Long Term Follow-Up of Tocilizumab in Refractory and Non-Infectious Uveitic Cystoid Macular Edema

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Vegas-Revenga, et al. Arch Clin Exp Ophthalmol Archives of Clinical and Experimental 2020; 2(2):35-43. Ophthalmology Short Communication

Nuria Vegas-Revenga1#, José Luis Martín-Varillas2#, Vanesa Calvo-Río3, Marina Mesquida4, Alfredo Adán4, David Díaz-Valle5, Luis F Linares6, Rosalía Demetrio-Pablo7, Elena Aurrecoechea2, José L. Hernández8†, Miguel A. González-Gay3†, Ricardo Blanco3†*

1Rheumatology, Hospital de Galdakao- Usánsolo, Galdakao, Vizcaya, Spain. Abstract 2Rheumatology, Hospital de Sierrallana. Objective: To assess the efficacy and safety of Tocilizumab (TCZ) for the treatment of cystoid macular Torrelavega, Cantabria, Spain edema (CME) associated to non-infectious uveitis in a series of 7 patients at 24 months of follow-up. 3 Rheumatology, Hospital Universitario Methods: Retrospective case series of 7 patients with CME secondary to noninfectious uveitis who had Marqués de Valdecilla, IDIVAL, Universidad de Cantabria, Santander, inadequate response to corticosteroids and at least 1 conventional immunosuppressive drug and in most Spain cases to other biological agent. Macular thickness, intraocular inflammation, best corrected visual acuity (BCVA) and steroid- sparing effect were the main variables analyzed. 4Ophthalmology. Hospital Clinic, Barcelona, Spain Results: 7 patients with a mean age of 38.9 ± 17.8 years with refractory uveitic CME were studied. 5Ophthalmology. Hospital Clínico San Underlying diseases associated were: juvenile idiopathic arthritis (n=3), Birdshot (n=2) and idiopathic Carlos, Madrid, Spain uveitis (n=2). All patients had bilateral involvement. TCZ was prescribed in combination with conventional immunosuppressive drugs in 5 of 7 patients. After 24 months of therapy, a statistically significant 6Rheumatology, Hospital Clínico Universitario Virgen de la Arrixaca, improvement in macular thickness (397.8 ± 232.1 µm vs. 231.3 ± 42.1 µm, P<0.01) and BCVA (0.32 ± 0.23 at Murcia, Spain baseline vs. 0.59 ± 0.33 at 24-month last visit, P=0.007) was obtained. A glucocorticoid sparing-effect was also observed. Remission was achieved in 6 patients and no severe adverse events were noticed at 2 years 7Ophthalmology, Hospital Universitario Marqués de Valdecilla, IDIVAL, follow-up. Santander, Spain Conclusions: TCZ seems to be effective and safe in refractory uveitic CME at 24 months follow-up. 8Internal Medicine, Hospital Universitario Marqués de Valdecilla, Keywords: Cystoid macular edema, Uveitis, Anti-TNF therapy, Tocilizumab. IDIVAL, Universidad de Cantabria, Santander, Spain Introduction #shared first authorship. †shared senior authorship. Uveitis includes a large spectrum of inflammatory disorders characterized by intraocular *Author for correspondence: inflammation. Most uveitis may complicate with cystoid macular edema (CME) and permanent Email: [email protected] blindness. CME is a swelling of the macula with fluid accumulation within the intracellular spaces of Received date: April 10, 2020 the retina, leading to the formation of cystic spaces [1]. Accepted date: May 08, 2020 According to anatomical location, panuveitis (36%-66%) and intermediate uveitis (40%- 60%) Copyright: © 2020 Vegas-Revenga are the patterns most commonly associated with CME [2]. The immune mediated systemic diseases N, et al. This is an open-access article most related to CME are sarcoidosis, juvenile idiopathic arthritis (JIA), Birdshot chorioretinopathy and distributed under the terms of the Creative Commons Attribution License, Behçet disease [3-9]. The pathogeny of non- infectious uveitic CME is not yet fully understood, and which permits unrestricted use, the etiology might be multifactorial [10]. Tumour necrosis factor-alpha (TNF-alpha) has traditionally distribution, and reproduction in any been considered one of the most important molecules in systemic inflammation processes, including medium, provided the original author and source are credited. those related to eye inflammation [11]. However, a substantial increase in Interleukin-6 (IL-6) levels has been demonstrated in the aqueous humor of patients with uveitic CME [12,13]. Exposure to high levels of IL-6 and other inflammatory mediators in the inner blood-retinal barrier results in increased Citation: Vegas-Revenga N, Martín- endothelial permeability and angiogenesis due to overproduction of vascular endothelial growth factor Varillas JL, Calvo-Río V, Mesquida (VEGF). This leads to the formation of aqueous cyst in the macula [14,15]. M, Adán A, Díaz-Valle D, et al. Long Term Follow-Up of Tocilizumab in Topic, oral or intravenous corticosteroids and conventional immunosuppressant agents are Refractory and Non-Infectious Uveitic generally the first step in the management of acute non-infectious uveitic CME. However, many Cystoid Macular Edema. Arch Clin Exp patients even present partially or no response to these therapies. In addition, long-term therapy with Ophthalmol 2020; 2(2):35-43.

