2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for microscopic polyangiitis

Ravi Suppiah; Joanna C Robson; Peter C Grayson; Cristina Ponte; Anthea Craven; Sara Khalid; Andrew Judge; Andrew Hutchings; Peter A Merkel; Raashid A Luqmani; Richard A Watts

doi:10.1136/annrheumdis-2021-221796

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2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for microscopic polyangiitis

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Authors' response to comments from Drs. Kardas and Küçük
Joanna C. Joanna C. Robson, Peter C. Grayson, Cristina Ponte, Ravi Suppiah, Anthea Craven, Andrew Hutchings, Andrew Judge, Sara Khalid, Richard A. Watts, Raashid A. Luqmani and Peter A. Merkel
Published on: 9 June 2022
Several points regarding 2022 ACR/EULAR classification criteria for ANCA-associated vasculitides
Rıza Can Kardaş, Hamit Küçük
Published on: 26 April 2022

Published on: 9 June 2022
Authors' response to comments from Drs. Kardas and Küçük
- Joanna C. Joanna C. Robson, Rheumatologist University of the West of England, and University Hospitals and Weston NHS Foundation Trust, UK
- Other Contributors:
  Peter C. Grayson, Rheumatologist
  
  Cristina Ponte, Rheumatologist
  
  Ravi Suppiah, Rheumatologist
  
  Anthea Craven, Researcher
  
  Andrew Hutchings, Statistician
  
  Andrew Judge, Statistician
  
  Sara Khalid, Statistician
  
  Richard A. Watts, Rheumatologist
  
  Raashid A. Luqmani, Rheumatologist
  
  Peter A. Merkel, Rheumatologist
We appreciate Drs. Kardas’ and Küçük’s interest in the new 2022 ACR/EULAR Classification Criteria for ANCA-associated vasculitis (1-3) and will take this opportunity to respond to the points they raised. The key concept to reiterate and clarify is that the classification criteria are only intended for use as inclusion criteria for clinical research. Therefore, it is not appropriate to use the criteria as diagnostic tools in a clinical setting. These criteria were designed to be used when considering who to include within a clinical trial of a particular subtype of AAV only after a complex clinical assessment has taken place. Thus, application of these criteria assumes drug exposure, malignancy, infection, and many other conditions that could mimic vasculitis have been excluded.

It is important to re-emphasize that inclusion and applications of weights for specific items in the criteria were based on rigorous data-driven methods and items were, in part, included to differentiate among the three forms of ANCA-associated vasculitis. Decisions about item selection and weighting were made keeping in mind the value of the items relative to other items through the regression methods used in the analyses. With these concepts in mind, it is easier to understand how items present in more than one type of vasculitis but in differing frequencies may be included in one but not another set of criteria. For example, pulmonary involvement incorporates multiple findings suc...
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We appreciate Drs. Kardas’ and Küçük’s interest in the new 2022 ACR/EULAR Classification Criteria for ANCA-associated vasculitis (1-3) and will take this opportunity to respond to the points they raised. The key concept to reiterate and clarify is that the classification criteria are only intended for use as inclusion criteria for clinical research. Therefore, it is not appropriate to use the criteria as diagnostic tools in a clinical setting. These criteria were designed to be used when considering who to include within a clinical trial of a particular subtype of AAV only after a complex clinical assessment has taken place. Thus, application of these criteria assumes drug exposure, malignancy, infection, and many other conditions that could mimic vasculitis have been excluded.

It is important to re-emphasize that inclusion and applications of weights for specific items in the criteria were based on rigorous data-driven methods and items were, in part, included to differentiate among the three forms of ANCA-associated vasculitis. Decisions about item selection and weighting were made keeping in mind the value of the items relative to other items through the regression methods used in the analyses. With these concepts in mind, it is easier to understand how items present in more than one type of vasculitis but in differing frequencies may be included in one but not another set of criteria. For example, pulmonary involvement incorporates multiple findings such as infiltrates, nodules, mass, fibrosis/interstitial lung disease, and others. Hence, inflammation on imaging is not the same as interstitial lung disease but is a broader finding. Inclusion of different forms of lung involvement in the criteria for granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) showed statistically significant differences between patients with these forms of vasculitis and patients from the comparator group (Supplementary Material 6).

A data-driven approach underpins the methodology of the DCVAS study, from definition of appropriate cases (e.g. GPA or EGPA) via use of an external panel of blinded experts, through to statistical analysis using large-scale international development and validation cohorts. It would not be appropriate to change the weightings of key items defined during this process in an ad hoc manner at the end of analysis. This process may have identified interesting features not previously noted in other, smaller datasets, such as the relatively high rate of eosinophilia in cases of GPA, that could warrant future investigation.

