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Rituximab for sight-threatening refractory pediatric Vogt–Koyanagi–Harada disease Raid M. R. Umran & Zaid Y. H. Shukur To cite this article: Raid M. R. Umran & Zaid Y. H. Shukur (2015): Rituximab for sightthreatening refractory pediatric Vogt–Koyanagi–Harada disease, Modern Rheumatology, DOI: 10.3109/14397595.2015.1071234 To link to this article:

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Date: 06 November 2015, At: 00:06 ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2015; Early Online: 1–3 © 2015 Japan College of Rheumatology DOI: 10.3109/14397595.2015.1071234


Rituximab for sight-threatening refractory pediatric Vogt–Koyanagi–Harada disease Raid M. R. Umran1, and Zaid Y. H. Shukur2 1Department of Pediatrics, University of Kufa, College of Medicine, Al- Zahraa Teaching Hospital, Najaf, Iraq, and 2Department of Physiology, University of Kufa, College of Medicine, Al Sader Teaching Hospital, Najaf, Iraq

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Abstract Rituximab was trialed in a refractory Vogt–Koyanagi–Harada disease (VKH). A 10-year-old girl with panuveitis recalcitrant to treatment, including corticosteroids, was diagnosed with VKH 20 months later. Following rituximab at 0, 1, 6, and 18 months, response was favorable after the second dose, usual life activity resumed after the third dose (uveitis was inactivated and vision improved), and eyes stabilized 9 months after the fourth dose. Rituximab is effective in the treatment and long-term control of advanced, pediatric VKH.

Introduction Vogt–Koyanagi–Harada disease (VKH) is an autoimmune, multisystem disease that manifests as panuveitis associated with vitiligo, alopecia, and neurological abnormalities [1]. VKH has a greater predilection in dark-skinned individuals between their third and fifth decades of life, with a slight predominance in women [2]. Systemic corticosteroid therapy is the mainstay of treatment for VKH in the early phase to prevent ocular and systemic complications [1]. Chronic and steroid unresponsive cases require the use of systemic immunosuppressive and immunomodulatory therapy, or biological agents [3]. Few cases of VKH have been reported in young children; however, delayed diagnosis, a more aggressive course, and vision-threatening complications represent a therapeutic challenge in this population [4]. Rituximab (RTX), an anti-CD20 monoclonal antibody, has been used in the treatment of refractory inflammatory diseases [5]. Very few previously published studies have reported that RTX may be helpful in selected patients with chronic uveitis refractory to corticosteroids and immunosuppression [6]. In this case report, we describe, for the first time, the efficacy of RTX in the treatment and long-term control of refractory sight-threatening pediatric VKH.

Case report A girl aged 10 years and 9 months from Najaf, Iraq, with a complaint of bilateral red itching eyes and decrease in vision was referred to a pediatrician on June 14, 2010 to exclude rheumatic or systemic cause of unresponsive bilateral chronic uveitis. A complete history provided by the girl’s parents revealed that the condition started a few weeks earlier. An ophthalmologist had managed her condition with topical steroid treatment without response and her visual acuity deteriorated. Physical examination showed that her weight and height were below the 3rd percentile, but all other systemic examinations were normal. Her first examination showed normal, Correspondence to: Dr. Raid M. R. Umran, MD, Assist. Prof. of Paediatrics, Head of paediatrics department, Medical college - University of Kufa, Al- Zahraa Teaching Hospital, Al Eshteraki st. P.O. box: Najaf 406, Najaf, Iraq. Tel: ⫹ 964 7801421961. E-mail: [email protected]

