Gupta 2021

JID: SOP
ARTICLE IN PRESS [mNS;April 10, 2021;3:7]

s u rv e y o f o p h t h a l m o l o g y x x x ( x x x x ) x x x
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/survophthal
Review article
Peripheral ulcerative keratitis
Yogita Gupta, MD, Alisha Kishore, MD, Pooja Kumari, MS,

Neelima Balakrishnan, MBBS, Neiwete Lomi, MD, Noopur Gupta, MS,
PhD, M. Vanathi, MD, Radhika Tandon, MD∗
Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India;
a r t i c l e i n f o a b s t r a c t
Article history: Peripheral ulcerative keratitis (PUK) is an inflammatory condition of the peripheral cornea
Received 11 August 2020 with hallmark features of epithelial defects and stromal destruction as a result of a com-
Revised 17 February 2021 plex interplay of factors including host autoimmunity and the peculiar anatomic and phys-
Accepted 23 February 2021 iologic features of the peripheral cornea and environmental factors. PUK may be the result
Available online xxx of local or systemic causes and infectious or noninfectious causes. Arriving at a specific
etiological diagnosis requires a meticulous clinical workup that may include a battery of
Keywords:
laboratory and radiological investigations. Management by a team of internists or rheuma-
Peripheral ulcerative keratitis
tologists and ophthalmologists and judicious use of immunosuppressive agents may yield
PUK
favorable results while minimizing adverse effects. We review current clinical knowledge
Mooren ulcer
on the diagnosis and management of PUK.
Mooren’s ulcer
© 2021 Elsevier Inc. All rights reserved..
peripheral keratitis
be a presenting manifestation of an underlying ocular or

1. Introduction systemic disease, which may be potentially lethal. Vasculi-
tides and collagen vascular diseases of autoimmune etiol-
Peripheral ulcerative keratitis (PUK) is a destructive inflam-
ogy, such as rheumatoid arthritis (RA), granulomatosis with
matory disease of the juxtalimbal cornea associated with
polyangiitis (GPA, formerly known as Wegener granulomato-
crescent-shaped corneal stromal thinning, an epithelial de-
sis), systemic lupus erythematosus (SLE), are well-known
fect, and inflammatory cells in the corneal stroma.107 , 161 The
systemic associations in as high as 53% of cases of PUK,
predilection of the peripheral cornea for PUK is explained by
and their presence often complicates the presentation and
its anatomical and physiological characteristics. PUK could
management.4 , 163 It has been proven that, in patients with
Abbreviations: ANCA, Antineutrophil cytoplasm antibody (ANCA); MU, Mooren’s ulcer; PUK, Peripheral ulcerative keratitis; RA, Rheuma-
toid arthritis; MHC, Major histocompatibility complex; HLA, Human leucocyte antigen; MMP, Matrix metalloproteinase; TIMP, Tissue in-
hibitor metalloproteinase; GPA, Granulomatosis polyangiitis; SLE, Systemic lupus erythematosus; PSS, Progressive systemic sclerosis;
SS, Sjogren’s syndrome; IMT, Immunomodulator therapy; PKP, Penetrating keratoplasty; DALK, Deep anterior lamellar keratoplasty; GA,
general anesthesia; TILK, Tuck-in lamellar keratoplasty; TPG, Tuck-in tenon patch graft; AMT, Amniotic membrane transplant; MPA, Mi-
croscopic polyangiitis (MPA); CSS, Churg- Strauss syndrome; MTX, Methotrexate; CsA, Cyclosporine A.
∗
Corresponding author: Radhika Tandon, MD; Professor and Head, Unit 6 - Cornea, Cataract and Refractive Surgery, Ocular Oncology and
Low Vision Services; Room no 490, 4th floor; Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences,
Ansari Nagar, Delhi-110029, India.
E-mail address: radhika_tan@yahoo.com (R. Tandon).
0039-6257/$ – see front matter © 2021 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.survophthal.2021.02.013
Please cite this article as: Yogita Gupta, Alisha Kishore, Pooja Kumari et al., Peripheral ulcerative keratitis, Survey of Ophthal-
mology, https://doi.org/10.1016/j.survophthal.2021.02.013
JID: SOP
2 s u rv e y o f o p h t h a l m o l o g y x x x ( x x x x ) x x x
scleritis, the detection of PUK indicates a poor ocular and ripheral cornea, along with the maximum mitogenic activity
systemic prognosis.139 Progressive ulceration may sometimes of the endothelial cells.114 , 115
lead to corneal perforation. Corneal perforation in cases with The corneal extracellular matrix (ECM) is composed of col-
underlying autoimmune etiology has serious ocular morbidity lagen fibrils embedded in the framework of glycosaminogly-
(65 % with poor visual outcome of counting fingers or worse) cans. The arrangement of collagen fibrils is in a well-organized
and is associated with significantly higher one-year all-cause manner in the central cornea as compared to the looser ar-
mortality (∼24% in unilateral and 50% in bilateral perfora- rangements in the peripheral cornea.92 A state of balance
tions).165 between collagenases and their tissue inhibitors maintains
Epidemiological studies in the United Kingdom estimate corneal integrity and the rate of corneal matrix turnover.31 An
the incidence of PUK to be nearly 0.2 to 3 per million popula- imbalance between levels of matrix metalloproteinase (MMP),
tion per year.105 , 139 , 165 There is generally a predilection for the a specific collagenase that causes degradation of ECM and tis-
female sex,165 with a few reports of equal incidence in males sue inhibitor of MMP (TIMP) in the corneal stroma may re-
and females.139 Based on etiology, PUK may be classified sult in disturbance of corneal matrix turnover towards in-
as infectious or noninfectious and whether associated with creased rates of keratolysis that has been postulated as the
ocular or systemic disease or idiopathic in origin. Such a major pathomechanism in PUK.37 , 135 MMPs are secreted by lo-
clinical categorization and establishment of a correct clinical cal fibroblasts, the invading mononuclear cells, and granulo-
diagnosis would help clinicians in choosing only appropriate cytes.82 , 135 TIMPs were found to be deficient when there was
investigative modalities and initiating appropriate therapy, a lesion in the cornea.67 There is a role of MMP-2 and MMP-9
targeting the specific underlying cause. In a small proportion secreted by corneal stromal keratocytes, lacrimal gland, con-
of cases, despite all investigations, no identifiable cause is junctival and corneal epithelial cells, and by inflammatory
found. Mooren ulcer (MU), a common cause of PUK (∼31.5%144 cells infiltration from neovascularization of the limbus, in the
of all PUK cases), is a rare, painful, chronic, serpiginous pe- disease process in PUK.149 Correlation has been found be-
ripheral ulcer of the cornea. Bowman first reported it in 1849, tween MMP-1 levels and corneal perforation in patients with
and then McKenzie described it as ‘ulcus roden’ of the cornea PUK.28 In addition to MMPs, other apoptotic and proteolytic
in 1854.22 , 104 , 140 It characteristically occurs in the absence factors may also contribute to stromal melt.
of any scleritis and is idiopathic. MU begins in the periphery The physiology of peripheral cornea also differs from the
and progresses circumferentially and centrally in the cornea central cornea. The peripheral cornea has less neural inner-
and has distinctive overhanging edges. It is a diagnosis of vation and therefore less sensitivity.115 Peripheral cornea has
exclusion made after ruling out all possible rheumatologic a higher level of cell surface-associated glycoprotein Mucin-
and autoimmune disorders. 4 gene (MUC4) that has epithelio-protective activity and also
PUK is an important disorder because it may be the regulates renewal and differentiation of epithelial cells.54 The
harbinger of a life-threatening systemic disease and may first nutritional sources of the central cornea are predominantly
present to an ophthalmologist. It is also known to be po- the tear film and aqueous humor, whereas, for peripheral
tentially devastating and vision-threatening, if relentlessly cornea, the major nutritional source is via the perilimbal cap-
progressive, so requires due attention. Though known since illaries that extend for about 0.5 mm in the cornea.50 , 178 Al-
the mid-nineteenth century, the disease is still quite an though the central cornea is avascular, the peripheral cornea
enigma, with ever-changing knowledge about its risk factors, has fairly good vascular supply, as well as lymphatics. Inter-
treatment, and prognosis. We shall provide a comprehen- ruption of this vascular supply may result in necrosis and ul-
sive update of relevant information of current knowledge and ceration.136 The perilimbal vascular and lymphatic arcades
practices. also act as a source for immunoglobulins (e.g., IgM) and im-
mune cells, including macrophages, plasma cells, and lym-
phocytes.7 The proximity to these arcades, therefore, puts the
peripheral cornea at a higher risk of exposure to inflamma-
2. Pathophysiology of PUK and relevant tory cells and mediators such as IgM, immune complexes, and
anatomy and physiology of peripheral cornea and complement proteins (e.g., C1).107
limbus The exact mechanism causing PUK remains unclear, but
research suggests that both humoral and cellular immune
There are major differences in the anatomy and physiology of mechanisms (Fig. 1) are involved.36 It has been hypothesized
the peripheral cornea compared to central cornea that make it that abnormal T cell responses initiate antibody production
more prone to furrowing, ulceration, and other manifestations from plasma cells, with subsequent formation of immune
of autoimmune and metabolic systemic disorders. The pe- complexes that get deposited in the stroma of the periph-
ripheral cornea is a transition zone between cornea and sclera eral cornea.110 This results in the activation of the comple-
and encompasses a few histologic characteristics that are a ment pathway, which leads to chemotaxis of furthermore in-
combination of cornea, conjunctiva, episclera, and sclera.136 flammatory cells and release of collagenases and proteases,
The thickness of the peripheral cornea is greater (∼1 mm) than which cause invasion and stromal destruction of the periph-
that of the central cornea (∼0.5 mm). The epithelial cells are eral cornea.110
more tightly adherent to the underlying basement membrane In patients with rheumatoid arthritis (RA), autoantibodies
and stroma in the corneal periphery than in its center.114 The and self-antigens unite to form immune complexes, which
concentration and replicative potential of epithelial stem cells cause further activation of B cells and complement proteins.
(reservoir for corneal epithelial cells) is the highest in the pe- B cells, in addition to producing autoantibodies, can also
JID: SOP
s u rv e y o f o p h t h a l m o l o g y x x x ( x x x x ) x x x 3
Fig. 1 – Pathophysiology of peripheral ulcerative keratitis involves an interplay of cellular and humoral immune responses,
ultimately causes peripheral corneal ulceration.
produce cytokines that stimulate pathogenic T cell responses. and coworkers evaluated 61 eyes and found that rheuma-
B cells also help in presenting antigenic peptides via MHC toid arthritis accounted for 34% of noninfectious PUK.163 In
class II molecules, which further causes T cells to secrete the setting of RA, PUK develops bilaterally in nearly 50% of
cytokines associated with RA.119 There is also an abnormal cases. Other important systemic autoimmune diseases asso-
expression of HLA class II antigens on keratocytes in pa- ciated with PUK include systemic vasculitides such as GPA)
tients with PUK, along with vasculitis of the adjacent con- SLE, relapsing polychondritis (RP), polyarteritis nodosa (PAN),
junctiva.82 , 106 , 142 Pannus formation is also a key event that is Sjögren’s syndrome (SS), progressive systemic sclerosis (PSS)
maintained through angiogenesis and immune cell clustering and giant cell arteritis (GCA). Dermatological disorders include
in the peripheral cornea.94 acne rosacea, cicatricial pemphigoid, and Stevens-Johnson
syndrome. Systemic inflammatory conditions include inflam-
matory bowel disease (Crohn disease).36 , 55 , 89 GPA is a systemic
3. Etiology of peripheral ulcerative keratitis vasculitis that causes inflammation in blood vessels of nose,
sinuses, throat, lungs and kidneys. PUK is a fairly common oc-
As with all diseases, adequate information on the etiology of ular manifestation of GPA and usually occurs secondary to a
PUK is important to drive a systematic approach to clinical di- necrotizing vasculitis of the anterior ciliary arteries or perilim-
agnosis, ordering of relevant investigations, and planning ap- bal arteries. Although PUK may be a presenting manifestation
propriate treatment. Knowledge of the various etiologies lead- of GPA, it tends to occur in later stages in RA.
ing to PUK has evolved over the years, and our clinical experi- The broad classification of the etiology has been summa-
ence over the past century has made the list more exhaustive rized in Table 1. The various key studies and reports eluci-
and comprehensive. It is also important for a clinician to know dating the clinical spectrum and manifestations and also pro-
every possible cause because PUK can be a rare manifestation viding new evidence confirming various etiologic associations
of a common systemic disease or a common manifestation of related to systemic diseases and PUK are described in detail to
a rare condition. develop a better understanding.
PUK can be caused by a variety of disorders, including both PUK can be caused by local or systemic infections.144 Any
ocular and systemic infectious and noninfectious conditions infection that happens to occur in the peripheral cornea is not
(Table 1). Ocular causes of PUK can be classified as infectious, automatically or by definition PUK. It is only in those situa-
traumatic, neurological, eyelid abnormalities, malignancy- tions where juxtalimbal crescentic stromal thinning with ep-
related, and autoimmune. Systemic causes of PUK may be ithelial defect and stromal inflammatory cells are present are
infectious, autoimmune, dermatological or collagen vascular catergorized as PUK. Studies report infections to be the sec-
diseases, or malignancies.48 ond commonest cause of PUK (∼19.7% of all cases), thereby
Nearly half of all cases of noninfectious PUK are found necessitating the need to rule out infection by appropriate
to have an associated connective tissue disease. RA is the microbiological investigations in all cases of PUK in tropical
most common systemic disease associated with PUK. Tauber countries like India.144 A local exogenous infection (micro-
JID: SOP
dysentery, Lyme disease), viral (varicella zoster, acquired im-

