Peripheral ulcerative keratitis `corneal melt' and rheumatoid arthritis: a case series
D. M. Squirrell,
J. Winfield1 and
R. S. Amos1
Department of Ophthalmology and
1 Department of Rheumatology, Royal Hallamshire Hospital, Sheffield, UK
Correspondence to:
R. S. Amos, Department of Rheumatology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK.
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Abstract
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Objectives. (1) To review the visual and systemic outcomes of patients who developed rheumatoid arthritis (RA)-associated peripheral ulcerative keratitis (PUK). (2) To describe the clinical and serological characteristics of the patients' arthropathy at the time of presentation of this rare condition. (3) To review the aetiology and management of RA-associated PUK.
Patients and methods. A case series is given of all nine patients within our unit who have developed RA-associated PUK since 1996. Details of the patients' arthropathy and the serological characteristics of the RA at presentation of PUK were noted. The patients' visual outcomes and the development of any significant systemic complications were recorded.
Results. All patients had long-standing seropositive, erosive RA. PUK was associated with a poor visual outcome in most patients, five requiring emergency corneal surgery to prevent perforation of the globe. Two patients developed systemic vasculitis within 1 month of PUK onset, one of whom died.
Conclusion. RA-associated PUK often has a poor visual outcome and its appearance may herald the transformation of a patient's RA into the systemic vasculitic phase. RA-associated PUK should be managed with aggressive immunosuppression if the associated morbidity and mortality are to be avoided. Cell-mediated mechanisms appear to be important in the aetiopathogenesis of PUK and a combination of corticosteroids and cyclosporin is therefore probably the regimen of choice.
KEY WORDS: Rheumatoid arthritis, Peripheral ulcerative keratitis, Immunosuppression, Cyclosporin
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Introduction
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The cornea and conjunctiva are frequently involved in rheumatoid arthritis (RA). Peripheral ulcerative keratitis (PUK) is a rare inflammatory disease of the peripheral cornea, usually associated with RA, which may lead to rapid corneal keratolysis, perforation of the globe and visual failure. PUK can be a manifestation of systemic vasculitis in patients with RA and without appropriate treatment may be associated with a poor visual outcome and a mortality of up to 30% [1].
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Case 1 (Patient number 1 in Table 1 )
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A 42-yr-old Caucasian male had seropositive, erosive RA for 18 yr. The RA had been unresponsive to sulphasalazine and azathioprine, he was intolerant of i.m. gold and D-penicillamine and alcohol-related liver disease precluded the use of methotrexate. For the previous 7 yr his disease had been well controlled on the combination of prednisolone (5 mg o.d.) and non-steroidal anti-inflammatory drugs (NSAIDs). In 1994 he underwent routine removal of a steroid-induced cataract of the right eye. His post-operative course was initially unremarkable, but on day 4 he developed severe ocular pain, photophobia and blurred vision. PUK was diagnosed at slit-lamp examination and treated immediately with pulsed i.v. methylprednisolone (1 g alternate days for 1 week). Despite treatment, the ulcer continued to extend and an emergency full thickness corneal graft was needed to prevent perforation of the globe (histology of the corneal button confirmed PUK). To maximize graft survival, cyclosporin (100 mg b.d.; a dose of 3 mg/kg) and high-dose prednisolone (60 mg o.d.) were started. Rapidly deteriorating renal function meant that the cyclosporin had to be withdrawn (it subsequently transpired that he had only one functional kidney) and despite introducing azathioprine (50 mg b.d.) the graft also developed PUK and failed. Although a further graft was attempted it was rejected, the eye perforated and became blind. His RA remained quiescent throughout.
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TABLE 1. Summary of the arthropathy at presentation of peripheral ulcerative keratitis (PUK) and patient outcomes after treatment
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Four years later he required cataract surgery to his left eye. Given the previous complications after cataract surgery high-dose prednisolone was administered in the peri-operative period (40 mg daily for 2 days before and 2 days after surgery, reducing by 10 mg increments every 3 days to a maintenance dose of 10 mg o.d.). Immediately after surgery the eye was quiet, but his post-operative recovery was complicated by a Staphylococcus aureus abscess in a finger which was drained and treated with i.v. antibiotics. One month after the abscess had resolved he presented with a widespread vasculitic rash and an intense inflammation within the left eye consistent with sympathetic endophthalmitis. The rash and intraocular inflammation responded rapidly to high-dose prednisolone (40 mg o.d.) and azathioprine (50 mg b.d.), but 3 weeks into this course of treatment he presented with a septic arthritis of the ankle. It is unlikely that this or his previous infection was secondary to either excessive hyperglycaemia or immunosuppression as at no time during treatment did hyperglycaemia or neutropenia occur. Despite aggressive management, including arthroscopic washout, broad spectrum antibiotics and ionotropic support, he died of overwhelming sepsis.
