Gene expression profiling and heterogeneity of nonspecific orbital inflammation affecting the lacrimal gland

James (Jim) Rosenbaum, Dongseok Choi, Christina (Chris) Harrington, David Wilson, Hans E. Grossniklaus, Cailin Sibley, Sherveen S. Salek, John Ng, Roger Dailey, Eric Steele, Brent Hayek, Caroline M. Craven, Deepak P. Edward, Azza M.Y. Maktabi, Hailah Al Hussain, Valerie A. White, Peter J. Dolman, Craig N. Czyz, Jill A. Foster, Gerald J. HarrisYoun Shen Bee, David T. Tse, Chrisfouad R. Alabiad, Sander R. Dubovy, Michael Kazim, Dinesh Selva, R. Patrick Yeatts, Bobby S. Korn, Don O. Kikkawa, Rona Z. Silkiss, Jennifer A. Sivak-Callcott, Patrick Stauffer, Stephen Planck

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1156-1162
Number of pages7
JournalJAMA Ophthalmology
Volume135
Issue number11
DOIs
StatePublished - Nov 1 2017

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Lacrimal Apparatus
Gene Expression Profiling
Inflammation
Biopsy
Sarcoidosis
Granuloma
Granulomatosis with Polyangiitis
Dacryocystitis
Gene Expression
Eye Diseases
Thyroid Diseases
Fibrosis
Saudi Arabia
Tears
Taiwan
Transcriptome
Canada
Adipose Tissue
Histology
Cohort Studies

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Gene expression profiling and heterogeneity of nonspecific orbital inflammation affecting the lacrimal gland. / Rosenbaum, James (Jim); Choi, Dongseok; Harrington, Christina (Chris); Wilson, David; Grossniklaus, Hans E.; Sibley, Cailin; Salek, Sherveen S.; Ng, John; Dailey, Roger; Steele, Eric; Hayek, Brent; Craven, Caroline M.; Edward, Deepak P.; Maktabi, Azza M.Y.; Al Hussain, Hailah; White, Valerie A.; Dolman, Peter J.; Czyz, Craig N.; Foster, Jill A.; Harris, Gerald J.; Bee, Youn Shen; Tse, David T.; Alabiad, Chrisfouad R.; Dubovy, Sander R.; Kazim, Michael; Selva, Dinesh; Yeatts, R. Patrick; Korn, Bobby S.; Kikkawa, Don O.; Silkiss, Rona Z.; Sivak-Callcott, Jennifer A.; Stauffer, Patrick; Planck, Stephen.

In: JAMA Ophthalmology, Vol. 135, No. 11, 01.11.2017, p. 1156-1162.

Research output: Contribution to journalArticle

Rosenbaum, JJ, Choi, D, Harrington, CC, Wilson, D, Grossniklaus, HE, Sibley, C, Salek, SS, Ng, J, Dailey, R, Steele, E, Hayek, B, Craven, CM, Edward, DP, Maktabi, AMY, Al Hussain, H, White, VA, Dolman, PJ, Czyz, CN, Foster, JA, Harris, GJ, Bee, YS, Tse, DT, Alabiad, CR, Dubovy, SR, Kazim, M, Selva, D, Yeatts, RP, Korn, BS, Kikkawa, DO, Silkiss, RZ, Sivak-Callcott, JA, Stauffer, P & Planck, S 2017, 'Gene expression profiling and heterogeneity of nonspecific orbital inflammation affecting the lacrimal gland', JAMA Ophthalmology, vol. 135, no. 11, pp. 1156-1162. https://doi.org/10.1001/jamaophthalmol.2017.3458
Rosenbaum, James (Jim) ; Choi, Dongseok ; Harrington, Christina (Chris) ; Wilson, David ; Grossniklaus, Hans E. ; Sibley, Cailin ; Salek, Sherveen S. ; Ng, John ; Dailey, Roger ; Steele, Eric ; Hayek, Brent ; Craven, Caroline M. ; Edward, Deepak P. ; Maktabi, Azza M.Y. ; Al Hussain, Hailah ; White, Valerie A. ; Dolman, Peter J. ; Czyz, Craig N. ; Foster, Jill A. ; Harris, Gerald J. ; Bee, Youn Shen ; Tse, David T. ; Alabiad, Chrisfouad R. ; Dubovy, Sander R. ; Kazim, Michael ; Selva, Dinesh ; Yeatts, R. Patrick ; Korn, Bobby S. ; Kikkawa, Don O. ; Silkiss, Rona Z. ; Sivak-Callcott, Jennifer A. ; Stauffer, Patrick ; Planck, Stephen. / Gene expression profiling and heterogeneity of nonspecific orbital inflammation affecting the lacrimal gland. In: JAMA Ophthalmology. 2017 ; Vol. 135, No. 11. pp. 1156-1162.
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abstract = "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.",
author = "Rosenbaum, {James (Jim)} and Dongseok Choi and Harrington, {Christina (Chris)} and David Wilson and Grossniklaus, {Hans E.} and Cailin Sibley and Salek, {Sherveen S.} and John Ng and Roger Dailey and Eric Steele and Brent Hayek and Craven, {Caroline M.} and Edward, {Deepak P.} and Maktabi, {Azza M.Y.} and {Al Hussain}, Hailah and White, {Valerie A.} and Dolman, {Peter J.} and Czyz, {Craig N.} and Foster, {Jill A.} and Harris, {Gerald J.} and Bee, {Youn Shen} and Tse, {David T.} and Alabiad, {Chrisfouad R.} and Dubovy, {Sander R.} and Michael Kazim and Dinesh Selva and Yeatts, {R. Patrick} and Korn, {Bobby S.} and Kikkawa, {Don O.} and Silkiss, {Rona Z.} and Sivak-Callcott, {Jennifer A.} and Patrick Stauffer and Stephen Planck",
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TY - JOUR

T1 - Gene expression profiling and heterogeneity of nonspecific orbital inflammation affecting the lacrimal gland

AU - Rosenbaum, James (Jim)

AU - Choi, Dongseok

AU - Harrington, Christina (Chris)

AU - Wilson, David

AU - Grossniklaus, Hans E.

AU - Sibley, Cailin

AU - Salek, Sherveen S.

AU - Ng, John

AU - Dailey, Roger

AU - Steele, Eric

AU - Hayek, Brent

AU - Craven, Caroline M.

AU - Edward, Deepak P.

AU - Maktabi, Azza M.Y.

AU - Al Hussain, Hailah

AU - White, Valerie A.

AU - Dolman, Peter J.

AU - Czyz, Craig N.

AU - Foster, Jill A.

AU - Harris, Gerald J.

AU - Bee, Youn Shen

AU - Tse, David T.

AU - Alabiad, Chrisfouad R.

AU - Dubovy, Sander R.

AU - Kazim, Michael

AU - Selva, Dinesh

AU - Yeatts, R. Patrick

AU - Korn, Bobby S.

AU - Kikkawa, Don O.

AU - Silkiss, Rona Z.

AU - Sivak-Callcott, Jennifer A.

AU - Stauffer, Patrick

AU - Planck, Stephen

PY - 2017/11/1

Y1 - 2017/11/1

N2 - 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.

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