Biomarkers of Disease Activity in Vasculitis

Alicia Rodriguez-Pla¹, Roscoe L. Warner², David Cuthbertson³, Simon Carette⁴, Gary S. Hoffman⁵, Nader A. Khalidi⁶, Curry L Koening⁷, Carol A. Langford⁸, Kathleen Maksimowicz-McKinnon⁹, Larry W. Moreland¹⁰, Christian Pagnoux⁴, Philip Seo¹¹, Ulrich Specks^12,13, Kenneth J. Warrington¹⁴, Steven R. Ytterberg¹⁵, Peter A. Merkel¹⁶, Kent J. Johnson², Paul A. Monach¹⁷ and For the Vasculitis Research Consortium¹⁸, ¹Rheumatology, Boston University, Boston, MA, ²Pathology, University of Michigan, Ann Arbor, MI, ³Department of Biostatistics, University of South Florida, Tampa, FL, ⁴Division of Rheumatology, University of Toronto, Toronto, ON, Canada, ⁵Center for Vasculitis Care and Research, Cleveland Clinic Foundation, Cleveland, OH, ⁶Internal Medicine/Rheumatology, McMaster University, Hamilton, ON, Canada, ⁷Division of rheumatology, George E. Wahlen Department of Veterans Affairs Medical Center Salt Lake City and University of Utah, University of Utah School of Medicine, Salt Lake City, UT, ⁸Center for Vasculitis Care and Research, Cleveland Clinic, Cleveland, OH, ⁹Rheumatology, Henry Ford Hospital, Detroit, MI, ¹⁰Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, ¹¹Rheumatology Division, Johns Hopkins Vasculitis Center, Johns Hopkins University, Baltimore, MD, ¹²Frederichs Dr NW, Mayo Clinic, Rochester, MN, ¹³Mayo Clinic, Rochester, MN, ¹⁴Division of Rheumatology, Mayo Clinic, Rochester, MN, ¹⁵Rheumatology Division, Mayo Clinic, Rochester, MN, ¹⁶University of Pennsylvania, Philadelphia, PA, ¹⁷Section of Rheumatology, Vasculitis Center, Boston University School of Medicine, Boston, MA, ¹⁸U Pennsylvania, Philadelphia, PA

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Biomarkers, giant cell arteritis, polyarteritis nodosa and vasculitis, Takayasu.s arteritis

Session Information

Title: Vasculitis

Session Type: Abstract Submissions (ACR)

Background/Purpose

To identify circulating proteins that distinguish between active vasculitis and remission in giant cell arteritis (GCA), Takayasu’s arteritis (TAK), polyarteritis nodosa (PAN) and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss), using a panel of markers known to be elevated in ANCA-associated vasculitis.

Methods

22 serum proteins (MMP-3, NGAL, ACE, sIL-6R, osteopontin, PAI-1, PDGF-AB, RANTES, sICAM-1, TIMP-1, BCA-1, G-CSF, GM-CSF, IFNγ, IL-15, IL-18, IL-18BPa, sIL-2Ra, IL-6, IL-8, IP-10, and sTNFRII) linked to possible pathways relevant to vasculitis were measured using a microarray platform. Disease activity during the past 28 days was classified by physician global assessment (PGA), where remission is indicated by PGA=0 and active disease by PGA 1-10. Spearman’s correlation was used to study the association between serum proteins and ESR. To compare marker values between active disease and remission, mixed models were used to account for repeated measures with unequal spacing between visits. Prednisone and immunosuppressive treatments were included as independent variables. Fold-change (FC) in marker values between active and mean remission values was used as the measure of effect.

Results

479 samples from 174 patients (66 GCA, 35 TAK, 31 PAN, 42 EGPA, with 1 active visit and 1-3 remission visit samples per patient) were tested. 440 samples (92%) were obtained while the patient was on treatment. Disease activity ranged from PGA 1 to 9. In GCA, sIL-6R (FC 1.1, p=0.024), BCA-1 (FC 2.08, p=0.008), GM-CSF (FC 32.5, p=0.04; 7 patients with FC>2), IL-18BPa (FC 1.16, p=0.026), sIL-2Ra (FC 2.03, p=0.018), IL-6 (FC 2.54, p=0.032), and TIMP-1 (FC 1.18, p=0.034) were significantly higher in active than remission samples; in TAK, only IL-18BPa was higher in active than in remission samples (FC 1.16, p=0.029); and in PAN, only MMP-3 was significantly different, being higher in remission samples (FC 0.71, p=0.045). ESR was significantly elevated in active GCA (FC 1.43, p=0.001) and PAN (FC 1.45, p=0.013), and no differences were observed in TAK or EGPA. The correlation of ESR with the majority of the protein markers was weak; the highest correlation was observed in GCA with IL-6 (r=0.34, p<0.0001). FC and p-values were similar when use of prednisone and other immune-suppressive drugs were included in the models. The majority of the samples were obtained while the patients were on prednisone (81.2% of the active and 79.1% of the remission samples). Trajectories of selected markers are shown in Figure 1.

Conclusion

This study identifies several potential biomarkers of disease activity in GCA, although effect sizes were modest in this partially-treated cohort. Promising markers included several cytokines (IL-6, GM-CSF, BCA-1), soluble cytokine receptors (sIL-6R, IL-18BPa), and the metalloproteinase inhibitor TIMP-1. Larger studies are needed to test the utility of these biomarkers for disease monitoring.

Disclosure:

A. Rodriguez-Pla,
None;

R. L. Warner,
None;

D. Cuthbertson,
None;

S. Carette,
None;

G. S. Hoffman,

Roche Pharmaceuticals,

N. A. Khalidi,
None;

C. L. Koening,
None;

C. A. Langford,
None;

K. Maksimowicz-McKinnon,
None;

L. W. Moreland,
None;

C. Pagnoux,
None;

P. Seo,
None;

U. Specks,
None;

K. J. Warrington,
None;

S. R. Ytterberg,
None;

P. A. Merkel,

Genentech and Biogen IDEC Inc.,

Bristol-Myers Squibb,

GlaxoSmithKline,

Actelion Pharmaceuticals US,

Sanofi-Aventis Pharmaceutical,

Chemocentryx,

K. J. Johnson,
None;

P. A. Monach,
None;

F. the Vasculitis Research Consortium,
None.

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