Grand Rounds Brett Mueller, D.O., Ph.D. June 16,

Grand Rounds Brett Mueller, D.O., Ph.D. June 16,

Grand Rounds Brett Mueller, D.O., Ph.D. June 16, 2017 Department of Ophthalmology and Visual Sciences Patient Presentation CC Left sided facial pain HPI

54 yo WM with significant PMH of lymphoma s/p chemotherapy and radiation in 2009, multiple MIs, CHF, COPD who presents with persistent left facial pain for several months that has progressed over the past week. CT demonstrated an infiltrating lesion from the ethmoid sinuses into the orbit. Primary team concerned for orbital cellulitis. He denies any changes in his visual acuity. History (Hx) Past Medical Hx:

- Multiple ER visits over the past year for shortness of breath - Chronic sinusitis being treated by ENT - CHF, COPD , HTN, B-cell lymphoma Meds: ASA, statin, flonase, gabapentin, imdur, lisinopril, symbicort, ventolin HFA, torsemide Allergies: NKDA Social Hx: 12 drinks per day, one PPD smoker, and uses marijuana/hash daily Review of Systems Multiple admissions for unstable angina without a

given cause Sinusitis that has been treated with multiple rounds of antibiotics without resolution 20 pound weight loss over the past 2-3 months with poor appetite, fevers, chills, and night sweats Increasing lymphadenopathy External Exam OD OS

VA 20/20 20/200 Refraction -1.00 sphere

-1.00 sphere Pupils 43mm IOP 12 mmHg 15 mmHg

EOM Full Full (Discomfort with motility) CVF Full

Full No rAPD 43mm Anterior Segment Exam SLE OD

OS Pertinent Positives: swelling along the parotid glands with palpable lymphadenopathy WNL External/Lids

Pertinent Negatives: erythema, chemosis, or conj injection Conj/Sclera WNL Cornea WNL

Ant Chamber WNL Iris WNL Lens

1+ NS 3+ NS with a 4+ PSC Posterior Segment Exam Fundus OD OS

Optic Nerve Pink and sharp Pink and sharp Macula Sharp foveal reflex Sharp foveal reflex

Vessels WNL WNL Periphery WNL

WNL CT Scan 2 months ago Current CT T1 Images T1 T1 Fat Suppression, post- contrast

T2 Image DWI/ADC Assessment 54 yo WM with a ill-defined iso-intense lesion to EOM on T1 that enhances post contrast and demonstrates a hyper-intensity on DWI that is encroaching from the maxillary and ethmoidal sinuses into the left and right orbits.

Differential Diagnosis Recurrence of lymphoma Infectious (Bacterial VS Fungal) Granulomatosis with polyangiitis Plan ENT to take the patient into surgery for a tissue biopsy. Also will start workup to rule out lymphoma and different inflammatory lesions.

Follow-up 2 Days After Surgery Pathology Results: Negative for malignant cells Bacterial and fungal cultures were negative Demonstrates scattered lymphocytes and stromal elements After surgery patient complains of decreased visual acuity down to count fingers OS with a new APD and limitation

of adduction Plan Oculoplastics service to take the patient for an orbitotomy for a definitive tissue diagnosis Pathology Pathology

Pathology Follow-up Results c-ANCA + CT of the chest demonstrated multiple cavitary lesions of the lung Diagnosis Granulomatosis with polyangiitis (GPA) Plan

Start the patient on 1mg/kg of oral steroids and send the patient to rheumatology for further management Follow-up 1 month later Pt has been started on Rituximab Still has APD and CF vision at 3 feet, but resolution of his limitation in adduction Granulomatosis with Polyangiitis Multisystem autoimmune disorder

characterized by the classic triad: Necrotizing granulomatous vasculitis of the upper and lower respiratory tract Focal segmental glomerulonephritis Necrotizing vasculitis of small arteries and veins Epidemiology Males affected more often than females, at an average age of 40 years, with peak incidence in the fifth decade.

