ANCA-Associated VasculitisI77.-

ANCA-associated vasculitides (AAV) are rare systemic diseases with a potentially life-threatening course. As they progress rapidly and can lead to life-threatening complications or severe irreversible organ damage within a short period of time (e.g. respiratory failure in alveolar hemorrhage syndrome, acute impairment of kidney function, damage to peripheral nerves, chronic damage to the ENT tract with saddle nose or subglottic stenosis), early interdisciplinary diagnostic clarification and initiation of treatment is necessary. Due to their high sensitivity and specificity, ANCA tests in particular often provide decisive diagnostic information, especially in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis, as well as biopsies of affected organs (especially the kidney) with histopathological examination.

In terms of nomenclature, AAVs are categorized according to their typical histopathological and clinical features using the Chapel Hill Consensus Conference (CHCC) nomenclature from 2012. As the classification criteria provide a good overview of typical constellations of the various AAVs with regard to frequent organ manifestations, histology and association with ANCA, the current classification criteria of the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) are used as a basis below.

Granulomatosis with polyangiitis

2022 ACR / EULAR criteria for granulomatosis with polyangiitis

Clinical criteria

• Nasal involvement: bloody discharge, ulcers, crusts, obstruction, blockage or septal defect/perforation. +3
• Cartilage involvement (inflammation of ear or nasal cartilage, hoarse voice or stridor, endobronchial involvement or saddle nose deformity +2
• Conductive or sensorineural hearing loss +1
• Laboratory, imaging and biopsy criteria cANCA or PR3 antibodies +5
• Pulmonary nodules, masses or cavities on chest imaging +2
• Granulomas, extravascular granulomatous inflammation or giant cells on biopsy +2
• Inflammation, consolidation or effusion of the nasal/paranasal sinus or mastoiditis on imaging +1
• Pauci-immune glomerulonephritis in the biopsy +1
• pANCA or MPO antibodies -1
• Eosinophil count in blood ≥ 1 x 109/liter -4

Conclusion: A score ≥ 5 is necessary for the classification of granulomatosis with polyangiitis.

Microscopic polyangiitis

2022 ACR / EULAR criteria for microscopic polyangiitis

Clinical criteria

• Nasal involvement: bloody discharge, ulcers, crusts, obstruction, blockage or septal defect/perforation. -3
• Laboratory, imaging and biopsy criteria pANCA or MPO antibodies +6
• Fibrosis or interstitial lung disease on chest imaging +3
• Pauci-immune glomerulonephritis on biopsy +3
• cANCA or PR3 antibody -1
• Eosinophil count in blood ≥ 1 x 109/liter -4

Conclusion: A score ≥ 5 is necessary for the classification of microscopic polyangiitis.

Eosinophilic granulomatosis with polyangiitis

2022 ACR / EULAR criteria for eosinophilic granulomatosis with polyangiitis

Clinical criteria

• Obstructive airway disease +3
• Nasal polyps +3
• Mononeuritis multiplex +1
• Laboratory, imaging and biopsy criteria Blood eosinophil count ≥ 1 x 109/liter +5
• Extravascular eosinophil-predominant inflammation in the biopsy +2
• cANCA or PR3 antibodies -3
• Hematuria -1

Conclusion: A score ≥ 6 is necessary for the classification of eosinophilic granulomatosis with polyangiitis.

Examples of potentially organ / life-threatening manifestations*

• Glomerulonephritis
• Alveolar hemorrhage
• Meningeal involvement
• Involvement of the central nervous system Lung round foci without cavern formation
• Cardiac involvement
• Mesenteric involvement
• Mononeuritis multiplex
• Involvement of the central nervous system

Examples of manifestations that are not necessarily organ / life threatening:

• Nasal or paranasal involvement without (erosive) bony involvement /
• Cartilage destruction / olfactory dysfunction / deafness
• Skin involvement without ulceration
• Myositis (skeletal muscle)
• Lung round foci without cavern formation
• Retrobulbar orbital involvement Episcleritis

The recommended basic examinations for the initial diagnosis are:

• Complete physical examination including clinical neurological examination;

Laboratory:

• Differential blood count,
• C-reactive protein (CRP), erythrocyte sedimentation rate (ESR),
• creatinine (glomerular filtration rate [GFR]), urea,
• electrolytes,
• gamma-glutamyl transferase (γ-GT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase (CK), lactate dehydrogenase (LDH),
• Urine status and sediment,
• ANCA-IFT and ANCA-ELISA or ANCA target antigen-specific test (see above);
• Electrocardiogram (ECG);
• Echocardiography;
• Chest x-ray in 2 planes;
• Pulmonary function test including body plethysmography and determination of diffusion capacity;
• abdominal sonography;
• Cranial magnetic resonance imaging including imaging of the paranasal sinuses and orbits (at least if GPA is suspected).

The extended diagnosis depends on the initial findings and the clinical symptoms as well as the differential diagnoses to be considered, whereby every symptom should be investigated in the sense of a complete spread diagnosis

Activity and spread diagnostics form the basis for individualized therapy. In principle, it is necessary to differentiate between non-organ-threatening disease and organ-threatening disease and to evaluate the activity of the disease (active disease, remission, response to therapy) when determining treatment. The consensus definition given in the classification corresponds to the EULAR Recommendations Update from 2022 (AWMF guideline).

The strict staging of the EUVAS (European Vasculitis Society, formerly European Vasculitis Study Group) (in localized disease, usually limited to the ENT tract, early systemic disease without organ threat, generalized disease with organ threat and severe disease with organ failure, Table 5) was abandoned in favor of the simpler classification into non-organ-threatening disease and organ-threatening disease).

Examples of organ-threatening and life-threatening and non-organ-threatening and non-life-threatening manifestations:

• Active stage EULAR consensus definition (Hellmich B et al. 2022)
• Active disease: Presence of typical signs, symptoms or other features (such as glomerulonephritis or pulmonary nodules) of active AAV
• Remission: Absence of typical signs, symptoms or other features of active AAV with or without immunosuppressive therapy
• Sustained remission: Absence of typical signs, symptoms or other features of active AAV for a defined time interval with or without immunosuppressive therapy
• Response: ≥ 50% reduction in disease activity score and absence of new manifestations
• Relapse: Recurrence of active AAV after a time interval of remission
• Refractory: Unchanged or intensified signs, symptoms or other features of active AAV after a time interval of standard induction therapy. Chronic organ damage, infections. Note: Side effects/concomitants of therapy or comorbidities must be excluded as potential causes of persistent or worsened disease manifestations.

1. Grayson PC et al. (2015) Value of commonly measured laboratory tests as biomarkers of disease activity and predictors of relapse in eosinophilic granulomatosis with polyangiitis. Rheumatology (Oxford) 54:1351-1359.
2. Hellmich B et al. (2022) EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update. Ann Rheum Dis. 2023.
3. Herrmann K et al. (2015) Diagnostic Value of Procalcitonin in ANCA-Associated Vasculitis (AAV) to Differentiate Between Disease Activity, Infection and Drug Hypersensitivity. Open Rheumatol J. 9:71-76.
4. https://register.awmf.org/assets/guidelines/060-012l_S3_Diagnostics-Therapy-ANCA-associated_vasculitis_2024-08_2.pdf
5. Kalsch AI et al. (2010) Use of highly sensitive C-reactive protein for followup of Wegener's granulomatosis. J Rheumatol 37:2319-2325
6. Kronbichler A et al. (2016) Evaluation and validation of biomarkers in granulomatosis with polyangiitis and microscopic polyangiitis. Nephrol Dial Transplant 31:930-936.