Peripheral Ulcerative Keratitis Associated with Autoimmune Diseases

Abstract

Peripheral ulcerative keratitis (PUK) is a destructive inflammatory disease of the juxtalimbal cornea associated with crescent-shaped corneal stromal thinning, epithelial defect, and inflammatory corneal infiltrate. Inflammation of other adjacent tissues, particularly the sclera, is seen quite frequently. Predilection of the peripheral cornea for PUK is explained by its anatomical and physiological characteristics. Both cell-mediated and humoral immunity, in conjunction with the corneal tissue-destroying action of metalloproteinases (MMPs), are implicated in the pathogenesis of PUK. Nearly half of all cases of noninfectious PUK are associated with connective tissue diseases (rheumatoid arthritis (RA) is the most frequent underlying disease) and vasculitis (mostly granulomatous with polyangiitis (GPA)). It is important to determine the etiology and exclude conditions that could mimic PUK e.g., marginal keratitis or Terrien’s marginal degeneration (TMD). Therapy should comprise the attenuation of ophthalmic inflammation, but the underlying disease should be treated as a priority. For autoimmune diseases, it is crucial to work closely with internist/rheumatologist to determine an effective immunomodulatory therapeutic approach. PUK is also known to be a potentially devastating and vision-threatening condition that may lead to corneal melting and perforation, requiring surgical intervention. This chapter provides a comprehensive update of current knowledge and therapeutic methods.

1. Introduction

Peripheral ulcerative keratitis (PUK) is a destructive inflammatory disease, defined as a clinical triad of a rapidly progressive, crescent-shaped area of peripheral corneal thinning, an epithelial defect, and an inflammatory corneal infiltrate. The inflammation often extends to adjacent tissues: conjunctiva, iris, episclera, and sclera [1]. Over time, progressive ulceration can lead to corneal perforation, which in the case of underlying autoimmune etiology has serious ocular morbidity [2]. Although the pathogenesis of PUK is still not fully understood, it is assumed that peculiar anatomical and physiological features of the peripheral cornea, environmental factors, and cell-mediated and auto-antibody-mediated responses are involved [1, 3, 4, 5, 6]. The postulated mechanisms causing PUK are autoimmune reactions to the corneal antigens, circulating immune complex depositions as well as hypersensitivity reaction to exogenous antigens [3].

PUK, after anterior uveitis, is the second most common ocular complication of autoimmune diseases [7]. However, its incidence varies by only 0.2–3 people per million annually [8, 9]. The prevalence is assumed to be higher in the female gender [9], although some studies indicate equal incidence in both sexes [10]. PUK may be caused by a variety of pathological processes, including both ocular and systemic infectious and noninfectious conditions. It is reported that approximately 50% of PUK cases are associated with collagen diseases and various types of vasculitis [11]. PUK can appear at any stage of an already diagnosed underlying systemic disorder and might suggest its exacerbation; however, it may also be the first symptom of a systemic condition. PUK-associated ocular complications and systemic morbidity and mortality can be decreased with timely diagnosis and prompt treatment [4, 5, 6].

2. Etiology

PUK may occur because of a variety of ocular and systemic disorders, including infectious and noninfectious conditions. Understanding the following causes of PUK is important for physicians, as PUK can be a rare manifestation of a common disease as well as a common manifestation of a rare disorder. Nearly half of all noninfectious PUK cases are associated with connective tissue diseases, most commonly rheumatoid arthritis (RA). RA is associated with 34% of noninfectious PUK cases; in 50%, it occurs bilaterally and appears in the later stages of the disease [11]. When associated with vasculitis, such as granulomatosis with polyangiitis (GPA), PUK is more often observed as the first manifestation of the underlying condition [12]. Studies suggest that infections are the second most common cause of PUK (about 20% of all cases); therefore, it is essential to rule out probable infectious etiology before starting any immunomodulatory therapy [13].

2.1 Local causes

1. Infectious

   • Bacterial (Staphylococcus, Streptococcus, Gonococcus, Moraxella, Hemophilus, and Pseudomonas aeruginosa)

   • Viral (Herpes simplex, Herpes zoster, and Epstein-Barr virus)

   • Parasite (Chlamydia trachomatis)

   • Amebic (Acanthamoeba)

   • Fungal (Aspergillus, Fusarium, and dematiaceous fungi)

2. Autoimmune (Mooren’s ulcer, allograft rejection, and autoimmune hepatitis)

3. Neurological (neuroparalytic, metaherpetic, and xerophthalmia)

4. Eyelid abnormalities (ectropion, entropion, eyelid tumors, trichiasis, and lagophthalmos)

5. Traumatic (corneal penetrating injury, chemical injury, thermal burns, and radiation injuries)

6. Postoperative (post-LASIK, trabeculectomy, and corneal crosslinking).

2.2 Systemic causes

1. Infectious

   • Bacterial (tuberculosis, syphilis, Lyme disease, salmonella gastroenteritis, bacillary dysentery, gonococcal arthritis, and cat scratch disease)

   • Viral (Varicella-zoster virus, viral hepatitis, and acquired immune deficiency syndrome)

