aliso Viejo, CA), Aldeyra Ther-apeutics(Lexington,MA),Bausch& Lomb(Bridgewater,NJ),ClearsideBiomedical (Alpharetta, GA), Dompé Pharmaceutical (Milan, Italy),EyegatePharma(Waltham,MA),MallinckrodtPharmaceuticals(Dublin,Ireland), Novartis Pharmaceuticals (Cambridge, MA), pSivida (Water-town, MA), and Santen (Osaka, Japan); payment for lectures includingservice on speaking bureaus: Alcon (Aliso Viejo, CA) and Allergan(Dublin, Ireland); and stock or stock options: Eyegate Pharma (Waltham,MA). The remaining authors have no con 󿬂 icting interests to disclose.Reprint requests: C. Stephen Foster, MD, FACR, FACS,Massachusetts Eye Research and Surgery Institution, 1440 MainStreet, Suite 201, Waltham, MA 02451; e-mail: sfoster@mersi.com  836  treatment of cases with noninfectious intermediateuveitis. Medical management has been changed withthe development of various conventional immunomod-ulatory agents and biologic response modi 󿬁 ers. In all,10% to 25% of patients need immunomodulatorytherapy because of the side effects caused by cortico-steroids. 13 – 15 Conventional immunomodulatory therapyand adalimumab have been studied in the treatment for noninfectious intermediate uveitis. 16,17 There are lim-ited studies with fewer patients that have used in 󿬂 ixi-mab in the treatment for noninfectious intermediateuveitis. 18,19 The aim of this study is to evaluate the ef  󿬁 cacy andsafety of in 󿬂 iximab therapy, speci 󿬁 cally in the treat-ment for noninfectious intermediate uveitis resistant toconventional immunomodulatory therapy. Methods This was a single-center, retrospective interven-tional case series. We reviewed the electronicmedical records of patients who were diagnosedwith noninfectious intermediate uveitis and treatedwith in 󿬂 iximab infusions at the Massachusetts EyeResearch and Surgery Institution from August 2005to February 2014. Approval for this study wasobtained through the New England InstitutionalReview Board, which issued a waiver of informedconsent based on standard operating procedures for retrospective chart reviews. This study was per-formed in accordance with the Declaration of Helsinki and was compliant with the Health Insur-ance Portability and Accountability Act.We included all patients with the clinical diagnosisof active idiopathic noninfectious intermediate uveitis(pars planitis and non – pars planitis) 1 who failed at least 1 conventional immunomodulatory treatment regimen and were treated with in 󿬂 iximab infusionsfor a minimum period of 3 months. Indications for treatment included visual acuity worse than 20/40,CME, retinal vasculitis, and signi 󿬁 cant   󿬂 oaters. 20 Intermediate uveitis was de 󿬁 ned as in 󿬂 ammation of peripheral retina, vitreous, and pars plana according tothe Standardization of Uveitis Nomenclature WorkingGroup de 󿬁 nition. 1 Patients presented with vitreousin 󿬂 ammation (anterior vitreous cell, vitreous haze,and/or snow balls) with or without snow bank andin 󿬂 ammation spillover in adjacent areas. At the initialvisit, all patients had extensive workup to rule out infectious causes of intermediate uveitis. Fluoresceinangiography (FA) and optical coherence tomography(OCT) were performed to investigate possible retinalvasculitis, macular leakage, optic nerve in 󿬂 ammation,and CME and to measure central macular thickness.All patients with infectious intermediate uveitis andnoninfectious systemic diseases such as sarcoidosis,retinochoroiditis, or ocular or systemic malignancywere excluded. Patients with intravitreal  󿬂 uocinoloneacetonide implant (Retisert) were also excluded.Demographic information including age, gender, andrace were collected for each patient. Human leukocyteantigen D (HLA-D) subtypes were recorded when it was available. Primary symptoms, best-corrected visualacuity with logarithm of the minimum angle of resolution (LogMAR); ocular manifestations; FA  󿬁 nd-ings; OCT  󿬁 ndings; previous immunomodulatory ther-apy regimens tried and the duration of therapy; startingdate, stopping date if it was stopped, and the dose of in 󿬂 iximab infusions; type and number of relapses andtheir treatments; ocular complications during in 󿬂 iximabtherapy; and major side effects of in 󿬂 iximab therapywere recorded.Before starting in 󿬂 iximab therapy, all patients weretested for tuberculosis via QuantiFERON-TB Gold,and it was repeated yearly while the patient wasreceiving in 󿬂 iximab infusions. Antinuclear antibodywas also checked before starting treatment, and it wasretested