Isolated ANCA-associated scleritis successfully treated with systemic rituximab; a case report and review of literature

Abstract

Background

Necrotizing scleritis is one of the most destructive ocular manifestations of underlying systemic diseases that can lead to a variety of severe complications, including globe perforation or vision loss. Necrotizing scleritis can occur in various conditions, such as systemic vasculitis like Anti-Neutrophil Cytoplasmic Antibody (ANCA) and ANCA-Associated vasculitis (AAV), systemic autoimmune disorders, infections, or as a result of surgical procedures.

Case presentation

In this case report, we present a patient with acute bilateral isolated necrotizing sclerokeratitis associated with positive c-ANCA without any manifestation of other organ involvement. A 52-year-old man with acute anterior bilateral necrotizing scleritis with diffuse areas of necrosis, thinning of the sclera, and the choroidal show was observed which was impending perforation on both sides. Systemic medications, including intravenous methylprednisolone and cyclophosphamide, and topical medications were administered. However, due to an incomplete response to these drugs, intravenous rituximab was initiated. Significant improvements in clinical manifestations were initiated after treatment with Rituximab.

Conclusion

Our case highlights the importance of systemic rituximab therapy in treating isolated ANCA-associated necrotizing scleritis when initial immunosuppressive treatments are not fully effective.

Introduction

Necrotizing scleritis, characterized by inflammation, stands as the most severe variant of scleritis, resulting in thinning of the scleral tissue in approximately 60% of patients [1]. Scleritis can serve as an initial indicator of immune-mediated systemic diseases, thus enabling ophthalmologists to not only preserve their patients’ vision but also safeguard their lives through accurate diagnosis of the underlying systemic condition [2].

Vasculitis associated with antineutrophilic cytoplasmic antibodies (ANCA) are a heterogeneous group of small-vessel vasculitis with positive serum ANCA. Anti-Neutrophil Cytoplasmic Antibody, directed against myeloperoxidase (MPO) or proteinase-3 (PR3), has a significant role not only in classification of vasculitis but also in pathogenesis and treatment of AAV. Based on clinical features AAV can be divided in three phenotypes– granulomatosis with polyangiitis (GPA; formerly known as Wegener’s granulomatosis), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA; previously known as Churg-Strauss syndrome) [3].

There are a few reports of severe bilateral idiopathic scleritis with positive test results of ANCA entitled isolated ANCA-associated scleritis. Anti-Neutrophil Cytoplasmic-associated scleritis presents as different forms of scleritis including nodular, diffuse, or necrotizing scleritis [4]. However, it tends to be more severe compared to other scleritis with higher rates of necrotizing scleritis as the most destructive type of scleritis [5]. Anti-Neutrophil Cytoplasmic-associated scleritis is often more difficult to treat, and requires systemic treatment more frequently and had lower remission rate after first-line treatment.

Herein, we present a 52-year-old patient who exhibited bilateral diffuse necrotizing scleritis and positive c-ANCA, which proved refractory to conventional treatments. Notably, significant scleral thinning was observed in the necrotic regions of the sclera, placing the patient at the risk of globe perforation. The distinctive aspect of this case lies in the employment of systemic rituximab to control the systemic vasculitis, coupled with the topical administration of erythropoietin to enhance vascularization and epithelialization within the necrotic areas.

Case presentation

A 52-year-old diabetic man presented with a chief complaint of painful red eyes and blurred vision. The symptoms initially manifested in the right eye approximately four months ago, gradually worsening over time. Subsequently, the symptoms appeared in the left eye in a few weeks later. Notably, there was no history of similar previous episodes. Furthermore, the patient denied experiencing any symptoms associated with underlying autoimmune and rheumatologic systemic diseases, with diagnosis of bilateral necrotizing scleritis the medication regimen consisted of daily oral prednisolone tablets (50 mg), weekly Methotrexate (20 mg), and betamethasone eye drops (administered four times daily for both eyes) since one month ago in another medical center; however, his condition continued to worsen and the patient was referred to our medical center.

Upon examination, the best corrected visual acuity (BCVA) of the right eye was measured at 20/100, while the left eye exhibited a BCVA of 20/30. Swelling was observed in both eyelids, accompanied by narrowed palpebral fissures. The intraocular pressure was recorded at 11mmHg for both eyes. Slit lamp examination of the right eye revealed conjunctival injection and the presence of three avascular patches of necrotic sclera in the inferior region (one measuring 4*3 mm, and two measuring 2*2 mm each). Additionally, two smaller avascular regions (measuring 2*2 mm each) was observed, accompanied by scleral edema in the temporal area of the sclera, conjunctival defect, and severe thinning of the sclera, which posed a risk of perforation (Fig. 1A and B). Involvement of the inferonasal and nasal sections of the cornea was evident through white infiltrations and a corneal epithelial defect. in the left eye were comparatively less severe, with two avascular necrotic patches (measuring 2*2 mm each) noted in the temporal side of the sclera, along with a conjunctival defect and an adjacent white infiltration of the cornea (Fig. 2A and B).

Fig. 1.

