Fuchs uveitis syndrome, also called Fuchs heterochronic uveitis, is an unilateral chronic recurrent non-granulomatous uveitis syndrome first described in 1906 by Fuchs, and its diagnosis is determined based on clinical manifestations[1]. In this paper, the clinical manifestations and ocular signs of 27 patients were studied in detail. We found our FUS patients were characterized by a mild uveitis with characteristic stellate KPs, iris heterochromia, iris nodule, complicated cataract and vitreous inflammatory reaction. The expression of inflammatory cytokines in the aqueous humor was significantly increased compared to the controls. Immune mediators play a crucial role in specific viral intraocular inflammation. The incidence of complicated cataract in FUS patients is positively correlated with the aqueous humor inflammatory cytokine levels.
The clinical features of FUS have been described in many studies, including blurred vision[13, 14], stellate KP[13, 15, 16], iris heterochromia[14], iris nodules[17], anterior chamber and vitreous opacities[18]. FUS is the most easily misdiagnosed uveitis because a comprehensive understanding of it is lacking, there are hidden incidence and its pathological mechanisms are complex. In the present study, the most common symptoms were blurred vision and floaters. Stellate KPs were noted in 16 eyes (57%). Heterochromia was observed in 21% of affected eyes. Iris nodules were present in 36% of the affected eyes. These results are similar to the above-mentioned studies.
Inflammatory mediators may play an important role in the development of uveitis, such as T helper 1 (TH1) cytokines, T helper 2 (TH2) cytokines, anti- and pro-inflammatory mediators. The TH1 cytokines are mainly responsible for the immune response against intracellular bacteria and protozoa, including IFN-γ, TNF-α, IL-2, IL-7, IL-8 and IL-12. The TH2 cytokines including IL-4, IL-5, IL-6, IL-10 and IL-13. The Th1 cells mainly mediate cellular immunity, activate macrophages to kill intracellular pathogens (including viruses and bacteria), and play an important role in immune regulation in the induction of organ-specific autoimmune diseases and anti-infective immunity. The Th2 cells are mainly involved in humoral immunity, resisting extracellular pathogens (such as parasites). As indictated in a previous report, Posner–Schlossman Syndrome (PSS) is a common misdiagnosis for FUS, and only on the basis of clinical findings, the confirmed diagnosis of FUS was often delayed (mean delay is 4.6 years)[13]. Recently, with the help of an analysis of levels of cytokine levels in the aqueous humor, Pohlmann D et al.[19] found that PSS patients showed a stronger and more active ocular inflammatory response, than FUS patients, IL-2, IL-4, IL-5, IL-6, IFN-γ and TNF-α were significantly higher in FUS and Posner-Schlossman-Syndrome patients compared to controls. Sijssens et al.[20] found that high IL-10 levels are associated with active infectious uveitis are considered to be important in early stage of infection. High IL-6 levels induce an increase in intraocular inflammation, as seen in idiopathic uveitis and in ocular infection such as toxoplasmosis gondii.
FUS is an unilateral chronic recurrent non-granulomatous uveitis syndrome accounts for 2 ~ 11% of all uveitis. There are also some studies that explore the changes in inflammatory factors in FUS patients. Pohlmann found that IL-2, IL-4, IL-5 and IL-6 were significantly higher in FUS patients compared to controls, but the level of IL-8 and IL-10 were not different. In our study, we tried to detect differences in inflammatory factors, mainly IL-6, IL-8 and IL-10, in FUS patients compared with normal eyes. We detected significantly increased levels of immune mediators (IL-6, IL-8 and IL-10) in FUS patients. High IL-10 levels are mainly associated with active infectious uveitis and are considered to be important in early stages of infection[20]. In FUS patients, increased levels of IL-10 are assumed to imply a distinctively acute inflammation triggered by RV. Our study also found an increase in the level of IL-6, which can stimulate the proliferation, differentiation and function of cells involved in immune responses and play an important role in anti-infective immune response. We also found high IL-8 levels in FUS patients, suggesting that RV induces IL-8 production and increases the gene expression of receptor of IL-8 in fibroblast cell lines. Interleukin-8 is a cytokine secreted by TH1 cells, which mainly mediate the production of immune antibodies related to the organism’s local inflammatory reaction and participate in cellular immunity and delayed hypersensitivity inflammation. IL-8 may act as a marker for inflammation in the aqueous humor in FUS. Because IL-6, IL-10 and IL-8 are expressed simultaneously, we suggest that IL-6, IL-10 and IL-8 control the migration and infiltration of monocytes/macrophages during inflammation and contribute to the viral response in FUS.