Keywords Rituximab, Uveitis, Vogt–Koyanagi–Harada, Pediatric History Received 16 April 2015 Accepted 2 July 2015 Published online 18 August 2015

complete blood counts, a normal erythrocyte sedimentation rate or ESR, and a negative antinuclear antibody or ANA test. Contact with the patient was lost for 14 months and when the patient returned, her condition had worsened with further deterioration in vision and increased intraocular pressure (IOP). A review of this lapsed period of time revealed that the family had consulted two different ophthalmologists who continuously treated her with local steroids and antibiotics with no response. Then the family traveled to Iran, on August 21, 2011, to consult a pediatric rheumatologist who reviewed her condition and found that HLA-B5 and -B51 statuses were positive and diagnosed Behçet’s disease, and prescribed methotrexate (10 mg/m2 weekly) and oral prednisolone (30 mg/day). The patient experienced a slight improvement over the next 2 weeks, but after 1 month, her condition deteriorated with ocular pain and marked decrease in vision. On October 1, 2011, her vision in the right eye (RE) and left eye (LE) were 6/9 and 6/36, respectively, with increased IOP in both eyes. On October 29, 2011, a decision was made to start interferon (IFN) alpha-2a for 10 weeks (three million units subcutaneously 3 times/ week), but without response; uveitis was more active and IOP was increased in the LE. Professor Tugal-Tutkan from Turkey was consulted to evaluate the patient’s condition on February 24, 2012. Based on the disease course and the history of the appearance of vitiligo during the previous period, which was not mentioned by the family earlier, the diagnosis of VKH was reported. Eye examination showed bilateral band keratopathy, extensive posterior synechia and diffuse mild opacification of the posterior capsule, and 1 ⫹ cell in the anterior vitreous. The IOP was 20 mmHg in the RE and 40 mmHg in the LE. The fundus showed bilateral granulomatous optic atrophy with greater advancement in the LE and foveal fibrotic scar, bilateral sunset glow, and 360o choroidal atrophic scars (Figure 1). Vision for counting fingers was limited to 3 meters, the patient was severely depressed, cushioned, and growth-retarded with glaucoma, and had stopped attending school for the last year. Professor Tugal-Tutkan recommended anti-tumor necrosis factor (TNF) treatment, which was not available, whereas RTX was available. Review of the literature showed that no one had used


R. M. R. Umran & Z. Y. H. Shukur

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Figure 1. Before RTX treatment. (a) right eye, (b) left eye.

it for the treatment of VKH in children, although there was one report documenting the use of RTX in a 41-year-old woman with refractory VKH [7]. Written consent was obtained from the Iraqi MOH Rheumatology consultancy committee, and written consent was provided by the parents to commence a trial of RTX 375 mg/m2 at 0, 1, 6, and 18 months, with close monitoring by the pediatrician and local ophthalmologist. There was no change in the patient’s condition during the first month of treatment, but during the first week after the second dose, there was marked improvement; uveitis activity decreased and vision improved with better IOP in the RE. It was decided to implant an Ahmed valve in the LE. One month after the third dose (May 13, 2013), the patient’s vision was 6/36 for both eyes, and IOP was 10 and 11 mmHg, with no inflammatory activity. The patient returned to school after 4 months and did well. The fourth dose was given in May 2014, and the Ahmed valve was removed with improved stability in both eyes (Fig. 2). The only adverse event associated with the use of RTX therapy was shivering, which was noticed after the first 10 mL of treatment was infused in the first dose. This was treated with hydrocortisone 100 mg intravenously, and by reducing the infusion rate, hence it was not required in subsequent RTX infusions.

Discussion To the best of our knowledge, this is the first report of the efficacy of RTX in the management and long-term control of childhood, sight-threatening, advanced, and refractory VKH. VKH has been reported in childhood in a very limited number of publications. Professor Tugal-Tutkan found that childhood disease was encountered in 15% of cases with VKH in the Turkish population [8]. It was reported that childhood VKH was more aggressive and less responsive to standard management, carried more severe ocular complications than that seen in adults, and caused rapid deterioration in vision [9].

