Peripheral Ulcerative Keratitis

Etiology

Table 1 summarizes the variety of ocular (local) and systemic disorders that can lead to PUK. Almost half of all noninfectious cases of PUK are associated with a connective tissue disorder, of which rheumatoid arthritis is the most common. PUK affects both eyes in nearly half of all late-stage rheumatoid arthritis cases. Tauber et al report that 34% of eyes with noninfectious PUK have an associated rheumatoid arthritis.[10] PUK is also a relatively common presenting feature of GPA, a systemic vasculitis that affects the sinuses, nose, throat, lungs, and kidneys. GPA-associated PUK is due to a necrotizing vasculitis affecting the anterior ciliary or perilimbal arteries. 

PUK manifests with crescentic stromal thinning, inflammatory cells in the juxtalimbal cornea, and an epithelial defect. Infections can involve the peripheral cornea without resulting in PUK. However, infection constitutes 19.7% of all PUK cases and must be ruled out when the ocular disorder is identified. Various microorganisms may cause PUK, including bacteria, viruses, fungi, and Acanthamoeba spp.

Table 1. Causes of PUK

Mooren Ulcer

This condition is a diagnosis of exclusion and is often accompanied by severe pain.[11] Complications such as anterior uveitis, secondary infection, cataract, glaucoma, and corneal perforation may develop in 35% to 40% of patients. Watson and colleagues have described 3 clinical subtypes.[12]

Type 1 - Unilateral Mooren Ulceration

• Unilateral
• Older than 60 years
• Female patients
• Severe pain
• Rapid progression
• Poor prognosis, recurrence
• Complications rare

Type 2 - Bilateral Aggressive Mooren Ulcer

• Bilateral
• Young (14-40 years)
• Male patients
• Mild-to-moderate pain
• Slow progression but aggressive initially
• Poor prognosis, recurrence
• Complications common

Type 3 - Bilateral Indolent Mooren Ulcer

• Bilateral
• Middle-aged (mid-50s)
• No gender predilection
• Mild pain
• Slow progression
• Better prognosis, recurrence rare
• Complications rare

Epidemiology

In the United Kingdom, estimates for PUK incidence range from 0.2 to 3 patients per million annually.[13][14][15] Female individuals are more likely to be affected generally, although this trend is reversed for Mooren ulcers.[16] Evidence does not support a racial or ethnic predilection for PUK, and the associated cause influences both the likelihood and the age at the initial presentation. Classification is generally clinical, enabling healthcare practitioners to choose appropriate investigations and treatments that target the underlying etiology.

• Incidence and prevalence: PUK is considered a rare condition globally, affecting fewer than 5 individuals per 100,000 annually. PUK is most commonly seen in association with systemic autoimmune diseases like rheumatoid arthritis or systemic vasculitis.[17]
• Sex distribution: Studies indicate a slight female predominance, particularly in cases linked to autoimmune conditions. This trend reflects the higher prevalence of autoimmunity in women.[18]
• Age groups: PUK primarily affects middle-aged and older adults, especially those in their 6th and 7th decade. However, PUK can occur in younger individuals if associated with autoimmune diseases.[19]
• Global distribution: The condition is reported worldwide, with higher frequencies in populations with higher rates of autoimmune disorders. In developing regions, infectious causes, such as bacterial or fungal keratitis, may be more common triggers for PUK than autoimmune disorders.[20]

Understanding the epidemiology helps identify at-risk populations and target preventative or early intervention strategies.

Pathophysiology

Several significant differences between the central and peripheral cornea make it susceptible to inflammation, ulceration, and furrowing. The peripheral cornea is the transition zone between the cornea, conjunctiva, episclera, and sclera, with a combination of histologic features.[21] Neural innervation and sensitivity are reduced in the peripheral compared with the central cornea.[22] The thickness of the peripheral cornea is around 1000 μm, which is greater than that of the central cornea, which is 550 μm. Epithelial cells adhere more tightly to the corneal basement membrane and stroma in the periphery than in other areas.[23]