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Arch Clin Exp Ophthalmol 2020; 2(2):35-43. 35 Citation: Vegas-Revenga N, Martín-Varillas JL, Calvo-Río V, Mesquida M, Adán A, Díaz-Valle D, et al. Long Term Follow-Up of Tocilizumab in Refractory and Non-Infectious Uveitic Cystoid Macular Edema. Arch Clin Exp Ophthalmol 2020; 2(2):35-43.

corticosteroids is associated with ocular and systemic side effects [16- Macular edema was considered persistent or unresponsive 20]. In this regard, the appearance of biological drugs targeted at to corticosteroids, to synthetic immunosuppressive drugs or to specific molecules (anti-TNF-alpha or anti-IL-6 receptor) has clearly biological agents when central foveal thickness was ≥ 300 µm and/ improved the prognosis of our patients [21-31]. or presence of cystic spaces was confirmed after regular evaluations. Tocilizumab (TCZ, Actemra®, Roche AG, Basel, Switzerland), Outcome variable the first IL-6 inhibitor that proved efficacy in humans, is a humanized To determine efficacy and safety, macular thickness, visual acuity, mouse monoclonal antibody inhibitor of IL-6 receptor. It binds to the intraocular inflammation and the sparing effect of glucocorticoids both membrane-bound and soluble receptor and inhibits downstream were assessed. signaling to inflammatory mediators. It can be used intravenously or subcutaneously. This biological drug has shown a good safety profile Intraocular inflammation was evaluated according to the SUN with the risk of malignancy, gastrointestinal perforation and dose- Working Group [39,40]. dependent neutropenia. The best-corrected visual acuity (BCVA) was estimated using the TCZ is currently approved for the treatment of rheumatoid Snellen chart [40]. arthritis (RA), juvenile idiopathic arthritis (JIA), and giant cell Macular thickening was defined as central macular thickness arteritis (GCA) by the FDA [32]. Several studies have reported the of >300 mm on optical coherence tomography (OCT), and CME efficacy of TCZ in non-infectious uveitic CME, but in most of them included the presence of radially oriented cystoid spaces in the the data are based in small sample size [13,23,33-37]. macula, visualized by OCT. However, Sepah et al. published the first prospective randomized Statistical analysis clinical trial (STOP- Uveitis) to assessed the safety and efficacy of TCZ in non-infectious uveitis, showing that this drug was well- Statistical analysis was performed using Statistica software tolerated and associated with a reduction in vitreous haze and cystoid (StatSoft). Results were expressed as the mean ± SD or median macular edema [38]. (interquartile range [IQR]) as appropriate. Wilcoxon’s signed rank test was used to compare continuous variables prior to and after TCZ The present study is a data extension from the original article therapy. Results were reported considering the number of affected by Vegas-Revenga et al. [2] to assess the efficacy and safety of TCZ eyes. in non-infectious uveitis-associated CME. Our group observed that treatment with TCZ in patients with refractory CME decreased Results macular thickness at one year of follow-up [2]. At this time, we report the results of 7 patients that were selected from the first work Demographic and clinical features at baseline to follow up over a 24-month period after TCZ was administered. Seven patients (6 women/1 man) with a mean age of 38.9 ± 17.8 years with uveitic CME refractory to conventional immunosuppressive drugs and in most cases to other biologic (n=6) Patients and Methods were studied. The underlying diseases were as follows: JIA (n=3), Design, Enrolment Criteria and Definitions Birdshot (n=2) and idiopathic uveitis (n=2). All patients had bilateral involvement and patterns of uveitis were anterior (n=2), intermediate This study is a subanalysis of a retrospective case series study (n=2), posterior (n=2) and panuveitis (n=1). [2] that evaluated the effect of TCZ administered intravenously Before TCZ infusion, 6 of the 7 patients received oral (TCZ-IV) or subcutaneously (TCZ-SC) to 7 subjects with refractory glucocorticoids (prednisone, mean dose of 40 ± 16.7 mg). All of them non-infectious uveitis CME, followed up over a 24-month period. received intraocular injection (Ozurdex). None received intravenous Written informed consent was requested and obtained from all methylprednisolone. Besides oral glucocorticoids and before the patients, and the drug administration protocol was approved by the onset of biologic therapy, patients had received the following drugs and therapeutics committee of each selected hospital. IRB/ immunosuppressive agents: methotrexate (n=5), cyclosporine A Ethical approval was also obtained from Spanish National authorities (n=7), azathioprine (n=1), sulfasalazine (n=1), leflunomide (n=1) (NVR- 2018.124.). mycophenolate (n=1) and acetazolamide (n=1). The mean number TCZ was administered intravenously (iv) at a dose of 8 mg/kg of conventional immunosuppressive drugs given before the start of every 4 weeks in all patients. Response was assessed by comparing to TCZ was 2.6 ± 0.9 per patient. Most patients had also received other baseline at weeks 1 and 2, and at months 1, 2, 3, 6, 12 and 24. Prior biologic agents before TCZ as follows: adalimumab (n=5); infliximab to TCZ administration, 6 of 7 patients had received treatment with (n=2), etanercept (n=1), rituximab (n=1) and abatacept (n=1). Only corticosteroids (local or systemic), at least one conventional synthetic one patient started TCZ as first biologic drug. immunosuppressive drug, and a biological agent (generally an anti- Outcome variables after TCZ treatment over 2 year TNFα inhibitor), and had presented partial or no response to these therapies. Only 1 patient received TCZ as the first biological agent. TCZ was prescribed in combination with conventional immunosuppressive drugs in 5 of 7 patients (methotrexate in 3 Prior to the administration of TCZ, the presence of tumors or patients and cyclosporine A in 2). chronic infections, including tuberculosis, hepatitis B, and hepatitis C, was ruled out as indicated in Spanish National Guidelines. When compared to the initial visit, a statistically significant

