Advances in cutaneous vasculitis research and clinical care

Introduction

Vasculitis is characterized by inflammation and destruction of blood vessels, leading to ischemic tissue damage. Unlike vasculopathy, which results from clotting and mechanical occlusion of blood vessels, vasculitis is marked by inflammatory destruction. The cutaneous manifestations of vasculitis and vasculopathy may overlap or appear similar, but their systemic manifestations, diseases associations, diagnostic evaluation, management, and prognosis diverge. Because the skin is one of the most frequently affected organs, dermatologists play a key role in accurate diagnosis and effective management of vasculitis and are well-positioned to help advance clinical care and research. This manuscript provides an update on recent developments in vasculitis, with a focus on nomenclature and classification, treatment advances and targeted therapies, research priorities, and future directions.

Nomenclature and classification—the Chapel Hill Consensus Conference

The 2012 International Chapel Hill Consensus Conference (CHCC2012) provided an update and modification to the 1994 Chapel Hill Consensus Conference nomenclature (1). CHCC2012 does not establish diagnostic criteria but provides standardized nomenclature and disease definitions based on clinical features, separating forms of vasculitis into categories based on those definitions.

This categorization is based primarily on affected blood vessels (e.g., large vessel vasculitis, medium vessel vasculitis, and small vessel vasculitis). This terminology refers to the type (structure and function), and not solely the size, of blood vessels. New to CHCC2012 is the definition of small vessel vasculitis. This category includes ANCA-associated vasculitides (AAV) and cryoglobulinemic vasculitis. Additionally, single organ vasculitis (SOV) was introduced to describe vasculitis limited to a single organ, such as skin-limited cutaneous vasculitis (cutaneous small vessel vasculitis). Patients with SOV who subsequently develop a systemic vasculitis should be recategorized.

This widely used classification system has advanced vasculitis research and care, but limitations remain.

Cutaneous vasculitis—beyond Chapel Hill

Although cutaneous vasculitis was included in CHCC2012, the specific features and varied morphologies of the different subtypes of cutaneous vasculitis were not fully addressed. A consensus group of vasculitis experts, including dermatologists, added a Dermatology Addendum to CHCC2012 (D-CHCC) to provide a nomenclature of vasculitis affecting the skin (2). This addendum reframes cutaneous vasculitis as falling within one of three categories: (I) a cutaneous component of systemic vasculitis; (II) a skin-limited or skin-predominant variant of a systemic vasculitis; or (III) a SOV of the skin that is distinct from recognized systemic vasculitides (2).

This addendum complements the CHCC2012 classification of vasculitis based on vessel size, including small vessels located in the dermis and observations regarding the morphology of skin lesions. It further emphasizes that leukocytoclastic vasculitis is a histopathologic descriptor and not a specific disease entity, and it standardizes names and definitions of skin-predominant vasculitides. These include cutaneous polyarteritis nodosa (PAN), nodular vasculitis, IgM/IgG cutaneous vasculitis, skin-limited IgA vasculitis, skin-limited cryoglobulinemic vasculitis, and erythema elevatum diutinum, among others. Urticarial vasculitis (UV) is divided into a hypocomplementemic type which frequently has systemic manifestations and a normocomplementemic type which does not.

Yet, while the Dermatologic Addendum adds considerable detail to CHCC2012 and enhances understanding of cutaneous vasculitis, it does not constitute an evidence-based set of diagnostic criteria.

The Diagnostic and Classification Criteria in Vasculitis (DCVAS) Study

The DCVAS Study is an international effort to develop and validate diagnostic and classification criteria for systemic vasculitis for use in practice and clinical trials (3). Analysis of data from nearly 7,000 patients at 136 sites is underway.

A draft set of diagnostic criteria for AAV has been proposed based on findings from DCVAS, using weighted scores for diagnosis of granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA) (4). These diagnostic scores achieve high sensitivity and specificity. While they do not rely on ANCA testing to arrive at a diagnosis, ANCA positivity is heavily weighted in the scoring system.