   • Parasite

   • Parinaud’s oculoglandular fever

2. Autoimmune (Table 1)

3. Dermatological diseases (acne rosacea, cicatricial pemphigoid, Stevens-Johnson syndrome, pyoderma gangrenosum, and psoriasis)

4. Malignancies (acute and chronic myelogenous leukemia)

5. Other (hemolytic uremic syndrome, gout, and iatrogenic drugs) [3, 4, 5, 6].

	Demographic; features	Systemic findings suggesting the diagnosis	Suggestive diagnostic evaluations
Rheumatoid arthritis (RA)	30–50 years; 3× more common in women	Symmetric pain and swelling in the joints of the hands and feet (rarely large joints), morning stiffness, rheumatoid subcutaneous nodules, myocardial and valvular lesions, rheumatoid nodules in lungs, pulmonary fibrosis, pleuritis, polyneuropathy, carpal tunnel syndrome, vasculitis	RF, anti-CCP; X-ray of joints
Systemic lupus erythematosus (SLE)	16–55 years; 6–10× more common in women	Fever, alopecia without scarring, oral ulcers, butterfly-shaped rash on the face involving the cheeks and bridge of the nose, skin lesions that appear or worsen with the sun exposure, synovitis, pressure pain, morning stiffness	ANA,; anti-dsDNA,; anti-SM
Sjogren’s syndrome	40–60 years; 90% are women	Dry eye and mouth, dryness and itching of the skin, Raynaud's phenomenon	Anti-La,; anti-Ro; Schirmer test,; TBUT, OSDI
Small—sized vessel vasculitis
Granulomatosis with polyangiitis (GPA)	45–65 years; more common in men	Epistaxis, ulcerations, sensation of nasal congestion, damage or perforation of the nasal septum, inflammation of the cartilages of the ear or nose, saddle nose, hearing loss, involvement of bronchi, lungs and kidneys	c-ANCA; X-ray or CT of sinuses, lungs; kidney, lung, skin or muscle biopsy
Microscopic polyangiitis (MPA)	50–60 years; slightly higher incidence in men	Fever, weight loss, palpable purpura, livedo reticularis; involvement of lungs and kidneys	p-ANCA,; MPO-ANCA; X-ray or CT of chest; kidney, lung or skin biopsy
Eosinophilic granulomatosis with polyangiitis	35–50 years; slightly higher incidence in woman	Asthma, nasal polyps, peripheral neuropathy, transient pulmonary infiltration	MPO-ANCA; eosinophilia; renal function tests; X-ray or CT of sinuses; lung biopsy
Medium-sized vessel vasculitis
Polyarteritis nodosa	40–60 years; more common in men	Fever, weight loss, palpable purpura, livedo reticularis, skin ulceration, subcutaneous nodules, neuropathy,; renal involvement, intestinal ischemia, testicular pain	CTA, MRA, arteriography to confirm microaneurysm; sural nerve or skin biopsy
Large-sized vessel vasculitis
Giant cell arteritis	70–80 years; 2× more common in women	Acute headache, bilateral temporal scalp hypersensitivity, soreness and swelling in the course of the temporal artery, jaw claudication	ESR and CRP; Doppler ultrasound, CTA, MR to confirm arteritis; temporal artery biopsy
Takayasu’s disease	under 50 years; 2–10× more common in men	claudication of the exterminities, absent or asymmetric pulse in the upper extremities, vascular murmurs over constricted arteries, various symptoms depending on the location of the arterial stenosis	USG, CTA, MRA indicating stenosis or obstruction of the aorta, its branches or proximal sections of the limb arteries
Other immune disease
Behçet's disease, sarcoidosis, inflammatory bowel disease, progressive systemic sclerosis, relapsing polychondritis

Table 1.

The characteristics of autoimmune causes of PUK [4, 6, 14, 15, 16].

ANA—antinuclear antibody; anti-CCP—anti-cyclic citrullinated peptide; anti-dsDNA—anti-double stranded DNA; anti-SM—anti-Smith; c-ANCA—anti-neutrophil cytoplasmic antibodies; MPO-ANCA—myeloperoxidase anti-neutrophil cytoplasmic antibody; OSDI—ocular surface disease index; p-ANCA—anti-neutrophil cytoplasmic antibodies; RF—rheumatoid factor; TBUT—tear breakup time.

3. Pathogenesis of PUK

3.1 Features of the peripheral cornea

The peripheral cornea has unique anatomical and physiological features, some of which make it more susceptible to hypersensitivity reaction, autoimmune processes, and ulcerations [1]. Different from the central part of the cornea, the peripheral cornea has a greater thickness (up to 0.7 mm), and the epithelium is firmly adherent to the underlying basement membrane [17]. Epithelial stem cells are more concentrated, have the highest proliferation rate whereas endothelial cells have maximum myogenic activity [17, 18]. Moreover, higher levels of the cell surface-associated glycoprotein Mucin-4 (MUC-4) gene, which has epithelial-protective activity and is responsible for regulating the renewal and differentiation of epithelial cells, have been found in the corneal periphery [19]. Furthermore, it has less innervation, and therefore sensitivity is lower in this region [18].

Differently from the avascular central cornea, where the main nutritional sources are the tear film and aqueous humor, the limbus and peripheral cornea obtain nutrients from the vascular arcade that originates from the anterior ciliary arteries extending approximately 0.5 mm into the clear cornea [20]. Perilimbal vascular and lymphatic arcades, along with the adjacent conjunctiva, provide a reservoir of different inflammatory cells and cytokines [1, 3].

