2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Granulomatosis With Polyangiitis.

OBJECTIVE: To develop and validate revised classification criteria for granulomatosis with polyangiitis (GPA). METHODS: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in 5 phases: 1) identification of candidate criteria items using consensus methodology, 2) prospective collection of candidate items present at the time of diagnosis, 3) data-driven reduction of the number of candidate items, 4) expert panel review of cases to define the reference diagnosis, and 5) derivation of a points-based risk score for disease classification in a development set using least absolute shrinkage and selection operator logistic regression, with subsequent validation of performance characteristics in an independent set of cases and comparators. RESULTS: The development set for GPA consisted of 578 cases of GPA and 652 comparators. The validation set consisted of an additional 146 cases of GPA and 161 comparators. From 91 candidate items, regression analysis identified 26 items for GPA, 10 of which were retained. The final criteria and their weights were as follows: bloody nasal discharge, nasal crusting, or sino-nasal congestion (+3); cartilaginous involvement (+2); conductive or sensorineural hearing loss (+1); cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or anti-proteinase 3 ANCA positivity (+5); pulmonary nodules, mass, or cavitation on chest imaging (+2); granuloma or giant cells on biopsy (+2); inflammation or consolidation of the nasal/paranasal sinuses on imaging (+1); pauci-immune glomerulonephritis (+1); perinuclear ANCA or antimyeloperoxidase ANCA positivity (-1); and eosinophil count ≥1 × 109 /liter (-4). After excluding mimics of vasculitis, a patient with a diagnosis of small- or medium-vessel vasculitis could be classified as having GPA if the cumulative score was ≥5 points. When these criteria were tested in the validation data set, the sensitivity was 93% (95% confidence interval [95% CI] 87-96%) and the specificity was 94% (95% CI 89-97%). CONCLUSION: The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for GPA demonstrate strong performance characteristics and are validated for use in research.

2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for granulomatosis with polyangiitis.

OBJECTIVE: To develop and validate revised classification criteria for granulomatosis with polyangiitis (GPA). METHODS: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in five phases: (1) identification of candidate criteria items using consensus methodology, (2) prospective collection of candidate items present at the time of diagnosis, (3) data-driven reduction of the number of candidate items, (4) expert panel review of cases to define the reference diagnosis and (5) derivation of a points-based risk score for disease classification in a development set using least absolute shrinkage and selection operator logistic regression, with subsequent validation of performance characteristics in an independent set of cases and comparators. RESULTS: The development set for GPA consisted of 578 cases of GPA and 652 comparators. The validation set consisted of an additional 146 cases of GPA and 161 comparators. From 91 candidate items, regression analysis identified 26 items for GPA, 10 of which were retained. The final criteria and their weights were as follows: bloody nasal discharge, nasal crusting or sino-nasal congestion (+3); cartilaginous involvement (+2); conductive or sensorineural hearing loss (+1); cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or anti-proteinase 3 ANCA positivity (+5); pulmonary nodules, mass or cavitation on chest imaging (+2); granuloma or giant cells on biopsy (+2); inflammation or consolidation of the nasal/paranasal sinuses on imaging (+1); pauci-immune glomerulonephritis (+1); perinuclear ANCA or antimyeloperoxidase ANCA positivity (-1); and eosinophil count ≥1×109 /L (-4). After excluding mimics of vasculitis, a patient with a diagnosis of small- or medium-vessel vasculitis could be classified as having GPA if the cumulative score was ≥5 points. When these criteria were tested in the validation data set, the sensitivity was 93% (95% CI 87% to 96%) and the specificity was 94% (95% CI 89% to 97%). CONCLUSION: The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for GPA demonstrate strong performance characteristics and are validated for use in research.

2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Eosinophilic Granulomatosis with Polyangiitis.

