The differential diagnosis of inflammatory PUK includes ocular conditions that cause peripheral corneal thinning or scarring (Table 9.1) Peripheral corneal ulceration can result from a variety of etiologies including infectious causes, local trauma (chemical and thermal injury), neurotrophic changes (diabetic or post-herpetic), eyelid abnormalities (entropion, ectropion, lagophthalmos, trichiasis), and rosacea-associated keratitis.

Non-inflammatory causes of peripheral corneal thinning include Terrien’s marginal degeneration, furrow degeneration, pellucid marginal degeneration. Systemic malnutrition and malignancy (leukemia) have also been reported to cause peripheral corneal thinning [4, 5].

Inflammatory causes of corneal ulceration include systemic conditions such as dermatologic disorders (Stevens-Johnson Syndrome, ocular cicatricial pemphigoid), and autoimmune connective tissue diseases such as rheumatoid arthritis, polyarteritis nodosa, dermatomyositis, and inflammatory bowel disease. Mooren’s ulcer is a diagnosis of exclusion. It is a type of inflammatory PUK characterized by a local autoimmune reaction without systemic involvement. Local inflammatory conditions such as staphylococcal marginal keratitis (“catarrhal” infiltrates), Fuchs superficial marginal keratitis, and post-surgical inflammation can also cause peripheral corneal ulceration.

Fully half of all cases of noninfectious peripheral ulcerative keratitis are due to an associated connective tissue disease [2]. Corneal involvement in these systemic conditions often portends severe disease in the setting of a systemic vasculitis, which can lead to significant morbidity and mortality. The pathophysiologic process is theorized to involve immune complex deposition in the peripheral cornea from inflammation of limbal and conjunctival vessels, leading to the release of collagenases and proteases by inflammatory cells and subsequent keratolysis. Rheumatoid arthritis, Wegener granulomatosis, polyarteritis nodosa, systemic lupus erythematosus, and relapsing polychondritis have all been identified as causes of PUK.

Rheumatoid Arthritis (RA) is the most common connective tissue disease associated with PUK. Rheumatoid arthritis is diagnosed by the presence of arthritis in three or more joints, morning stiffness, positive IgG rheumatoid factor, and serum autoantibodies to IgG. IgM rheumatoid factor is also correlated with disease activity, but is not specific to RA. Anticyclic citrullinated peptide (anti-CCP) antibody has high specificity but low sensitivity for RA, and its presence identifies patients who are more likely to have severe aggressive disease.

In one study, RA accounted for 34% of noninfectious PUK [2]. PUK tends to occur in rheumatoid patients with chronic disease of longstanding duration, often over 20 years, and in patients with high RF and anti-CCP antibody titers. PUK in the setting of RA occurs bilaterally in nearly 50% of cases. Keratoconjunctivitis sicca and erosive arthritis are also predisposing factors for the development of rheumatoid PUK, may herald the presence of systemic vasculitis and potentially life-threatening disease. Other ocular manifestations of RA include episcleritis, diffuse anterior scleritis, necrotizing scleritis, and scleromalacia perforans. Severe keratoconjunctivitis sicca may lead to the formation of corneal epithelial defects, non-inflammatory corneal melts, and perforation, but dry eye alone does not cause PUK.

Corneal involvement in RA may manifest as peripheral corneal thinning or marginal furrows. The corneal epithelium may remain intact with peripheral guttering. There may be corneal neovascularization and an associated scleritis. PUK is a more severe form of RA-associated corneal pathology. Infiltration by inflammatory cells and neovascularization of the cornea results in inflammatory ulceration of the perilimbal cornea, with epithelial breakdown and progressive thinning to the point of corneal perforation. Keratoconjunctivitis sicca contributes to the rapid progression of keratolysis, as severe aqueous tear deficiency causes ocular surface instability and leads to epithelial defects. In later stages of PUK, the cornea exhibits diffuse neovascularization and scarring. Sterile ulceration and corneal melt in RA patients has also been reported in the postoperative setting after routine cataract surgery. The pathophysiology of RA-associated PUK has not been clearly elucidated. It has been theorized to result from an imbalance between matrix metalloproteinases and their inhibitors, or an immune complex-mediated limbal vasculitis that results in localized stromal keratolysis [4, 6]. Activation of local collagenases is believed to contribute to the corneal melt [6].

PUK-associated RA should be considered a life-threatening disease and its management therefore necessitates aggressive systemic immunosuppression in addition to treatment of local ocular pathology [7]. The use of topical corticosteroid therapy is controversial. In cases of infiltrative keratitis, topical steroids may be used cautiously with frequent follow-up. However, topical steroid use can cause corneal perforation in some cases of peripheral ulceration and can impair corneal wound healing.

