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Original Investigation
November 2017

Gene Expression Profiling and Heterogeneity of Nonspecific Orbital Inflammation Affecting the Lacrimal Gland

Author Affiliations
  • 1Casey Eye Institute, Oregon Health & Science University, Portland
  • 2Devers Eye Institute, Legacy Health System, Portland, Oregon
  • 3Department of Medicine, Oregon Health & Science University, Portland
  • 4Oregon Health and Science University–Portland State University School of Public Health, Oregon Health & Science University, Portland
  • 5Graduate School of Dentistry, Kyung Hee University, Seoul, Korea
  • 6Integrated Genomics Laboratory, Oregon Health & Science University, Portland
  • 7Department of Ophthalmology, Emory University, Atlanta, Georgia
  • 8Research Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
  • 9Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, British Columbia, Canada
  • 10Department of Ophthalmology, Ohio University, Columbus
  • 11Ophthalmic Surgeons and Consultants of Ohio, Columbus
  • 12Department of Ophthalmology, The Ohio State University, Columbus
  • 13Department of Ophthalmology, Medical College of Wisconsin, Milwaukee
  • 14Department of Ophthalmology, Kaohsiung Veteran’s General Hospital, Kaohsiung City, Taiwan
  • 15Department of Ophthalmology, University of Miami, Miami, Florida
  • 16Department of Ophthalmology, Columbia University, New York, New York
  • 17Ophthalmology Network, Royal Adelaide Hospital, Adelaide, Australia
  • 18Department of Ophthalmology, Wake Forest University, Winston-Salem, North Carolina
  • 19Department of Ophthalmology, University of California, San Diego
  • 20currently in private practice in Oakland, California
  • 21Department of Ophthalmology, University of West Virginia, Morgantown
JAMA Ophthalmol. 2017;135(11):1156-1162. doi:10.1001/jamaophthalmol.2017.3458
Key Points

Question  Is nonspecific orbital inflammation affecting the lacrimal gland a single disease or multiple different diseases, and is it a limited form of other diseases, such as sarcoidosis or granulomatosis with polyangiitis?

Findings  This cohort study comparing the expression of 40 genes from biopsy specimens of 48 patients having lacrimal nonspecific orbital inflammation with healthy controls indicates that such inflammation is a heterogeneous collection of diseases and suggests that it is often a limited form of known lacrimal inflammation.

Meaning  Gene expression patterns can subdivide lacrimal gland nonspecific orbital inflammation, having the potential to lead to more precise therapy and new insights into pathogenesis.


Importance  Although a variety of well-characterized diseases, such as sarcoidosis and granulomatosis with polyangiitis, affect the lacrimal gland, many patients with dacryoadenitis are diagnosed as having nonspecific orbital inflammation (NSOI) on the basis of histology and systemic disease evaluation. The ability to further classify the disease in these patients should facilitate selection of effective therapies.

Objective  To test the a priori hypothesis that gene expression profiles would complement clinical and histopathologic evaluations in identifying well-characterized diseases and in subdividing NSOI into clinically relevant groups.

Design, Setting, and Participants  In this cohort study, gene expression levels in biopsy specimens of inflamed and control lacrimal glands were measured with microarrays. Stained sections of the same biopsy specimens were used for evaluation of histopathology. Tissue samples of patients were obtained from oculoplastic surgeons at 7 international centers representing 4 countries (United States, Saudi Arabia, Canada, and Taiwan). Gene expression analysis was done at Oregon Health & Science University. Participants were 48 patients, including 3 with granulomatosis with polyangiitis, 28 with NSOI, 7 with sarcoidosis, 4 with thyroid eye disease, and 6 healthy controls. The study dates were March 2012 to April 2017.

Main Outcomes and Measures  The primary outcome was subdivision of biopsy specimens based on gene expression of a published list of approximately 40 differentially expressed transcripts in blood, lacrimal gland, and orbital adipose tissue from patients with sarcoidosis. Stained sections were evaluated for inflammation (none, mild, moderate, or marked), granulomas, nodules, or fibrosis by 2 independent ocular pathologists masked to the clinical diagnosis.

Results  Among 48 patients (mean [SD] age, 41.6 [19.0] years; 32 [67%] female), the mclust algorithm segregated the biopsy specimens into 4 subsets, with the differences illustrated by a heat map and multidimensional scaling plots. Most of the sarcoidosis biopsy specimens were in subset 1, which had the highest granuloma score. Three NSOI biopsy specimens in subset 1 had no apparent granulomas. Thirty-two percent (9 of 28) of the NSOI biopsy specimens could not be distinguished from biopsy specimens of healthy controls in subset 4, while other examples of NSOI tended to group with gene expression resembling granulomatosis with polyangiitis or thyroid eye disease. The 4 subsets could also be partially differentiated by their fibrosis, granulomas, and inflammation pathology scores but not their lymphoid nodule scores.

Conclusions and Relevance  Gene expression profiling discloses clear heterogeneity among patients with lacrimal inflammatory disease. Comparison of the expression profiles suggests that a subset of patients with nonspecific dacryoadenitis might have a limited form of sarcoidosis, while other patients with NSOI cannot be distinguished from healthy controls.