Peripheral ulcerative keratitis: A review of aetiology and management

corticosteroid as a fast-acting agent to halt the inflammatory process while cytotoxic therapy maintains long term disease control. Failure to achieve disease control with CTT, necessitates the use of a biologic agent. Conclusion: Peripheral ulcerative keratitis is a severe inflammatory disease of the peripheral cornea that needs a thorough diagnostic workup and stepwise management approach.


Introduction
Peripheral ulcerative keratitis (PUK) is a rare inflammatory disease of the peripheral cornea with an incidence of 0.2-3.0 per million population per year. 1 It is characterised by a juxtalimbal crescent shaped epithelial defect, stromal thinning and inflammatory stromal infiltrate. 1 Peripheral ulcerative keratitis develops in the peripheral cornea because of its unique anatomical and physiological characteristics. 1 It is associated with many local and systemic conditions that are broadly classified into infective and non-infective. 1 Peripheral ulcerative keratitis is an important condition as the presence of comorbid systemic disease is associated with significant morbidity and increased mortality. 2 It may be the first presentation of systemic disease, and early diagnosis and management has the potential to not only preserve vision but also reduce mortality. 2 The purpose of this review was to provide an overview of the pathophysiology, aetiology, clinical features, diagnosis and management of PUK. A PubMed search was conducted using the keywords, 'peripheral ulcerative keratitis' and 'Mooren's ulcer'.
The exact mechanism of PUK is not fully understood. The basic tenets of the process are the deposition of circulating immune complexes in the limbal vascular arcades. 3 This causes an activation of the classical complement pathway and resultant vasculitis. 3 The subsequent chemotaxis of inflammatory cells into the peripheral cornea results in the release of proinflammatory cytokines and matrix metalloproteinases (MMP), 4 MMP-2 and 9 hydrolyse type 4 collagen, altogether leading to epithelial breakdown and stromal melt. 3,6,7 This occurs in a crescentic fashion and is the hallmark of PUK. 1

Aetiology
The causes of PUK are extensive ( Figure 1) and can be divided into systemic and local causes. Non-infectious causes account for half the cases, with rheumatoid arthritis (RA) cited as the most common associated systemic disease in approximately 34% of the cases. 1,8 Other important associations include granulomatosis with polyangiitis (GPA), inflammatory bowel disease (IBD), human immunodeficiency virus (HIV), hepatitis C and dermatological conditions. The most common local ocular conditions are bacterial and viral keratitis that involve the peripheral cornea. 1

Rheumatoid arthritis
Rheumatoid arthritis is an autoimmune disease that is characterised by chronic inflammation of the joints, resulting in damage to the underlying cartilage and bone. 9 In developed countries, the prevalence rate of RA is 0.5% -1% of adults compared with a higher prevalence of 0.13% -2.5% in developing countries. 9,10 Women are affected three times more than men, with a peak incidence over the age of 65 years. 9,11,12 Associated risks have not been fully elucidated; however, genetic factors are thought to account for 50.0% of the risk, and smoking doubles the risk of developing RA. 9 The diagnosis of RA is based on the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) criteria of 2010. 13 This criteria take into account synovitis, serology for antibodies, acute phase reactants and the duration of symptoms. 13 Synovitis is diagnosed clinically by the presence of tender and swollen large or small joints. 13 Serology can be performed for diagnostic antibodies in RA, which can precede the clinical onset of disease by several years. 13 These include rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). 9,13 Rheumatoid factor are the classic anti-bodies where IgM and immunoglobulin A (IgA) rheumatoid factors are directed against the Fc fragment of immunoglobulin G (IgG). 9 Anticitrullinated protein antibodies are more specific and sensitive for the diagnosis of RA and are associated with a more severe course of disease and poorer outcomes. 9 These have been found to be positive in 50% -80% of patients with RA. 9 The management of RA revolves around two pillars, symptom management and disease modification. 9 Analgesia and nonsteroidal anti-inflammatory drugs help to reduce the symptoms of pain and stiffness; however, these have no effect on disease progression. 9 Disease-modifying anti-rheumatic drugs (DMARDS) are a group of agents that are used to halt the progression of disease, thereby reducing morbidity and mortality. 9 The most commonly used agent in RA is methotrexate followed by more expensive biological agents. 9 Rheumatoid arthritis is the most common systemic association with PUK, present in up to 75% of patients with a known systemic cause. 14 The prevalence of PUK in RA is approximately 1.4%, with a mean age of presentation of 65-73 years and a female preponderance. 11