The reservoir of corneal epithelial stem cells and the mitogenic activity of corneal endothelial cells are also highest in the peripheral cornea. An imbalance between collagenase and tissue inhibitor activity has been hypothesized to cause the loss of corneal integrity and increased corneal matrix turnover. Elevated levels of matrix metalloproteinases, which degrade the extracellular matrix, along with reduced tissue metalloproteinase inhibitors, can result in increased keratolysis.[24][25]

The central cornea is avascular and derives most of its nutrition through the tear film and aqueous humor. In contrast, the peripheral cornea has a well-developed vascular and lymphatic supply, with perilimbal vessels extending 0.5 mm into the cornea. This area is a source of immunoglobulins, macrophages, lymphocytes, plasma cells, and other immune cells that mediate the inflammatory process.[26] 

A combination of humoral and cellular immune mechanisms is often involved in PUK's pathogenesis. In PUK secondary to rheumatoid arthritis, autoantibodies and self-antigens combine to form immune complexes, which activate B cells and complement proteins. B cells can further stimulate T cells to secrete cytokines associated with rheumatoid arthritis. The combination of angiogenesis and immune cell clusters contributes to pannus formation in PUK.[27]

Histopathology

Histopathology is vital in diagnosing PUK and understanding its underlying causes. The key findings of microscopic tissue examination are:

• Inflammatory cell infiltration: Dense infiltration of neutrophils, lymphocytes, and plasma cells is often observed in the corneal stroma, particularly in autoimmune-related PUK cases. This inflammation leads to tissue destruction and corneal thinning.
• Necrosis and stromal loss: Severe corneal epithelium and stroma necrosis are hallmarks of active PUK. Necrotic tissue may be observed, especially at the periphery of the cornea.[28]
• Immune complex deposition: In systemic autoimmune diseases like rheumatoid arthritis, evidence of immune complex deposition (immunoglobulins G and M and complement components) may be seen along the corneal blood vessels. Immune complex deposition contributes to inflammation.[29]
• Angiogenesis: In longstanding cases, neovascularization may be observed within the peripheral cornea. This feature is a sign of chronic inflammation and healing attempts.[30]

Histopathological findings help confirm the diagnosis and differentiate PUK from other causes of peripheral corneal thinning, guiding targeted treatment strategies.

History and Physical

PUK is more often unilateral than bilateral at the initial presentation. Bilateral PUK is often asymmetrical and is associated with systemic disease. Patients typically complain of ocular pain, photophobia, and tearing. The eyes are injected and appear red. Pain is variable but comprises an important feature of PUK. In Mooren ulcers, the pain is often out of proportion to the clinical signs. Reduction in vision is due to inflammation and may be mild or severe. 

The classic clinical signs of PUK include peripheral crescentic ulceration, superimposed epithelial defect, stromal loss, and limbal infiltrates with an overhanging edge (see Image. Peripheral Ulcerative Keratitis in Rheumatoid Arthritis). When PUK is associated with a systemic disease, the inflammation may also involve the surrounding conjunctiva, episclera, and sclera, with additional nodular or necrotizing scleritis. Persistent inflammation and stromal lysis can progress to corneal perforation, and iris tissue is clinically visible as a "plug" at the perforation site. Perforation is an ocular emergency. Chronic PUK with peripheral thinning and corneal vascularization results in significant irregular astigmatism, scarring, and reduced vision. 

Mooren ulcer arises from an unknown cause. Please refer to the Etiology section for descriptions of the 3 types of Mooren ulcer by Watson et al.

A detailed clinical history and physical examination can identify most causes of PUK. Information to note during history taking includes associated constitutional symptoms, musculoskeletal pain, as well as gastrointestinal, respiratory, skin, cardiac, and neurological signs and symptoms. 

Clinical History

Patients often report sudden onset of pain, redness, photophobia, and tearing in the affected eye(s). A history of autoimmune disease, such as rheumatoid arthritis, GPA, or SLE, is common. The progression may be rapid, leading to corneal thinning. A history of recent eye infections, autoimmune disorders, or previous ocular surgeries may increase the risk for PUK. Although less common, trauma and contact lens overuse predispose to peripheral corneal ulceration.[31]

Physical Examination

The hallmark finding in PUK is peripheral corneal thinning, often with associated ulceration. The lesion usually affects the peripheral 2 to 4 mm of the cornea. Severe limbal and conjunctival hyperemia (redness), inflammation, and scleral involvement may be observed. Signs of impending corneal perforation may be seen in advanced cases, with visible Descemet membrane or prolapse of intraocular contents. Gray-white stromal infiltrates may be adjacent to the thinning area, suggesting active inflammation. Anterior uveitis or hypopyon may be present in severe cases, indicating a significant inflammatory response.

