ANCA-associated vasculitis
The ANCA-associated vasculitides (AAV) comprise a triad of disorders that cause various degrees of vascular inflammation, both affecting the kidney and often other organs. The overarching name derives from the autoantibodies that characteristically develop in these diseases, that comprise:
The nomenclature as well as the understanding of the pathology, immunology, clinical features, treatment and management of AAV, has progressed apace over the past 40-50 years in large part due to the collaborations between investigators and disciplines on an international scale. UK nephrologists, along with UK colleagues in rheumatology, have played a significant role.
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In the 1970s, much focus was on rapidly progressive glomerulonephritis (RPGN), the hallmark features of crescents and fibrinoid necrosis occurring either with or without linear staining for IgG along the glomerular basement membrane (GBM). The presence of linear IgG staining was equated with anti-GBM antibody mediated disease (see history article xxx), while absence of such staining was argued to be due to an immune complex mediated process since immune complexes were deemed detectable in some of these patients using a radiolabelled C1q deviation test. The success of the Hammersmith Hospital group (including Keith Peters, Andy Rees and Martin Lockwood) in treating anti-GBM disease with high dose corticosteroids, cyclophosphamide, azathioprine and plasma exchange, led to its application in patients without anti-GBM antibodies but who had RPGN, often with pulmonary haemorrhage (again, common to both groups).
During the 1970s and early 1980s, making a diagnosis of RPGN was difficult since ultrasound guided renal biopsies were in their infancy and tricky in a sick patient. The reassuring ANCA test was years away! Urine microscopy was diligently examined, often in the middle of the night, for red blood cells and cellular casts in individuals with AKI/RPGN. If there was a hint of a nasal problem, ENT were called to look up noses and biopsy any unusual lesions that may signify a granuloma. Shadows on chest X-rays led to questions of whether it was infection or pulmonary haemorrhage, so the introduction of the single breath carbon monoxide uptake test for detection of bleeding into the alveoli by the respiratory team (Pam Ewan, Mike Hughes) at Hammersmith Hospital was a godsend, avoiding bronchoscopy in a respiratory compromised patient, before CT angiography and MRI scanning became available and widely accessible.
Despite these challenges and the real scare of immunosuppressing a patient with RPGN, a rash and an active urine sediment lest bacterial endocarditis or other infection was lurking, diagnoses were made allowing treatment to be administered. In 1977, the Hammersmith group reported on nine patients, five of whom had a striking early improvement in renal function, two had an improvement in renal function that occurred up to 4 weeks later and in one patient renal function was stabilised; only one patient did not recover renal function and renal biopsy showed 23 of 25 glomeruli were obliterated by crescents. Despite these remarkable results, two patients subsequently died from pneumocystis pneumonia and pseudomonas septicaemia. Indeed, it quickly became apparent that the new approach to treatment was reversing the decline in renal function but that infective complications were taking a toll. Infection was also linked to acute relapse in a seminal paper with Tony Pinching as first author (1980). Jon Cohen, Tony Pinching, Andy Rees and Keith Peters undertook the first systematic attempt to study the problem of infection in 75 patients with immunologically mediated disease (including 18 with GPA and 16 with systemic vasculitis) and noted a strong association in 23 patients of severe infective complications with renal impairment and increasing doses of prednisolone (1982), leading the group to cut back significantly on the steroid doses employed and introduce a tapered prednisolone regime. Thereafter the quest to use less and less corticosteroid continued, even until the advent of the PEXIVAS and ADVOCATE trials over 30 years later (see below).
Disease description and characterisation were also progressing. GPA had been described in the 1930s by 1931 Hans Klinger (1931) and Friedrich Wegener (1936) but MPA remained elusive and usually viewed as a form of periarteritis nodosa despite the report from J Davson, J Ball and Robert Platt (University of Manchester) in 1948 linking the presence of primary systemic vasculitis with segmental necrotising glomerulonephritis in a subgroup of patients, suggesting such patients had a “microscopic form” of polyarteritis, distinct from periarteritis nodosa. Two studies put MPA firmly on the map as a distinct entity – Stuart Cameron and colleagues from Guys Hospital (1983) and Caroline Savage, Chris Winearls, David Evans, Andy Rees and Martin Lockwood (1985) describing patients with vasculitis affecting the kidney under the banner of microscopic polyarteritis.
The diagnosis and pathogenic understanding of AAV accelerated with the exciting discoveries of anti-neutrophil cytoplasm antibodies (ANCA) and rapid identification of their autoantigens, myeloperoxidase and proteinase 3. The first inkling that such antibodies might exist came with a letter to the British Medical Journal (1982) by DJ Davies from University of Melbourne describing their presence in 8 patients. Then Fokko van der Woude (from the Netherlands) and Niels Rasmussen (Denmark) published an extensive study of their joint cohorts (1985) using immunofluorescence to demonstrate presence of antibodies to antigens in the cytoplasm of neutrophils and monocytes in GPA.
