Systemic disorders associated with peripheral corneal ulceration

John G. Ladas, MD, PhD, and Bartly J. Mondino, MD

Peripheral ulcerative keratitis may be associated with a variety
of autoimmune diseases. In some diseases, corneal
involvement occurs after the systemic disease has been
present for many years, whereas in others, it may be the first
manifestation. Regardless of the time of presentation, the
development of corneal ulceration in the setting of systemic
autoimmune disease may represent progression of a
potentially life threatening disease. The relatively rare incidence
of these diseases has limited publications over the past year to
a few case series that have further characterized the natural
history of the diseases associated with peripheral ulcerative
keratitis. Current laboratory research has been directed at
describing the antigenic targets within the cornea of the
abnormal immune response in these patients and also the
mechanism of keratolysis that results in ulceration. Curr Opin
Ophthalmol 2000, 11:468471 2000 Lippincott Williams & Wilkins, Inc.
Peripheral ulcerative keratitis (PUK) is a crescent-
shaped, destructive, inflammatory lesion of the perilim-
bal cornea [1]. It is always associated with an epithelial
defect and typically has a subepithelial infiltrate at its
central edge. These features help differentiation from
noninflammatory lesions such as Terriens marginal de-
generation. In addition, most but not all forms of PUK
have associated inflammation of the adjacent conjunc-
tiva, episclera and sclera.
Approximately 50% of all noninfectious peripheral ulcer-
ative keratitis have an associated collagen vascular dis-
ease [2]. Some of these require a thorough history, physi-
cal examination, or tissue biopsy to establish the diagno-
sis. It is important to recognize and treat PUK in the
setting of systemic disease, because a high mortality rate
has been demonstrated in these patients [3]. Treatment
in most cases is with systemic corticosteroids and cyto-
toxic agents, which can alter the natural history of the
ocular and systemic manifestations of the particular disease.
The mechanism by which keratolysis occurs likely in-
volves multiple factors. The peripheral cornea is an ideal
site to manifest signs of collagen vascular disease, be-
cause specific types of immune complex deposition oc-
cur here. Increased deposition of these complexes and
increased immunologic activity results in production of
proteinases and collagenases by inflammatory cells and
adjacent conjunctival tissue. Recent studies have dem-
onstrated that the cornea is a target for the irregular au-
toimmune response in these patients. Although the exact
pathway by which keratolysis occurs is not known, it
appears that there is dysregulation of specific keratolytic
enzymes involved in the process.
The purpose of this review is to summarize peripheral
ulcerative keratitis in the setting of systemic disease and
to familiarize the reader with papers published on this
subject over the last year.
Epidemiology and disease associations
There are many systemic diseases that are associated
with peripheral ulcerative keratitis. It has been described
in patients with rheumatoid arthritis, Wegener granulo-
matosis, relapsing polychondritis, systemic lupus erythe-
matosus, classic polyarteritis nodosa, and its variants, mi-
croscopic polyangiitis and Churg-Strauss syndrome. Pe-
ripheral ulcerative keratitis can occur at any point during
Jules Stein Eye Institute and the Department of Ophthalmology, UCLA School of
Medicine, Los Angeles, CA, USA
Correspondence to Bartly J. Mondino, MD, Jules Stein Eye Institute, 100 Stein
Plaza, UCLA, Los Angeles, CA 90095, USA; e-mail: mondino@jsei.ucla.edu
Current Opinion in Ophthalmology 2000, 11:468471
Abbreviations
RA rheumatoid arthritis
MMP matrix metalloproteinase
PUK peripheral ulcerative keratitis
ISSN 10408738 2000 Lippincott Williams & Wilkins, Inc.
468
the systemic disease, but tends to occur after systemic
manifestations have been present. However, it may be
the presenting sign of an autoimmune disease. There-
fore, an understanding of the differential diagnosis and
work-up of these patients is important to the ophthal-
mologist who encounters a patient with PUK.
