This report presents a rare case of scleritis with peripheral ulcerative keratitis secondary to granulomatosis with polyangiitis (GPA). A 65-year-old Caucasian male presented to a regional ophthalmology service with an atypical red eye. His immune work-up demonstrated positive anti-neutrophil cytoplasmic IgG autoantibodies (ANCA) with anti-proteinase 3 antibody (PR3) elevation. Multi-system vasculitis was discovered including lung, liver, bladder, prostate, nasal and paranasal sinuses involvement. His ocular sequelae included significant peripheral corneal thinning requiring cyanoacrylate gluing, juxtalimbal conjunctival resection, and bandage lens placement. He was treated with systemic methylprednisolone and rituximab achieving remission with ongoing prednisone and methotrexate maintenance therapy. This case demonstrates the importance of recognizing ocular manifestations of GPA as a first presentation of systemic vasculitis.

© 2023 The Author(s). Published by S. Karger AG, Basel

Granulomatosis with polyangiitis (GPA), formerly known as Wegener’s granulomatosis, is a rare small-vessel necrotizing vasculitis. It can have serious organ-threatening implications making accurate diagnosis and early treatment essential. This report describes a rare case of GPA diagnosis following first presentation with ocular manifestations. It includes the multidisciplinary management approach with a primary focus on the relative ocular sequelae. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see www.karger.com/doi/10.1159/000529459).

A 65-year-old Caucasian male was referred to a provincial ophthalmology service with a 2-week history of bilateral eye redness, photophobia, and ocular discomfort. He also described intermittent spontaneous epistaxis, fatigue, lethargy, and unintentional weight-loss. He had a background of ischaemic heart disease, hyperlipidaemia, hypertension and right hip osteoarthritis awaiting replacement. His medication history included: aspirin, metoprolol, and atorvastatin. He was a retired truck driver and ex-smoker. He had no previous ophthalmic history of note with no prior ocular surgery.

His best corrected visual acuities on presentation were 6/5 (right) and 6/9 (left) with normal intraocular pressures. Nodular scleritis extended to the right nasal limbus (shown in Fig. 1). The cornea was clear without defect. The anterior and posterior segments were quiescent in both eyes, with normal fundus and optic nerve appearance. Systemic blood work and a punch biopsy of his right scleral mass were taken.

Presenting anterior segment photo of right eye demonstrating nodular scleritis (a) with magnified appearance under slit-lamp (b).

He subsequently represented acutely to the emergency department 10 days later with frank haematuria, dizziness, and new confusion. He displayed word-finding difficulties and atypical dysarthria leading to admission for further systemic work-up and neuroimaging.

His blood work demonstrated anti-neutrophil cytoplasmic IgG autoantibody (ANCA) positivity with an anti-proteinase 3 antibody (PR3) level of 112 U/mL. His complement studies showed C3 elevation (1.95 g/L) and normal C4 (0.46 g/L). Anti-myeloperoxidase antibody levels were <3 U/mL. Glomerular basement membrane antibodies were not detected. Infectious screen including sarcoidosis, tuberculosis, and syphilis was negative. Rheumatology factor and anti-cyclic citrullinated peptide were both negative. Coagulation studies returned normal. His creatinine was 96 μmol/L with an estimated glomerular filtration rate of 71 mL/min/1.73 m2. Urine cytology demonstrated red blood cells, polymorphonuclear leucocytes without evidence of malignant cells. Liver function tests demonstrated normal transaminase levels, however, elevated alkaline phosphatase (199 U/L) and Gamma-glutamyl transferase (164 U/L). Hepatitis B and C serology along with human immunodeficiency virus serology were negative. Multi-system computed tomography imaging demonstrated lung, liver, prostate, bladder, nasal, and ethmoidal/maxillary sinus involvement (shown in Fig. 2). Biopsies of both his right nasal sclera and nasal cavity mass demonstrated inflamed granulation tissue with reactive atypical squamous epithelium without frank dysplasia or malignancy. Multinucleate giant cells were visible in both biopsied samples. The histopathology slide of the right scleral biopsy is shown in Figure 3.

Multi-system CT. a Demonstrates extensive polypoid mucosal thickening of the maxillary antrum (m), nasal turbinates (*), ethmoidal and frontal sinuses. b Demonstrates multiple solid lung nodules within the upper (arrow) and lower lobes. c Shows a large bladder mass (b).

H&E stained right sclera histopathology sample demonstrating inflamed granulation tissue with reactive atypical squamous epithelium and multinucleate giant cells (*).

An acute infarct of the left inferior parietal cortex was present on magnetic resonance angiography without evidence of cerebral vasculitis. Stenosis of both proximal internal carotid arteries with >80% critical stenosis on the left side was revealed on duplex carotid ultrasound.

A diagnosis of granulomatous with polyangiitis was made and a multidisciplinary approach employed including ophthalmology, otolaryngology (ENT), rheumatology, urology, and vascular surgery subspecialties. He was commenced on intravenous methylprednisolone 1 g for three consecutive days. He received two, 1 g rituximab infusions 14 days apart and cotrimoxazole 960 mg 3 times-weekly. He remained on aspirin, metoprolol, and atorvastatin. Dual antiplatelet therapy was avoided due to his ongoing haematuria and epistaxis. He successfully underwent left endarterectomy.

