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Peripheral Ulcerative Keratitis in Systemic Lupus Erythematosus
Digital Journal of Ophthalmology 1997
Volume 3, Number 5
May 30, 1997
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Benalexander A. Pedro, M.D. | Division of Immunology, Massachusetts Eye and Ear Infirmary, Harvard Medical School
Amyna Merchant, M.D. | Division of Immunology, Massachusetts Eye and Ear Infirmary, Harvard Medical School
C. Stephen Foster, M.D. | Massachusetts Eye and Ear Infirmary, Harvard Medical School

Abstract
Objective
Systemic Lupus Erythematosus (SLE) is a chronic multisystem disease with a wide range of inflammatory involvement in almost every organ of the body. The manifestations of SLE in the eye are as protean as those seen in the other organs of the body. We present the saga of a patient who presented with uncommon but significant manifestations of SLE and discuss its evaluation and management. Conclusion
This case underscores the uniqueness of SLE as a disease affecting the eye. Careful patient evaluation, as well as a logical stepwise approach to management of the ocular and systemic manifestations prove to be an effective way to prevent the blinding ocular consequences of this disease.
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Introduction
Systemic Lupus Erythematosus (SLE) was first described by Rose and Pillsbury in 1939.1 It is a chronic, often progressive and pleomorphic multisystem disease of unknown etiology. The clinical course of SLE may be mild or severe, recurrent or continuous, with a wide range of inflammatory manifestations in almost every organ of the body. The manifestations of SLE in the eye are as protean as those seen in the other organs of the body. The following case underscores the uniqueness of SLE and the difficulty sometimes encountered in clinical evaluatione and management of the ocular manifestations.

History of Present Illness
A 55 year old white female was referred to the Uveitis and Immunology service of the Massachusetts Eye & Ear Infirmary on January 21, 1993 by her primary ophthalmologist for symptoms of recurrent bilateral eye pain and redness.

History revealed a diagnosis of SLE since 1981. The patient had a history of peripheral corneal infiltrates, OS which were occurring more frequently over the past year, with a total of seven prior episodes. She had symptoms of eye pain and redness.

At the time of presentation, the patient's symptoms had improved following treatment with Pred Mild OS TID, Artificial Tears OU prn, Naprosyn 500 mg. prn and Prednisone which were instituted by her primary ophthalmologist.

Past Medical History
was significant for episodes of pericarditis in 1990, thyrotoxicosis in 1984, osteoporosis (manifesting as fractures in the feet), arthritis (elbows & knees), depression and migraine. The patient had had an MRI which had shown bilateral non-specific temporal lobe changes.

Examination
revealed vision of 20/20 OD and 20/40 OS. External inspection did not reveal a malar rash. The patients lids exhibited a positive 'toothpaste' sign of meibomian gland inspissation. There was trace chemosis with 1+ injection on the conjunctiva. The left cornea had a peripheral haze inferiorly. Posterior subcapsular changes, OS>OD were present in both eyes. Fundus examination was within normal. Schirmer's test with anesthetic showed wetting of 15 mm on the right and 5 mm. on the left.

Initial Impressions
1) Meibomitis, OU
2) Keratoconjunctivitis sicca (KCS), OS
3) Resolving Recurrent Corneal Infiltrate, OS
4) Cataracts, OU (OS>OD)
5) Systemic Lupus Erythematosus
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Materials and Methods
Patient Course
The management initiated by the patient's primary ophthalmologist was continued, since the corneal infiltrate appeared to be resolving. Doxycycline 100 mg BID was added to the treatment regimen, along with lubrication, lid hygiene and warm compress for the meibomitis and KCS.

In March of 1993 the patient presented with red eye and foreign body sensation, in her left eye. The visual acuity in the left eye was down to 20/100. There was 1+ conjunctival injection and a new peripheral corneal infiltrate was noted noted in the left eye. This can be seen superotemporally in Figure 1.

