igg4-associated orbital and ocular inflammation relapsing, sclerosing inflammation in virtually...
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IgG4-associated orbital and ocular inflammationCecilia S. LeeWashington University School of Medicine in St. Louis
George J. HarocoposWashington University School of Medicine in St. Louis
Courtney L. KrausWashington University School of Medicine in St. Louis
Aaron Y. LeeWashington University School of Medicine in St. Louis
Gregory P. Van StavernWashington University School of Medicine in St. Louis
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Recommended CitationLee, Cecilia S.; Harocopos, George J.; Kraus, Courtney L.; Lee, Aaron Y.; Van Stavern, Gregory P.; Couch, Steven M.; and Rao, P.Kumar, ,"IgG4-associated orbital and ocular inflammation." Journal of Ophthalmic Inflammation and Infection.5,1. 15. (2015).http://digitalcommons.wustl.edu/open_access_pubs/3917
AuthorsCecilia S. Lee, George J. Harocopos, Courtney L. Kraus, Aaron Y. Lee, Gregory P. Van Stavern, Steven M.Couch, and P. Kumar Rao
This open access publication is available at Digital Commons@Becker: http://digitalcommons.wustl.edu/open_access_pubs/3917
BRIEF REPORT Open Access
IgG4-associated orbital and ocular inflammationCecilia S Lee1,2, George J Harocopos1,3, Courtney L Kraus1,4, Aaron Y Lee1,5, Gregory P Van Stavern1,Steven M Couch1 and P Kumar Rao1*
Background: IgG4-associated orbital and ocular inflammation is a relatively unknown entity characterized bysclerosing inflammation with infiltration of IgG4-positive plasma cells. Some so-called idiopathic inflammationsyndromes are being re-classified as IgG4-associated inflammation with histopathologic evaluation.
Findings: We report three cases with differing manifestations of IgG4-associated ocular and orbital inflammation:a case of recurrent, treatment-refractory sclero-uveitis that was diagnosed as granulomatosis with polyangiitis with anIgG4-related component, a case of pachymeningitis with optic neuritis that resulted in permanent visual loss, and acase of orbital inflammatory pseudotumor. All three would have been incompletely diagnosed without thoroughhistopathologic evaluation (including immunohistochemistry).
Conclusions: IgG4-associated disease is an idiopathic, multi-organ inflammatory state that can manifest aschronic, relapsing, sclerosing inflammation in virtually any organ system. There is a wide range of presentations inocular and orbital inflammation. Ophthalmologists should keep IgG4-associated inflammation in mind when examiningchronic, sclerofibrosing inflammation with multi-system involvement. The histology of biopsy specimens is crucial inmaking the correct diagnosis. Timely assessment may lead to fewer diagnostic tests and more targeted therapy.
Keywords: IgG4-associated ocular inflammation; IgG4-associated orbital inflammation; Histopathology
FindingsIgG4-associated disease is a relatively newly discoveredentity characterized by sclerosing inflammation, a lym-phoplasmacytic infiltration full of IgG4-positive plasmacells and frequently associated with elevated serum IgG4concentrations . It was first described as a systemiccondition in 2003 when extra-pancreatic manifestationswere identified in patients with autoimmune pancrea-titis, a condition known to be associated with elevatedlevels of IgG4 . Since that discovery, the presence ofIgG4-related inflammation has been detected in virtuallyall organs, particularly the pancreas, liver, kidney, lung,and thyroid [1, 3, 4, 5]. The histopathological featuresexhibit remarkable consistency across organ systems. Inophthalmology, IgG4-positive sclerosing inflammationmost frequently presents with involvement of the orbit/lacrimal gland [1, 5, 6], but recent case reports have
described conjunctival and scleral involvement [3, 7]. Wereport a series of three heterogeneous patients includingsome unusual presentations of IgG4-associated ocular/orbital inflammatory disease: sclero-uveitis, pachymenin-gitis with associated bilateral optic neuropathy/perineuritis,and inflammatory pseudotumor of the orbit.