Arch Clin Exp Ophthalmol 2020; 2(2):35-43. 36 Citation: Vegas-Revenga N, Martín-Varillas JL, Calvo-Río V, Mesquida M, Adán A, Díaz-Valle D, et al. Long Term Follow-Up of Tocilizumab in Refractory and Non-Infectious Uveitic Cystoid Macular Edema. Arch Clin Exp Ophthalmol 2020; 2(2):35-43.

decrease in macular thickness (397.8 ± 232.1 µm vs. 231.3 ± 42.1 improvement was observed in BCVA (0.32 ± 0.23 at baseline vs. 0.59 µm, P<0.01) was observed at 24 months of follow-up (Figure 1A). ± 0.33 at 24 month last visit, P=0.007) (Figure 1B). In addition, the remaining variables related to ocular inflammation showed rapid and sustained improvement after the onset of TCZ. Median prednisone dose was reduced from 7.5 [7.5-40] mg/day Based on the SUN classification criteria for anterior chamber cells at baseline to 0 [0-5] mg/day at month 24 (P=0.02), achieving a (AC cells) and vitritis, all patients had a decrease to grade 0 in the nearly complete glucocorticoid sparing effect. level of ocular inflammation. Five of 14 eyes (35.7%) affected at first It should be noted that in 6 of 7 patients’ ocular remission was visit showed a complete improvement at month 24. achieved after a mean follow-up of 25.1 ± 1.5 months, and none of Furthermore, resolution of prominent vitritis was observed in the patients showed any adverse effects, either mild or severe. most patients (9 of 11 eyes affected at baseline). Similarly, a significant

Vegas-Revenga et al. long term follow-up of TCZ

FIGURE A

450

400 * 350 * 300 * * 250 * µm 200

150

100 * P < 0.01 50

0 baseline 1st week 1st month 3rd month 6th month 1st year 2nd year

0,9

0,8

0,7 * * 0,6 *

0,5 * * 0,4

0,3

0,2 * P < 0.01 0,1

0 baseline 1st week 1st month 3rd month 6th month 1st year 2nd year

Figure 1: A) Time course of macular thickness at 24 months follow-up (affected eyes). B) Mean changes of best corrected21 visual

acuity (BCVA) after TCZ therapy (affected eyes).

Arch Clin Exp Ophthalmol 2020; 2(2):35-43. 37 Citation: Vegas-Revenga N, Martín-Varillas JL, Calvo-Río V, Mesquida M, Adán A, Díaz-Valle D, et al. Long Term Follow-Up of Tocilizumab in Refractory and Non-Infectious Uveitic Cystoid Macular Edema. Arch Clin Exp Ophthalmol 2020; 2(2):35-43.

