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

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Long Term Follow-Up of Tocilizumab in Refractory and Non-Infectious Uveitic Cystoid Macular Edema Vegas-Revenga, et al. Arch Clin Exp Ophthalmol Archives of Clinical and Experimental 2020; 2(2):35-43. Ophthalmology Short Communication Long Term Follow-Up of Tocilizumab in Refractory and Non-Infectious Uveitic Cystoid Macular Edema 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. This article is originally published by ProBiologist LLC., and is freely available at probiologists.com 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
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