Introduction

Antineutrophil cytoplasmic antibodies (ANCA) are serum autoantibodies directed against neutrophils. ANCA show two principal patterns of staining in immunofl uorescence testing: a diffuse cytoplasmic pattern and a perinuclear pattern, designated cANCA and pANCA, respectively. In addition to these two patterns, an ambiguous staining

pattern is called atypical. The development of an enzyme immunoassay has revealed that cANCA is directed mainly against proteinase 3 (PR3), while pANCA is directed mainly against myeloperoxidase (MPO), leading to new terminol-ogy for cANCA and pANCA: PR3-ANCA and MPO-ANCA, respectively.1–3

ANCA was initially found in patients with certain types of glomerulonephritis: rapidly progressive glomerulone-phritis in the clinical presentation, and crescentic glomeru-lonephritis or segmental necrotizing glomerulonephritis in histopathological diagnoses obtained by renal biopsy.4–7 Later, the serum positivity of ANCA was found to be asso-ciated with several types of diseases that affect small blood vessels, including capillaries, venules, and arterioles, and sometimes involve middle-sized arteries.8,9 These diseases

Jpn J Ophthalmol 2007;51:131–138 DOI 10.1007/s10384-006-0408-z© Japanese Ophthalmological Society 2007

CLINICAL INVESTIGATION

Eye Manifestations in Patients with Perinuclear Antineutrophil Cytoplasmic Antibody-Associated

Vasculitis: Case Series and Literature Review

Toshihiko Matsuo

Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan

Abstract

Purpose: To report and summarize eye manifestations of patients with perinuclear pattern antineutrophil cytoplasmic antibody [pANCA, myeloperoxidase (MPO)-ANCA]-associated vasculitis.

Methods: The medical records of four consecutive patients with pANCA (MPO-ANCA) vasculitis who showed eye manifestations were retrospectively reviewed. In addition, the medical literature databases, PubMed and Japana Centra Revuo Medicina for Japanese literature, were searched for pANCA vascu-litis patients with eye manifestations.

Results: Three of the four patients treated at the Okayama University Hospital showed unilateral or bilateral scleritis. In the literature review, eight of the 27 patients showed ocular surface manifestations such as scleritis and peripheral keratitis. Other frequent eye presentations were posterior segment manifestations such as central or branch retinal vein occlusion, optic neuropathy, and acute posterior multifocal placoid pigment epitheliopathy (APMPPE). Systemically, the most frequent manifestations were glomerulonephritis in the present patients as well as in the patients reported in the past studies.

Conclusions: Ocular surface manifestations and posterior segment manifestations were major eye pre-sentations in patients with pANCA-associated vasculitis. ANCA testing including both pANCA and cytoplasmic pattern antineutrophil cytoplasmic antibody would help establish a systemic diagnosis in patients with eye manifestations such as scleritis, retinal vein occlusion, optic neuropathy, or APMPPE. Jpn J Ophthalmol 2007;51:131–138 © Japanese Ophthalmological Society 2007

Key Words: acute posterior multifocal placoid pigment epitheliopathy (APMPPE), myeloperoxidase (MPO)-ANCA, optic neuropathy, perinuclear antineutrophil cytoplasmic antibody (pANCA), retinal vein occlusion

Received: February 2, 2006 / Accepted: October 27, 2006Correspondence and reprint requests: Toshihiko Matsuo, Depart-

ment of Ophthalmology, Faculty of Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japane-mail: matsuot@cc.okayama-u.ac.jp

132 Jpn J Ophthalmol Vol 51: 131–138, 2007

are collectively called “ANCA-associated vasculitis,”8,9 and the major categories defi ned at the Chapel Hill Nomen-clature Conference are microscopic polyangiitis, Wegener granulomatosis, Churg-Strauss syndrome, and pauci-immune necrotizing glomerulonephritis.10

In general, cANCA (PR3-ANCA) is associated with Wegener granulomatosis, while pANCA (MPO-ANCA) is associated with microscopic polyangiitis and Churg-Strauss syndrome. Such associations are not necessarily exclusive and occur interchangeably. The role of cANCA (PR3-ANCA) testing is well recognized to aid in the diagnosis of Wegener granulomatosis in a general setting as well as in an ophthalmological presentation.11–14 In contrast, pANCA (MPO-ANCA) testing is useful for the differential diagno-sis of glomerulonephritis and systemic vasculitis; however, its role in the ophthalmological setting remains to be estab-lished. In this study, ophthalmological and systemic features of four consecutive patients with positive pANCA (MPO-ANCA) are reported, and pANCA-positive patients’ char-acteristics described in past studies are summarized.

