Clinical Syndromes, Classifications, and Differential Diagnosis

Systemic diseases

1. Rheumatoid arthritis

2. Wegener’s granulomatosis

3. Systemic lupus erythematosus

4. Polyarteritis nodosa

5. Relapsing polychondritis

6. Progressive systemic sclerosis

7. Giant cell arteritis

8. Churg-Strauss syndrome

9. Inflammatory bowel disease

10. Behcet’s disease

11. Sarcoidosis

12. Malignancy

13. Immune deficiency disorders

Fig. 7.1

Peripheral ulcerative keratits in a case of rheumatoid arthritis with sterile corneal melt and iris tissue prolapse

Fig. 7.2

Same case with patch graft done for corneal melt with perforation

A.

Pathogenesis

The pathophysiology of perilimbal corneal involvement in PUK with systemic disease is multifactorial.

1.

Role of immune complexes: The unique anatomical feature of the limbal area makes it an easy target for antigen–antibody reactions [1, 5]. There are vascular arcades which originate from capillaries up to 0.5 mm into the cornea. Moreover, subconjunctival lymphatics are also accessible to the peripheral corneal stroma. Both of these factors bring in antigens which enable immune complexes to get deposited in the perilimbal cornea [6–8]. Immunoglobulin M (IgM) deposition triggers the classical pathway of the complement cascade leading to chemotaxis of neutrophils and macrophages to the stroma with increased phagocytic activity and release of proteolytic enzymes [6, 7]. There is increased release of cytokines from basophils and mast cells. These chemicals cause collagen degradation leading to corneal stromal ulceration.

A 66 KDalton protein autoantigen called cytokeratin 3 has been reported to be overexpressed in rheumatoid arthritis and Wegener granulomatosis. This cytokeratin is present in corneal epithelium and can lead to increased autoantibody formation in the peripheral cornea [9].
2.

Role of matrix metalloproteinases (MMP): The release of cytokines such as tumor necrosis factor alpha (TNF alpha) in the complement cascade causes activation of conjunctival goblet cells, lymphoid tissues, and corneal keratocytes to release MMPs [10]. These enzymes digest extracellular matrix leading to corneal tissue degradation. MMPs are found in higher concentration in active stromal melts compared to healed ulcers [11].

The above-mentioned factors lead to progressive thinning of the peripheral cornea with a perilimbal spread of the area of involvement. Cytokines and MMPs present in tears also contribute to the disease process [11].

B.

Clinical features

Nearly all of the systemic diseases show a similar manifestation of PUK that initially begins as a breakdown of the corneal epithelium in the perilimbal area. The concomitant keratoconjunctivitis sicca in these patients aid in this epithelial breakdown. Without adequate disease control, the underlying corneal stroma undergoes lysis with whitish, sterile infiltrates at the edges of the necrosed tissue. The ulcer may progress in a ringlike juxtalimbal pattern or move toward the central cornea. Inflammation of the adjoining conjunctiva, episclera, and sclera is common. The patient mainly complains of severe pain, redness, and watering of the eyes. Associated scleritis can aggravate the symptoms [2]. In Wegener granulomatosis, a granulomatous inflammation is noted distinctively in the cornea and sclera [12, 13].

1.
PUK in rheumatoid arthritis: The incidence of PUK in rheumatoid arthritis is reported to be 30–40% in different studies [2, 6, 7]. There is bilateral involvement in more than one-third of cases [2, 6]. Although PUK manifests in the later part of the disease process, the mortality rate is as high as 50% at a 10-year period [3]. The onset of PUK may in fact be a marker of worsening of the rheumatoid process [2, 3]. Most cases also show associated inflammation of conjunctiva, episclera, and sclera [14].
Systemic features of rheumatoid arthritis manifests as a chronic, symmetrical, inflammatory polyarthritis of peripheral joints [15]. The incidence is nearly 3% of the general population and middle aged women are affected three times more often than men [16]. Extra-articular involvement in rheumatoid arthritis occurs in approximately 25% of patients [15]. This includes the heart, lung, skin, and the central nervous system [17]. The diagnostic criteria of rheumatoid arthritis are as follows [18]:
a.