Case summariesCase 1A 79-year-old woman was referred to our institutionwith a 1-year history of tearing, blurry vision, pain,photophobia, and redness in her right eye. Past medicalhistory was significant for breast cancer, which requiredright lumpectomy 14 years prior and left lumpectomyplus radiation that was completed about 1 year prior toreferral. The patients symptoms in the right eye hadbegun about 1 month following the completion of theradiation treatment for breast cancer, at which point shewas diagnosed with nodular scleritis inferotemporally inthe right eye, and she was found to have elevated peri-nuclear accentuated anti-neutrophil cytoplasmic anti-bodies (p-ANCA), leading to suspicion for granulomatosis
* Correspondence: firstname.lastname@example.orgDepartment of Ophthalmology and Visual Sciences, Washington Universityin St. Louis, CB 8096, 660 S. Euclid, St. Louis, MO 63110, USAFull list of author information is available at the end of the article
2015 Lee et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproductionin any medium, provided the original work is properly credited.
Lee et al. Journal of Ophthalmic Inflammation and Infection (2015) 5:15 DOI 10.1186/s12348-015-0047-y
with polyangiitis. She was managed by multiple ophthal-mologists and rheumatologists. Medical history alsoincluded insulin-dependent diabetes, hypertension, hyper-lipidemia, anemia, and colon cancer about 16 years prior.There was a history of maxillary and sphenoid sinusitis,for which the patient had right mastoid surgery, as well asa history of bilateral ear tubes. The patient also had, atthe time of presentation, bilateral renal oncocytomastreated with cryoablation, but renal function was normal.Past ocular history included open-angle glaucoma initiallywell-controlled with topical therapy alone but later exac-erbated by an inflammatory/corticosteroid-induced com-ponent in the right eye. Prior to referral, the patient hadbeen treated with oral prednisone, with good response, butexperienced recurrences whenever the dose was tapered.She had also been treated with cyclophosphamide and indo-methacin but had a history of poor response to azathioprine.Upon referral to our institution, best corrected visual acuity(BCVA) was 20/80 in the right eye. Slit-lamp examinationdemonstrated 360 of conjunctival and scleral injection, nod-ules in the temporal sclera, and 1+ nuclear sclerotic cataract.Dilated fundus examination and B-scan ultrasound showedpanuveitis and serous retinal detachment associated withsubretinal fluid (Fig. 1). A T sign was also noted on ultra-sound, consistent with posterior scleritis. Left eye exam
was unremarkable. The differential diagnosis included in-flammatory sclero-uveitis and intraocular lymphoma but fa-voring a diagnosis of inflammatory anterior/posteriorscleritis and uveitis. An extensive work-up for sclero-uveitis was only positive for p-ANCA with a titer of>1:640 (normal
with hyalinization of vessels, raising the possibility thatthese findings represented the late stage of a vasculiticprocess, and accordingly, granulomatosis with polyangiitisremained in the differential diagnosis (Fig. 1b, c).Treatment subsequently included methotrexate and
infliximab infusions, but the patient continued to haverecurrent eye pain and eventually developed a blind,painful right eye with end-stage glaucoma and persistentvitritis, besides evidence of optic nerve sheath inflamma-tion on imaging, leading to an enucleation. The histo-pathology of the globe showed necrotizing and fibroticgranulomatous scleritis and granulomatous panuveitis(Fig. 2). Of note, microbial stains were negative. Chronicoptic neuritis was also noted, with optic cupping and at-rophy (Fig. 2a, e). There was serous detachment of theretina with subretinal protein, correlating with the clin-ical appearance (Fig. 2a). The retina exhibited severe at-rophy, with chronic vasculitis seen in some of the retinalvessels (Fig. 2f ), and a neovascular epiretinal membranewas appreciated overlying the pars plana. There were noatypical lymphocytes or any evidence of lymphoma onimmunohistochemistry, with T cells (CD3-positive) faroutnumbering the B cells (CD20-positive), and with insitu hybridization demonstrating a relatively even mix-ture of kappa- and lambda-positive plasma cells (notshown). Many of the plasma cells stained positive withIgG4 (Fig. 2g), i.e., about 70 per high-power field, com-prising over 50 % of the total plasma cell p