Associated Findings

In some cases, patients may also have accompanying scleritis or episcleritis, which can signal underlying systemic vasculitis. While unilateral PUK is more common, patients with systemic autoimmune diseases may present with bilateral involvement.[32]

Importance of Systemic Evaluation

Given PUK's strong association with systemic conditions, a thorough systemic history is essential to identify any underlying diseases that may need treatment alongside the ocular condition. A thorough history and physical examination can provide significant insights into the cause of PUK and guide appropriate management and intervention.[33]

Evaluation

A well-structured physical examination can yield clues to the systemic cause of PUK. Findings of subcutaneous nodules in the upper and lower limbs, combined with rheumatoid factor and serum autoantibody detection, characterize rheumatoid arthritis. A saddle nose appearance and auricular pinnae deformity suggest relapsing polychondritis. This recurrent inflammatory disease of unknown etiology produces selective destructive inflammatory lesions of cartilaginous structures.[34]

Features of SLE include oropharyngeal mucosal ulcers, a malar facial rash, facial and scalp hypopigmentation or hyperpigmentation, and alopecia. A temporal headache with jaw claudication is often reported in giant cell arteritis. Raynaud phenomena may manifest in SLE, Sjögren syndrome, and progressive systemic sclerosis. GPA usually presents in the 4th or 5th decade, with a male preponderance of 3:2. The characteristic triad of necrotizing, granulomatous, and vasculitic lesions occurs in the respiratory tract and kidneys, causing focal segmental glomerulonephritis.[35]

Several laboratory and radiographic tests are recommended to diagnose PUK, assess corneal damage, and identify underlying systemic diseases. Commonly employed tests recommended by national and international guidelines include the following:

• Laboratory tests: Important components to note in the autoimmune panel include ANA, rheumatoid factor, and anti-citrullinated protein antibodies (ACPA). These markers help diagnose autoimmune conditions like rheumatoid arthritis and SLE. C-reactive protein and erythrocyte sedimentation rate are elevated in systemic vasculitis and other autoimmune diseases associated with PUK. ANCA testing can help diagnose vasculitides like GPA.[36]
• Microbiological testing: If infection is suspected, corneal scrapings with bacterial, fungal, and viral cultures can help identify the pathogen involved. Viruses such as herpes simplex and varicella zoster may be detected using polymerase chain reaction.[37]
• Imaging studies: Chest radiography may reveal hilar lymphadenopathy or lung involvement in patients with systemic causes, such as sarcoidosis and tuberculosis. Sinus and orbital computed tomography is useful in cases of systemic granulomatous diseases, such as GPA.[38]
• Ocular investigations: Anterior segment optical coherence tomography helps measure the depth of corneal thinning and assess the extent of corneal damage. Corneal topography assesses peripheral corneal irregularities and thinning.[39] Ultrasound biomicroscopy is useful in anterior segment evaluation, especially if deep corneal or scleral involvement is suspected.

National and International Guidelines

The American Academy of Ophthalmology recommends an interprofessional approach involving ophthalmologists, rheumatologists, and infectious disease specialists. The European Society of Cataract and Refractive Surgeons provides guidelines for early detection and management of systemic autoimmune associations.

Treatment / Management

Medical Management: Aims and Strategy

A tailored approach is best, aiming to restore epithelial integrity, halt further stromal lysis, and prevent superinfections. PUK with confirmed noninfectious etiology may be managed with a combination of topical lubricants, oral steroids, and collagenase inhibitors. The role of topical corticosteroids is controversial. These agents can increase the risk of corneal perforation in patients with autoimmune disease and should thus be considered cautiously. 