As a result of tight collagen bundle packing and vascular architecture at the periphery of the cornea, there is an accumulation of high molecular weight compounds (such as IgM, complement component 1 (C1)) and immune complexes, which are unable to diffuse into the central cornea from the limbal vessels [21, 22]. Besides, compared to the central cornea, there is a higher density of Langerhans’ cells, which are highly potent antigen-presenting dendritic cells [22].

3.2 B-cell and antibodies

Patients with RA demonstrate loss of normal B-cell tolerance for their own antigens; some have serum IgM directed against their own IgG (RF), and the immune complexes aggregate at the corneal periphery causing complement activation and corneal damage [1]. Anti-CCP antibodies, present in some RA patients, are associated with a more severe presentation of PUK [23]. In SLA, impaired immune tolerance triggers the production of ANA that form immunocomplexes by which the clearance of apoptotic cells is impaired and subsequently causes profound tissue damage [24].

In GPA, ANCA also binds to both monocyte and neutrophil receptors, increasing the release of destructive enzymes and proinflammatory cytokines [25] (in the course of various corneal inflammatory diseases, including PUK, upregulated expression of interleukin (IL)-6, IL-1b and tumor necrosis factor (TNF)-α is important) [3]. Among patients with PUK during RA and GPA, antibodies targeting directly the corneal epithelium have been identified [26, 27].

Besides the production of antibodies, B-cells are involved in producing cytokines that affect pathological T-cell response, regulate Th1/Th2 balance, and participate in presenting antigenic peptides via major histocompatibility complex (MHC) class II molecules [28].

3.3 Complement and innate immunity

Circulating antigen-antibody complexes act on C1, the first element of the classical complement activation pathway [29]. The large size of C1 inhibits its diffusion through the cornea, so it persists at the periphery and corneal stroma [21]. During the activation of complement cascade, C3a and C5a polypeptides are formed, demonstrating chemotactic activity, particularly on neutrophils and eosinophils. Ultimately, the complement system causes stromal destruction and lysis of cell membranes [30, 31]. Studies of corneas affected by PUK have shown a large number of various proinflammatory cells of the innate immune system, e.g., neutrophils, mast cells, plasma cells, eosinophils, which are a source of destructive and collagenolytic enzymes that trigger corneal damage [3].

3.4 T-cell immunity

T-cell response is crucial in protection against pathogens but also plays an important role in immunopathological conditions, e.g., the number of CD4 cells is significantly greater among patients with RA [32]. Adaptive T-cell-mediated immunity has been shown to be involved in PUK formation. T-cells can cause tissue damage either directly or through dysregulated autoantibody and proinflammatory cytokine production [3].

3.5 Matrix metalloproteinases

Metalloproteinases (MMPs) are proteolytic enzymes that cause disruption and disintegration of specific extracellular matrix components. MMPs can be divided according to substrate specificity: collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and others. The release of cytokines such as IL-1 from inflammatory cells enables stromal keratocytes to produce MMP-1 and MMP-2. The imbalance between MMPs and their respective tissue inhibitors (TIMPs) results in high collagenase activity, increased tissue destruction, ulceration as well as disruption of the tissue repair process by breaking down the newly formed noncrosslinked collagen [33].

MMP-1 (produced by macrophages and fibroblasts) and MMP-8 (produced by neutrophils and invading inflammatory cells near the limbus) play a pathogenic role in the course of PUK, initiating the hydrolysis of fibrillar type 1 collagen, the main component of corneal stroma. The gelatinases (MMP-2, -9) can cleave basement membrane components (collagen type IV, VII; fibronectin, laminin) and stromal collagen types IV, V, VI, the core protein decorin, and denatured collagens [34].

4. Clinical presentation

The majority of PUK occurs unilaterally and affects one segment of the cornea, while it rarely presents in both eyes, in such cases, the lesions are usually asymmetrical [13]. The eye redness, photophobia, tearing, and pain are the initial symptoms of PUK. Pain is an important feature and can vary in intensity. Deterioration of visual acuity can occur in the active phase of the disease as a result of inflammation or in the chronic phase secondary to corneal astigmatism with corneal opacity [4].

Slit lamp examination demonstrates peripheral, crescentic destructive inflammation at least 2 mm from the limbus, associated with epithelial defect and corneal thinning. The leading edges are undermined, infiltrated, and de-epithelialized. The involvement of the lower part of the cornea is reported to be prevalent compared to the upper part. The spread is circumferential and occasionally central. The ulceration initially involves the superficial one-third of the cornea and may enlarge over time resulting in corneal perforation. It should be noted that the epithelial defect will predispose to secondary infection [4, 13].

Analysis of anterior segment optical coherence tomography (AS-OCT) is useful in the monitoring of disease activity and the evolution of changes. In the active phase, the absence of corneal epithelium, scrambled appearance of the anterior stroma, and heterogeneous stromal reflectivity are observed. As the inflammation intensity declines, irregular hyporeflective epithelium, a smoother anterior stroma, and a homogeneous hyperreflective stroma can be seen. On the other hand, healed PUK lesion is characterized by a filled corneal defect with a hyporeflective thick epithelium, a demarcation line, and the persistence of the hyperreflective underlying stroma [35, 36].