Collagenase inhibitors such as 1% topical medroxyprogesterone and oral doxycycline (100 mg PO bid) may slow the keratolytic process in rheumatoid PUK. Bandage contact lenses, punctal occlusion, topical cyclosporine, and autologous serum tears are also helpful in the management of associated keratoconjunctivitis sicca in PUK cases. In cases of impending or frank perforation, tissue adhesive (cyanoacrylate glue) may stabilize and preserve ocular integrity.

Corneal grafting (lamellar tectonic patch grafts or full-thickness corneal transplants) may be necessary to restore ocular integrity in cases of severe ulceration. However, the prognosis of corneal grafting for PUK in RA tends to be poor, especially in cases of active local inflammation or corneal neovascularization. Control of the underlying inflammatory process is crucial prior to tectonic or full-thickness corneal transplantation.

The management of RA-associated vasculitis involves systemic corticosteroids as first-line therapy, unless contraindicated by the rheumatologist. Both oral and intravenous pulsed corticosteroids have rapid onset and demonstrate potent anti-inflammatory effects. Other immunomodulatory drugs such as azathioprine, methotrexate, and cyclosporine (which will be discussed later in this chapter) may be necessary both as steroid-sparing agents and as adjunctive immunosuppressive therapy. More recently, biologic agents such as infliximab, rituximab, and to a lesser extent, etanercept, have demonstrated efficacy even as either adjuvant or even monotherapy, both for control of the systemic connective tissue disease, and its associated PUK [8, 9].

Wegener’s granulomatosis (WG), also termed Granulomatosis with Polyangiitis, is a necrotizing granulomatous vasculitis of small arteries and veins that involves the respiratory tract and renal system. WG typically presents in the fourth to fifth decades, with a male to female predominance of 3:2. Symptoms include sinus infections, nosebleeds, hemoptysis, fever, fatigue with general malaise, and weight loss. Pulmonary involvement manifests as infiltrative lesions, nodules, or cavitations in the lungs, while upper respiratory tract involvement can lead to sinus fistulae and nasal septal perforation. Focal necrotizing glomerulonephritis can cause impaired renal function and hematuria, and heralds poor systemic prognosis with high mortality rate.

Laboratory testing is helpful in the diagnosis of WG. Antineutrophil cytoplasmic antibody toward proteinase PR3 with the cytoplasmic immunofluorescence pattern (c-ANCA) has specificity of over 90% for WG. Rheumatoid factor is positive in over 50% of WG patients. Histopathologic studies reveal a systemic granulomatous occlusive vasculitic process of the affected organs with tissue necrosis and giant cell reaction. The pathophysiology of WG is believed to represent immune complex-mediated vasculitis.

PUK is a common ocular manifestation in WG and occurs secondary to a necrotizing vasculitic involvement of the anterior ciliary arteries or perilimbal arteries. Unlike in RA, where PUK tends to occur with chronic, late-stage disease, PUK may be the presenting manifestation of WG. It often presents bilaterally and is always associated with scleritis, which may lead to severe scleral necrosis. PUK in WG may also be triggered by local trauma in the postoperative period, similar to RA. Other ocular manifestations of WG result from granulomatous paranasal sinus disease, which can cause severe orbital inflammation, nasolacrimal duct obstruction, ocular muscle involvement, and optic neuropathy.

Local treatment of WG-associated PUK is similar to that for rheumatoid PUK. Conjunctival resection, preservation of globe integrity with tissue adhesive, and anti-collagenolytic agents may be beneficial to prevent corneal perforation, but systemic immunosuppression is required for definitive cure, especially given the high mortality rate of systemic disease.

Although systemic corticosteroids are a mainstay of WG therapy, they do not affect long-term prognosis when used alone. However, the combination of corticosteroids with the alkylating agent cyclophosphamide usually given intravenously, have proven quite effective to achieve remission in advanced WG disease. Biologic agents such as rituximab, a chimeric monoclonal antibody against CD20, have some efficacy in treating WG-associated PUK. There are case reports of WG-associated ocular disease, with PUK recalcitrant to corticosteroids and cyclophosphamide or methotrexate, that have responded to rituximab therapy [10, 11].

Polyarteritis nodosa (PAN) is a necrotizing nongranulomatous vasculitis of small to medium-sized vessels. PAN can be divided into three main categories: classic PAN, allergic granulomatosis/Churg-Strauss angiitis, or and overlap syndrome of systemic necrotizing vasculitis. Classic PAN occurs more in middle-aged males and most commonly presents in 20- to 40-year-olds. [1] The diagnosis is made by clinical signs and histopathologic findings on biopsy of affected tissues. PAN can be associated with hepatitis B or C antigenemia, suggesting a molecular mimicry process involving the hepatitis viruses, with immune complex-mediated vasculitis.

PAN presents with a variety of clinical symptoms, including fever, malaise, muscle loss, arthralgia, and myalgia. It is typically a progressive disease involving multiple organ systems. Polyarteritis of the renal system can manifest as proteinuria, hematuria, and renal failure, a major cause of death in PAN. Skin involvement in the form of tender subcutaneous nodules is known as livedo reticularis. Cardiovascular complications such as myocardial infarction and congestive heart failure due to coronary arteritis are a major cause of morbidity in PAN. Gastrointestinal involvement is also common. Bowel infarction secondary to superior mesenteric arteritis and hepatic infarction from vasculitis can occur in PAN.

