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• W2022644412 abstract "In this issue, Verin et al. [ 1] have shown that nedocromil eye drops are significantly more effective than the established treatment, sodium cromoglycate, at treating vernal keratoconjunctivitis, a severe form of ocular allergy which affects children. It is time to consider the future role of sodium cromoglycate in the management of ocular allergy in general. Hay fever conjunctivitis, known as seasonal allergic conjunctivitis (SAC), is a common, troublesome but not serious condition. Its clinical features can largely be attributed to the IgE-dependent release of mast cell products, which include histamine, prostaglandin D2 and leukotrienes C4 and D4. A late phase reaction has also been described, following challenge with high doses of antigen, in which persisting symptoms are associated with an increase in eosinophils and neutrophils in conjunctival scrapings and tears [ 2]. However, it is not clear to what extent these cells contribute to symptomatology in SAC, in which the main cellular change is a mast cell hyperplasia [ 3]. Treatments for SAC target mast cells and mast cell products. Oral antihistamines are effective, and conveniently address both ocular and nasal symptoms with a single preparation. Newer compounds such as astemizole, cetirizine, loratidine and terfenadine are much less sedating than the older antihistamines, although other systemic side-effects, including cardiac dysrhythmia, may rarely occur. Levocabastine, a highly specific H1 antagonist, is available in topical form. In two randomized trials comparing levocabastine (eye drops and nasal spray) with oral terfenadine, levocabastine was more effective overall, especially on days with a high pollen count [ 4, 5]. Sodium cromoglycate is an established and safe treatment for SAC, which is believed to work through inhibition of mast cell degranulation, although inhibitory effects on other cells including eosinophils have also been reported [ 6]. In comparisons with sodium cromoglycate, levocabastine has either been equally effective [ 7, 8], or better [ 9, 10] at controlling symptoms and signs, but with a similar safety profile. The superiority of levocabastine was particularly apparent during the first few days of treatment, which is an advantage given the episodic nature of SAC [ 10]. Nedocromil and lodoxamide are newer agents which in rat experiments are more potent inhibitors of mast cell mediator release than sodium cromoglycate [ 11, 12], and may have direct inhibitory effects on other cells including eosinophils [ 131415]. In one placebo-controlled clinical trial, nedocromil provided better symptom control during weeks of peak birch pollen counts [ 16], and in another trial during the peak ragweed pollen season gave significant improvements in overall disease severity [ 17]. High placebo effects, probably due to the dilution of inflammatory mediators in tears, are frequent in SAC and were found in both studies. One small clinical trial found that lodoxamide gave a significant improvement in clinical symptoms and signs compared with placebo, and was associated with a reduction in eosinophil numbers in conjunctival scrapings [ 18]. How do the newer mast cell inhibitors compare with sodium cromoglycate in treating SAC? When nedocromil, sodium cromoglycate and placebo were compared during the birch pollen season [ 19], full or moderate control of symptoms was reported for the majority of patients in each of the three groups. While some symptoms (photophobia, grittiness and itch) were better controlled by the two active preparations, there was no significant difference between these. Other studies concur that nedocromil and sodium cromoglycate are equally effective in treating SAC [ 20]. Lodoxamide was more effective than sodium cromoglycate at treating a group of patients with various types of ocular allergy, although the results for SAC were not analysed separately [ 21]. Perennial allergic conjunctivitis (PAC) is a variant of SAC in which symptoms occur throughout the year, commonly from exposure to house dust mite antigen [ 22]. It responds to the same treatments as SAC [ 6]. One study found that nedocromil was effective in treating symptoms not fully controlled by sodium cromoglycate [ 23]. Vernal keratoconjunctivitis (VKC) is a more dramatic disease which predominantly affects children and adolescents, boys more than girls. Although some patients suffer spring-time exacerbations, relapses can occur at any time of year. Symptoms of itch, burning and mucoid discharge are more intense than in SAC; signs seen in VKC but not SAC include giant conjunctival papillae and limbitis, but the most important difference is involvement of the cornea, ranging from punctate breakdown of the epithelium to plaque deposition and subepithelial scarring, sometimes with permanent visual impairment [ 24]. Important immunological differences underlie