Autoimmune causes Autoimmune causes
Mooren's ulcer 11,12,15,16,17,18,19,33,40,48,53,63,66,78,79,80,81,82  Ocular cicatricial pemphigoid 100 Other with long-standing quiescent RA, rendering the ACR/ EULAR criteria less relevant in this situation. 12 Although the mean duration of RA before the onset of PUK is 12-19 years, 2,11,12,15 it may rarely be the presenting feature. 16,17 Serology for RA antibodies in PUK has a higher positivity rate than non-PUK patients at 100% and 88% for RF and ACPA, respectively. 12,13,15 Peripheral ulcerative keratitis may be bilateral in up to 52% of patients, and scleritis has been found to be present in 38% -100%. 2,15 Patients with RA have an increased risk of developing PUK after surgery, even if their systemic disease has been controlled for years. 18,19 It is therefore important to have stringent followup in the initial post-operative period. Corneal perforation is a severe complication of PUK and has been reported in 15% -73% of patients with RA. 11,12,14 The pathogenesis of PUK in patients with RA has not been fully described. The hypothesis is that immune complexes from the circulating antibodies deposit in the vascular arcades of the peripheral cornea and elicit an inflammatory cascade that leads to peripheral corneal melt and PUK. 20 Peripheral ulcerative keratitis in RA is therefore thought to herald the onset of a systemic vasculitis which is associated with a significant 5-year mortality. 2 One study showed the development of systemic vasculitis in 22% of patients within two months of the onset of PUK and a 50% associated mortality. 12 Malik et al. 11 described a series of patients with RA and keratolysis. PUK was diagnosed in 55% of patients in this series, with a 5-year mortality rate of 24%. 11 With the increased utilisation of DMARDS and biologics, there has been a decrease in the prevalence of PUK and an increased life expectancy in patients with RA. 2 Foster et al. 2 compared patients with RA and PUK and/or scleritis and their outcomes with and without the use of cytotoxic therapy. Patients receiving CTT had a mortality rate of 6%, whereas the patients who did not receive CTT had a mortality rate of 53%. 2 Similarly, the incidence of perforation has been reduced in recent years with the increased use of modern therapy. A perforation rate of up to 73% in the past has been reduced to only 13% in more recent case series. 11,15 Two case series reported in the same hospital over two successive time periods echoed these results. The perforation rate was 65% between 1987 and 2002, which had reduced to 14% for the subsequent period from 2002 to 2012. 11,14 This was largely attributed to the increased use of immunosuppressive therapy.

