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 Table of Contents  
Year : 2021  |  Volume : 1  |  Issue : 2  |  Page : 305-307

Rituximab for refractory necrotizing scleritis and peripheral ulcerative keratitis secondary to antineutrophil cytoplasmic antibody-negative granulomatosis with polyangiitis

1 Department of Ophthalmology, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Bandar Tun Razak, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur; Department of Ophthalmology, Hospital Tengku Ampuan Afzan, Kuantan, Jalan Tanah Putih, Kuantan, Pahang, Malaysia
2 Department of Ophthalmology, Hospital Tengku Ampuan Afzan, Kuantan, Jalan Tanah Putih, Kuantan, Pahang, Malaysia
3 Department of Ophthalmology, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Bandar Tun Razak, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia

Date of Submission19-Sep-2020
Date of Acceptance28-Nov-2020
Date of Web Publication01-Apr-2021

Correspondence Address:
Prof. Mae-Lynn Catherine Bastion
Department of Ophthalmology, Faculty of Medieine, Universiti Kebangsaan Malaysia Medical centre, Jalan Yaacb Latif, 56000 Kuala Lumpur
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijo.IJO_3013_20

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A 52-year-old woman was diagnosed with bilateral necrotizing scleritis (NS) and peripheral ulcerative keratitis secondary to the antineutrophil cytoplasmic antibody (ANCA)-negative granulomatosis with polyangiitis (GPA) as evidenced by increased erythrocyte sedimentation rate, bilateral multiple cavitation lung nodules, and persistent microscopic hematuria. Infective workup and autoimmune tests were negative including the ANCA test. She received multiple courses of high dose intravenous methylprednisolone, intravenous cyclophosphamide, and oral methotrexate. Multiple tectonic patching operations were performed. Despite all the treatment, the disease continued to progress. Eventually, few doses of rituximab were given and the disease was stable for at least a year without any reactivation.

Keywords: Antineutrophil cytoplasmic antibody, granulomatosis with polyangiitis, necrotizing scleritis, peripheral ulcerative keratitis, rituximab

How to cite this article:
Chow JY, Wan Muda WN, Catherine Bastion ML. Rituximab for refractory necrotizing scleritis and peripheral ulcerative keratitis secondary to antineutrophil cytoplasmic antibody-negative granulomatosis with polyangiitis. Indian J Ophthalmol Case Rep 2021;1:305-7

How to cite this URL:
Chow JY, Wan Muda WN, Catherine Bastion ML. Rituximab for refractory necrotizing scleritis and peripheral ulcerative keratitis secondary to antineutrophil cytoplasmic antibody-negative granulomatosis with polyangiitis. Indian J Ophthalmol Case Rep [serial online] 2021 [cited 2021 Aug 3];1:305-7. Available from: https://www.ijoreports.in/text.asp?2021/1/2/305/312402

Granulomatosis with polyangiitis (GPA) is a rare autoimmune disease involving multiple body organs characterized by necrotizing granulomatous inflammation and paucity of immune vasculitis. It affects mainly small blood vessels and is often associated with antineutrophil cytoplasmic antibodies (ANCA). Among GPA patients, 10–20% of cases were ANCA negative.[1] GPA with ocular manifestation can occur up to 50% of cases and 15% of patients presented with ocular symptoms as first signs of the disease.[2] Scleritis and peripheral ulcerative keratitis are the common presentations of GPA and can occur in around 50% of patients.

The treatment regimen for GPA is a combination of corticosteroids and immunosuppressive agents. There is limited evidence on rituximab therapy in ocular inflammatory disease secondary to ANCA-negative GPA. Thus, we report a case of rituximab therapy in treating the patient with refractory necrotizing scleritis and peripheral ulcerative keratitis secondary to ANCA-negative GPA.