Table 1 – Etiologies reported with peripheral ulcerative
mune deficiency syndrome, hepatitis), fungal, and parasitic
keratitis
diseases (e.g., hookworm infestations).
Mooren ulcer is a rare and idiopathic form of PUK with no
Systemic causes Local causes
associated scleritis occurring in the absence of any identifi-
Infections Infections able systemic disease.141 MU is more common in Africa, China,
Tuberculosis 59 , 12 Staphylococcus13
and India. MU followed by collagen vascular diseases and in-
Syphilis85 , 131 Streptococcus13
fections are 3 important causes of PUK in these regions.144
Lyme disease39 Gonococcus167
Salmonella gastroenteritis179 , Moraxella38 , 178 There are also reports of association of MU with some environ-
Bacillary dysentery117 mental factors such as exposure to viruses (hepatitis C) and
Gonococcal arthritis163 , 167 Hemophilus157 helminthic infections, as well as genetic factors such as the
Varicella zoster121 Pseudomonas aeruginosa162 presence of HLA-DR17 or DQ2 antigens.184
Acquired immune deficiency Herpes simplex132 , 183 Once one has considered the more common disorders, if
syndrome121 , 131 , 53 , 70
not satisfied with the outcome of the investigations or re-
Viral hepatitis35 , 176 , 177 Herpes zoster121
sponse to therapy or if faced with a clinical presentation not
Cat scratch disease133 Chlamydia trachomatis27
Parasitic infections185 Filamentous fungi quite fitting into the expected spectrum, it is useful to look for
-Aspergillus, Fusarium8 other possibilities. The differential diagnosis of PUK includes
Parniaud’s oculoglandular fever27 Dematicious fungi62 the conditions of the peripheral cornea that may present as
Acanthamoeba72 , 112 peripheral corneal thinning or opacification, such as nonin-
Epstein Barr virus101 flammatory conditions (e.g., Terrien marginal degeneration,
Auto-immune causes Auto-immune causes
pellucid marginal degeneration, and senile furrows) and in-
Rheumatoid arthritis163 Mooren’s ulcer177
Wegener’s granulomatosis76 Allograft rejection150
flammatory conditions (e.g., staphylococcal marginal kerati-
Polyarteritis nodosa2 Autoimmune hepatitis45 tis, phlyctenulosis, vernal keratoconjunctivitis). Local insults
Microscopic polyangiitis 89 Traumatic due to other causes e.g., poorly-fitting contact lenses, expo-
Churg-Strauss syndrome18 Corneal penetrating injury77 sure keratitis, trichiasis, malapposed lids may also lead to pe-
Sjögren syndrome152 Chemical injuries71 ripheral corneal disease.
Sarcoidosis147 Thermal burns88
Knowledge of the etiology of PUK is important as it helps
Relapsing polychondritis100 , 181 Radiation injuries118
develop a systematic approach to the diagnosis and manage-
Behcet’s disease116 , 15 Eyelid/margin abnormalities
Temporal arteritis127 Ectropion and Entropion43 ment of cases. There are numerous possible etiologies of PUK,
Takayasu arteritis107 Eyelid tumors87 but a systematic approach based on existing knowledge helps
Systemic lupus erythematosus63 Trichiasis43 in sifting out the possibilities based on the clinical presen-
Inflammatory bowel disease159 Lagophthalmos150 tation and provides a path to steer along for ordering the
Dermatological diseases Neurological causes relevant investigations and planning the most appropriate
Acne rosacea97 , 3 Neuroparalytic150
treatment.
Cicatricial pemphigoid83 Metaherpetic138 , 163
Stevens-Johnson syndrome16 Xerophthalmia102 , 91
Pyoderma gangrenosum69
Other systemic causes Post-surgical
Malignancies – leukemias, etc87 , 113 Post lasik30 , 26 4. Clinical presentation and patient
Hemolytic uremic syndrome108 Post trabeculectomy126 evaluation
Systemic drugs49
Gout180
4.1. Clinical features
PUK has varied clinical presentations. It may be bilateral, but

the majority of cases are unilateral.144 If bilateral, PUK is of-
bial keratitis or conjunctivitis) causing PUK may be caused ten asymmetrical. Injection, pain, tearing, and photophobia
by bacteria (e.g., Staphylococcus spp., Streptococcus spp., Gonococ- are the initial symptoms in the majority of cases. Pain is a
cus, Moraxella spp. and Hemophilus spp.), viruses (Epstein Barr prominent feature of PUK and may be of variable intensity.161
virus, Herpes simplex and Herpes zoster), fungi (e.g., Aspergillus Pain is seen out of proportion to the apparent severity in MU.
spp., Fusarium spp., Pseudomonas spp.), Acanthamoeba spp, etc. Diminution of vision can be seen in both acute and chronic
Gonococcal conjunctivitis is one of the few bacterial diseases cases. In acute cases, decreased vision may be due to inflam-
in which the intense conjunctival inflammation predisposes mation and vary from mild to severe. Chronic PUK leads to
to PUK and corneal perforation.121 Sharma and coworkers re- corneal astigmatism and corneal opacity, which leads to de-
ported nearly 19.7% (out of 76 eyes of 65 patients) of PUK creased vision.
cases to be caused by local infections in a prospective inter- There are various signs that suggest PUK.89 , 146 The most
ventional study over 18 months.144 Of these, 11 cases were important finding, peripheral crescentic ulceration, is charac-
bacterial (73.3%). The culture was positive in 13 eyes (17%) for terized by an epithelial defect, corneal thinning, and infiltra-
coagulase-negative Staphylococci (7 cases), Staphylococcus au- tion at the limbus with overhanging edges (Fig. 2a,b). The ulcer
reus (2 cases), Aspergillus niger (2 cases), Proteus vulgaris (1 case) involves the superficial one-third of the cornea initially and
and Pseudomonas aeuroginosa (1 case).144 Systemic infections may later progress to corneal perforation (Fig. 2c,d).81 To sum-
causing PUK include bacterial (tuberculosis, syphilis, bacillary marize PUK may clinically present as one of the following –
JID: SOP
Fig. 2 – Various clinical presentations of peripheral ulcerative keratitis (PUK) (A) Peripheral corneal guttering (black arrow) in
a case of Mooren’s ulcer (B) Infectious PUK with intense anterior chamber inflammation, hypopyon (white arrow) in a case
of syphilis (C,D) Corneal perforation (white stars) and iris tissue prolapse following corneal weakening in PUK (E) Complete
healing with peripheral vascularization and corneal scarring in a mild variety of PUK.
• Commonly as acute, sub-acute or chronic peripheral ker- tive keratitis case should include a careful systematic review.
atitis with ulceration, stromal thinning (Fig. 2), and infil- Basic investigations include a complete blood hemogram with
tration involving the juxtalimbal cornea. A hypopyon may erythrocyte sedimentation rate, C-reactive protein, blood urea
be present.(Fig. 2b) nitrogen, fasting blood sugar, and urinalysis are to be done for
• Inflammation in PUK, besides involving the juxtalimbal all cases of PUK.
cornea, may involve the adjacent conjunctiva, episclera, If the history and examination give clues about PUK then
and sclera, i.e., nodular scleritis, necrotizing scleritis, etc. the investigation is tailored to a specific suspected underly-
These are seen as manifestations of systemic diseases and ing case. In cases with an inconclusive history and exami-
are mostly associated with autoimmune diseases and in- nation, a battery of investigations is required. Immunological
fectious causes such as tuberculosis. Iritis with anterior investigations such as antineutrophil cytoplasmic antibodies
chamber cells and flare can lead to a painful loss of vision. (c-ANCA, p-ANCA) titers, antinuclear antibodies, rheumatoid
• Healing or healed peripheral keratitis – with a healed ep- factor, anti-CCP antibodies, angiotensin-converting enzyme to
ithelial defect and peripheral corneal thinning and vascu- reach a diagnosis of GPA, SLE, sarcoidosis and RA.152 Comple-
larization and/or corneal scars and opacities seen on ex- ment factor levels such as C3, C4 and CH50 also add to the
amination Fig. 2e). Corneal scarring and vascularization diagnosis of certain immunological causes. Imaging includes
can be severe enough to reduce vision in a few chronic chest X-ray and contrast-enhanced computed tomography is
cases. required for reaching a diagnosis of tuberculosis, sarcoidosis,
• Rarely as corneal perforations or impending perforations GPA, SLE, PSS, etc. Syphilis can be diagnosed by performing
(Fig. 2c,d). Iris tissue may be seen to plug the area of perfo- VDRL and FTA-ABS. Hepatitis B, hepatitis C, and HIV antibod-
ration. These are often ocular emergencies and potentially ies are required in cases where viral infections are suspected.
serious complications in PUK. Local epidemiology of the suspected underlying diseases (e.g.,
tuberculosis/TB), Disease prevalence among the local popu-
4.2. Investigative modalities lation and in the geographical area, is a useful guide for tai-
loring of investigations to avoid over-testing, e.g., testing for
Identification of the exact cause of PUK is important for proper TB in Scandinavian and Nordic regions will have less likeli-
management. In most cases, it is possible to identify the cause hood of being positive because of the low prevalence of TB
based on a detailed history and meticulous clinical evaluation; in these areas, whereas positivity rate will be high in coun-
however, in certain cases with no identifiable cause, one has tries endemic for TB like India, China, Indonesia, Pakistan,
to perform a battery of investigations to find the underlying Philippines, Bangladesh, Nigeria, and South Africa and also in
etiology. immunocompromized patients. The results of these investi-
A wide range of investigative modalities is required to gations must also be correlated with clinical symptoms and
reach a clinical diagnosis. Evaluation of a peripheral ulcera- signs.
JID: SOP
Systemic infections e.g., tuberculosis, syphilis, Lyme dis- GPA typically presents in a patient in the fourth or fifth
ease, cat-scratch disease, parasitic infections (Table 1) may decade of life, with a male to female ratio of 3:2. Usually de-
be investigated for depending upon the local prevalence and scribed as a triad of necrotizing, granulomatous, vasculitic le-
epidemiology of the disease suspected, whereas discouraging sions in the respiratory tract and kidney, where it presents
blind testing for all cases of PUK. Laboratory results support- as focal segmental glomerulonephritis. Recurrent sinus infec-
ing TB infection include elevated ESR and CRP, raised lympho- tions, nosebleeds, hemoptysis with pulmonary involvement
cyte count, normocytic anemia, positive tuberculin skin test, are also seen with constitutional symptoms. PAN is a pro-
and positive serum QuantiFERON gold test. Pulmonary tuber- gressive necrotizing nongranulomatous vasculitis of small to
culosis is strongly suggested based by above positive labora- medium-sized vessels involving multiple organ systems. PAN
tory findings and hilar nodules or lung parenchymal lesions presents with a variety of constitutional symptoms, such as
on chest X-ray, along with symptoms: persistent cough (>14 fever, malaise, muscle thinning, myalgia, and joint pain. Re-
days), shortness of breath, and constitutional symptoms of lapsing polychondritis is a recurring inflammatory disorder
weight loss, fever, and night sweats. There may be a history of unknown etiology that causes destructive inflammatory le-
of exposure to a TB infected individual. TB may often co-exist sions in the cartilaginous structures in the ears, nose, trachea,
with other conditions causing PUK, requiring timely diagno- and joints.
sis and appropriate modifications in the treatment.59 Testing
for TB and opportunistic infections is also imperative before 4.5. Mooren ulcer
starting anti-TNFα drugs like Infliximab. Microbiological ex-
aminations such as corneal scrapings and conjunctival swab MU, an important cause of PUK, may be unilateral or bilat-
for bacterial and fungal culture are indicated when infectious eral. As outlined above, MU is a diagnosis of exclusion, charac-
PUK is suspected. MU is considered a diagnosis of exclusion if teristically associated with severe pain.153 Typically, the ulcer
all the above tests are inconclusive. heals completely between 4 to 18 months with signs of vas-
cularization and scar formation.161 MU may develop compli-
cations such as iritis, intense anterior chamber inflammation,
4.3. Differential diagnosis
secondary infections, glaucoma, cataract, and corneal perfo-
ration in ∼35–40% of cases. MU begins in the peripheral clear
The usual differential diagnoses of PUK are marginal kerati-
cornea at the corneoscleral limbus and progresses centrally
tis, infectious corneal ulcers, herpetic keratitis, phlyctenules,
and circumferentially with overhanging edges of the ulcer.
and peripheral corneal degenerations such as senile furrow
Watson and coworkers described 3 clinical types of MU
degeneration, Terrien marginal degeneration Unlike PUK and
(Table 2) based on clinical presentation, fluorescein angiogra-
MU, these conditions have little or no infiltrate and are mild
phy pattern, and response to therapy. The first type manifests
and usually self-limited. Marginal keratitis often occurs due
as unilateral, progressive corneal ulceration in elderly individ-
to staphylococcal infections, and the infiltrates show a clear
uals. There is vascular nonperfusion of the conjunctiva adja-
space from the limbus. Peripheral corneal degenerations are
cent to the ulcer and superficial vascular plexus at the limbus.
noninflammatory, lack infiltrates, and have intact corneal ep-
The second type is bilateral, aggressive, and is seen in rela-
ithelium.
tively young patients and shows vascular leakage and prolif-
eration of new leaky vessels (a sign of neovascularization) into
4.4. Etiological diagnosis the ulcer in angiography study. The third type of MU is bilat-
eral indolent corneal guttering seen in middle-aged patients
Symptoms and signs pointing towards a systemic diagnosis with relatively less inflammation and a relatively normal
help in management. These include constitutional symptoms, vasculature.49
musculoskeletal, gastrointestinal, cardiovascular, respiratory,
skin, and neurological manifestations. Recurrence of symp-
toms is commonly seen in PUK. Hence, detailed history taking 5. Management of inflammatory peripheral
is important to establish a diagnosis. ulcerative keratitis (PUK)
Some specific clinical signs are seen in systemic diseases
which help in identifying the exact cause of PUK. Saddle nose 5.1. Evidence-based approach to management of PUK
deformity and auricular pinnae deformity are features of
relapsing polychondritis, whereas oral cavity mucosal ulcers, PUK requires a tailored management and an evidence-based
butterfly facial rash, alopecia, and hypo/hyperpigmentation approach based on the underlying etiology. Merely treating the
of scalp and face are seen in SLE. Progressive systemic corneal disease may yield dismal results unless the ocular or
sclerosis has clinical signs such as loss of expressions on systemic underlying disease is targeted.
the face, telangiectasia of small facial vessels, rhinophyma
rosacea, whereas rash and ulcers are seen in most vasculitis (i) Treatment of infectious PUK: Any coexisting active
syndromes. Temporal artery tenderness is seen in giant cell infection, local or systemic, should be managed with
arteritis. Raynaud phenomena are seen in PSS, SLE, and appropriate and specific topical and/or systemic an-
Sjögren’s syndrome. RA is characterized by subcutaneous timicrobial agents. In cases with suspected infectious
nodules in arms and legs, the presence of arthritis in 3 or etiology, corneal ulcer scrapings should first be col-
more joints (usually small joints), positive rheumatoid factor, lected for microbiological evaluation, before initiation
and serum autoantibodies. of antimicrobial agents. Empirical therapy (usually a
JID: SOP
Table 2 – Watson’s classification of Mooren’s ulcer types175
Clinical characteristics Type I Type II Type III
Laterality Unilateral Bilateral Bilateral

