The Role of Sex in Uveitis and Ocular Inflammation

Ian Y. L. Yeung, MD; Nicholas A. Popp, BS; Chi-Chao Chan, MD

Disclosures

Int Ophthalmol Clin. 2015;55(3):111-131. 

In This Article

Female Predominant Uveitides With Systemic Involvement

Systemic autoimmune diseases affect approximately 8% of population, mostly among women.[4] Uveitides with systemic involvement are quite similar with a higher prevalence in women than men (Table 1).[3] Juvenile idiopathic arthritis (JIA) is a group of autoimmune arthritides that affect children below the age of 16.[25,26,77] It is more common in females and depending on the subtype, 50% to 80% of JIA patients are female.[27] Uveitis is a common manifestation of the disease, occurring in 10% to 45% of JIA patients.[25,26,28] The most typical uveitic presentation is a chronic insidious bilateral anterior uveitis, which is thought to confer the greatest risk to vision due to the lack of a red eye and its onset in preverbal children.[29] Female, antinuclear antibody-positive, and oligoarticular arthritic JIA children are at the highest risk for uveitis.[25,26,29,78,79] Whereas females are more likely to develop uveitis, males with JIA can present with enthesitis, which is linked to the presence of human leukocyte antigen (HLA)-B27 (60% to 70%).[29] However, when uveitis is found in male patients, it is often more severe with a higher rate ocular complications, including posterior synechiae.[29,80] Males also have a higher rate of complications; after 8 years of follow-up in a cohort of patients with JIA-associated uveitis, 40% of males had at least 1 ocular complication compared with 10% of females.[81] This increased severity, however, reduced prevalence in the male sex is also seen in other autoimmune diseases.

SLE is an autoimmune disorder that causes immune complex–mediated damage affecting many organs, which is associated with the production of autoantibodies against nuclear material.[7] Eighty-eight percent to 90.5% of SLE patients are women.[7,10,11] SLE commonly affects Asian and African women in their reproductive years.[82–84] Increased levels of estrogen and progesterone (eg, pregnancy, postpartum status) can cause worsening of SLE.[5,7] This is likely due to upregulation of a Th2 immune response leading to increased antibody synthesis. Although ocular findings are not one of the components of the classification criteria for SLE, SLE is associated with keratoconjunctivitis sicca and posterior-segment pathology.[5,85] SLE can cause lupus retinopathy with the clinical appearance of a Purtscher-like retinopathy.[86] Retinal vasculitis and retrobulbar optic neuritis are the uncommon inflammatory complications of SLE.[87] Although men have a lower prevalence of SLE than women, they are at higher risk for SLE-related complications, including systemic thromboses, nephropathy, and central nervous system involvement. Thus, male sex has been proposed as a predictor for poor systemic outcomes, but the exact etiology remains unclear.[5,88,89]

Multiple sclerosis (MS) is a chronic episodic demyelinating noninfectious autoimmune disease of the central nervous system. MS is much more prevalent in women, with 78% of patients being female with a mean age of diagnosis of around 37 years.[12,90] MS varies geographically with a lower incidence in Asia and a higher incidence in countries away from the equator.[91] This suggests a role for genetic, epigenetic, or noninfectious environmental factors.[12] Hormonal changes have been implicated in the disease; it is known that women, although more likely to develop MS, will have fewer relapses during pregnancy, suggesting that changes to the hormonal profile of these women affects the course of the disease.[12,90] This hypothesis has been supported by further testing in rodent MS models, wherein T-lymphocyte transfer from female rats was more effective at instigating disease than from male rats.[92] Ocular manifestations of MS range from optic neuritis, internuclear ophthalmoplegia, nystagmus, and uveitis including intermediate uveitis (IU) and retinal periphlebitis.[12] Interestingly, 56% of cases are granulomatous and >90% are bilateral.[93,94] Uveitis, in particular, shows a female predisposition, although it is uncertain if this is solely because MS is more common in females (upwards of 88% of MS patients with uveitis are female).[12,93,94] Idiopathic IU that often has similar clinical findings of MS is slightly more prevalent in females, with 56% of IU patients being female. However, IU in children under the age of 16 are more common in males (61%).[95]

Sarcoidosis is a systemic granulomatous inflammation in multiple organs of unknown etiology. Globally, it is slightly more prevalent in women (55% to 64% of those diagnosed are female).[34,96,97] Although sarcoidosis can affect many organs and both the sexes, ocular involvement is more common to females.[96] Ethnically, it is 10 to 20 times more prevalent in African Americans than whites.[5] However, female sex and white race are associated with a worse visual outcome, with white females having the highest occurrence of cystoid macular edema.[5,97–100] A second peak in sarcoidosis diagnoses occurs after the age of 50; 83.3% of patients diagnosed with late-onset sarcoidosis were female, compared with 50% in the younger cohort. Uveitis in this older group was also more likely in females (80%) compared with males.[101] In the eye, sarcoidosis commonly presents as a bilateral granulomatous anterior uveitis. Posterior/pan-uveitis and periphlebitis can also occur, and posterior segment involvement is associated with a worse visual outcome.[5,97]

Vogt-Koyanagi-Harada disease (VKH) is an autoimmune disorder that involves the eyes, ears, skin, hair, and meninges. Worldwide, women are more frequently affected than men. In Brazil, 70% of VKH patients were female,[14] in the United States, 78.7%,[15] and in India, 84.4%.[16] VKH tends to affect patients with Asian, Middle Eastern, Hispanic, and Native American ancestry.[102,103] Acute VKH uveitis frequently presents with bilateral multifocal exudative retinal detachments. Other signs include mutton-fat keratic precipitates, anterior uveitis, iris nodules, posterior synechiae, vitritis, diffuse choroidal infiltration, Dalen-Fuchs nodules, and papillitis. Sugiura sign and a sunset-glow fundus can occur in the convalescent (chronic) stage.[17] Long-term sequelae include choroidal neovascularization (CNV), subretinal fibrosis, and cataracts.[102,104] Similar to other uveitic conditions with systemic involvement, sex affects the prognosis;[17] a male VKH patient is significantly more likely to have a poorer visual outcome than a female patient. An Indian group found that 37.5% of their male VKH patients had vision worse than 20/80, compared with only 3.3% of their female VKH cohort.[105] The reason for the poorer male visual outcomes is unclear, although female sex hormones and HLA-DR genes have been associated with the female predisposition to the disease.[17,106–108]

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