OBJECTIVE: To develop and validate revised classification criteria for eosinophilic granulomatosis with polyangiitis (EGPA). METHODS: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in five phases: (1) identification of candidate criteria items using consensus methodology, (2) prospective collection of candidate items present at the time of diagnosis, (3) data-driven reduction of the number of candidate items, (4) expert panel review of cases to define the reference diagnosis and (5) derivation of a points-based risk score for disease classification in a development set using least absolute shrinkage and selection operator logistic regression, with subsequent validation of performance characteristics in an independent set of cases and comparators. RESULTS: The development set for EGPA consisted of 107 cases of EGPA and 450 comparators. The validation set consisted of an additional 119 cases of EGPA and 437 comparators. From 91 candidate items, regression analysis identified 11 items for EPGA, 7 of which were retained. The final criteria and their weights were as follows: maximum eosinophil count ≥1×109/L (+5), obstructive airway disease (+3), nasal polyps (+3), cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or anti-proteinase 3-ANCA positivity (-3), extravascular eosinophilic predominant inflammation (+2), mononeuritis multiplex/motor neuropathy not due to radiculopathy (+1) and haematuria (-1). After excluding mimics of vasculitis, a patient with a diagnosis of small- or medium-vessel vasculitis could be classified as having EGPA if the cumulative score was ≥6 points. When these criteria were tested in the validation data set, the sensitivity was 85% (95% CI 77% to 91%) and the specificity was 99% (95% CI 98% to 100%). CONCLUSION: The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Eosinophilic Granulomatosis with Polyangiitis demonstrate strong performance characteristics and are validated for use in research.

The complexity of classifying ANCA-associated small-vessel vasculitis in actual clinical practice: data from a multicenter retrospective survey.

The different sets of criteria for diagnosis or classification of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) lead to numerous overlapping and reclassified diagnoses in clinical practice. We designed this study to assess the difficulties in classifying patients with AAV. As a secondary objective, different variables were tested to predict prognosis. We conducted a retrospective chart review in a Western Spain multicentre survey. A total of 115 adult patients diagnosed with AAV from 2002 to 2013 and followed for at least 3 years were included. They were classified according to (1) Chapel Hill Consensus Conference (CHCC), (2) European Medicines Agency algorithm and (3) French Vasculitis Study Group/European Vasculitis Society phenotypes. Fifty-three patients (46%) had neither distinctive histopathological data of a single AAV definition nor any surrogate markers for granulomatous inflammation and thus did not fulfill any diagnostic criteria. Ocular, ear, nose, throat, skin, and lung involvement were more frequent with proteinase 3 (PR3) antibodies, whereas peripheral neuropathy was more frequent with myeloperoxidase (MPO) antibodies. When the disease was severe at diagnosis, the HR for mortality was 10.44. When induction treatment was not given in accordance with the guidelines, the HR for mortality was 4.00. For maintenance treatment, the HR was 5.49 for mortality and 2.48 for relapse. AAV classification is difficult because many patients had neither specific clinical data nor distinctive histological features of a single CHCC definition. A structured clinical assessment of patient severity is the best tool to guide the management of AAV.

Clinical implication of chronic paranasal sinusitis for the classification of microscopic polyangiitis.

BACKGROUND: Chronic paranasal sinusitis (CPS) has been known as a surrogate marker for granulomatosis with polyangiitis (GPA). We investigated whether CPS at diagnosis may have an influence on the classification and outcomes of microscopic polyangiitis (MPA). METHODS: We retrospectively reviewed the medical records of 106 immunosuppressive drug-naïve patients with MPA. We compared variables at diagnosis of MPA patients with CPS with either MPA patients without CPS or 29 GPA patients with CPS. We applied the algorithm for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) proposed by the European Medicine Agency to 22 MPA patients with CPS and reclassify them. Death, relapse and end-stage renal disease were assessed as the poor outcomes. RESULTS: Except for ENT manifestations, only pulmonary manifestation was more frequently observed in MPA patients with CPS than those without (77.3% vs 47.6%). No proteinase 3-ANCA was detected in all MPA patients with CPS. Meanwhile, general (63.6% vs 27.6%) and renal manifestations (81.8% vs 44.8%) more often developed in MPA patients with CPS than GPA patients with CPS. Of 22 MPA patients with CPS, 21 patients underwent biopsies. When CPS was not considered as a surrogate marker for GPA, all patients with CPS were reclassified as MPA. Ground glass opacity and reticulation on high-resolution computed tomography and renal vasculitis were helpful clues supporting the classification of MPA in patients with CPS. CPS at diagnosis was not associated with the outcomes of MPA. CONCLUSION: CPS might not be a sufficient surrogate marker for GPA in the classification of AAV.