Age Old Young Middle-aged or old
Gender Females > males Males > Females No predilection
Pain +++ (severe) + or ++ + (mildest)
Progression Rapid Slow; aggressive at presentation Slow
Management outcomes Poor. Recurrence common Poor. Recurrence common Fair. Rare recurrence
Complications Rare Common Rare
combination of a cephalosporin and an aminoglyco- 5.3. Medical management

side, e.g., fortified cefazolin plus tobramycin drops, or
monotherapy with a fourth generation fluoroquinolone, The medical management of PUK depends upon the identi-
e.g., moxifloxacin) is started for suspected bacterial fied cause of PUK. During the treatment of the ocular lesions,
infections. These may be replaced with specific antibi- a simultaneous referral to a rheumatologist will help in the
otics depending of culture and drug sensitivity results. initiation of therapy targeting the underlying cause.
Topical steroids can be started to suppress local inflam- (i) Local treatment
mation after 48 hours (or up to one week) of response The mainstay of topical medical treatment will depend on
to antimicrobial agents after a reevaluation. For fungal the etiology of the PUK. PUK occurring as a result of infection
infections, it is prudent to start steroids 2 weeks after necessitates prompt diagnostics to identify the pathogenic
treatment with antifungal agents. If no improvement microorganism and start appropriate antimicrobial therapy
is seen in 48 hours of antibiotics, drug resistance or a informed by the corneal scraping and culture results. Adjunct
polymicrobial etiology must be considered and repeat therapy with antiglaucoma medications (topical or systemic
corneal scraping may be warranted. For PUK with as warranted), along with cycloplegics, may be of great help in
suspected herpetic etiology, topical antiviral drugs alleviating morbidity. Cases of immune PUK will require less
(acyclovir or ganciclovir) are started. For systemic infec- frequent instillation of topical antibiotics (such as polymyxin
tions, specific antimicrobial agents as per the treatment B, moxifloxacin, or tobramycin qid) than in cases with an ep-
protocols are administered (e.g., antitubercular ther- ithelial defect or local bacterial infections. Any viral infection
apy is started for suspected Mycobacterium tuberculosis is also treated with topical medications.
infections). Topical lubrication with preservative-free artificial tear
(ii) Treatment of noninfectious immune-inflammatory supplements remains the mainstay in PUK medical man-
PUK: For PUK with a noninfectious immune or in- agement and will help to promote epithelial healing, treat
flammatory etiology, topical steroids and lubricants tear film abnormalities and the keratoconjunctivitis sicca
are administered, along with oral/topical collagenase (KCS) associated with PUK.90,151,183 These also help in the
inhibitors. Topical corticosteroids must be used with washout of the inflammatory mediators on the ocular surface.
caution in patients with underlying auto-immune dis- Some of the available preparations are: carboxymethylcellu-
ease as they inhibit collagen production and, therefore, lose (0.25%, 0.5%, 1%), hydroxypropyl methylcellulose (0.3%),
increase the risk of corneal perforation.178 If improve- sodium hyaluronate (0.1%), polyethylene glycol (0.4%, 1%),
ment is seen with these agents, steroids are tapered glycerine (1%), etc. The frequency of instillation depends on
accordingly, whereas oral steroids and/or systemic the severity of KCS and may be given up to q1h frequency.
immunosuppressants are started for the underlying The addition of lubricant ointment formulation application at
systemic condition. Topical cyclosporine is a useful nighttime will aid in epithelial healing.
adjunctive agent to control inflammation. Systemic im- Topical collagenase inhibitors like acetylcysteine, 10–20%
munosuppressants usually take 4-6 weeks to achieve concentration (bid to qid), or 1% medroxyprogesterone acetate
effective control of the disease. Oral steroids have (bid to qid) may prevent further stromal lysis, though with lim-
an important role during these initial 4-6 weeks. A ited benefits.28 , 178 Topical antibiotics (e.g., polymyxin B, mox-
practical guide to treatment in specific autoimmune ifloxacin, or tobramycin qid) may be added depending on the
systemic disorders will be reviewed in the subsequent case and microbiology results.
subsections. Topical steroids will be required in cases of immune/
inflammatory PUK. The desired antiinflammatory potency
5.2. Main goals of therapy in PUK of topical steroids will depend on the severity of the in-
flammation that needs to be controlled. The potency of
Prompt management of PUK and its underlying condition is steroids may be: low (e.g., fluorometholone 0.1%, lotepred-
of utmost importance to reduce mortality and ocular and sys- nol etabonate 0.2% and 0.5%), moderate (prednisolone
temic morbidity.152 , 163 , 178 The primary goals of treatment in sodium phosphate 0.5%, betamethasone 0.1%, dexametha-
PUK are to promote epithelial healing, halt any further stro- sone 0.1%) or high (e.g., prednisolone acetate 1%). The
mal lysis by minimizing inflammation, and prevent superin- dosage is usually started as qid, adjusted as per re-
fections.161 , 178 sponse, and finally tapered down slowly, Corticosteroids are
JID: SOP
very useful in inflammatory PUK as they suppress the Aggressive systemic immunosuppressants (systemic cor-
local immune response; however, these must be used with ticosteroids plus a cytotoxic agent) are the mainstay to treat
caution in PUK with underlying auto-immune conditions (e.g., inflammatory PUK that have underlying conditions and have
RA) as they have been reported to inhibit new collagen forma- a vision-threatening presentation (Table 3).52 , 178 Level II evi-
tion, increase the chances of corneal perforation, and delay dence supports the role of immunomodulatory therapy (IMT)
epithelial healing in PUK.10 , 28 , 52 , 154 , 171 Topical steroidal agents in the reduction of mortality in patients of PUK with necro-
delay the wound healing process by inhibiting fibroblast infil- tizing scleritis.48 , 56 , 124 Foster and coworkers first described
tration. Thus, in cases of PUK with RA, topical steroids are usu- the role of adequate systemic immunosuppression in low-
ally not advised to avoid corneal perforation.161 Topical steroid ering mortality rates in RA patients with ocular manifesta-
use may also lead to adverse effects like steroid-induced glau- tions.48 , 124 In patients with PUK and scleritis due to various
coma, cataract, and increased susceptibility to ocular infec- underlying conditions (e.g., RA, GPA, SLE), mean time to death
tions. has been reported to be 24.7 years in subjects on IMT, ver-
Topical nonsteroidal anti-inflammatory drugs (NSAIDs) sus 10.7 years in those without IMT.124 Presence of necro-
(e.g., ketorolac, diclofenac, bromfenac, nepafenac, flurbipro- tizing scleritis and PUK in RA and other autoimmune dis-
fen) may be used to relieve inflammation in PUK; however, eases signify a lethal form of systemic vasculitis and requires
these may occasionally lead to silent corneal perforations and IMT;106 , 130 , 152 , 163 , 177 however, IMT is recommended even in
corneal melts, especially in elderly patients with concurrent PUK without any diagnosed underlying systemic condition.124
ocular surface diseases.25 Thus, in cases of PUK with RA with a. Systemic steroids
a dry ocular surface, a short course of low potency steroids Oral corticosteroids are added for cases with progressive
bid or tid, may be chosen over prescribing NSAIDs for anti- thinning. Oral prednisone is started usually at a dose of
inflammatory effect. 1mg/kg/day (maximum 100 mg/day), followed by slow taper-
Topical cyclosporine A (CsA) 2% and topical tacrolimus ing according to the clinical response.107 In vision-threatening
0.03% are calcineurin inhibitors that suppress the local presentation of PUK, intravenous pulse methylprednisolone
immune response by inhibiting T-cell receptor-mediated (1g/day x 3 days), followed by switching to oral prednisone can
interleukin-2 synthesis from T-lymphocytes, i.e., im- be administered to prevent further ocular complications.52
munomodulatory action.52 , 158 CsA is a useful and safe In general, prednisolone is the preferred steroid because of
adjunct therapy in PUK, promotes ulcer healing and circum- only moderate glucocorticoid effects, mild effects on serum
vents the nephrotoxicity noted after systemic administration electrolyte profile, and its limited half-life in the body.10 The
of CsA.59,67,191 Addition of autologous serum drops promote addition of H2 blockers to prevent steroid-related gastric ul-
re-epithelialization of the ulcer.103 A subconjunctival or cers and calcium supplements to prevent significant bone loss
peribulbar steroid depot application may be used in cases must be added to oral steroid therapy. Other side effects of sys-
with associated scleritis, but confer a risk of scleral perfora- temic steroids, e.g., hypertension, hyperglycemia, hirsutism,
tion.5 , 52 , 166 etc., must be watched for.
(ii) Systemic medications b. Immunosuppressive agents
As discussed in the section on etiology, PUK is associated The presence of PUK may herald an impending life-
with many autoimmune diseases, the most common being threatening vasculitis, and immunosuppressive agents are of-
RA.24 , 52 , 89 , 163 , 178 Systemic therapy targeting these underlying ten required to induce disease remission in cases with under-
systemic conditions, many of which may be life-threatening,88 lying autoimmune disorders.75 These agents reduce disease
greatly alters the disease course, mortality, and ocular morbid- mortality and ocular morbidity47 , 52 , 129 and are usually started
ity. along with high dose systemic steroid. These agents have an
(a) Systemic therapy for the management of ocular mor- important role in the treatment of PUK as “corticosteroid-
bidity sparing agents”, i.e., they may be added along with systemic
Oral NSAIDs (flurbiprofen or indomethacin) may be added steroids, when systemic steroids alone fail to control the dis-
to relieve the pain and inflammation in cases of severe PUK ease at less than 10 mg daily dose or when glucocorticoid-
or those with accompanying scleritis. Oral ascorbic acid (500 related adverse effects are concerning.74 The choice of
mg bid) is added in cases of peripheral corneal melting. Ani- agent usually differs according to underlying systemic
mal studies have confirmed direct evidence of therapeutic ef- diagnoses.
fect of ascorbic acid on corneal epithelial wound healing32 and As these are cytotoxic agents, careful monitoring and
has also been shown to reduce the formation of corneal opac- frequent follow-up visits are required to detect any drug-
ity resulting from healing of keratitis.33 Oral doxycycline (100 related or dose-related adverse effects. Immunosuppression
mg bid) helps in the prevention of local collagenolysis by ir- may also lead to life-threatening opportunistic infections,
reversibly inhibiting MMP by chelating the catalytically and which raises concerns in cases of pandemics due to viral
structurally active metal ions. It may also play a role by halting agents e.g., COVID-19.111 This risk must be discussed with
the migratory keratocytes or fibroblasts that lead to formation the patient at the time of initiation of immunosuppressive
of scar tissue and promote complete coverage of the ocular therapy.
surface by epithelial basal cells. This helps in development of Methotrexate (MTX), the most extensively used immuno-
a stable, stratified epithelium.148 suppressive agent is the first-line agent in severe PUK in RA.107
(b) Systemic therapy required for management of the un- MTX mainly affects rapidly dividing cells, e.g., T- and B- lym-
derlying systemic condition phocytes. Its dosing is convenient (5-25 mg once a week), and
it has less systemic toxicity than most other IMT agents.
JID: SOP
Table 3 – Therapeutic agents for PUK with underlying auto-immune conditions (The therapies listed in this table have
been described in case reports or case series; none have been evaluated in randomized trials.)
Drug name Mechanism of action Route Usual dose Specific adverse events
A. Corticosteroids
Methylprednisolone129 Suppress gene transcription Intravenous 1 g/day for 3 days Gastric ulcers, Osteopenia,
through nuclear receptors, hyperglycemia
decreasing the production of
inflammatory mediators
Prednisolone79 Oral 1 mg/kg daily
A. Cytotoxic agents
Cyclophosphamide129 Alkylating agent that decreases Oral, intravenous Up to 150 mg daily orally Leukopenia, nausea, vomiting,
T cell replication hemorrhagic cystitis, diarrhea
Methotrexate79 Antimetabolite: inhibits Oral, subcutaneous 7.5-25 mg weekly Hepatotoxicity, nephrotoxicity,
dihydrofolate reductase (DHFR) leukopenia, stomatitis, nausea,
thus decreases DNA synthesis fatigue
Azathioprine50 Purine synthesis inhibitor. DNA Oral 1-2.5 mg/kg/day The occurrence of neoplasias,
synthesis of proliferating cells nausea, vomiting,
affected hypersensitivity reactions,
nephrotoxicity, hepatotoxicity
Mycophenolate Inosine-5 -monophosphate Oral 1-1.5 g twice daily Malaise, fatigue, diarrhea,
mofetil151 dehydrogenase inhibitor, thereby raised liver enzymes,
inhibits purine synthesis leukopenia
pathway required for replication
of lymphocytes
Cyclosporine A Calcineurin inhibitor that Oral, intravenous 1.25 mg/kg orally twice Leukopenia, Nephrotoxicity,
58
(Sandimmun Inhibits transcription of IL-2, daily, increase by 0.5 mg hyperkalemia,
optoral) affecting T cell activity after 8 weeks and then as hypomagnesemia, gum
per response (maximum hyperplasia, pancreatitis,
daily dose 4 mg/kg) anaphylaxis, tremor, infections,
hypertension, dizziness,
nausea, hirsutism
B. Biological agents
Rituximab50 Anti-CD20 monoclonal antibody Intravenous 2 injections of 1000 mg per Infusion-related reactions,
injection dose (2-weeks part) after cardiac toxicity, reactivation of
every 6 months infections such as tuberculosis
Infliximab62 anti-TNFα monoclonal antibody Intravenous 3-5 mg/kg/dose at 0,2,6 Pulmonary tuberculosis
weeks and then every 8 reactivation, increased
weeks incidence of infections,
lupus-like reaction,
demyelinating diseases
Adalimumab112 anti-TNFα monoclonal antibody Subcutaneous 40 g every week (2 weeks Malignancies, infections,
injection apart) after every 6 months anaphylaxis
Golimumab125 anti-TNFα monoclonal antibody Subcutaneous 50 mg per dose at 0,4 and Serious infections, reactivation
injection then every 8 weeks of tuberculosis and other viral
infections, infusion-related
reactions
Certolizumab125 anti-TNFα monoclonal antibody Subcutaneous 400 mg (2 ml) dose at 0,2,4 Serious infections, reactivation
injection weeks then 200 mg (1 ml) of tuberculosis and other viral
every 4 weeks. infections, infusion-related
reactions
Anakinra Recombinant human IL-1 Subcutaneous 100 mg once daily Serious infections, reactivation
receptor antibody injection of tuberculosis and other viral
infections, infusion-related
reactions
Tocilizumab125 Anti-IL6 monoclonal antibody Subcutaneous or 162 mg sc every week Serious infections, reactivation
intravenous 4 mg/kg iv every 4 weekly of tuberculosis and other viral
injection infections, infusion-related
reactions
(continued on next page)
JID: SOP
Table 3 (continued)
Drug name Mechanism of action Route Usual dose Specific adverse events
Etanercept57 anti-TNFα Subcutaneous 25 mg twice a week or 50 Serious infections, reactivation