Granulomatosis with polyangiitis
Granulomatosis with polyangiitis is a multi-system autoimmune condition characterised by a small vessel vasculitis that classically affects the upper respiratory tract, lower respiratory tract and kidneys. 21 In patients where kidney involvement is spared, the diseased to considered to be in a 'limited' form. 22 The incidence ranges from 5 to 10 cases per million annually, with the peak age of onset between 65 years and 70 years. 21 There is no gender predilection; however, the prevalence rate is higher amongst Caucasians. 21,23 The onset of GPA is thought to be triggered by environmental or infectious factors in patients with an underlying genetic predisposition. 21 The most common of these is a Staphylococcus Aureus colonisation of the nasal passages. 21 This results in the activation of the complement system and production of pro-inflammatory cytokines that lead to the activation of neutrophils and anti-neutrophil associated antibodies (ANCAs). 24 This creates a cycle of inflammation that leads to vasculitis and target organ damage. 24 Granulomatosis with polyangiitis does not have defined diagnostic criteria. The diagnosis of this condition is based on a combination of clinical, serological and histological findings. 21 The most common clinical findings include an upper and lower respiratory tract inflammation and features of a glomerulonephritis. 21 Serology for ANCA is positive in 88% of GPA patients, but is not essential to make the diagnosis. 21 In patients with 'limited' disease, the sensitivity of this test decreases to 50%. 24 Histology shows evidence of granulomatous inflammation and necrotising vasculitis in the target organ. 21 The standard treatment for severe GPA is a combination of systemic corticosteroids (CS) and cyclophosphamide (CyP) for the induction of remission (3-6 months). Maintenance therapy consists of methotrexate or leflunomide. 22 The CS/CyP combination achieves partial remission in 91% and complete remission in 75% of patients. 23 In patients only receiving CS, the condition is uniformly fatal. 23 The current challenge in the management of GPA is the reduction in the rate of recurrence. The CS/CyP combination still has a recurrence rate of 50%. 23 This has led to the use of rituximab, which has been shown to be non-inferior to CS/CyP combination for induction therapy but superior for managing disease relapse and the prevention of major relapses. 24,25 Ocular involvement in GPA occurs in 50% -60% of patients, with ocular features being the initial presentation of GPA in 8% -60% of patients. 22,23,26 The most common ocular manifestations include scleritis, uveitis, PUK and orbital inflammation. 22 Peripheral ulcerative keratitis is predominantly unilateral, with concomitant scleritis present in 80% of patients. 26 Anti-neutrophil associated antibodies is positive in the majority of patients with PUK; however, GPA cannot be excluded if negative. 26 The combination therapy of CS and CyP is effective for disease control in the majority of cases; 26 however, in resistant cases, rituximab infusions have been successful. 25,27,28 Inflammatory bowel disease Inflammatory bowel diseases are a group of autoimmune conditions of the bowel, which include Chron's disease (CD) and ulcerative colitis (UC). 29 The global prevalence is estimated at 147 cases/million with ocular involvement in 0.3% -13% of patients. 29 The diagnosis is made on clinical presentation and confirmed with biopsies of the involved gastrointestinal tract. 30 Ocular involvement includes mainly episcleritis and uveitis, with PUK as a rare association. 29,30,31,32,33 Peripheral ulcerative keratitis in IBD can be the presenting feature of IBD or presents after previously diagnosed disease. 29,30,31,32,33 It affects men and women equally, favouring a younger onset from 33 years to 55 years. 29,30,31,32,33 This cohort of patients have a more severe form of PUK, with most needing escalation of immunosuppressive therapy to biological agents in order to achieve disease control. 29,30,31,32,33 Human immunodeficiency virus The HIV, first described in the 1980s, has led to a worldwide pandemic with its epicentre in Sub-Saharan Africa. 34 New infections continue to occur at a rate of 1.2 million cases a year. 34 Human immunodeficiency virus primarily affects the cluster of differentiation 4 (CD4) T-lymphocyte population, with its depletion directly correlated with an acquired immune deficiency. 34 Once the CD4 count falls under 200/µL, it is classified as an acquired immunodeficiency syndrome (AIDS). 34 This immune deficiency predisposes individuals to a range of opportunistic infections and cancers. 34 The spread of disease occurs primarily through sexual transmission. 34 Diagnosis is made on serology, with the stage of disease determined by the CD4 cell count or presence of an acquired immunodeficiency syndrome (AIDS)-defining condition. 34 Highly active antiretroviral therapy is the preferred treatment regimen consisting of a combination of three agents that suppress viral replication. 34 This allows for recovery of the immune system and has reduced morbidity and mortality rates by 80%. 34 The effectiveness of Highly active antiretroviral therapy (HAART) is monitored by the reduction in serum viral load. 34 The pathophysiology of PUK in HIV is two pronged. Firstly, the chronic HIV infection causes high levels of circulating immune complexes. 35 As described earlier, these can precipitate in the peripheral cornea and initiate an inflammatory cascade with resultant keratolysis. Secondly, HIV predisposes to other infective conditions, which in themselves may be associated with PUK. 36 HIV has been described as a cause of PUK in several case reports. 35,37,38,39,40,41,42 This association has been made in newly diagnosed patients with no co-morbid conditions or in the presence of conditions associated with PUK. 38,39,42 These associated conditions were mostly infective in nature and included tuberculosis, herpes zoster ophthalmicus, RA, and syphilis. 35,37,40,41 All the patients who had HIV as an isolated risk for PUK required only local therapy and initiation of HAART in order to achieve disease control, suggesting that HIV alone is not an aggressive factor for the development of PUK. 38,39,42 Hepatitis C

