Arthritis and inflammatory eye disease.

The rheumatologist ignores the association between connective tissues diseases and the eye at his or her peril. Failure to recognize the significance of temporal headaches indicative of temporal arteritis in patients with polymyalgia rheumatica may result in acute loss of vision with blindness. In contrast, visual symptoms may only present when irreversible damage to the eye has occurred, as in the case of the insidious onset of intermediate uveitis in children with pauci-articular JCA with a positive ANA. Abnormal connective tissue components such as collagen or fibrillin (in the case of Marfan’s syndrome) may lead to different forms of arthropathy and visual loss depending on the type of collagen in the tissues involved. For example, defective synthesis of type I collagen leads to osteoporosis and blue sclera in osteogenesis imperfecta. In the very rare condition of osteoporosis–pseudoglioma syndrome, where there is a mutation in the low-density lipoprotein receptor-related protein 5 (LRP5), there is an association between reduced bone mass, resulting in osteoporosis, and a defect in vitreal macrophage function with vitreal vessel regression, resulting in blindness [1]. Patients with Stickler’s syndrome, who have a defect in the synthesis of type II A collagen, present with premature osteoarthritis requiring early joint replacement, and loss of vision due to defects in the synthesis of collagen in the vitreus, resulting in retinal detachment [2]. Defects in the synthesis of type II B collagen results in arthrogryposis and keratoconus, in which visual loss is due to changes in physical properties of the cornea [3]. Similarly, inflammatory disorders of the eye may be associated with different connective tissue disorders. There may be a strong association with particular genes but the phenotypic presentation may depend on the anatomical site of the ocular lesion. The classical example of this is the unilateral acute onset of anterior uveitis in patients with ankylosing spondylitis and other seronegative arthritides, associated with a high frequency of HLA B27. Each acute attack usually responds to local steroid drops and mydriatics and if promptly treated does not result in any residual damage to the eye. Genetic variations in proinflammatory mediators and their receptors appear to influence the susceptibility and severity of the inflammatory response within the eyes of patients prone to development of idiopathic acute anterior uveitis [4]. Intermediate uveitis involves the anterior and posterior (pars plana) ciliary body, the former affected sometimes in patients with sarcoidosis, and the latter, presenting with pars planitis, may be associated with multiple sclerosis (MS). The posterior uveal tract may be involved in patients with a number of systemic diseases, including Behçet’s syndrome. This is a polygenic disease and although no clear pattern of inheritance has been established, the most closely associated risk factor is HLA B5. It is of interest that chromosome 6 contains the HLA B5 locus and in close proximity to it are several other genes related to inflammation, including tumour necrosis factor (TNF). The TNF inhibitor infliximab has demonstrated great promise in the treatment of Behçet’s disease. In Behçet’s syndrome there is not only an inflammatory process but also a thrombotic risk, possibly related to the presence of factor V Leiden. Recently a study has shown that 44% of patients with retinal occlusive disease have the factor V Leiden mutation [5]. The Vogt–Koyanagi–Harada (VKH) syndrome is a multisystem disease characterized by acute bilateral panuveitis. Patients may present with a polyarthritis but the organs that contain melanocytes are targets of inflammation, resulting in areas of depigmentation in the skin and eyebrows (poliosis). Involvement of the central nervous system with sterile meningitis and the inner ears may also be affected. Involvement of the uveal tract results in retinal detachment. VKH is considered to be an autoinflammatory disease against melanocyte antigens [6]. VKH, like rheumatoid arthritis, is associated with HLA DR4 but the implicated HLA DR4 subtypes differ for the two diseases. Evidence suggests that a defective Fas-mediated apoptosis response is found in lymphocytes of VKH and Behçet’s disease patients [7]. Recently there has been great interest in an autosomal dominantly inherited triad of granulomatous inflammation in the uveal tract, skin and joints in a condition called familial juvenile systemic granulomatosis or Blau syndrome [8]. Mutations in the Nod 2/Card 15 genes were reported to be associated with familial juvenile systemic granulomatosis in four families [9] and different mutations of the same gene are associated with Crohn’s disease. Patients with Blau syndrome present with features consistent with Crohn’s disease. The Nod 2/Card 15 gene encodes an intracellular protein that is thought to be involved in sensing intracellular bacteria and participates in important signalling cascades leading to NFB activation and possibly apoptosis [10]. Nod 2 proteins specifically detect the muramyl dipeptide component of peptidoglycan, a cell wall constituent of both Gram-positive and Gram-negative bacteria [11]. It is suggested that Nod 2 may be expressed not only in the inflammatory cells migrating to tissues (i.e. monocytes, macrophages) but also in the tissues themselves, especially cell types that are involved in gatekeeper functions during the process of inflammation with respect to the intestinal epithelium and vascular endothelium [12]. Rheumatoid arthritis is associated with scleritis, scleromalacia perforans and corneal melt. Traditionally it was assumed that the cornea was an immunologically privileged site due to paucity of blood vessels and lymphatics. However, it is now thought that immune cells may in fact pass between the eye and the systemic vascular and lymphatic circulations but, through a process of apoptosis, become inactivated. Griffith and colleagues [13] demonstrated that the apoptosis-inducing cell membrane molecule Fas ligand is expressed on multiple ocular cells, including the corneal epithelium and endothelium. Inflammatory cells such as neutrophils and activated T cells are especially vulnerable to apoptosis induced by Fas ligand expressed on ocular cells. Approximately 50% of the corneal grafts from donor mouse strains that expressed functional Fas ligand on the corneal epithelium and endothelium, experienced long-term survival. By contrast, rejection occurred in 89–100% of the corneal grafts prepared from mutant mice that failed to express functional Fas ligand. Thus, Fas ligand creates a functional blockade of the efferent arm of the immune response. As far as the uveal tract is concerned, there are two animal models that may have relevance to uveitis seen in the human. Endotoxin-induced uveitis was described by Rosenbaum et al. [14], who showed that injection of lipopolysaccharide into the footpad