PUK may clinically present as:

1. Acute, subacute, or chronic peripheral keratitis with ulceration, stromal thinning, and infiltration involving juxtalimbal cornea; hypopyon may be present.

2. Inflammation, in addition to the juxtalimbal cornea, may additionally involve the adjacent conjunctiva, iris, episclera, and sclera, as is particularly often seen when the cause of PUK is autoimmune. Concomitant scleritis (e.g., nodular scleritis, necrotizing scleritis) can exacerbate the course of PUK and increase the risk of complications. In addition, the intensity of keratitis correlates with the course of scleritis, which can be explained by the similar underlying pathological process of collagenolysis in both cases.

3. Healing or healed PUK with a recovered epithelial defect and peripheral corneal thinning. The cornea exhibits diffuse corneal neovascularization and scarring, which can significantly impair visual acuity (Figures 1–4).

4. Corneal perforation or impending perforation is uncommon but is the most serious complication of PUK. Occasionally, accompanying iris prolapse in the area of corneal defect may be observed (Figure 5) [5].

Figure 1.

Crescent-shaped peripheral corneal thinning.

Figure 2.

360 degrees of peripheral corneal thinning.

Figure 3.

Sectorial corneal thinning with superficial vascularization.

Figure 4.

Peripheral corneal scarring and vascularization. Posterior synechiae due to PUK-associated iritis.

Figure 5.

Corneal perforation and iris tissue prolapse.

5. Differential diagnoses

The differential diagnosis of PUK should include inflammatory conditions (e.g., marginal keratitis and catarrhal infiltrates, phlyctenulosis, rosacea-associated keratitis, MGD-associated keratitis, peripheral infectious keratitis, vernal keratoconjunctivitis). Furthermore, local damage from improperly fitted contact lenses, exposure keratitis, trichiasis, and lid malposition can implicate peripheral corneal diseases [4, 5, 6].

1. Marginal keratitis represents an immune response to staphylococcal antigens and can appear either in the course of symptomatic blepharoconjunctivitis or asymptomatic eyelid colonization [37]. Moreover, catarrhal infiltrates emerge secondary to blepharitis and meibomianitis caused by other bacteria (e.g., Hemophilus, Moraxella, and Streptococcus) [38]. Following an immune response to toxins produced by bacteria causes circumscribed infiltrates to deposit at the points of contact of the eyelids to the peripheral cornea [39]. A lucid interval of clear cornea between the infiltrates and the limbus is present, unlike in PUK and phlyctenulosis. Marginal keratitis responds quickly to topical treatment, while PUK, despite receiving topical ophthalmic therapy, may worsen due to other untreated underlying diseases [40].

2. Phlyctenulosis is another immune-mediated peripheral corneal lesion observed primarily in the course of longstanding staphylococcal blepharoconjunctivitis. Phlyctenules are subepithelial nodules that initially appear in the limbus and extend toward the cornea later in the disease. Both marginal keratitis and corneal phlyctenulosis have a similar clinical presentation to PUK and can be difficult to differentiate during ulcerative stages. However, unlike PUK, their symptoms are less severe and usually self-limited [41].

3. Compared to marginal keratitis, herpetic infection begins with an epithelial defect, and then subepithelial infiltrates appear. HSV-induced keratitis may be associated with minor pain due to decreased corneal sensation due to infected corneal neurons [42].

When diagnosing PUK, it is also important to consider noninflammatory corneal disorders associated with peripheral corneal thinning or opacification such as peripheral corneal degeneration, e.g., Terrien’s marginal degeneration (TMD), senile furrow degeneration, pellucid marginal degeneration.

1. TMD is distinguished from PUK by the presence of intact epithelium while the juxtalimbal corneal stroma is progressively thinning. TMD usually begins in the upper quadrant of the cornea as fine punctate stromal opacities; superficial neovascularization is present in most cases, and lipid deposits emerge at the ends of vessels over time. A characteristic feature of TMD is a clear gray line of demarcation between the normal cornea and the affected area. The thinned zone can slowly expand circumferentially, causing irregular astigmatism. Patients with this type of degeneration do not report pain [43, 44].

2. Senile furrow degeneration reveals as thinning in the lucid interval between an arcus senilis and limbus, mainly in older individuals. Unlike PUK, the epithelium remains intact, and infiltration and inflammation are absent. Besides, corneal vascularization is absent, which is a distinctive feature of TMD. The furrow is shallow with sloping central and peripheral edges, and the progression of lesions is remarkably slow [4].

MU is a rare, idiopathic form of peripheral corneal ulceration. This can present as unilateral, slowly progressive lesions in older adults and bilateral, rapidly progressing ulcers in younger adults. MU occurs without a specific general underlying disease likely to cause PUK, and it is an exclusion diagnosis. MU is more common in Africa, China, and India; it shows an association with viral exposure (hepatitis C), helminthic infections, HLA-DR17, and DQ2 antigens. The pathological process begins with the involvement of the peripheral cornea, spreads circumferentially, and then centrally with overhanging edges. A distinctive feature of MU, unlike PUK, is the absence of scleritis and the pain being more intense, poorly tolerated, and inadequate in relation to the size of the ulceration [4, 13, 45, 46].