Within two years (1987), Martin Lockwood had enthusiastically set up an indirect immunofluorescence test for ANCA (after spending hours in a dark room staring down a microscope) and had “repurposed” the solid phase radioimmunoassay for anti-GBM antibodies, for detection of ANCA. This allowed the Hammersmith group (including Caroline Savage, Chris Winearls, Martin Lockwood) to confirm presence of antibodies not only in GPA, but also in MPA (1987). Even Princess Alexandra was impressed (see photo).
Interesting, Van der Woude’s initial description was of anti-neutrophil cytoplasmic antibodies, but Chris Winearls insisted this was a misnomer and that it should be cytoplasm, not cytoplasmic! The following two years were equally exciting, with recognition of two patterns of binding for ANCA, perinuclear (pANCA) and cytoplasmic granules (cANCA), and identification of myeloperoxidase as the antigen responsible for pANCA (Ron Falk and Charles Jennette in North Carolina, 1988), and identification of proteinase 3 as the antigen responsible for cANCA (Roel Goldschmeding in the Netherlands, 1989). The identification of ANCA opened the flood gates, not only for development of diagnostics, but also heightened interest in the autoimmune pathogenesis. Diagnostics focused on indirect immunofluorescence using isolated human neutrophils or ELISAs using purified antigens.
There followed intense interest in developing tools to support clinical studies of therapies for AAV, as well as formation of new consortia to design and implement clinical trials in these rare diseases.
Amongst the tools, UK nephrologists and rheumatologists led by Paul Bacon from University of Birmingham, developed the Birmingham Vasculitis Activity Score (BVAS, with the first iteration in 1994) and the Vasculitis Damage Index (VDI, 1998) that were used in many subsequent clinical studies, being modified to increase their utility as skills and knowledge of AAV developed. The now ubiquitous test of inflammation, C-reactive protein (CRP), was developed by Mark Pepys’ team at Hammersmith Hospital, being applied to GPA and MPA in two separate studies as early as 1984, with Charles Hind, Caroline Savage, Chris Winearls, and Andy Rees.
The first AAV workshop took place in Copenhagen in 1988. From the UK, Martin Lockwood and Caroline Savage participated. It was organised by Niels Rasmussen from Denmark who went on to lead a grant application for the European Union BIOMED 1 programme (1994), to develop clinical trials for vasculitis. The ECSYSVASTRIAL project led four trials being developed and published:
Many UK centres and nephrologists participated in these, including David Jayne, Gill Gaskin, Caroline Savage, and Charles Pusey.
A BIOMED 2 grant supported the AVERT project, which led to further landmark trials, again with heavy UK support and participation including from Charles Pusey, Caroline Savage, David Jayne, and Lorraine Harper:
Further clinical trials were to follow, often in partnership with industry, examining the role of:
ADVOCATE deserves special mention as it showed that Avacopan combined with rituximab resulted in the same degree of remission at 6 months as conventional treatment, and a higher rate of remission at 1 year, but with less steroid exposure. Finally, in 2021, the steroid burden of treating AAV was starting to be reduced.
Alongside the considerable progress in clinical treatments to which UK nephrology made significant contributions, UK investigators were also making major contributions to understanding the pathogenesis of AAV.
Genetically distinct subsets with AAV were defined using a UK discovery cohort with control data from the Wellcome Trust Case Control Consortium in an international study led by Paul Lyons and Kenneth Smith and with other UK nephrologists actively involved. A UK Glomerular DNA Bank funded jointly by the MRC/NKRF that was established by Andy Rees, Peter Ratcliffe and John Feehally provided the core resource. Importantly the study showed genetic distinctions between GPA and MPA that are associated with ANCA specificity, suggesting the response against proteinase 3 is a central pathogenic feature of proteinase 3 ANCA associated vasculitis (typically GPA).
Laboratory based work from UK centres such as Hammersmith Hospital and University of Birmingham laid much of the early base for understanding the interplay between autoantibodies, autoantigens, neutrophils, endothelial cells and the wider immune system.
This effort over so many years would be of little significance if it did not make a difference to patients’ lives, particularly their quality if life. UK nephrologists and rheumatologists have been at the forefront of efforts to understand what matters to patients most, such as a seminal study led by Neil Basu to identify the determinates of fatigue amongst patients with AAV (2013). Sleep disturbance and pain (both potentially modifiable) were important determinates of fatigue.
To follow …
First published May 2025
Last Updated on May 26, 2025 by neilturn