Arthritis and inflammatory eye disease

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 rheumatic 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 .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 .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.

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.

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 .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 .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 .

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 .Mutations in the Nod 2/Card 15 genes were reported to be associated with familial juvenile systemic granulomatosis in four families 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 NF-κB activation and possibly apoptosis .Nod 2 proteins specifically detect the muramyl dipeptide component of peptidoglycan, a cell wall constituent of both Gram-positive and Gram-negative bacteria . 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 .

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 .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. who showed that injection of lipopolysaccharide into the footpad of rats induced an acute anterior uveitis, the cellular infiltrate being mainly neutrophils. In experimental autoimmune uveoretinitis retinal antigens were injected into rats. The inflammation occurred in the posterior uveal tract and the dominant cell type was a CD4 lymphocyte.

The treatment of inflammatory eye disease is at present somewhat controversial. With respect to peripheral ulcerative keratitis (corneal melt), the treatment of choice would appear to be cyclophosphamide given intravenously, on the basis that this probably represents a form of vasculitis .

The use of TNF-α-blocking therapy in the treatment of uveitis is at present a controversial area In a recent trial of infliximab therapy in refractory uveitis, of 31 enrolled subjects 28 reached 10 weeks in the study. At the initial end-point for assessing efficacy, 18 reached 1 yr and five reached the 2-yr end-point. At these time points 22/28, 9/18 and 1/5 were characterized by treatment successes. However, there was a high frequency of adverse events, with three cases of drug-induced lupus, one neoplasm, three thromboembolic side-effects, one case of congestive heart failure and one infectious complication. Thirteen of the 18 patients who reached 1 yr of the study developed positive ANA, but this did not correlate with treatment efficacy or toxicity. Several published observations have suggested that etanercept, in spite of its efficacy in treating arthritis, may actually induce attacks of uveitis in patients who have not previously experienced such episodes. In a retrospective study of 16 patients with a variety of inflammatory eye and joint diseases, there was a universal benefit from TNF inhibition for the joint disease, but only a 38% response rate for the associated uveitis or scleritis, and in five patients ocular inflammation began only after etanercept therapy was started. However, Rosenbaum reported that three randomized studies on the effect of etanercept for ankylosing spondylitis provided reassuring data. However, more recently a report has indicated that in the context of juvenile chronic arthritis the use of etanercept was associated with an increase in relapse rates and first attacks of uveitis in children treated with it]. In a case report by Taban, a patient treated with etanercept for ankylosing spondylitis and bilateral anterior uveitis exhibited acute exacerbation of uveitis that were temporally related to etanercept injections .A recent report of 18 patients treated with anti-TNF therapy using both infliximab and etanercept showed that 13 out of 15 patients treated with infliximab had either complete or partial control of ocular inflammation, whereas all seven patients treated with etanercept failed therapy and five of these were changed to infliximab therapy; four of these achieved either complete or partial response after initiation of infliximab treatment .

In conclusion the jury is still out regarding the benefits and toxicity of different TNF-α-blockers in relation to inflammatory eye disease. It is of interest that in the endotoxin-induced uveitis model, mice treated with TNF-α antibody demonstrated an exacerbation of uveitis .Furthermore, the inflammation proceeded despite the genetic deletion of TNF-α receptors . This probably represents a neutrophil-mediated inflammatory process in comparison with the favourable effect of TNF inhibition in a T-cell mediated model of uveitis .The differential effects of infliximab versus etanercept may lie in the fact that infliximab induces cell lysis after binding to TNF-α and induces apoptosis of T lymphocytes .whereas etanercept neutralizes lymphotoxin-α. This may explain why infliximab and not etanercept is beneficial in the treatment of Crohn’s disease, but in the case of arthritis in JCA etanercept may be the drug of choice.


About Mosarrof Hossain

I am very simple person who is a pharmacist and dedicated to well being of mankind.
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