every 6 months. In 󿬂 iximab was started at a dose of 5 mg/kg. There were 2 induction doses2 weeks apart and monthly thereafter for 6 months.Based on the clinical response and ancillary test  󿬁 ndings such as FA and OCT  󿬁 ndings, the dose wasadjusted to a maximum of 10 mg/kg. After 6 months,the interval between doses was lengthened by 1 week after every 4 infusions, and it was stopped when thepatient reached 4 doses at an interval of 12 weeks.Before deeming the treatment to have failed ina patient, with each relapse the decision was madeto shorten the interval and/or boost the dose of in 󿬂 iximab infusions (Figure 1). Antitumor necrosisfactor alpha inhibitor antibody was tested when therewas a relapse on the maximum dose of in 󿬂 iximab(10 mg/kg) or a high clinical suspicion of formingantitumor necrosis factor alpha inhibitor antibody.Remission was de 󿬁 ned as complete resolution of allpositive  󿬁 ndings such as anterior chamber and anterior vitreous cells (Grade 0); vitreous haze, snow balls, andsnow bank; active vasculitis; and optic nerve involve-ment on FA with no steroid therapy. In bilateral cases,resolution of all positive  󿬁 ndings in both eyes wasnecessary to be considered as remission state. Durableremission was de 󿬁 ned as remission during the entireperiod of tapering. Relapse was de 󿬁 ned as recurrenceof anterior chamber and vitreous cells (Grade 1 or higher); newly formed vitreous haze, snow balls, andsnow bank; active vasculitis; and optic nerve involve-ment after a period of being in remission. Failure wasde 󿬁 ned as the presence of active in 󿬂 ammation based INFLIXIMAB IN INTERMEDIATE UVEITIS   MALEKI ET AL  837  on clinical judgment and FA  󿬁 ndings for at least 2 months on maximum tolerable dose of in 󿬂 iximabinfusions or 3 months on maximum tolerable dose of conventional immunomodulatory regimens.Ef  󿬁 cacy was evaluated by the rate of remissioninduced by in 󿬂 iximab therapy. Safety was evaluatedby the occurrence of major side effects of in 󿬂 iximabinfusions. Major side effects were de 󿬁 ned as sideeffects requiring immature termination of in 󿬂 iximabinfusions. High-risk blood monitoring and review of systems were performed at each visit so that major sideeffects could be detected. Statistical Analysis Descriptive analysis was done using SPSS 16.0(SPSS Inc, Chicago, IL). SPSS 16.0 (SPSS Inc) andMedCalc software 8.2.0.3 (MedCalc, Mariakerke,Belgium) were used for statistical analysis. Categoricvariables were described as counts and percentages,and continuous variables were described as means andstandard deviations. Fisher  ’ s exact test was used tocalculate the correlation between categoric variablesand rate of remission. Logistic regression analysiswas used to describe correlation between continuousvariables with the rate of remission. We used paired t  -test to compare LogMAR visual acuity, and centralmacular thickness was measured by OCT betweenbefore starting in 󿬂 iximab and at 6 months after achiev-ing remission in patients who achieved remission within 󿬂 iximab therapy. Because the incidence of remissionrate varied over time, the proportion of patients inremission was calculated using the Kaplan – Meier sur-vival curve to show the cumulative remission rate asa time-to-event outcome. The eye was the unit of allcalculations except for demographics and systemicside effects, where the patient was the unit of calculations. Results Forty-four eyes of 23 patients were included in thestudy. All patients were diagnosed with idiopathic Fig. 1.  Flow chart for in 󿬂 iximabtherapy in patients with non-infectious intermediate uveitis(proposal with no validation). 838  RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES   2017   VOLUME 37   NUMBER 5  noninfectious intermediate uveitis (pars planitis or non – pars planitis). Of those 23 patients, 15 patients (65.2%)were women. The mean age at presentation to Massa-chusetts Eye Research and Surgery Institution was30.15 ± 13.56 years (range, 7 – 56). Twenty-one patients(91.3%) had bilateral involvement. Of the 11 patientswho were tested for HLA-D subtypes, 2 patients werepositive for HLA-DR15.Common presenting symptoms were  󿬂 oater and blurryvision in 23 (52.2%) and 22 (50%) eyes, respectively.The average of LogMAR visual acuity at the initial visit was 0.28 ± 0.58 (  20/40). Of 44 eyes, 26 eyes (59%)had anterior chamber cells with or without   󿬂 are; 42 eyes(95.4%) had anterior vitreous cells; 28 eyes (63.6%) hadvitreous haze; 16 eyes (36.3%) had snow balls; and 12eyes (27.2%) had snow banking. Fluorescein angiogra-phy showed retinal vasculitis in 20 eyes (45.4%); macular leakage in 14 eyes (31.8%); optic nerve head leakage and/ or staining in 11 eyes (25%); and typical petaloid patternin 6 eyes (13.6%). Optical coherence tomography re-vealed macular thickening with or without cystic changesin 21 eyes (47.7%). Based on both FA and OCT, macular edema was observed in 24 eyes (54.5%). At the 󿬁 rst visit,the average central macular thickness was 302.73 ±87.62  m m (range, 118 – 643  m m).Vitrectomy with endolaser therapy was done on 13eyes (29.5%) of 9 patients (39.1%). At least oneconventional immunomodulatory regimen was tried inall patients before proceeding with in 󿬂 iximab therapy.The most common conventional immunomodulatoryagents tried were methotrexate in 17 patients (73.9%),mycophenolate mofetil in 12 patients (52.1%), andcyclosporine A in 9 patients (39.1%) (Table 1). Treat-ments failed these patients because of ineffectivenessand/or major side effects. In those patients who hadbeen treated with conventional immunomodulatorytherapy, the average number of failed treatment regi-mens per patient was 1.86 ± 0.83 (range, 1 – 4). Pre-vious therapies also included adalimumab andgevokizumab in 1 patient each, which were stoppedbefore the initiation of in 󿬂 iximab therapy because of ineffectiveness (Table 1).Nineteen patients (82.6%) achieved remission within 󿬂 iximab therapy. At the 6-month follow-up visit after remission, the average LogMAR visual acuity was0.06 ± 0.14 (  20/20 – 20/25) and the average centralmacular thickness was 266.35 ± 44.13  m m (range,195 – 377  m m). Ten patients (43.7%) were also on addi-tional conventional immunomodulatory therapy includingmethotrexate alone in 5 patients (17.2%), mycophenolatemofetil alone in 5 patients (21.7%), and both mycophe-nolate mofetil and cyclosporine A in 1 patient (4.3%).The mean duration of treatment to induce remissionwas 3.99 ± 3.06 months (range, 1.5 – 14.7). The averageduration of treatment (including ongoing treatment) was33.28 ± 12.43 months (range, 15.2 – 53.2). The treatment course was completed and stopped in 8 patients (34.7%)with complete resolution of in 󿬂 ammation and CME. Theaverage duration of follow-up after stopping in 󿬂 iximabinfusions in this group of patients was 27.5 ± 27.9 months(range, 23.4 – 83.7).Five patients had  󿬂 are-ups during in 󿬂 iximab therapy.Of these  󿬁 ve patients, treatment with the maximum tolerable dose of in 󿬂 iximab therapy failed in threepatients. In the other two patients,  󿬂 are-ups werecontrolled by increasing the dose and shortening theinterval of in 󿬂 iximab infusions.One patient (4.3%) developed a signi 󿬁 cant increasein liver function enzymes requiring termination of in 󿬂 iximab infusions after 15 months of in 󿬂 iximabtherapy, and this was considered as the only major sideeffect in our cohort.Cystoid macular edema did not respond to in 󿬂 ix-imab therapy in 2 eyes (4.5%) of 2 patients (8.6%)with bilateral involvement. One eye (2.2%) devel-oped CME during in 󿬂 iximab therapy, and this wasthe only complication observed during the course of treatment. Cystoid macular edema in these eyes wastreated with topical nonsteroidal antiin 󿬂 ammatorydrugs, intravitreal steroid injections and/or intra-vitreal vascular endothelial growth factor inhibitorsinjections, and systemic angiotensin-convertingenzyme inhibitors. In 󿬂 iximab therapy did not failin any of these patients.Our analysis by paired  t  -test at 6 months after achieving remission showed that LogMAR visual acu-ity ( P  = 0.006) and central macular thickness on OCT( P  = 0.03) improved signi 󿬁 cantly in those patientswho achieved remission on in 󿬂 iximab therapy from the baseline, before starting in 󿬂 iximab infusions.We did not   󿬁 nd any correlation between remissionrate and demographic factors, genetic factors, or treat-ment history (Table 2). Table 1. Conventional Immunomodulatory Therapy andBiologic Response Modi 󿬁 er Treatment Before In 󿬂 iximabInfusions in Patients With Resistant NoninfectiousIntermediate UveitisType of ImmunomodulatoryTherapyNo. PatientsTreated(n = 23)* (%)Methotrexate 17 (73.9)Mycophenolate mofetil 12 (52.1)Cyclosporine A 9 (39.1) Azathioprine 4 (17.3)Chlorambucil 3 (13.0) Adalimumab 1 (4.3)Gevokizumab 1 (4.3) *Some patients received more than one agent. INFLIXIMAB IN INTERMEDIATE UVEITIS   MALEKI ET AL  839

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