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Case 2 (Patient number 2 in Table 1 )
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A 55-yr-old Caucasian male with a 35-yr history of seropositive, erosive RA and secondary Sjögren's syndrome presented to the ophthalmologists with a foreign body sensation in his left eye. His RA had been well controlled since methotrexate (7.5 mg p.o. weekly) had been started 2 yr previously, but the development of alveolitis led to its withdrawal 6 weeks before his eye lesion developed. His medication at presentation was prednisolone (10 mg o.d.) and NSAIDs; the RA was quiescent. PUK was diagnosed and treated with a reducing course of high-dose oral prednisolone (60 mg o.d.). The response to treatment was initially good but the PUK recurred as the prednisolone dose was reduced. Cyclosporin (100 mg b.d.; a dose of 3 mg/kg) was therefore introduced and within 2 months the eye lesion had completely resolved.
A combination of cyclosporin (100 mg b.d.) and prednisolone (7.5 mg o.d.) held the PUK and RA in remission for 18 months when, without a reduction of immunosuppression, the PUK spontaneously recurred. Although a temporary improvement in the ulcer was effected by increasing both the prednisolone (to 60 mg o.d.) and cyclosporin (to 150 mg b.d.; a dose of 4 mg/kg), it became secondarily infected and despite prompt recognition and treatment, extensive corneal scarring occurred. His current visual acuity is 6/60 and although corneal grafting may improve vision, there could be a recurrence of PUK in the graft with the risk of losing the eye completely.
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A review of all (nine) patients with RA-associated PUK treated in Sheffield since 1996
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The clinical and serological characteristics of the arthritis at the time of presentation of PUK are summarized in Table 1
. All patients had a long history of high-titre seropositive, nodular, erosive RA which on presentation of PUK had been quiescent or well controlled for many years. There had been no clinical evidence of either synovitis, raised inflammatory markers or any progressive extra-articular feature for many years in eight of the nine patients reviewed in this series. The one exception to this was the patient detailed as case 2 above, who developed interstitial shadowing on his chest radiograph 6 weeks before presenting with PUK. This shadowing resolved on cessation of methotrexate suggesting that it represented a drug effect rather than an active extra-articular feature of the underlying RA. Six of the nine patients had documented long-standing secondary Sjögren's syndrome. The remaining three patients had a long history of dry eyes requiring the use of ocular lubricants and on slit-lamp examination were found to have keratoconjunctivitis sicca.
The visual outcome of our patients was generally poor (Table 1
). One patient retained her visual acuity, two had vision reduced to `no perception of light' and three had visual acuity of 6/60 or less. The eye disease was controlled with medical therapy in four patients using a combination of prednisolone and azathioprine or cyclosporin. Five patients required emergency corneal surgery and the visual outcome of this group was especially poor (Table 1
).
Two of our patients developed a systemic vasculitis within 2 months of presenting with PUK; one of whom died (case 1 detailed above). The other patient was case 8 (Table 1
) who developed a vasculitic rash, lymphopenia and anaemia which responded to a combination of prednisolone and azathioprine.
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Discussion
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The clinical presentation of PUK is variable; it may present after intraocular surgery or arise de novo, and typically patients describe a non-specific foreign body sensation with pain, a watering eye and reduced visual acuity [2]. On simple inspection there may be localized injection of the corneal limbus, but the remainder of the eye may be misleadingly quiet. Slit-lamp examination reveals a non-infiltrating ulcer at the periphery of the cornea with a surrounding inflammatory infiltrate and adjacent conjunctival injection. Keratoconjunctivitis sicca is a common associated feature. These findings are non-specific and may be indistinguishable from those seen in other necrotizing, inflammatory diseases of the peripheral cornea. Ophthalmic referral is therefore mandatory if the diagnosis of PUK is suspected. Although PUK is classically associated with RA it has also been described in primary Sjögren's syndrome, polyarteritis nodosa, Wegener's granulomatosis and relapsing polychondritis [3].
The extracellular matrix of the cornea comprises a series of highly organized lamellae of collagen fibrils embedded in a framework of glycosaminoglycans. Lying between adjacent lamellae are flattened fibroblasts (keratocytes), with the occasional macrophage, lymphocyte and polymorphonuclear leucocyte. Corneal fibroblasts are responsible for the continual turnover and maintenance of the matrix and one of the principal mechanisms governing the rate of matrix turnover is the local balance between collagenases and their tissue inhibitors [4]. The cellular source of these enzymes includes both local fibroblasts and invading mononuclear cells [5, 6].
