Use of intravenous cyclophosphamide in the prevention of corneal melt: justified or not?

A. R. Clewes, E. J. Tunn, S. Kaye1 and R. C. Bucknall

Rheumatic Diseases Unit and 1 Department of Ophthalmology, St Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, UK

Correspondence to: A. R. Clewes, Rheumatic Diseases Unit, Link 7c, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, UK. E-mail: adrian{at}aclewes.freeserve.co.uk

Sir, Peripheral ulcerative keratitis (PUK), or corneal melt, is an aggressive destructive or necrotizing ulceration of the peripheral cornea presumed to be due to a microangiopathic vasculitis. It can occur following surgery that involves the cornea or sclera. It can lead to rapid (hours to days) corneal melting (keratolysis), perforation and eventual complete visual loss. Importantly, it heralds the onset of a systemic vasculitis in more than 50% of cases and is associated with a high mortality [1].

PUK poses a significant problem in patients with rheumatoid arthritis (RA) undergoing surgery on the anterior segment of the eye, such as cataract surgery. Messmer et al. [2] reported that the development of necrotizing scleritis or PUK was associated with prior cataract surgery in 31% of their study population. They suggested special vigilance should be exercised in these patients postoperatively for 12 months and those patients with high risk should be immunosuppressed prior to surgery. Unfortunately, once PUK has developed, its treatment after cataract surgery has a poor ocular prognosis, despite immunosuppression and surgery, and the results are devastating (Fig. 1).



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FIG. 1. Development of a corneal scleral melt a week following surgery. Note the iris (dark) filling the centre of the defect. Figure 1b shows a failing corneal tectonic patch graft at 10 days, without immunosuppression. Note the necrotic circular tissue overlying the underlying melt. This figure may be viewed in colour as supplementary data at Rheumatology Online.

 
We have successfully used intravenous cyclophosphamide in two cases as prophylactic therapy prior to cataract surgery. These two cases were considered to have high risk of developing PUK in that both had previously lost the sight in one eye due to PUK and required cataract surgery in the remaining eye.

Case 1 was a 47-yr-old Caucasian lady with a 30-yr history of seropositive erosive RA controlled with d-penicillamine. She underwent routine cataract surgery in January 1995. There was no previous history of ocular or extra-articular manifestations of her disease. Unfortunately, she developed post-surgical PUK, eventually resulting in loss of vision. Her rheumatoid disease remained quiescent over the following 2 yr but she then developed a dense cataract in the remaining left eye.

On this occasion she was prophylactically pulsed with intravenous cyclophosphamide. This was given over a 6-month period; she received 1 g monthly 3 months prior to surgery and 3 months after surgery.

Case 2 was a 72-yr-old Caucasian lady with a 40-yr history of nodular, seropositive RA with associated Sjögren's syndrome. She had been treated previously with various second-line therapies and then maintained on oral prednisolone (2.5 mg). In 1993 she presented with a painful inflamed left eye consistent with PUK, which was treated with local therapy. This failed to respond, necessitating a corneal tectonic transplantation. No systemic therapy was given and her eye failed to recover, becoming phthisical. In 1995 she developed a PUK of her right eye. Again, she received extensive topical therapy and corneal tectonic transplantation but on this occasion also received systemic immunosuppression with two doses of intravenous cyclophosphamide totalling 1.5 g. Her eye settled, but later she developed a dense cataract. Prior to cataract surgery she received intravenous cyclophosphamide: four pulses prior to surgery and four pulses following surgery. A total dose of 6 g was given.

Surgery was successful in both cases and there was no reoccurrence of PUK or complications related to immunosuppression. Throughout, their articular disease remained quiescent and to date there has been no evidence of systemic vasculitis.

PUK is a sight-threatening condition characterized by collagen destruction, cellular infiltration and limbal vascular changes indicative of vasculitis [3, 4].

Corneal fibroblasts are responsible for the continual turnover and maintenance of the extracellular matrix of the cornea, which is in turn maintained by the balance between tissue matrix metalloproteinases (MMP-1) and their tissue inhibitors (TIMP-1). It has been suggested that possible imbalance between these is responsible for rapid corneal keratolysis [5]. It has also been postulated that the process is a cell-mediated response to corneal epithelial damage, which would help explain why PUK can be a recurrent problem with the potential of being reactivated by corneal stimuli such as intra-ocular surgery [3, 5].

The incidence of PUK in patients with RA increases after cataract surgery [2, 3, 6]. In particular, there are suggested links with the presence of Sjögren's syndrome, previous PUK or scleritis or the presence of active rheumatoid vasculitis.

Bernauer et al. [7] reported on the surgical management of 29 patients with RA-complicated corneal perforations. The authors concluded that immunosuppression significantly improved the survival of penetrating grafts (42% graft survival after 1 yr vs 11% without immunosuppression; P = 0.02) and suggested delaying graft surgery if possible for 6 weeks to allow time for adequate preoperative immunosuppression.

Treatment for spontaneous PUK is with immunosuppressive therapy and local ocular treatment. Although treatment in the form of immunosuppression is generally accepted [1, 4, 8–10], there is little consensus on which immunosuppressive agents to use. The authors have had very good results with the use of intravenous cyclophosphamide in the treatment of spontaneous PUK, and it has been widely used in destructive ocular inflammatory conditions and systemic vasculitis.

Although immunosuppression may reduce mortality following the development of PUK, there is often significant residual ocular damage. It is apparent, therefore, that prophylactic immunosuppression in high-risk patients may not only reduce mortality but also prevent the ocular complications and therefore reduce visual morbidity.

The authors have declared no conflicts of interest.

References

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Accepted 17 September 2004