Eosinophilic Granulomatosis with Polyangiitis: Experiences in Korean Patients.

Eosinophilic granulomatosis with polyangiitis (EGPA) is one form of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Identical to what has been called Churg-Strauss syndrome, EGPA exhibits both allergic and vasculitis features. EGPA was first described as a syndrome consisting of asthma, fever, eosinophilia, and organ involvement including heart failure, neuropathy, and kidney damage, by Churg and Strauss in 1951. On the basis of the 2012 Chapel Hill Consensus Conferences Nomenclature of Vasculitis, EGPA comprises three typical allergic components, including asthma, peripheral eosinophilia, and eosinophil-rich granuloma of the respiratory tracts. EGPA has three clinical and histological stages. The first is an allergic stage composed of asthma and sinusitis, and the second is an eosinophilic stage characterised by peripheral hypereosinophilia and intra-organ infiltration of eosinophils. The last is a vasculitic stage, including necrotising inflammation of small vessels and end-organ damage. In this review, we describe the classification criteria for EGPA and recommendations for the evaluation and management of EGPA with conventional and newly suggested drugs for EGPA. Also, we discuss a variety of clinical aspects such as predictive values for prognosis and associations with other Th2-mediated diseases and hepatitis B virus.

Clinical impact of subgrouping ANCA-associated vasculitis according to antibody specificity beyond the clinicopathological classification.

OBJECTIVES: In ANCA-associated vasculitis (AAV), classifications have emerged to individualize homogeneous clinical and outcomes patterns, including the recently defined anti-MPO granulomatosis with polyangiitis (GPA) subgroup. This study aimed to retrospectively evaluate the impacts of re-classification based on clinicopathological criteria and/or ANCA specificity. METHODS: A retrospective monocentric study conducted at Caen University Hospital led to the identification of PR3 or MPO-ANCA AAV patients from January 2000 or September 2011, respectively, to June 2016. Eosinophilic GPA patients were excluded. AAVs were thereby also classified either as GPA or microscopic polyangiitis (MPA) according to the European Medicines Agency vasculitis algorithm. RESULTS: A total of 150 AAV patients were included (94 GPA, 56 MPA; 87 anti-PR3 and 63 anti-MPO patients). GPA patients exhibited a worse relapse-free survival but a better renal survival (P < 0.001 and P = 0.021, respectively) than MPA patients. Overall, relapse-free and renal survival rates were similar between anti-PR3 and anti-MPO patients (P = 0.35, 0.17 and 0.15, respectively). Similarly, the prognosis was identical between anti-MPO MPA patients and anti-PR3 MPA patients (P = 0.33, 0.19 and 0.65, respectively), and between anti-MPO GPA patients and anti-PR3 GPA patients (P = 0.06, 0.99 and 0.64, respectively). Moreover, anti-PR3 GPA and anti-MPO GPA patients exhibited no differences in clinical manifestations or BVAS score. CONCLUSION: Clinicopathological classification appeared to be the strongest criterion for distinguishing among homogeneous prognoses of AAV. Individualizing the anti-MPO GPA subgroup does not appear to bring additional value to clinical practice, but multicentre studies are required to confirm this trend.

The utility of the ACR/EULAR 2017 provisional classification criteria for granulomatosis with polyangiitis in Korean patients with antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVES: We applied the ACR/EULAR 2017 provisional classification criteria for granulomatosis with polyangiitis (GPA) to 150 Korean patients with previously diagnosed antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and investigated how many patients with AAV were reclassified as GPA. METHODS: We included patients with 30 GPA, 30 eosinophilic GPA (EGPA) and 90 microscopic polyangiitis (MPA) patients. Patients can be classified as GPA, when the sum of scores is more than 5. RESULTS: At diagnosis the mean age of 150 patients with AAV was 60.1 years old, and 101 patients (67.3%) were women. Overall, 33 of 150 patients with AAV (22.0%) were classified as GPA according to the 2017 provisional criteria for GPA. The 2017 provisional criteria for GPA dropped to 10.0% of previously diagnosed GPA patients and the major factor to drop 3 GPA patients was the deletion of 2 items of the 1990 criteria, urinary sediment and infiltrates on chest radiograph. Meanwhile, one of 30 patients with EGPA (3.3%) and 5 of 90 patients with MPA (5.6%) were newly classified as GPA based on the 2017 provisional criteria for GPA. We could also find that items of the 2017 provisional criteria to contribute to reclassifying EGPA and MPA patients as GPA were PR3-ANCA, mass-like lung lesion and nasal congestion in Korean patients with AAV. CONCLUSIONS: The use of the 2017 provisional criteria for GPA excluded 10.0% of previously classified GPA patients and newly classified 3.3% of EGPA patients and 5.6% of MPA patients as GPA in Korean patients with AAV.

