Orbital pseudo-tumor secondary to IgG4 disease

Summary: BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that affects one or multiple organs, and manifests in every organ system. Patients often present with subacute to chronic development of mass or diffuse enlargement of the organ. IgG4-related ophthalmic disease is seen in approximately 17 to 23 percent of patients with IgG4-RD and involves orbital, peri-orbital tissues, including extraocular muscles. Here, we present a case with predominant and isolated ophthalmic involvement of IgG4 disease without any other systemic organ involvement. CASE PRESENTATION: 67-year-old Hispanic male with a past medical history significant for chronic obstructive pulmonary disease, hypertension, acid reflux, and chronic sinusitis presented to the clinic with complaints of chronic bilateral painless peri-orbital swelling, left worse than right, for 15 years which is progressively worse in past two months. He had CT scan of orbits that showed infiltrative bilateral orbital mass involving muscle, fat, lacrimal gland, and trigeminal nerve with suspicion for IgG4 disease versus lymphoma. He underwent bilateral anterior orbitotomy with excisional lacrimal gland biopsy by ophthalmology that showed dense lymphoplasmacytic infiltrate with numerous IgG4 positive plasma cells(greater than 100/HPF), IgG4/IgG cells ratio greater than 40 percent and associated storiform fibrosis. He was started on oral prednisone 60 milligrams daily for 1 month, with improvement of orbital swelling, prednisone was tapered to 40 milligrams daily for second month of treatment. He complained of right hip pain, with the possibility of avascular necrosis of femur, prednisone was tapered faster, and when the patient was on prednisone 5 milligram daily, he had recurrence of orbital swelling, resulting in increasing the dose of prednisone to 20 milligram daily. Rheumatology was consulted for evaluation and initiation of steroid-sparing therapy. On evaluation, he was noted to have mild bilateral peri-orbital swelling, shortness of breath with exertion that is better with prednisone, and noted to have diffuse pruritic papular lesions on the back/ solitary lesion on the anterior sternum for 5-6 months. Labs showed elevated serum IgG4 105 mg/dL, normal IgG and decreased IgG1/IgG2 (Table 1). Autoimmune workup revealed the absence of any connective tissue diseases and vasculitis. Rituximab was planned as steroid-sparing therapy but due to insurance issues, Cellcept was initiated at 500 milligrams twice daily as alternate regimen with monitoring of cell counts and was titrated up to 2 gram daily. Prednisone was tapered from 20 milligrams/day to a current dose of 7.5 milligrams/day while monitoring for recurrence of disease activity. Rituximab will be used as therapy if unable to maintain quiescent disease with CellCept and unable to taper off prednisone. High-resolution CT scan chest done for evaluation of shortness of breath showed ground glass opacities in the anterior upper lobe and tiny nodules but imaging was not conclusive for findings of interstitial lung disease. He was also referred to pulmonology for further evaluation. Skin lesions on evaluation by dermatology were determined to be dermatitis ruling out IgG4-associated skin disease. The patient’s disease is currently quiescent on Cellcept 2 grams/day and prednisone 7.5 milligram/day. The plan is to decrease prednisone to 5 milligrams/day for 2 months with plans to wean off steroids as tolerated in the future. DISCUSSION: IgG4-related ophthalmic disease (IgG4-ROD) was first reported in 2007 as dacryoadenitis. Lacrimal gland is the most common site involved (62-88%), other sites include trigeminal nerve (10-39%), extraocular muscles (19-25%), orbital fat (29-40%), eye lid (12%) and nasolacrimal duct system. Patients with IgG4-ROD tend to present with painless, unilateral, or bilateral periorbital/eyelid swelling, erythema, and proptosis. Imaging techniques such as CT or MRI of the orbits can identify enlargement of extraocular structures but are not diagnostic of IgG4 disease. A biopsy of the lacrimal gland should be done for histopathological diagnosis and to rule out benign, malignancy, or infectious processes. Diagnostic criteria for IgG4-ROD developed by Goto et.al in 2015 include: 1) imaging studies showing enlargement of the lacrimal gland, trigeminal nerve, and masses/enlargement of ophthalmic tissues 2) histopathology identifying IgG4 plasma cells and meeting criteria that includes more than 50 IgG4 cells/HPF, ratio of IgG4/IgG cells of 40% or above 3) elevated serum IgG4(>= 135 mg/dL). 40% of biopsy-proven IgG4-RD will have normal serum IgG4 levels and it is important to rule out other differentials when evaluating patients with IgG4-ROD such as granulomatosis with polyangiitis, Sjogren syndrome, sarcoidosis, lymphoma and thyroid eye disease with diagnostic tests. First-line therapy for eye disease is systemic corticosteroids for 2-4 weeks as induction therapy with prednisone 0.6mg/kg/day with relapses that tend to occur during steroid taper. Serum IgG4 levels may be used as a marker for treatment response in IgG4-ROD. Disease-modifying therapies used include rituximab, Cellcept, Imuran, methotrexate, cyclosporine, and TNF inhibitors, with rituximab being the most commonly used disease-modifying therapy. CONCLUSION: IgG4-ROD diagnosis is based on clinical presentation with a characteristic appearance on imaging, elevated serum IgG4 levels, distinctive features in histopathological and immunohistochemical studies. Treatment consists of steroids initially followed by long-term immunosuppressive therapy with steroid sparing agents.