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New research on complement activation in anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis underscores its important role in the pathogenesis of this disease, an autoimmune condition defined by inflammation of small- and medium-caliber blood vessels.1 ANCA testing is commonly performed to help diagnose granulomatosis with polyangiitis and microscopic polyangiitis, both of which are forms of ANCA-associated vasculitis.
Two main types of ANCA-associated vasculitis exist: MPO-ANCA, defined by the presence of antibodies against myeloperoxidase, and PR3-ANCA, defined by the presence of antibodies against proteinase 3. These differ in genetic predisposition, pathophysiologic mechanism, cytokine profile, organ predilection and treatment response, which makes phenotyping important, says one of the study’s authors, Eveline Wu, MD, MSCR, an allergist/immunologist, pediatric rheumatologist and researcher at the University of North Carolina (UNC), Chapel Hill.
“We know complement is an important part of our innate immune system, defending against microbes or pathogens while ‘complementing’ other parts of the immune system,” Dr. Wu says. “It is a complex process, involving more than 30 proteins that act sequentially, creating a cascade.” Complement can be activated in three different ways, via the alternative, classical and lectin pathways, although for this condition the alternative pathway may be more important. The pathways converge at C3.
A Critical Role in ANCA
Historically, complement activation was not thought to have a significant role in ANCA-associated vasculitis, because there is typically little immunoglobulin or complement deposition at the site of tissue injury. An experimental mouse model of ANCA-associated vasculitis was developed at UNC, with injection of the anti-MPO antibody producing a vasculitis similar to microscopic polyangiitis.2 The investigators discovered that mice deficient in certain complement components were protected from developing the condition, which was the start of accumulating evidence showing complement activation is, in fact, critical in ANCA-associated vasculitis, as well as in certain other autoimmune conditions.3
Dr. Wu
“The primary objective of our study was to investigate complement activation in human MPO-ANCA and PR3-ANCA-associated vasculitis,” the authors note. A secondary objective was to determine whether FUTHAN, a broad-specificity protease inhibitor that blocks in vitro complement activation, could aid in more accurately measuring complement activation in patients with ANCA-associated vasculitis and healthy controls, given the risk for complement activation caused by sampling procedures.
Plasma from 98 patients with ANCA-associated vasculitis and 35 healthy controls was obtained and immediately frozen. ELISA measures and Wilcoxon two sample tests were conducted to compare plasma levels of circulating complement activation products among groups. Levels of C3a, C5a and sC5b-9 were found to be higher in active MPO-ANCA-associated vasculitis patients than in healthy controls, and C3a, C5a, sC5b-9 and C4d were higher in active PR3-ANCA-associated vasculitis patients than in healthy controls.
Looking for Markers
Providers who care for patients with ANCA-associated vasculitis can appreciate the continued challenges of managing this disease, Dr. Wu says. One such challenge is the toxicity associated with long-term steroid use and other immunosuppressive therapies.
“We are looking for a marker, or panel of markers, to assess how active the disease is, its response to treatment, when the patient is about to relapse or when the disease is quiet enough to take the patient off treatment. We’re hoping to learn whether complement activation can be one of those markers,” Dr. Wu says. “Our results further substantiate the contribution of complement activation in ANCA-associated vasculitis, although the clinical implications are as yet uncertain.”
Could measures of complement activation predict who will relapse soon or experience complete remission? “And could complement activation be a possible target for therapy?” she asks
‘Our results further substantiate the contribution of complement activation in ANCA-associated vasculitis, although the clinical implications are as yet uncertain.’ —Dr. Wu
Peter Heeringa, PhD, professor in the Department of Pathology and Medical Biology, Vasculitis Expertise Center, University Medical Center, Groningen, The Netherlands, and a leading researcher in this field, notes that data from experimental animal models and from histopathological, serological and in vitro studies on human material strongly support a role for complement in the pathogenesis of ANCA-associated vasculitis—a role that may be amenable to therapeutic intervention.
Targeting the C5a–C5aR axis, in particular, seemed a logical step in the treatment of ANCA-associated vasculitis, given the availability of drugs specific to C5aR or C5 that were already approved for other indications, he tells The Rheumatologist in an email. “The study by Dr. Wu et al. investigated for the first time complement activation in plasma from PR3-ANCA patients, which has been one of the unresolved questions in the field. Prior to this study, investigations had mainly focused on MPO-ANCA patients.”
The new research has established that complement activation also occurs in PR3-ANCA positive patients, Dr. Heeringa says. This is important because MPO-ANCA and PR3-ANCA positive patients are the main serological subtypes of this disease, with increasing evidence that these subgroups differ with respect to pathophysiologic mechanisms.
Importantly, the study also took care to optimize the processing of serum samples to more accurately measure complement activation analytes in plasma samples by adding futhan to block in vitro complement activation, he says. It is important to prevent complement activation due to sample processing, which can lead to false-positive results.
The clinical impact of measuring complement activation analytes in terms of distinguishing active disease from disease remission or predicting lower relapse risk is less clear from this study, as acknowledged by the authors, Dr. Heeringa notes. “An important question that will need to be addressed in the future is whether all ANCA-associated vasculitis patients will benefit from C5aR-targeted therapy and whether profiles of complement analytes can aid in this.”
Drugs Under Development
Current drugs and those under development target the complement system, Dr. Wu says. “Naturally, we’re interested in looking at the place for these medications as potential treatments for ANCA-associated vasculitis.” These include eculizumab, which was developed by Alexion and works by selectively inhibiting complement component C5, and avacopan, an orally administered drug candidate developed by ChemoCentryx that inhibits the C5a receptor.
“We are excited about the direction we are going, with ongoing projects to longitudinally follow a group of ANCA-associated vasculitis patients with a spectrum of disease manifestations to see if complement activation can reliably predict or correlate with disease activity, disease remission and treatment response,” Dr. Wu says.
The clinical implications aren’t clear yet. “We need to better understand the role of complement activation in the emergence of disease using mechanistic studies. We know it’s important, but don’t fully understand its clinical applications yet.” she says. “Can we predict which patients might benefit from a particular treatment? What is on the horizon is answering if complement-targeting therapy would be helpful to all ANCA-associated vasculitis patients, or just a subset, and could that subset be identified sooner.”
Larry Beresford is a medical journalist in Oakland, Calif.
References
- Wu EY, McInnis EA, Suavet SB, et al. Measuring circulating complement activation products in myeloperoxidase and proteinase 3 antineutrophil cytoplasmic antibody vasculitis. Arthritis Rheumatol. 2019 Nov;71(11):1894–1903.
- Jennette JC, Xiao H, Falk R, et al. Experimental models of vasculitis and glomerulonephritis induced by antineutrophil cytoplasmic autoantibodies. Contrib Nephrol. 2011;169:211–220.
- Chen M, Daha MR, Kallenberg CGM. The complement system in systemic autoimmune disease. J Autoimmun. 2010 May;34(3):J276–J286.