A, Necrotic scleral patches of the right eye with severe scleral thinning and impending to perforation in the inferior site. B, Necrotic scleral patches of the left eye with an adjacent white infiltration of the cornea

Fig. 2.

Complete vascularization, epithelialization and improvement of scleral thinning areas are observed at six months after the beginning the treatment

Other evaluations revealed no further significant pathologic finding in anterior chamber and vitreoretinal examinations. Consequently, the patient was admitted with a diagnosis of bilateral necrotizing sclerokeratitis. Initial laboratory tests and screenings for infections includes complete blood counts, liver function tests, kidney function tests, antinuclear antibodies (ANA), Rheumatoid factor (RF), ANCA, erythrocyte sedimentation rate (ESR), angiotensin converting enzyme (ACE) level, Purified protein derivative (PPD) test, Venereal disease research laboratory (VDRL), Rapid plasma regain (RPR), Hepatitis B surface antigen (HBsAg), Hepatitis C antibody test and human immunodeficiency viruses antibody test. Scleral scraping at the edge of the affected areas and microbiological was done and revealed no sign of underlying infectious causes. Treatment was initiated with the administration of betamethasone and levofloxacin eye drops four times daily and frequent lubrications. The patient was initiated on intravenous methylprednisolone at a dose of 1 gram daily for the first three days, followed by 500 milligrams daily for the subsequent three days. After two days of admission, a topical eye drop containing Erythropoietin (CinnaPoetin 10000 IU, CinnaGen, Tehran, Iran) was started for the patient [5]. The prescribed dosage was 6000 units, to be administered four times daily. The purpose of this treatment was to improve vascularization and epithelization of necrotic areas of the sclera.

Autoimmune screening tests revealed the presence of high c-ANCAs (561.5 Au/ml with normal range fewer than 20). Therefore, an autoimmune cause, most likely ANCA-Associated vasculitis GPA type, was considered as the main underlying systemic disease. To address this, the patient received a single dose of cyclophosphamide (Endoxan 500 mg, Asta Pharma) intravenously at a dosage of 2 g. Furthermore, the patient underwent additional systemic investigations to detect any involvement of other organs by systemic vasculitis.

Upon conducting an Otorhinolaryngology consult to detect the potential engagement of the upper respiratory tract, the patient underwent diagnostic endoscopy and biopsy of the upper airway tract. These procedures revealed no signs of inflammation or necrosis. To eliminate the possibility of lower airway and lung involvement, a high-resolution computed tomography scan (CT scan) was performed, which indicated normal results. Additionally, orbital and paranasal CT scans yielded unremarkable findings. The patient’s renal function was assessed through lab tests, ruling out any nephrological engagement. Consequently, the diagnosis was isolated ANCA-associated scleritis. The patient was admitted in the hospital for recieving intravenous methylprednisolone at a dose of 1 gram daily for the first three days, followed by 500 milligrams daily for the subsequent three days. In addition, the patient received a single dose of cyclophosphamide (Endoxan 500 mg, Asta Pharma) intravenously at a dosage of 2 g. Methotrexate (Methotrexate, 2.5 mg tablet, Zahravi, Tehran, Iran) with dosage of 25 mg was initiated for the patient based on rheumatologic consultation. Following a week of observation, the patient was discharged with a prescribed regimen comprising prednisolone at a daily dosage of 50 mg orally which tapered every one week to half dosage, lubricants, betamethasone eye drops and levofloxacin single-dose eye drops and erythropoietin 6000 U eye drops administered four times daily. However, due to the limited improvement in disease activity after one month of treatment with corticosteroids, methotrexate, cyclophosphamide, two doses of IV rituximab 500 mg/50 ml (Zytux™, AryoGen Pharmed) were also started.

Following the patient’s regular visits for a duration of one month, the patient’s condition began to show the initial signs of vascularization of necrotic patches in both eyes. Consequently, adjustments were made to the treatment plan. Additionally, another IV dose of rituximab 500 mg/50 ml (Zytux™, AryoGen Pharmed) was prescribed for the patient. Monthly visits were maintained to monitor progress.

After three months, the necrotic areas of the left eye had completely vascularized and epithelialized, leading to the discontinuation of its topical medications. However, in the right eye there was one remaining necrotic patch in the inferonasal site that had not fully epithelialized. Hence, the patient continued using topical drugs for this particular area, with a dosage of twice a day. The oral prednisolone dosage was decreased to 5 mg daily.

After a span of 6 months, the necrotic areas of both eyes have undergone complete vascularization and epithelialization (Fig. 2). Notably, there have been no indications of disease flare-ups. As a result, all topical medications have been discontinued, and an additional dose of subcutaneous rituximab has been prescribed for the patient. Throughout this period, the patient has been under the care of the rheumatology department, ensuring comprehensive monitoring. Remarkably, there have been no signs of systemic disease flare-ups or involvement of other organs. All systemic workups and laboratory examinations including rheumatologic tests, complete blood counts, liver function tests, kidney function tests and fasting blood sugar were normal in duration of monitoring. Over a six-month period, the patient received Rituximab on three occasions: two initial doses, followed by a single dose after one month and another dose at six months, to effectively control active necrotizing scleritis. Each administration consisted of Rituximab delivered intravenously. As the sole maintenance therapy, Rituximab was administered every six months, totaling three maintenance doses. The patient’s total treatment duration has extended to two years to date. Moreover, the patient’s prescribed medications have been diligently scrutinized for any local or systemic side effects. Fortunately, no significant adverse effects have been observed during this duration. To ensure the patient’s well-being, blood pressure and CBC have been regularly assessed both before and during the use of topical erythropoietin. Encouragingly, no notable changes in blood pressure or CBC have been detected. Additionally, thorough examinations have revealed no signs of corneal or retinal neovascularization in the patient.