CBC, renal and hepatic function tests, anti ss-A (Ro), anti-ss-B (La), ANA, Anti-DNA Ab (ds), Anti-cardiolipin IgG & IgM, anti-RNP, Anti-SM and thyroid function tests were reviewed. These were negative except for a decreased hemoglobin and hematocrit.

A conjunctival biopsy was performed and this disclosed lymphocytic perivasculitis around the conjunctival and episcleral vasculature next to the area of peripheral keratitis, a finding typical of marginal keratitis associated with systemic lupus erythematosus.

The patient was treated with Dexamethasone ointment BID, OS and Ocumycin BID, OS post-biopsy with the plan to consider Plaquenil therapy if the corneal infiltration were to recur.

Four months later, in August 1993, a recurrence of the keratitis was noted, left eye. There was a significant history of stress, as her 16 y/o old dog had died. The patient's visual acuity was 20/30 OD and 20/40 OS. A new peripheral corneal infiltrate was again noted, left eye (Figure 2).

Plaquenil therapy was instituted at 200 mg/day along with topical Pred Forte 6x/day. While on Plaquenil, the patient continued to have recurrences of keratitis, though these were fewer and less severe. Documented recurrences occurred October 1993, February 1994 and April 1994. Due to the apparent inability of the current regimen to curb recurrences of the disabling keratitis, the patient was started on Methotrexate initially at a dose of 2.5 mg/week which was gradually increased to 7.5 mg/ week. This regimen resulted in decresing the recurrence, frequency and severity of the keratitis episodes.

A second opinion was sought by the patient at the National Eye Institute. A recommendation to use cyclosporine eye drops was made, if recurrences of the keratitis persisted. Cyclosporine eye drops was added to her treatment regimen in August 1994 because the patient continued to have several more episodes of recurrent keratitis. However, no additional benefit was seen with the use of cyclosporine.

In October 19, 1994, the patient again presented with redness and severe eye pain, left eye. Examination disclosed visual acuities of 20/25 OD and 20/40 OS, 1+ conjunctival injection, and a small peripheral corneal infiltrate at 6 o'clock which stained with fluorescein (Figure 3). The patient was advised to continue her medications. However, two days later, the patient returned with increased ocular pain with a picture of a large, ulcerated peripheral corneal lesion (Figure 4).

The diagnosis of Peripheral Ulcerative Keratitis (PUK) was made. Differential diagnosis for this condition is shown in TABLE 1.

The most likely etiology for this patient's PUK included a local ocular infectious cause versus a systemic non-infectious process, specifically secondary to SLE.

Gram stain and culture were performed on corneal scrapings. GS revealed occasional Gram (+) cocci in clusters. While waiting for culture results, the patient was started on a double regimen consisting of fortified Tobramycin and Vancomycin Eye Drops. Pred Forte drops were discontinued. The cultures failed to grow any microorganisms.

The patient did not improve on four (4) days of antibiotic therapy. Repeat corneal scrapings and cultures were performed after discontinuing topical medications for 24 hours. Ciloxan therapy was initiated, but the keratitis showed no improvement on this treatment. Voltaren p.o. was prescribed prn for pain and Provera was started q 2 hours as anti-collagenitic therapy. The cultures were again negative. At this point, we concluded that the process was most likely to be immune peripheral keratitis associated with SLE, rather than an infectious keratitis. We therefore suggested to her rheumatologist to increase her current Methotrexate dose or switch to another agent since she was HAVING significant breakthrough episodes on her current dose.

Her medication was subsequently changed FROM Methotrexate. to Imuran . Months later, by January 1995, the patientís condition appeared to be under control on Imuran at 50 mg qd. Examination revealed increasing cataracts, especially in the left eye. Repeat laboratory investigation revealed (+) ANA (Hep2 cells) this time.

Over the ensuing 18 months, the patient had fewer recurrences of the keratitis and the patientís concern at that point was blurred vision OS, due to the cataracts.