6. Medical management

Prompt treatment of PUK and, in particular, the underlying disease is crucial in order to reduce mortality with ocular and systemic morbidity [11, 40]. The main purposes of PUK treatment are to reduce inflammation, minimize stromal loss, obtain epithelial healing, and prevent infection [4, 40].

6.1 Topical treatment

1. Lubricating eye drops belong to the primary management of PUK. They improve the quality of the tear film, reduce discomfort, and when used regularly, preservative-free drops contribute to the washout of inflammatory mediators involved in the process of keratolysis from the ocular surface. The frequency of instillation depends on the severity of the patient’s symptoms. Supplementary administration of lubricant ointment formulations, especially overnight, may improve comfort and enhance epithelialization [4, 5].

2. Topical steroids extensively implemented in the treatment of PUK, suppress the local autoimmune response. According to the severity of inflammation, steroids of varying potency can be used:

   • low (e.g., fluorometholone 0.1%, loteprednol etabonate 0.2%, and 0.5%)

   • moderate (e.g., prednisolone sodium phosphate 0.5%, betamethasone 0.1%, and dexamethasone 0.1%)

   • high (e.g., predinosolone acetate 1%).

3. Subconjunctival or periocular administration of steroids may be beneficial in cases of PUK accompanied by scleritis; however, the risk of scleral perforation occurs. The administration of drops is typically started with q.i.d.; the dosage is modified according to the patient’s response and is eventually gradually, slowly reduced. However, these should be used with caution, considering the fact that steroids inhibit collagen production and the wound healing process [7, 47, 48, 49]. In RA-related PUK, topical steroids have been shown to increase the chances of corneal perforation by inhibiting fibroblast infiltration [4]. Moreover, their chronic use can lead to a number of side effects such as steroid-induced glaucoma, cataract, or increased susceptibility to ocular infections [5].

4. Topical nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., ketorolac, diclofenac, bromfenac, nepafenac, and flurbiprofen) are used to reduce the inflammation in PUK. However, they have the potential to induce corneal melts or perforation, especially in elderly patients with additional ocular surface disease [50]. Therefore, low-potency steroids applied b.i.d. or t.i.d. in short courses are preferable to NSAID therapy for patients with RA-related PUK and concomitant dry eye syndrome [5].

5. N-acetylcysteine (NAC) 10–20% concentration, applied b.i.d. or t.i.d.. NAC, by chelating MMP-associated calcium or zinc, irreversibly inhibits MMPs. Moreover, NAC reduces the release of proinflammatory cytokines [51].

6. Topical cyclosporine A (CsA) 2% and topical tacrolimus 0.03% are calcineurin inhibitors, they inhibit T-cell function as well as signaling [52]. While CsA shows less efficacy in suppressing the innate immune response in PUK, it is still a useful adjuvant therapy. It enhances ulcer healing, and its topical, unlike general, administration is not associated with nephrotoxicity [53, 54].

7. Progestins (e.g., medroxyprogesterone 1%) have anti-inflammatory activity by binding to glucocorticoid receptors. In addition, by inhibiting neutrophil-related collagenases, they can inhibit corneal stroma degradation and facilitate collagen synthesis [55, 56]. However, there is still a lack of studies demonstrating their efficacy in the treatment of PUK.

6.2 Systemic treatment

Management of PUK associated with autoimmune diseases requires close cooperation between an ophthalmologist and an internist/rheumatologist. Systemic therapy should be directed to both reduce ophthalmological as well as the life-threatening complications of underlying systemic disease [4, 5, 6]. The choice of treatment depends on multiple factors including etiology, clinical presentation, severity of disease, systemic co-morbidities, preferred route of drug administration, side effects of medications as well as the patient’s general condition including the hematological, liver, and kidney profile [5].

6.2.1 Systemic treatment for the management of ocular morbidity

1. Oral doxycycline is administered at a dose of 100 mg b.i.d. Doxycycline irreversibly inhibits the action of MMPs by chelating metal ions that play catalytic and structural roles. What is more, doxycycline prevents the formation of scar tissue by inhibiting the migration of keratocytes and fibroblasts, instead promoting complete wound surface overlay with epithelial basal cells and the formation of stable stratified epithelium [57, 58].

2. Oral ascorbic acid is taken as an additional treatment, 500 mg b.i.d., for peripheral corneal melting. Animal studies have shown its therapeutic effect on corneal epithelial lesions and influence on the formation of minor corneal opacities after the inflammation has healed [59, 60].

3. Oral NSAIDs (e.g., flurbiprofen, indomethacin) are taken to reduce pain and inflammation for severe cases of PUK, especially those associated with scleritis [5].

6.2.2 Systemic treatment for the management of the underlying systemic condition

The current treatment regimen at the active phase includes application of systemic steroids with their rapid therapeutic effect along with immunomodulatory agents, which are often necessary to induce remission of autoimmune disease. This is followed by gradual tapering of steroids and maintaining the immunomodulatory agent to avoid disease recurrence. Foster et al. found that the mean survival rate in patients having PUK and scleritis in the course of RA, GPA, and SLE is 24.7 years if systemic immunomodulatory therapy is administered versus 10.7 years without this treatment [61].