  Case Report Top

A 52-year-old woman presented with bilateral eye pain and redness for a week which was not relieved by topical antibiotics. Ocular examination showed bilateral scleral and peripheral corneal thinning with prominent tortuous and dilated scleral vessels which were more severe in the left eye, edematous cornea, deep anterior chamber with the activity of grade 1, as well as high intraocular pressure in both eyes [Figure 1]. Otherwise, the posterior segment and systemic examination were normal. She was diagnosed with bilateral necrotizing scleritis (NS) and peripheral ulcerative keratitis (PUK) with secondary high intraocular pressure in February 2017.
Figure 1: Anterior segment photograph of both eyes showing conjunctival injection, superior scleral thinning with the avascular necrotic area and slough tissues, peripheral cornea thinning with the mild edematous cornea, and anterior chamber activity

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Infective workup was done and the results were negative for tuberculosis, syphilis, human immunodeficiency virus, and hepatitis B and C. Conjunctival swab for culture was negative. Further investigations such as full blood count, eosinophil count, renal profile, liver function test, and C-reactive protein (CRP) were normal. Erythrocyte sedimentation rate (ESR) was elevated at 60 mm/h. Other autoimmune tests were negative including antinuclear antibodies, rheumatoid factor, cytoplasmic-ANCA (c-ANCA), and perinuclear-ANCA (p-ANCA). Chest X-ray revealed multiple lung nodules and contrasted-enhanced computed tomography of the thorax (CECT thorax) showed bilateral cavitatory lesion at the right upper and lower zone with surrounding minimal fibrotic changes. However, the patient refused a lung biopsy. Serial urine full examination and microscopic examination tests were done and showed persistent microscopic hematuria without protein. Ultrasound of the abdomen showed fatty liver infiltration without obstructive uropathy. She was referred to the otorhinolaryngology team for further assessment but the findings were normal. She was diagnosed by a rheumatologist with ANCA-negative granulomatosis with polyangiitis.

She was admitted seven times to the ward from the year 2017–2020 due to reactivation and worsening of NS and PUK. She had received multiple courses of pulse intravenous methylprednisolone for the flare-ups of her ocular disease. Oral methotrexate was started concurrently with oral steroid. After the third course of IV high dose MP, unfortunately, she was diagnosed clinically with bilateral exogenous endophthalmitis secondary to infected scleral melting as evidence by worsening anterior chamber activity, vitritis [Figure 2], and significant loculation on B-scan ultrasonography of both eyes. There was no scleral perforation. Prompt treatment with intravitreal antibiotics for both eyes followed by bilateral scleral patching combined with right trans pars plana vitrectomy was performed. Intraoperatively, severe pars planitis with abscess was noted. However, vitreous biopsy for gram stain, culture, polymerase chain reaction for tuberculosis, and viruses were negative. She had completed a systemic broad-spectrum antibiotic and antifungal medication for a month. Oral prednisolone was tapered from 60 mg to 40 mg daily while oral methotrexate was maintained during the infective period. After the infection settled, the fourth course of high-dose intravenous MP was given as the disease was still active, and right eye cystoid macular edema was noted. Given there was no improvement in the disease, intravenous cyclophosphamide 1 g (15 mg/kg) was given for six cycles and oral methotrexate was changed to oral azathioprine. Cystoid macular edema improved after cyclophosphamide therapy. Subsequently, multiple scleral and amniotic membrane patching were done on both eyes for the severe melting of both eye sclera [Figure 3]. Unfortunately, despite all the treatment given, the left eye continued to progress. Eventually, after 2.5 years from the start of her therapy, two intravenous infusions of 1 g rituximab were attempted 2 weeks apart and another infusion of 500 mg rituximab was given after 6 months. Since rituximab treatment, the disease was stable for at least a year without any reactivation [Figure 4]. Currently, the patient is on low-dose oral prednisolone (10 mg daily) maintenance and has managed to wean off azathioprine. Her latest right vision is 6/6 and her left vision is perception of light.
Figure 2: (a and b) Anterior segment photograph of both eyes showing scleral melting and (c) limited and magnified anterior segment photograph of the left eye showing anterior vitreous opacity

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Figure 3: Appearance of both eyes following scleral patching (arrows) for severe melting of the sclera

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Figure 4: Anterior segment appearance of both eyes pre- (left photo) and post- (right photo) rituximab treatment showing marked reduction in erythema and vessel engorgement

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  Discussion Top

In our case scenario, this patient likely to have granulomatosis with polyangiitis with a sensitivity of 88.2% and a specificity of 92% as she has fulfilled two criteria which are the presence of multiple cavitary lung nodules and persistent microhematuria based on the 1990 American College of Rheumatology Classification Criteria.[3] Thus, a rheumatologist who assisted us to manage the disease had diagnosed her with ANCA-negative granulomatosis with polyangiitis. It was challenging to establish a definite diagnosis for this patient as no biopsy was performed and the ANCA test was negative twice. Non-ANCA vasculitis is a rare and more severe form of the disease for which biologic treatment has been found to have higher efficacy and benefit. In our case, the disease was refractory to previous induction of remission treatments which are oral methotrexate and pulse corticosteroid. However, there was a delay in cyclophosphamide initiation. Cyclophosphamide treatment was only given when the patient developed cystoid macular edema. Cyclophosphamide administration in this case was pulse therapy which had lesser side effects compared to daily cyclophosphamide.[4] Repeated CECT thorax after cyclophosphamide treatment showed the cavitary lung nodules were smaller in size which indicated the lung lesion was more suggestive of inflammation rather than infection or malignancy. However, her left eye's anterior NS progressed to a sight-threatening stage with perception of light vision.

