28 Anterior uveitis

Background

Anterior uveitis (AU) is inflammation of the anterior uvea, that is the iris, ciliary body, or both. No population-based study has established the incidence of uveitis. Most studies emanate from sub-specialist tertiary referral centres and are subject to patient selection and referral bias. Nevertheless, there is some level of agreement that in the West (from where all such studies emanate) the annual incidence of uveitis is about 15 to 20 cases per 100 000 population. McCannel1 makes a direct contemporaneous comparison between uveitis presenting to generalists and specialists. The higher proportion of AU (about 90%) in these generalist studies is striking and almost certainly more representative of uveitis in the general population.

From these figures, one would expect an average general ophthalmologist serving a population of 90,000 in the United Kingdom to encounter a new episode of uveitis about once every three weeks, the vast majority being AU, as this is quite a common disease. A small minority of cases of AU have infective causes and require specific treatment (such as herpetic uveitis). However, the majority, despite perhaps being associated with HLA-B27 or a systemic inflammatory diseases, are idiopathic.

Untreated recurrent AU frequently led to blindness. Duke-Elder, writing in 1966,2 found that “eventually the iris becomes widely scarred, atrophic and completely bound down to the lens by annular fibrous synechiae, the pupil becomes occluded by a connective tissue membrane, and cataract, glaucoma or phthisis results”. Prior to the introduction of topical corticosteroids for uveitis in the late 1940s, treatment was confined to mydriasis and cycloplegia with heat, rest and fresh air, in some cases supplemented by sub-conjunctival mercury or iodine; oral gold, arsenic, or salicylates; fever therapy induced by repeated intramuscular cow’s milk; irradiation, paracentesis, or iridectomy. Frequently unsuccessful, Duke-Elder concluded that “when all ameliorative measures have failed and the eye is shrinking or hard and painful, relief may be gained by a retrobulbar injection of alcohol … or the final expedient of evisceration or excision”. The introduction of topical steroid treatment for anterior uveitis was immediately perceived as a huge success; controlled studies were not performed, but the results compared with previous experience were strikingly improved.3,4

Idiopathic AU is currently treated on the basis of clinical appearance. The ophthalmologist will wish to remove inflammation as quickly as possible, to provide adequate analgesia, to minimise complications largely caused by progressive scarring subsequent on the release of fibrinogen into the aqueous humour, and to restore the patient to normal vision while sparing any undesirable consequences of treatment. How is this best achieved?

Question

There is such a paucity of high-quality evidence on the management of AU that only a small number of questions can be approached. Some important questions for which there are no evidence-based answers appear in the final summary. Those that have some supporting evidence are:

1Do topical steroids modify the course of AU?

2Are some topical steroids better than others?

3Are some steroids more likely to induce glaucoma?

4Are topical or systemic non-steroidal anti-inflammatory drugs effective?

5Are there any other effective treatments?

6Is there any treatment available that inhibits recurrences of AU?

Question

Do topical steroids modify the course of AU?

The evidence

No controlled trials were performed when topical steroids were first introduced to treat uveitis. Their use rapidly became widespread in the early 1950s and their efficacy unquestioned. In 1979 Dunne and Travers5 published the results of the first trial, a randomised doublemasked placebo-controlled comparison of topical treatment with betamethasone or clobetasone. In addition, all patients received the same dose of cycloplegic. The test population (60, reducing to 48 after exclusions) was too small to allow

analysis of the comparison between steroids to reach statistical significance. Treatment failures (all on placebo) were excluded from the analysis. However, topical betamethasone was found to be significantly better than placebo.

Young et al.6 compared topical prednisolone with a topical non-steroidal anti-inflammatory drug (NSAID) and placebo in 92 patients. Cycloplegia was used. There were multiple observers, and the treatment was adjusted according to perceived clinical need, but not according to a protocol. At the 21-day stage (defined as the end-point) cases were described as cured or not cured (the term “cured” was not defined). On this basis there was no significant difference between treatments, but at seven days only prednisolone showed an effect, and at 14 days, only prednisolone and NSAID.

Comment

The Dunne and Travers study was notable for being the first in this area to use a controlled structure and appropriate statistical analysis. However, it used an empirical and subjective scoring system for measurement of efficacy and did not use a single observer. The use of symptoms to measure efficacy is of dubious validity when cycloplegics are used (even when used in an identical fashion for all patients).

In the Young study the assessment criteria were of dubious value and the sample size was again almost certainly too small.

The evidence, albeit sparse, is that topical steroids are effective in treating AU.

Question

Are some topical steroids better than others?

The evidence

Dunne and Travers5 compared betamethasone and clobetasone but their sample size was too small. Dunne et al.7 compared prednisolone with betamethasone (and a NSAID) in a three-arm randomised double-masked trial, again using cycloplegia in all patients. While betamethasone was consistently better than prednisolone, the comparison did not reach statistical significance, probably because the test population was too small.

Topical loteprednol has been compared with prednisolone acetate8 in a randomised double-masked trial. Symptom evaluation, including pain level, was part of the assessment of efficacy, but variable doses of cycloplegia were permitted. Nevertheless, prednisolone acetate was found to be statistically better than loteprednol in its anti-inflammatory effect.

Comment

The evidence supports a difference in efficacy between certain topical steroids. Unfortunately comparisons have not been made between the most commonly used steroids.

Question

Are some steroids more likely to induce glaucoma?

The evidence

The loteprednol etabonate US uveitis study group8 compared that drug with prednisolone acetate, in a randomised double-masked study on 175 patients. Loteprednol was felt to have a less marked effect in intraocular pressure, but the difference was not statistically significant.