JOINT DISTRIBUTION (0–5)

i.

1 large joint—0

ii.

2–10 large joints—1

iii.

1–3 small joints (large joints not counted)—2

iv.

4–10 small joints (large joints not counted)—3

v.

>10 joints (at least one small joint)—5

b.

SEROLOGY (0–3)

i.

Negative rheumatoid factor (RF) and negative anti-citrullinated protein antibody (ACPA)—0

ii.

Low positive RF or low positive ACPA—2

iii.

High positive RF or high positive ACPA—3

c.

SYMPTOM DURATION (0–1)

i.

Less than 6 weeks—0

ii.

Greater or equal to 6 weeks—1

d.

ACUTE PHASE REACTANTS (0–1)

i.

Normal C reactive protein (CRP) and normal erythrocyte sedimentation rate (ESR)—0

ii.

Abnormal CRP or abnormal ESR—1
Histopathology shows early deposition of IgM-RF IgG complexes in synovial vessels with endothelial swelling, perivascular cellular infiltration, thrombosis, and interstitial edema of the joint synovium [19, 20]. Common ocular involvements are keratoconjunctivitis sicca, episcleritis, anterior scleritis, marginal ulcerative keratitis, cataracts, optic nerve swelling, and choroidal or retinal vasculitis secondary to posterior scleritis [21]. Scleral involvement includes nodular and diffuse anterior scleritis, necrotizing scleritis, scleromalacia perforans, and posterior scleritis [22]. Nearly 50–70% of patients with scleral involvement have corneal changes [13, 23].

Severe keratoconjunctivitis sicca or secondary Sjögren syndrome is seen in up to 34% of patients with rheumatoid arthritis. This dryness causes epithelial breakdown of cornea and inadequate epithelial healing, thus contributing to the PUK mechanism. [24, 25] Patients of rheumatoid arthritis undergoing cataract surgery should be strictly monitored preoperatively and postoperatively for corneal melts [14, 26, 27]. Histopathology of conjunctival and scleral tissues in rheumatoid patients show microangiopathy with fibrinoid necrosis, neutrophil invasion of the vessels, and deposits of vascular immune complexes with IgA, IgG, IgM, C3, and C4 [14]. Unless aggressive immunosuppression is done, rheumatoid arthritis with PUK has a high mortality rate [3, 16].
2.
PUK with granulomatosis with polyangitis or Wegeners granulomatosis: Wegeners granulomatosis is a multisystem autoimmune disorder with majority of cases presenting in the fifth to sixth decade [28, 29]. It is broadly divided into two types. Ocular involvement has equal representation in both types of the disease.
a.

Classic or generalized Wegeners granulomatosis: In this form, there is necrotizing granulomatous vasculitis of entire respiratory tract including nasal septal collapse with saddle nose deformity, pulmonary nodules and cavitations [30, 31]. There is focal necrotizing glomerulonephritis which is usually seen late in the disease course [32].

b.

Limited Wegeners granulomatosis: In this form, there may be sparing of kidney involvement with lesser mortality [33, 34]. However, if left untreated, the limited form may progress to generalized form and cause death.

The diagnosis of Wegeners granulomatosis is based on clinical and laboratory investigations. Chest X-ray shows lung infiltrates and cavitations. Urine may show haematuria. Serum antineutrophil cytoplasmic antibody (ANCA) toward proteinase 3 with cytoplasmic immunofluorescence staining has nearly 100% sensitivity in classical form of the disease, while the sensitivity is around 70% in the limited form [34, 35]. The limited form shows greater sensitivity to the perinuclear immunofluorescent staining pattern (pANCA) [36]. Confirmatory diagnosis is established with nasal biopsy which shows necrotizing giant cell granulomas with occlusive small arteries vasculitis [37].