A study by Jone et al. revealed that 75% of patients with refractory disease achieved complete remission after rituximab treatment and there were no differences between the 4 × 375 mg/m2/week and 2 × 1 g regimens.[5] Thus, rituximab therapy was given in this case and the regimen is two infusions of 1 g rituximab given 2 weeks apart, and then 500 mg after 6 months of postinduction treatment. This induction treatment is based on the European Vasculitis Society (EUVAS) as well as European League Against Rheumatism (EULAR) recommended regimen and maintenance treatment based on the MAINRITSAN study.[6] After rituximab initiation, NS and PUK improved and became inactive for months. There was no reactivation sign detected during her latest follow-up at the eye clinic which was a year post-treatment. She did not have any adverse effects from rituximab. There is limited evidence of rituximab treatment for ANCA-negative vasculitis. Until now, there is only one on-going randomized clinical trial BIOVAS study about rituximab for refractory primary non-ANCA-associated vasculitis.[7] There is one small randomized clinical trial that reported that rituximab was effective and well-tolerated in 75% of cases with refractory autoimmune scleritis[8] and another study concluded that an aggressive rituximab regimen can result in long-term drug-free remission.[9] In our case, rituximab showed a safe and effective treatment to control her disease activity clinically and serologically.

  Conclusion Top

In this case report, rituximab is an effective and safe treatment option for inducing remission of refractory noninfectious necrotizing scleritis and peripheral ulcerative keratitis secondary to ANCA-negative granulomatosis with polyangiitis as well as maintenance of remission for up to a year. Early administration of rituximab treatment in ANCA-negative GPA with ocular manifestation should be considered when other treatment options failed, to avoid irreversible loss of vision.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

McCarthy E, Mustafa M, Watts M. ANCA-negative granulomatosis with polyangiitis: A difficult diagnosis. Eur J Case Rep Intern Med 2017;4:000625.  Back to cited text no. 1
Sfiniadaki E, Tsiara I, Theodossiadis P, Chatziralli I. Ocular manifestations of granulomatosis with polyangiitis: A review of the literature. Ophthalmol Ther 2019;8:227-34.  Back to cited text no. 2
Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend WP, et al. The American college of rheumatology 1990 criteria for the classification of Wegener's granulomatosis. Arthritis Rheum 1990;33:1101-7.  Back to cited text no. 3
De Groot K, Harper L, Jayne D, Flores Suarez L, Gregorini G, Gross W, et al. EUVAS (European vasculitis study group). Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: A randomized trial. Ann Intern Med 2009;150:670-80.  Back to cited text no. 4
Jones RB, Ferraro AJ, Chaudhry AN, Brogan P, Salama AD, Smith KG, et al. A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody–associated vasculitis. Arthritis Rheum 2009;60:2156-68.  Back to cited text no. 5
Terrier B, Pagnoux C, Karras A, Khouatra C, Aumaitre O, Cohen P, et al. OP0213 rituximab versus azathioprine for maintenance in Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (MAINRITSAN): Follow up at 34 months. Ann Rheum Dis 2013;72(Suppl 3):A124.  Back to cited text no. 6
Bajema IM, Bruijn JA, Casian A, Cid MC, Csernok E, Van Daalen E, et al. The European vasculitis society 2016 meeting report. Kidney Int Rep 2017;2:1018-31.  Back to cited text no. 7
Suhler EB, Lim LL, Beardsley RM, Giles TR, Pasadhika S, Lee ST, et al. Rituximab therapy for refractory scleritis: Results of a phase I/II dose-ranging, randomized, clinical trial. Ophthalmology 2014;121:1885-91.  Back to cited text no. 8
Cao JH, Oray M, Cocho L, Foster CS. Rituximab in the treatment of refractory noninfectious scleritis. Am J Ophthalmol 2016;164:22-8.  Back to cited text no. 9


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]


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