Grand Rounds

Eddie Apenbrinck M.D.University of Louisville School of

MedicineDepartment of Ophthalmology & Visual

Sciences3/7/2014

SubjectiveCC: 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 Started on clindamycin and prednisone PO

Minimal improvement on antibiotics and steroids CT sinuses: erosion of nasal septum Nasal Mucosa Biopsy:

Initially read as likely granulomatosis with polyangiitis (GPA)

Second opinion read biopsy as possible Epstein Bar Virus (EBV) lymphoma

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: 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 OSAnterior Segment

L/L: WNL slight swelling of left inferotemporal periorbital areaC/S: WNL OU K: WNL OU AC: No cell or flare OU

I/L: WNL OUVitreous: WNL OU

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.

DDx Granulomatosis with polyangiitis (GPA) EBV lymphoma Chronic Sinusitis

Plan Plan

Admission for further workup and treatment

Started on IV ampicillin-sulbactam (Unasyn) 3,000mg q6h

Repeat biopsy of nasal mucosa Biopsy of left inferior nasal septum and left

inferior turbinate obtained and sent to pathology

Ophthalmology follow-up as outpatient following discharge

Hospital CourseLabs

ESR: 65 (0-25)CRP: 166.7 (1.0-9.0)Proteinase-3 Auto

Antibodies: positivec-ANCA: negativep-ANCA: negativeMyeloperoxidase Auto

antibodies: negativeTSH: wnlFree T4: wnl

Immunoglobulin Panel: (all WNL)C3 149C4 25IgA 165IgG 949IgM 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

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

Anatomic Pathology Both biopsy samples showed necrotizing

granulomatous inflammation consist with GPA

Pathology

Necrotizing granulomatous inflammation

10x magnification

20x magnification

eosinophiles

Multinucleated giant cell

granuloma

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

VA(cc): 20/20 OUPupils: 4 3 OU; No RAPDIOP: 13 14EOM Full OU without painAnt Segment: WNL OUDFE: 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 Patient with increased energy, no epistaxis and

improved nasal congestion CBC & CMP: WNL CRP = 15.8 (<10.0)

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

Incidence: 3 per 100,000 reported in United States

Differential Diagnosis: 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

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 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

91% sensitivity and 99% specificity in active disease 8

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

90% of patients report ear, nose, or throat problems

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.

Clinical Features

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 4447- 4460. 2008.

Treatment There is no standardized treatment regimen for

granulomatosis with polyangiitis

Treatment is aimed at inducing remission 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

Remission maintained with cyclophosphamide, methotrexate or azathioprine

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.

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.

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. 2014 Feb

Thank You

References1. BCSC: Intraocular Inflammation and Uveitis. Pgs :145-1462. BCSC: Update on General Medicine. Optic Neuritis. Pgs 177-1793. Pakrou N, Selva D, Leibovitch I. Wegener;s Granulomatosis:

ophthalmic manifestations and management. Semin Arthritis Rheum. 2006;35(5):284-292

4. Berden A, Göçeroglu A, Jayne D, et al. Diagnosis and management of ANCA associated vasculitis. BMJ. 2012 Jan 16;344:e26.

5. Schilder AM. Wegener's Granulomatosis vasculitis and granuloma. Autoimmun Rev. 2010 May;9(7):483-7.

6. Tan LT, Davagnanam I, et.al. Clinical and Imaging Features Predictive of Orbital Granulomatosis with Polyangiitis and the Risk of Systemic Involvement. Ophthalmology. 2014 Feb 20. pii: S0161-6420(13)01175-5. doi: 10.1016/j.ophtha.2013.12.003. [Epub ahead of print]

7. Foster CS, Yang J. Wegener’s Granulomatosis. Albert & Jakobiec's Principles and Practice of Ophthalmology. Pages 4447- 4460. 2008.

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; 178-84

9. 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. 2013 Aug 1;369(5):417-27.