Discussion old boy with idiopathic uveitis and refractory to conventional We followed up over 24-month period 7 patients with CME immunomodulatory therapy [52]. This case report is the first refractory to conventional immunosuppressive drugs and to publication about the utility of tocilizumab in idiopathic paediatric biological agents. After TCZ infusion, most patients experienced a uveitis, especially in pars planitis with refractory macular edema [52]. rapid and maintained response. There was complete resolution of CME and gross reduction in the diffuse leakage on fluorescein angiography (FA) [52]. Anti-TNF-a therapy, specifically adalimumab, is the first-line biological agent recommended in the treatment of uveitis refractory to Afterwards, Wennink et al [53] presented a case series of seven topic/systemic corticosteroids and conventional immunosuppressive children with refractory non-anterior uveitis treated with tocilizumab drug [41,42]. In general, TNF blockade is effective and has minimal 8 mg/kg intravenously every 4 weeks. In all patients, there was an and manageable side effects. Despite these benefits, most studies improvement of macular edema and capillary leakage on FA. BCVA show that approximately 50% of patients with non-infectious improved in five eyes and worsened in one eye due to cataract. No uveitis treated with anti-TNF are unresponsive/intolerant [43]. systemic or ocular complications were reported. Those patients non-responsiveness to adalimumab suggest that, A letter to the editor was published by Adán et al. [54] with a apart from TNF-a, there are other biological targets involved in the 26-year-old female patient presented with CME in both eyes. CME disease process. IL-6 has emerged as an important cytokine in the became refractory to conventional immunosuppressive drugs and pathogenesis of non-infectious uveitis, including those with CME. In TCZ-IV was initiated. After 12 infusions, TCZ was stopped due this sense, TCZ has demonstrated efficacy in patients with refractory to grade 1 neutropenia. However, in the following examinations ocular inflammatory diseases [6,8,33-37,44-48]. visual acuity of the right eye decreased and spectral domain optical Infection and inflammation cause significant upregulation coherence tomography (SD-OCT) revealed CME. Subcutaneous of IL-6, which features pleiotropic activity and mediates various TCZ was initiated, after six injections ophthalmic examination biological functions: induction of acute-phase reactants in liver, revealed no signs of active inflammation, and central foveal T cell differentiation, regulates inflammatory cells, homeostasis, thickness decreased [54]. Adán et al. [54] suggest that the results and healing after tissue injury [43]. Various systemic autoimmune previously observed with TCZ-IV in patients with CME secondary diseases including chronic rheumatoid arthritis, juvenile idiopathic to JIA-associated uveitis could be extrapolated with TCZ-SC. Even arthritis, systemic lupus erythematosus, Behçet’s disease, and systemic Quesada–Masachs [55] reported that ocular disease in JIA associated sclerosis have been associated with dysregulation in IL-6 production uveitis is more readily controlled with TCZ-IV than with TCZ- SC. [43]. This interleukin has also been found to be significantly elevated Subcutaneous route of administration has important advantages, in ocular fluids of: diabetic macular edema, retinal vein occlusion, and switching from TCZ- IV to TCZ- SC administration may chronic uveitis, glaucoma, dry eye disease, chemical burn injuries, provide greater flexibility and quality of life to patients who follow corneal infections and allergic eye diseases [43]. Murray et al. [49] TCZ treatment. The efficacy of the SC route over IV route in RA thirty years ago were the first to demonstrate elevated aqueous humor has been evaluated in several studies [56-62]. The results ensure that levels of IL-6 in human subjects with uveitis, including, Fuchs’ switching from TCZ-IV to SC is generally successful over time. heterochromic iridocyclitis and toxoplasma uveitis. However, to our knowledge, there are no reports on the results of Paediatric uveitis is a very challenging condition to treat, it is the switching from TCZ-IV to TCZ-SC in patients with JIA. Maybe most common extra- articular manifestation of JIA [43,50]. Anterior the results previously observed in patients with RA cannot be uveitis is the most frequently reported type (83%), followed by extrapolated to patients with JIA. We could speculate that ocular intermediate uveitis (9%), pan‐uveitis (7%) and posterior uveitis (1%) disease is more readily controlled with TCZ-IV than with TCZ-SC [50]. JIA- associated uveitis leads to irreversible visual impairment in because of high blood levels achieved during the first few days after up to one-third of the affected children [43]. Risk factors for the IV infusion [55]. development of uveitis in JIA patients are young age at JIA diagnosis, Clinical success of TCZ was encouraging, which led female sex, oligoarthritis, presence of serum antinuclear antibodies pharmaceutical industry to undertake research in discovering other (ANA) and elevated erythrocyte sedimentation rate [50,51]. IL-6 blocking pathways. Currently, several IL- 6/IL-6R inhibitors are Infliximab and adalimumab are used for JIA‐associated uveitis under investigation in various phases of different studies [43]. in childhood; some studies have demonstrated that adalimumab is Sarilumab (Kevzara®, Sanofi Genzyme, Regeneron as effective as infliximab during the first year of treatment, but it Pharmaceuticals, USA) is a fully human anti-IL-6Ra mAb that seems to have a higher probability of maintaining remission during blocks both classic and trans-signaling pathway by binding to a longer follow‐up [50]. There are no current guidelines for treating membrane-bound as well as soluble forms of IL-6Ra, with higher JIA‐ associated uveitis and CME with TCZ, data mainly come from affinity as compared to tocilizumab [63]. In the SATURN study published case series. An updated literature review on this topic is [64], it was demonstrated that subcutaneous sarilumab may provide summarized in Table. clinical benefits in the management of non- infectious uveitis of the posterior segment, especially in eyes with uveitic CME. Nevertheless, Several cases about the use of TCZ in pediatric patients have further studies are needed to evaluate efficacy and safety of sarilumab been reported in the last few years. Babu K. et al. [52] describe the in this group of patients, also in comparison with other biological improved response of CME and vascular permeability in a 13-year- molecules.

Arch Clin Exp Ophthalmol 2020; 2(2):35-43. 38 Citation: Vegas-Revenga N, Martín-Varillas JL, Calvo-Río V, Mesquida M, Adán A, Díaz-Valle D, et al. Long Term Follow-Up of Tocilizumab in Refractory and Non-Infectious Uveitic Cystoid Macular Edema. Arch Clin Exp Ophthalmol 2020; 2(2):35-43.