Cataract surgery was advised, but the potential danger of excessive post-operative inflammation and immune complex-mediated vasculitic wound ëmeltingí seen in patients with collagen vascular disease remains a concern. The patient was informed adjunctive therapy with low dose of cyclosporine (5 mg/kg BW/day) or boosting of the Prednisone prior to surgery would be indicated for prohylaxis against activation of her immune system..

As of her last follow-up, the patientís keratitis has remained under control. Her vision is 20/40 OD and Counting Fingers (CF) at 6 feet (CF 6í) pinholing to 20/70 OS. She is scheduled for cataract surgery.
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Results
Diagnosis
The diagnosis of SLE is complex since currently, there is no absolute clinical or laboratory abnormality that is pathognomonic of SLE. Diagnosis is based on a combination of clinical and laboratory criteria. Because SLE patients SHOW marked variability in their clinical manifestations and laboratory findings, a GROUP of criteria has been established/developed. The American Rheumatism Association10 revised (1982) a set of 11 diagnostic criteria for the diagnosis of SLE, as seen in TABLE 3. A patient is said to have SLE if any four (4) or more of the eleven (11) criteria present serially or simultaneously .

Another useful criteria is the Hahn Criteria in 1980, seen here in TABLE 4. A patient is said to have SLE with a positive ANA plus a score of seven (7) points.

It is strongly believed that ocular inflammatory lesions (scleritis, uveitis, choroiditis and retinal vasculitis) should be added to the diagnostic criteria. Some patients ultimately diagnosed with SLE would have been diagnosed earlier and followed more closely if their ocular inflammation had been included as a diagnostic criterion.

OCULAR INVOLVEMENT

Corneal
The corneal manifestations of SLE are usually confined to the epithelium. Sicca syndrome is common in inadequately controlled disease. Sjogren's syndrome in SLE is relatively rare and usually mild. The issue of whether SPK in SLE is due exclusively to sicca syndrome or whether it can occur as the result of direct corneal epithelial damage is still unclear.

PUK, as seen in our case, had been reported in patients with SLE but these lesions are uncommon.

Conjunctival/Scleral
Chemosis, recurrent episcleritis or scleritis may occur in patients with SLE and may be the initial presenting manifestation of the disease.

The incidence of episcleritis in SLE is low, ranging FROM 0.5 to 1.9%. In Fosterís series, one case (1/94), representing 1% of their study patients, presented with unilateral simple episcleritis without keratitis or anterior uveitis, without the decrease in visual acuity.16

The incidence of scleritis reported in SLE is about 1%, and is a reasonably accurate guide to the systemic activity of SLE. The attacks of scleritis become more severe and recurrent as the disease worsens. Scleritis resolves with adequate control of the systemic disease; it does not respond to topical therapy. Occasionally, scleritis may be the presenting sign of SLE. It generally takes the form of diffuse anterior scleritis or nodular anterior scleritis. Necrotizing anterior scleritis may occur, especially if systemic vasculitic lesions become significant.

Posterior Scleritis, though uncommon, may also be a manifestation of SLE. Patients with any type of scleritis must be screened for SLE. Inflammation may spread FROM the sclera to the adjacent structures causing keratitis and/or anterior uveitis. Although anterior uveitis is unusual in SLE (incidence 0.5 to 1.6%), its incidence increases with the presence of SLE scleritis.

In Foster's study of 172 patients with scleritis, 4% (7) has SLE. Of these two (28%) had bilateral scleritis. All were women with a mean age of 39 (range 22 to 57). Four had diffuse anterior scleritis, two had nodular anterior scleritis and one had posterior scleritis. Mean time of scleritis presentation was 6 months after the diagnosis of SLE. About 57% of patients with SLE scleritis had at least one episode of anterior uveitis.

Retinal/Choroidal
Posterior segment involvement is more common and serves as a better barometer of the disease and its severity than do anterior segment manifestations.

Several authors have emphasized that the presence of retinal lesions may correlate with the systemic course of the disease. For example, Rothfield18 discovered that hard exudates seem to correlate with CNS disease activity (seizures and organic brain disease).