Methods

The medical records of four consecutive patients with a diagnosis of pANCA (MPO-ANCA)-positive vasculitis who showed both systemic manifestations and eye manifes-tations and were treated at the Okayama University Hos-pital during a 5-year period from 2000 to 2004 were retrospectively reviewed. In addition, medical literature databases, PubMed (http://www.ncbi.nlm.nih.gov/PubMed/) from 1966 to 2004, and Igaku Chuo Zasshi (Japana Centra Revuo Medicina) for Japanese literature (http://www.jamas.

or.jp) from 1983 to 2004, were searched for pANCA-positive patients with eye manifestations by employing the key words “ANCA,” “scleritis,” “eye,” “ocular,” “ophthal-mic,” and “microscopic polyangiitis.” Case reports with suf-fi cient information were selected.

Case Reports of Four Patients at Okayama University Hospital

Case 1

A 52-year-old man had a 1-year history of scleritis on the temporal side of his left eye. He had been given topical 0.1% betamethasone without effect. His best-corrected visual acuity was 1.5 in the right eye and 0.9 in the left eye. The intraocular pressure was 15 mmHg in the right eye and 10 mmHg in the left eye. The right eye was normal. The left eye had scleritis involving the whole circumference with high activity in the lower half, together with marginal corneal infi ltrates, 1+ aqueous cells, and posterior iris syn-echiae at the 12 and 6 o’clock meridians (Fig. 1). The fundus was normal. Blood examinations disclosed serum C-reac-tive protein elevated to 2.4 mg/dl, and positive pANCA but negative cANCA. Detailed examination by an internist did not reveal any systemic involvement. The patient was started on oral prednisolone tapering from 30 mg daily. One year later, he experienced a recurrence of scleritis in asso-ciation with peripheral keratitis in the left eye, and concur-rently developed high-grade fever, hoarseness, dysarthria, and dysphagia. Serum C-reactive protein was markedly elevated at 16.7 mg/dl. He was diagnosed with neuropathy caused by ANCA-associated vasculitis, and underwent one

Figure 1. The left eye of the case 1 patient, a 52-year-old man, at the initial visit. Note scleritis involving the whole circumfer-ence, together with marginal corneal infi ltrates, iritis, and pos-terior iris synechiae.

T. MATSUO 133EYE MANIFESTATIONS IN pANCA VASCULITIS

course of pulse corticosteroid therapy consisting of three days of 1000 mg daily methylprednisolone, followed by tapering of prednisolone from 90 mg daily in combination with 50 or 100 mg daily of cyclophosphamide and 10–15 mg weekly of methotrexate. The scleritis subsided dramatically, and the neurological symptoms gradually disappeared.

Case 2

A 59-year-old woman developed scleritis on the nasal side of her right eye. Her best-corrected visual acuity was 1.2 in both eyes, and the intraocular pressure was 20 mmHg in both eyes. The anterior segments and the fundi in both eyes were otherwise normal. She was given 0.1% betamethasone four times daily.

Five years previously, the patient had developed a cough, low-grade fever, and general fatigue, and examinations revealed anemia, marked elevation of serum C-reactive protein of over 10 mg/dl, and microscopic hematuria. In tests, she had shown a high titer of pANCA (219 EU) but negative cANCA. After renal biopsy, she had been diag-nosed as having microscopic polyangiitis. Prednisolone 40 mg daily was prescribed, which was tapered and discon-tinued within 1 year.

At the time of scleritis development, tests also showed microscopic hematuria. Chest computed tomography dem-onstrated no interstitial pneumonitis. With the diagnosis of the relapse of ANCA-associated vasculitis, she underwent intravenous administration of cyclophosphamide, 500 or 750 mg per day four times during 4 months, combined with tapering of prednisolone from 40 mg daily. Scleritis and glomerulonephritis subsided during the course of the treatment.

Case 3

A 42-year-old man developed scleritis involving the whole circumference in both eyes. The intraocular pressure was elevated to 30 mmHg in both eyes. His best-corrected visual acuity was 1.0 in both eyes. He showed no infl ammation in the aqueous and no abnormalities in the fundus of either eye. He was given 0.1% betamethasone six times daily, 0.5% timolol twice daily, and 1% dorzolamide three times daily. After 2 months, the intraocular pressure returned to normal, but scleritis in both eyes persisted. He was then referred to an internist because of a high titer of pANCA (>640 EU). The white blood cell count was 9200/µl, and serum C-reactive protein was 3.1 mg/dl. Tests showed nega-tive cANCA. Urinalysis results were normal. Chest com-puted tomography revealed interstitial pneumonitis. The patient’s height was 178 cm, and his weight was 116 kg.