Muselier et al, Adan et al, 2013 Adan et al, 2013 Adan et al, Papo et al, 2014 Mesquida et al, Tappeiner C, Deroux A, 2011 [37] [13] [65] 2014 [66] [45] 2014 [34] 2016 [67] 2016 [68]

No. of patients 2 5 1 1 2 7 5 1 with CME

Sex, (W/M), n 2/0 5/0 1/0 1/0 2/0 7/0 NS 1/0

Age, years 27-69 30-68 56 29 21-47 23-70 7-30 23

BSRC (n=3), JIA Spondyloarthropathy BSRC (n=3), JIA Underlying BSRC and Idiopathic (n=1), idiopathic JIA (n=1), idiopathic (n=3), idiopathic JIA BSRC disease idiopathic uveitis panuveitis panuveitis (n=1) panuveitis (n=1) uveitis (n=1).

JIA- associated Posterior JIA- associated Posterior uveitis uveitis uveitis+CME Uveitis-related Severe bilateral anterior uveitis Posterior Uveitis pattern + CME, Vitritis + complicated Panuveitis + CME (n=6) and CME CME complicated with uveitis + CME vasculitis + CME. with CME and panuveitis + CME VPRT CME (n=1)

MTX, CsA, MMF, MTX, AZA, CYC, MTX, CsA, MMF, MTX, AZA, Previous MTX, AZA, MMF, MTX, CsA, IFX, MTX, CsA, LFN, IFX, ADA, RTX, MTX, IFX, ADA CsA, IFN- α, IFX, IFX, ADA, ABA, CsA, IFX, ADA, treatment ADA ADA, IFX, ADA, ABA. ABA ADA, ABA, ANK RTX ANK

8 mg/kg every 4 8 mg/kg every 4 8 mg/kg every 4 8 mg/kg every 4 8 mg/kg every 4 8 mg/kg every 4 8 mg/kg every 4 8 mg/kg every TCZ regimen weeks weeks weeks weeks weeks weeks weeks 4 weeks

Leukopenia (n=1), Adverse effects None None None None thrombocytopenia NS None None related to TCZ (n=1)

Months of TCZ 6-8 6-12 6 12 7- 25 12-18 3-12 12 treatment

Improvement Improvement Improvement Ocular outcome Inactive Improvement Improvement (n= 2) Inactive (n=2) Inactive (n=2) (n=5) (n=5)

Table continued in next page

Arch Clin Exp Ophthalmol 2020; 2(2):35-43. 39 Citation: Vegas-Revenga N, Martín-Varillas JL, Calvo-Río V, Mesquida M, Adán A, Díaz-Valle D, et al. Long Term Follow-Up of Tocilizumab in Refractory and Non-Infectious Uveitic Cystoid Macular Edema. Arch Clin Exp Ophthalmol 2020; 2(2):35-43.

No. of patients 5 12 37 25 1 1 7 7 with CME

Sex, (W/M), 3/2 10/2 22/15 17/8 0/1 1/0 3/4 6/1 n

38.9±17.8 Age, years 23-57 15-62 26- 60 12-75 13 26 3-11 years

BSRC (n=2), JIA (n=6), sarcoidosis BSRC (n=2), Behçet (n=2),idiopathic disease (n=1), JIA (n=2), JIA (n=9), BSRC panuveitis Vogt-Koyangi- JIA (n=3), ankylosing (n=4),sarcoidosis (n=2), Harada Birdshot Underlying spondylitis (n=1), Behçet Idiopathic sympathetic syndrome (n=2), JIA JIA (n=2) and disease (n=1), disease (n=7), pediatric uveitis ophthalmia Punctate Inner idiopathic rheumatoid idiopathic uveitis (n=1), Choroiditis uveitis (n=2) arthritis (n=2) (n=4) ankylosing (n=1), TINU spondylitis syndrome (n=1) (n=1) idiopathic uveitis (n=4)

Chronic anterior uveitis Anterior Anterior uveitis (n=2), JIA- Intermediate uveitis (n=7), intermediate Par planitis associated Intermediate + CME (n=3), ME with uveitis (n=6), intermediate uveitis(n=2), Uveitis [both eyes] and anterior uveitis (n=5), acute anterior quiescent posterior uveitis uveitis (n= 4), posterior pattern recurrent CME uveitis panuveitis uveitis + uveitis (n=5), panuveitis posterior uveitis uveits [right eye] complicated (n=2) CME (n=1), (n=26). (n=5) and (n=2) and with CME intermediate panuveitis (n= 9). panuveitis uveitis + CME (n=1). (n=1).