Ocular involvement in Wegeners granulomatosis ranges from 30 to 58% [38, 39]. The commonest involvement is seen in the orbit due to contiguous spread from the nasal tract leading to orbital inflammation, orbital myopathy, nasolacrimal duct obstruction or optic nerve compression due to granulomatous reaction of orbital tissues [40, 41]. The necrotizing scleritis and PUK seen in the disease are due to small vessel vasculitis of the intrascleral part of anterior ciliary arteries and perilimbal arteries [42, 43]. In Wegeners granulomatosis, PUK may be the initial manifestation of the systemic disease [39]. It presents as a granulomatous inflammation in the peripheral cornea and adjoining sclera with progressive ulceration and thinning. Histopathology of scleral and corneal tissue shows occlusive necrotizing vasculitis of anterior ciliary and perilimbal arteris with vascular and extravascular multinucleated giant cell granulomas along with rich infiltration of polymorphous cells such as lymphocytes, eosinophils, and epithelioid histiocytes [42, 43].

Wegeners granulomatosis is reported to coexist with rheumatoid arthritis, primarily in female patients [44–47]. The rheumatoid arthritis involvement precedes Wegeners granulomatosis. All cases reported till date had good outcome with immunosuppressive therapy. However, the predominant feature in rheumatoid arthritis is vascular occlusion whereas it is neovascularization in Wegeners granulomatosis. Corneal involvement in rheumatoid arthritis is confined to the limbus whereas there is continuous scleral involvement also in Wegeners granulomatosis. Corneal melt occurs early in Wegeners granulomatosis as compared to late occurrence in rheumatoid arthritis.

Figure 7.3 shows imbal corneal melt with peripheral ulcerative keratitis in a case of Wegeners granulomatosis.

Fig. 7.3

Limbal corneal melt with peripheral ulcerative keratitis in a case of Wegeners granulomatosis
3.

Systemic lupus erythematosus ( SLE ): This is a multisystem disorder involving the skin, kidneys, lungs, cardiovascular system, joints, blood, and the central nervous system [48]. Ocular involvement is seen in nearly a third of these patients [8]. The disease primarily affects females of child-bearing age [49]. Skin involvement includes the typical “butterfly rash” in the malar area and the nose along with discoid lesions, photosensitivity, and alopecia. Some patients develop Raynaud’s phenomenon of the extremities. There can be associated arthritis, proteinuria, pleural effusion, arthritis, pericarditis, pancytopenia, and convulsions with psychosis [48]. The disease follows a protracted course with frequent exacerbations.

The commonest ocular symptom is dryness, seen in 34–40% of patients. Superficial punctate keratitis can be as high as 88%, thereby suggesting immune mechanism along with dry eye for the corneal involvement [50]. Isolated case reports of unilateral or bilateral PUK with adjoining scleritis and cicatrizing conjunctivitis have been reported. The cases responded well to immunosuppressive therapy [51].

Cataract (20–40%) and glaucoma (4–8%) occur secondary to chronic steroid use [52]. Lupus retinopathy occurs in 20–29% of patients in the later part of the disease [51, 53, 54]. This includes cotton-wool spots, hemorrhage, and vascular occlusion with neovascularization. The underlying pathogenesis involves microvascular occlusion by circulating immune complexes causing retinal nerve fiber layer infarction. A rare but severe form of occlusive ocular vascular disease can occur comprising of diffuse arteriolar occlusion with extensive capillary nonperfusion. This can lead to chronic retinal vein or artery occlusion and optic neuropathy. Incidence of maculopathy due to hydroxychloroquine cumulative toxicity has also been reported [55].

The pathogenesis of SLE involves loss of the regulatory capacity of a subset of T cells over B lymphocytes, allowing constant polyclonal B-cell production with formation of different antibodies such as anti-DNA, antinuclear, antiphospholipid (lupus anticoagulant and anticardiolipin), antithyroid, and antilymphocyte antibodies [56–59]. There is also dysfunction of B-cell apoptosis. Acquired complement deficiency is common in SLE patients, leading to poor neutralization of immune complexes.

SLE diagnosis is based on clinical features, histopathology of skin and other tissues with laboratory investigations. Biopsy shows subepithelial and perivascular cellular infiltration, granulomatous reaction, and immune complex deposition on vessel wall and epithelial basement membrane [60]. Blood anti-DNA and antinuclear antibody levels are strong markers for disease positivity. Antiphospholipid antibodies such as anticardiolipin and lupus anticoagulant can also be used for disease identification [61].

