Grand Rounds Eddie Apenbrinck M.D. University of Louisville School of Medicine Department of Ophthalmology & Visual Sciences 3/7/2014

Subjective CC: Left inferotemporal periorbital tenderness and swelling HPI: 17 year old white female with a 2 ½ month history of chronic sinus congestion presents to Kosair ED with 1 day of tenderness and swelling of the left inferotemporal orbital rim

Treatment prior to ED Diagnosed with pansinusitis 2 week prior to ED visit Diagnosed with pansinusitis 2 week prior to ED visit Started on clindamycin and prednisone PO Started on clindamycin and prednisone PO Minimal improvement on antibiotics and steroids Minimal improvement on antibiotics and steroids CT sinuses: erosion of nasal septum CT sinuses: erosion of nasal septum Nasal Mucosa Biopsy: Nasal Mucosa Biopsy: I nitially read as likely granulomatosis with polyangiitis (GPA) I nitially read as likely granulomatosis with polyangiitis (GPA) Second opinion read biopsy as possible Epstein Bar Virus (EBV) lymphoma Second opinion read biopsy as possible Epstein Bar Virus (EBV) lymphoma Treated with pulse steroids and scheduled for pediatric rheumatology appointment Treated with pulse steroids and scheduled for pediatric rheumatology appointment

POH: Myopic PMHx: saddle nose deformity FHx: seasonal allergies ROS: intermittent headaches, epistaxis, myalgia and fatigue (~2½ months) Allergies: Allergies: cefprozil (hives) Meds: none

Exam OD OS VA(sc,n): 20/20 OU Pupils: 3 2 OU No RAPD IOP: 12 OU EOM: Full OU slight inferior periorbital tenderness on upgaze Orbits: No proptosis, No lid retraction, No ecchymosis

Exam OD OS Anterior Segment L/L: WNL slight swelling of left inferotemporal periorbital area C/S:WNLOU K:WNLOU AC:No cell or flare OU I/L:WNLOU Vitreous: WNLOU Dilated Fundus Exam: WNL OU

MRI T2 Coronal MRI of orbits shows enhancement of ethmoid sinus with erosion into left medial orbit

MRI T1 Axial with gadolinium shows enhancement of ethmoid sinus with erosion into left medial orbit

Assessment Assessment: 17yo white female with chronic sinus congestion found to have an ethmoid sinus lesion with extension into the left orbit. Assessment: 17yo white female with chronic sinus congestion found to have an ethmoid sinus lesion with extension into the left orbit. DDx DDx Granulomatosis with polyangiitis (GPA) Granulomatosis with polyangiitis (GPA) EBV lymphoma EBV lymphoma Chronic Sinusitis Chronic Sinusitis

Plan Plan Plan Admission for further workup and treatment Admission for further workup and treatment Started on IV Started on IV ampicillin-sulbactam (Unasyn) 3,000mg q6h Repeat biopsy of nasal mucosa Repeat biopsy of nasal mucosa Biopsy of left inferior nasal septum and left inferior turbinate obtained and sent to pathology Biopsy of left inferior nasal septum and left inferior turbinate obtained and sent to pathology Ophthalmology follow-up as outpatient following discharge Ophthalmology follow-up as outpatient following discharge

Hospital Course Labs ESR: 65 (0-25) CRP: ( ) Proteinase-3 Auto Antibodies: positive c-ANCA: negative p-ANCA: negative Myeloperoxidase Auto antibodies: negative TSH: wnl Free T4: wnl Immunoglobulin Panel: (all WNL) C3 149 C4 25 IgA 165 IgG 949 IgM 67 CBC, CMP and UA: wnl Gram Stain: positive for gram negative bacillus Nasal Mucosa Culture: Klebsella Pneumonia

Hospital Course Imaging CXR, MRI/MRA brain: WNL CXR, MRI/MRA brain: WNL Flow Cytometry normal percentages and absolute numbers of T-cell, B-cell and natural killer cell populations. No evidence of B-cell monoclonality or increased blast population normal percentages and absolute numbers of T-cell, B-cell and natural killer cell populations. No evidence of B-cell monoclonality or increased blast population Anatomic Pathology Both biopsy samples showed necrotizing granulomatous inflammation consist with GPA Both biopsy samples showed necrotizing granulomatous inflammation consist with GPA