injection mg once a week of tuberculosis and other viral
infections
Abatacept125 CD80/86 receptor inhibitor, T Subcutaneous or Iv: 500-1000 mg at 0,2,4 and Serious infections, reactivation
cell-blocking Fc portion protein intravenous then every 4 weeks of tuberculosis and other viral
of the extracellular domain of injection sc: 125 mg once a week infections, infusion-related
CTLA-4 reactions
Secukinumab Anti-IL-16 monoclonal antibody Subcutaneous 150-300 mg once a week for Serious infections, reactivation
injection 4 weeks and then every 4 of tuberculosis and other viral
weekly infections, infusion-related
reactions
Cyclophosphamide (up to 2mg/kg/d) is another preferred clonal antibody [mAb] with afucosylated Fc portion and en-
drug for achieving additional immunosuppression when the hanced affinity for Fcγ receptor III has been tried in the
response to systemic steroids is inadequate.48,144,161 It has management of rheumatoid arthritis and found to induce
been found as a very successful agent for halting disease pro- a superior B cell cytotoxic response to rituximab.134 In a
gression in PUK in GPA.42 , 174 Because of its high cytotoxic- recently published multi-center study, other drugs such as
ity, blood cell counts should be repeated at least every 2-3 certolizumab pegol, golimumab, tocilizumab, belimumab and
weeks. Clewes and coworkers34 and Sule and coworkers156 re- abatacept were tried in severe cases of PUK refractory to im-
ported the successful use of intravenous cyclophosphamide munosuppressant therapy and were found to be promising
in patients of RA-related PUK, in combination with systemic alternatives.41 JAK inhibitors such as tofacitinib, which have
steroids and local therapy. been used in the management of immune-mediated diseases
Mycophenolate mofetil is also an effective cytotoxic agent are also likely to be effective in the treatment of noninfectious
with steroid-sparing action and manageable side effects when inflammatory eye disorders, including PUK.125
used in the dose of 1-3 g in daily 2 divided doses.161 , 164 The potential adverse effects of biologicals at the required
Azathioprine, an immunosuppressive agent has been found doses and their possible benefits, as per clinician’s past experi-
to be a safer option than cyclophosphamide, but has lesser ef- ence with the drug, should be considered and weighed against
ficacy than cyclophosphamide. Induction of its response takes each other before the initiation of therapy.68 Although the ini-
at least 3-4 weeks after initiation of therapy.182 tial clinical response is good and ocular disease stabilizes well
Cyclosporine A (CsA) has been shown to improve healing of with most of these biological agents, yet the emergence of side
epithelial defects and thereby provide symptomatic relief by effects and progression of systemic disease course may com-
alleviating the pain in bilateral, progressive PUK that is failing pel rheumatologists to switch to other therapeutic agents.61
with standard medical and surgical therapy.65 CsA is reported Rituximab a monoclonal antibody targeting CD-20, which
to increase systemic immunoglobulin levels;65 however, the is a B-cell receptor, is the most useful agent to maintain remis-
severe systemic side effects of CsA including nephrotoxic- sion in ANCA-associated vasculitides (e.g., GPA, microscopic
ity, hepatotoxicity, and predisposition to lymphomas limit its polyangiitis, ANCA-associated renal vasculitis).174 Its role as a
use.65 maintenance agent is superior to azathioprine or cyclophos-
Among patients treated with systemic immunomodula- phamide.57 , 155 Rituximab is efficacious in the induction ther-
tory therapy, a marked difference in mean survival was noted apy in refractory PUK with RA61 and has also been successfully
with a mean estimated survival of 24.7 years with immuno- used to prevent blindness in refractory PUK with underlying
suppressive therapy compared to 10.7 years without ther- GPA with sinus involvement failing on IV cyclophosphamide
apy.124 therapy.51
c. Biological therapy TNF alpha inhibitors, including infliximab,68 adali-
Biological agents or biological response modifiers are be- mumab,86 , 120 etanercept64 have been used in cases of
ing increasingly used for the management of PUK, refrac- refractory PUK failing to respond to all other treatments.
tory to all conventional immunosuppressant agents. These Korsten and coworkers86 first reported the successful use of
agents may be classified as novel anti-TNF alpha-blockers, combination therapy of prednisone, MTX, and adalimumab
anti-interleukin agents drugs (directed against interleukins for sight-threatening PUK.
like IL-1 and IL-6), B-cell-receptor inhibitors (directed against Recently, a multi-center trial was conducted to compare
ligands CD20, CD22), therapy targeting co-activation signaling anti-TNFα versus rituximab in 24 patients of refractory PUK,
(CTLA4-antibody), and intravenous immunoglobulin (IVIG).137 defined as an inadequate response to systemic corticos-
Although infliximab is the most commonly used biolog- teroid and at least one immunosuppressive drug.A Anti-TNFα
ical agent (an anti-TNF alpha agent), rituximab is the most agents, viz. adalimumab, infliximab, and etanercept were used
commonly used nonanti TNF alpha agent.41 . Newer biologic in 17 patients, and rituximab in 7 patients. Both were found to
agents, such as obinutuzumab, a Type II anti-CD20 mono- be equally effective in refractory PUK due to various rheumatic
JID: SOP
diseases. Biologic therapy has been compared to immunosup- prove chances of graft survival and the outcomes of surgery.
pressing agents as well. Cyclophosphamide and infliximab, Penetrating keratoplasty has been shown to have 20-40% graft
both, have been found to have a rapid onset of action and high survival at 6 months, and many patients therefore require
steroid-sparing effects.B multiple grafts.20 , 106
d. Biologicals or immunosuppressants ? Surgical management is required for tectonic reconstruc-
Biological agents are usually tried in cases of severe PUK, tion in cases with extensive corneal melt/ thinning, progres-
where management with systemic steroids and immunosup- sive annular/central extension advancing close to the visual
pressants (e.g., antimetabolites such as methotrexate) has axis, corneal perforation, or impending perforations or de-
failed to control the ocular or systemic inflammatory disease. scemetocele (tectonic indication), or ulcers extending circum-
The most commonly used biological agents are the anti-TNF ferentially (therapeutic indication) and for visual rehabilita-
alpha agents, e.g., infliximab and adalimumab. These biolog- tion (optical indication), but considered only along with sys-
ical agents are mostly utilized in conjunction with immuno- temic immunosupression.161 Corneal perforation is an acute
suppressants. Typically, immunosuppressants are started in complication of PUK, commonly seen in cases with multiple
the remission phase to suppress disease activity, and biolog- recurrences, inadequate immunosuppression, or poor compli-
ical agents are preferred for the maintenance phase (i.e., af- ance to treatment.124 Early surgical intervention along with
ter the course of immunosuppressant agent), whereas treat- optimal cytotoxic immunosuppressant therapy is successful
ing the systemic underlying disease causing PUK. Infliximab in achieving restoration of tectonic integrity of the globe in
is given as intravenous infusions (5-10 mg/kg/dose given 2 92% of cases and visual acuity improvement/stabilization in
weeks apart), whereas adalimumab is administered as weekly 68% of cases;106 however, the graft outcomes are usually poor,
subcutaneous injection (40 mg per dose). The adverse effects and there is a high graft rejection rate in cases with underlying
are discussed in Table 2. systemic diseases.
Because of the possible side effects of infliximab infusion, Surgical options are chosen based on factors like the
e.g., reactivation of latent tuberculosis, infusion related reac- size of perforation or thinning, the extent of ocular dis-
tions, congestive heart failure, myocardial infarction and deep ease. In cases with corneal thinning, one may decide be-
vein thrombosis, infliximab is not indicated in the first in- tween surgical options like – amniotic membrane transplan-
stance for PUK treatment. Adalimumab has relatively fewer tation (AMT),74 , 122 , 151 conjunctival resection/recession,44 or
adverse effects, easier administration and better patient com- conjunctival flaps. Conjunctival resection of surrounding 2-3
pliance among the anti-TNFalpha agents. Cordero-Coma and clock hours of the conjunctiva, adjacent to the inflamed area
coworkers reported promising results of adalimumab in cases is effective in PUK.44 , 107 It helps remove the conjunctival tis-
of refractory PUK failing with oral steroids and immunosup- sue that has inflammatory cells, collagenases, and other me-
pressant agents and in a case when infliximab had to be dis- diators. Cryotherapy and raising of conjunctival flaps may be
continued after an infusion-related reaction. Not all patients combined with these surgeries.96 Lamellar patch graft surgery
with PUK respond to their first anti-TNF agent. also has been tried successfully in PUK. It offers the benefit of
The decision of choosing one agent over the other de- fewer chances of graft rejection than full-thickness penetrat-
pends upon multiple factors, including the etiology, clinical ing keratoplasty (PKP).60 Deep anterior lamellar keratoplasty
presentation, severity of disease, the systemic co-morbidities, (DALK), which preserves the host endothelium and Descemet
the side effects of drugs expected at the required dose membrane, has also led to successful outcomes in PUK with
(dose-dependent side effects), infusion-related reactions, corneal melt.
convenience of route of drug administration to patient, and Perforations of size ≤ 3mm may be dealt with the use
the baseline hematological, liver, and kidney test profile of of tissue adhesive (e.g., cyanoacrylate) with bandage contact
the patient. A referral to a rheumatologist should be made lenses.4 Tuck-in Tenon patch graft (TPG) may be useful for per-
for appropriate pretreatment evaluation, selection of an forations of 3 to 5 mm size.143 TPG is safe and inexpensive
appropriate agent, proper administration and follow-up of and offers the advantage of the autologous nature of the graft.
the biological response modifier drug. In a recently published Extension of perforation size over 3 mm would often require
study on the use of biologic agents, 48% of patients who were full-thickness patch grafts and tectonic keratoplasty, which
initially started on an anti-TNF alpha agent had to be switched may or may not be combined with AMT. Such extended per-
to another biological agent because of treatment failure or forations should be operated in general anesthesia to reduce
adverse effects. Biologic therapy in most of the patients in the incidence of hemorrhagic choroidal detachments. Suture-
this series showed a rapid and maintained improvement in less patch grafts punched using dermatological trephine and
the efficacy outcome variables after 3 months of initiation of secured with fibrin adhesive60 have been reported to have
therapy.41 successful outcomes in cases with peripheral corneal melt.
Lamellar patch graft surgery also has been tried successfully
in PUK. It offers the benefit of fewer chances of graft rejec-
6. Surgical management tion.60 PKP may also be performed depending upon the size of
perforation or corneal melt. Sutureless lamellar keratoplasty
In general, for PUK, surgery should be delayed until adequate using fibrin tissue adhesive79 and “tuck in” lamellar kerato-
immunosuppression has been achieved, due to high chances plasty (TILK)168 are other surgical options. TILK is usually pre-
of graft melts and recurrence of PUK.98 , 123 Systemic immuno- ferred over PKP in cases where 360 degrees of peripheral tec-
suppression controls the active underlying inflammation in tonic support is required at the graft-host junction. Shaped
PUK, reduce graft melts and graft rejection rates and thus im- corneal surgery e.g., banana grafts, ‘match and patch’ and
JID: SOP
stenciling-based ‘prick and print’ technique have also been necrotizing scleritis and PUK, as these cases otherwise
described for dealing with PUK.29 , 128 have a poor visual prognosis and herald a severe form
Among tectonic corneal grafts, lamellar keratoplasty and of underlying systemic vasculitis.56
patch grafts generally have better graft survival rates than (c) In SLE and RP also, systemic steroids and a cytotoxic
PKP.9 The reasons for an increased incidence of tectonic fail- agent are used for the management of PUK. Foster and
ure in cases of PUK are active inflammation or infection, sys- coworkers suggested systemic vasculitis occurs in the
temic preponderance to repeat corneal melts, higher rejection later phase of this disease, and its presence indicates
and secondary glaucoma rates. and placement of the graft too relentless disease progression in RP and possibly inade-
peripherally.9 , 169 quate immunosuppression, as cases with systemic vas-
culitis have a higher mortality.48
(d) Special situations: In cases of PUK in pediatric patients
7. Treatment protocols in PUK due to various with underlying systemic disease, MTX is the immuno-
etiologies suppressant of choice. Cyclosporine is considered if no
response is seen to MTX. In pregnancy, due to risk of ter-
The current treatment strategy of PUK with underlying sys- atogenicity, IMT is best avoided, whereas managing dis-
temic disease in its acute phase is systemic corticosteroid plus ease activity through oral steroids only, with great cau-
an immunosuppressive agent (a cytotoxic or a biological drug). tion.
Among the biological agents, antiTNF (infliximab) and antiCD (e) Patients already on IMT on clinical presentation: Often
20 (rituximab) drugs have been found to have almost compa- in clinical practice one may face situations where pa-
rable effect. The preferred agent depends upon the underly- tients already on IMT (started for control of activity of a
ing systemic condition and benefit-to-risk ratio with the cho- diagnosed underlying disease) present with PUK, e.g., an
sen agent. Diseases like RA and GPA are rapidly progressive RA patient already taking anti-TNF agent. In such situa-
and are associated with high mortality rates. Thus, these re- tions, one should look for any other sign of acute exac-
quire aggressive IMT for systemic control of the disease activ- erbation of the systemic disease, whereas patient is on
ity along with local management of the corneal lesion. Often, IMT, and follow a ‘step-up up or maintenance’ approach.
an ophthalmologist and a rheumatologist have to decide and Rheumatologists should assess the systemic clinical re-
monitor the treatment to improve the disease course. sponse to IMT agent used so far and decide on continu-
ing the therapy if the response has been favorable and
(a) For the management of PUK with RA, the currently clinical remission has been achieved, or decide on revis-
recognized treatment is a systemic corticosteroid, ing the therapy to use a stronger agent (step-up) if the
plus a cytotoxic agent (e.g., MTX).107 , 173 Ocular surface response (remission of inflammation) has been inade-
management and topical medications for the heal- quate. Usually, an immunosuppressive agent becomes
ing of peripheral corneal lesion, along with systemic effective after a period of 6 months.161 One should con-
therapy (systemic corticosteroid plus methotrexate) to sider switching to other IMT agents if clinical response
control the systemic disease is the usual management is inadequate in these 6 months.
approach in PUK with RA. The systemic therapy is (f) MU: All underlying systemic diseases must have been
usually decided in consultation with rheumatologist ruled out before the diagnosis of MU can be made.17
or immunologist. Azathioprine and cyclophosphamide Vilaplana and coworkers recommend surgical treat-
are second-line agents in severe PUK in RA and are used ment only in cases of MU at risk of or presenting
for drug-intolerant, rapidly progressive cases failing to with corneal perforation or acute necrosis.170 Ashar
respond to MTX.106 and coworkers14 evaluated step ladder treatment in the
(b) Patients of PUK with GPA and PAN are managed with ag- current era of biotherapy and recommended an ag-
gressive IMT: systemic steroids plus cyclophosphamide gressive immunosuppressive regimen tailored to the
(first line immunosuppressor agent for GPA) initiated severity of presentation of MU should be first-line
in the early course of the disease. Cyclophosphamide therapy to achieve disease control. There is, however,
and rituximab, either alone or in combination with no RCT that compares medical and surgical treat-
other agents, have proven to be the most successful ment strategies for MU (Table 4).6 The treatment goal
agents in controlling inflammation in cases of PUK in MU is to achieve complete epithelialization of ul-
GPA.42 Based on the current evidence on response of cer and filling of stromal defect with no fluorescein
GPA-associated PUK, one should consider an aggressive staining.6 , 175 The current treatment strategy for MU
IMT: cyclophosphamide plus steroids in remission is a ‘stepladder approach’24 (Table 4, Fig. 3): initial
phase and rituximab for maintenance phase. In cases treatment with topical corticosteroids,17 , 161 topical cy-
of treatment failure with cyclophosphamide, ‘stepping closporine 0.05 to 2%, followed by limbal conjuncti-
up’ to rituximab should be considered. Ebrahimiadib val resection or excision6 , 17 , 23 , 161 in cases with no re-
and coworkers42 reported excellent remission rates sponse, then systemic immunosuppression (e.g., oral
and better inflammation control with rituximab and corticosteroids, methotrexate, cyclophosphamide, cy-
cyclophosphamide than with other immunosuppres- closporine, etc), other surgical interventions and fi-
sive agents in cases of PUK with GPA in a retrospective nally rehabilitation to treat astigmatism and to save
case series. Gu and coworkers recommended aggres- globe integrity.24 , 140 , 17 , 161 One must remember that
sive immunotherapy in cases of GPA presenting with because of the underlying autoimmune process in-
JID: SOP
Table 4 – Therapeutic options for Mooren’s ulcer (The therapies listed in this table have been described in case reports or
case series; none have been evaluated in randomized trials.)
Mode of therapy Reference (Author, Reported outcomes with Current role in Mooren’s Comments
year) therapy (if available) ulcer treatment
A. Local therapy
Topical Brown, 198424 Useful agent in the Should be used with