In this case, the diagnosis of VKH was very late and corticosteroid treatment was started in the advanced, complicated phase of disease when vision was severely affected. Immunosuppressive therapy (methotrexate) showed no effect and even when INF was used, the patient did not respond. INF was used by Gueudry et al. [10] for the treatment of severe sight-threatening uveitis associated with Behçet’s disease. They showed long-term response in 88% of treated patients and associated this response to the suppressive effect of this immune modulator agent. The ineffective use of INF in our case may be because of severe, late, and complicated presentation. Infliximab, an antibody to TNF-alpha, has been shown to be effective in the treatment of both anterior and posterior uveitis. The response was rapid in Behcet’s related uveitis whereas nonBehcet’s uveitis responds more variably [11]. Tugal-Tutkun et al. found similar results in a study of 20 children with uveitis [12]. Infliximab has shown good results in pediatric and adult patients with acute VKH disease refractory to conventional treatment with combination of immune-modulatory agents and corticosteroids [1,3,9]. Some patients showed relapse despite increasing the dose and frequency of infliximab infusions, while others developed infusion-related allergic reactions. These, with the reports of serious adverse effects of infliximab therapy, including increased risk of malignancy, tuberculosis, multiple sclerosis, and lupus-like reactions [11] were the main limitations for the use of infliximab in children, as well as the U.S. Food and Drug Administration (FDA) report of the association between TNF-alpha inhibitors and an increased risk of lymphoma in children [9]. Rituximab (RTX) was approved by the FDA for treatment of patients with relapsed or refractory lymphoma, and the use was extended to non-malignant conditions like rheumatoid arthritis (RA) and autoimmune diseases. The mechanism at which RTX causes B-cell death is, however, likely to be a combination of antibody-dependent cell-mediated cytotoxicity, complement-mediated lysis, growth inhibition, and apoptosis [13]. The effectiveness of Figure 2. After one year from the start of RTX treatment. (a) left eye, (b) right eye.

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DOI 10.3109/14397595.2015.1071234

Rituximab for sight-threatening refractory pediatric VKH disease

treatment with an anti-CD-20 monoclonal antibody RTX in a T-cell-mediated disease like VKH disease might be surprising; however, changes in B and T lymphocytes after RTX treatment in multiple sclerosis have been analyzed [7]. Therefore, B-cell depletion with RTX might represent a therapeutic strategy not only in the autoantibody-associated disorders, but also in T-cell-mediated diseases. Further investigations on the role of B lymphocytes in VKH disease are needed to explain and establish RTX’s effectiveness in difficult-to-treat patients. Arnd Heiligenhaus et al. [14] reported successful use of RTX in the achievement of inactivation in 7 out of 10 cases with juvenile idiopathic arthritis (JIA)-associated uveitis. This referred to the anti-CD20 effect of RTX and confirmed the role of B cell in the pathogenesis of JIA-associated uveitis by serial measuring of peripheral blood CD20 cells, which was decreased within 6 months and returned to pretreatment levels within 12 months. The favorable results on the efficacy of RTX in intractable ocular lesions of patients with Behcet’s disease, in spite of the fact that it is mainly a T-cell-driven disease and the response of inducing long-term remissions in different ocular and rheumatic inflammatory diseases such as the report of response of recalcitrant and long-standing chronic JIA-associated uveitis in adults and children, [13] all these observations encouraged us to use RTX in our patient. Rituximab’s (RTX’s) safety and tolerability has been well described in the clinical trials of patients with RA and nonHodgkin’s lymphoma. The most frequent adverse event is an infusion reaction. The main caution with the use of RTX, especially when used with concomitant immunosuppressive therapy, is the high incidence of systemic infections; conversely, no infectious complications have been reported for patients in whom RTX was used alone [13]. Depending on these reports that documented the limited adverse effects of RTX in comparison with infliximab and the successful use of RTX in the previous adult reports [7,15], we decided to treat this patient with RTX. In this patient, we report a favorable tolerance to RTX infusion in children; no significant adverse effect of the drug was recorded. After 28 months, the follow-up showed unremarkable events. We conclude that RTX showed notable efficacy in a pediatric patient with refractory, complicated, VKH, with good long-term control. We recommend further studies and trials to comprehensively assess this promising low-risk, effective treatment for the management of this condition.

Acknowledgements We deeply appreciate the cooperation of Professor Tugal-Tutkan from the Ophthalmology Department of Istanbul University. We are also grateful


to the pharmacists and the pharmacy department for their cooperation in making the drugs available.

Conflict of interest None.

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Rituximab for sight-threatening refractory pediatric Vogt-Koyanagi-Harada disease.

Rituximab was trialed in a refractory Vogt-Koyanagi-Harada disease (VKH). A 10-year-old girl with panuveitis recalcitrant to treatment, including cort...
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