Biomarkers in Vasculitis

The primary systemic vasculitides, a heterogeneous group of multisystem syndromes characterized by the caliber of the blood vessels involved and the organ systems affected, are clinically challenging.  Many of them follow an unpredictable, relapsing course that can lead to permanent damage, while there is no good way to differentiate active disease from infection or prior damage or to predict disease flares. This makes it difficult to plan treatment, weighing the benefits of potent immunosuppressive medications against the potential toxicities.  

We urgently need good biomarkers to distinguish active disease from damage or infection and to predict relapse, treatment response, and prognosis. Existing options are unsatisfactory.

In the prototypic small-vessel vasculitis, antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV), the autoantibodies for which it is named are unsuitable as biomarkers of disease activity. A recent meta-analysis concluded that the data is insufficient to support using persistently positive or rising ANCA titer alone to guide treatment decisions.¹  Also, traditional acute-phase reactants such as erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) lack sufficient sensitivity and specificity to predict relapse in a clinically significant manner.^2,3  

An intensive search for better biomarkers is now under way. Most of the potential biomarkers in AAV are "not ready for primetime," as they are not yet commercially available or validated in large, prospective cohorts.⁴  

Among the most promising candidates:

•  Subsets of B and T cells, both implicated in the pathogenesis of AAV, may prove useful to discriminate active disease from remission. 
 
Compared to AAV patients in remission or healthy controls, patients with active AAV show higher levels of activated (CD19+/CD38+) B cells,⁵ while patients in remission show higher levels of CD25+ regulatory B cells than healthy controls or those with active disease.⁶ 

Also, decades-long followup of Mayo Clinic patients treated repeatedly with rituximab for refractory AAV reveals that all observed flares occurred in those with B cell reconstitution, concurrent with a rise in levels of PR3, a type of ANCA.⁷   While time to B-cell reconstitution varied between patients, the authors concluded that for some patients taking rituximab the combination of B cell reconstitution and PR3 level can serve as a biomarker for relapsing disease.  

Activated T cells are detectable in the sera of AAV patients with both active and quiescent disease, but transcriptome analysis has identified CD8+ T cell expression profiles that divided patients into two distinct subgroups differing only in their risk of relapse.⁸

•  Activation of the alternative complement pathway is also implicated in AAV pathogenesis.  Patients with active renal AAV show higher circulating plasma levels of C5a, a common pathway component, and of fragment Bb, a measure of alternative pathway activation, than do those in remission or healthy controls.^9,10

•  Well-characterized longitudinal cohorts from therapeutic trials offer a rich resource to identify and verify other potential biomarkers for AAV. For instance, recently, Monach et al attempted to find candidate serum biomarkers for AAV using data from participants in the RAVE (Rituximab in ANCA-Associated Vasculitis) trial.^11,12 They identified three proteins CXCL13 (BCA-1), matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinases-1 (TIMP-1) that may distinguish active AAV from remission better than ESR and CRP. The specificity of these markers for AAV versus other sources of inflammation remains to be seen.

In the large vessel vasculitides, Giant Cell Arteritis (GCA) and Takayasu Arteritis (TA), elevations of traditional inflammatory markers are not specific for active vasculitis (and may be affected by therapy).  As with AAV, several biomarkers found promising for GCA and TA will require validation in larger cohorts and standardization of measurement techniques to prove their clinical utility:

•  The pro-inflammatory cytokine IL-6 is elevated in the arterial lesions and the peripheral circulation in GCA and TA. IL-6 levels in the serum correlate with disease activity.¹³ This observation may inform therapy:  A large study using IL-6 blockade with tocilizumab is under way for the treatment of new and relapsing GCA.¹⁴  

•  Levels of another pro-inflammatory cytokine, IL-17, are also increased in the inflammatory lesions in active GCA. They may predict response to glucocorticoid treatment.¹⁵ 

•  Certain circulating proteins including several matrix metalloproteinases have been suggested to be useful biomarkers for TA disease activity.¹⁶ 