Rheumatoid arthritis (RA) is the most common systemic
disease associated with PUK. There is usually an associ-
ated area of adjacent inflammation of the conjunctiva,
episclera, or sclera. It has been reported [2] to be bilateral
in greater than one third of these patients. It tends to
occur late in the disease process and may indicate wors-
ening of the disease. Indeed, it is thought by some that
the onset of PUK may indicate transformation of RA into
the systemic vasculitic phase.
The diagnosis of RA includes four of the following cri-
teria: morning stiffness lasting greater than 1 hour; swell-
ing of the soft tissue of three or more joints; swelling of
the soft tissue of three or more hand joints; symmetrical
soft tissue swelling; subcutaneous nodules; serum rheu-
matoid factor; or periarticular osteopenia [4]. The diag-
nosis of RA with PUK should be considered a life-
threatening disease that is associated with a high mortal-
ity rate if not treated with aggressive cytotoxic therapy [3].
In addition to RA, PUK is associated with other autoim-
mune diseases. Wegener granulomatosis also has a high
rate of ocular involvement. Nonspecific conjunctival and
episcleral inflammation occurs initially, but may progress
to peripheral ulceration if diagnosis and treatment are
delayed. Unlike RA, it is common to have PUK as a
presenting sign of the systemic manifestations of Wege-
ner granulomatosis. The systemic manifestations include
respiratory symptoms, urinary tract involvement, and ar-
thritis. When systemic disease is present, antineutrophil
cytoplasmic antibody has a 99% sensitivity in patients
with Wegener, which drops to less than 70% in patients
with limited disease [5].
Relapsing polychondritis is an autoimmune disorder that
also has PUK as a manifestation. Although ocular in-
volvement in this disease is high, with episcleritis or
scleritis, the prevalence of PUK in this disease is less
than 10% [6]. Diagnosis is based on the history and ob-
jective findings of chondritis of the ears, nose, and lar-
ynx. There is no current laboratory test available, and,
thus, the diagnosis is made on clinical grounds alone.
The prevalence of corneal involvement in systemic lu-
pus erythematosus is rare and is usually secondary to
kerotoconjunctivitis sicca; however, reports of peripheral
ulceration have been documented [1]. Diagnosis is based
on meeting four of 11 criteria, including the abnormal
laboratory tests that have been set forth by the American
Rheumatism Association [7].
Polyarteritis nodosa, Churg-Strauss syndrome, and mi-
croscopic polyangiitits also are associated with peripheral
corneal ulceration. Polyarteritis nodosa can be manifest
in almost any organ system and has a very high mortality
rate. There is no specific blood test that can aid in the
diagnosis, although patients frequently have elevated
leukocyte counts and sedimentation rates.
Two case series [8,9] have been published within the
past year that have examined the epidemiology of PUK
in the setting of a collagen vascular disease. McKibben et
al. [8] analyzed all patients diagnosed with corneal melt-
ing during a 3-year period in the Yorkshire region of
Great Britain. They identified 27 patients during the
study period, which was calculated as an incidence of
approximately 3 cases per million per year.
Of the 27 patients, 26 had either rheumatoid arthritis or
Wegener granulomatosis. One patient had microscopic
polyangiitis. As described in previous studies, corneal
melting, in association with rheumatoid arthritis, ap-
peared as a late phenomenon. Indeed, the mean time
between diagnosis of RA and the onset of the corneal
melt was 19.6 years. In contrast, PUK in the setting of
Wegener was an early finding being diagnosed on aver-
age within 6 months of the presentation. Importantly,
peripheral ulcerative keratitis was the initial manifesta-
tion of the disease in half of these patients.
In another report, Squirrel et al. [9] examined those pa-
tients with PUK and RA. They identified nine patients
with both PUK and RA in their practices during a 3-year
period. As in the study by McKibben et al. [8], PUK in
the setting of RA is a late phenomenon, occurring 12 to
35 years after the initial diagnosis. This report also em-
phasized both the poor visual prognosis and the associ-
ated mortality in this setting. Five of the nine patients
required emergent surgery to preserve the integrity of
the globe. The fact that it is believed that PUK may
represent the onset or progression of the vasculitic phase
of RA was also observed in this patient population. Two
patients with both PUK and RA developed systemic vas-
culitis, and one of these patients died. The life-
threatening nature of the disease at this stage has been
reported by Foster et al. [3], who demonstrated the im-
portance of cytotoxic therapy on the survival outcome of
the disease.