Validated diagnostic criteria are vital for clinical practice and research and may inform understanding of the underlying disease states. Notably, as reflected in the new criteria, AAV is increasingly classified and conceptualized in terms of ANCA type (e.g., PR3, MPO, ANCA-negative) rather than by disease definition or nomenclature (e.g., GPA, MPA, EGPA). The ANCA type offers clinical and prognostic information and facilitates disease differentiation (5-9).

A recent study expands our understanding of cutaneous manifestations of AAV by disease and ANCA type, using data from DCVAS (10). Cutaneous manifestations are common in all AAV subtypes but vary between them, with certain findings more frequently associated with specific diseases. For example, “allergic” manifestations like hives more often occur in EGPA than in other types of AAV (P<0.01). When present, skin findings are associated with more severe systemic manifestations of vasculitis, such as glomerulonephritis and mononeuritis, with a hazard ratio of ~2.0 in GPA and EGPA (P<0.01). Finally, though underutilized, skin biopsy is frequently diagnostic of vasculitis when performed. These findings underscore the diagnostic and prognostic importance of the cutaneous examination in evaluation and management of AAV.

Evidence-based evaluation of cutaneous vasculitis

Small vessel vasculitis presenting in the skin is frequently skin-limited and self-limited. However, important systemic manifestations of vasculitis or underlying disease states may occur, necessitating careful evaluation. Unfortunately, no evidence-based protocol exists to help guide the evaluation of patients presenting with cutaneous vasculitis.

Emerging data from a cohort of patients with biopsy-proven small vessel vasculitis of the skin may provide some insights (11). Findings suggest extensive, unguided testing evaluating for systemic involvement is unlikely to be helpful. Tests such as erythrocyte sedimentation rate and C-reactive protein are non-specific and do not aid identification of patients with underlying disease, while ANCA, ANA, screening radiographs (e.g., chest X-ray, computed tomography), cryoglobulins, and other tests can be helpful in certain circumstances but are insensitive and have limited diagnostic value when broadly applied. Tests utilized for screening purposes in this manner, absent other signs or symptoms of systemic disease, have low predictive value and contribute to increased healthcare expenditures. Efforts are underway using these data to create an evidence-based algorithm to help guide the work-up of small vessel vasculitis of the skin using a targeted, stepwise approach (12,13).

Treatment of vasculitis: towards targeted therapies

Vasculitis subtype, severity, and patient comorbidities drive treatment selection, with a goal of induction and long-term maintenance of disease remission, with minimal drug toxicity. A number of high-quality publications over the last several years have shifted the standard of care for systemic vasculitis toward more targeted, less immunosuppressive regimens. Multicenter collaborative efforts, largely via the Vasculitis Clinical Research Consortium (VCRC), have driven this progress.

Updates in AAV

Nowhere has this shift toward targeted therapies been more pronounced than in the treatment of AAV. Traditional AAV therapies, such as cyclophosphamide and high-dose glucocorticoids for induction and azathioprine or methotrexate for maintenance therapy, are life-saving but associated with significant treatment-related side effects and a high relapse rate (14,15). Over the last decade, a paradigm shift toward more targeted, less broadly immunosuppressive therapies has occurred, based on an improved understanding of disease pathogenesis.

Rituximab for AAV

The RAVE and RITUXVASC trials showed that the combination of rituximab plus glucocorticoids is non-inferior to cyclophosphamide plus glucocorticoids for inducing remission in AAV (16,17). In the RAVE trial, within a specified subgroup, patients with relapsing disease who received rituximab did better than those who received cyclophosphamide (16). In addition, loss of PR3 positivity was more frequent in the rituximab treated group (16). In RITUXVASC, all patients treated with rituximab were ANCA negative by 6 months (17). In addition to inducing remission, rituximab has more recently been shown to be an effective therapy for prevention and treatment of relapsed disease (14,18). These trials included patients with GPA and MPA but not EGPA. Rituximab for EGPA is limited to case series and case reports; its use is considered for severe or refractory disease (19).