Pathology Necrotizing granulomatous inflammation 10x magnification20x magnification eosinophiles Multinucleated giant cellgranuloma Granuloma with necrotic center

Hospital Course  Started on Solumedrol 1g once followed by oral taper as outpatient  Started on rituximab (15mg/kg) and cyclophosphamide (15mg/kg) once  Patient discharged with plan for readmission in 2 weeks for second dose of rituximab and cyclophosphamide

Ophthalmology 1 week follow up OD OS OD OS VA(cc): 20/20 OU Pupils: 4 3 OU; No RAPD IOP: EOMFull OU without pain Ant Segment: WNL OU DFE: WNL OU Assessment: Patient with GPA currently asymptomatic Plan: Observe with follow-up in 6 months

Clinical Course Second dose of rituximab and cyclophosphamide 2 weeks after discharge Second dose of rituximab and cyclophosphamide 2 weeks after discharge Patient with increased energy, no epistaxis and improved nasal congestion Patient with increased energy, no epistaxis and improved nasal congestion CBC & CMP: WNL CBC & CMP: WNL CRP = 15.8 (<10.0) CRP = 15.8 (<10.0) Patient was started on maintenance therapy of Azathioprine, Bactrim, and continued prednisone taper Patient was started on maintenance therapy of Azathioprine, Bactrim, and continued prednisone taper

Granulomatosis with Polyangiitis GPA is a multisystem autoimmune disorder characterized by the classic triad of necrotizing granulomatous vasculitis of the upper and lower respiratory tract, focal segmental glomerulonephritis, and necrotizing vasculitis of small vessels GPA is a multisystem autoimmune disorder characterized by the classic triad of necrotizing granulomatous vasculitis of the upper and lower respiratory tract, focal segmental glomerulonephritis, and necrotizing vasculitis of small vessels Incidence: 3 per 100,000 reported in United States Incidence: 3 per 100,000 reported in United States Differential Diagnosis: Differential Diagnosis: Clinical: Orbital pseudotumor, Sarcoidosis, fungal infections, Histiocytosis X, IGG4-related disease,, Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy), Clinical: Orbital pseudotumor, Sarcoidosis, fungal infections, Histiocytosis X, IGG4-related disease,, Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy), Pathology: polyarteritis nodosa, microscopic polyangiitis, Churg- Strauss syndrome Pathology: polyarteritis nodosa, microscopic polyangiitis, Churg- Strauss syndrome

Anti-cytoplasmic Nuclear Antibodies (ANCA): staining occurs in two patterns Anti-cytoplasmic Nuclear Antibodies (ANCA): staining occurs in two patterns Cytoplasmic staining pattern (C-ANCA), which is specific for Proteinase- 3 (PR3) also called myeloblastin Cytoplasmic staining pattern (C-ANCA), which is specific for Proteinase- 3 (PR3) also called myeloblastin Perinuclear staining pattern (P-ANCA), which is specific for myeloperoxidase Perinuclear staining pattern (P-ANCA), which is specific for myeloperoxidase 32% to >95% of patients with GPA are positive C-ANCA depending on disease activity 7 32% to >95% of patients with GPA are positive C-ANCA depending on disease activity 7 91% sensitivity and 99% specificity in active disease 8 91% sensitivity and 99% specificity in active disease 8 Less than 5% of patient with GPA are positive for P-ANCA Less than 5% of patient with GPA are positive for P-ANCA Granulomatosis with Polyangiitis

Clinical Features Patient typically have flu-like symptoms lasting several days or weeks including fever, polymyalgia, polyarthralgia, headache, malaise, anorexia, unintended weight loss Patient typically have flu-like symptoms lasting several days or weeks including fever, polymyalgia, polyarthralgia, headache, malaise, anorexia, unintended weight loss 90% of patients report ear, nose, or throat problems 90% of patients report ear, nose, or throat problems 75% of patients seek care because of upper and lower respiratory complaints 75% of patients seek care because of upper and lower respiratory complaints Ocular or orbital involvement is seen in 15% of patients at presentation and up to 50% during the course of the disease. Ocular or orbital involvement is seen in 15% of patients at presentation and up to 50% during the course of the disease.