MTX,CsA, MTX, MMF, MTX, MMF, DMARDs, IFX, AZA, SSZ, CsA, LFN, MTX, MMF, MTX, Previous CsA, ADA, IFX, MTX, MMF, ADA, ETN, GLM, MTX, ADA, LFN, MMF, Acet, ADA, deflazacortisone, CsA, ADA, treatment ETN, ANK, Tacrolimus, ADA RTX, ABA, ANK, IFX Acet, ADA, ETN, ABA, AZA, CsA MA, GLM DCZ IFX, ETN, GLM RTX, ABA

10 mg/kg body, 8 mg/kg/ every 4 14 injections 8 mg/kg every 8 mg/kg every 8 mg/kg every 4 weeks (n=23), over 12 months. 4 weeks over 8 mg/kg 8 mg/kg TCZ 8 mg/kg every 4 weeks weeks 8 mg/kg/ every The last injection 12 months every 4 every 4 regimen 4 weeks 4 mg/kg every 4 mg/kg every 4 2 weeks (n= 1), the dose was 162 mg/sc/ weeks weeks 4 weeks weeks 162 mg/sc/ every reduced to 8 every week week (n=1) mg/kg Grade 1 neutropenia Grade 1 Adverse Nausea (n=1), (n=1) and Low absolute neutropenia effects viral conjunctivitis NS community- neutrophil Leukopenia and multiple NS NS related to and bullous acquired counts (n=2) paracervical TCZ impetigo (n=1). pneumonia adenopathies (n=1)

Months of TCZ 4-35 24 12 1.5-31 13 20 6-12 24 treatment

Ocular Improvement Improvement Inactive (n=12) Inactive (n=14) Inactive Inactive Improvement Improvement outcome (n=5) (n=37)

ABA: abatacept; Acet: Acetazolamide; ADA: Adalimumab; ANK: Anakinra; AZA: Azathioprine; BSRC: Birdshot retinochoroidopathy; CME: Cystoid macular edema; CsA: Cyclosporine A; CYC: cyclophosphamide; DCZ: Daclizumab; DMARDS: Disease Modifying Antirheumatic Drugs; ETN: Etanercept; GLM: Golimumab; IFN-a: Interferon alpha; IFX: Infliximab; JIA: Juvenile Idiopathic Arthritis; LFN: Leflunomide; MA: Mycophenolic Acid; MMF: Mycophenolate Mofetil; MTX: Methotrexate; NS: Not Specified; RTX: Rituximab; SSZ: Sulfasalazine; TCZ: Tocilizumab; TINU: Tubulointerstitial Nephritis and Uveitis; VPRT: Retinal Vasoproliferative Tumor.

Arch Clin Exp Ophthalmol 2020; 2(2):35-43. 40 Citation: Vegas-Revenga N, Martín-Varillas JL, Calvo-Río V, Mesquida M, Adán A, Díaz-Valle D, et al. Long Term Follow-Up of Tocilizumab in Refractory and Non-Infectious Uveitic Cystoid Macular Edema. Arch Clin Exp Ophthalmol 2020; 2(2):35-43.