He underwent one course of pulse corticosteroid therapy consisting of 3 days of 1000 mg daily methylprednisolone followed by tapering of prednisolone from 70 mg daily. One month later, when he was on prednisolone 60 mg daily, he experienced a relapse of interstitial pneumonitis and scleritis in both eyes. C-reactive protein was elevated to

22.9 mg/dl. He underwent another course of pulse cortico-steroid therapy followed by tapering of prednisolone from 70 mg daily. This time, cyclophosphamide, 100–200 mg daily, was combined with prednisolone. Interstitial pneumonitis and scleritis subsided, but pANCA remained at a high titer (>640 EU).

Case 4

A 72-year-old woman had developed myalgia and arthral-gia, together with dry mouth and dry eye, half a year earlier. She showed proteinuria and hematuria. Renal biopsy revealed crescentic glomerulonephritis. She had a positive pANCA titer (285 EU) but a negative cANCA titer. Anti-nuclear antibody and Sjögren syndrome-A (SS-A) antibody were also positive, while Sjögren syndrome-B (SS-B) anti-body was negative. Her best-corrected visual acuity was 0.7 in the right eye and 0.9 in the left eye. Schirmer test without anesthetic was 1 mm in 5 min in both eyes, and tear fi lm breakup time was 0 s in both eyes. The corneal and conjunc-tival surfaces of both eyes showed diffuse and massive fl uo-rescein staining. The fundi in both eyes were normal. With the diagnosis of pANCA-associated rapidly progressive glo-merulonephritis and Sjögren syndrome, she underwent one course of pulse corticosteroid therapy consisting of 3 days of 500 mg daily methylprednisolone, which was followed by tapering of prednisolone from 30 mg daily in combination with cyclophosphamide 25 mg/day. Ophthalmologically, the ocular surface improved with the application of eye drops.

Results

The present four patients, two women and two men, ranged in age from 42 to 72 (mean, 56) years (Table 1). The oph-thalmological presentations were scleritis in three patients and Sjögren syndrome in one patient. Scleritis occurred bilaterally in one patient and unilaterally in two patients. In one patient (case 1), scleritis was associated with peripheral keratitis. Systemically, renal involvement was noted in two patients, neuropathy in one, and lung involvement in one. All patients were treated with oral or intravenous pred-nisolone combined with oral or intravenous cyclopho-sphamide. In addition, three patients underwent pulse corticosteroid therapy with methylprednisolone. Metho-trexate once a week was used concurrently in one patient. The scleritis in three patients subsided dramatically with systemic therapy.

Literature Review

In the literature review, 27 patients reported in the past studies met the selection criteria for this study: positivity of pANCA (MPO-ANCA) and the presence of eye and systemic manifestations (Table 2).15–34 The 27 patients, 17 women and 10 men, ranged in age from 11 to 79 (mean, 55) years. Only one of the 27 patients showed positive cANCA

134 Jpn J Ophthalmol Vol 51: 131–138, 2007

Table 1. Summary of four patients with pANCA and eye manifestations in this study

Case No./Sex/Age(years) Eye manifestations Diagnosis and systemic manifestations Systemic treatment

1/Male/52 Scleritis OS Hoarseness Intravenous methylprednisolone pulse (1000 mg/day)Peripheral keratitis OS Dysarthria Intravenous and oral prednisolone (tapered from

Dysphagia (Bulbar palsy) 90 mg/day)Oral methotrexate (10–15 mg/week)Oral cyclophosphamide (50–100 mg/day)

2/Female/59 Scleritis OD Microscopic polyangiitis Intravenous and oral prednisolone (tapered fromGlomerulonephritis 40 mg/day)

Intravenous cyclophosphamide pulse (500–750 mg, once in a month)

3/Male/42 Bilateral scleritis Interstitial pneumonitis Intravenous methylprednisolone pulse (1000 mg/day)Intravenous and oral prednisolone (tapered from 70 mg/day)Oral cyclophosphamide (100–200 mg/day)

4/Female/72a Sjögren syndrome Crescentic glomerulonephritis Intravenous methylprednisolone pulse (500 mg/day)Chronic thyroiditis Oral cyclophosphamide (25 mg/day)

pANCA, perinuclear antineutrophil cytoplasmic antibody; OS, left eye; OD, right eye.aReported partly in References 41 and 42.

(PR3-ANCA) in addition to pANCA (MPO-ANCA). Most common eye manifestations were bilateral or unilateral ocular surface manifestations, such as scleritis, episcleritis, ulcerative or nonulcerative peripheral keratitis, and bulbar conjunctival nodular lesions, in eight patients. Other common eye presentations were posterior segment mani-festations: central or branch retinal vein occlusion in four patients, unilateral or bilateral optic neuropathy in four patients, acute posterior multifocal placoid pigment epithe-liopathy (APMPPE) in two patients, bilateral posterior scleritis in one, bilateral multifocal choroiditis in one, ante-rior ischemic optic neuropathy in one, and papilledema in one patient. Two patients showed orbital manifestations such as a unilateral lacrimal gland mass and bilateral extra-ocular muscle enlargement.