References
1 Grayson PC, Ponte C, Suppiah R, et al. 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Eosinophilic Granulomatosis with Polyangiitis. Ann Rheum Dis 2022;81:309–14. doi:10.1136/annrheumdis-2021-221794

2 Robson JC, Grayson PC, Ponte C, et al. 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for granulomatosis with polyangiitis. Ann Rheum Dis 2022;81:315–20. doi:10.1136/annrheumdis-2021-221795

3 Suppiah R, Robson JC, Grayson PC, et al. 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for microscopic polyangiitis. Ann Rheum Dis 2022;81:321–6. doi:10.1136/annrheumdis-2021-221796
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Conflict of Interest:
None declared.
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Published on: 26 April 2022
Several points regarding 2022 ACR/EULAR classification criteria for ANCA-associated vasculitides
- Rıza Can Kardaş, Fellow Gazi University
- Other Contributors:
  Hamit Küçük, Associate Professor
We read with great interest the recently published classification criteria for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides [1–3]. As stated elsewhere, it is hoped these criteria will further allow more homogenous patients groups to be included in clinical studies [4]. Here we would like to make several points of interest.
First, we believe the weight of laboratory criteria for granulomatosis with polyangiitis and microscopic angiitis is too high. Although it is stated in both the methodology and discussion sections that these criteria should only be applied after a diagnosis of small or medium vessel vasculitis has been made and vasculitis mimics have been excluded, this may not always be possible in a real-life setting. For instance, drug-induced [5] or paraneoplastic [6] vasculitis cases without overt clinical findings typically associated with microscopic polyangiitis (MPA) may inadvertently classified as primary MPA by the virtue of having perinuclear ANCA or anti-myeloperoxidase antibody positivity. We believe this may be prevented by lowering the point value of laboratory criteria or requiring the concomitant presence of both clinical and laboratory, imaging or biopsy criteria for classification, similar to other classification criteria used for other conditions such as systemic lupus erythematosus [7].
Second, nearly one third of patients classified as granulomatosis with polyangiitis (GPA) were reported to have maximum eosinophil...
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We read with great interest the recently published classification criteria for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides [1–3]. As stated elsewhere, it is hoped these criteria will further allow more homogenous patients groups to be included in clinical studies [4]. Here we would like to make several points of interest.
First, we believe the weight of laboratory criteria for granulomatosis with polyangiitis and microscopic angiitis is too high. Although it is stated in both the methodology and discussion sections that these criteria should only be applied after a diagnosis of small or medium vessel vasculitis has been made and vasculitis mimics have been excluded, this may not always be possible in a real-life setting. For instance, drug-induced [5] or paraneoplastic [6] vasculitis cases without overt clinical findings typically associated with microscopic polyangiitis (MPA) may inadvertently classified as primary MPA by the virtue of having perinuclear ANCA or anti-myeloperoxidase antibody positivity. We believe this may be prevented by lowering the point value of laboratory criteria or requiring the concomitant presence of both clinical and laboratory, imaging or biopsy criteria for classification, similar to other classification criteria used for other conditions such as systemic lupus erythematosus [7].
Second, nearly one third of patients classified as granulomatosis with polyangiitis (GPA) were reported to have maximum eosinophil count of ≥1×10⁹/L. Although atypical GPA cases with eosinophilia have been rarely reported in the literature [8] and this rate is lower than the comparator group (45%), we feel both rates are uncharacteristically high and requires further discussion.
Finally, presence of interstitial lung disease as a classification criterion has been included in MPA but not for GPA. The Diagnostic and Classification Criteria in Vasculitis Study (DCVAS) cohort data for pulmonary involvement shows 13.7% of GPA cases had inflammation on imaging, compared to 23.4% of MPA cases [9]. While the rate is lower, about one in every ten cases classified as GPA had pulmonary inflammation. In addition, ANCA can be positive in primary interstitial lung diseases, with varying rates reported in the literature [10]. We feel these also require further discussion.
1 Grayson PC, Ponte C, Suppiah R, et al. 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Eosinophilic Granulomatosis with Polyangiitis. Ann Rheum Dis 2022;81:309–14. doi:10.1136/annrheumdis-2021-221794
2 Robson JC, Grayson PC, Ponte C, et al. 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for granulomatosis with polyangiitis. Ann Rheum Dis 2022;81:315–20. doi:10.1136/annrheumdis-2021-221795
3 Suppiah R, Robson JC, Grayson PC, et al. 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for microscopic polyangiitis. Ann Rheum Dis 2022;81:321–6. doi:10.1136/annrheumdis-2021-221796
4 Koster MJ, Warrington KJ. ACR and EULAR bring AAV classification into the twenty-first century. Nat Rev Rheumatol Published Online First: 7 April 2022. doi:10.1038/s41584-022-00777-5
5 Pendergraft WF, Niles JL. Trojan horses: drug culprits associated with antineutrophil cytoplasmic autoantibody (ANCA) vasculitis. Curr Opin Rheumatol 2014;26:42–9. doi:10.1097/BOR.0000000000000014
6 Folci M, Ramponi G, Shiffer D, et al. ANCA-Associated Vasculitides and Hematologic Malignancies: Lessons from the Past and Future Perspectives. J Immunol Res 2019;2019:1732175. doi:10.1155/2019/1732175
7 Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis 2019;78:1151–9. doi:10.1136/annrheumdis-2018-214819
8 Shoda H, Kanda H, Tanaka R, et al. Wegener’s Granulomatosis with Eosinophilia. Intern Med 2005;44:750–3. doi:10.2169/internalmedicine.44.750
9 Makhzoum J-P, Grayson PC, Ponte C, et al. Pulmonary involvement in primary systemic vasculitides. Rheumatology 2021;61:319–30. doi:10.1093/rheumatology/keab325
10 Kadura S, Raghu G. Antineutrophil cytoplasmic antibody-associated interstitial lung disease: a review. Eur Respir Rev 2021;30. doi:10.1183/16000617.0123-2021
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Conflict of Interest:
None declared.
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