Are the 1990 American College of Rheumatology vasculitis classification criteria still valid?

Objectives: Advances in diagnostic techniques have led to better distinction between types of vasculitis, potentially affecting the utility of the 1990 ACR classification criteria for vasculitis. This study tested the performance of these criteria in a contemporary vasculitis cohort. Methods: The Diagnosis and Classification in Vasculitis Study provided detailed clinical, serological, pathological and radiological data from patients with primary systemic vasculitis and clinical context-specific comparator conditions. Fulfilment of six ACR criteria sets and their diagnostic performance was evaluated in patients with a given type of vasculitis and its comparator conditions. Results: Data from 1095 patients with primary systemic vasculitis and 415 with comparator conditions were available. For classification, sensitivities and specificities for ACR classification criteria were, respectively, 81.1% and 94.9% for GCA; 73.6% and 98.3% for Takayasu's arteritis; 65.6% and 88.7% for granulomatosis with polyangiitis; 57.0% and 99.8% for eosinophilic granulomatosis with polyangiitis; 40.6% and 87.8% for polyarteritis nodosa; 28.9% and 88.5% for microscopic polyangiitis; and 72.7% and 96.3% for IgA-vasculitis. Overall sensitivity was 67.1%. Of cases identified by their respective criteria, 16.9% also met criteria for other vasculitides. Diagnostic specificity ranged from 64.2 to 98.9%; overall, 113/415 comparators (27.2%) fulfilled at least one of the ACR classification criteria sets. Conclusion: Since publication of the ACR criteria for vasculitis, the sensitivity for each type of vasculitis, except GCA, has diminished, although the specificities have remained high, highlighting the need for updated classification criteria.

Different responses to treatment across classified diseases and severities in Japanese patients with microscopic polyangiitis and granulomatosis with polyangiitis: a nationwide prospective inception cohort study.

INTRODUCTION: This study aims to elucidate the prognosis and the effectiveness of current treatments for Japanese patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). METHODS: Patients with newly diagnosed MPA and GPA were enrolled in a nationwide, prospective, inception cohort study from 22 tertiary Japanese institutions, and treatment patterns and responses were evaluated for 24 months. Primary outcome measures were rates of remission (Birmingham Vasculitis Activity Score, 0) and remission with low-dose glucocorticoids (GC) (prednisolone ≤ 10 mg) (GC remission). RESULTS: Of 156 enrolled patients, 78 MPA patients and 33 GPA patients were included. Concomitant cyclophosphamide (CY) was used in 24 MPA (31 %) and 20 GPA (60 %) patients during the initial 3 weeks of treatment. After 6 months, remission was achieved in 66 MPA (85 %) and 29 GPA (87 %) patients, while GC remission was obtained in only 31 MPA (40 %) and 13 GPA (39 %) patients. During the 24-month period, 14 MPA patients and 2 GPA patients died; end stage renal disease (ESRD) was noted in 13 MPA patients but no GPA patients. Patients with severe disease, according to the European Vasculitis Study Group (EUVAS) classification, showed poorer ESRD-free and overall survival rates than those with generalized disease (p < 0.0001). There were no differences in relapse-free survival rates between GPA and MPA, among EUVAS-defined disease severity categories, and between anti-neutrophil cytoplasmic antibody subspecialties. CONCLUSIONS: The majority of Japanese patients with MPA and GPA received treatment with high-dose GC and limited CY use, and showed high remission and relapse-free survival rates but low GC remission rates in clinical practice. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry UMIN000001648 . Registered 28 February 2009.

Current landscape of antineutrophil cytoplasmic antibody-associated vasculitis: classification, diagnosis, and treatment.