Vegas- Deuter et al, Mesquida et Sepah et al, Vegas-Revenga Babu et al, 2019 Adán et at, Wennink et Revenga et 2017 [35] al, 2018 [23] 2017 [38] et al, 2019 [2] [52] 2019 [54] al, 2020 [53] The present study is a long term follow up of TCZ in 7 patients Aurrecoechea, MD, PhD; J.L. Hernández, MD, PhD. al, present (6 women/1 man, mean age of 38.9 ± 17.8 years) selected from the No. of original article by Vegas-Revenga et al [2]. Underlying inflammatory References patients 5 12 37 25 1 1 7 7 diseases were: JIA, Birdshot and idiopathic uveitis. All patients had with CME 1. Bringmann A, Reichenbach A, Wiedemann P. Pathomechanisms of bilateral involvement and all patterns of uveitis were present. Besides Cystoid Macular Edema. Ophthalmic Res. 2004;36(5):241–9. Sex, (W/M), oral glucocorticoids patients had received immunosuppressive 3/2 10/2 22/15 17/8 0/1 1/0 3/4 6/1 n agents (methotrexate, cyclosporine A, azathioprine, sulfasalazine, 2. Vegas-Revenga N, Calvo-Río V, Mesquida M, Adán A, Hernández leflunomide, mycophenolate and acetazolamide) and biological MV, Beltrán E, et al. Anti-IL6-Receptor Tocilizumab in Refractory and Noninfectious Uveitic Cystoid Macular Edema: Multicenter Study of 38.9±17.8 Age, years 23-57 15-62 26- 60 12-75 13 26 3-11 therapies (adalimumab, infliximab, etanercept, abatacept, rituximab). 25 Patients. Am J Ophthalmol. 2019 Apr;200:85–94. years Only one patient started TCZ as first biologic drug. Unlike our study, neither of the studies to which we are compared included a 3. Riancho-Zarrabeitia L, Calvo-Río V, Blanco R, Mesquida M, Adan AM, BSRC (n=2), large number of patients who had been refractory to other therapies Herreras JM, et al. Anti-TNF-α therapy in refractory uveitis associated JIA (n=6), sarcoidosis with sarcoidosis: Multicenter study of 17 patients. Semin Arthritis BSRC (n=2), Behçet prior to TCZ treatment. TCZ was prescribed in combination with (n=2),idiopathic disease (n=1), Rheum. 2015 Dec;45(3):361–8. JIA (n=2), JIA (n=9), BSRC conventional immunosuppressive drugs in 5 of 7 patients. When panuveitis Vogt-Koyangi- JIA (n=3), ankylosing (n=4),sarcoidosis (n=2), Harada Birdshot compared to the initial visit, a statistically significant decrease 4. Bonfioli AA, Orefice F. Sarcoidosis. Semin Ophthalmol. 2005 Jan Underlying spondylitis (n=1), Behçet Idiopathic sympathetic syndrome (n=2), JIA JIA (n=2) and 1;20(3):177–82. disease (n=1), disease (n=7), pediatric uveitis in macular thickness was observed at 24 months of follow-up. In ophthalmia Punctate Inner idiopathic rheumatoid idiopathic uveitis addition, the remaining variables related to ocular inflammation (n=1), Choroiditis uveitis (n=2) 5. Varron L, Abad S, Kodjikian L, Sève P. Sarcoid uveitis: Diagnostic and arthritis (n=2) (n=4) ankylosing (n=1), TINU showed rapid and sustained improvement after the onset of TCZ. therapeutic update. Rev Med Interne. 2011 Feb;32(2):86–92. spondylitis syndrome (n=1) All in all, in 6 out of 7 patients ocular remission was achieved and (n=1) idiopathic uveitis 6. Calvo-Río V, Santos-Gómez M, Calvo I, González-Fernández MI, (n=4) none of the patients showed any adverse effects. Once more, our López-Montesinos B, Mesquida M, et al. Anti–Interleukin-6 Receptor group confirms the good response of CME to TCZ after a 24-month Tocilizumab for Severe Juvenile Idiopathic Arthritis–Associated Chronic period. There are some limitations in the study, including the small Uveitis Refractory to Anti–Tumor Necrosis Factor Therapy: A anterior uveitis Anterior sample size for the follow-up period. However, our results are from Multicenter Study of Twenty-Five Patients. Arthritis Rheumatol. Anterior uveitis (n=2), JIA- Intermediate uveitis (n=7), intermediate daily practice emphasizing the beneficial effect of TCZ in refractory 2017 Mar 1;69(3):668–75. Par planitis associated Intermediate + CME (n=3), ME with uveitis (n=6), intermediate uveitis(n=2), Uveitis [both eyes] and anterior uveitis (n=5), CME. acute anterior quiescent posterior uveitis uveitis (n= 4), posterior 7. Angeles-Han ST, McCracken C, Yeh S, Jenkins K, Stryker D, Rouster- pattern recurrent CME uveitis panuveitis uveitis + uveitis (n=5), panuveitis posterior uveitis uveits Stevens K, et al. Characteristics of a cohort of children with Juvenile [right eye] complicated (n=2) CME (n=1), (n=26). (n=5) and (n=2) and Funding/Support Idiopathic Arthritis and JIA- associated Uveitis. Pediatr Rheumatol with CME intermediate panuveitis (n= 9). panuveitis Online J. 2015 Jun 2;13. uveitis + CME (n=1). The study was partially supported by RETICS Programs, (n=1). RD08/0075 (RIER) and RD12/0009/0013 from ‘‘Instituto de Salud 8. Zulian F, Martini G, Falcini F, Gerloni V, Zannin ME, Pinello L, et al. Carlos III’’ (ISCIII) (Spain). Early predictors of severe course of uveitis in oligoarticular juvenile MTX,CsA, MTX, MMF, idiopathic arthritis. J Rheumatol. 