Sharon A. Chung,¹ Carol A. Langford,² Mehrdad Maz,³Andy Abril,⁴ Mark Gorelik,⁵ Gordon Guyatt,⁶ Amy M. Archer,⁷ Doyt L. Conn,⁸Kathy A. Full,⁹ Peter C. Grayson,¹⁰Maria F. Ibarra,¹¹ Lisa F. Imundo,⁵ Susan Kim,¹ Peter A. Merkel,¹²Rennie L. Rhee,¹²Philip Seo,¹³ John H. Stone,¹⁴Sangeeta Sule,¹⁵Robert P. Sundel,¹⁶ Omar I. Vitobaldi,¹⁷ Ann Warner,¹⁸ Kevin Byram,¹⁹ Anisha B. Dua,⁷ Nedaa Husainat,²⁰Karen E. James,²¹ Mohamad A. Kalot,²²Yih Chang Lin,²³ Jason M. Springer,³Marat Turgunbaev,²⁴ Alexandra Villa-Forte,² Amy S. Turner,²⁴ and Reem A. Mustafa²⁵

Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology (ACR) are intended to provide guidance for particular patterns of practice and not to dictate the care of a particular patient. The ACR considers adherence to the recommendations within this guideline to be voluntary, with the ultimate determination regarding their application to be made by the physician in light of each patient’s individual circumstances. Guidelines and recommendations are intended to promote beneficial or desirable outcomes but cannot guarantee any specific outcome. Guidelines and recommendations developed and endorsed by the ACR are subject to periodic revision as warranted by the evolution of medical knowledge, technology, and practice. ACR recommendations are not intended to dictate payment or insurance decisions, and drug formularies or other third-party analyses that cite ACR guidelines should state this. These recommendations cannot adequately convey all uncertainties and nuances of patient care.

The American College of Rheumatology is an independent, professional, medical and scientific society that does not guarantee, warrant, or endorse any commercial product or service.

Objective. To provide evidence-based recommendations and expert guidance for the management of  antineutrophil cytoplasmic antibody– associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA).

Methods. Clinical questions regarding the treatment and management of AAV were developed in the population, intervention, comparator, and outcome (PICO) format (47 for GPA/MPA, 34 for EGPA). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel.

Results. We present 26 recommendations and 5 ungraded position statements for GPA/MPA, and 15 recommendations and 5 ungraded position statements for EGPA. This guideline provides recommendations for remission induction and maintenance therapy as well as adjunctive treatment strategies in GPA, MPA, and EGPA. These recommendations include the use of rituximab for remission induction and maintenance in severe GPA and MPA and the use of mepolizumab in nonsevere EGPA. All recommendations are conditional due in part to the lack of multiple randomized controlled trials and/or low- quality evidence supporting the recommendations.

Conclusion. This guideline presents the first recommendations endorsed by the American College of Rheumatology and the Vasculitis Foundation for the management of AAV and provides guidance to health care professionals on how to treat these diseases.

The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) comprise granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss). These diseases affect small- and medium-sized vessels and are characterized by multisystem organ involvement. 

GPA is characterized histologically by necrotizing granulomatous inflammation in addition to vasculitis. Common clinical manifestations include destructive sinonasal lesions, pulmonary nodules, and pauci-immune glomerulonephritis. GPA is most commonly associated with cytoplasmic ANCA and antibodies to proteinase 3 (PR3). Among European populations, prevalence ranges from 24 to 157 per million, with the highest prevalence reported in Sweden and the UK.[1] 

MPA is characterized histologically by vasculitis without granulomatous inflammation. Common clinical manifestations include rapidly progressive pauci-immune glomerulonephritis and alveolar hemorrhage. MPA is most commonly associated with perinuclear ANCA and antibodies to myeloperoxidase. The prevalence of MPA ranges from 0 to 66 cases per million among European countries and 86 cases per million in Japan.[1, 2] 

EGPA is characterized histologically by eosinophilic tissue infiltration in addition to vasculitis. Common clinical manifestations include asthma, peripheral eosinophilia, and peripheral neuropathy. Only 40% of patients produce detectable ANCA. The overall prevalence of EGPA in European populations has been estimated to range from 2 to 38 cases per million.[1, 3] 