In corneas affected by PUK, a local imbalance between levels of a specific collagenase (MMP-1) and its tissue inhibitor (TIMP-1) has been described and it has been suggested that this imbalance is responsible for the rapid corneal keratolysis which is the hallmark of PUK [5]. The events initiating and perpetuating PUK are uncertain. Circulating autoantibodies to specific corneal proteins, exposed after corneal epithelial damage, were initially thought to be responsible for initiating PUK. However, it has been found that these circulating autoantibodies only appear after the eye disease has resolved, prompting some to question this hypothesis [7]. More recently, the finding that PUK is associated with aberrant expression of HLA class II antigens on corneal epithelial cells and keratocytes in the area of the ulcer [6, 8] and a vasculitis of the adjacent conjunctiva [9, 10], has led to the suggestion that the process represents an aberrant cell-mediated response to corneal epithelial damage [5]. This may explain why PUK can be a recurrent problem as it therefore has the potential of being reactivated by corneal damage, by whatever mechanism, including intraocular surgery.
Systemic corticosteroids are the treatment most frequently used in the acute management of PUK, but alone they are often unable to halt the disease or influence mortality [1]. Additional vigorous immunosuppression is therefore recommended [10]. Currently there is no consensus about which immunosuppressant is preferable and cyclophosphamide, methotrexate, azathioprine and cyclosporin have all been used successfully [1, 2, 6, 8, 1013]. Accumulated data from the use of cyclosporin in RA [14], severe inflammatory eye disease [8, 12] and high-risk keratoplasty [15] (defined as inflamed eyes which have already rejected one or more grafts), suggest that cyclosporin may now be the immunosuppressant of choice. As yet the ideal dosage regimen of cyclosporin has not been determined, but experience suggests that 35 mg/kg body weight would be a suitable starting dose. Consideration of the mechanisms involved in RA-associated PUK suggests that topical cyclosporin may also have a role. Although early reports of its use in severe anterior segment inflammatory disease [16], including RA-associated PUK [17], were encouraging, in our experience local toxicity to the cornea (resulting in ocular pain, visual loss and marked epiphora) often necessitates its withdrawal. Furthermore, any underlying systemic element to the vasculitis remains untreated with this route. The continual development of immunomodulatory drugs should lead to new therapeutic options in the future and the treatment of RA-associated PUK must therefore be under constant review.
There is no clear consensus on the duration of treatment for RA-associated PUK and PUK can often represent a complex ophthalmic management problem. The decision regarding the duration of treatment will be influenced by: (i) whether the corneal disease is associated with an underlying systemic vasculitis; (ii) whether it responds to medical treatment; or (iii) whether it requires surgical intervention; and (iv) whether it becomes secondarily infected. Each case therefore has to be treated individually and optimal care can only be achieved by the close collaboration between rheumatologists and ophthalmologists.
As yet, little has been published about the clinical and serological characteristics of patients' RA at the onset of PUK. All our patients had long-standing seropositive, erosive RA in keeping with the only other published report [10]. Rheumatological experience suggests that even without ocular involvement, RA patients who develop systemic vasculitis may do so at a time when the synovitis is relatively quiescent.
Rheumatologists should be aware that PUK may present with non-specific ocular symptoms and on simple inspection alone the clinical signs are insufficient to make a firm diagnosis. Urgent ophthalmic referral is therefore recommended if the patient describes ocular pain (as opposed to grittiness/discomfort), visual loss, marked localized conjunctival injection (suggesting sclerokeratitis) and sudden watering in a previously dry eye, as these features are highly suggestive of serious corneal disease. PUK is a disease of long-standing, seropositive, erosive RA which may have serious implications for the eye and may be associated with a systemic vasculitis. PUK should therefore be regarded as a serious complication of RA and these patients should be kept under close observation and a regular careful search made for an evolving vasculitis. PUK should be treated with rapid and vigorous immunosuppression and close collaboration between rheumatologists and ophthalmologists is recommended if the poor visual outcome and associated mortality from other complications of systemic RA are to be avoided. That PUK may represent an aberrant cell-mediated response to corneal epithelial damage raises the question of whether RA patients who have previously had PUK should be considered for vigorous immunosuppression before undergoing future intraocular surgery.
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Acknowledgments
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We are indebted to Mr M. E. Nelson of the Department of Ophthalmology at the Royal Hallamshire Hospital, Sheffield, Dr R. Powell of the Department of Immunology at Queens Medical Centre, Nottingham and Miss M. Sloper of the Department of Ophthalmology at Queens Medical Centre, Nottingham, for their valued review of this manuscript.
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Submitted 17 March 1999;
revised version accepted 13 July 1999.