Effect of Intravitreal Methotrexate and Rituximab on Interleukin-10 Levels in Aqueous Humor of Treated Eyes with Vitreoretinal Lymphoma

Abstract

Intraocular cytokines are promising diagnostic biomarkers of vitreoretinal lymphoma. Here, we evaluate the utility of IL-10, IL-6 and IL-10/IL-6 for discriminating lymphoma from uveitis and report the effects of intraocular methotrexate and rituximab on aqueous cytokine levels in eyes with lymphoma. This is a retrospective case series including 10 patients with lymphoma and 7 patients with uveitis. Non-parametric Mann-Whitney analysis was performed to determine statistical significance of difference in interleukin levels between lymphoma and uveitis. Compared to eyes with uveitis, eyes with lymphoma had higher levels of IL-10 (U = 7.0; two-tailed p = 0.004) and IL-10/IL-6 (U = 6.0; two-tailed p = 0.003), whereas IL-6 levels were more elevated, although insignificant, in those patients with uveitis than in lymphoma (U = 15.0; two-tailed p = ns). Using a receiver operating characteristic analysis to identify threshold values diagnostic for lymphoma, optimal sensitivity and specificity improved to 80.0% and 100%, respectively, for IL-10>7.025 pg/ml and 90.0% and 100.0%, respectively, for IL-10/IL-6>0.02718. In patients in whom serial interleukin levels were available, regular intravitreal treatment with methotrexate and rituximab was associated with reduction in IL-10 levels over time. In conclusion, optimal IL-10 and IL-10/IL-6 threshold values are associated with a diagnostic sensitivity ≥80% and specificity of 100%. Therefore, these cytokines may serve as a useful adjunct in the diagnosis of lymphoma. While negative IL-10 and IL-10/IL-6 values do not exclude a diagnosis of lymphoma, elevated levels do appear to be consistent with lymphoma clinically. Moreover, elevated levels of IL-10 in the setting of a clinically quiet eye may point to impending disease recurrence. Lastly, once lymphoma is diagnosed, IL-10 levels can be monitored over time to assess disease activity and therapeutic response.

Vitreoretinal Lymphoma versus Uveitis: Cytokine Profile and Correlations

“…An IL-10:IL-6 ratio 41.0 is highly suggestive of PVRL [15][16][17] and this can be measured in the vitreous fluid as well as in the aqueous humor due to diffusion of interleukins from the posterior to the anterior chamber. 18 Even though the determination of IL-10 and IL-6 concentration in the anterior chamber appears to have insufficient sensitivity and specificity to be used as the sole diagnostic tool, 19 we have recently demonstrated that IL-10 concentration in aqueous humor correlates with disease activity and therefore may be useful to evaluate the effect of treatment in PVRL 20 .…”

Cytokine Profiles in Aqueous Humor and Plasma of HIV-infected Individuals with Ocular Syphilis or Cytomegalovirus Retinitis

“…Intravitreal drugs targeting different cytokines for the treatment of local inflammation in chronic non-infectious uveitis have given promising results. [34][35][36][37][38] Identification of the cytokines involved in the pathogenesis of different OIs in HIV-infected individuals has important implications for the development of drugs targeting these cytokines, particularly in cases of persistent inflammation after successful treatment of active ocular infections.…”

Primäre vitreoretinale Lymphome

“…Einige Zentren setzen sich für die Bestimmung der Zytokinlevel innerhalb der okulären Flüssigkeiten ein, um eine weitere diagnostische Hilfestellung zur Zytologie mit Nachweis oder Ausschluss der PVRL zu erhalten [2, 51,55,56,57,58,59,60]. Dies betrifft das Kammerwasser und die Glaskörperflüssigkeit.…”

“…Der exakte Wert für die IL-10-Konzentration oder die IL-10:IL-6-Ratio variiert zwischen den verschiedenen Laboratorien hauptsächlich wegen der Unterschiede der angewendeten Methoden und der unterschiedlichen Konditionen in der Probengewinnung, der Techniken und der Gerätschaften, die zur Bestimmung benutzt werden, einschließlich der (bekannten oder nicht bekannten) Verdünnung der Glaskörperproben und der eigenen Laborerfahrung. Interleukinwerte und -verhältnis wurden auch während der Therapie als Krankheitsverlaufsmarker eingesetzt [57,59,60].…”