Comment

No statistically significant evidence from controlled trials has been published to support the contention that different steroids are more or less likely to induce glaucoma.

Question

Are topical or systemic non-steroidal anti-inflammatory drugs (NSAIDS) effective?

The evidence

Dunne et al.7 compared the topical NSAID tolmetin with prednisolone and betamethasone, in a randomised doublemasked trial. This three-way comparison was too complex for a population of 71 (decreasing to 60 after exclusions) to answer the question satisfactorily. Tolmetin was the least effective of the three methods of treatment, but none of the comparisons was clinically significant. It was claimed that tolmetin was an effective treatment, but the study was not placebo-controlled.

Young et al.6 compared topical tolmetin with prednisolone in a placebo-controlled trial. Tolmetin was reported to be less effective than prednisolone but more effective than placebo. No comparison reached statistical significance, possibly because of an inadequate sample size.

Sand and Krogh9 compared topical dexamethasone with topical indometacin in 49 patients (falling to 43 after exclusions). It appears that the patients were recruited from 10 different centres, with multiple observers, and the use of cycloplegia was uncontrolled. The measures of disease

activity were crude and subjective. Dexamethasone was found to be significantly better. The study concluded that indometacin was a useful alternative to a topical steroid, but this study was not placebo-controlled.

Hunter et al.10 compared oral oxyphenbutazone (with topical placebo) with topical hydrocortisone (with oral placebo) in a randomised double-masked trial sponsored by its manufacturer. A single observer was used. An effect for oxyphenbutazone was reported, but the trial was not placebo-controlled and there was no statistical analysis. The choice of hydrocortisone as a steroid comparator was interesting, as this is probably the weakest of the available steroids and was not generally used to treat uveitis. There is inadequate evidence from this study for a therapeutic effect from oral oxyphenbutazone.

Comment

There is no evidence that topical or oral NSAIDs are effective in endogenous AU.

Question

Are there any other effective treatments?

The evidence

Van Rooij et al.11 examined the effect of oral vitamins C and E on AU, in patients who were otherwise treated identically with topical steroid and cycloplegia. The rationale for the study was that both vitamins are known scavengers of free radicals. The study is the only one to use an objective measure of activity, in the laser cell/flare meter, and was randomised and double-masked. The study size was 145, reducing to 130 after exclusions. The vitamins did not have a significant effect on inflammation.

Comment

There is no evidence of any effective treatment for AU, other than steroids.

Question

Is there any treatment available that inhibits recurrences of AU?

The evidence

We found two studies that have addressed this issue. Palestine and Nussenblatt12 observed the effect of oral

bromocriptine on a group of 14 patients. The study was randomised and double-masked. No effect was demonstrated over one year.

Comment

There is no evidence that any treatment can prevent recurrences of AU.

Implications for practice

Evidence of the management of AU is limited both in quantity and quality. We found only nine controlled trials that have addressed any aspect of management. The little evidence that exists does support the efficacy of topical steroids, and this treatment is well-established. Hard evidence on the efficacy of other modes of treatment requires further research.

Implications for research

One trial was excluded from review because of poor quality. Others referred to have relatively low statistical power and in several cases, poor study design. The use of topical steroids in AU is so well-established that placebocontrolled trials will be considered unethical. Nevertheless, many questions remain unanswered. What is the best mydriatic/cycloplegic regime for AU? Can cyclopentolate provoke inflammation? When, if ever, are sub-conjunctival steroids necessary? What is the true relationship between the commonly used steroids in terms of efficacy? What are the true relative risks of induced glaucoma for the different steroids, and is there simply an inverse relationship between efficacy and glaucoma induction? Are all the topical steroids cataractogenic? In what circumstances, if ever, should intracameral fibrinolysis be used? Are systemic steroids ever justified? Can we prevent recurrences of AU?

We do have the ability to answer these questions with carefully designed trials of adequate statistical power, using objective methods of assessment and controlled observation. Such studies are long overdue.

References

1.McCannel CA, Holland GN, Helm CJ et al. Causes of uveitis in the general practice of ophthalmology. Am J Ophthalmol 1996;121:35–46.

2.Duke-Elder S. The treatment of uveitis. In: Duke-Elder S. System of Ophthalmology Vol IX: Diseases of the Uveal Tract. London: Henry Kimpton, 1966, pp.167–78.

3.Duke-Elder S. The clinical value of cortisone and ACTH in ocular disease. Br J Ophthalmol 1951;35:637–71.

4.Duke-Elder S, Duthie OM, Foster J et al. A series of cases treated locally by cortisone. Br J Ophthalmol 1951;35:672–94.

Glaucoma as a subspecialty holds the largest number of trials in ophthalmology, but unfortunately most of them are of limited relevance to clinical practice since they are largely comparative studies of the effect of medications or other interventions on intraocular pressure. The question, “Are interventions for lowering IOP effective in preventing progression of disease?” has been much less frequently dealt with. The former studies have been omitted from this section as they add a huge, and uninformative excess to the content of the section which needs to be brief and succinct to adhere to the overall requirements of the book.

Space limitations mean the section deals with issues relevant only to the treatment of disease. Organisation of

care, and case detection methods are of course very important, but are not covered here. Management of secondary disease is also not included but there are very few trials dealing with this.

Until quite recently, the evidence base for the effectiveness of therapy has been thin, but recent National Eye Institute funded studies have changed this.

Modification of wound healing in glaucoma surgery has been the subject of numerous RCTs and hence a separate chapter focusing on these has been included.