Caucasians are affected more than African Americans Incidence in the United States: 4 per 1,000,000.6 Prevalence in the United States: 1-5 per 100,000.6 Clinical Presentation Persistent pneumonitis with bilateral nodular and cavitary infiltrates (95%) Chronic sinusitis (90%) Renal disease (80%) Mucosal ulcerations of the nasopharynx (75%)

Clinical Presentation Skin rashes Muscle pains Articular involvement Mononeuritis or polyneuritis Fever Ophthalmic Manifestations Ocular and orbital involvement is seen in 15% of patients at presentation and up to

50% of patients during the course of the disease. Orbital involvement usually secondary from contiguous extension of the granulomatous inflammatory process from the paranasal sinuses into the orbit. Ophthalmic Manifestations Orbital pseudotumor, orbital cellulitis and dacryocystitis may arise from secondarily infected nasal mucosa.

40% of patients develop scleritis of any type (diffuse anterior or necrotizing disease) w/ or w/o peripheral ulcerative keratitis. 10% of patients can develop anterior, intermediate or posterior uveitis. Ophthalmic Manifestations Patients can also develop vaso-occlusive disease, including branch or central retinal artery or vein occlusion. Also there are reports of patients getting

ischemic optic neuropathy. 40% of patients with GPA will suffer some form of vision loss. Diagnosis Tissue biopsy is the gold standard CXR: nodular diffuse or cavitary lesions Proteinuria or hematuria Elevated ESR and CRP + ANCAs (c-ANCA)

Differential Diagnosis Infectious Malignancy Inflammatory (orbital pseudotumor or IgG4) Differential Diagnosis Goodpastures Syndrome

Other vasculitis Microscopic polyangiitis Churg-Strauss Polyarteritis Nodosa Pathogenesis Unknown Similar to PAN and serum sickness suggest some form of a hypersensitivity, possibly to an inhaled infectious or environmental agent Presence of granulomas and dramatic

response to immunosuppressive therapy support an immunologic mechanism Treatment Combination of oral corticosteroids and immunomodulatory therapy (IMT), specifically cyclophosphamide, and rituximab Without therapy, the 1 year mortality is 80% With treatment, 93% of patients treated achieve remission with resolution of ocular manifestations

Literature Review Purpose: To determine the efficacy of rituximab for the treatment of Granulomatosis with polyangiitis (GPA) Design: Randomized, double blind, noninferiority trial of rituximab compared to cyclophosphamide for the treatment of GPA. Primary end-point was remission of disease w/o the use of prednisone at 6 months.

Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Specks U; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010 Jul 15;363(3):221-32. doi: 10.1056/NEJMoa0909905. PubMed PMID: 20647199; PubMed Central PMCID: PMC3137658 Literature Review Results: 67% of rituximab group as compared to 42% of the cyclophosphamide group reached their

primary end point Conclusion: Rituximab therapy was not inferior to daily cyclophosphamide Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Specks U; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010 Jul 15;363(3):221-32. doi: 10.1056/NEJMoa0909905. PubMed PMID: 20647199; PubMed Central PMCID: PMC3137658 Conclusions

GPA is a triad of: necrotizing granulomatous vasculitis of the upper and lower respiratory tract, focal segmental glomerulonephritis, and necrotizing vasculitis This disease has an 80% mortality without treatment Pathogenesis remains unknown, but likely a mixed b-cell and t-cell dysregulation that is causing this disease References

1) 2) 3) 4) 5) 6) 7) Kanskis Clinical Ophthalmology A systemic Approach, Eighth Edition. Brad Bowling Retina and Vitritis, BSCS Oculoplastics, BSCS

https://www.aao.org/bcscsnippetdetail.aspx?id=e805c10e-5182-4a54-90d0-ee5a3111ff4 Robbins and Cotran Pathologic Basis of Desease, 7 th Edition Cecil Medicine 23rd Edition Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Specks U; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010 Jul 15;363(3):221-32. doi: 10.1056/NEJMoa0909905. PubMed PMID: 20647199; PubMed Central PMCID: PMC3137658 8) Up-to-date, looking up Granulomatosis with polyangiitis

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