First-line management of RA-associated PUK involves systemic steroids and a cytotoxic agent (e.g., methotrexate (MTX)) [62]. Second-line agents such as azathioprine and cyclophosphamide are used for severe, refractory PUK cases unresponsive to MTX [63]. Immunosuppressive treatment in the acute phase of GPA is usually initiated with systemic corticosteroids along with cyclophosphamide, and if no improvement is observed, treatment may be changed to rituximab [64].

In pediatric patients, MTX is considered a first-line immunosuppressant in the treatment of underlying systemic treatment, but if it is ineffective second-line cyclosporine is considered [65]. In pregnant women, immunomodulatory therapy should be avoided due to its teratogenic effects, and oral steroids should be used with greater caution [5].

1. Systemic steroids

   Due to their availability and quick therapeutic effect, are used as first-line therapy in acute inflammatory diseases. Oral prednisone treatment is usually started with a dose of 1 mg/kg/day (maximum 100 mg/day) and then gradually tapered depending on clinical response [1]. For severe PUK, which threatens vision, intravenous pulses of methylprednisolone (1 g/day for 3 days) are used, followed by a switch to orally administered prednisone and a gradual reduction in dose [48]. Still, the side effects of chronic steroid administration should be kept in mind: glucocorticoid effect, electrolyte disturbances, hypertension, and hyperglycemia. Adjuvant use of H2-blockers to prevent steroid-related gastric ulcers is advisable as well as calcium supplementation to prevent bone density reduction [66].

2. Cytotoxic agents

   • Antimetabolites

     Methotrexate (MTX) administered typically in a dose of 5–25 mg once a week, inhibits dihydrofolate reductase (DHFR) and therefore decreases DNA synthesis. Its action is on rapidly dividing cells including B and T lymphocytes, making it the widely used immunosuppressive drug in the first-line treatment of PUK in RA. It presents less severe drug toxicity than the majority of other immunosuppressants [1, 67, 68].

     Azathioprine is administered by 1–2.5 mg/kg/day; a purine synthesis inhibitor, which inhibits DNA synthesis in proliferating cells. It has been reported that among patients with RA-associated PUK unresponsive to steroid therapy, both MTX and azathioprine show high efficacy. Additionally, azathioprine is considered a much safer but less effective drug than cyclophosphamide [67, 69, 70].

     Mycophenolate mofetil is administered as 1–1.5 g twice daily; an inosine-5′-monophosphate dehydrogenase inhibitor, thereby inhibiting the purine synthesis pathway required for replication of lymphocytes. It comes as an effective treatment when combined with steroids. The drug seems to be more effective and safer in the treatment of PUK, compared to MTX and azathioprine, especially in cases where the side effects of the former drugs are not well tolerated [71, 72].

   • Alkylating agents

     Trigger an irreversible DNA crosslinking, leading to apoptosis in rapidly dividing cells such as T lymphocytes. These drugs are reserved for the treatment of immune disorders unresponsive to steroids and antimetabolites. They have demonstrated efficiency in the treatment of chronic PUK [63].

     Cyclophosphamide is administered at a dose of up to 2 mg/kg/d; it has shown good efficacy in the treatment of GPA-related PUK. Treatment of patients with RA-related PUK, in the combination with systemic steroid treatment along with local treatment, has also shown promising results. Considering its high cytotoxicity, during therapy, morphology should be repeated every 2–3 weeks [64, 67, 73, 74].

     Chlorambucil [75].

   • T-cell inhibitors

     Cyclosporine A (CsA) administered at a dose of 1.25 mg/kg b.i.d., with an increase by 0.5 mg after 8 weeks and subsequently as per response (maximum daily dose 4 mg/kg). It is a calcineurin inhibitor, suppresses transcription of IL-2, affecting T-cell activity and promotes healing of epithelial defects therefore reducing associated pain. It shows success in the management of bilateral progressive PUK that is not responsive to treatment with the standard agents. However, there is limited application of this drug considering its serious side effects including nephrotoxicity, hepatotoxicity, and increased incidence of lymphoma [52, 67, 76, 77].

     Tacrolimus [78].

3. Biological therapy

   • Rituximab

     A monoclonal antibody, interacts with the CD-20 receptor found on the surface of B lymphocytes. This is the most widely used agent for maintaining remission in ANCA-associated vasculitis (e.g., GPA and MPA). It shows to be more potent in maintaining remission compared to azathioprine or cyclophosphamide [79, 80, 81, 82].

   • TNF-α inhibitors

     Etanercept (decoy receptor for TNF-α); infliximab, adalimumab, golimumab (monoclonal anti-TNF-α antibodies) inhibit the activity of TNF-α (a proinflammatory cytokine released by macrophages and other inflammatory cells) along with the production of MMPs. They are used for PUK refractory to treatment with other immunosuppressive therapeutics. Preliminary studies demonstrate similar efficacy of rituximab and TNF-α inhibitors in the management of PUK in the course of various rheumatologic diseases [4, 5, 83]. Infliximab has the potential to cause serious side effects such as myocardial infarction, pulmonary embolism, deep vein thrombosis, infusion related reactions, and reactivation of tuberculosis [84]. Etanercept is less effective than infliximab and can cause secondary scleritis, which limits its applications in autoimmune diseases [85]. Adalimumab shows a more effective, safer profile and better patient compliance among anti-TNF-α agents [86, 87].

