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Serological tests for monitoring and predicting disease severity, course, and outcome of autoimmune intraocular inflammation
  1. Department of Ophthalmology, University of Aberdeen

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    Around 50% of cases of uveitis are classified as idiopathic, while many of the others are associated with or form part of other disease entities.12 Idiopathic uveitis comprises a spectrum of CD4+ T cell mediated MHC class II restricted, chronic autoimmune intraocular inflammatory conditions,3the underlying immunological effector mechanisms of which have many features in common with systemic conditions associated with intraocular inflammation—for example, sarcoidosis, Behçet’s disease, seronegative spondyloarthropathies, and multiple sclerosis.4 Therapy for these conditions must be tailored to treat both ocular and systemic disease, although successful immunosuppression for the ocular inflammatory component can be achieved using the same approach as for idiopathic chronic intraocular inflammation, especially if the systemic component is inactive.5 Recognising whether intraocular inflammation is idiopathic or associated with systemic disease either at the time of presentation or in the future is difficult. For example, the term “intermediate uveitis”, which includes pars planitis, not only embraces an undetermined number of disease entities, but is frequently associated with underlying systemic diseases such as sarcoidosis and multiple sclerosis. Thus a major management problem which commonly arises is because the presently available clinical tests cannot predict whether patients with intermediate uveitis have or will develop an associated systemic disease. It is well recognised that in sarcoidosis up to 30% of cases present with uveitis, sometimes years before the onset of clinical signs of the disease.6 However, this diagnostic dilemma should not cause delay in instituting early and adequate immunosuppression for sight threatening disease.

    The management of intermediate uveitis, or indeed any autoimmune chronic intraocular inflammatory conditions, centres on two broad issues: firstly, what is the likely course of disease and in particular, is there any evidence of underlying systemic disease; and secondly, when is immunosuppressive therapy required and for how long?

    Klok et al in this issue of theBJO (p 871) have shown that in a cohort of patients with presumed idiopathic intermediate uveitis, elevated serum IL-8 levels correlate with severity of disease and, in addition, testing for IL-8 may predict who will develop systemic diseases, such as sarcoidosis. Often a decision to immunosuppress is based on the natural history (that is, known poor prognosis) of the presenting clinical entity such as serpiginous choroiditis, and presence of sight threatening disease—for example, cystoid macular oedema (CMO) and/or choroiditis or vasculitis affecting the macula or optic nerve. However, as is the case with intermediate uveitis the course of disease varies between patients and is unpredictable, and unless complications, such as CMO, are present when the patient presents, the decision to commence immunosuppression may be difficult. Furthermore, despite current therapeutic strategies using combination therapy,5treatment is still constrained by side effects and/or unresponsiveness and by relapses on dose reduction. The latter is particularly apparent because the only method of monitoring disease activity is by clinical assessment, which may not reflect the true level of underlying immune activation.

    We, therefore, urgently need to develop methods of assessing immune activation, predicting outcome of disease and monitoring immunosuppressive therapy so as to anticipate relapses and reduce side effects by dose adjustments without loss of efficacy. There have to date been several preliminary reports of immunological tests which have been used to monitor therapy because of their possible correlation with inflammatory activity—for example, antineutrophil cytoplasmic antibodies (ANCA) titres in ANCA positive systemic vaculitides and ANCA positive uveitides,7 as well as in Wegener’s granulomatosis.8 Other tests include markers of CD4+ T cell activation of this cell subset (which may be reduced during immunosuppression)9-11 or the activation products which these cells produce (soluble IL-2r) since they can be identified in serum.12 More recently, raised levels of the immunomodulatory molecule IL-1ra have been found in ocular Behçet’s disease,13 indicating that the therapeutic effect may be mediated by this. All these studies remain largely unconfirmed or have not been adequately studied longitudinally and therefore currently their role in predicting disease severity remains unclear.

    Routine examination for the detection of systemic disease in chronic intraocular inflammation is frequently unrewarding. Measurements of inflammatory activity including acute phase reactants, which can be sensitive indicators of systemic inflammation (for example, C reactive protein (CRP)), are generally within normal values in uveitis,14 as confirmed in this present study. More recently, indicators of polymorphonuclear (PMN) activation, including PMN elastase and calprotectin, have been found to be raised in untreated uveitis and potentially may be used to monitor uveitis.715 IL-8 is a C-X-C chemokine interleukin produced by a variety of cells including monocytes and macrophages and has two important roles, particularly when considering the underlying pathology of uveitis and other granulomatous inflammatory diseases, such as sarcoidosis. The first is neutrophil activation, in which IL-8 combines synergistically with TNF-α facilitating leucocyte adhesion and diapedesis; the second is as a chemoattractant particularly for non-specific naive T cells. The overall effect is to increase the access of effector cells into target tissue sites of inflammation. It is not surprising, therefore, that raised serum IL-8 levels are found in patients with uveitis. The interest of the data of Kloket al is that a significantly large number of patients with intermediate uveitis and/or known sarcoid uveitis compared with other uveitides had raised IL-8 levels, although the study was not constructed specifically to measure outcome or relation to severity of disease. It also showed that IL-8 levels correlated with disease activity and the development of sarcoidosis and multiple sclerosis. Are we therefore now near to answering some of the patients’ major concerns?

    Predicting the course and outcome of disease (whether treated with immunosuppressive therapy or not) is unlikely to be available based on a single analysis of IL-8 levels. Although the present data suggest that high IL-8 levels correlate with disease activity, further study is required to provide definitive evidence that these levels vary with immunosuppression or disease activity. Furthermore, additional data are also required to provide greater predictability for IL-8 testing in systemic disease risk assessment. Future developments which incorporate a series of tests—for example, IL-8 measurement in combination with genetic susceptibility markers, may offer better predictive outcomes for individual patients, similar to strategies under development for systemic sarcoidosis which involve “genetic fingerprinting” via HLA association and specific allelic polymorphisms.1617These approaches can be adopted for ocular inflammatory disease. In addition to the association with HLA-A28 and intermediate uveitis,18 recent reports suggest that patients who are HLA-DR15 positive and have intermediate uveitis have an increased incidence of systemic findings of other diseases linked to HLA-DR15, including multiple sclerosis.19 If we can identify possible genetic polymorphisms, such as those recently reported for the HLA linked LMP2 locus polymorphisms which determine development of HLA-B27+ acute anterior uveitis (AAU) in patients with ankylosing spondylitis,2021 in combination with immunological tests such as serum IL-8 levels, we could see the development of individual risk assessment which may predict not only severity but also course and outcome of disease.


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