Systemic immunosuppressants can take 4 to 6 weeks to take effect, but oral steroids may be prescribed in the interim. Localized or systemic infection should be treated with the appropriate antimicrobials. Corneal scrapings should be taken at the initial presentation for gram staining and microbiological evaluation. Empirical therapy, such as 4th-generation fluoroquinolone monotherapy for bacterial keratitis, should be initiated afterward. Therapy may be adjusted as needed once sensitivities are identified.

Topical steroids may be started to reduce the local inflammatory response after clinical improvement has been observed with antimicrobial treatment. However, topical steroid use should be delayed in cases of fungal infections. Topical acyclovir or ganciclovir should be started if a herpetic cause is suspected. Systemic infection requires specific protocols and shared care with the relevant specialties.  

Peripheral Ulcerative Keratitis Associated with Systemic Autoimmunity

PUK management should include therapy specific to the underlying cause. Some of these interventions are discussed below.

Rheumatoid arthritis

Current first-line management for rheumatoid arthritis includes systemic corticosteroids and cytotoxic agents like methotrexate (MTX). Topical lubricants help protect the ocular surface and encourage the epithelial healing of peripheral corneal ulcers.[40] Systemic therapy is initiated with rheumatology or immunology teams. Second-line agents include azathioprine and cyclophosphamide, which are used in severe, refractory PUK cases unresponsive to MTX.[41] (B3)

Granulomatosis with polyangiitis and polyarteritis nodosa

Aggressive treatment is needed for PUK secondary to GPA or PAN. The first-line immunosuppressant agents for GPA include cyclophosphamide and systemic corticosteroids, ideally started early in the disease course. Rituximab or cyclophosphamide, with or without other agents, is the most effective in controlling inflammation in GPA-associated PUK.[42] Cyclophosphamide and corticosteroids are typically used in the remission phase, while rituximab is administered in the maintenance phase. A lack of response to cyclophosphamide warrants consideration of rituximab. GPA-associated PUK presenting with necrotizing scleritis has a particularly poor visual prognosis, as this condition is usually a sign of severe systemic vasculitis.[43]

Systemic lupus erythematosus

Foster et al have suggested that systemic vasculitis only develops in the latter stages of SLE. Systemic corticosteroids and a cytotoxic agent are used in SLE-associated PUK. SLE with evidence of systemic vasculitis has significantly higher mortality.[44]

Special Circumstances

Some patients with PUK require complex therapeutic approaches. These special circumstances are explained below.

Pediatric patients

MTX is considered a first-line immunosuppressant for pediatric patients with PUK related to systemic disease. Cyclosporine may be considered if MTX does not elicit a response. These agents should be avoided during pregnancy due to their potential teratogenicity. Oral steroids may be used cautiously in children.

Patients on existing immunosuppression regimens

Infectious etiologies should be excluded before planning further PUK treatment in these individuals. Evaluation for potential acute exacerbations of systemic disease should be initiated. A change in systemic disease status may prompt the medical team to implement a step-up or maintenance strategy. Rheumatologists or immunologists evaluate the clinical response to immunosuppression, typically 6 months from treatment initiation.

Mooren Ulcer

The diagnosis of Mooren ulcer is one of exclusion. The management strategy is a stepladder approach, with topical corticosteroids and cyclosporine (0.05% to 2%) initially, then progressing to limbal conjunctival resection or excision, systemic immunosuppressants, such as oral corticosteroids, MTX, cyclophosphamide, and cyclosporine, and surgery, including astigmatism treatment. Surgery alone is unlikely to be curative due to the underlying autoimmune pathophysiology.[45]

An association between hepatitis C infection and a Mooren ulcer clinical phenotype has been reported.[46] Therapy with interferon-α2b is effective in treating corneal ulceration while inducing hepatic disease remission.[47] (B3)

Surgical Management

Surgery has a higher risk of PUK recurrence and graft melts. Thus, this approach should be delayed until adequate control of inflammation is achieved.[48] Graft survival is less than 50% at 6 months; hence, multiple grafts are required in many patients. Emergency surgical management depends on the indication. A therapeutic indication would be ulcers extending circumferentially, inducing corneal melt. A tectonic indication is a perforation or descemetocele. An optical indication is visual rehabilitation.(B2)