•  Radiologic biomarkers can also help in determining disease activity in TA.  Several studies including a recent meta-analysis suggest the FDG-PET scan can detect disease activity in TA patients, even while they are taking immunosuppressive therapy.^17,18,19

References:

REFERENCES

1. Tomasson G, Grayson PC, Mahr AD et al.Value of ANCA measurements during remission to predict a relapse of ANCA-associated vasculitis-a meta-analysis.Rheumatology (Oxford) (2012) 51:100-109
2. Finkielman JD, Merkel PA, Schroeder D et al.Antiproteinase 3 antineutrophil cytoplasmic antibodies and disease activity in Wegener granulomatosis.Ann Intern Med (2007) 147:611-619
3. Kalsch Al, Csernok E, Munch D et al.Use of highly sensitive C-reactive protein for followup of Wegener’s granulomatosis.J Rheumatol (2010) 37:2319-2325
4. Lally L and Spiera RF. Biomarkers in ANCA-associated vasculitis.Curr Rheumatol Rep. (2013) 15:363
5. Popa ER, Stegeman CA, Bos NA et al.Differential B-and T-cell activation in Wegener’s granulomatosis.J Allergy Clin Immunol (1999) 103:885-894
6. Eriksson P, Sandell C, Backteman K et al. B cell abnormalities in Wegener’s granulomatosis and microscopic polyangiitis: role of CD25+-expressing B cells. J Rheumatol (2010) 37:2086-2095
7. Cartin-Ceba R, Golbin J, Keogh KA, et al.Rituximab for remission induction and maintenance in refractory granulomatosis with polyangiitis (Wegener’s): a single-center ten-year experience.Arthritis Rheum. (2012) 64:3770-3708
8. McKinney EF, Lyons PA, Carr EJ. A CD8+ T cell transcription signature predicts prognosis in autoimmune disease. Nat Med. (2010) 16:586-5919. Yuan J, Gou SJ, Huang J et al.C5a and its receptors in human anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis.Arthritis Res Ther (2012) 14:R140
10. Gou SJ, Yuan J, Chen M, et al.Circulating complement activation in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis.Kidney Int (2013) 83:129–137
11. Monach PA, Warner RL, Tomasson G et al.Serum proteins reflecting inflammation, injury, and repair as biomarkers of disease activity in ANCA-associated vasculitis.Ann Rheum Dis (2012) 0:1-9
12. Stone JH, Merkle PA, Spiera R et al.Rituximab versus cyclophosphamide for ANCA-associate vasculitis.N Engl J Med (2010) 363:221-232
13. Roche NE, Fulbright JW, Wagner AD et al. Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis.Arthritis Rheum. (1993) 36:1286-1294
14. Unizony SH, Dasgupta B, Fisheleva E et al. Design of the tocilizumab in giant cell arteritis trial.Int J Rheumatol. (2013) 2013:912562
15. Espígol-Frigolé G, Corbera-Bellalta M, Planas-Rigol E, et al.Increased IL-17A expression in temporal artery lesions is a predictor of sustained response to glucocorticoid treatment in patients with giant-cell arteritis.Ann Rheum Dis. (2013) 72:1481-1487
16. Ishihara T, Haraguchi G, Tezuka D et al.Diagnosis and assessment of Takayasu arteritis by multiple biomarkers.Circ J. (2013) 77:477-483
17. Lee KH, Cho A, Choi YJ et al.The role of (18) F-fluorodeoxyglucose-positron emission tomography in the assessment of disease activity in patients with takayasu arteritis.Arthritis Rheum. (2012) 64:866-875
18. Karapolat I, Kalfa M, Keser G et al.Comparison of F18-FDG PET/CT findings with current clinical disease status in patients with Takayasu's arteritis.Clin Exp Rheumatol. (2013) Jan-Feb;31(1 Suppl 75):S15-21 19. Cheng Y, Ly N, Wang Z et al.18-FDG-PET in assessing disease activity in Takayasu arteritis: a meta-analysis.Clin Exp Rheumatol. (2013) Jan-Feb;31(1 Suppl 75):S22-7.