corticosteroid Alhassan, 20146 Healing in 12/37 patients24 initial treatment stages caution as may increase
chances of corneal
perforation
Topical cyclosporine Zhao, 1992,186 Effective treatment in 61.1% Useful and safe adjunct Promotes ulcer healing,
Tandon, 2008160 of affected eyes at 24-31 in recalcitrant cases causes local
months follow-up,186 ; immunosuppression.
Complete healing in 12 Doses: 0.5 %, 2%
eyes160
Subconjunctival Aronson,197011 Effective in 6/10 patients Unproven role -
heparin injection
Artificial tears Sangwan,1997140 - Useful adjunct for Can be given as an
promotion of epithelial ointment or drops up to
healing q1h, e.g.,
carboxymethylcellulose
0.5%, HPMC 1%
Autologous serum Mavrakanas, 2007103 Significant improvement of Effective supplementary Given in conjunction
PUK, BCVA improvement drug with corticosteroids and
with regression of antibiotics
symptoms in 2 weeks103
Topical collagenase Sangwan,1997140 - Useful adjunct as arrest Acetylcysteine
inhibitors further stromal (Mucomyst 10%) and
destruction L-cysteine (0.2 molL-1)
Lecithinated Shimmura, 2003145 Average ulcer size, relative Supplementary role in Lipophilic analog of SOD
superoxide to entire cornea, decreased persistent epithelial is used
dismutase (SOD) from 18.2±15.1 % to defects (PEDs). Reduces
10.1±15.0% after 2 weeks the PEDs
B. Systemic therapy
Oral corticosteroids Brown, 198424 Healing n 4/13 eyes24 Initiated when Controls aggressive
conjunctival resection bilateral disease
fails
Cyclophosphamide Foster, 198548 Resolution of PUk in 16/17 First-line Initiated early in cases
eyes48 immunosuppressive with bilateral or
agent sight-threatening
presentation and in
extensive corneal melts.
Azathioprine Foster, 198548 Clinical response seen in 4 Second-line Takes 3-4 weeks for
weeks with stable corneas immunosuppressive onset of action.
on follow up of 4 years48 agent Required for a longer
duration and
recurrences common
when therapy stopped
Methotrexate Brown, 198424 Healing in 4/ 13 eyes24 ; First-line Convenient weekly
Ashar,201314 Recovery rate of 78.5%14 immunosuppressive dosage
agent
Cyclosporine A Brown, 198424 Healing in 4/ 13 eyes24 ; Effective agent in Reduces inflammation
Foster, 198548 Resolution of ulceration sight-threatening and destruction of the
Wakefield, 1987172 within 2 weeks of disease corneal stroma. Use is
treatment and remained in limited by severe
remission after 15 months systemic side effects
of therapy172
Interferon α2b Moazami, 1995109 Resolution of ocular Indicated in Mooren’s Good efficacy of
Wilson, 1994177 inflammation with 2 weeks ulcer with hepatitis C treatment in hepatitis C
of therapy109 ; Marked virus infection cases
improvement in 2 cases
treated177
(continued on next page)
JID: SOP
Table 4 (continued)
Mode of therapy Reference (Author, Reported outcomes with Current role in Mooren’s Comments
year) therapy (if available) ulcer treatment
Monoclonal Fontana, 200746 Marked reduction in Useful agents after the Arrest keratolysis and
antibodies (e.g., Van der Hoek, 200366 conjunctival inflammation, failure of oral and promote rapid healing
Infliximab) Guindolet, 201658 no recurrence of corneal topical steroids,
thinning on 2 year follow azathioprine,
up after Infliximab methotrexate, and
therapy46 ; Marked decrease cyclosporine
in inflammation after 5-day
course66 ;
Complete healing of ulcer
within 2 weeks in all
patients treated with
Rituximab58
C. Surgical
Conjunctival Brown,198424 Healing in 8/22 cases24 ; Useful in arresting Resection of at least 2

resection Kalogeropoulos, Disease progression halted progression when an clock hours of limbal
200478 in all 6 patients without inadequate response to conjunctiva, 4 mm
recurrence in follow up topical steroids alone behind the limbus is
period of 1-2 years.78 performed
Bandage contact Lal I, 201590 Median recurrence free Reduce the ocular Does not prevent
lenses, tissue survival of 141 days; discomfort. May be used recurrence of the ulcer
adhesives Probability of recurrence for small corneal and cannot substitute
free survival 42.5% (1 year) perforations (up to 3 systemic
and 21.3% (2 years)90 mm) immunosuppression.
Lamellar Liu J, 201595 Favorable anatomical Effective to treat Complete or a patch of
keratoplasty Nian,1979187 recovery in 87.1% eyes with perforated corneal the corneal graft may be
Kinoshita, 199184 significant improvement in ulcers, when combined used, fashioned out as
vision in all patients95 ; 90% with per the shape of the
eyes showed complete immunosuppressive defect
remission promptly after agents and steroid
surgery84 therapy
Lamellar Brown, 198424 Healing in 6/6 eyes and Useful in perforated Acts by removal of
keratectomy Martin,198799 resolution of inflammation corneal ulcers. antigenic stimulus
in all24 Decreases ocular triggering inflammation
inflammation
Corneal patch graft Bhandari, 201521 BCVA improved to 6/36 in Good visual outcomes A crescent-shaped
right eye and 3/60 in left and tectonic customized corneal
eye21 improvement in patch graft that may be
perforated corneal combined with amniotic
ulcers. membrane graft
Patch graft of Dingeldein, 199040 Responded well with final Good response in Autogenous tissue used
periosteum or fascia visual acuity of 20/4040 recurrent ulcerations
lata
Amniotic membrane Spelsberg, 2007151 Clinical healing with stable Useful when Anti-inflammatory role.
transplantation Ngan, 2011122 corneal surfaces in all 3 immunosuppressive
patients151 ; agents are unavailable
Mean time to complete or contraindicated. May
epithelization of 12.4 days be performed in early
in 16 of 18 eyes122 stages of ulcers or
nonhealing ulcers
Conjunctival Agrawal V, 19961 Complete healing in 82.4% Role in debulking the Resulted in complete
resection with with formation of inflamed tissue and healing with the
cyanoacrylate glue vascularized scars1 helps in the removal of formation of
and superficial antigenic stimulus that vascularized scars
keratectomy initiates the
auto-immune local
process
JID: SOP
Fig. 3 – Stepwise treatment protocol for Mooren ulcer.14 ,21
Fig. 4 – Management algorithm for peripheral ulcerative keratitis (PUK): Medical and surgical options are chosen as per the
clinical presentation. Surgical interventions are often required for acute cases and as adjunctive role in chronic cases of PUK.
volved in the pathophysiology of MU, systemic im- tion. This treatment has been shown to help in the resolution
munosuppression is the mainstay of therapy, and of corneal ulceration and also had an impact on the liver func-
surgery alone will not prevent recurrences.90 tion tests of the patient.177 Although these patients present-
ing with corneal ulceration may not be exhibiting any symp-
toms, they often had an underlying severe hepatic disease. So
A rare association has been reported between corneal ul-
therapy with interferon α2b might be lifesaving by inducing
cers that resemble MU and hepatitis C.164 Treatment with in-
remission of the hepatic disease.101
terferon α2b is indicated in cases of MU with hepatitis C infec-
JID: SOP
8. Overview of treatment in PUK 11. Method of literature search
Overall, the treatment of PUK is guided by the etiological diag- An electronic search of the MEDLINE/PubMed database was
nosis, the severity of ocular findings, and the extent and na- performed for the years 1781-2020 with the keywords: “PUK”
ture of the systemic disease (Fig. 4).28 , 52 , 178 Despite recent ad- OR “peripheral AND ulcerative keratitis” OR “Mooren’s ulcer”
vances in pharmacological therapy of PUK, the outcomes de- OR “Mooren ulcer” OR “corneal ulcers in autoimmune dis-
pend upon the underlying disease, the extent of ocular and eases OR disorders”. Some articles that were not found by our
systemic involvement, and early diagnosis and timely initia- PubMed search were taken from the references from other ar-
tion of treatment. ticles and books. English abstracts available on PubMed were
included in certain important non-English language articles
on PUK.
9. Recent advances
In recent times, the diagnostic and treatment modalities for Disclosure statement
PUK have progressed tremendously. Apart from the overt clin-
ical aspects, advances in basic science have helped in pro- Conflict of interest
viding better insights into the mechanisms of pathogenesis.
Role of inflammasomes (chromosomes responsible for inflam- The authors have no conflicts of interest.
matory cascade mediation) e.g., NLRP395 and their cascades
e.g., NLRP3-CASP1-IL1β are being explored in the causation of Financial disclosure
PUK, particularly MU, and are detected using real-time poly-
merase chain reaction (PCR). Increased expression of GPR91 Financial support: None
succinate receptor in conjunctival and corneal tissues has also Conflict of interest: No conflicting relationship exists for any
been linked to the pathogenesis of PUK through elevated NF- author.
κB activity.93 These inflammasomes can be targets of therapy
in the future. Other cited material
Biotherapy (treatment with biological agents such as inflix-
imab, rituximab) is now being increasingly utilized to man- A. Dominguez -Casas LC, Calvo-Rio V, Maiz O, Blanco A, Beltran
age inflammatory PUK due to its major benefits: reduction E, Martinez-Costa L, Alvarez De Buergo MC, Rubio-Romero E,
of disease morbidity and mortality and arresting destruc- Diaz-Valle D, Lopez-Gonzalez R, Garcia-Aparicio AM, Mas AJ,
tion of the corneal stroma. It is now realized that performing Palmou-Fontana N, Gonzalez-Gay MA, Blanco R. Biologic ther-
surgery in PUK cases where inflammation is not adequately apy in severe peripheral ulcerative keratitis (PUK). Multicenter
controlled would lead to graft failure.9 Thus, biotherapy holds study of 27 patients. Arthritis and rheumatology. Conference:
a promising future for patients of PUK presenting with im- american college of rheumatology/association of rheumatol-
pending/frank perforations as adequate immunosuppression ogy health professionals annual scientific meeting, ACR/ARHP
would also help surgeons achieve successful outcomes with 2016. United states. Conference start: 20161111. Conference
corneal graft surgeries in PUK.19 Use of newer therapeutic op- end: 20161116 2016; 68(null): 3941-3942.
tions, e.g., Cacicol® (a matrix regenerating agent) are being ex- B. Dominguez Casas LC, Calvo-Rio V, Maiz-Alonso O, Blanco A,
plored.141 Beltran E, Martinez Acosta L, Alvarez De Buergo MC, Rubio-
Response to therapy can be monitored with immunologi- Romero E, Diaz-Valle D, Lopez-Gonzalez R, Garcia-Aparicio A,
cal markers such as c-ANCA in cases with underlying autoim- JuanMas A, Pons E, Demetrio-Pablo R, Vegas-Revenga N, Blanco
mune disease. Among surgeries, lamellar keratoplasty com- R, Gonzalez-Gay M. Anti-TNFα versus rituximab in refrac-
bined with AMT is emerging as a popular surgical option for tory peripheral ulcerative keratitis associated to rheumatic
perforations smaller than 4 mm.80 Lastly, the option of kerato- diseases. Multicenter study of 24 patients. Annals of the
prosthesis is also being explored for severe cases.73 rheumatic diseases 2018; 77(null): 591-592.
references
10. Conclusion
PUK is a corneal disorder of major concern to ophthalmol-