Hepatitis C virus (HCV) is a systemic infection with a global
seroprevalence rate of 3%. 43 Transmission occurs through blood contact with an infected individual. 43 In the past, this occurred mainly from blood transfusions, but this method of transmission has almost completely been abolished with improved screening at blood banks. 43 The leading cause of HCV transmission currently is through the use of shared needles by intravenous drug users. 43 Hepatitis C virus infection is mostly asymptomatic and resolves spontaneously within 18 months in 15% -25% of individuals. 43 In patients with chronic HCV infection, the sequelae are variable, including chronic hepatitis with liver cirrhosis and failure, hepatocellular carcinoma, mixed cryoglobulinaemia (MC) and extra-hepatic manifestations. 43 Mixed cryoglobulinaemia is a condition characterised by cold-insoluble immune complexes that deposit in small and medium blood vessels causing a vasculitis. 43 More than 90% of patients with MC have HCV infection. 43 In the case reports reviewed, half of the patients with PUK and HCV infection had associated MC. 44,45,46 Elevated RF levels and reduced levels are C3 and C4 may be present in patients with MC. 43 A rare extrahepatic manifestation of both HCV infection and MC is the development of PUK. 43 Peripheral ulcerative keratitis develops in chronic HCV infection, with associated necrotising scleritis being a common clinical finding. 44,45,46,47,48,49 The management of choice for HCV infection is interferon-alpha and ribavirin. 43 The patients who were refractory to this have responded well to a combination of interferon-alpha, ribavirin and rituximab. 43

Dermatosis
Pyoderma gangrenosum is a neutrophilic dermatosis that is characterised by non-infective necrotic ulceration of the skin. 50,51 It is a rare condition with an annual incidence of 3-10 per million. 50 It is associated with a unilateral PUK that responds well to systemic CS and immunosuppression agents. 50,51,52,53,54 Erythema elevatum diutinum (EED) is a rare chronic dermatosis that is characterised by brown to purple plaques of the extensor surfaces of the skin. 55 Diagnosis is confirmed on skin biopsy. 55 Although EED occurs mainly in the age group 50-70 years, PUK associated with EED has been described in patients from 22 years to 81 years without a gender predisposition. 55,56,57,58,59 All patients respond to dapsone therapy. 55,56,57,58,59 Sweet syndrome is a neutrophilic dermatosis that is characterised by fever and sudden onset of painful erythematous nodules on the face, neck and extremities. 60 It has several ocular manifestations of the anterior segment, including conjunctivitis, episcleritis, scleritis, anterior uveitis and glaucoma. 60 Rarely, it may be associated with PUK. 53

Clinical features
The symptoms associated with PUK depend on the severity at presentation and the presence of associated scleritis. Most patients will present with pain, epiphora, conjunctival injection and reduced visual acuity. 12 On further questioning and examination, features of associated diseases may be present. In conditions such as RA, the diagnosis will often already be made, and features of RA will be present. 14 In other associated conditions, such as GPA, the PUK may be the presenting feature of the underlying disease. 26 On clinical examination, visual acuity is reduced, conjunctiva is injected, and a crescentic epithelial defect with stromal infiltrate and thinning is present. 63 The thinning and ulceration spread circumferentially before there is central spread (Figure 2). 63 Associated features that may be present depend on the associated conditions and severity, which include scleritis, perforation, secondary infection, uveitis, hypopyon and raised intra-ocular pressures. 38,61,63

Diagnosis and workup
The differential diagnosis for PUK is large, and a detailed history, systemic and ocular examination is needed to guide the workup for associated conditions. As some patients may present with more than one comorbidity is essential to do a workup in all patients even if a known comorbidity is present.
Basic blood investigations that should be conducted include full blood count with platelets and differential count; urea, creatinine and electrolytes; erythrocyte sedimentation rate; C-reactive protein and urinanalysis. 1 More specific blood and radiological investigations are detailed in Figure 3. Some conditions may benefit from a biopsy to aid in the confirmation of a diagnosis (Table 1). All patients should have corneal scrapes performed to exclude an underlying infection. 1

Management
The management of PUK is largely determined by the underlying cause. Infective causes need topical and/or systemic therapy, whilst other causes require individualised management approaches. The majority of PUK is associated with underlying autoimmune disease, and thus, the focus of this review is to provide an overview of the management options for this group of patients. 12,15 The main goals of therapy in these patients were to control the systemic and local inflammatory process, halt keratolysis, prevent infection and promote healing (Figure 4).