Pathogenesis
Recent laboratory research on a molecular level has at-
tempted to characterize the mechanism for the develop-
ment of PUK. Studies have examined the cornea as a
target of the immune response as well as proteins that
may have a role in the keratolysis.
Two studies during the review period examined the
presence of matrix metalloproteinases (MMPs) present
Systemic disorders associated with peripheral corneal ulceration Ladas and Mondino 469
in ocular samples. Matrix metalloproteinases are en-
zymes involved in the degradation of extracellular ma-
trix. These enzymes have been implicated in the patho-
genesis of RA throughout the body and are not limited to
the eye. The cellular source of these enzymes in the eye
are inflammatory cells, conjunctival epithelium, and
keratocytes, which secrete the MMP and result in sub-
sequent keratolysis.
Geerling et al. [10] analyzed tear samples from patients
for MMP-2 and MMP-9, two MMPs that were previously
found in tears after corneal grafting and wound healing.
They demonstrated increased levels of MMPs in pa-
tients with connective tissue disease, compared with
controls. The highest levels were found in patients with
RA. They found greater concentrations of MMP-2 and
MMP-9 in patients with active or previous corneal ulcers,
compared with normal patients. Matrix metalloprotein-
ase-2 was found in higher concentrations in active ulcers,
compared with healed ulcers. Although their research
did not define a causal role for these proteins, it did
suggest that MMPs may play a role in keratolysis.
Smith et al. [11] reported on the role of MMPs in the
pathogenesis of PUK. These authors studied cornea
specimens from patients who underwent penetrating
kerotplasty for management of the disease and compared
these specimens with corneal specimens from eye banks.
They used substrate gel electrophoresis in these speci-
mens to demonstrate overexpression of MMP-2 in pa-
tients with PUK.
They also examined the role of possible modulators of
these enzymes. Interestingly, there was no effect of cor-
ticosteroids on the in vitro activity or production of those
enzymes. In contrast, the activity of the enzymes was
inhibited by altering the concentration of divalent cat-
ions, which are required for activity. The authors sug-
gested that future treatment modalities may be based on
these findings.
Other studies have examined the autoantibodies associ-
ated with the specific disease and its corneal target. Re-
search by Reynolds et al. [12] have examined the sera of
patients with rheumatoid arthritis, Wegener granuloma-
tosis, and Churg-Strauss Syndrome to determine the cor-
neal targets of the autoimmune process. A number of
autoantigens present in the cornea are recognized from
sera of patients with RA, Wegener granulomatosis, or
Churg-Strauss Syndrome. Among these is a 66kDa pro-
tein found in the corneal epithelium that is found in
patients with Wegener granulomatosis and RA, regard-
less of whether there is current ophthalmic involvement.
The strongest association was found in those patients
with Wegener granulomatosis and PUK. The authors
suggested that the autoantibodies directed at the corneal
epithelium may contribute to the autoimmune response
in the involved eye.
Follow-up work by the same group identified the 66kDa
protein recognized by the sera of patients with Wegener
granulomatosis [13]. Using a corneal epithelial cDNA
expression library, they reported that the protein was
cytokeratin 3. This protein is specific to corneal epithe-
lium. Knowledge of this relation brings about the possi-
bility of a further diagnostic test in patients suspected of
having PUK with associated Wegener, because cANCA
may not be detectable early in the disease.
Ocular involvement in Churg-Strauss syndrome is rare
and occurs in many forms. A 66kDa protein directed at
corneal epithelium has been detected in 60% of patients
with Churg-Strauss syndrome [12]. However, this 66kDa
autoantibody is distinct from a 66kDa protein for pa-
tients with RA or Wegener granulomatosis, as mentioned
above. The protein that this antibody recognizes is cur-
rently not known.