1. Agrawal V, Kumar A, Sangwan V, Rao GN. Cyanoacrylate
ogists and internists as it may be a harbinger of impend- adhesive with conjunctival resection and superficial
ing serious medical problems.165 There is considerable ocu- keratectomy in mooren’s ulcer. Indian J Ophthalmol.
lar morbidity associated with corneal perforations from PUK. 1996;44(1):23.
Recurrences are commoner in cases of PUK than in scleritis 2. Akova YA, Jabbur NS, Foster CS. Ocular presentation of
alone, especially in those treated with inadequate immuno- polyarteritis nodosa. Ophthalmology. 1993;100(12):1775–81
10.1016/S0161-6420(93)31405-3.
suppression.124 Recurrences tend to occur early, especially the
3. Akpek EK. A case of peripheral ulcerative keratitis
first two years, in the treatment course while the physician
associated with ocular rosacea.
is titrating the dose.124 Adequate background knowledge and 4. Al-Qahtani B, Asghar S, Al-Taweel HM, Jalaluddin I.
practical knowhow of the right clinical approach is a neces- Peripheral ulcerative keratitis: our challenging experience.
sary to provide optimal care. Saudi J Ophthalmol. 2014;28(3):234–8.
JID: SOP
5. Albini TA, Zamir E, Read RW, Smith RE, See RF, Rao NA. 24. Brown SI, Mondino BJ. Therapy of Mooren’s ulcer. Am J
Evaluation of subconjunctival triamcinolone for Ophthalmol. 1984;98(1):1–6.
nonnecrotizing anterior scleritis. Ophthalmology. 25. Brunton L, Chabner BA, Knollmann BC. Goodman and
2005;112(10):1814–20. Gilman’s the pharmacological basis of therapeutics. Twelfth;
6. Alhassan MB, Rabiu M, Agbabiaka IO. Interventions for 2011. Published online.
Mooren’s ulcer. Cochrane Database Syst Rev. 2014(1). 26. Burkholder BM, Kuo IC. Peripheral Ulcerative Keratitis
7. Allansmith MR, McClellan BH. Immunoglobulins in the following Laser in situ Keratomileusis. Case Rep
human cornea. Am J Ophthalmol. 1975;80(1):123–32. Ophthalmol. 2016;7(1):9–15.
doi:10.1016/0002- 9394(75)90882- x. 27. Buus DR, Pflugfelder SC, Schachter J, Miller D, Forster RK.
8. Amiel H, Chohan AB, Snibson GR, Vajpayee R. Atypical Lymphogranuloma venereum conjunctivitis with a marginal
Fungal Sclerokeratitis. Cornea. 2008;27(3). corneal perforation. Ophthalmology. 1988;95(6):799–802.
https://journals.lww.com/corneajrnl/Fulltext/2008/04000/ doi:10.1016/S0161- 6420(88)33121- 0.
Atypical_Fungal_Sclerokeratitis.29.aspx. 28. Cao Y, Zhang W, Wu J, Zhang H, Zhou H. Peripheral ulcerative
9. Ang M, Mehta JS, Sng CCA, Htoon HM, Tan DTH. Indications, keratitis associated with autoimmune disease: pathogenesis
outcomes, and risk factors for failure in tectonic and treatment. J Ophthalmol. 2017:2017.
keratoplasty. Ophthalmology. 2012;119(7):1311–19. doi:10.1155/2017/7298026.
10. Araki-Sasaki K, Katsuta O, Mano H, Nagano T, Nakamura M. 29. Chai HCC, Lin HA, Tan D. C-shaped lamellar corneal patch
The effects of oral and topical corticosteroid in rabbit grafts “Match and Patch” Technique. In: Peripheral
corneas. BMC Ophthalmol. 2016;16(1):1–6. Ulcerative Keratitis. Springer; 2017. p. 121–7.
11. Aronson SB, Elliott JH, Moore TE, O’Day DM. Pathogenetic 30. Chanbour W, Mokdad I, Mouhajer A, Jarade E. Late-onset
approach to therapy of peripheral corneal inflammatory sterile peripheral ulcerative keratitis post-corneal collagen
disease. Am J Ophthalmol. 1970;70(1):65–90. crosslinking. Cornea. 2019;38(3):338–43.
doi:10.1016/0002- 9394(70)90670- 7. 31. Chapman, Hall.The Cornea, Wolff’s Anatomy of the Eye and
12. Arora T, Sharma N, Shashni A, Titiyal JS. Peripheral Orbit. (Bron A, R T, B T, eds.).; 1997.
ulcerative keratitis associated with chronic malabsorption 32. Chen J, Lan J, Liu D, et al. Ascorbic acid promotes the
syndrome and miliary tuberculosis in a child. Oman J stemness of corneal epithelial stem/progenitor cells and
Ophthalmol. 2015;8(3):205. accelerates epithelial wound healing in the cornea. Stem
13. Asbell P. Ulcerative keratitis. Arch Ophthalmol. Cells Transl Med. 2017;6(5):1356–65.
1982;100(1):77. doi:10.1001/archopht.1982.01030030079005. doi:10.1002/sctm.16-0441.
14. Ashar JN, Mathur A, Sangwan VS. Immunosuppression for 33. Cho Y-W, Yoo W-S, Kim S-J, Chung I-Y, Seo S-W, Yoo J-M.
Mooren’s ulcer: evaluation of the stepladder Efficacy of systemic vitamin C supplementation in reducing
approach—topical, oral and intravenous corneal opacity resulting from infectious keratitis. Medicine
immunosuppressive agents. Br J Ophthalmol. 2013;97(11) (Baltimore). 2014;93(23):e125.
1391 LP - 1394. doi:10.1136/bjophthalmol- 2012- 302627. doi:10.1097/MD.0000000000000125.
15. Ayar O, Yazgan S, Akdemir MO, Işık M, Alpay A, Uğurbaş SH. 34. Clewes AR, Dawson JK, Kaye S, Bucknall RC. Peripheral
Behçet Hastalığında Nadir Görülen Bir Oküler Bulgu: ulcerative keratitis in rheumatoid arthritis: successful use of
Periferik Ülseratif Keratit. Türk Oftalmol Derg. intravenous cyclophosphamide and comparison of clinical
2014;44(6):484–5. doi:10.4274/tjo.68094. and serological characteristics. Ann Rheum Dis.
16. Bachmann B, Jacobi C, Cursiefen C. Augenentzündungen bei 2005;64(6):961–2.
entzündlichen Systemerkrankungen: Keratitis. Klin Monbl 35. Coelho P, Menezes C, Gonçalves R, Rodrigues P, Seara E.
Augenheilkd.. 2011;228(05):413–18. Peripheral ulcerative keratitis associated with HCV-related
doi:10.1055/s- 0031- 1273326. cryoglobulinemia. Case Rep Ophthalmol Med.. 2017:2017.
17. Bagheri N, Wajda B, Calvo C, Durrani A. The Wills Eye 36. Dana MR, Qian Y, Hamrah P. Twenty-five-year panorama of
Manual: Office and Emergency Room Diagnosis and corneal immunology: emerging concepts in the
Treatment of Eye Disease. Lippincott Williams & Wilkins; immunopathogenesis of microbial keratitis, peripheral
2017. ulcerative keratitis, and corneal transplant rejection. Cornea.
18. Bawazeer AM, Jackson WB. Marginal infiltrative ulcerative 2000;19(5):625–43. doi:10.1097/00003226- 200009000- 00008.
keratitis secondary to Churg–Strauss syndrome: a case 37. Daniilidis M. Peripheral corneal ulceration associated with
report. Cornea. 2000;19(3). rheumatoid arthritis. Am J Case Rep. 2013;14:318–21.
https://journals.lww.com/corneajrnl/Fulltext/2000/05000/ doi:10.12659/AJCR.883998.
Marginal_Infiltrative_Ulcerative_Keratitis.30.aspx. 38. Das S, Constantinou M, Daniell M, Taylor HR.
19. Benchérifa S, Amine B, El Binoune I, Rostom S, Bahiri R. Two <em>Moraxella</em> keratitis: predisposing
cases of perforated corneal ulcers complicating rheumatoid factors and clinical review of 95 cases. Br J Ophthalmol.
arthritis treated successfully by biological therapy. BMC 2006;90(10) 1236 LP - 1238. doi:10.1136/bjo.2006.095182.
Rheumatol. 2020;4(1):6. 39. deLuise VP, O’Leary MJ. Peripheral Ulcerative Keratitis
20. Bernauer W, Ficker LA, Watson PG, Dart JKG. The Related to Lyme Disease. Am J Ophthalmol.
management of corneal perforations associated with 1991;111(2):244–5. doi:10.1016/S0002- 9394(14)72270- 6.
rheumatoid arthritis: an analysis of 32 eyes. Ophthalmology. 40. Dingeldein SA, Insler MS, Barron BA, Kaufman HE. Mooren’s
1995;102(9):1325–37. ulcer treated with a periosteal graft. Ann Ophthalmol.
21. Bhandari V, Siddharthan KS. Bilateral Mooren’s 1990;22(2):56–7. http://europepmc.org/abstract/MED/2316952.
ulcer–Customised corneal graft with additional amniotic 41. Dominguez-Casas LC, Sánchez-Bilbao L, Calvo-Río V,
membrane graft. Saudi J Ophthalmol. 2015;29(3):235–7. et al. Biologic therapy in severe and refractory peripheral
22. Bowman W. Lectures on the Parts Concerned in the ulcerative keratitis (PUK). Multicenter study of 34 patients
Operations on the Eye, and on the Structure of the Retina: To Seminars in Arthritis and Rheumatism. Elsevier; 2020.
Wich Are Added a Paper on the Vitreous Humor; and Also a 42. Ebrahimiadib N, Modjtahedi BS, Roohipoor R, Anesi SD,
Few Cases of Ophthalmic Disease. Longman; 1849. Foster CS. Successful treatment strategies in granulomatosis
23. Brown SI. Mooren’s ulcer. Treatment by conjunctival with polyangiitis-associated peripheral ulcerative keratitis.
excision. Br J Ophthalmol. 1975;59(11):675–82. Cornea. 2016;35(11):1459–65.
JID: SOP
43. Erie JC. Incidence of ulcerative keratitis in a defined affecting the conjunctiva. Eye. 1996;10(4):425–32.
population from 1950 through 1988. Arch Ophthalmol. doi:10.1038/eye.1996.94.
1993;111(12):1665. 64. Hernandez-Illas M, Tozman E, Fulcher SFA, Jundt JW, Davis J,
doi:10.1001/archopht.1993.01090120087027. Pflugfelder SC. Recombinant human tumor necrosis factor
44. Erikitola OC, Jawaheer L, Ramaesh K, Anijeet D. Conjunctival receptor Fc fusion protein (Etanercept): experience as a
resection for peripheral ulcerative keratitis (PUK). Invest therapy for sight-threatening scleritis and sterile corneal
Ophthalmol Vis Sci. 2016;57(12):1261. ulceration. Eye Contact Lens. 2004;30(1):2–5.
45. Eshraghi H, Mahtabfar A, Dastjerdi MH. A case of peripheral 65. Hill JC, Potter P. Treatment of Mooren’s ulcer with
ulcerative keratitis associated with autoimmune hepatitis. cyclosporin A: report of three cases. Br J Ophthalmol.
Case Rep Med.. 2017:2017. 1987;71(1):11–15.
46. Fontana L, Parente G, Neri P, Reta M, Tassinari G. Favourable 66. van der Hoek J, Azuara-Blanco A, Greiner K, Forrester J V.
response to infliximab in a case of bilateral refractory Mooren’s ulcer resolved with campath-1H. Br J Ophthalmol.
Mooren’s ulcer. Clin Experiment Ophthalmol. 2003;87(7) 924 LP - 925. doi:10.1136/bjo.87.7.924.
2007;35(9):871–3. doi:10.1111/j.1442-9071.2007.01609.x. 67. Hsieh J-L, Shiau A-L, Lee C-H, et al. CD8+ T Cell-Induced
47. Foster CS. Immunosuppressive therapy for external ocular expression of tissue inhibitor of metalloproteinses-1
inflammatory disease. Ophthalmology. 1980;87(2):140–50. exacerbated osteoarthritis. Int J Mol Sci.
48. Foster CS, Forstot SL, Wilson LA. Mortality rate in 2013;14(10):19951–70. doi:10.3390/ijms141019951.
rheumatoid arthritis patients developing necrotizing 68. Huerva V, Ascaso FJ, Grzybowski A. Infliximab for peripheral
scleritis or peripheral ulcerative keratitis: effects of systemic ulcerative keratitis treatment. Medicine (Baltimore).
immunosuppression. Ophthalmology. 1984;91(10):1253–63. 2014;93(26).
49. Fraunfelder FW, Harrison D. Peripheral ulcerative 69. Imbernón-Moya A, Vargas-Laguna E, Aguilar A, Gallego MÁ,
keratitis-like findings associated with filgrastim. Cornea. Vergara C, Nistal MF. Peripheral ulcerative keratitis
2007;26(3):368–9. with pyoderma gangrenosum. Case Rep Dermatol Med.
50. Freeman RD. Oxygen consumption by the component layers 2015;2015.
of the cornea. J Physiol. 1972;225(1):15–32. 70. Ingole A, Murade S, Soni N. An unusual case of peripheral
doi:10.1113/jphysiol.1972.sp009927. ulcerative keratitis as a presenting feature in an otherwise
51. Fujita Y, Fukui S, Endo Y, et al. Peripheral ulcerative keratitis healthy patient with undiagnosed human
associated with granulomatosis with polyangiitis emerging immunodeficiency virus infection and low CD4 counts.
despite cyclophosphamide, successfully treated with Indian J Ophthalmol. 2013;61(3):138.
rituximab. Intern Med. Published online. 2018:215–17. doi:10.4103/0301-4738.109391.
52. Galor A, Thorne JE. Scleritis and peripheral ulcerative 71. Iovieno A, Anand S, Dart JK. Late-onset peripheral ulcerative
keratitis. Rheum Dis Clin North Am. 2007;33(4):835–54. sclerokeratitis associated with alkali chemical burn. Am J
53. Gharai S, Venkatesh P, Tandon R, Garg S. Peripheral Ophthalmol. 2014;158(6) 1305-1309.e4.
ulcerative keratitis and central retinal vein occlusion as the doi:10.1016/j.ajo.2014.08.038.
initial manifestation of HIV infection. Ocul Immunol 72. Iovieno A, Gore DM, Carnt N, Dart JK. Acanthamoeba
Inflamm. 2007;15(5):407–9. sclerokeratitis: epidemiology, clinical features, and
54. Gipson IK, Hori Y, Argueso P. Character of ocular surface treatment outcomes. Ophthalmology. 2014;121(12):2340–7.
mucins and their alteration in dry eye disease. Ocul Surf. doi:10.1016/j.ophtha.2014.
2004;2(2):131–48. doi:10.1016/s1542- 0124(12)70149- 0. 06.033.
55. Gregory JK, Foster CS. Peripheral ulcerative keratitis in the 73. Jerez-Peña M, Salvador-Culla B, de la Paz MF, Barraquer RI.
collagen vascular diseases. Int Ophthalmol Clin. Bilateral Boston keratoprosthesis type 1 in a case of severe
1996;36(1):21–30. doi:10.1097/00004397- 199603610- 00005. Mooren’s ulcer. Eur J Ophthalmol. March
56. Gu J, Zhou S, Ding R, Aizezi W, Jiang A, Chen J. Necrotizing 2020:1120672120909768 Published online.
scleritis and peripheral ulcerative keratitis associated with doi:10.1177/1120672120909768.
Wegener’s granulomatosis. Ophthalmol Ther. 74. Jia Y, Gao H, Li S, Shi W. Combined anterior chamber
2013;2(2):99–111. washout, amniotic membrane transplantation, and topical
57. Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus use of corticosteroids for severe peripheral ulcerative
azathioprine for maintenance in ANCA-associated keratitis. Cornea. 2014;33(6):559–64.
vasculitis. N Engl J Med. 2014;371(19):1771–80. doi:10.1097/ICO.0000000000000130.
58. Guindolet D, Reynaud C, Clavel G, et al. Management of 75. Jifi-Bahlool H, Saadeh C, O’Connor J. Peripheral ulcerative
severe and refractory Mooren’s ulcers with rituximab. Br J keratitis in the setting of rheumatoid arthritis: treatment
Ophthalmol. 2017;101(4):418–22. with immunosuppressive therapy. Semin Arthritis Rheum.
59. Gupta N, Chawla B, Venkatesh P, Tandon R. Necrotizing 1995;25(1):67–73. doi:10.1016/s0049- 0172(95)80019- 0.
scleritis and peripheral ulcerative keratitis in a case of 76. John SL, Morgan K, Tullo AB, Holt PJL. Corneal autoimmunity
Sweet’s syndrome found culture-positive for Mycobacterium in patients with peripheral ulcerative keratitis (PUK) in
tuberculosis. Ann Trop Med Parasitol. 2008;102(6):557–60. association with rheumatoid arthritis and Wegener’s
60. Gupta N, Sachdev R, Tandon R. Sutureless patch graft for granulomatosis. Eye. 1992;6(6):630–6.
sterile corneal melts. Cornea. 2010;29(8):921–3. doi:10.1038/eye.1992.136.
61. Hardy S, Hashemi K, Catanese M, et al. Necrotising Scleritis 77. Johnson CC, Ohlstein DH. Peripheral Ulcerative Keratitis and
and peripheral ulcerative keratitis associated with Necrotizing Scleritis Initiated by Trauma in the Setting of
rheumatoid arthritis treated with rituximab. Klin Monbl Mixed Cryoglobulinemia. Case Rep Ophthalmol.
Augenheilkd. 2017;234(04):567–70. 2011;2(3):392–7. doi:10.1159/000334496.
62. Hayashi Y, Eguchi H, Toibana T, Mitamura Y, Yaguchi T. 78. Kalogeropoulos CD, Malamou-Mitsi VD, Aspiotis MB,
Polymicrobial sclerokeratitis caused by Scedosporium Psilas KG. Bilateral Mooren’s ulcer in six patients: diagnosis,
apiospermum and Aspergillus cibarius. Cornea. surgery and histopathology. Int Ophthalmol. 2004;25(1):1–8.
2014;33(8):875–7. doi:10.1023/b:inte.0000018510.06715.c9.
63. Heiligenhaus A, Dutt JE, Foster CS. Histology and 79. Kaufman HE, Insler MS, Ibrahim-Elzembely HA, Kaufman SC.
immunopathology of systemic lupus erythematosus Human fibrin tissue adhesive for sutureless lamellar
JID: SOP
keratoplasty and scleral patch adhesion: a pilot study. keratoplasty and immunosuppressive therapy guided by in
Ophthalmology. 2003;110(11):2168–72. vivo confocal microscopy for perforated Mooren’s ulcer. Br J
doi:10.1016/S0161- 6420(03)00832- 7. Ophthalmol. 2015;99(6):778–83.
80. Ke L, Shen D, Wang H, Qiao C, Zeng Q. Lamellar keratoplasty doi:10.1136/bjophthalmol- 2014- 306012.
combined with amniotic membrane transplantation for the 96. Lu C-W, Zhou D-D, Wang J, Hao J-L. Surgical treatment of
treatment of corneal perforations: a clinical and in vivo peripheral ulcerative keratitis and necrotizing scleritis in
confocal microscopy study. Biomed Res Int. granulomatosis with polyangiitis. Saudi Med J.
2020;2020:7403842. doi:10.1155/2020/7403842. 2016;37(2):205–7. doi:10.15537/smj.2016.2.13390.
81. Keenan JD, Mandel MR, Margolis TP. Peripheral ulcerative 97. Macsai MS, Mannis MJ, Huntley AC. Acne rosacea. Eye Ski
keratitis associated with vasculitis manifesting Dis Philadelphia Lippincott-Raven. 1996:335–41 Published
asymmetrically as fuchs superficial marginal keratitis and online.
terrien marginal degeneration. Cornea. 2011;30(7):825–7. 98. Maeno A, Naor J, Lee HM, Hunter WS, Rootman DS. Three
doi:10.1097/ICO.0b013e3182000c94. decades of corneal transplantation: indications and patient
82. Kervick GN, Pflugfelder SC, Haimovici R, Brown H, Tozman E, characteristics. Cornea. 2000;19(1):7–11.
Yee R. Paracentral rheumatoid corneal ulceration. 99. Martin NF, Stark WJ, Maumenee AE. Treatment of Mooren’s
Ophthalmology. 1992;99(1):80–8. and Mooren’s-like ulcer by lamellar keratectomy: report of
doi:10.1016/S0161- 6420(92)32006- 8. six eyes and literature review. Ophthalmic Surg.
83. Kiire CA, Srinivasan S, Inglis A. Peripheral ulcerative keratitis 1987;18(8):564–9.
after cataract surgery in a patient with ocular cicatricial 100. Matoba A, Plager S, Barber J, McCulley JP. Keratitis in
pemphigoid. Cornea. 2011;30(10). relapsing polychondritis. Ann Ophthalmol.
https://journals.lww.com/corneajrnl/Fulltext/2011/10000/ 1984;16(4):367–70.
Peripheral_Ulcerative_Keratitis_After_Cataract.21.aspx. http://europepmc.org/abstract/MED/6721348.
84. Kinoshita S, Ohashi Y, Ohji M, Manabe R. Long-term results 101. Matoba AY, Wilhelmus KR, Jones DB. Epstein-Barr viral
of keratoepithelioplasty in Mooren’s ulcer. Ophthalmology. stromal keratitis. Ophthalmology. 1986;93(6):746–51.
1991;98(4):438–45. doi:10.1016/s0161- 6420(91)32272- 3. doi:10.1016/S0161- 6420(86)33668- 6.
85. Kiss S, Damico FM, Young LH. Ocular manifestations and 102. Mattern RM, Ding J. Keratitis with Kocuria palustris and Rothia
treatment of syphilis. Semin Ophthalmol. 2005;20(3):161–7. mucilaginosa in vitamin A deficiency. Case Rep Ophthalmol.
doi:10.1080/08820530500232092. 2014;5(1):72–7. doi:10.1159/000360391.
86. Korsten P, Bahlmann D, Patschan SA. Rapid healing of 103. Mavrakanas NA, Kiel R, Dosso AA. Autologous serum
peripheral ulcerative keratitis in rheumatoid arthritis with application in the treatment of Mooren’s ulcer. Klin Monbl
prednisone, methotrexate and adalimumab combination Augenheilkd. 2007;224(4):300–2 10.1055/s-2007-962935.
therapy. Rheumatology (Oxford). 2017;56(7):1094. 104. Mckenzie H.Diseases of the Eye.; 1854.
doi:10.1093/rheumatology/kex007. 105. McKibbin M, Isaacs JD, Morrell AJ. Incidence of corneal
87. de la Maza MS, Foster CS. Peripheral ulcerative keratitis and melting in association with systemic disease in the
malignancies. Cornea. 1994;13(4):364–7. Yorkshire Region, 1995-7. Br J Ophthalmol. 1999;83(8):941–3.
doi:10.1097/00003226- 199407000- 00014. doi:10.1136/bjo.83.8.941.
88. de la Maza MS, Foster CS. The diagnosis and treatment of 106. Messmer EM, Foster CS. Destructive corneal and scleral
peripheral ulcerative keratitis. Semin Ophthalmol. disease associated with rheumatoid arthritis: medical and
1991;6(3):133–41. doi:10.3109/08820539109060192. surgical management. Cornea. 1995;14(4).
89. Ladas JG, Mondino BJ. Systemic disorders associated with https://journals.lww.com/corneajrnl/Fulltext/1995/07000/
peripheral corneal ulceration. Curr Opin Ophthalmol. Destructive_Corneal_and_Scleral_Disease_Associated.10.
2000;11(6). https: aspx.
//journals.lww.com/co-ophthalmology/Fulltext/2000/12000/ 107. Messmer EM, Foster CS. Vasculitic peripheral ulcerative
Systemic_disorders_associated_with_peripheral.14.aspx. keratitis. Surv Ophthalmol. 1999;43(5):379–96.
90. Lal I, Shivanagari SB, Ali MH, Vazirani J. Efficacy of doi:10.1016/S0039- 6257(98)00051- 4.
conjunctival resection with cyanoacrylate glue application 108. Mishra A V, Cadieux DC, Gjerde H, Lewis DR. Peripheral
in preventing recurrences of Mooren’s ulcer. Br J ulcerative keratitis secondary to atypical hemolytic uremic
Ophthalmol. 2016;100(7) 971 LP - 975. syndrome. Cornea. March 2020 Published online.
doi:10.1136/bjophthalmol- 2015- 307350. doi:10.1097/ICO.0000000000002317.
91. Lange AP, Moloney G, Sheldon CA, Sasaki S, Holland SP. 109. Moazami G, Auran JD, Florakis GJ, Wilson SE, Srinivasan DB.
Bilateral corneal ulceration caused by vitamin a deficiency Interferon treatment of Mooren’s ulcers associated with
in eosinophilic gastroenteropathy. Case Rep Ophthalmol. hepatitis C. Am J Ophthalmol. 1995;119(3):365–6.
2011;2(3):302–6. doi:10.1159/000331886. doi:10.1016/s0002- 9394(14)71182- 1.
92. Lavker RM, Dong G, Cheng SZ, Kudoh K, Cotsarelis G, Sun TT. 110. Mondino BJ. Inflammatory diseases of the peripheral cornea.
Relative proliferative rates of limbal and corneal epithelia. Ophthalmology. 1988;95(4):463–72.
Implications of corneal epithelial migration, circadian doi:10.1016/S0161- 6420(88)33164- 7.
rhythm, and suprabasally located DNA-synthesizing 111. Monti S, Balduzzi S, Delvino P, Bellis E, Quadrelli VS,
keratinocytes. Invest Ophthalmol Vis Sci. 1991;32(6): Montecucco C. Clinical course of COVID-19 in a series of
1864–1875. patients with chronic arthritis treated with
93. Li L, Dong Y-L, Liu T, Luo D, Wei C, Shi W-Y. Increased immunosuppressive targeted therapies. Ann Rheum Dis.
succinate receptor GPR91 involved in the pathogenesis of 2020;79(5):667–8. doi:10.1136/annrheumdis- 2020- 217424.
Mooren’s ulcer. Int J Ophthalmol. 2018;11(11):1733–40. 112. Moreira AT, Prajna NV. Acanthamoeba as a cause of
doi:10.18240/ijo.2018.11.01. peripheral ulcerative keratitis. Cornea. 2003;22(6).
94. Lin Y-Y, Jean Y-H, Lee H-P, et al. Excavatolide B attenuates https://journals.lww.com/corneajrnl/Fulltext/2003/08000/
rheumatoid arthritis through the inhibition of Acanthamoeba_as_a_Cause_of _Peripheral_Ulcerative.18.
osteoclastogenesis. Mar Drugs. 2017;15(1):9. aspx.
doi:10.3390/md15010009. 113. Morjaria R, Barge T, Mordant D, Elston J. Peripheral ulcerative
95. Liu J, Shi W, Li S, Gao H, Wang T. Modified lamellar
JID: SOP
keratitis as a complication of acute myeloid leukaemia. BMJ Augenheilkd. 1996;208(02):73–81.

