Complement system in ANCA vasculitis

          Classically associated with a pauci immune RPGN, ANCA disease has traditionally been not associated with complement activation. Recent data in JASN 2014 from the UNC group suggests otherwise.  Passive transfer of anti MPO in mice induced ANCA associated necrotizing crescentic GN with activation of alternate complement system.  The researcher highlighted the role of C5a receptor in the mediation of this disease. As we know, C5 has a role more downstream close to the MAC system in the complement cascade.  Hence blocking C5a receptor will halt alternate pathway.  The researchers then showed that C5a receptor/CD88 engagement enhances the inflammation and C5L2 ( C5 a like receptor) suppresses inflammation.  Given an oral agent that blocks C5a receptor/CD88 ameliorated the GN in the mouse model. No human trials have been suggested yet but pharmaceuticals are already on the go for this proof of concept.

          http://ir.chemocentryx.com/releasedetail.cfm?ReleaseID=811237

          In a different study, the elevated plasma and urinary C5a levels indicated complement activation in human ANCA disease. CD88 expression was downregulated, and C5L2 was upregulated in ANCA-associated glomerulonephritis.

          The role of complement in ANCA disease is not completely novel. If C5A receptor can be of help, why not block C5 directly with an agent we already have for C3GN, DDD, PNH and aHUS: eculizumab.
Looking at clinicaltrials.gov, we find a withdrawn study.( thanks to anonymous for pointing this out)