Management of dry eyes is of utmost importance in SLE cases as it usually precedes PUK and can delay healing with subsequent corneal perforation.
4.
Polyarterits nodosa ( PAN ): This a necrotizing vasculitis involving small and medium-sized vessels throughout the body. The reaction is nongranulomatous and has minimal respiratory involvement [62]. PAN has an incidence of 2.4/million [63]. It is seen in middle-aged males more commonly than females [62]. Childhood PAN has also been reported [64]. The diagnosis of PAN needs fulfillment of any 3 of the following 10 criteria [65]
Weight loss ≥4 kg

Livedo reticularis

Testicular pain or tenderness

Myalgias, weakness, or leg tenderness

Mononeuropathy or polyneuropathy

Diastolic blood pressure >90 mmHg

Elevated urea or creatinine

Positivity for hepatitis B virus (HBV) infection

Arteriographic abnormality

Biopsy of small- or medium-sized artery containing polymorphonuclear leukocytes.
Ocular involvement in PAN is about 10–20% [62, 66]. Necrotizing vasculitis of anterior ciliary arteries lead to conjunctival, scleral, and corneal lesions. Posterior segment is affected due to similar vessel infiltration and necrosis. Orbital pseudotumour with myopathy and papillitis are seen [67]. PUK presents in a similar way as Mooren’s ulcer. Biopsy of resected conjunctival tissue shows fibrinoid necrosis and endothelial swelling with immune complex deposits and rich neutrophilic invasion of vessels and extravascular tissues [8]. Biopsies of nodular lesions, sural nerve, or affected muscle show similar picture.

The exact etiology of PAN is unknown, though strong association is seen with Hepatitis B or C infection [8]. Nearly 30–50% of hepatitis B and around 20% of Hepatitis C cases have been associated with occurrence of PAN. Viral antigen and antibody induced immune mechanism by molecular mimicry process is proposed as the probable cause of immune reaction in these hepatitis patients.

The 5-year mortality rate without immunosuppressive therapy in PAN is 12% [68]. Cardiac, central nervous system, and gastrointestinal involvement are poor prognostic markers. Antiviral therapy for Hepatitis B and C need to be concomitantly given as required.
5.
Churg – Strauss syndrome and microscopic polyangitis: These are pauci immune, ANCA positive or negative small vessel vasculitis.
Churg-Strauss syndrome is characterized by multiorgan necrotizing vasculitis along with eosinophilia. Allergic rhinitis and asthma, lung infiltrates, myocarditis, and mononeuritis multiplex are seen. The diagnostic criteria are fulfilled if four of the following six criteria are present in a patient:
Asthma

Eosinophils greater than 10% of a differential white blood cell count

Presence of mononeuropathy or polyneuropathy

Unfixed pulmonary infiltrates

Presence of paranasal sinus abnormalities

Histological evidence of extravascular eosinophils.
Only 30–50% of patients of Churg-Strauss syndrome show positive pANCA values [69]. Pathogenesis of pANCA negative cases is hypothesized to be due to cytotoxic products of eosinophils.

Microscopic polyangitis involves granulomatous inflammation in kidneys, respiratory tract, and other organs. The positive pANCA cases can be as high as 70% in this disease entity [63].

Ocular involvement in Churg-Strauss syndrome may be in the form of conjunctival granuloma, scleritis, PUK, uveitis, ischemic optic neuropathy, multifocal choroidal ischemia, and muscle palsies [70–75]. Ocular involvement in microscopic polyangitis is rarely reported. PUK resembling Mooren’s ulcer is seen in both disease entities [62]. Scleral involvement is however present along with PUK.
6.
Relapsing polychondritis: This is a rare immune disorder involving cartilaginous tissue in the body. It occurs in the middle ages equally in both sexes [8]. The ear and nose are commonly affected. McAdam laid diagnostic criteria for the disease and three out of six of the criteria need to be fulfilled [76]
Bilateral auricular chondritis

Nonerosive seronegative inflammatory polyarthritis

Nasal chondritis

Ocular inflammation

Respiratory tract chondritis

Audiovestibular damage.
The patient usually presents with saddle nose, drooping ears, vertigo, and tinnitus with deafness. Cardiac valve or aortic involvement can lead to mortality. Laryngotracheal collapse has also been reported [8].