Clinical Features Chronic Complications : Orbital socket contracture, enophthalmos, restrictive ophthalmopathy, chronic orbital pain Chronic Complications : Orbital socket contracture, enophthalmos, restrictive ophthalmopathy, chronic orbital pain Foster CS, Yang J. Wegener’s Granulomatosis. Albert & Jakobiec's Principles and Practice of Ophthalmology. Pages Albert & Jakobiec's Principles and Practice of Ophthalmology

Treatment There is no standardized treatment regimen for granulomatosis with polyangiitis There is no standardized treatment regimen for granulomatosis with polyangiitis Treatment is aimed at inducing remission Treatment is aimed at inducing remission General approach includes high-dose steroids and cyclophosphamide General approach includes high-dose steroids and cyclophosphamide Rituximab-based regimen plus steroids may be considered as alternative in patients with relapsing or refractory disease Rituximab-based regimen plus steroids may be considered as alternative in patients with relapsing or refractory disease Remission maintained with cyclophosphamide, methotrexate or azathioprine Remission maintained with cyclophosphamide, methotrexate or azathioprine Plasma exchange may be beneficial in patients with severe renal disease Plasma exchange may be beneficial in patients with severe renal disease

Randomized double blind clinical trial included 197 patients, compared rituximab (once a week for 4 weeks) followed by placebo to cyclophosphamide administered for 3 to 6 months followed by azathioprine for 12 to 15 months. Randomized double blind clinical trial included 197 patients, compared rituximab (once a week for 4 weeks) followed by placebo to cyclophosphamide administered for 3 to 6 months followed by azathioprine for 12 to 15 months. Both groups showed comparable rates of remission at 6, 12 and 18 months Both groups showed comparable rates of remission at 6, 12 and 18 months Conclusion: a single course of rituximab was as effective as continuous conventional immunosuppressive therapy for the induction and maintenance of remission over the course of 18 months. Conclusion: a single course of rituximab was as effective as continuous conventional immunosuppressive therapy for the induction and maintenance of remission over the course of 18 months. Literature Search Aug 2013

Literature Search  Retrospective noninterventional comparative case series including 247 patients with orbital inflammation, compared GPA with other causes of orbital inflammation to identify the presenting clinical and radiographic features most likely to predict GPA  Features highly suggestive of GPA: sinonasal symptoms, sinonasal changes, or paranasal bone erosion on imaging.  22% of patients (8/37) with GPA had evidence of systemic involvement at presentation, and no patient presenting with only orbital GPA developed later systemic disease over a median follow-up of 2.7 years. Ophthalmology Feb

Thank You Thank You

References 1. BCSC: Intraocular Inflammation and Uveitis. Pgs : BCSC: Update on General Medicine. Optic Neuritis. Pgs Pakrou N, Selva D, Leibovitch I. Wegener;s Granulomatosis: ophthalmic manifestations and management. Semin Arthritis Rheum. 2006;35(5): Berden A, Göçeroglu A, Jayne D, et al. Diagnosis and management of ANCA associated vasculitis. BMJ Jan 16;344:e26. BMJ Jan 16;344:e26.BMJ Jan 16;344:e Schilder AM. Wegener's Granulomatosis vasculitis and granuloma. Autoimmun Rev May;9(7): Autoimmun Rev May;9(7):483-7.Autoimmun Rev May;9(7): Tan LT, Davagnanam I, et.al. Clinical and Imaging Features Predictive of Orbital Granulomatosis with Polyangiitis and the Risk of Systemic Involvement. Ophthalmology Feb 20. pii: S (13) doi: /j.ophtha [Epub ahead of print] Ophthalmology. 7. Foster CS, Yang J. Wegener’s Granulomatosis. Albert & Jakobiec's Principles and Practice of Ophthalmology. Pages Albert & Jakobiec's Principles and Practice of OphthalmologyAlbert & Jakobiec's Principles and Practice of Ophthalmology 8. Schonermarck U, Lamprecht P, Csernok E, Gross WL. Prevalence and spectrum of rheumatic diseases associated with proteinase 3-antineutrophil cytoplasmic antibodies (ANCA) and myeloperoxidases- ANCA. Rheumatology 2001; 40; Specks U, Merkel PA, Seo P, Spiera R et al. RAVE-ITN Research Group. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N Engl J Med Aug 1;369(5):