The corneal defect size determines the appropriate surgical technique. Multilayered amniotic membrane transplant and conjunctival resection, recession, or flaps may be options in areas with corneal thinning.[49] Conjunctival resection removes the tissue supplying inflammatory mediators to the cornea. Lamellar patch grafts reduce graft rejection risk compared with a full-thickness patch or tectonic grafts.[50][51] Corneal glue, ie, cyanoacrylate, with a bandage contact lens may be deployed if the perforation is less than 3 mm in diameter.[52](B3)

Differential Diagnosis

The differential diagnosis of PUK includes all conditions that can present as peripheral corneal thinning or opacification, as described in Table 2. In marginal keratitis, a clear cornea is often visible between the limbus and the infiltrates. Peripheral corneal degenerations are noninflammatory, have intact epithelium, and lack infiltrates.

Table 2. Differential Diagnosis of Peripheral Ulcerative Keratitis

Ruling out clinical mimics is crucial when determining the appropriate management. The following conditions should be considered:

• Mooren ulcer: A chronic, progressive, and idiopathic condition that leads to peripheral corneal ulceration and thinning similar to PUK but without systemic involvement.
• Infectious keratitis: This condition encompasses bacterial, fungal, viral, and Acanthamoeba infections. Cultures and corneal scrapings are vital to the evaluation process, as their management approaches differ significantly.
• Terrien marginal degeneration: Terrien degeneration is a noninflammatory thinning of the peripheral cornea. Unlike PUK, this condition usually lacks the overlying epithelial defect and inflammatory response.
• Scleritis-associated keratitis: Scleritis can involve the cornea in severe cases. This condition must be distinguished from primary corneal diseases like PUK, especially when associated with systemic vasculitis.
• Neurotrophic keratopathy: This condition is characterized by corneal ulceration due to reduced corneal sensation. Neurotrophic keratopathy can mimic peripheral ulceration, but it usually occurs in different regions of the cornea and lacks the autoimmune or systemic inflammatory signs of PUK.[53]
• Ocular surface disease: Conditions such as severe dry eye syndrome or limbal stem cell deficiency can lead to peripheral corneal thinning without the acute inflammatory component seen in PUK.[54]
• Rosacea keratitis: Peripheral corneal involvement can occur in ocular rosacea, often presenting with punctate epithelial erosions, marginal infiltrates, or peripheral corneal thinning.[55][56]
• Rheumatoid arthritis-associated keratitis: Systemic autoimmune diseases, like rheumatoid arthritis, are strongly associated with PUK. Primary corneal disease must be distinguished from secondary keratitis due to systemic conditions.
• Limbal vernal keratoconjunctivitis: This disorder can cause peripheral corneal ulcers, known as Shield ulcers, which tend to be large and oval, often involving the central cornea.[57]
• Corneal degeneration: Peripheral corneal degenerative conditions such as pellucid marginal and furrow degeneration may present with peripheral corneal thinning but lack PUK's ulcerative and inflammatory nature.[58]
• Relapsing polychondritis: A rare autoimmune condition affecting cartilage, relapsing polychondritis can cause peripheral corneal ulceration and thinning, mimicking PUK in patients with multisystem involvement.[59]
• Stevens-Johnson syndrome and toxic epidermal necrolysis: These conditions may present with peripheral corneal ulceration and scarring resulting from ocular surface damage, especially in severe cases.[60]
• Limbal stem cell deficiency: This condition can lead to peripheral corneal thinning and ulcers due to failure of corneal epithelial regeneration. However, limbal stem cell deficiency generally presents with more chronic, diffuse corneal surface changes.[61]
• Granulomatosis with polyangiitis: This systemic vasculitis can lead to peripheral corneal ulceration and should be considered in cases of PUK with systemic manifestations like sinusitis and lung involvement.[62]
• Systemic lupus erythematosus: SLE can cause peripheral corneal involvement similar to PUK, particularly in active systemic disease. Differentiation is critical for systemic management.[63]
• Sarcoidosis: This condition can involve the eye, including the cornea, leading to keratitis or corneal thinning that mimics PUK, particularly in cases with systemic granulomatous involvement.[64]

Recognizing the broad spectrum of conditions that can mimic PUK is essential for accurate diagnosis and treatment. Each condition requires a different therapeutic approach, particularly in the presence of systemic involvement. A comprehensive history, clinical evaluation, and diagnostic tests, such as blood work and imaging, are critical to differentiate PUK from similar corneal conditions. Proper clinical, microbiological, and, sometimes, histopathological examinations are essential to differentiate between causes of PUK. Early and accurate diagnosis is critical for appropriate treatment and prevention of complications such as corneal perforation.