2002 Nov 1;29(11):2446–53. MTX, MMF, DMARDs, IFX, AZA, SSZ, CsA, LFN, MTX, MMF, MTX, Financial Disclosures Previous CsA, ADA, IFX, MTX, MMF, ADA, ETN, GLM, MTX, ADA, LFN, MMF, Acet, ADA, deflazacortisone, CsA, ADA, 9. Hirano T Ohguro N, Hohki S, Hagihara K, Shima Y, Narazaki M, treatment ETN, ANK, Tacrolimus, ADA RTX, ABA, ANK, IFX Acet, ADA, ETN, ABA, AZA, CsA MA, Dr.Nuria Vegas-Revenga, MD; received grants/research supports et al. A case of Behçet’s disease treated with a humanized anti- GLM DCZ IFX, ETN, GLM interleukin-6 receptor antibody, tocilizumab. Mod Rheumatol. 2012 RTX, ABA from AbbVie, Roche, Pfizer, Lilly, Gebro Pharma, MSD, Novartis, Bristol- Myers, Janssen, Sanofi, Celgene and UCB. Dr. José Luis Apr 1;22(2):298–302. 10 mg/kg body, 8 mg/kg/ every 4 Martín-Varillas received grants/research supports from AbbVie, 10. Horai R, Caspi RR. Microbiome and Autoimmune Uveitis. Front 14 injections 8 mg/kg every 8 mg/kg every 8 mg/kg every 4 weeks (n=23), Pfizer and Celgene. Dr.Vanesa Calvo- Río MD, PhD; received grants/ Immunol. 2019;10:232. over 12 months. 4 weeks over 8 mg/kg 8 mg/kg TCZ 8 mg/kg every 4 weeks weeks 8 mg/kg/ every The last injection 12 months every 4 every 4 research supports from MSD and Roche, and had consultation fees/ regimen 4 weeks 4 mg/kg every 4 mg/kg every 4 2 weeks (n= 1), 11. Zelová H, Hošek J. TNF-α signalling and inflammation: interactions the dose was 162 mg/sc/ weeks weeks 4 weeks weeks 162 mg/sc/ every participation in company sponsored speaker’s bureau from Abbott, between old acquaintances. Inflamm Res. 2013 Jul 1;62(7):641–51. reduced to 8 every week week (n=1) Lilly, Celgene, Grünenthal and UCB pharma. Dr. Marina Mesquida, mg/kg MD, PhD; is currently employed by Hoffmann-La Roche Ltd, Basel, 12. Perez VL, Papaliodis GN, Chu D, Anzaar F, Christen W, Foster CS. Grade 1 Switzerland. Dr. Alfredo Adán, MD, PhD; had advisory boards, Elevated levels of interleukin 6 in the vitreous fluid of patients with neutropenia Grade 1 pars planitis and posterior uveitis: the Massachusetts eye & ear Adverse Nausea (n=1), lectures and grants from Abbvie. Dr. David Diaz-Valle, MD, PhD; (n=1) and Low absolute neutropenia experience and review of previous studies. Ocul Immunol Inflamm. effects viral conjunctivitis NS community- neutrophil Leukopenia and multiple NS NS had consultation fees/participation in company sponsored speaker´s related to and bullous 2004 Sep;12(3):193–201. acquired counts (n=2) paracervical TCZ impetigo (n=1). bureau from Abbvie, MSD, Allergan, Bausch & Lomb and Thea. pneumonia adenopathies Dr. Miguel A González-Gay, MD, PhD; received grants/research 13. Adán A, Mesquida M, Llorenç V, Espinosa G, Molins B, Hernández MV, (n=1) supports from Abbott, MSD and Roche, and had consultation fees/ et al. Tocilizumab treatment for refractory uveitis-related cystoid macular edema. Graefes Arch Clin Exp Ophthalmol. 2013 Nov Months participation in company sponsored speaker´s bureau from Abbvie, 1;251(11):2627–32. of TCZ 4-35 24 12 1.5-31 13 20 6-12 24 Pfizer, Roche, Novartis, MSD, Lilly and Sanofi. Dr. Ricardo Blanco, treatment MD, PhD; received grants/research supports from Abbott, MSD 14. Noma H, Funatsu H, Mimura T, Harino S, Hori S. Vitreous Levels of and Roche, and had consultation fees/participation in company Interleukin-6 and Vascular Endothelial Growth Factor in Macular Edema with Central Retinal Vein Occlusion. Ophthalmology. 2009 Ocular Improvement Improvement sponsored speaker´s bureau from Abbvie, Pfizer, Roche, Bristol- Inactive (n=12) Inactive (n=14) Inactive Inactive Improvement Improvement Jan 1;116(1):87–93. outcome (n=5) (n=37) Myers, Lilly, Janssen and MSD. 15. Zahir-Jouzdani F, Atyabi F, Mojtabavi N. Interleukin-6 participation ABA: abatacept; Acet: Acetazolamide; ADA: Adalimumab; ANK: Anakinra; AZA: Azathioprine; BSRC: Birdshot retinochoroidopathy; CME: Cystoid macular No Financial Disclosure Declared in pathology of ocular diseases. Pathophysiol Off J Int Soc edema; CsA: Cyclosporine A; CYC: cyclophosphamide; DCZ: Daclizumab; DMARDS: Disease Modifying Antirheumatic Drugs; ETN: Etanercept; GLM: Pathophysiol. 2017 Sep;24(3):123–31. Golimumab; IFN-a: Interferon alpha; IFX: Infliximab; JIA: Juvenile Idiopathic Arthritis; LFN: Leflunomide; MA: Mycophenolic Acid; MMF: Mycophenolate Mofetil; Luis F Linares, MD; Rosalia Demetrio- Pablo, MD, PhD; Elena MTX: Methotrexate; NS: Not Specified; RTX: Rituximab; SSZ: Sulfasalazine; TCZ: Tocilizumab; TINU: Tubulointerstitial Nephritis and Uveitis; VPRT: Retinal 16. Oray M, Samra K. A, Ebrahimiadib N, Meese H, Foster C.S. Long-term Vasoproliferative Tumor.

Arch Clin Exp Ophthalmol 2020; 2(2):35-43. 41 Citation: Vegas-Revenga N, Martín-Varillas JL, Calvo-Río V, Mesquida M, Adán A, Díaz-Valle D, et al. Long Term Follow-Up of Tocilizumab in Refractory and Non-Infectious Uveitic Cystoid Macular Edema. Arch Clin Exp Ophthalmol 2020; 2(2):35-43.

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