Frequent posterior segment findings include cotton-wool spots, retinal hemorrhages, retinal edema and optic disk edema; other reported fundus changes include hard exudates, retinal vasculitis, central retinal vein occlusion, arteriolar narrowing, AV crossing changes, macular pigmentary mottling and retinal scarring. Lupus anticoagulants and anticardiolipin antibodies are recognized markers for increased risk of thrombosis and may also play a role in the compromise of the retinal vasculature (i.e. CRAO and CRVO).

Though some retinal findings in SLE appear similar to changes seen in hypertensive retinopathy, some findings appear as independent signs as well. Thus, it is difficult to differentiate the between SLE and hypertensive retinopathy if there are no other SLE manifestations like anterior segment changes are seen. Foster and Regan postulate that since purely localized SLE manifestations (e.g. skin, eye and kidney) may sometimes occur without systemic evidence of SLE, it is very likely that retinal vasculitis may also be seen even without systemic exacerbation of SLE.

Other Ocular Findings
Lower tarsal plaques, erosion of lower lid margins, conjunctival scarring and symblepharon may occur in patients with lupus.

Central nervous system SLE vasculitis may produce ocular abnormalities such as internuclear ophthalmoplegia (INO), nystagmus, cranial nerve palsies, homonymous hemianopsia and papilledema.

Finally, iatrogenic ocular lesions occur in SLE patients treated with corticosteroids and antimalarial drug therapy.

TREATMENT

Ocular
Therapy for the ocular surface manifestations of SLE is based on the control of the underlying disease, as well as local therapy for the keratitis and tear deficiency. This may be in the form of tear replacement, soft contact lenses, punctal occlusion and others. Topical steroid therapy has been an effective adjunct to systemic steroid therapy. Retinopathy resolves with the successful control of the underlying systemic disease and is the key to successful treatment and resolution of other acute ocular manifestations of lupus.

Systemic
Systemic therapy is done in a step-wise manner. Many patients with SLE have relatively mild disease and may lead relatively normal lives with conservative therapy. In the form of adequate rest (sleep and avoidance of fatigue) and nutrition, use of protective sun-screens and avoidance of the sun.

NSAIDs may be used for control of arthralgia, myalgia, low grade serositis and mild constitutional symptoms. Antimalarials (hydroxychloroquine) 200-400 mg. once daily may be added if the response to NSAIDs appear incomplete. Patient should be carefully watched for secondary retinopathy.

Systemic prednisone is added for severe manifestations of SLE and if the first two steps are inadequate to bring about a resolution of the disease. Severe disease involving the central nervous, pulmonary, cardiovascular or renal systems may require high dose oral (60-300 mg./day) steroids or IV steroid therapy.

Cytotoxic therapy, alone or on combination with steroids, may be helpful in cases which are not responsive to steroids or where steroids cannot be tapered below toxic levels without clinical exacerbation of disease. [Cyclophosphamide, Methotrexate, Azathioprine]

Other Modalities
Plasmapheresis for lupus crisis is under investigation. Some studies have found it to be effective in patients with high anti-DNA antibody titers, while another study reports of its lack of effect on T- and B-cell function.

Other studies have investigated long term intravenous IgG treatment, plasma exchange, and even the odious splenic perfusion method has been tried.

This may be proof that the precise and effective solution to this perplexing condition currently still eludes us and is still a mystery to us all.
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Discussion
The exhaustive saga of this patient exemplifies a difficult management case of SLE related PUK.

Epidemiology
The incidence of SLE is 2.7 to 7.6 per 100,000 new cases per year and the prevalence in the urban areas of the US is 15.5 to 50 cases per 100,000.3 The onset of symptoms is most frequent between the ages of 15 to 45 years, with women noted to be nine times more likely to be affected than men. The disease is more common in blacks than in Caucasians; and in black women between ages 15 to 64 years, prevalence is 1 case per 245 compared to a prevalence of 1 in 700 for all women of the same age.