Prior to the use of alkylating agents, survival with these diseases was quite poor (e.g., median survival of patients with GPA was ~5 months).[4] Current treatment regimens have reversed this poor prognosis, but treatments are still associated with toxicity. Recent clinical trials have investigated the efficacy and toxicity of both biologic and nonbiologic immunosuppressive agents for the treatment of AAV. Observational studies have provided additional insight regarding management strategies for these diseases. Therefore, this guideline was developed to provide evidence-based recommendations for the treatment and management of GPA, MPA, and EGPA. Although this guideline may inform an international audience, these recommendations were developed considering the experience and availability of treatment and diagnostic options in the US. 

This guideline followed the American College of Rheumatology (ACR) guideline development process (https://www.rheumatology.org/Practice-Quality/Clinical-Support/Clinical-Practice- Guidelines) using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence and develop recommendations (5,6). ACR policy guided the management of conflicts of interest and disclosures (https://www.rheumatology.org/Practice-Quality/Clinical-Support/ Clinical-Practice-Guidelines/Vasculitis). Supplementary Appendix 1 (available on the Arthritis & Rheumatology website at
http:// onlinelibrary.wiley.com/doi/10.1002/art.41773/abstract) presents a detailed description of the methods. Briefly, the Literature Review team undertook systematic literature reviews for predetermined questions addressing specific clinical populations, interventions, comparators, and outcomes (PICO). An in-person Patient Panel of 11 individuals with different types of vasculitis (4 patients with GPA, 1 patient with MPA, and 2 patients with EGPA) was moderated by a member of the Literature Review team (ABD). This Patient Panel reviewed the evidence report (along with a summary and interpretation by the moderator) and provided patient perspectives and preferences. The Voting Panel comprised 9 adult rheumatologists, 5 pediatric rheumatologists, and 2 patients; they reviewed the Literature Review team’s evidence summaries and, bearing in mind the Patient Panel’s deliberations, formulated and voted on recommendations.

The Voting Panel was assembled for the ACR and Vasculitis Foundation’s broad effort to develop recommendations for 7 forms of systemic vasculitis: giant cell arteritis, Takayasu arteritis, polyarteritis nodosa, Kawasaki syndrome, and the 3 AAVs presented in this report. The physicians on this panel included rheumatologists who could provide insight on all of these diseases and did not include other subspecialists who would not have experience with many of the other vasculitides addressed in this effort (e.g., pulmonologists who would not have experience with large- or medium-sized vessel vasculitis). The Literature Review team chair was a nephrologist. The patients on the Voting Panel presented the views of the Patient Panel, which consisted of patients with different types of vasculitis. A recommendation required ≥70% consensus among the Voting Panel.

How to interpret the recommendations

A strong recommendation is usually supported by moderate- to high-quality evidence (e.g., multiple randomized controlled trials). For a strong recommendation, the recommended course of action would apply to all or almost all patients. Only a small proportion of clinicians/patients would not want to follow the recommendation. In rare instances, a strong recommendation may be based on very low– to low-certainty evidence. For example, an intervention may be strongly recommended if it is considered benign, low-cost, without harms, and the consequence of not performing the intervention may be catastrophic. An intervention may be strongly recommended against if there is high certainty that the intervention leads to more harm than the comparison with very low or low certainty about its benefit (7).

In this guideline, we present the first ACR/Vasculitis Foundation recommendations for the management of GPA, MPA, and EGPA. Although these recommendations provide a general guide for disease management, the patient’s clinical condition, preferences, and values should influence their treatment. Overall, these recommendations reflect the evolving management of these diseases, including the new roles for biologic therapies and aggressive strategies to minimize glucocorticoid toxicity. The recommendations for GPA and MPA are supported by a greater number of randomized trials than are currently available in EGPA. All of the recommendations made for these 3 diseases are conditional, which indicates that there are settings in which the evidence is not strong or an alternative is a reasonable consideration. These recommendations should not be used by any agency to restrict access to therapy or require that certain therapies be utilized prior to other therapies.

