Wide-angled proteomics in giant cell arteritis reveals complement pathway activation

Abstract

Giant cell arteritis (GCA) is an immune-mediated vasculitis that can cause serious morbidity including sight loss, stroke and aortic aneurysm. There is an unmet need for blood-based biomarkers and novel therapeutics. We measured plasma protein levels using the SomaScan v4.1 platform, comprising 7,273 protein measurements (SOMAmers) reflecting 6,596 unique protein targets. We profiled the proteome in 113 patients who presented acutely with possible GCA. 56 had biopsy-proven GCA and 57 did not have GCA (non-GCA). We found 144 SOMAmers increased and 151 reduced in GCA. Dysregulated biological pathways included IL6-JAK-STAT3 signalling, chemokines for both myeloid (e.g. CXCL2, CXCL3, CCL18, CCL23) and lymphoid cells (e.g. CXCL9, CXCL13), and the complement system (e.g. C9, CFHR5, C5a, Factor B). Enzyme-Linked Immunosorbent Assays (ELISAs) confirmed elevated plasma levels of C5a, the terminal complement complex, Factor B and CFHR5 in GCA. We developed a 26-protein signature that distinguished GCA from non-GCA (area-under-the curve, AUC, 0.93) and validated the diagnostic signature in external datasets. Our data implicate terminal complement pathway activation in GCA, raising the possibility of complement-directed therapies. We show proof-of-principle that a multiplex protein biomarker could be used as a diagnostic adjunct in suspected GCA.

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BibTeX RIS

BibTeX

@misc{whittle2026wideangled,
  title = {{Wide-angled proteomics in giant cell arteritis reveals complement pathway activation}},
  author = {B. J. Whittle and M. Williams and H. Lomax-Browne and L. Sorensen and R. T. Maughan and M. Porteous and A. Chakrabarty and R. A. Luqmani and M. C. Pickering and A. W. Morgan and J. E. Peters},
  howpublished = {medRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.14.26365544},
  url = {https://www.medrxiv.org/content/10.64898/2026.10.14.26365544v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Wide-angled proteomics in giant cell arteritis reveals complement pathway activation
AU  - B. J. Whittle
AU  - M. Williams
AU  - H. Lomax-Browne
AU  - L. Sorensen
AU  - R. T. Maughan
AU  - M. Porteous
AU  - A. Chakrabarty
AU  - R. A. Luqmani
AU  - M. C. Pickering
AU  - A. W. Morgan
AU  - J. E. Peters
PY  - 2026
DA  - 2026/10/14
PB  - medRxiv
DO  - 10.64898/2026.10.14.26365544
UR  - https://www.medrxiv.org/content/10.64898/2026.10.14.26365544v1
AB  - Giant cell arteritis (GCA) is an immune-mediated vasculitis that can cause serious morbidity including sight loss, stroke and aortic aneurysm. There is an unmet need for blood-based biomarkers and novel therapeutics. We measured plasma protein levels using the SomaScan v4.1 platform, comprising 7,273 protein measurements (SOMAmers) reflecting 6,596 unique protein targets. We profiled the proteome in 113 patients who presented acutely with possible GCA. 56 had biopsy-proven GCA and 57 did not have GCA (non-GCA). We found 144 SOMAmers increased and 151 reduced in GCA. Dysregulated biological pathways included IL6-JAK-STAT3 signalling, chemokines for both myeloid (e.g. CXCL2, CXCL3, CCL18, CCL23) and lymphoid cells (e.g. CXCL9, CXCL13), and the complement system (e.g. C9, CFHR5, C5a, Factor B). Enzyme-Linked Immunosorbent Assays (ELISAs) confirmed elevated plasma levels of C5a, the terminal complement complex, Factor B and CFHR5 in GCA. We developed a 26-protein signature that distinguished GCA from non-GCA (area-under-the curve, AUC, 0.93) and validated the diagnostic signature in external datasets. Our data implicate terminal complement pathway activation in GCA, raising the possibility of complement-directed therapies. We show proof-of-principle that a multiplex protein biomarker could be used as a diagnostic adjunct in suspected GCA.
ER  -

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