This article provides an update on the diagnosis and management of the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides, granulomatosis with polyangiitis (formerly Wegener), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss). Focus is on new schemes of classification and the importance of ANCAs in the diagnosis and prognosis of these systemic vasculitides. Current therapeutic strategies consisting of glucocorticoids in conjunction with conventional or biologic agents for both induction of remission and remission maintenance are outlined. Future research directions include investigation of the optimal duration and frequency of maintenance therapy and development of targeted therapeutic agents.

Diagnosis and classification of granulomatosis with polyangiitis (aka Wegener's granulomatosis).

Granulomatosis with polyangiitis (GPA, formerly known as Wegener's Granulomatosis) is an autoimmune small vessel vasculitis which is highly associated with anti-neutrophil cytoplasmic antibodies (ANCA). The hallmarks of this condition are systemic necrotising vasculitis, necrotising granulomatous inflammation, and necrotising glomerulonephritis. The aetiology of granulomatosis with polyangiitis is linked to environmental and infectious triggers inciting onset of disease in genetically predisposed individuals. Anti-neutrophil cytoplasmic antibodies are pathogenic and play an important role in the pathogenesis of this disease, although ANCA positivity is not essential for a clinical diagnosis of granulomatosis with polyangiitis. Granulomatosis with polyangiitis is diagnosed based on clinical manifestations of systemic vasculitis and histological evidence of necrotising vasculitis or granulomatous inflammation. This small vessel vasculitis may present as limited disease of the ears, nose and upper airways or mild, moderate or severe systemic disease. Immunosuppression and adjuvant therapies have contributed to the improved prognosis of granulomatosis with polyangiitis over the past decades. Treatment strategies are tailored to the severity of the disease. They are based on published evidence of the efficacy and safety of the immunosuppressive drugs indicated to manage active vasculitis and maintain clinical remission. This review will summarise the history, aetiology, pathogenesis, classification, diagnosis and management of granulomatosis with polyangiitis.

Validation of the consensus methodology algorithm for the classification of systemic necrotizing vasculitis in Indian patients.

AIM: Many patients with systemic necrotizing vasculitis (SNV) satisfy classification criteria of different disease entities when different classification systems are used. A new classification algorithm has been proposed recently by using the American College of Rheumatology criteria, Chapel Hill Consensus Criteria (CHCC) and Sorensen surrogate markers for a more uniform classification of patients suffering from these rare disorders. METHODS: We applied this algorithm to patients diagnosed as having systemic vasculitis between 2007 and 2011. We also analyzed the data using this algorithm by incorporating the recently proposed revised CHCC nomenclature of vasculitis in place of the older criteria. RESULTS: Seventy-nine patients with SNV were studied. One patient diagnosed as microscopic polyangiitis (MPA) had to be excluded from analysis as she had previously been diagnosed as having Behcet's disease. All patients of eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA) and MPA were reclassified to the same diagnostic subcategory after application of the algorithm. Three (16.7%) of 18 polyarteritis nodosa patients were unclassifiable after application of the consensus algorithm while two (11.1%) were reclassified as MPA. All previously unclassifiable patients could be classified either as MPA or GPA after application of the new algorithm. There was no difference in the results when the CHCC 2012 nomenclature was used instead of the older CHCC in the consensus algorithm. CONCLUSION: The new classification algorithm is a reliable method for classification of SNV for epidemiological purposes in our population.

Uncommon presentations of primary systemic necrotizing vasculitides: the Great Masquerades.