Medical Topical
In autoimmune disease, topical therapy has a supportive role and cannot be used as monotherapy. Topical anti-inflammatory

Granulomatosis with polyangiitis
Granulomatous inflammation and necrotising vasculitis in the conjunctiva, and necrotising glomerulonephritis. 21

Temporal arteritis
Granulomatous inflammation of the internal elastic layer of the temporal artery. 115

Inflammatory bowel disease
Inflammation of the mucosa and superficial submucosa in ulcerative colitis and transmural inflammation and epithelioid granulomas in Chron's disease. 115

Ocular cicatricial pemphigoid
Linear deposits of immunoglobulins and complement on the conjunctival basement membrane and positive direct immunofluorescence. 116 Psoriasis Regular epidermal hyperplasia. 115

Pyoderma gangrenosum
Neutrophil infiltrate of the dermis and hypodermis with small vessel necrosis. 117 Erythema elevatum diutinum Vascular infiltrate of upper-to-mid dermis, storiform sclerosis and plasma cells. 118 Sweet syndrome Neutrophil infiltrate of the dermis with the absence of vasculitis. 60 Pityriasis rubra pilaris Follicular plugging, hyperkeratosis, acanthosis, lymphohistiocytic infiltrate of the dermis. 105 Ocular surface squamous neoplasia Thickened disorganised conjunctival epithelium with mitotic figures superficial to the basal epithelium. 119 agents, such as CS, cyclosporin and tacrolimus, have been successfully used as an adjunct. 2,120 Topical steroids should be used with caution as they inhibit collagen synthesis and may increase the risk of perforation. 21 Topical collagenase inhibitors can be used to halt keratolysis and include 1% medroxyprogesterone and 20% N-acetylcysteine. 21 Lubricants and serum derivatives can be used to promote healing of the ocular surface. 2

Systemic
Wound healing may cause a local deficiency of vitamin C, and therefore, oral vitamin C (500 mg BD [twice a day]) has been shown to have a positive effect on wound healing, whilst oral doxycycline (100 mg BD) helps to inhibit collagenolysis by inhibiting MMP. 2 Systemic corticosteroids (oral or intravenous [IV]) have a rapid onset of action and are the initial treatment of choice for patients with an underlying autoimmune disease. 31,88,121,122 Intravenous methyl prednisolone is usually given at 1 g for 3 days and oral prednisone at 1 mg/kg per day to a maximum of 60 mg/day. 1 They do have significant side effects and do not show a disease-modifying effect, and therefore, need to be combined with additional therapies. 1,20 Cytotoxic therapies are steroid sparing agents that have become the mainstay of therapy for PUK associated with autoimmune disease. These agents include CyP, methotrexate, azathioprine, mycophenolate mofetil and cyclosporine A ( Table 2). Cytotoxic therapy takes 4-6 weeks to reach efficacy, and therefore, a cross taper with CS is important to maintain a constant anti-inflammatory effect. 1 Foster et al. 2 was the first to highlight the benefit of CTT in patients with RA and PUK. He highlighted that PUK is an early indicator of the progression of RA from articular disease to systemic vasculitis with significant associated mortality. 2 They reported a mortality rate of 53% in patients not using CTT compared with 6% in those who did over a 10-year follow-up. 2 The patients who received CTT had no adverse events that required hospitalisation. 2 Ogra et al. 123 reviewed mortality rates in patients with PUK and necrotising scleritis, and found that CTT increased time to death from 11 years to 25 years. Similar findings were found in subsequent case series, which has led to the universal adoption of CTT in PUK associated with autoimmune disease. 8,122,124,125 The use of CTT has also increased the effectiveness of other treatment modalities, such as keratoplasty. 122 Biological therapy forms the next step in the immunosuppression ladder for PUK. The biologics can roughly be divided into anti-tumour necrosis factor alpha (TNFα) (adalimumab, infliximab, and etanercept) and non-TNFα (rituximab, tocilizumab, belimumab, and abatacept) groups (Table 3). Patients who fail combination corticosteroid and cytotoxic therapy can be started on one of the biologics. 16,31,33,88,121,125,126,127 Geetha et al. 128 compared rituximab with oral CyP in ANCAassociated vasculitis, and found that it was non-inferior to CyP and possibly better at preventing relapsing disease. 128 A recent study showed greater efficacy of the non-TNFα agents in the management of PUK. 88 Forty-eight percent of patients in the anti-TNFα group needed to change to another biological agent, whereas none of the patients in the non-TNFα group needed to change therapy. 88 This study also found that 18% of patients using biologics developed severe adverse events that required either a change in therapy or a change to another agent. 88 One of the most commonly used biologics is rituximab. There are two main treatment doses for rituximab, 500 mg or 1000 mg. Both are given two weeks apart at the initiation of treatment, which can be repeated at six months. Several studies compared the efficacy of these two regimens and found that clinical response was not statistically different between the two, but that the higher dose was more effective at halting joint damage in patients with RA. 129,130,131,132 When  assessing the response to therapy, it has been shown that patients with a high lymphocyte and plasmablast count do not perform well on rituximab therapy, and that the 6-month dose is not uniformly required. 16 This should be kept in mind when choosing a biological agent.

