The alternative complement pathway in ANCA-associated vasculitis: further evidence and a meta-analysis
Sergey Moiseev1,2*, Jiwon M. Lee3*, Anastasiia Zykova1,2, Nikolai Bulanov1, Pavel Novikov1, Eugeniy Gitel1, Mayra Bulanova4, Elizaveta Safonova2, Jae Il Shin5,6,7, Andreas Kronbichler8,9, David R.W. Jayne9
1Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Moscow, Russia
2Lomonosov Moscow State University, Moscow, Russia
3Department of Pediatrics, Chungnam National University Hospital and College of Medicine, Daejeon, Korea
4Vladimir Clinical Hospital, Vladimir, Russia
5Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea
6Division of Pediatric Nephrology, Severance Children’s Hospital, Seoul, Korea
7Institute of Kidney Disease Research, Yonsei University College of Medicine, Seoul, Korea
8Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria
9Department of Medicine, University of Cambridge, Cambridge, UK
Corresponding Authors:
Jae Il Shin, M.D., Ph.D. Address: Yonsei-ro 50, Seodaemun-gu, C.P.O. Box 8044, Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Republic of Korea. Tel.: +82-2-2228-2050; Fax: +82-2-393-9118; E-mail: shinji@yuhs.ac
Anastasiia Zykova, M.D., Ph.D. Address: Rossolimo, 11/5, Moscow, Russia. Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University. E-mail: ansezy@gmail.com
* These authors contributed equally to this work
Objectives. We compared the common pathway components C3a, C5a and membrane attack complex (MAC), also known as C5b-9, and the alternative pathway components factor B and properdin in patients with ANCA-associated vasculitis (AAV) and healthy controls, and conducted a meta-analysis of the available clinical evidence for the role of complement activation in the pathogenesis of AAV.
Methods. Complement components were evaluated in 59 patients with newly diagnosed or relapsing granulomatosis with polyangiitis or microscopic polyangiitis and 36 healthy volunteers. In 28 patients, testing was repeated in remission. Next, we performed a meta-analysis by searching databases to identify studies comparing complement levels in AAV patients and controls. A random-effects model was used for statistical analyses.
Results. The median concentrations of MAC, C5a, C3a, and factor B were higher in active AAV patients (p<0.001). Achievement of remission was associated with reductions in C3a (p=0.005), C5a (p=0.035), and factor B levels (p=0.045), whereas MAC and properdin levels did not change. In active AAV, there were no effects of ANCA specificity, disease phenotype, previous immunosuppression, or disease severity on complement levels.
A total of 1122 articles were screened, and five studies, including this report, were entered in the meta-analysis. Plasma MAC, C5a, and factor B in patients with active AAV were increased compared to patients in remission (excluding factor B) and controls. Changes in C3a were of borderline significance.
Conclusion. Our findings and the results of the meta-analysis support activation of the complement system predominantly via the alternative pathway in AAV patients.