SLE occurs in relatives of patients with a frequency of between 0.4 to 5%, a several hundredfold increase in prevalence over the general population. Studies of families with SLE suggest that both genetics and environment are equally important in the development of the disease. Multiple interacting genes (with and without the MHC) and environmental stimuli such as viral infection, UV irradiation or drugs (hydralazine, procainamide, penicillin, sulfonamides, gold phenytoin, isoniazide and methyldopa) appear to induce immunological alterations resulting in formation of autoantibodies, including anti-nuclear antibody (ANA).

Pathogenesis
It is hypothesized that genetic predisposition to the development of defective regulatory T-lymphocyte function, is triggered after the immune system is disturbed by some environmental factor. Defective regulatory T-cell function results in inadequately controlled helper T- lymphocytes and B-lymphocyte function, with resultant production of antibodies (e.g. ANA, anti-thyroid antibodies). The antigen-antibody complexes formed in the circulation are deposited in certain tissues and organs, primarily because of physical factors and molecular sieving restrictions. These activate complement pathways locally, both the classical and alternate routes, causing chemotaxis of neutrophils and macrophages, release of proteolytic enzymes and activation of the clotting cascade sequence, as well as activation of various kinins. Tissue damage results FROM the latter reactions and tissue digestion by proteolytic enzymes, resulting in a wide range of systemic manifestations.

Systemic Manifestations
Symptoms are usually present at the time of diagnosis. Patients with fatigue, weight loss, fever, malaise and anorexia with ANA in serum should be carefully studied for possible SLE. Almost every organ in the body can be affected as seen below in TABLE 2.
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References
1) Abdou NI, et al. Supressor T-cell Abnormality in Idiopathic Systemic Lupus Erythematosus. Immunopathol 6:192, 1976
2) Albert & Jakobiec. Principles and Practice of Ophthalmology. Vol. 5. WB Saunders and Co., 1994
3) Aronson AJ, Ordonez, NG, et al. Immune Complex Deposition in the Eye in Systemic Lupus Erythematosus. Arch Intern Med 139:1312, 1979
4) Blaszcyzyk M, et al. Plasmapheresis in the Treatment of Systemic Lupus Erythematosus. Arch Immunol Ther Exp (Warz.) 29:769 1981
5) Cohen AS, et al. Preliminary Criteria for the Classification of Sytemic Lupus Erythematosus. Bull Rheum Dis. 21:643, 1971
6) Copetto J, Lessell S. Retinopathy in Systemic Lupus Retinopathy. Arch Ophthalmol 95:794, 1977
7) Drosos AA, et al. Unusual Eye Manifestations in Systemic Lupus Erythematosus Patients. Clin Rheumatol 8:49, 1989
8) Foster CS, Sainz de la Maza M. The Sclera. Springer Verlag New York Inc., 1994
9) Foster CS. Immunosuppressive Therapy in External Ocular Inflammatory Disease. Ophthalmology 87:146, 1980
10) Foster CS. Ocular Surface Manifestations of Neurological and Systemic Disease. Int Ophth Clin 19:207, 1979
11) Gold DH, Morris DA, et al. Ocular Systemic Findings in Systemic Lupus Erythematosus. Br J Ophth 56:800, 1972
12) Jackson G, Miller M, et al. Bilateral Internuclear Ophthalmoplegia in Systemic Lupus Erythematosus J Rheumatol 13:1161 1986
13) Reeves JA. Keratopathy Associated with Systemic Lupus Erythematosus. Medicine 47:337, 1968
14) Ribrioux A. Sjogren's Syndrome in Systemic Lupus Erythematosus J Rheumatol 17:201, 1990
15) Tan EM, Cohen AS, Fries JF, et al. The 1982 Revised Criteria for Classification of Systemic Lupus Erythematosus Arthritis & Rheum 25:1271, 1982
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Tables

TABLE 1. Peripheral Ulcerative Keratitis(2)

Causes Conditions
Local InfectiousAny microbe
Local Non-InfectiousMooren's
Peripheral Degeneration (Terrien's, Pellucid)
Systemic InfectiousGonococcal, TB, Bacillary Dysentery, AIDS, Syphilis
Systemic Non-InfectiousRA, SLE, PAN, Wegener's, Sarcoid, Rosacea, Leukemia, etc.