Disease control
The basic pathogenesis of autoimmune PUK is the deposition of immune complexes in the limbal vascular arcades with activation of the complement system and associated immune response. It has been shown that the conjunctiva adjacent to the area of PUK has collagenase activity, whereas distant conjunctival sites do not. 5 This led to the idea that removing the conjunctiva adjacent to the ulcer would reduce the source of inflammatory enzymes and reduce the corneal melting process. 5,8,133,134 Conjunctival resection was favoured as a treatment modality from the 1970s to 1990s. 5,8,133,134 It was mostly found to be useful in patients without an associated conjunctival vasculitis. 8,135 The use has subsequently been less reported, most likely because of the increased utilisation and effectiveness of systemic therapies, such as CS, cytotoxic and biological agents.

Tectonic
Corneal perforation is a severe complication of PUK, which can be managed by several ways, including corneal glue, multi-layer amniotic membrane or a corneal patch graft (full thickness or lamellar). 11,125,126 Corneal glue is a simple office procedure to seal a small corneal perforation. 20 This is often a temporising procedure before definitive surgery; however, this occasionally may allow for healing without further surgery. Before the regular use of CTT and biological agents, the need for corneal patch grafts was as high as 56% -75% with loss of the globe occurring in 10% -21% of patients. 11,12,122,135 Fortunately, with the increased use of biological agents, the need for patch grafts has reduced to 12% -14% with good tissue survival and improved visual outcomes. 15,126 Patients with GPA seem to have a more severe course of disease, with 50% -60% of patients requiring patch grafts to maintain globe integrity despite the use of CTT and biologics. 26,125 Various techniques have been described to assist the surgeon in fashioning these crescentic grafts. 136,137,138,139

Discussion
Peripheral ulcerative keratitis is a severe inflammatory condition of the peripheral cornea that can be caused by local factors or systemic inflammatory disease. The peripheral cornea has unique characteristics that make the individual liable to the development of PUK. These include fine capillary arcades that allow for deposition of immune complexes and subsequent activation of an inflammatory cascade with corneal melt.
Several conditions have been implicated in the aetiology of PUK. The most commonly reported systemic causes include RA, GPA and dermatoses. In patients with RA, the PUK usually presents in established disease, whereas in GPA it may be the presenting feature in up to 60% of cases. 26 In RA, it heralds the onset of a systemic vasculitis with significantly associated morbidity and mortality. Because of the large number of associated conditions and the possibility of multiple associated conditions in one patient, it is important to conduct a full workup in all patients who present with PUK.
The management of PUK follows an individualised stepwise approach. All patients require supportive measures to encourage healing and halt the process of keratolysis ( Figure 3). Systemic autoimmune conditions require systemic corticosteroids as a fast-acting agent to halt the inflammatory process. As there are many associated side effects with steroid therapy and they do not alter the course of disease for conditions such as RA, they should be combined with additional therapy. Cytotoxic therapy are the initial choice as disease modifying agents. The time to efficacy for CTT ranges from 4 to 6 weeks, and therefore, they should be commenced at the same time as the steroids with a cross taper in the dosing of both agents. Failure to achieve disease control with CTT necessitates the use of a biological agent. In order to ensure safe use of CTT and biological agents, these should be prescribed in conjunction with a rheumatologist.
As PUK is a challenging condition, a thorough workup for an underlying cause and managing the patient with a multidisciplinary team can improve ocular outcomes and reduce mortality rates.