During the initial stages of his intravenous methylprednisolone treatment, he developed right peripheral ulcerative keratitis (PUK). This occurred 12 days from presentation, 2 days after systemic steroid commencement. There was significant corneal thinning with loss of the nasal juxtalimbal corneal stroma. Due to the high risk of morbidity, corneal scraping was not conducted. His topical eye drops included g.chloramphenicol 0.5% four-times daily, g.hyaluronate sodium 0.1% every 2-hours, and g.acetylcysteine 10% four-times daily in addition to oral doxycycline and ascorbic acid. Rapidly progressive corneal thinning was noted with extensive stromal tissue loss exposing Decement’s membrane. Due to the high risk of perforation, surgical temporizing measures were necessary. Corneal cyanoacrylate gluing with nasal juxtalimbal conjunctival resection with bandage lens placement was carried out (see online suppl. materials for intraoperative surgical video). There was no descemetocele formation, corneal perforation, or secondary microbial keratitis. His visual acuities following the procedure were 6/9+1 (left) and 6/12−1 (right). His C-reactive protein reduced from 387 mg/L to 8.7 mg/L supporting GPA remission 3 months following presentation. He is currently on tapering oral prednisone with weekly methotrexate 20 mg maintenance therapy without evidence of recurrence. A 5-month progress anterior segment photo is shown in Figure 4. The patient remains under the care of ophthalmology, rheumatology, and urology outpatient departments at time of publishing.

Progress anterior segment photo 5 months following presentation (a) including with fluorescein sodium stain (b).

GPA is a rare condition, occurring in an estimated 5–10 per million with significant geographic variation [1]. Ocular manifestations are reported to occur in approximately 30–50% of individuals with GPA [2]. In this case, the patient’s ocular manifestations included PUK with concomitant juxtalimbal scleritis. The peripheral cornea is known to have a predilection for immune-related damage due to its proximity to the perilimbal vascular and lymphatic arcades [3]. Inflammatory cells and immune-mediators commonly reach the peripheral cornea via chemotaxis from the adjacent sclera and episcleral [3]. Messmer and Foster [4] describe that the presence of PUK and scleritis are poor prognostic indicators for systemic GPA severity. Preventing corneal perforation has been shown to have significant long-term impact on both visual and systemic health outcomes [5]. Fu and Jones [6] demonstrated 65% of their patient cohort with corneal perforations had final visual outcomes of hand movements or less, and a 1-year mortality of 24%. Medical management with systemic immunosuppression remains the mainstay of treatment with adjuvant surgical techniques aimed at maintaining corneal stromal integrity [5]. Cyanoacrylate glue with juxtalimbal conjunctival resection was employed in this case before corneal perforation could occur. A tectonic graft would have been used in this case if corneal perforation occurred. Cyanoacrylate has been shown to provide tectonic strength to the cornea as well as provide a physical barrier from the influx of inflammatory cells from the neighbouring sclera and episcleral [6]. Sabhapandit et al. [7] supports the use of cyanoacrylate glue and amniotic membrane grafting and recommends them as first-line temporising measures in the acute setting. Corneal transplantation by either patch grafting, lamellar or penetrating keratoplasty is generally reserved for large central perforations or visual rehabilitation following systemic disease remission [7]. Maeno et al. [8] described a <50% graft survival rate in the setting of active GPA-associated PUK corneal melts, with multiple grafts usually required. Krysik et al. [9] described a 29% complication rate (from total 247 eyes) with the most common complications being persistent epithelial defects, graft melt, vascular ingrowth, and early suture loosening. Non-antigenic glycerol preserved corneas, as described by Lin et al. [10] and Shi et al. [11], have been shown to have a lower graft melt rate in autoimmune-PUK-related perforations, however, their current availability in many centres is limited. Acetylcysteine acts by reducing the production of matrix metalloproteinases (MMP) of migrating corneal epithelial cells [12]. MMP-9 levels have been shown to be upregulated in corneal destructive disease such as PUK [12]. Topical acetylcysteine was utilized in this case for its anti-collagenolytic properties, as part of a multimodal approach to reduce the rate of corneal stromal ulceration and promote remodelling and healing.

In this case, a combined glucocorticoid and rituximab-regiment was chosen for systemic induction therapy. The Rituximab for ANCA-Associated Vasculitis (RAVE) trial demonstrated equivocal remission rates and adverse event rates in rituximab-treated patients compared to those treated with cyclophosphamide but with greater remission rates in relapsing disease [13]. It should be noted that the rituximab dosing regimen used in this case differed from that used in the RAVE trial (375 mg/m2 per week for 4 weeks). As PR3-ANCA-positive patients are known to have a higher risk of relapse, methotrexate maintenance therapy was commenced 6 weeks from induction in this case. The Wegener Granulomatosis-Entretien (WEGENT) trial demonstrated comparable safety and efficacy of methotrexate and azathioprine in GPA maintenance [14]. Currently, there is no single agent consensus for induction or maintenance therapy by the American College of Rheumatology with significant treatment variation existing amongst clinicians [15].

Although GPA is a rare disease entity, this case demonstrates the importance of recognising the ocular manifestations of GPA and the relative morbidity and mortality implications associated. This case report highlights the ophthalmologist’s role in providing life-saving care extending beyond primary ocular disease.

We would like to acknowledge the multidisciplinary team involved in this case. Significant contributions from Dr. Graham Chiu (Rheumatology), Dr. Kumar Thangaraj (ENT), Dr. Alice Flavell-Birch (ENT), Dr. Sarit Dina Hochberg-Klein (General Medicine), Dr. Nicole Smith (Pathology), and Dr. Janaka Wickremesekera (Vascular surgery) are recognized with gratitude.

Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images. Outside the participant’s informed consent, ethical approval was not required in accordance with local guidelines and policy.

The authors have no conflicts of interest to declare.

There is no external funding or sponsorships to declare.

According to the ICMJE criteria, primary authorship is accredited to Dr. Louis Antoine Bonnet. Dr. Lior Lipsky and Dr. Richard Holmes are recognized as co-authors having provided substantial clinical and academic contributions to this body of work.

All data generated and analysed during this report are included in the article and its online supplementary material. Further enquiries can be directed to the corresponding author.

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