ANCA Associated Vasculitis Subtypes: Recent Insights and Future Perspectives

Figures & data

Figure 1 Pathways involved in the pathogenesis of ANCA vasculitis, and their drug targets.

Abbreviations: ANCA, anti-neutrophil cytoplasmic antibody; IL, interleukin; MPO, myeloperoxidase; NETs, neutrophil extracellular traps; PR3, proteinase 3; ROS, reactive oxygen species; TNF, tumour necrosis factor.

Table 1 Clinical Phenotypes, Genetic Polymorphisms and Biomarkers Associated with PR3 and MPO ANCA Subtypes

	PR3	MPO
Proportion of patients with each clinical phenotype thought to display ANCA subtype	GPA 75% MPA 30% EGPA 5%	GPA 20% MPA 60% EGPA 45%
Genetic associations	Polymorphisms in HLA-DP, PRTN3 and SERPINA1 genes	Polymorphisms in HLA-DQ
Associated serum biomarkers	IL-6, GM-CSF, IL-15, IL-18, CXCL8/IL-8, CCL17/TARC, IL-18BP, sIL-2Rα, NGFβ	sIL6R, sTNFRII, NGAL, sICAM-1

Abbreviations: PR3, anti-proteinase 3 antibody; MPO, anti-myeloperoxidase antibody; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; EGPA, eosinophilic granulomatosis with polyangiitis; HLA, human leukocyte antigen.

Table 2 Core Clinical Features of MPA, GPA and EGPA

MPA	● Renal disease – necrotising glomerulonephritis ● Lung disease – alveolar haemorrhage
GPA	● Ear nose and throat disease – nasal crusting, epistaxis, sinusitis, nasal ulceration, septal perforation, subglottic stenosis, hearing loss ● Eye disease – episcleritis, orbital granuloma or pseudo-tumour ● Lung disease – nodules, alveolar haemorrhage ● Renal disease – pauci-immune crescentic glomerulonephritis
EGPA	● Ear nose and throat disease – polyposis, rhinitis ● Lung disease – asthma ● Neurological – peripheral neuropathy, mononeuritis multiplex ● Cardiovascular - myocarditis ● Renal disease – necrotising glomerulonephritis

Abbreviations: GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; EGPA, eosinophilic granulomatosis with polyangiitis.

Table 3 Summary of ACR 2021 and EULAR 2017 Guidelines for the Management of AAV

	Granulomatosis with Polyangiitis	Microscopic Polyangiitis	Eosinophilic Granulomatosis with Polyangiitis
American College of Rheumatology 2021 Guideline
Induction
Severe	High dose IV or PO GC RTX > CYC* IVIg if unable to receive conventional immunosuppression (due to sepsis, pregnancy etc) PLEX not routinely recommended in glomerulonephritis or alveolar haemorrhage*		High dose IV or PO GC CYC or RTX
Non severe	MTX + GC*		MEP + GC MTX or AZA or MMF + GC
Refractory disease	Switch induction therapy* Add IVIg to induction therapy*
Remission	RTX with scheduled re-dosing MTX or AZA > MMF or LEF*		Remission achieved on CYC: MTX or AZA or MMF > RTX or MEP
	Ungraded position: duration of GC treatment should be guided by the patient’s clinical condition, preferences and values
Relapse
Severe disease	If not on RTX: RTX > CYC* On RTX: Switch RTX to CYC* Alternatively add IVIg*		RTX > CYC*
Non-severe			Asthma and/or sinonasal disease: add MEP
EULAR 2017 Guideline
Induction
Organ or life-threatening	CYC or RTX + GC
Rapidly progressive renal failure or pulmonary haemorrhage	Consider PLEX
Non organ-threatening disease	MTX or MMF + GC
Refractory disease	Switch induction therapy (reconsider diagnosis and seek expert centre support ± recruitment into RCT)
Remission	AZA or MTX or RTX + GC taper After 2 years taper MTX or AZA; stop RTX
Relapse Major	CYC or RTX + GC

Note: *Conditional recommendation (ACR 2021 guideline).

Abbreviations: ACR, American College of Rheumatology; AZA, azathioprine; CYC, cyclophosphamide; EULAR, European League Against Rheumatism; GC, glucocorticoid; IV, intravenous; IVIg, intravenous immunoglobulin; LEF, leflunomide; MEP, mepolizumab; MMF, mycophenolate; MTX, methotrexate; PLEX, plasma exchange; PO, oral; RCT, randomised controlled trial; RTX, rituximab.