Uveitis- a rare disease often associated with systemic diseases and infections- a systematic review of 2619 patients

Uveitis is a sight-threatening inflammation inside the eye that affects both the uveal tract (which is composed of the iris, choroid, and ciliary body and which is the blood-supplying layer inside of the eye), and adjacent structures (including the sclera, cornea, vitreous humor, retina and optic nerve head). Because the disease involves recurrent intraocular inflammation, uveitis can cause transient or permanent visual impairment and ocular complications that are not responsive to therapy [1‐4]. Uveitis can occur either as a co-manifestation of various autoimmune disorders and infections or as a side effect of medications and toxins, or it can arise as a purely idiopathic ocular inflammation [3, 5‐10].

The prevalence of uveitis is estimated at 38 cases per 100,000 people, so it meets the criteria for classification as a rare disease [2, 11‐19]. It is particularly prevalent in younger people; the mean age of uveitis patients at the onset of the disease is less than 40 years of age [20‐22].

Although it is an orphan disease, uveitis is the fourth most common cause of blindness among the working-age population in the developed world, and its economical and social impact not yet been evaluated [3, 20‐22].

The referral of a patient to a uveitis expert is often delayed because uveitis is commonly unknown, and it is therefore under-recognized. This delay in diagnosis and referral increases the risk that uveitis will result in irreversible damage to various ocular structures. Prompted by the hypothesis that highlighting systemic associations would optimize the referral of patients with uveitis, we conducted this systematic review to analyze the distributions of uveitis subtypes and their extra-organ manifestations.

The institutional review board of the Medical University of Vienna approved this study. Since September 1995, data from all patients referred to the Uveitis Unit of the Department of Ophthalmology, Medical University of Vienna, were systematically recorded. A total of 2619 consecutive patient records were analyzed for this study.

The uveitis subtypes were classified based on the specific disease patterns and diagnoses following the recommendations of the International Uveitis Study Group and the Standardization of Uveitis Nomenclature (SUN) working group [23, 24]. Guided by the medical history of each patient, investigations of the anatomical location and character of the inflammation as well as subsequent diagnostics were performed using a tailored approach [25, 26]. All patients were treated in a multidisciplinary setting and referred to the respective specialist if systemic disease was suspected. Factors considered to satisfy the criteria of specific diagnosis included well-defined a etiology, typical clinical appearance and history or classification based on pathological or pathognomonic laboratory parameters.

All patients with acute anterior uveitis were typed selectively for presence of the HLA-B27 antigen, as HLA-B27–associated acute anterior uveitis with or without systemic disease is recognized as a specific uveitis entity [27]. All uveitis patients with multifocal choroiditis showing the typical clinical appearance of birdshot choroidopathy were typed for the HLA-A29 antigen [28]. These two HLA-antigen predispositions are considered to be pathognomonic when combined with the typical clinical appearance.

Diseases belonging to the white dot syndromes which will be discussed in this article are acute posterior multifocal placoid pigment epitheliopathy (APMPPE), multiple evanescent white dot syndrome (MEWDS), birdshot retinochoroidopathy (BSRC), multifocal choroiditis (MFC), punctuate inner choroidopathy (PIC), acute zonal occult outer retinopathy (AZOOR) and serpiginous choroiditis.

Descriptive statistics were computed using SPSS 17.0. Values are given as ranges, percentages or means ± standard error of the mean, as applicable.

The patient sample comprised 1339 women and 1278 men (51.1% and 48.2%, respectively). Uveitis occurred at a mean age of 38.8 ± 18.3 years (range 1-87). The age at the onset of the disease was between 17-60 years in 79.8% of the patients. 9.2% of all cases were children (<17 years) and 11% were elderly patients (>60 years).

The anatomical classification of uveitis was anterior in 59.9%, intermediate in 14.8%, posterior in 18.3% and panuveitis in 7% of cases. Figure 1 summarizes the distribution of unclassified and classified cases in these four groups.

In this study, we were able to establish specific diagnoses in 60.6% of 2619 patients; this is consistent with previous studies that reported ranges between 47 and 75% [29]. The relative frequencies of anatomical classifications are comparable to data published in other Middle European series from tertiary care centers but differ from the data of other Northern European countries, where up to 96% of the cases were reported to have anterior uveitis [30‐35]. In the posterior and panuveitis groups, the rate of unclassified cases was the lowest at around 20%, and in the posterior uveitis group the frequency of toxoplasmosis was even higher than that among unclassified cases.

Overall, the largest diagnostic group comprised patients with ocular syndromes, followed by those with infectious diseases, arthritic diseases and, lastly, non-infectious systemic diseases.

When considering all patients, the major specific entities were HLA-B27 + AAU with or without systemic disease (19.5%), herpetic uveitis (7.1%) and ocular toxoplasmosis (6.6%).

The differential diagnosis of uveitis has changed over time. Tuberculosis and syphilis, the former main causes of uveitis, are now diagnosed in only 2.4% of patients [36, 37]. More recently, however, increased frequency of these diseases has been noted. Factors that affect the changing patterns of uveitis include the rise of autoimmune diseases, appearance of new infections, description of new disease entities, better treatment of certain diseases, availability of new diagnostic tests and more refined classification of uveitis cases.

In the present study, the frequencies of different uveitis entities in different age groups were analyzed. In small children, only a few entities were discerned, including JIA, ocular toxoplasmosis, herpetic uveitis, pars planets, sarcoidosis, reactive arthritis, systemic infections and idiopathic anterior uveitis. With increasing age, the diversity of possible entities grew, reaching a peak between 30–40 years. In the elderly, the spectrum of specific diagnoses was again narrower; the major specific entities consisted of infections (herpes virus and toxoplasmosis) and masquerade syndromes. Some uveitis entities such as HCF, Behçet´s disease, and APMPPE appeared to affect adolescents or young adults with the greatest frequency; in children, JIA-associated Uveitis was most frequent. Nevertheless, most entities were observed in all age groups.

The high percentage of uveitis patients with systemic diseases and infections underpins the necessity of an interdisciplinary approach to uveitis therapy. Furthermore, rheumatologists and ophthalmologists have to be aware that a plethora of systemic autoimmune diseases and infections, as well as purely ocular syndromes, can cause uveitis. Infectious agents were involved in the cross a etiology of uveitis in almost 19% of all cases. This high percentage was mainly due to the high numbers of ocular toxoplasmosis (7.0%) and herpetic uveitis (7.1%) patients. These numbers imply that correct classification can have a decisive impact on the success or failure of therapies, and that immunosuppressive medications should not be given without ruling out infectious a etiology. However, the diagnostic quest should not lead to generalized and extensive investigations that generate unnecessary costs. The recommended course is a tailored approach in the hands of uveitis specialists and/or rheumatologists/immunologists/infectiologists with uveitis experience. This would help to reinforce existing international guidelines, raise the standards of treatment, facilitate drug development, and shed light on the prognosis and course of the disease.