The diagnosis of PAN is based on the presence of the above clinical disease combined with histopathologic findings of nongranulomatous vasculitis of small and medium-size arteries. Laboratory tests are generally not useful. Biopsy of skin lesions and affected muscles may demonstrate immunoglobulin and complement deposits.

Ocular manifestations of PAN are secondary to diffuse vasculitis and include painful diffuse or nodular scleritis, retinal vasculitis, choroiditis, optic atrophy from involvement of posterior ciliary vessels, exudative retinal detachment, and central retinal artery occlusion. Hypertensive retinopathy may occur secondary to renal involvement.

PUK is the most common corneal manifestation of PAN and may be its presenting manifestation [1]. Clinically, PAN-associated PUK may exhibit similar features to Mooren’s ulcer. However, associated adjacent scleritis distinguishes this from classic Mooren’s ulcer, which typically does not demonstrate scleral involvement. Management strategies for PAN-associated PUK include conjunctival resection, tissue adhesive, and the use of topical collagenase inhibitors 1% medroxyprogesterone acetate and oral doxycycline. Topical corticosteroids may be deleterious as they can inhibit new collagen synthesis, delay wound healing, and lead to corneal melt. As with other types of inflammatory PUK, definitive treatment requires control of systemic disease. Untreated PAN has a high mortality rate, with a reported 5-year-survival rate of 13%. Treatment of systemic disease includes systemic immunosuppression with corticosteroids and alkylating agents, and can increase the 5-year-survival rate to 80% [12].

Microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CSS) are ANCA-positive vasculitides distinct from PAN. MPA is a rare vasculitis of small vessels and can cause glomerulonephritis and respiratory tract lesions. Unlike WG, the inflammation in MPA and CSS is nongranulomatous. 50% of MPA patients are ANCA- positive, and 70% of these patients have antineutrophil cytoplasmic antibodies against myeloperoxidase (p-ANCA) [1]. CSS presents as a systemic necrotizing vasculitis accompanied by asthma and eosinophilia. Both MPA and CSS may be associated with PUK. For milder disease, methotrexate may be effective, while severe systemic vasculitis requires systemic corticosteroids and alkylating agents.

Systemic lupus erythematosus (SLE) is a chronic relapsing autoimmune disease with the production of antinuclear antibodies (ANA). 90% of patients are women, and the disease typically presents in the fourth or fifth decade of life. The pathophysiology of SLE is hypothesized to be related to dysfunction of suppressor T-lymphocytes, resulting in the production of autoantibodies and immune complex formation and deposition in various tissues. Activation of the complement pathway in these organs leads to local tissue destruction.

SLE involves inflammation in multiple organ systems. It is diagnosed by the presence of clinical and laboratory criteria, along with dermatologic findings (discoid lupus, facial rash, alopecia, photosensitivity, Raynaud phenomenon), renal involvement (proteinuria, urinary sediment cellular casts), hematologic abnormalities (anemia, leukopenia, thrombocytopenia), pleuritis, and pericarditis. Corneal involvement in the form of keratoconjunctivitis sicca is the most common ocular manifestation of SLE, whereas PUK is rare. Treatment of SLE-associated PUK should include therapy for sicca with topical anti-inflammatory medications, bandage contact lenses, punctal occlusion, and ocular surface lubrication with artificial tears or autologous serum tears. Close follow-up of the ocular surface is required, especially in cases wherein bandage contact lenses have been used. Corneal ulceration, while uncommon, signals active systemic vasculitis and necessitates therapy with oral corticosteroids or immunomodulators such as cyclophosphamide, azathioprine, methotrexate, cyclosporine, and mycophenolate mofetil [13, 14].

Relapsing polychondritis (RP) is a connective tissue disease characterized by inflammation of cartilaginous tissues especially in the ears and nose. There is no gender predilection and onset is typically in the fourth through sixth decade of life. RP is an autoimmune disease associated with anti-type II collagen antibodies, and typically responds to high-dose systemic corticosteroids and anti-inflammatory medications. Clinical features include red, swollen, and painful ears, destruction of nasal cartilage, and nasal deformities. Relapsing polychondritis may lead to cardiovascular and respiratory morbidity with involvement of the aortic ring and trachea. Ocular findings include episcleritis, conjunctivitis, iridocyclitis, scleritis, and keratitis. The prevalence of PUK in RP is less than 10% [15].

PUK associated with RP has been reported to respond to high-dose systemic corticosteroids, as well as immunomodulators such as azathioprine, cyclosporine, cyclophosphamide, and chlorambucil [15]. Variable response to methotrexate has been reported in the literature. Refractory RP has also been successfully treated with biologics such as infliximab [16].