Ocular involvement is common in this disease and can be an initial presenting feature in up to 30% of cases [77]. The commonly involved tissues are the episclera and sclera, followed by uveal tract, orbital tissue and muscles, retina, and optic nerve. PUK is seen in only 4–11% of cases, mostly in conjunction with scleritis. Biopsy of conjunctiva shows immune complex deposits on vessel wall in these patients [8].

The pathogenic mechanism is hypothesized to be autoimmune reaction to type II, IX, and XI collagen along with vasculitis of medium and large vessels [8, 77]. The disease may coexist with other immune disorders such as rheumatoid arthritis, Behcet’s disease, Wegeners granulomatosis, and Sjogren’s syndrome.
7.

Behcet’s disease: This disease involves skin lesions, genital and oral aphthous ulcers with anterior or posterior uveitis. PUK is rare, having being reported till date in three cases [78–81]. One of the cases progressed to corneal perforation. Tear film abnormality along with the autoimmune reaction may contribute to the corneal ulceration. The association of this disease with HLA B51 has been established [82]. Increased cytokine production and an antigen driven immune response leads to inflammatory reaction in the blood vessels and T-cell mediated damage to perivascular and other tissues.
8.

Inflammatory bowel disease ( IBD ): Crohn’s disease and ulcerative colitis are two immune mediated disorders of the gastrointestinal tract. The ocular involvement in these disease entities includes iritis, scleritis, PUK, and retinal vascular disease. However, only 0.3–5% of IBD patients develop ocular complications [83].
9.

Malignancies: PUK has been reported in patients with multiple myeloma, sebaceous cell carcinoma, chronic myeloid leukemia, and acute lymphocytic leukemia [84–86]. The malignant cells infiltrate the perilimbal capillaries along with neutrophils and lymphocytes and incite an inflammatory reaction. Similar vascular spread may target the choroid and retina. Local immunosuppression is needed along with therapy for malignancy.
10.

Sarcoidosis: This granulomatous inflammatory disease usually manifests as interstitial keratitis in the cornea. Only two cases of PUK have been reported till date [87, 88]. The commonest ocular involvement is of the uveal tract, retina, and choroid. Panuveitis with choroiditis and optic neuritis is frequently encountered. The extraocular manifestations are commonly seen in the respiratory tract. Almost every organ of the body can be affected by these granulomatous nodules. There is a strong genetic predilection, with helper T-cell overproduction leading to inflammatory cascade [89, 90]. Management of this disease is similar to other autoimmune disorders.
11.

Immune deficiency disorder: PUK has been reported in patients of human immunodeficiency virus (HIV) infection either as an isolated finding or in association with central retinal vein occlusion or herpes zoster ophthalmicus [91–93]. The PUK resolved with localized immunosuppression in all cases. Antiretroviral therapy was initiated in the patients with good response. The patients with concomitant zoster infection were prescribed topical acyclovir along with oral acyclovir therapy.

Although cellular immunity is low in HIV patients, the humoral immunity leading to complement cascade can induce inflammation in these eyes. Moreover, viral particles can directly cause vascular occlusion and ulceration of tissues.

Differential Diagnosis

1.

Mooren’s ulcer: This is an idiopathic peripheral ulcer with no scleral involvement which differentiates it from PUK [94, 95]. The disease may be unilateral or bilateral. Majority of the cases occur after the fourth decade. The patient usually is more symptomatic with severe pain. There is an overhanging edge of the ulcer toward the central cornea. Systemic investigations are negative for specific disease and surgical management with conjunctival resection and trimming of the overhanging edge is the preferred treatment. Cyanocrylate glue with bandage contact lens is used to prevent corneal perforation. Postoperative management with topical steroids and lubricants lead to adequate control. However, recurrences are seen in bilateral disease [95]. There may be need for systemic immunosuppression in such cases.

