• Uveitis

    Acute anterior uveitis (AU) is the most frequent and prevalent form of uveitis, and about half of all patients with AU are HLA-B27-positive. HLA-B27 is the strongest genetic link to AU reported in most population studies. This article discusses the significant progress that has been made in our understanding of the clinical features, natural history and treatment of this disease.

    HLA-B27 and anterior uveitis pathogenesis

    HLA-B27 is not a single genetic entity. At least 31 different alleles encode HLA-B27 subtypes (which include HLA-B*2701 through HLA-B*2728). The distribution of these subtypes varies between populations, which accounts for the varying strengths of HLA-B27 disease associations observed between different ethnic groups. HLA-B*2705 accounts for about 90 percent of HLA-B27-positive northern Europeans, while the less common B*2702 and B*2704 are strongly associated with ankylosing spondylitis and both HLA-B*2705 and B*2702 are associated with AU.1

    Evidence from twin concordance studies and familial aggregation studies indicate that there are other non-HLA-B27 genes, both within and outside of the major histocompatibility complex (MHC) that may predispose individuals to develop AU. For example, HLA-B27-positive first-degree relatives of HLA-B27-AU patients have a 13 percent greater risk of developing AU than HLA-B27-positive individuals with unaffected relatives. Genome-wide scans of families with multiple HLA-B27-affected members with AU have identified several chromosomal regions, including parts of chromosomes 3, 5, 9, 13 and 15, associated with AU. Strong linkage was observed at a locus at chromosome 9p21-9p24, which is associated with AU.2

    Extensive studies using animal models of HLA-B27-associated inflammatory diseases have clearly demonstrated the direct pathogenic role of HLA-B27.1 Similarly, extensive evidence from clinical studies also supports a role for microbial triggers in the etiology of AU. Chlamydia trachomatis and gram-negative bacteria, such as species of Salmonella, Shigella, Campylobacter, Klebsiella, Yersinia, and recently Helicobacter pylori and Coxiella Burnetti (Q fever), have been implicated in the pathogenesis of HLA-B27-associated seronegative spondyloarthropathies and AU.1 The precise pathogenic mechanisms by which micro-organisms cause AU in HLA-B27 patients remain unclear, but it has been proposed that microbe-derived antigens presented by HLA-B27 molecules on the surface of antigen presenting cells, such as dendritic cells, may trigger CD8+ T cell immune responses. Such microbial derived antigens may have peptide sequences similar to self-antigens that are only found in uveal or joint tissue, resulting in cross-reactivity and auto-inflammation.1

    Toll-like receptors

    Toll-like receptors (TLR) of the innate immune system play an important role in protection from microbial infection and may play a role in the pathogenesis of uveitis. TLR4 expression, for example, has been shown to be expressed by uveal antigen presenting cells in the human iris and ciliary body. This provides a novel mechanism by which microbial triggers could initiate the development of AU and explains the apparent high sensitivity of the uvea to LPS (lipopolysaccharide), the ligand for TLR4. Changes in the expression and function of TLR4 and TLR2 have been observed in patients with active AU, further supporting the potential pathogenic role of these pattern recognition receptors in the development of AU.3 These TLRs could provide the missing molecular link between observations of microbial triggers and the development of AU and other immune-mediated inflammatory disorders.

    Inflammatory diseases

    HLA-B27-AU has a distinct clinical phenotype and may be associated with severe intraocular inflammation and systemic inflammatory diseases, particularly the seronegative spondyloarthropathies (SNA), such as ankylosing spondylitis (AS) and reactive arthritis.1 A recent, large, retrospective study of the prevalence of spondyloarthritis in Chinese patients with HLA-B27-AU found a high prevalence of AS (42.5 percent), which was more common among male patients, and a significant prevalence of undifferentiated spondyloarthritis (28.8 percent), which was more common among female patients. AU occurred more frequently and with an earlier onset in spondyloarthritis patients.4 In a systematic literature review of the prevalence and characteristics of AU in SNA patients, uveitis was found to occur in 33 percent of patients with AS and 25 percent with psoriatic arthritis.5 AU prevalence increased with increasing SNA duration and was higher in subjects with HLA-B27.