Table 2. Common Systemic Manifestations of SLE(9)

Organ System Clinical Manifestations
Articular arthralgias, arthritis
Cutaneous rash, alopecia, ulcers, photosensitivity
Renal glomerulonephritis
Cardiovascular pericarditis, Raynaud's phenomenon, thrombophlebitis
Gastrointestinal nausea, vomiting, abdominal pain
Neurological behavioral disturbance, seizures, mononeuritis
Pulmonary pleural effusions, pleurisy, pneumonitis
Miscellaneous splenomegaly, lymphadenopathy, parotid swelling
Ocular keratitis episcleritis, scleritis, retinopathy

Table 3. ARA Revised Criteria for the Diagnosis of SLE.(1982)Four or more of the following:

Criteria Description
1. Malar Rash fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds
2. Discoid Rash erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions
3. Photosensitivity skin rash as a result of unusual reaction to sunlight, by patient history or physician observation
4. Oral or nasopharyngeal ulceration usually painless, observed by physician
5. Arthritisl non-erosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling or effusion
6. Serositis
a. Pleuritis OR convincing history of pleuritic pain or rub heard by a physician or rub heard by a physician or evidence of pleural effusion
b. Pericarditis documented by ECG or rub or evidence of pericardial effusion.
7. Renal disorder persistent proteinuria greater than 0.6g/day or greater than 3+ if quantitative determination was not performed

OR

cellular casts: may be red, hemoglobin, granular, tubular or mixed

8. Neurological Disorder
a. Seizures in the absence of offending drugs or known metabolic derangement, e.g. uremia, ketoacidosis or electrolyte imbalance
b. Psychosis in the absence of offending drugs or known metabolic derangement, e.g. uremia, ketoacidosis or electrolyte imbalance
9. Hematologic Disorder
a. Hemolytic anemia OR with reticulocytosis
b. Leukopenia

c. Lymphopenia OR

< 4000/mm total on two or more occasions

< 1500/mm on two or more occasions

d. Thrombocytopenia < 100,000/mm in the absence of offending drugs
10. Immunological Disorder
a. LE cell preparation

b. Anti-DNA antibody to native DNA

c. Anti-Sm OR

positive

in abnormal titers

presence of antibody to Sm nuclear antigen

d. False Positive SY Serological Test if known to be positive for at least 6 months and confirmed by T. pallidum immobilization or fluorescent treponemal antibody absorption test
11. Anti-nuclear antibodyan abnormal titer of ANA by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with "drug-induced lupus syndrome"

TABLE 4. The Hahn Criteria

Criteria Point(s)
Butterfly Rash 2
Rash biopsy findings consistent with SLE 2
Polyarthritis 2
Serositis 2
Glomerulonephritis biopsy findings compatible with SLE 2
LE cells 2
Rash compatible with SLE, not biopsy proved 1
Clinical nephritis, no biopsy 1
Organic brain syndrome 1
Localizing neurologic signs 1
Alopecia 1
Raynaud's phenomenon 1
Nail-bed capillary abnormality 1
Arthralgia 1
Fever 1
Retinal cytoid bodies 1
Polymyositis 1
Myocarditis 1
Hemolytic anemia 1
Leukopenia 1
Thrombocytopenia 1
Lymphadenopathy 1
Positive results on direct Coombsí test 1
False-positive serologic test for syphilis results 1
Antibodies to DNA 1
Hypergammaglobulinemia 1
Hypocomplementuria 1
Circulating Anti-coagulant 1
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Clinical Pictures
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