   • Tocilizumab

     Anti-IL-6 monoclonal antibody. To date, relatively few studies exist on their efficacy in PUK, but these drugs are likely to have better results than TNF-α inhibitors in PUK that are resistant to standard therapy [29].

7. Surgical management

Treatment of the underlying disease and management of the local inflammation is crucial in cases of PUK associated with an autoimmune etiology. Surgical procedures for PUK should be performed only after adequate immunosuppression, therefore reducing the risk of subsequent corneal graft melts or rejection, recurrence, and exacerbation of the inflammatory changes [4, 5]. However, this is often not possible. In the case of the most severe complication of PUK, corneal perforation, urgent surgical intervention is required despite the current immune status. The surgical method is selected based on the extent of corneal thinning or perforation and the severity of the ocular condition.

Indications for surgical management of PUK:

1. Tectonic—to maintain or restore the integrity of the eyeball when there is significant corneal thinning, descemetocele, impending corneal perforation, or it has already appeared.

2. Therapeutic—as an additional treatment, in case the peripheral ulceration extends, e.g., removal of the adjacent conjunctiva can be performed.

3. Optical—for visual rehabilitation due to severe astigmatism that is not improving with glasses or contact lenses or for the case of contact lens intolerance. Procedures aimed to improve visual acuity should be performed only when PUK is adequately controlled to prevent deterioration of the local disease [4, 88].

7.1 Surgical techniques

1. Conjunctival resection considering the limbal conjunctiva is a reservoir of immune cells, proinflammatory cytokines, and proteolytic enzymes including collagenase, removal of the adjacent conjunctiva in an area involving 2–3 clock hours is among the therapeutic options to limit the inflammation. However, due to the regeneration of the conjunctiva and the reactivation of the immune response, this procedure has limited efficacy [89, 90].

2. Tissue adhesives with subsequent application of a bandage contact lens is a simple and widely used method for treating descemetocele and corneal perforations that are less than 2–3 mm. This corneal stroma enhancement can bridge to subsequent surgical interventions.

   • Cyanoacrylate glue (butyl monomers) has optimal tectonic strength and rapid polymerization making it widely used for the closure of corneal perforations under 3 mm in PUK of autoimmune etiology [91]. Additionally, it acts as a barrier preventing the inflow of inflammatory cells from the conjunctiva [92]. This adhesive remains for at least a month on the corneal surface followed by spontaneous displacement typically due to epithelial healing that occurs beneath [91]. However, since it is not biodegradable, it has the potential to produce foreign body sensation, papillary conjunctivitis (hence the need for a bandage lens application), corneal neovascularization, infection, and tissue necrosis. If the glue enters the anterior chamber, it can cause corneal adhesion to the iris, pupillary block, secondary glaucoma, granulomatous reaction, and cataract [93, 94].

   • Fibrin glue is a biological and biodegradable adhesive manufactured from fibrinogen and thrombin (fibrin glue is associated with a significant cost) [95]. The incidence of complications after its use is quite low and includes mostly the formation of granulomas or cysts [96]. Unlike cyanoacrylate glue, it does not have tectonic strength, which is why it is usually used in conjunction with amniotic membrane graft (AMG) [88].

3. Amniotic membrane graft (AMG) provides mechanical support and reduces the risk of corneal perforation. AM contains protease inhibitors, induces apoptosis of inflammatory cells, inhibits cytokine expression in the damaged corneal surface, and inhibits stromal lysis [97]. In addition, it boosts epithelialization and provides nerve growth factor, which facilitates corneal surface regeneration [98]. AMG has been shown to significantly reduce pain symptoms and stabilize visual acuity in up to 50% of patients [99]. Multilayer AMG is used for corneal perforations of less than 0.5 mm in the treatment of PUK of autoimmune etiology. It is absorbed relatively faster in eyes with inflammation, but, if necessary, it is possible to perform repeated AMG [100]. For perforations <3 mm good results have been shown with a combination of fibrin glue and AMG, as well as a lamellar keratoplasty (LK) in combination with AMG [101].

4. Patch graft

   • Corneal patch graft

     Crescentic or circular corneal patch graft provides a favorable anatomical result in patients with concomitant autoimmune disease. Vascular ingrowth, chronic epithelial defect, rapid suture loosening, and dissolution of the transplanted tissue are all frequent complications [102]. The new alternative is to use as donor tissue the lenticule obtained during small incision refractive lenticule extraction (SMILE) [103].

   • Scleral patch graft

     Scleral tissue from cadaveric eyeballs provides tectonic stability and is often used in conjunction with cyanoacrylate glue. It is an easy, inexpensive, and effective surgical solution for perforations that are 3–5 mm in size [104]. However, like corneal patch graft, it is associated with a high risk of graft vascularization and opacification, postoperative irregular astigmatism and is limited by the availability of donor tissue [88].

   • Tenon’s patch graft (TPG)

     Tenon’s patch graft (TPG) is a simple and affordable method used for perforations of 3–5 mm, benefiting from the autologous nature of the graft [105].