Case Rep. 2014:2014. doi:10.1136/bcr- 2014- 206399. doi:10.1055/s- 2008- 1035173.
114. Müller LJ, Pels E, Schurmans LRHM, Vrensen GFJM. A new 131. Ploysangam P, Mattern RM. Perforating peripheral
three-dimensional model of the organization of ulcerative keratitis in syphilis. Case Rep Ophthalmol.
proteoglycans and collagen fibrils in the human corneal 2019;10(2):267–73.
stroma. Exp Eye Res. 2004;78(3):493–501. 132. Praidou A, Androudi S, Kanonidou E, Konidaris V,
doi:10.1016/S0014- 4835(03)00206- 9. Alexandridis A, Brazitikos P. Bilateral herpes simplex
115. Müller LJ, Vrensen GFJM, Pels L, Cardozo BN, Willekens B. keratitis presenting as peripheral ulcerative keratitis.
Architecture of human corneal nerves. Investig Ophthalmol Cornea. 2012;31(5):570–1. doi:10.1097/ICO.0b013e31822f3c18.
Vis Sci. 1997;38(5):985–94. 133. Prasher P, Di Pascuale M, Cavanagh HD. Bilateral chronic
116. Murphy C, Gregory ME, Ramaesh K. Peripheral ulcerative peripheral ulcerative keratitis secondary to cat-scratch
keratitis: an unusual primary ocular manifestation in disease. Eye Contact Lens. 2008;34(3):191–3.
Behcet’s disease? Rheumatology. 2009;48(12):1490. doi:10.1097/ICL.0b013e31815788be.
doi:10.1093/rheumatology/kep232. 134. Reddy V, Klein C, Isenberg D, Cambridge G, Cragg M,
117. Muytjens HL, Eggink CA, Dijkman FCAP, Bakkers JMJE, Leandro M. OP0159 improving B-cell depletion in
Melchers WJG. Keratitis due to Shigella flexneri. J Clin rheumatoid arthritis and systemic lupus erythematosus:
Microbiol. 2006;44(6):2291–4. doi:10.1128/JCM.00481-06. resistance to rituximab and the potential of obinutuzumab.
118. Nakissa N, Rubin P, Strohl R, Keys H. Ocular and orbital Ann Rheum Dis. 2016;75(Suppl 2):116.
complications following radiation therapy of paranasal doi:10.1136/annrheumdis- 2016- eular.6065.
sinus malignancies and review of literature. Cancer. 135. Riley GP, Harrall RL, Watson PG, Cawston TE, Hazleman BL.
1983;51(6):980–6. Collagenase (MMP-1) and TIMP-1 in destructive corneal
119. Nakken B, Munthe LA, Konttinen YT, et al. B-cells and their disease associated with rheumatoid arthritis. Eye (Lond).
targeting in rheumatoid arthritis — current concepts and 1995;9(Pt 6):703–18. doi:10.1038/eye.1995.182.
future perspectives. Autoimmun Rev. 2011;11(1):28–34. 136. Robin JB, Schanzlin DJ, Verity SM, et al. Peripheral corneal
doi:10.1016/j.autrev.2011.06.010. disorders. Surv Ophthalmol. 1986;31(1):1–36.
120. Neri P, Zucchi M, Allegri P, Lettieri M, Mariotti C, doi:10.1016/0039- 6257(86)90049- 4.
Adalimumab Giovannini A. HumiraTM ): a promising 137. Rosman Z, Shoenfeld Y, Zandman-Goddard G. Biologic
monoclonal anti-tumor necrosis factor alpha in therapy for autoimmune diseases: an update. BMC Med.
ophthalmology. Int Ophthalmol. 2011;31(2):165–73. 2013;11:88. doi:10.1186/1741- 7015- 11- 88.
doi:10.1007/s10792- 011- 9430- 3. 138. Meta-Herpetic Sahin O. Keratitis and therapeutic approach:
121. Neves RA, Rodriguez A, Power WJ, et al. Herpes Zoster case report. Open J Ophthalmol. 2014;04(03):75–8.
peripheral ulcerative keratitis in patients with the acquired doi:10.4236/ojoph.2014.43012.
immunodeficiency syndrome. Cornea. 1996;15(5). 139. Sainz de la Maza M, Foster CS, Jabbur NS, Baltatzis S. Ocular
https://journals.lww.com/corneajrnl/Fulltext/1996/09000/ characteristics and disease associations in
Herpes_Zoster_Peripheral_Ulcerative_Keratitis_in.2.aspx. scleritis-associated peripheral keratopathy. Arch
122. Ngan ND, Chau HTM. Amniotic membrane transplantation Ophthalmol (Chicago, Ill 1960). 2002;120(1):15–19.
for Mooren’s ulcer. Clin Experiment Ophthalmol. doi:10.1001/archopht.120.1.15.
2011;39(5):386–92. doi:10.1111/j.1442-9071.2010.02479.x. 140. Sangwan VS, Zafirakis P, Foster CS. Mooren’s ulcer: current
123. Nobe JR, Moura BT, Robin JB, Smith RE. Results of concepts in management. Indian J Ophthalmol.
penetrating keratoplasty for the treatment of corneal 1997;45(1):7–17.
perforations. Arch Ophthalmol. 1990;108(7):939–41. 141. Sevik MO, Turhan SA, Toker E. Topical treatment of
124. Ogra S, Sims JL, McGhee CNJ, Niederer RL. Ocular persistent epithelial defects with a matrix regenerating
complications and mortality in peripheral ulcerative agent. J Ocul Pharmacol Ther Off J Assoc Ocul Pharmacol
keratitis and necrotising scleritis: The role of systemic Ther. 2018;34(9):621–7. doi:10.1089/jop.2018.0025.
immunosuppression. Clin Experiment Ophthalmol. 142. Shaharuddin B, Ahmad S, Md Latar N, Ali S, Meeson A. A
2020;48(4):434–41. doi:10.1111/ceo.13709. human corneal epithelial cell line model for limbal stem cell
125. Paley MA, Karacal H, Rao PK, Margolis TP, Miner JJ. biology and limbal immunobiology. Stem Cells Transl Med.
Tofacitinib for refractory uveitis and scleritis. Am J 2017;6(3):761–6. doi:10.5966/sctm.2016-0175.
Ophthalmol Case Rep. 2019;13:53–5. 143. Sharma N, Singhal D, Maharana PK, Vajpayee RB. Tuck-in
126. Papaconstantinou D, Georgopoulos G, Kalantzis G, Krassas A, tenon patch graft in corneal perforation. Cornea.
Georgalas I. Peripheral ulcerative keratitis after 2019;38(8):951–4. doi:10.1097/ICO.0000000000001955.
trabeculectomy in a patient with rheumatoid arthritis. 144. Sharma N, Sinha G, Shekhar H, et al. Demographic profile,
Cornea. 2009;28(1):111–13. doi:10.1097/ICO.0b013e318182fc01. clinical features and outcome of peripheral ulcerative
127. Papathanassiou M, Elezoglou A, Nikita E, Theodossiadis PG, keratitis: a prospective study. Br J Ophthalmol.
Vergados I. A rare case of peripheral ulcerative keratitis in 2015;99(11):1503–8. doi:10.1136/bjophthalmol- 2014- 306008.
temporal arteritis. Eur J Ophthalmol. 2009;19(5):866–9. 145. Shimmura S, Igarashi R, Yaguchi H, Ohashi Y, Shimazaki J,
doi:10.1177/112067210901900529. Tsubota K. Lecithin-bound superoxide dismutase in the
128. Parmar GS, Ghodke B, Bose S, Meena AK. Stenciling-based treatment of noninfectious corneal ulcers. Am J Ophthalmol.
“Prick and Print” technique for harvesting shaped corneal 2003;135(5):613–19. doi:10.1016/S0002- 9394(02)02151- 7.
grafts for management of peripheral corneal perforations. 146. Shiuey Y, Foster CS. Peripheral ulcerative keratitis and
Cornea. 2019;38(1):105–9. doi:10.1097/ICO.0000000000001774. collagen vascular disease. Int Ophthalmol Clin.
129. Petrushkin HJD, Stanford M, Fortune F, Jawad A. Improving 1998;38(1):21–32. doi:10.1097/00004397- 199803810- 00004.
morbidity and mortality in peripheral ulcerative keratitis 147. Siracuse-Lee D, Saffra N. Peripheral ulcerative keratitis in
associated with rheumatoid arthritis. Clin Exp Rheumatol. sarcoidosis. Cornea. 2006;25(5):618–20.
2016;34(1 Suppl 95):S18–19. doi:10.1097/01.ico.0000183486.93259.c9.
130. Pleyer U, Bergmann L, Krause A, Hartmann C. 148. Smith VA. Doxycycline–a role in ocular surface repair. Br J
Autoimmunerkrankungen der peripheren Hornhaut - Ophthalmol. 2004;88(5):619–25. doi:10.1136/bjo.2003.025551.
Immunpathologie, Klinik und Therapie. Klin Monbl 149. Smith VA, Hoh HB, Easty DL. Role of ocular matrix
JID: SOP
metalloproteinases in peripheral ulcerative keratitis. Br J 168. Vajpayee RB, Jhanji V, Beltz J, Moorthy S. Tuck In” lamellar
Ophthalmol. 1999;83(12):1376–83. doi:10.1136/bjo.83.12.1376. keratoplasty for tectonic management of postkeratoplasty
150. Soukiasian SH. Peripheral ulcerative keratitis. Ophthalmol corneal ectasia with peripheral corneal involvement.
E-b; 2018. Published online239. Cornea. 2011;30(2). https://journals.lww.com/corneajrnl/
151. Spelsberg H, Sundmacher R. Amniotic membrane Fulltext/2011/02000/
transplantation and high-dose systemic cyclosporin A _Tuck_In__Lamellar_Keratoplasty_for_Tectonic.12.aspx.
(Sandimmun optoral) for Mooren’s ulcer. Klin Monbl 169. Vanathi M, Sharma N, Titiyal JS, Tandon R, Vajpayee RB.
Augenheilkd. 2007;224(2):135–9. doi:10.1055/s- 2006- 927400. Tectonic grafts for corneal thinning and perforations.
152. Squirrell DM, Winfield J, Amos RS. Peripheral ulcerative Cornea. 2002;21(8):792–7.
keratitis ‘corneal melt’ and rheumatoid arthritis: a case doi:10.1097/00003226- 200211000- 00013.
series. Rheumatology. 1999;38(12):1245–8. 170. Vilaplana F, Temprano J, Riquelme JL, Nadal J, Barraquer J.
doi:10.1093/rheumatology/38.12.1245. Úlcera de Mooren: 30 años de seguimiento. Arch Soc Esp
153. Srinivasan M, Zegans ME, Zelefsky JR, et al. Clinical Oftalmol. 2016;91(7):337–40. doi:10.1016/j.oftal.2016.01.021.
characteristics of Mooren’s ulcer in South India. Br J 171. Virasch VV, Brasington RD LA. No Title. In: Cornea:
Ophthalmol. 2007;91(5):570–5. doi:10.1136/bjo.2006.105452. Fundamentals, Diagnostic, Management. Corneal Disease in
154. Steinberg JS, Herwig MC, Holz FG, Loeffler KU. [Peripheral Rheumatoid Arthritis.
ulcerative keratitis in a 24-year-old patient]. 172. Wakefield D, Robinson LP. Cyclosporin therapy in Mooren’s
Ophthalmologe. 2014;111(8):772–4. ulcer. Br J Ophthalmol. 1987;71(6):415–17.
doi:10.1007/s00347- 013- 2947- 2. doi:10.1136/bjo.71.6.415.
155. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus 173. Watanabe R, Ishii T, Yoshida M, et al. Ulcerative keratitis in
cyclophosphamide for ANCA-associated vasculitis. N Engl J patients with rheumatoid arthritis in the modern biologic
Med. 2010;363(3):221–32. doi:10.1056/NEJMoa0909905. era: a series of eight cases and literature review. Int J Rheum
156. Sule A, Balakrishnan C, Gaitonde S, et al. Rheumatoid Dis. 2017;20(2):225–30. doi:10.1111/1756-185X.12688.
corneal melt. Rheumatology (Oxford). 2002;41(6):705–6. 174. Watkins AS, Kempen JH, Choi D, et al. Ocular disease in
doi:10.1093/rheumatology/41.6.705. patients with ANCA-positive vasculitis. J Ocul Biol Dis Infor.
157. Sykes SO, Riemann C, Santos CI, et al. 2010;3(1):12–19. doi:10.1007/s12177- 009- 9044- 4.
<em>Haemophilus influenzae</em> associated 175. Watson PG. Management of Mooren’s ulceration. Eye.
scleritis. Br J Ophthalmol. 1999;83(4) 410 LP-413. 1997;11(3):349–56. doi:10.1038/eye.1997.74.
doi:10.1136/bjo.83.4.410. 176. Wei DW, Pagnoux C, Chan CC. Peripheral ulcerative keratitis
158. Szamel M, Bartels F, Resch K. Cyclosporin A inhibits T cell secondary to chronic hepatitis B infection. Cornea.
receptor-induced interleukin-2 synthesis of human T 2017;36(4):515–17.
lymphocytes by selectively preventing a transmembrane 177. Wilson SE, Lee WM, Murakami C, Weng J, Moninger GA.
signal transduction pathway leading to sustained activation Mooren-type hepatitis C virus-associated corneal ulceration.
of a protein kinase C isoenzyme, protein kinase C-β. Eur J Ophthalmology. 1994;101(4):736–45.
Immunol. 1993;23(12):3072–81. doi:10.1002/eji.1830231205. doi:10.1016/S0161- 6420(94)31291- 7.
159. Tan MH, Chen SDM, Rubinstein A, Bron AJ. Corneal 178. Yagci A. Update on peripheral ulcerative keratitis. Clin
perforation due to severe peripheral ulcerative keratitis in Ophthalmol. 2012;6(1):747–54. doi:10.2147/OPTH.S24947.
Crohn disease. Cornea. 2006;25(5):628–30. 179. Yang J, Baltatzis S, Foster CS. Peripheral ulcerative keratitis
doi:10.1097/01.ico.0000214206.29823.2d. after Salmonella gastroenteritis. Cornea. 1998;17(6):672–4.
160. Tandon R, Chawla B, Verma K, Sharma N, Titiyal JS. Outcome doi:10.1097/00003226- 199811000- 00017.
of treatment of Mooren ulcer with topical cyclosporine a 2%. 180. Yazdanyar A, Rizzuti AE, Mechel E, Denisova K, Lazzaro DR.
Cornea. 2008;27(8):859–61. Gout keratitis: A case of peripheral ulcerative keratitis
doi:10.1097/ICO.0b013e3181702d0c. secondary to gout with a review of the literature. Cornea.
161. Tandon R, Galor A, Sangwan VS, Ray M. Peripheral Ulcerative 2018;37(3):379–81.
Keratitis. Springer International Publishing; 2017. 181. Yoo JH, Chodosh J, Dana R. Relapsing polychondritis:
doi:10.1007/978- 3- 319- 50404- 9. systemic and ocular manifestations, differential diagnosis,
162. Tarr KH, Constable IJ. Pseudomonas endophthalmitis management, and prognosis. Semin Ophthalmol.
associated with scleral necrosis. Br J Ophthalmol. 2011;26(4-5):261–9. doi:10.3109/08820538.2011.588653.
1980;64(9):676–9. doi:10.1136/bjo.64.9.676. 182. Yy DT, Clements PJ, Peter JB, Levy J, Paulus HE, Barnett EV.
163. Tauber J, Sainz de la Maza M, Hoang-Xuan T, Foster CS. An Lymphocyte characteristics in rheumatic patients and the
analysis of therapeutic decision making regarding effect of azathioprine therapy. Arthritis Rheum.
immunosuppressive chemotherapy for peripheral ulcerative 1974;17(1):37–45. doi:10.1002/art.1780170107.
keratitis. Cornea. 1990;9(1):66–73. 183. Zaher SS, Sandinha T, Roberts F, Ramaesh K. Herpes simplex
164. Thorne JE, Jabs DA, Qazi FA, Nguyen QD, Kempen JH, keratitis misdiagnosed as rheumatoid arthritis-related
Dunn JP. Mycophenolate mofetil therapy for inflammatory peripheral ulcerative keratitis. Cornea. 2005;24(8):1015–17.
eye disease. Ophthalmology. 2005;112(8):1472–7. doi:10.1097/01.ico.0000159758.36230.c1.
doi:10.1016/j.ophtha.2005.02.020. 184. Zegans ME, Srinivasan M. Mooren’s ulcer. Int Ophthalmol
165. Timlin HM, Hall HN, Foot B, Koay P. Corneal perforation from Clin. 1998;38(4). https://journals.lww.com/internat-
peripheral ulcerative keratopathy in patients with ophthalmology/Fulltext/1998/03840/Mooren_s_Ulcer.8.aspx.
rheumatoid arthritis: epidemiological findings of the British 185. Zelefsky JR, Srinivasan M, Kundu A, et al. Hookworm
Ophthalmological Surveillance Unit. Br J Ophthalmol. infestation as a risk factor for Mooren’s ulcer in South India.
2018;102(9):1202–98. doi:10.1136/bjophthalmol- 2017- 310671. Ophthalmology. 2007;114(3):450–3.
166. Tu EY, Culbertson WW, Pflugfelder SC, Huang A, Chodosh JC. doi:10.1016/j.ophtha.2006.08.014.
Therapy of nonnecrotizing anterior scleritis with 186. Zhao JC, Jin XY. Immunological analysis and treatment of
subconjunctival corticosteroid injection. Ophthalmology. Mooren’s ulcer with cyclosporin A applied topically. Cornea.
1995;102(5):718–24. doi:10.1016/S0161- 6420(95)30963- 3. 1993;12(6):481–8. doi:10.1097/00003226-199311000-
167. Ullman S, Roussel TJ, Culbertson WW, et al. Nersseria 00004.
gonorrhoeae keratoconjunctivitis. Ophthalmology. 187. Zu DUN, Qi CJIA, Ming GX, Tao XUH. Mooren’s ulcer treated
1987;94(5):525–31. doi:10.1016/S0161- 6420(87)33415- 3. by lamellar keratoplasty. Published online 1979.
JID: SOP
further reading Scott DG, Bacon PA. Intravenous cyclophosphamide plus

