Candidate Biomarkers in ANCA-Associated Vasculitis Identified Using a Proteomic Approach

Paul A. Monach¹, Hemang Parikh², Laurie Conklin³, Jesse Damsker⁴, Peter C. Grayson⁵, David Cuthbertson⁶, Simon Carette⁷, Nader A. Khalidi⁸, Curry L. Koening⁹, Carol Langford¹⁰, Carol A. McAlear¹¹, Larry W. Moreland¹², Christian Pagnoux¹³, Philip Seo¹⁴, Ulrich Specks¹⁵, Antoine G. Sreih¹⁶, Steven R. Ytterberg¹⁷, Eric Hoffman⁴ and Peter A. Merkel¹⁸, ¹Rheumatology, VA Boston Healthcare System, Boston, MA, ²University of South Florida, Tampa, FL, ³ReveraGen BioPharma, Rockville, MD, ⁴ReveraGen Biopharma, Rockville, MD, ⁵National Institute of Arthritis, Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, MD, ⁶Biostatistics and Informatics, Department of Pediatrics, Department of Biostatistics and Informatics, Department of Pediatrics, University of South Florida, Tampa, FL, ⁷Division of Rheumatology, Mount Sinai Hospital, Toronto, ON, Canada, ⁸Rheumatology, McMaster University, Hamilton, ON, Canada, ⁹Rheumatology, Division of Rheumatology, University of Utah, Salt Lake City, UT, ¹⁰Rheumatic and Immunologic Diseases, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, OH, ¹¹Division of Rheumatology, University of Pennsylvania; Perelman School of Medicine, Philadelphia, PA, ¹²Division of Rheumatology and Clinical Immunology, Division of Rheumatology, University of Pittsburgh, Pittsburgh, PA, ¹³Division of Rheumatology, Division of Rheumatology, Mount Sinai Hospital, Toronto, ON, Canada, ¹⁴Medicine, Division of Rheumatology, Johns Hopkins University, Baltimore, MD, ¹⁵Mayo Clinic College of Medicine, Rochester, MN, ¹⁶Rheumatology, Division of Rheumatology, University of Pennsylvania, Philadelphia, PA, ¹⁷Rheumatology, Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN, ¹⁸Division of Rheumatology and the Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: biomarkers and vasculitis

Session Information

Date: Tuesday, October 23, 2018

Title: Vasculitis – ANCA-Associated Poster II

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Concentrations of many circulating proteins are elevated during severe, active ANCA-associated vasculitis (AAV). Finding biomarkers associated with milder disease, a more clinically relevant need, has proved challenging. In addition, some biomarkers may be directly affected by glucocorticoids.

Methods: 30 patients with AAV participating in a longitudinal cohort were studied. Serum samples from 2 visits were used for this study: i) a visit during active disease and when off prednisone; and ii) a visit approximately 3 months later when in clinical remission and on prednisone. A proteomic approach (SOMAscan, SomaLogic, Boulder, CO, USA) was used to assess more than 1000 circulating proteins simultaneously. Using Wilcoxon signed rank tests, a randomly selected sub-cohort of 15 patients was analyzed first, and markers significant at p <0.01 were then analyzed in the remaining sub-cohort of 15 patients, with p <0.05 regarded as validation. WebGestalt was used to test for enrichment in components of functional pathways.

Results: The cohort included 23 patients with GPA, 5 with EGPA, and 2 with MPA. Mean age was 52, and 18 were female. Thirteen were taking a non-steroid immunosuppressive drug at the time of flare, and 21 afterward. Disease activity was relatively low: physician global assessment of severity on a 0-10 scale had a mean of 3.2 (median 3, range 1-7), and only 7 patients had a “major” manifestation by BVAS/WG. Fourteen proteins were validated as associated with active disease (Table 1). Few of these markers have been previously identified in vasculitis, and only one (thrombospondin, TSP) in AAV. Four markers (CCL3/Mip-1a, CCL15/Mip-5, TNFRSF9/4-1BB, prolactin) are associated with the KEGG pathway Cytokine-cytokine receptor interaction.

Conclusion: In a cohort of patients with active but relatively mild AAV, 14 serum proteins were associated with significant change after successful treatment with prednisone. Thirteen of these markers have not been reported in AAV. These proteins, all of which are measurable by commercial immunoassays, are candidates for further study in real-world cohorts of partially-treated patients with AAV with mildly active disease.

Table 1. Protein biomarkers in active ANCA-associated vasculitis
	Discovery (n=15)		Validation (n=15)
Protein	Fold-change*	p-value	Fold-change*	p-value
Prolactin	1.17	0.002	1.12	<0.01
CCL15/MIP-5	1.26	<0.001	1.20	<0.01
RET	0.77	0.004	0.77	0.02
PAPP-A	0.58	0.007	0.70	0.02
SERPINA7	0.91	0.005	0.92	0.02
TSP4	0.69	<0.001	0.74	0.02
FAP/Seprase	0.87	0.002	0.87	0.02
Siglec-9	0.89	0.007	0.87	0.02
TNFRSF9/4-1BB	0.89	0.002	0.96	0.03
Factor B	0.85	0.002	0.88	0.04
REG4	1.2	0.004	1.12	0.04
CD200R1	0.86	<0.001	0.93	0.04
ADAM12	0.91	0.002	0.94	0.04
CCL3/MIP1a	0.83	0.003	0.92	0.05
* Fold change (mean) calculated by dividing post-treatment by pre-treatment values; values <1 indicate higher concentrations in active disease.

Disclosure: P. A. Monach, None; H. Parikh, None; L. Conklin, ReveraGen BioPharma, 9; J. Damsker, ReveraGen, 3; P. C. Grayson, None; D. Cuthbertson, None; S. Carette, None; N. A. Khalidi, None; C. L. Koening, None; C. Langford, None; C. A. McAlear, None; L. W. Moreland, None; C. Pagnoux, None; P. Seo, None; U. Specks, None; A. G. Sreih, None; S. R. Ytterberg, None; E. Hoffman, ReveraGen, 3; P. A. Merkel, None.

To cite this abstract in AMA style:

Monach PA, Parikh H, Conklin L, Damsker J, Grayson PC, Cuthbertson D, Carette S, Khalidi NA, Koening CL, Langford C, McAlear CA, Moreland LW, Pagnoux C, Seo P, Specks U, Sreih AG, Ytterberg SR, Hoffman E, Merkel PA. Candidate Biomarkers in ANCA-Associated Vasculitis Identified Using a Proteomic Approach [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/candidate-biomarkers-in-anca-associated-vasculitis-identified-using-a-proteomic-approach/. Accessed .

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