5. Lamellar keratoplasty (LK) like penetrating keratoplasty (PK), LK is relatively expensive, requires a highly trained surgeon, depends on donor tissue availability and is associated with long postoperative care [88]. However, the advantages of LK over PK are the smaller risk of rejection and while avoiding the intraocular procedure (if no perforation is present), reduction of potential development of cataract, glaucoma, and endophthalmitis. Besides, the LK, by increasing the thickness of the host cornea, reduces the risk of future perforation [106].

   • Crescentic lamellar keratoplasty is commonly used in cases of significant thinning of the marginal area of the cornea in the case of PUK. It involves the placement of a ring-shaped lamellar graft on the periphery of the cornea and attachment with sutures to the host cornea. The size of the graft depends on the shape and size of the thinning zone. The visual acuity obtained after this procedure is reported to be significantly better compared to total LK. Several modifications of this technique exist [107].

   • Compressive crescentic (C-shaped) lamellar keratoplasty comprises the use of undersized crescentic donor tissue and tight sutures, causing a flattening perpendicular to the circumference and correcting the steepening and high astigmatism that occurs in the course of the disease [4, 108].

   • Lamellar corneoscleroplasty can restore ocular integrity and maintain the angle structures when scleral melting is present as well [109].

   • Superficial anterior lamellar keratoplasty (SALK): Decentrated large-diameter SALK has the potential to be used successfully in PUK [110].

   • Deep anterior lamellar keratoplasty (DALK) preserves the host endothelium and Descemet’s membrane. Decetrated DALK has shown favorable results in PUK with corneal melt [5].

6. Penetrating keratoplasty (PK) is the method of choice in cases of significant corneal thinning or perforation. However, removal of the inflamed peripheral portion of the cornea associated with large-size PKs (9–9.5 mm) carries twice the risk of rejection compared to standard-size grafts due to the proximity of limbal vessels [107, 111]. There is a greater risk of secondary glaucoma from trabecular meshwork damage due to the placement of sutures and anterior adhesions [112]. The risk of rejection further increases due to the presence of an active inflammatory process. It is reported that PKs performed for perforations in the course of PUK of autoimmune etiology have higher rejection rate compared to PKs performed for other reasons, for instance, due to impaired tissue healing [113]. It has been shown that the 6-month average survival of grafts performed for PUK is 20–40%, which requires subsequent PK [63, 114]. To decrease the rejection rate, it is suggested to use small-size tectonic grafts from 3 to 5.5. mm, however, these are associated with worse visual outcomes [107]. In severe cases of PUK associated with PK failure, keratoprosthesis might be considered [115].

8. Conclusions

PUK is a destructive inflammatory disease of the juxtalimbal cornea. This may occur in the course of an autoimmune disease that has already been diagnosed or may be its first manifestation, with serious systemic consequences. The underlying pathogenesis is not fully understood but appears to involve both cell-mediated as well as auto-antibody-mediated components, resulting in the breakdown of peripheral corneal tissue. PUK is potentially devastating and vision-threatening condition that may lead to corneal melting and perforation. However, surgical procedures performed in the management of PUK associated with collagen vascular disease or vasculitis involve various complications and a high incidence of failure.

When dealing with PUK of autoimmune etiology, the collaboration of an ophthalmologist and an internist/rheumatologist is crucial. It is important to control inflammation of the involved ocular tissues, but especially systemic inflammation, through prompt and optimal management including systemic corticosteroids and tailored immunomodulatory drugs. A great glimpse into the future of PUK management is provided by evolving biological therapies with promising results.

Conflict of interest

The authors declare no conflict of interest.

Acronyms and abbreviations

AMG	amniotic membrane graft
ANA	antinuclear antibody
anti-CCP	anti-cyclic citrullinated peptide
anti-dsDNA	anti-double stranded DNA
anti-SM	anti-Smith
AS-OCT	anterior segment optical coherence tomography
C1	complement component 1
c-ANCA	anti-neutrophil cytoplasmic antibodies
CsA	cyclosporine A
DALK	deep anterior lamellar keratoplasty
DHFR	dihydrofolate reductase
GPA	granulomatous with polyangiitis
HSV	Herpes simplex virus
IL	interleukin
LK	lamellar keratoplasty
MHC	major histocompatibility complex
MMP	metalloproteinase
MPA	microscopic polyangiitis
MPO-ANCA	myeloperoxidase anti-neutrophil cytoplasmic antibody
MTX	methotrexate
MU	Mooren’s ulcer
MUC4	Mucin-4
NAC	N-acetylcysteine
NSAID	nonsteroidal anti-inflammatory drug
OSDI	ocular surface disease index
p-ANCA	anti-neutrophil cytoplasmic antibodies
PK	penetrating keratoplasty
PUK	peripheral ulcerative keratitis
RA	rheumatoid arthritis
RF	rheumatoid factor
SALK	superficial anterior lamellar keratoplasty
SLE	systemic lupus erythematosus
SMILE	small incision refractive lenticule extraction
TBUT	tear breakup time
TIMP	tissue inhibitor of metalloproteinase
TMD	Terrien’s marginal degeneration
TNF	tumor necrosis factor
TPG	Tenon’s patch graft