methylprednisolone in treatment of systemic rheumatoid
vasculitis. Am J Med. 1984;76(3):377–84.
doi:10.1016/0002- 9343(84)90654- 5.
Holland EJ, Mannis MJ, Lee WB. Ocular Surface Disease: Cornea,
Silva BL, Cardozo JB, Marback P, Machado FC, Galvão V,
Conjunctiva and Tear Film: Expert Consult-Online and Print.
Santiago MB. Peripheral ulcerative keratitis: a serious
Elsevier Health Sciences; 2013.
complication of rheumatoid arthritis. Rheumatol Int.
Li Z, Wei C, Wang S, Liu T, Zhai H, Shi W. Upregulation of NLRP3
2010;30(9):1267–8. doi:10.1007/s00296- 009- 1161- 7.
inflammasome components in Mooren’s ulcer. Graefe’s Arch
Clin Exp Ophthalmol=Albr von Graefes Arch fur Klin und Exp
Ophthalmol.. 2017;255(3):607–12.
doi:10.1007/s00417- 016- 3516- 6.

Gupta 2021

Uploaded by

Copyright:

Available Formats

You might also like

Gupta 2021

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Gupta 2021

Uploaded by

Copyright:

Available Formats

JID: SOP

ARTICLE IN PRESS [mNS;April 10, 2021;3:7]

Available online at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/survophthal

Peripheral ulcerative keratitis

Yogita Gupta, MD, Alisha Kishore, MD, Pooja Kumari, MS,

be a presenting manifestation of an underlying ocular or

dysentery, Lyme disease), viral (varicella zoster, acquired im-

PUK has varied clinical presentations. It may be bilateral, but

Table 2 – Watson’s classification of Mooren’s ulcer types175

Clinical characteristics Type I Type II Type III

Laterality Unilateral Bilateral Bilateral

combination of a cephalosporin and an aminoglyco- 5.3. Medical management

(continued on next page)

Etanercept57 anti-TNFα Subcutaneous 25 mg twice a week or 50 Serious infections, reactivation

Topical Brown, 198424 Useful agent in the Should be used with

(continued on next page)

Conjunctival Brown,198424 Healing in 8/22 cases24 ; Useful in arresting Resection of at least 2

Fig. 3 – Stepwise treatment protocol for Mooren ulcer.14 ,21

8. Overview of treatment in PUK 11. Method of literature search

PUK is a corneal disorder of major concern to ophthalmol-

keratitis as a complication of acute myeloid leukaemia. BMJ Augenheilkd. 1996;208(02):73–81.

further reading Scott DG, Bacon PA. Intravenous cyclophosphamide plus

You might also like