Medical management
Peripheral ulcerative keratitis, in the setting of systemic
disease, is life threatening and requires immunosupres-
sion. Therefore, communication and prompt referral to a
rheumatologist comfortable with cytotoxic agents for ini-
tiation of therapy is of utmost importance. The ophthal-
mologist must also deal with the cornea as the systemic
disease is brought under control. Regardless of the man-
agement of the corneal disease, the result will be disap-
pointing at best and only marginally better unless aggres-
sive treatment of the systemic disease is taken at the
same time.
Current treatment strategies for the systemic disease in-
volve systemic corticosteroids plus a cytotoxic agent in
the acute phase of the disease. The exact cytotoxic agent
may differ based on the type of the disease. Topical
corticosteroids are generally of little use and may be
harmful in specific diseases such as rheumatoid arthritis.
The currently recognized treatment for RA with associ-
ated PUK is systemic corticosteroids plus a cytotoxic
agent, with methotrexate (MTX) being the first line by
most physicians [1]. Stronger immunosuppressives are
reserved for those who are unable to tolerate the side
effect profile of MTX or have progressive disease while
on MTX. Cytotoxic agents not only can improve the
systemic disease, but have been reported to improve
graft survival in patients with RA [14]. Although MTX is
still the first-line treatment in patients with RA, newer
medications are being evaluated in larger studies. Among
these is mycophenolate mofetil, which has demonstrated
promising results in some studies [15].
Wegener granulomatosis and polyarteritis nodosa are
considered rapidly progressive, life-threatening diseases
with high mortality rates that require aggressive cyto-
toxic therapy at the time of diagnosis. Therefore, pa-
470 Ocular manifestations of systemic disease
tients with Wegener granulomatosis or polyarteritis no-
dosa typically are started on a regimen of corticosteroids
and cyclophosphamide. It also should be noted that re-
sponse to therapy can be monitored by following cANCA
in Wegener granulomatosis.
Although PUK in the setting of systemic lupus erythem-
atosis is rare, it signifies advanced disease that requires
systemic corticosteroids, and, possibly, cytotoxic therapy.
Relapsing polychondritis generally warrants the use of a
cytotoxic agent in addition to steroids.
Local management
Because it is likely that a significant number of patients
with PUK also suffer from keratoconjunctivitis sicca, it is
imperative that the ophthalmologist pay attention to
treatment of the ocular surface with aggressive lubrica-
tion, and, possibly, the use of punctal plugs. Conjunctival
resection remains a potential treatment because it may
decrease conjunctival production of collagenases and
proteinases, and reduce local access of immune cells and
factors to the peripheral cornea. Surgical management of
ulcerative keratitis is reserved for some cases to preserve
the integrity of the globe. Options include penetrating
keratoplasty, lamellar grafts, use of a tissue adhesive, or
a bandage contact lens. Despite improvement of graft
survival with cytotoxic therapy, the outcomes of pen-
etrating keratoplasty are disappointing. This has been
emphasized in a recent review [16] of indications for
corneal transplantation. Maeno et al. [16] showed that
although the number of penetrating keratoplasties per-
formed for ulcerative keratitis remains low, it had the
highest likelihood of requiring a regraft. In the presence
of severe dry eye, a tarsorraphy may enhance the chance
of survival of the graft.
Conclusions
The diagnosis of peripheral ulcerative keratitis in a set-
ting of systemic disease should be considered an emer-
gency by the diagnosing physician. Recent publications
have highlighted the variety of presentations among the
specific diseases. Management of the systemic disease,
in association with a physician who has expertise in cy-
totoxic therapies, is of paramount importance.
Current laboratory research continues to identify the tar-
gets of the immune response in these diseases as well as
the mechanism of keratolysis. Future research will be
directed at treatment of the local disease in hopes of
modifying the keratolysis at a local level.
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Systemic disorders associated with peripheral corneal ulceration Ladas and Mondino 471