the clinical picture. As in SAC, there is conjunctival mast cell hyperplasia, but this is more pronounced and associated with a marked mast cell migration to the conjunctival epithelium [ 25]. In contrast with SAC, the conjunctiva is infiltrated with T cells of the TH2 subtype in VKC [ 26] and topical cyclosporin (not commercially available), which selectively inhibits CD4+ T cells, has shown good short-term efficacy [ 27]. A key role for eosinophils in this disease has been proposed on the basis of increased eosinophil numbers in conjunctival biopsies and tear fluid, and of eosinophils and eosinophil-derived cytotoxic products including eosinophil cationic protein in tear fluid [ 28]. VKC has usually been managed with sodium cromoglycate, although this does not give full control and supplementation with topical steroids is often required during exacerbations. However, topical steroids have serious local side-effects including glaucoma and cataract, which are particularly hard to monitor and treat in the paediatric population. Alternative safer treatments for VKC would be welcomed by clinicians. In this issue, Verin et al. have compared the use of topical nedocromil with cromoglycate in treating VKC over a period of five months, and found that nedocromil was significantly more effective, but equally well tolerated [ 1]. Importantly, nedocromil was more effective at controlling keratitis, and reduced the need for additional topical steroid therapy. These findings are in line with a previous short-term comparative study [ 29]. A further placebo-controlled study showed that nedocromil was associated with symptomatic improvement and significantly reduced neutrophils, eosinophils and lymphocytes in tear fluid [ 30]. The other newer mast cell stabilizer lodoxamide has also been compared with sodium cromoglycate in the treatment of VKC. In two studies it was superior at relieving symptoms and signs including corneal epitheliopathy [ 31, 32] Additionally, lodoxamide significantly reduced eosinophil cationic protein levels in tears, in contrast with sodium cromoglycate [ 31]. It is now known that conjunctival mast cells contain a range of proinflammatory cytokines, including IL-4, IL-5, IL-6 and TNFα, which gives them the potential to upregulate inflammation by the recruitment of other cells including eosinophils, neutrophils and T lymphocytes [ 33]. Inhibition of mast cells might therefore reduce not only inflammation caused by mediators of immediate hypersensitivity, but also the recruitment of other inflammatory cells. Whether or not this is an important mechanism in allergic conjunctivitis needs to be established: the reported inhibition of other inflammatory cells (such as eosinophils) by mast cell stabilizers in clinical studies is interesting but could also be due at least in part to a direct effect on these cells. Atopic keratoconjunctivitis, the most serious form of allergic eye disease, is virtually confined to individuals with atopic dermatitis, and leads to chronic conjunctival inflammation with fibrosis, as well as corneal vascularization and scarring [ 34]. It is clear that the pathology is complex, involving mast cells, eosinophils, activated T cells and macrophages [ 35]. There are no controlled trials of treatments, but the usual management is with a mast cell stabilizer, and topical or systemic steroids for exacerbations [ 34]. Other treatments, including topical cyclosporin and plasmapheresis, have also been tried. For SAC and PAC, current evidence favours the use of topical levocabastine as a first-line treatment. There are undoubtedly some patients who prefer the convenience of an oral antihistamine, even if this may not be quite so effective. Where alternative or additional treatments are needed, the newer mast cell inhibitors lodoxamide and nedocromil are likely to be at least as effective as sodium cromoglycate. Sodium cromoglycate with its excellent safety record will retain a role as an over-the-counter medication. For treating VKC, the evidence is clearer: sodium cromoglycate has been superseded by the newer mast cell inhibitors and either nedocromil or lodoxamide should be used: it is currently unknown which is better. As Verin's paper indicates, additional topical steroids will still be required in some cases. For AKC, the most severe and least understood type of ocular allergy, treatments remain empirical and are largely based on studies of SAC and VKC. These suggest maintenance treatment with either lodoxamide or nedocromil in preference to sodium cromoglycate, but it is likely that additional therapy with topical steroids will remain essential, until a better understanding of the immunopathology leads to a more fully effective treatment." @default.
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• W2022644412 title "The treatment of allergic eye disease: has sodium cromoglycate had its day?" @default.
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