Discussion

We presented a patient with bilateral necrotizing sclerokeratitis with diagnosis of isolated Anti-Neutrophil Cytoplasmic-associated scleritis. Despite the utilization of initial treatments including systemic corticosteroids and cyclophosphamide, they proved ineffective in managing the ocular manifestations. However, upon transitioning to Rituximab as an alternative systemic medication, a marked improvement in the manifestations was observed without any subsequent recurrence.

Anti-Neutrophil Cytoplasmic Antibody-Associated Scleritis frequently presents as a sudden and bilateral fashion, with a diffuse anterior involvement with higher risk of scleromalacia in comparison with ANCA-negative idiopathic scleritis. In addition, systemic medications is more frequently needed in ANCA-associated scleritis. Scleritis in ANCA-positive patients tends to recur more than ANCA-negative ones and treatment of scleritis in these patients is more often difficult. It should be highlighted that the inflamed avascular and ischemic areas in necrotizing scleritis can lead to perforation, therefore necrotizing scleritis could be vision threatening if not treated properly and promptly [6].

To analyze similar cases, PubMed, and Google Scholar were searched. Two patients with adequate description [7–10] were found and summarized in Table 1. One patient was female and one patient was male with the age at the initial visit ranging from 52 to 75 years. Two patients had high level anti MPO-ANCA at initial visit and our patient had high anti-PR3-ANCA level at initial visit. None of the patients had previous history of confirmed AAV before ocular manifestations. None of the patients revealed other organs involvement in systemic evaluation.

Table 1.

Review of three patients with ANCA- associated vasculitis who showed scleritis including the present patient

authors	CASE NO/ GENDER/ AGE AT ONSET	MPO-ANCA At initial visit	PR3-ANCA at initial visit	Organs involved	Right eye	Left eye	Systemic treatment
[11]	1/Male/75	19.8 U/mL up to 129 U/ mL 1 year later	Undetectable	None	Scleritis Corneal melt & perforation	Scleritis Corneal melt & perforation	Azathioprine 50 mg daily Steroid mini-pulse four doses of rituximab Prednisolone 5 mg daily Dead of pneumonia
[10]	2/female/69	124.2 U/ml	neg	none	none	Nodular scleritis, posterior scleritis, serous retinal detachment, macular edema	Steroid pulse therapy and four doses of rituximab in four weeks
This case	3/male/52	neg	> 500 U/ml	none	Necrotizing scleritis, PUK	Necrotizing scleritis, PUK	Methylprednisolone 1000 mg daily 3 doses then 500 mg daily 3 doses, one dose cyclophosphamide 2 gr intravenous, methotrexate 20 mg weekly, controlled with 2 doses of rituximab, prednisolone tapered to 5 mg daily

It is possible that isolated ANCA-associated scleritis eventually be converted to systemic AAV. AAV impacts various structures of the eye, including scleritis, iritis, PUK, retinal vasculitis, optic nerve involvement (optic papillitis and Ischemic optic neuropathy) and oculomotor nerve disorders [11].

Rituximab, a therapeutic option of notable efficacy, proves effective in inducing remission in refractory AAV [12]. Exclusively in the realm of ocular GPA, long-term follow up studies have indicated that Rituximab effectively induces remission in ocular manifestations of both localized and generalized GPA [13]. the superiority of Rituximab in maintaining remission of ANCA-associated vasculitis especially for GPA patients to Azathioprine reported in MAINRITSAN Study [14].

Moreover, Rituximab has shown greater efficacy in patients with refractory GPA-associated scleritis when compared to the combination of cyclophosphamide and high-dose glucocorticoids used in induction therapy [15, 16].

In conclusion, this case of isolated ANCA-associated necrotizing scleritis demonstrated resistance to conventional treatment with systemic corticosteroids and cyclophosphamide. However, the patient exhibited a favorable therapeutic response to Rituximab. This biologic agent proved to be effective in both inducing and maintaining remission of necrotizing scleritis. Consequently, Rituximab may be considered a viable therapeutic option for severe cases of necrotizing scleritis, potentially mitigating the risk of further ocular complications.

Author contributions

MT gathered the data, followed the patient; KH and SF had the idea of reporting, treated the patient, supervised the manuscript writing; MAJ and MMS revised the manuscript, consulted the treatment.

Funding sources

The authors declare no financial disclosures.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This case complies with the principles of the Declaration of Helsinki.

Consent for publication

The patient has given written informed consent for publication of this case report.

Competing interests

The authors have no conflicts of interest to declare.