Figure 7.4 shows Mooren’s ulcer with central corneal edema and peripheral circumscribed thinning.

Fig. 7.4

Mooren’s ulcer with central corneal edema and peripheral circumscribed thinning
2.

Infective PUK: Peripheral herpetic lesions may resemble noninfective PUK. However, presence of an infiltrate with minimal pain and low corneal sensitivity are hallmarks of herpetic diseases. Other organisms will also demonstrate infiltrates in corneal stroma prior to corneal melting. Microbiology workup is mandatory to rule out infective etiology before starting immunosuppressive therapy for PUK.
3.

Terrien’s marginal degeneration: This is a bilateral, noninflammatory degeneration of the peripheral cornea. The disease starts usually from the superior cornea. The overlying epithelium is intact while the juxtalimbal corneal stroma undergoes progressive thinning. There is a clear gray line of demarcation between the normal cornea and the involved area. Patients with this degeneration are mostly asymptomatic except for high oblique astigmatism [96, 97]. Superficial vascularisation of affected area with lipid deposits at ends of vessels is seen in late stage.

Figure 7.5 shows inflammatory Terrien’s marginal degeneration.

Fig. 7.5

Inflammatory Terrien’s marginal degeneration
4.

Catarrhal ulcers: These are commonly seen in patients with blepharitis and meibomianitis. The inciting agent is reported to be Staphylococcus aureus toxin [98]. Immune reaction to the toxin causes circumscribed infiltrates to deposit at the points of contact of the eyelids to the peripheral cornea, i.e., 2, 4, 7, and 11 o’clock [99]. There is a lucid interval of clear cornea between the infiltrate and the limbus with intact epithelium. Without treatment, the epithelium may break down with spread of the infiltrate. Superficial vascuarisation is a common sequela. The management of this condition comprises of lid scrubs with warm compresses, macrolide antibiotics such as oral doxycyline and broad spectrum antibiotics eyedrops. Once infection is controlled, topical steroids are needed to control the immune reaction.
5.

Phlyctenular keratitis: Phlyctens are circumscribed, gelatinous, elevated lesions of the conjunctiva and limbus [100]. Occasionally the peripheral cornea is involved as a whitish infiltrate with a tuft of superficial vessels. Later a wedge-shaped marginal ulcer may form. Patients have ocular pain with watering. The etiology is believed to be immune reaction to different antigens such as tuberculoprotein, Staphylococcal antigens, helminthiasis, and herpes simplex virus particles. Corneal perforation is rare and most patients respond to antibiotic and steroid topical therapy.
6.

Ocular rosacea: This condition is seen in patients who have acne rosacea characterized by pustule formation on face and neck due to blockage of sebaceous glands [101]. The glands undergo hyperplasia, leading to secondary infection, rhinophyma of nose, skin erythema, and telangiectasia. The condition spreads from lower eyelids to the ocular surface causing blepharoconjunctivitis, PUK, and pannus formation. Nearly half of acne rosacea cases show such ocular involvement. The condition is easily differentiated from other forms of PUK due to the significant skin and eyelid changes. Such cases respond well to oral antibiotics such as tetracycline or doxycycline.

Management

Treatment of PUK associated with systemic diseases becomes a multidisciplinary approach. The mainstay of treatment is control of systemic inflammation after consultation with a physician or rheumatologist. Local management of the ulcer should happen concurrently. This can be done medically or surgically.

Investigations for systemic disease: There is a wide array of laboratory and radiological investigations associated with diagnosis of autoimmune diseases. However, the clinician has to correlate the disease history, symptoms, and signs to arrive at a differential diagnosis and advise investigations accordingly. The commonly done tests are complete haemogram (total leucocyte count, differential leucocyte count, hemoglobin, erythrocyte sedimentation rate), C reactive protein, antinuclear antibody titre, and chest X-ray. Disease specific tests are given in Table 7.2.

Table 7.2

Laboratory and radiological investigations done in autoimmune diseases