Pertinent Studies and Ongoing Trials

Key Historical Studies

Research has shown that systemic immunosuppressive therapy, eg, methotrexate or azathioprine administration, improves outcomes in autoimmune-related PUK by reducing recurrence rates. Meanwhile, numerous studies have demonstrated the effectiveness of corticosteroids in controlling local inflammation and preventing corneal perforation in noninfectious PUK.[65]

Trials Investigating Biologics

Ongoing trials explore the use of antitumor necrosis factor-α agents like infliximab and adalimumab in cases of rheumatoid arthritis-associated PUK. Trials with drugs such as tocilizumab, which blocks the interleukin-6 receptor, are being conducted to determine their ability to control severe, refractory cases of autoimmune PUK.

Radiation Therapy in Ocular Inflammatory Diseases

The efficacy of low-dose radiation therapy for managing severe, sight-threatening ocular inflammation has been investigated. Research has shown mixed results but is worth exploring in chronic, unresponsive cases.[66]

Corneal Grafting and Limbal Stem Cell Research

Newer techniques in corneal grafting and advancements in limbal stem cell transplantation for long-term vision restoration in patients with PUK have been gaining attention.[67]

The evidence from these trials helps guide treatment decisions, particularly in severe or refractory cases of PUK where conventional therapies may not be effective. These studies also offer promising avenues for future treatment strategies, improving patient outcomes and minimizing complications.

Treatment Planning

Treatment planning for PUK involves an interprofessional approach to managing the local corneal pathology and any underlying systemic autoimmune conditions. The essential components include the following:

• Local management
  • Initial treatment involves topical corticosteroids or immunosuppressive agents to control inflammation.
  • Antibiotic drops may be necessary to prevent or treat secondary infections.
  • Surgical interventions, such as tissue glue or keratoplasty, may be needed to address corneal thinning or perforation.[68]
• Systemic immunosuppression
  • The choice of immunosuppressive therapy (eg, corticosteroids, methotrexate, and azathioprine) depends on the severity of the systemic autoimmune disease.
  • Long-term maintenance therapy may be necessary to prevent recurrence.[69]
• Collaboration with rheumatologists
  • Collaboration with rheumatologists is crucial for systemic disease management since PUK is often associated with autoimmune diseases.
  • Adjusting systemic immunosuppressive therapy is often required to control both ocular and systemic symptoms.[70]
• Regular monitoring
  • Ongoing monitoring through regular ophthalmic exams and systemic workups ensures local and systemic control, helping to prevent complications like corneal perforation.

This plan allows for comprehensive management of ocular and systemic PUK involvement.

Toxicity and Adverse Effect Management

Toxicity and adverse events from managing PUK are primarily related to the systemic immunosuppressive therapies used to control the underlying autoimmune disease. An outline of potential toxicities and their management is provided below.

• Corticosteroids
  • Toxicity: Prolonged use can lead to cataract formation, glaucoma, and systemic effects such as hyperglycemia, hypertension, osteoporosis, and adrenal suppression.
  • Management: Regular intraocular pressure checks, monitoring blood glucose levels, and tapering steroids when appropriate are typical strategies. Using topical steroids with the lowest effective dose can mitigate systemic side effects.[71]
• Methotrexate
  • Toxicity: Liver toxicity, bone marrow suppression, and lung toxicity are potential concerns with long-term use of this drug.
  • Management: Regular blood tests can help monitor liver function and complete blood counts. Folic acid supplementation is often used to reduce toxicity. Pulmonary function tests may also be required.[72]
• Cyclophosphamide
  • Toxicity: Hemorrhagic cystitis, bone marrow suppression, increased risk of infections, and secondary malignancies are risks.
  • Management: The standard approach includes hydration, using mesna to prevent bladder toxicity, regular blood work, and infection prophylaxis where appropriate.[73]
• Azathioprine
  • Toxicity: Adverse effects include bone marrow suppression, liver toxicity, and increased infection risk.
  • Management: The usual strategies include regular blood counts, liver function tests, and dose adjustments based on tolerance and side effects.[74]
• Biologic agents, including tumor necrosis factor inhibitors
  • Toxicity: These agents increase the risk of infections, including tuberculosis, and potential infusion reactions.
  • Management: The standard approach includes screening for tuberculosis before initiating therapy, monitoring for signs of infection, and managing infusion reactions with premedication if necessary.[75]

