Characterization of Early and Progressive Autoimmunity in Sjogrens Syndrome: The Incomplete Sjogrens Syndrome Model

Astrid Rasmussen¹, Christopher J Lessard², Indra Adrianto¹, Graham B. Wiley¹, Donald U Stone^3,4, C. Erick Kaufman⁵, Lida Radfar⁶, David M. Lewis⁷, Stephen K Young⁸, Michael H. Weisman⁹, Daniel J Wallace¹⁰, Swamy Venuturupalli¹¹, Barbara M. Segal¹², John A. Ice¹, Juan-Manuel Anaya¹³, Michael D. Rohrer¹⁴, Raj Gopalakrishnan¹⁵, Glen D Houston¹⁶, James Chodosh¹⁷, Pamela J Hughes¹⁸, Nelson L. Rhodus¹⁹, Jennifer A. Kelly²⁰, Kiely Grundahl²¹, Kimberly Hefner²², R. Hal Scofield^1,23,24 and Kathy L. Sivils¹, ¹Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, ²Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, ³Research Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia, ⁴Department of Ophthalmology, Johns Hopkins University, Riyadh, Saudi Arabia, ⁵College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, ⁶Oral Diagnosis and Radiology Department, University of Oklahoma Health Sciences Center College of Dentistry, Oklahoma City, OK, ⁷College of Dentistry, Department of Oral and Maxillofacial Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, ⁸College of Dentistry, University of Oklahoma Health Sciences Center, Oklahoma City, OK, ⁹Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, ¹⁰Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, ¹¹Cedars-Sinai Medical Center, West Hollywood, CA, ¹²Rheumatology, Hennepin County Medical Center, Minneapolis, MN, ¹³Center for Autoimmune Diseases Research (CREA), Universidad del Rosario., Bogota, Colombia, ¹⁴Diagnostic and Biological Sciences, University of Minnesota, Minneapolis, MN, ¹⁵Diagnostic and Biological Sciences, Division of Oral Pathology, University of Minnesota, Minneapolis, MN, ¹⁶Heartland Pathology, Oklahoma City, OK, ¹⁷Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, ¹⁸Division of Oral and Maxillofacial Surgery, University of Minnesota, Minneapolis, MN, ¹⁹Department of Oral Surgery, University of Minnesota School of Dentistry, Minneapolis, MN, ²⁰Arthritis & Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, ²¹Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma CIty, OK, ²²Hefner Eye Care and Optical Center, Oklahoma City, OK, ²³Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, ²⁴US Department of Veterans Affairs Medical Center, Oklahoma City, OK

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: diagnosis and interferons, Sjogren's syndrome

Session Information

Date: Tuesday, November 10, 2015

Title: Sjögren's Syndrome II: Clinical Discoveries

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Autoimmune diseases are often preceded by subclinical serologic and functional abnormalities that predate diagnosis by several years. The insidious and progressive nature of these incomplete syndromes results in a lag in diagnosis, preventive and therapeutic strategies, and likely contributes to damage accrual.

Methods: : To explore possible markers of transition from incomplete Sjögren’s Syndrome (iSS) to complete Sjögren’s Syndrome (SS), 467 iSS patients were compared to 364 SS (SS) meeting AECG classification criteria in a multi-disciplinary sicca clinic. All subjects were evaluated for AECG classification measures, clinical and serological features (25 autoantibodies), and gene expression profiling of 64 interferon (IFN)-inducible genes. We developed an IFN-score based on the most informative 14 genes, which were differentially expressed (p<0.05, fold-change>2, and log2[SD(expression)]<1.75 for each group) in nine controls from previous microarray and RNASeq experiments with known high (n=4) and low (n=5) IFN-signature expression. A logistic regression model was created to calculate the probability of having a high interferon level for each iSS case; the resulting probability output is the IFN score.

Results: Nineteen iSS subjects had anti-Ro antibodies (4.1%), and 33 (7.1%) were biopsy (+); the remaining 415 had nonSS-sicca. Ro (+) iSS constituted a distinct subgroup from all Ro (-) iSS: they were younger (p=0.001), less white (p=1.95E10-7), more anti-La (+) (p=8.8E10-6), and had more hypergammaglobulinemia (p=0.02) and lymphopenia (p=0.009); 14/19 had extraglandular manifestations. These same statistically significant clinical differences were also observed when Ro (+) iSS to biopsy (+) iSS and Ro (-)/biopsy (-) iSS. Subsets of Ro (-) iSS subjects were (+) for other autoantibodies associated with SLE or Scleroderma: 14 had anti-Cenp-B and 10 had anti-dsDNA. Quantitatively, IFN-inducible gene expression occurs in a gradient: non-SS sicca patients have low IFN scores, biopsy (+)/Ro (-) have intermediate scores, and Ro (+) have high IFN scores, which are similar to those identified in autoantibody (+) pSS patients. High IFN-scores correlated with presence of any autoantibodies (p=1.08E-08), Ro (+) iSS (p=4.53E-06), and biopsy (+) iSS (p=6E-03), but only marginally with reduced salivary flow (p=0.018). There was no significant difference in IFN scores between SS and Ro (+) iSS, but SS had higher IFN scores than both biopsy (+) iSS and non-SS sicca (p=8.6E-3 and 1.95E-30, respectively).

Conclusion: Patients with iSS may represent a forme frustre of SS, but it is plausible that some subsets, in particular Ro (+) iSS and dsDNA(+) iSS, will progress to SS, SLE, or overlap syndromes, respectively. The fact that they present similar IFN-signatures as those observed in SS further supports this notion, and therefore, iSS patients warrant careful follow up to characterize the transition to full-blown SS. Understanding the early events of disease has the strongest potential to lead to improvements in prevention, early diagnosis, and therapeutics.

Disclosure: A. Rasmussen, None; C. J. Lessard, None; I. Adrianto, None; G. B. Wiley, None; D. U. Stone, None; C. E. Kaufman, None; L. Radfar, None; D. M. Lewis, None; S. K. Young, None; M. H. Weisman, None; D. J. Wallace, None; S. Venuturupalli, None; B. M. Segal, None; J. A. Ice, None; J. M. Anaya, None; M. D. Rohrer, None; R. Gopalakrishnan, None; G. D. Houston, None; J. Chodosh, None; P. J. Hughes, None; N. L. Rhodus, None; J. A. Kelly, None; K. Grundahl, None; K. Hefner, None; R. H. Scofield, None; K. L. Sivils, None.

To cite this abstract in AMA style:

Rasmussen A, Lessard CJ, Adrianto I, Wiley GB, Stone DU, Kaufman CE, Radfar L, Lewis DM, Young SK, Weisman MH, Wallace DJ, Venuturupalli S, Segal BM, Ice JA, Anaya JM, Rohrer MD, Gopalakrishnan R, Houston GD, Chodosh J, Hughes PJ, Rhodus NL, Kelly JA, Grundahl K, Hefner K, Scofield RH, Sivils KL. Characterization of Early and Progressive Autoimmunity in Sjogrens Syndrome: The Incomplete Sjogrens Syndrome Model [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/characterization-of-early-and-progressive-autoimmunity-in-sjogrens-syndrome-the-incomplete-sjogrens-syndrome-model/. Accessed .

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