    Anterior uveitis prognosis

    An AU episode typically lasts six to eight weeks. Recurrent anterior uveitis has been reported to occur at a rate as high as 0.9 episodes per year, with two-thirds of subjects having at least one relapse and one-third having three relapses. The median time until relapse has been reported as 24 months between the first and second attack and 14 months between the second and third.

    AU is generally associated with a good visual prognosis, although it is not without its complications or visual morbidity. Complications in HLA-B27-AU patients are related to the number of recurrent attacks. In a study on the causes of visual impairment and blindness in individuals with intraocular inflammatory diseases, 10 percent of patients with HLA-B27-associated AU suffered legal blindness or severe visual impairment. Another case series found that seven percent of 177 patients with HLA-B27-AU demonstrated significantly decreased visual acuity of greater than two Snellen lines.

    The most important cause of reduced vision in AU patients is cystoid macular edema. Its prevalence has been reported to range from four to 30 percent (14 percent after 10 years) in HLA-B27-AU patients, although these figures were influenced by referral bias. Cataracts develop in two to 30 percent (14 percent after 10 years) of HLA-B27-AU subjects followed in long-term studies and glaucoma in five to 11 percent.6 Although AU is typically acute in onset and relatively short in duration, a recent long-term follow-up study found that chronic AU developed in 14 to19 percent of cases.6

    Diagnostic testing

    There is no consensus on the diagnostic tests indicated for initial acute AU episodes. We recommend, at minimum, a careful ocular and systemic evaluation, HLA-B27 typing, chest X-ray and syphilis serology. A recently published Canadian study of the cost effectiveness of diagnostic testing of AU patients found that ophthalmologists consistently ordered more tests than recommended by evidence-based guidelines.7 Complete blood count, erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody and rheumatoid factor, which are of little etiological relevance in adult AU patients, were the most commonly ordered extraneous tests.

    Treatment

    There are exciting new therapeutic modalities being evaluated for the treatment of SNA and associated AU, including anti-TNFa therapy and anti-CD20 (rituximab). Interestingly, anti-TNFa therapy has been reported both to cause and ameliorate AU attacks in patients treated for SNA.8 However, there is currently insufficient evidence to support the use of these newer agents. More studies are required to establish their clinical indications, efficacy and safety for treating AU.8 Fortunately, most AU attacks respond to topical treatment with steroids and mydriatics.

    References

    1. Chang JH, McCluskey PJ, Wakefield D. Acute anterior uveitis and HLA-B27. Surv Ophthalmol. 2005;50(4):364-388.
    2. Martin TM, Zhang G, Luo J, et al. A locus on chromosome 9p predisposes to a specific disease manifestation, acute anterior uveitis, in ankylosing spondylitis, a genetically complex, multisystem, inflammatory disease. Arthritis Rheum. 2005;52(1):269-274.
    3. Chang JH, Hampartzoumian T, Everett B, Lloyd A, McCluskey PJ, Wakefield D. Changes in toll-like receptor (TLR)-2 and TLR4 expression and function but not polymorphisms are associated with acute anterior uveitis. Invest Ophthalmol Vis Sci. 2007;48(4):1711-1717.
    4. Chung Y-M, Liao HT, Lin KC, et al. Prevalence of spondyloarthritis in 504 Chinese patients with HLA-B27-associated acute anterior uveitis. Scand J Rheumatol. 2009;38(2):84-90.
    5. Zeboulon N, Dougados M, Gossec L. Prevalence and characteristics of uveitis in the spondyloarthropathies: a systematic literature review. Ann Rheum Dis. 2008;67(7):955-959.
    6. Braakenburg AM, de Valk HW, de Boer J, Rothova A. Human leukocyte antigen-B-27-associated uveitis: long-term follow-up and gender differences. Am J Ophthalmol. 2008;145(3):472-479.
    7. Noble J, Hollands H, Forooghian F, et al. Evaluating the cost-effectiveness of anterior uveitis investigation by Canadian ophthalmologists. Can J Ophthalmol. 2008;43(6):652-657.
    8. Taban M, Dupps WJ, Mandell B, Perez VL. Etanercept (enbrel)-associated inflammatory eye disease: case report and review of the literature. Ocul Immunol Inflamm. 2006;14(3):145-150.