In summary, toxicity management involves regular monitoring through laboratory work, dose adjustments, and appropriate prophylactic measures to mitigate the risks of long-term immunosuppressive therapy.

Staging

PUK is not typically classified into formal stages. However, this condition can be categorized based on the severity of corneal involvement and systemic disease activity. Below is a practical way of staging this condition:

• Mild stage: This stage involves localized peripheral corneal ulceration, with the lesion's extent limited to less than 2 to 3 clock hours. The ulceration does not penetrate deeply into the stroma, and signs of impending perforation are absent. The patient may present with mild-to-moderate symptoms, including redness, irritation, and tearing.
• Moderate stage: Corneal ulceration becomes more extensive, involving 3 to 5 clock hours of the peripheral cornea. Stromal thinning is moderate, but the patient may exhibit significant symptoms, including pain, photophobia, and decreased vision. The risk of corneal perforation begins to increase, and signs of greater systemic inflammatory activity or associated autoimmune disease are evident.
• Severe stage: This stage is characterized by extensive corneal damage, usually with more than 5 clock hours or circumferential involvement. Corneal thinning is significant, and the risk of perforation is high. Patients are often in severe pain, with the risk of visual loss considerably elevated. This stage is likely to require surgical intervention, eg, tissue gluing or corneal transplant. Systemic disease activity may also be at its peak, potentially warranting aggressive immunosuppressive therapy.[76]
• Perforated or complicated stage: Corneal perforation occurs if the disease is uncontrolled or progresses rapidly, requiring emergency surgical management. This stage may also involve secondary complications such as glaucoma, secondary infections, or vision loss.

Systemic staging may also be considered based on the activity of the associated autoimmune or systemic disease, such as rheumatoid arthritis or GPA.

Prognosis

PUK cases with systemic associations and late disease presentation are harder to manage and generally have higher morbidity and mortality. The combination of scleritis and PUK often bears poor ocular and systemic prognosis.

Corneal perforation results in a poor visual outcome despite response to treatment, with 65% of patients having a final vision of counting fingers or worse. Corneal perforation is associated with 1-year mortality rates of 24% for unilateral cases and 50% for bilateral cases.

The prognosis of PUK depends largely on the underlying cause, the promptness of diagnosis, and the adequacy of treatment. Below are some key points regarding the prognosis.

• Early diagnosis and treatment: The prognosis for preserving vision is generally better if PUK is diagnosed early and treated appropriately, especially if the underlying systemic disease is controlled. Delayed treatment can lead to more severe complications and visual loss.[77]
• Risk of recurrence: PUK can recur, especially if associated with systemic autoimmunity. Continuous management of the underlying disease is crucial to prevent recurrence.
• Severity of disease: The prognosis is poorer in cases complicated with corneal perforation or extensive scleral involvement. Surgical intervention like corneal transplantation or conjunctival resection may be necessary but carries risks of graft failure and further damage.[78]
• Systemic involvement: Patients with associated systemic conditions such as vasculitis or collagen vascular diseases may face a more guarded prognosis, as these conditions can cause ongoing ocular and systemic issues that complicate recovery and management.[79]
• Visual prognosis: The extent of corneal involvement significantly influences visual outcomes. Mild cases with peripheral ulceration that do not affect the central visual axis often have a better visual prognosis, while central involvement can lead to permanent visual impairment.
• Risk of corneal perforation: The risk of corneal perforation increases when ulceration progresses rapidly, worsening the prognosis. Corneal perforation may necessitate emergency surgical intervention, such as corneal gluing, patch grafts, or full-thickness corneal transplantation.[80]
• Impact of immunosuppressive therapy: The prognosis improves with systemic or corticosteroid therapy, especially in autoimmune-related PUK. Appropriate systemic treatment can prevent further disease progression and avoid complications such as perforation or loss of the eye (phthisis bulbi).
• Need for ongoing monitoring: Due to the chronic and relapsing nature of PUK, patients require long-term follow-up to monitor for recurrence or complications. Lifelong management of any associated systemic disease is critical to maintaining eye health and preventing future episodes of PUK.
• Surgical outcomes: In severe cases requiring procedures like corneal transplantation, the success rate of surgery may be influenced by the activity of the underlying systemic disease. The risk of graft rejection or failure is higher if inflammation is not well-controlled.
• Quality of life: PUK, especially in advanced or recurrent cases, can significantly affect the patient's quality of life due to chronic pain, frequent need for medical appointments, and visual impairment. Psychological and social support may be necessary for patients with severe disease.[81]
• Long-term management: For patients with autoimmune diseases, the long-term prognosis depends not only on ophthalmologic treatment but also on controlling the systemic condition. Ongoing collaboration between ophthalmologists, rheumatologists, and internists is essential to provide comprehensive care and improve long-term outcomes.
• Potential for severe complications: PUK can lead to serious complications if left untreated or inadequately managed, including severe scarring, secondary glaucoma, and even phthisis bulbi in extreme cases.[82]