Cataract is a common complication of chronic or recurrent uveitis and is a sequelae to chronic intraocular inflammation and chronic systemic and/or topical corticosteroid therapy. The expression of pro-inflammatory cytokines in the cataract formation of non-infectious uveitis is gradually understood. Recurrent uveitis attacks may lead to lens permeability, then result in cataract[21]. Cataracts occur in many types of uveitis, such as FUS, juvenile idiopathic arthritis-associated uveitis, Behcet's disease, Vogt–Koyanagi–Harada syndrome (VKH) and ocular toxoplasmosis. In FUS patients, the incidence of complicated cataract in patients with uveitis is as high as 50%-70%. Cataract occurs in 17–36% of ocular Behcet's disease patients and the most frequent complication is posterior capsular opacification (PCO)[22, 23]. In VKH, cataract is the most common complication, with a prevalence of about 40%.
Previous clinical studies have emphasized that cataract is the most common complications in FUS patients[13, 16, 24]. Tugal-Tutkun et al.[16] found a 56% risk of cataract formation in FUS patients who did not receive steroid treatment over their 8-year follow-up period. Yang et al.[13] found cataract was appeared in 70.7% of their FUS patients. Similarly, cataract was observed in 57.14% of patients in our study. The variations reported in different studies may be related to disease duration and the chronic nature of the disease. The use of hormonal drugs to treat of inflammation also promotes the development of cataract. Current studies have confirmed the high probability of complicated cataract in patients with FUS, and there is a correlation between cataract and intraocular inflammation, but few studies have explored the association between cataract in FUS patients and the high expression of inflammatory cytokines in the aqueous humor. Thus, the relationship between the levels of intraocular cytokines and cataract in FUS is evaluated in this study. In the current study, there was a statistically significant positive correlation between the severity of cataract and IL-6 and IL-8 levels in the aqueous humor. These results confirm that the occurrence of complicated cataract in patients with FUS is positively correlated with the intraocular high expression of inflammatory factors. Studies have found that IL-8 levels are significantly higher in patients with active uveitis, while IL-6 levels rise in chronic uveitis. Cataract in FUS patients are mainly characterized by PCO. This may be because IL-6 can regulate the activity of transforming growth factor-β (TGF-β), epidermal growth factor (EGF), matrix metalloproteinase (MMP-2/-9) and immune cells, thereby playing a role in the formation of PCO. The pro-inflammatory cytokine IL-8 exerts a defence mechanism by regulating the activity of neutrophil cells. However, the persistence of IL-8 in the inflammatory response can cause different degrees of tissue damage. These main that proinflammatory cytokines play an important role in the development of complicated cataract in uveitis by interacting with other cytokines. Further studies are needed to confirm their exact effect on the course of uveitis and complicated cataracts.
The study has also several limitations. First, this study only analysed some inflammatory factors (IL-6, IL-10 and IL-8) in the patients’ aqueous humor, but did not analyse and compare the other inflammatory factors; second, the sample sizes and exploratory analysis were still limited. Further study should focus on exploring the progression of other inflammatory factors in the aqueous humor, such as TH1 cytokines, TH2 cytokines, anti- and pro-inflammatory mediators (IL-1RA, MIP-1α), chemokines (IP-10, Eotaxin, MCP-1) and growth factors(G-CSF, PDGF, FGFbasic,VEGF, GM-CSF) during the course of FUS, and their associations with PCO grade.