Sharon A. Chung,¹ Mark Gorelik,² Carol A. Langford,³ Mehrdad Maz,⁴Andy Abril,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,² 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,⁴Marat Turgunbaev,²⁴ Alexandra Villa-Forte,³ 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 systemic polyarteritis nodosa (PAN).

Methods. Twenty-one clinical questions regarding diagnostic testing, treatment, and management were developed in the population, intervention, comparator, and outcome (PICO) format for systemic, non–hepatitis B–related PAN. 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 16 recommendations and 1 ungraded position statement for PAN. Most recommendations were graded as conditional due to the paucity of evidence. These recommendations support early treatment of severe PAN with cyclophosphamide and glucocorticoids, limiting toxicity through minimizing long-term exposure to both treatments, and the use of imaging and tissue biopsy for disease diagnosis. These recommendations endorse minimizing risk to the patient by using established therapy at disease onset and identify new areas where adjunctive therapy may be warranted.

Conclusion. These recommendations provide guidance regarding diagnostic strategies, use of pharmacologic agents, and imaging for patients with PAN.

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that primarily affects medium-sized vessels (1). Patients frequently present with systemic symptoms such as fever and weight loss.

The most common clinical presentations include neurologic manifestations such as mononeuritis multiplex and peripheral neuropathy, cutaneous manifestations such as nodules and livedo reticularis, renal manifestations such as hypertension, and gastrointestinal manifestations such as abdominal pain (2). Diagnosis is generally confirmed by tissue biopsy of an affected organ or angiography if tissue biopsy cannot be obtained. Typical histologic findings include mixed-cell inflammatory infiltrates in the vessel wall and fibrinoid necrosis, with an absence of granulomas and giant cells (3). Findings on angiography include saccular or fusiform aneurysms and stenotic lesions in the mesenteric, hepatic, and renal arteries and their subsequent branches. Although PAN is becoming increasingly rare due to the prevention of hepatitis B viral (HBV) infection, it remains a potentially devastating diagnosis, with severe PAN having a mortality rate of 40% at 5 years (3).

Given the increasing options available to treat systemic vasculitis, the American College of Rheumatology (ACR) and the Vasculitis Foundation (VF) supported the development of guidelines for the management of large, medium, and small vessel vasculitis. This guideline presents evidence-based recommendations for the diagnostic testing, treatment, and management of PAN as an exemplar of medium vessel vasculitis. Of note, this guideline focuses on systemic PAN. Since HBV-associated PAN as well as cutaneous PAN are generally managed differently from systemic idiopathic PAN, they were excluded from this guideline.

Although this guideline may inform an international audience, these recommendations were developed considering the experience with and availability of treatment and diagnostic options in the US.

This guideline followed the 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 (4,5). 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.41776/abstract) presents a detailed description of the methods. Briefly, the Literature Review team undertook systematic literature reviews for predetermined questions specifying the clinical population, intervention, comparator, and outcomes (PICO). An in-person Patient Panel of 11 individuals with different types of vasculitis (1 patient with PAN) 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. An Expert Panel provided expert knowledge to inform discussion of the PICO questions and findings of the literature review. 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. A recommendation required ≥70% consensus among the Voting Panel.

How to interpret the recommendations

A strong recommendation is typically supported by moderate to high-quality evidence 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 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 (6).

A conditional recommendation is generally supported by lower-quality evidence or a close balance between desirable and undesirable outcomes. For a conditional recommendation, the recommended course of action would apply to the majority of the patients, but the alternative is a reasonable consideration. Conditional recommendations always warrant a shared decision-making approach. We specify conditions under which the alternative may be considered.

In some instances, the committee found that the evidence for a particular PICO question did not support a graded recommendation or did not favor one intervention over the other. However, the Voting Panel believed that the PICO question addressed a commonly encountered clinical question and thus felt that providing guidance for this question was warranted. For these situations, we present “ungraded position statements,” which reflect general views of the Voting Panel.

In this evidence-based guideline, we explicitly used the best evidence available and present that in a   transparent manner for the clinician reader/user (7). In some instances, this includes randomized trials in which the interventions under consideration are directly compared. The GRADE system rates evidence that comes exclusively from the collective experience of the Voting Panel and Patient Panel members as “very low quality” evidence (5).

For each recommendation, details regarding the PICO questions and the GRADE evidence tables can be found in Supplementary Appendix 2 (http://onlinelibrary.wiley.com/doi/10.1002/art.41776/ abstract).

This is the first guideline issued by the ACR, in conjunction with the VF, for the management of systemic PAN. These recommendations constitute a guide to help physicians treat patients with this disease. Because many recommendations are conditional, a patient’s clinical condition, values, and preferences should influence the management decisions that are made. 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.

Classic systemic PAN, although rare, remains a disease with a high mortality rate (22). Therefore, recommendations in this guideline indicate that patients with severe disease should be treated with cyclophosphamide and glucocorticoids. However, when patients present with nonsevere disease (i.e., without life-or organ-threatening manifestations such as renal insufficiency and tissue ischemia), use of alternative immunosuppressive agents and a glucocorticoid-sparing regimen is reasonable for remission induction. Use of diagnostic procedures such as angiography, electromyography/nerve conduction studies, and nerve and muscle biopsy is recommended to aid in diagnosis. However, the use of routinely repeated procedures during periods of disease quiescence is discouraged.

PAN has become increasingly rare, and no large clinical trials that focused solely on idiopathic (non–BV-associated) PAN have been published. In addition, studies of PAN conducted prior to the recognition of microscopic polyangiitis may have included such patients and should be interpreted with caution. Many recommendations were based on expert experience of the Voting Panel and/or trials that were performed several years and, in some cases, decades ago. Strong recommendations will require larger interventional studies but will be challenging to conduct due to the rarity of this disease.

The process of developing these guidelines has brought to our attention other gaps in our understanding of the optimal treatment for PAN. These gaps include the role of longitudinal vascular imaging studies, the comparative effectiveness of nonglucocorticoid immunosuppressive agents, and the lack of biomarkers to inform disease activity or treatment response. Therefore, we encourage continued research in this disease. Future study and specific areas to investigate include the following: 1) determining how informative longitudinal vascular imaging is for assessing disease activity and determining disease prognosis; 2) conducting randomized clinical trials (including comparative efficacy  trials) to assess the efficacy of nonglucocorticoid immunosuppressive agents, as well as identifying the optimal dosing, duration, and population that would benefit from these agents; 3) developing novel, targeted, and/or glucocorticoid-sparing therapies with minimal toxicity; and 4) identifying biomarkers to inform assessment of disease activity and prognosis.

In summary, the ACR and the VF present these recommendations to assist physicians in managing PAN, and this guideline can serve as a touchstone for basic principles of management. We hope this guideline will evolve as new research is conducted and new diagnostic and treatment strategies for PAN are identified.

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 Gorelik 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, Gorelik, Langford, Maz, Abril, Guyatt, Archer, Full, Grayson, Merkel, Seo, Stone, Sule, Sundel, Vitobaldi, Turner, Mustafa.

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

Analysis and interpretation of data. Chung, Gorelik, Langford, Maz, Abril, 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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