Article Text
Abstract
Diffuse subretinal fibrosis uveitis (DUS) syndrome is a rare form of granulomatous multifocal choroiditis (MFC) characterised by enlarging areas of subretinal fibrosis (SRF) which coalesce with subsequent macular involvement and visual loss. First described by Palestine, DUS carries a poor visual prognosis despite use of high-dose corticosteroids and systemic immunosuppression. We report two cases of bilateral DUS successfully treated with rituximab. We believe given the B-cell predominance in the underlying pathogenesis of the disease, rituximab should be considered first line in the management of this potentially devastating disease.
- Immunology
- Inflammation
- Retina
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Introduction
Diffuse subretinal fibrosis uveitis (DUS) syndrome is a rare form of granulomatous multifocal choroiditis (MFC) characterised by enlarging areas of subretinal fibrosis (SRF) which coalesce with subsequent macular involvement and visual loss. First described by Palestine et al,1 DUS carries a poor visual prognosis despite use of high-dose corticosteroids and systemic immunosuppression (SI). We report two cases of bilateral DUS successfully treated with rituximab.
Report of cases
Patient 1
A 48-year-old man was referred in February 2007 with perception of light and count fingers vision in his right (RE) and left eye (LE), respectively. Anterior segments (AS) were unremarkable with normal intraocular pressure (IOP). Inferior serous retinal detachments (SRD) were present, confirmed on ultrasound (figure 1A,B,E,F). Visual evoked potentials were normal, but electroretinography (fERG) responses were reduced in LE and undetectable in RE. The patient's eye condition had previously not responded favourably to high-dose systemic steroids and tacrolimus, with which he was treated for the previous 6 months. One month after referral, he was treated with rituximab using a protocol designed for treatment of non-Hodgkin's lymphoma,2 namely intravenous infusion of 375 mg/m2 body surface area/once weekly for a period of 8 weeks, while continuing on 20 mg oral prednisolone daily. The SRD completely resolved after the third rituximab dose. A year after his last infusion, the patient developed a lesion on one toe of his right foot. A biopsy of this lesion revealed a soil-based fungus pleosporaceae, which was treated with systemic antifungals. After his last rituximab infusion, the SRD had resolved completely. Eight weeks from the end of treatment, visual acuity (VA) improved to 20/200 RE and 20/80 LE but his fERG were still severely reduced. He continued to improve and at the latest review, following a drug free period of 34 months, VA were RE 20/200 and LE 20/30. Both eyes were quiescent with inactive, non-progressive SRF. ERG showed amplitude improvement in both eyes (figure 1I,L).
Patient 2
A 14-year-old woman was referred with a 2-year history of 20/200 vision in her LE (RE was 20/20). AS and IOP were normal. There was an inactive subfoveal inflammatory membrane which had been treated with photodynamic therapy elsewhere and a small area of SRF in the infero-temporal mid-peripheral retina in RE (figure 1C,D). Her LE revealed gross cystoid macular oedema (CMO) with an underlying macular scar, peripapillary SRD and a mid-peripheral circumferential ring of SRF, which was extending, despite treatment with systemic steroids, tacrolimus and mycophenolate mofetil. In January 2007, she was treated with rituximab infusions over a period of 8 weeks as per protocol reported above for Patient 1. Systemic steroids were tapered over 2 years and stopped in February 2010. At latest follow-up, both eyes were quiescent with no further progression of SRF and VA of 20/20 in RE and 20/200 in LE (figure 1G,H,J,K). The poor vision in the left eye was attributed to the longstanding CMO and underlying structural macular changes.
Comment
DUS is characterised by progressive SRF and visual loss despite the use of SI.1 Usually seen in otherwise healthy patients, it has also been associated with VKH.3 Histopathological studies of enucleated eyes revealed retinal and SRF with loss of photoreceptors and an inflammatory cell infiltrate with B-cell predominance.4 For this reason, the anti-B cell monoclonal antibody rituximab2 was our choice of treatment for the patients who had not responded to previous therapies of systemic steroids and immunosuppressants.
Alternative immunomodulatory therapies have been applied in previous cases of DUS. Both cyclophosphamide5 and Infliximab6 (antitumour necrosis factor-α monoclonal antibody) are reported in the literature, but neither showed stabilisation nor improvement of retinal function.
Rituximab is a chimeric-monoclonal antibody that binds to CD20 expressed on B-cells, a molecule involved in complement activation, cell-mediated cytotoxicity and apoptosis. In the two patients reported herein, the total white blood cell count was normal prior, during and after treatment with rituximab. Detailed flow cytometry of peripheral white cells from the Case 2 revealed post-rituximab B- and T-cell (including CD4 and CD8 cells) lymphopenia, which lasted for approximately 2 years. These then returned to normal values, and have remained normal in subsequent follow-up. Our report highlights the efficacy and safety of rituximab in halting the progression of the disease by specifically targeting B-cells.
In Case 1, the patient had no previous history of toe infection and had developed the disease 1 year following his last rituximab infusion. In retrospect, a subclinical fungal infection may have contributed to or even been the inciting trigger for the posterior uveitis, leading to DUS. The presence of subclinical infectious disease should be considered in cases of sight-threatening uveitis, and treatment using a combination of an antimicrobial and immunosuppressant drugs used in an attempt to preserve sight.
Footnotes
Contributors Conception and design: KSC, LK, JVF; Drafting article: KSC; Revising and critical appraisal: KSC, LK, JVF; Final approval: KSC, LK, JVF.
Competing interests None.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.