Successful Treatment of Resistant Orbital Eye Disease in Granulomatosis with Polyangiitis with the Addition of Methotrexate to Standard of Care

Background Granulomatosis with polyangiitis (GPA) is an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis involving small to medium-sized vessels and characterized by multisystem involvement. The standard induction treatment for organ or life-threatening GPA includes pulse steroids with rituximab or cyclophosphamide.[1] We present a patient with systemic GPA with sinusitis, otomastoiditis, pachymeningitis, pulmonary nodules, splenic involvement, and positive PR3. Despite undergoing standard induction therapy, the patient developed persistent orbital disease, which responded to the addition of methotrexate.

Case Report A previously healthy 44-year-old female presented with several months of fatigue, myalgias, weight loss, and right-sided headaches. Examination revealed binocular diplopia, right-sided cranial nerve V, VI, and VII neuropathies, and bilateral positive Babinski reflex. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were elevated at 154mg/L (<1mg/L) and 120mm/h (<20mm/h), respectively, with PR3 positivity of 148RU/mL (<20RU/mL). Imaging showed right sided pachymeningeal thickening, pulmonary nodules, paraspinal soft tissue masses, and splenic lesions. Splenic biopsy confirmed a diagnosis of GPA. She received pulse steroids and IV cyclophosphamide for induction therapy. Four months later, the patient developed right eye swelling and proptosis, causing significant difficulty with eye opening. Inflammatory markers and PR3 levels remained elevated. There was persistent pachymeningeal thickening with new right orbital involvement on repeat imaging. Conjunctival biopsy showed neutrophilic and granulomatous inflammation. Induction treatment was switched to rituximab, but response was limited despite 4 doses. Repeat conjunctival biopsy confirmed persistent GPA with perivascular neutrophils and eosinophils with focal areas of necrosis and granulomatous inflammation despite undetectable PR3 level. Surgical debulking and addition of oral cyclophosphamide provided limited improvement. Given her persistent ocular symptoms, oral methotrexate at 15mg was added to rituximab maintenance and 15 mg of prednisone after a multidisciplinary review. The patient showed a good response, with CRP decreasing to 16.5mg/L and prednisone successfully tapered to 5mg, with significant improvement in her orbital symptoms.

Conclusion Orbital involvement, particularly orbital mass, in GPA can be associated with refractory disease. Emerging evidence supports the use of combined rituximab and methotrexate therapy to prevent irreversible damage.[2,3] This case demonstrates successful treatment of resistant orbital GPA with combination therapy, without major complications or infections. In severe GPA with orbital eye disease, early consideration of rituximab and methotrexate combination therapy may improve outcomes and prevent damage.

References [1.] Hellmich B. Ann Rheum Dis 2024;83:30-47. [2.] Moroni L. Arthritis Rheumatol 2024;76. [3.] Neary E. J Rheumatol 2025;52:75-76.