INTRODUCTION: Systemic vasculitides are great masqueraders and at times their presenting manifestations can be very different from the usual recognized patterns. Such uncommon presentations of granulomatosis with polyangiitis (Wegener's granulomatosis), classical polyarteritis nodosa and unclassifiable vasculitides are described here with the relevant review of literature. METHODS: All patients diagnosed as having systemic vasculitides and classified as having granulomatosis with polyangiitis (Wegener's granulomatosis), classic polyarteritis nodosa, microscopic polyangiitis and unclassifiable vasculitis according to EMEA consensus methodology and followed up prospectively from June 2007 to December, 2011 were included. Details of uncommon presentations of these disorders were identified. RESULTS: Seventy-nine patients with systemic vasculitides were seen under our rheumatology services during this period. These included 45 patients with granulomatosis with polyangiitis (Wegener's granulomatosis), 18 with classic polyarteritis nodosa, five with microscopic polyangiitis, four with Churg-Strauss syndrome and seven with unclassifiable vasculitis. The uncommon presentations of granulomatosis with polyangiitis were a tumefactive subcutaneous mass in the thigh; prostatomegaly with obstructive uropathy and advanced renal failure; and predominant gastrointestinal (GI) vasculitis with thrombocytopenia and coagulopathy at presentation. The uncommon manifestations of classic polyarteritis nodosa were secondary antiphospholipid antibody syndrome and Budd-Chiari syndrome. One patient with massive lower GI bleeding required surgical resection of the large bowel which showed isolated necrotizing granulomatous GI vasculitis. Single organ vasculitis of the GI tract was diagnosed. CONCLUSIONS: Systemic necrotizing vasculitides may present with uncommon manifestations and a high index of suspicion is required for early diagnosis and prompt treatment to prevent adverse outcomes.

Classification of ANCA-associated vasculitis.

Classification of the ANCA-associated vasculitides remains controversial. Existing systems, developed by the American College of Rheumatology (ACR) in 1990, the Chapel Hill Consensus Conference (CHCC) in 1994 and updated in 2012, and the European Medicines Agency algorithm, all have deficiencies, especially when applied to unselected patients. The ACR system did not include ANCA or microscopic polyangiitis, and the CHCC (1994) included MPA but not ANCA (this was rectified in the 2012 revision). These systems were developed as classification criteria and not as diagnostic criteria. There are currently no validated diagnostic criteria for AAV. The Diagnostic and Classification Criteria for Vasculitis (DCVAS) study is a global study with the objective of developing and validating diagnostic criteria.

[Vasculitis. New nomenclature of the Chapel Hill consensus conference 2012]. / Vaskulitis. Neue Nomenklatur der Chapel-Hill-Konsensuskonferenz 2012.

In recent years, many advances have been made in our understanding of vasculitis etiopathology as well as of different disease courses. The revised Chapel Hill Consensus Conference (CHCC) 2012 nomenclature reflects current knowledge about etiopathology, in addition to the descriptive principles of vessel size and type of inflammation. Anti-neutrophil cyptoplasmic antibody (ANCA)-associated vasculitides have been classified as a separate group, as opposed to immune complex small vessel vasculitis. In cases where consensus was achieved, eponyms have been replaced by systematic names, such as granulomatosis with polyangiitis (Wegener's) or eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Moreover, clinically important but less well-known types of vasculitis have now been included in the CHCC nomenclature. This article presents the changes, focussing on those types that are relevant to the histopathologist, and summarizes the results of important new articles on morphology and clinical picture of vasculitis.

Antineutrophil cytoplasmic antibody-associated vasculitides: is it time to split up the group?

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides are a heterogeneous group of diseases corresponding to necrotising inflammation of small vessels with a wide range of clinical presentations. At least two of the diseases are believed to exhibit a common ground of pathophysiological mechanisms. These are granulomatosis with polyangiitis (GPA, formerly known as Wegener's granulomatosis) and microscopic polyangiitis (MPA). ANCA directed against proteinase 3 (PR3) are preferentially associated with GPA, and anti-myeloperoxidase (MPO) ANCA are associated mainly with MPA and eosinophilic GPA (formerly known as Churg-Strauss syndrome). Anti-MPO and anti-PR3 antibodies can activate neutrophils in vitro. In vivo data are available for humans and mice on the pathogenicity of anti-MPO but it is more controversial for PR3-ANCA. A recent genome-wide association study of patients with ANCA-associated vasculitides confirmed the genetic contribution to the pathogenesis of these conditions, with significant association of PR3-ANCA and human leukocyte antigen-DP and the genes encoding α1-antitrypsin and PR3. MPO-ANCA were significantly associated with human leukocyte antigen-DQ. Thus, recent results from epidemiological studies, genome-wide association study and therapeutic trials have suggested that these entities are, in fact, distinct. We have summarised these results and discuss the idea that these two entities should be studied separately as the nature of the two auto-antigens suggests at a molecular level despite shared ANCA involvement.