Systemically, nineteen patients showed renal involve-ment manifested as glomerulonephritis or chronic renal failure. Diagnoses were established in seven of the 27 patients: Wegener granulomatosis in one patient, ulcerative colitis in one, rheumatoid arthritis in one, and microscopic polyangiitis in four.

Discussion

The goal of this study was to summarize ocular manifesta-tions in patients with pANCA-associated vasculitis. Com-bining the present four patients with the 27 patients described in past studies, there were 31 patients in all, 19 women and 12 men, with ages ranging from 11 to 79 years. The most common ocular manifestations were ocular surface diseases such as episcleritis and scleritis. Other ocular surface manifestations such as peripheral keratitis and bulbar conjunctival nodular lesions might be consid-ered as extensions of scleritis or episcleritis. These manifes-tations occurred either bilaterally or unilaterally. Scleritis in association with pANCA has been reported in other

series of patients.35,36 In addition, peripheral ulcerative ker-atitis has been described in patients with microscopic poly-angiitis or Churg-Strauss syndrome, in which pANCA is frequently positive.36 The predominance of ocular surface manifestations such as scleritis is, therefore, the same between pANCA-associated vasculitis and cANCA-associated vasculitis. Indeed, scleritis is a hallmark of Wegener granulomatosis, in which cANCA is frequently positive.

It should be noted that the second most common eye presentations of pANCA-associated vasculitis were poste-rior segment manifestations such as central or branch retinal vein occlusion, optic neuropathy, APMPPE, anterior isch-emic optic neuropathy (AION), posterior scleritis, and multifocal choroiditis. AION is indeed caused by vascular accidents resulting from either arteriosclerosis or arteritis. The association of APMPPE and multifocal choroiditis with pANCA-associated vasculitis supports the vasculitic nature of these fundus diseases. APMPPE in association with pANCA is particularly noteworthy because a previous survey of ANCA in uveitis patients described one patient with APMPPE who showed positive pANCA.37 Uveitis in general was not associated with pANCA in the present survey, in contrast to a few previous studies that described positive pANCA in a small number of patients with non-specifi c uveitis36,38–40

The most common systemic presentation of pANCA-associated vasculitis with eye manifestations was renal involvement such as glomerulonephritis and chronic renal failure. Glomerulonephritis often took a clinical form of rapidly progressive glomerulonephritis and was pathologi-cally diagnosed as necrotizing or crescentic glomerulone-phritis by renal biopsy. These renal diagnoses are known as hallmarks of ANCA-associated glomerulonephritis in general.4–7 Interstitial pneumonitis is another well-known presentation of ANCA-associated vasculitis. Neuropathy, especially cranial nerve palsy, is also a manifestation of

T. MATSUO 135EYE MANIFESTATIONS IN pANCA VASCULITIS

Tab

le 2

. Su

mm

ary

of 2

7 pa

tien

ts w

ith

pAN

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T. MATSUO 137EYE MANIFESTATIONS IN pANCA VASCULITIS

pANCA-associated systemic vasculitis. In the present series of four patients, one patient experienced hoarseness, dys-arthria, and dysphagia caused probably by bulbar palsy involving bilateral vagus nerves. In addition, multiple cranial nerve palsies were described in two patients in the literature review. Ophthalmologists may encounter such cranial nerve palsies as the clinical presentations of pANCA-associated vasculitis.

For treatment, strong immunosuppression was required to control the systemic manifestations such as glomerulone-phritis and interstitial pneumonitis in the present four patients. These treatments were pulse corticosteroid therapy with methylprednisolone 500 or 1000 mg daily followed by intravenous or oral prednisolone, in combination with oral or intravenous cyclophosphamide and oral methotrexate. The same kinds of treatment were carried out in patients with pANCA-associated vasculitis in past studies. The eye manifestations usually did not respond well to topical cor-ticosteroids, but subsided dramatically in response to the systemic medication.

In conclusion, ocular surface diseases such as scleritis and peripheral keratitis were the most common ocular man-ifestations of pANCA-associated vasculitis, similar to the association of scleritis with Wegener granulomatosis, which is frequently cANCA-positive. In contrast with cANCA-associated vasculitis, posterior segment manifestations such as retinal vein occlusion, optic neuropathy and APMPPE were often seen in patients with pANCA-associated vascu-litis. ANCA testing, including both cANCA and pANCA, in such ocular manifestations would help establish the underlying systemic diagnoses.

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