Effective interprofessional management involving specialists such as ophthalmologists and rheumatologists is essential to improving the long-term prognosis of PUK.

Complications

Below are the possible complications of PUK.

• Corneal perforation: Severe inflammation can lead to corneal thinning and perforation, requiring urgent surgical intervention, such as corneal patch grafts or amniotic membrane transplantation.[83] This condition is the most serious ocular complication of PUK and may involve both eyes. Corneal perforation has a detrimental effect on final vision and can result in visual loss. The risk of mortality increases in patients with PUK due to systemic associations, particularly when perforation occurs.
• Vision loss: Chronic or untreated PUK may result in significant vision loss due to scarring, irregular astigmatism, or corneal opacity.[84]
• Secondary infections: The ulcerative nature of PUK makes the cornea more susceptible to secondary bacterial, fungal, or viral infections, complicating management and delaying healing.[85]
• Recurrence of autoimmune disease: PUK is often associated with systemic autoimmune conditions. Systemic or ocular disease may recur despite treatment, requiring ongoing immunosuppressive therapy.
• Scleral involvement: Inflammation can extend from the cornea to the sclera, leading to scleritis, which can cause intense pain, further tissue damage, and pose a significant risk to the eye's structural integrity.
• Corneal melting: Rapid stromal degradation and "melting" of the corneal tissue may occur, requiring prompt treatment to prevent perforation or further complications.[86]
• Glaucoma: Secondary glaucoma can arise from chronic inflammation or corticosteroid treatment. Glaucoma may increase intraocular pressure, potentially damaging the optic nerve.[87]
• Anterior uveitis: Inflammation in the front of the eye, ie, iritis or anterior uveitis, is commonly associated with PUK and contributes to pain, light sensitivity, and visual impairment.[88]
• Cataract formation: Long-term corticosteroid use, often needed for autoimmune conditions associated with PUK, can accelerate the development of cataracts, leading to cloudy vision.[89]
• Symblepharon formation: Severe ocular surface disease and chronic inflammation may induce the formation of adhesions between the eyelid and eyeball, also known as symblepharon, which can impair eye movement and eyelid function.[90]
• Corneal neovascularization: Chronic inflammation may lead to the growth of abnormal blood vessels into the cornea, which can cause further vision impairment and reduce corneal transparency.[91]
• Steroid-induced complications: Potential adverse effects of prolonged corticosteroid therapy include delayed wound healing, cataracts, and increased susceptibility to infections.[92]
• Chronic pain: Persistent inflammation and damage to the ocular surface can produce chronic pain, which can affect a patient’s quality of life.
• Endophthalmitis: Infection may penetrate the deeper eye structures in rare and severe cases, leading to endophthalmitis, a sight-threatening condition requiring urgent medical attention.[93]

Prevention of these complications requires prompt diagnosis, aggressive treatment, and an interprofessional approach to management.