The physicians on the Voting Panel were primarily rheumatologists, because the recommendations were being developed for rheumatologists in the US. Since AAVs are multisystem diseases, patients with AAVs often receive care from other medical subspecialists (e.g., nephrologists, pulmonologists, and/or otolaryngologists). While the recommendations presented in this guideline are driven by the published data, other medical subspecialists may favor a different management strategy. We encourage rheumatologists to discuss treatment plans and coordinate care with other subspecialists as needed.

Recently, a clinical trial of avacopan in patients with GPA and MPA was published (55). This guideline development effort did not include consideration of avacopan, since the guidelines consider therapies that are approved by the FDA for use for any indication at the time of the last literature search. Therapies approved by the FDA after that date will be considered for inclusion in future updates to this guideline.

This guideline highlights gaps in our knowledge for the treatment of AAV. Most glaring is the lack of biomarker assessments or other noninvasive diagnostic testing with minimal toxicity that can accurately assess disease activity and predict outcomes. In addition, while we have evidence from randomized clinical trials to support recommendations regarding initial remission induction and maintenance therapy, critical questions remain unanswered, such as the optimal duration of therapy.

These gaps in knowledge reinforce the need for ongoing research in these diseases. Specific areas to investigate include the following:
1) biomarker studies to identify more specific, reliable indicators of disease activity that can guide treatment decisions;
2) trials to clarify how best to use the currently available medications (e.g., dosing, duration, effective combinations, and in which population to use which drugs);
3) trials to identify novel, targeted, and/or glucocorticoid- sparing agents with minimal toxicity; and
4) long- term studies to understand the course of disease and the safety of current therapies.

We hope significant progress will be made in these areas such that future recommendations provide a more tailored approach to disease management, minimize treatment toxicity, and prevent organ damage in these patients.

We thank Anne M. Ferris, MBBS, Ora Gewurz- Singer, MD, Rula Hajj-Ali, MD, Eric Matteson, MD, MPH, Robert F. Spiera, MD, Linda Wagner- Weiner, MD, MS, and Kenneth J. Warrington, MD, for serving on the Expert Panel. We thank Antoine G. Sreih, MD, and Gary S. Hoffman, MD, MS, for their contributions during the early phases of this project as members of the Core Team. Dr. Hoffman’s participation ended July 2018 due to personal reasons. Dr. Sreih’s involvement ended in December 2018 when he became primarily employed by industry, which precluded his continued participation in this project. We thank Joyce Kullman (Vasculitis Foundation) for her assistance with recruitment for the Patient Panel. We thank the patients who (along with authors Kathy A. Full and Omar I. Vitobaldi) participated in the Patient Panel meeting: Jane Ascroft, Scott A. Brunton, Dedra DeMarco, Thomas Fitzpatrick, Jenn Gordon, Maria S. Mckay, Sandra Nye, Stephanie Sakson, and Ben Wilson. We thank Robin Arnold, Catherine E. Najem, MD, MSCE, and Amit Aakash Shah, MD, MPH, for their assistance with the literature review. We thank the ACR staff, including Ms Regina Parker, for assistance in organizing the face- to- face meeting and coordinating the administrative aspects of the project, and Ms Robin Lane for assistance in manuscript preparation. We thank Ms Janet Waters for help in developing the literature search strategy and performing the initial literature search, and Ms Janet Joyce for performing the update searches.

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Drs. Chung and Langford had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Chung, Langford, Maz, Abril, Gorelik, Guyatt, Archer, Full, Grayson, Merkel, Seo, Stone, Sule, Sundel, Vitobaldi, Turner, Mustafa.

Acquisition of data. Chung, Langford, Maz, Abril, Gorelik, Full, Imundo, Kim, Merkel, Stone, Vitobaldi, Byram, Dua, Husainat, James, Kalot, Lin, Springer, Turgunbaev, Villa- Forte, Turner, Mustafa.

Analysis and interpretation of data. Chung, Langford, Maz, Abril, Gorelik, Archer, Conn, Full, Grayson, Ibarra, Imundo, Kim, Merkel, Rhee, Seo, Stone, Vitobaldi, Warner, Byram, Dua, Husainat, Kalot, Lin, Springer, Turgunbaev, Mustafa.

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