Plasma exchange in AAV

GPA and MPA with severe kidney disease or pulmonary hemorrhage have traditionally been treated with plasma exchange to reduce circulating ANCAs (20). A recent large-scale trial, PEXIVAS, evaluated >700 patients with severe GPA and MPA to compare efficacy of plasma exchange vs. no plasma exchange for prevention of death and end-stage kidney disease. The study also evaluated a reduced-dose glucocorticoid regimen (20). The study found that plasma exchange did not result in a lower incidence of end-stage kidney disease or death and that a reduced-dose glucocorticoid regimen was non-inferior to standard regimens (20).

Avacopan: complement pathway inhibition in AAV

Based on evidence that activation of the alternative complement pathway plays a role in the pathogenesis of AAV, studies are underway to evaluate avacopan, a novel C5a receptor inhibitor (21-23). Phase I and II data suggest targeted inhibition of the interaction between C5a and C5aR by avacopan can improve outcomes in AAV and reduce glucocorticoid exposure (24-28). A large, phase III, multicenter, double-blind RCT is now underway (ADVOCATE) (23).

Anti-IL-5 antibodies in EGPA

Management of EGPA is often suboptimal, with a high risk of relapse and a need for ongoing immunosuppression. Clinical observation and genome-wide association studies suggest ANCA status imparts prognostic and genetic meaning. Candidate targets for future therapies have also been identified (29).

IL-5 is a cytokine central to the pathogenesis of eosinophilia in EGPA (30,31). Mepolizumab, a humanized monoclonal antibody to IL-5, demonstrated efficacy for EGPA, with a low incidence of side effects, in open-label studies and a randomized, placebo-controlled trial (32,33). The MIRRA trial in 2017 evaluated mepolizumab at a dose of 300 mg every 4 weeks for relapsing or refractory EGPA (34). Treatment with mepolizumab was associated with more time in remission and a lower relapse rate compared to placebo, allowing for reduced corticosteroid use. Based on these findings, mepolizumab became the first drug approved for EGPA by the Food and Drug Administration (FDA). Nevertheless, only 53% of participants achieved remission (34).

Benralizumab and reslizumab are other IL-5 antagonists that have been approved for severe asthma (35). Case series suggest improvement in patient-reported outcomes and reduced use of glucocorticoids in those receiving these medications for EGPA (36-38). Clinical trials are now ongoing. (ClinicalTrials.gov Identifiers: NCT04157348 and NCT02947945).

Skin-limited vasculitis

While large clinical trials have reshaped AAV therapy over the last decade, treatment of skin-limited vasculitis continues to be based on case reports, case series, and expert opinion. There has been only one small, and brief, randomized-controlled trial (RCT) of colchicine for treatment of skin-limited small vessel vasculitis (39). However, a multicenter collaborative effort of dermatologists and rheumatologists through the VCRC is currently underway to develop efficacy data for commonly used agents for management of skin-limited vasculitis.

A randomized multicenter trial for isolated skin vasculitis (ARAMIS) is a sequential multiple assignment randomized trial comparing the efficacy of three drugs—azathioprine, colchicine, and dapsone—for treatment of cutaneous small vessel vasculitis, skin-limited immunoglobulin A (IgA) vasculitis (skin-limited Henoch-Schönlein purpura), and cutaneous PAN (40). This study aims to provide evidence regarding the efficacy and comparative effectiveness of these therapies commonly used for management of chronic/recurring skin-limited vasculitis.

Cutaneous transcriptomics in systemic vasculitis (CUTIS) is another multicenter collaborative effort of dermatologists and rheumatologists through the VCRC. In CUTIS, cutaneous manifestations of systemic vasculitis are biopsied for detailed histopathologic and transcriptomic analysis. The information obtained through this study has the potential to enhance understanding of disease pathophysiology and may result in targeted approaches to disease management based on the specific inflammatory pathways identified (NCT03004326).

Neutrophil extracellular traps (NETs) and vasculitis

NETs have been implicated in a range of autoimmune, and inflammatory conditions, including systemic lupus erythematosus, rheumatoid arthritis, and vasculitis (41). NETs are extracellular, web-like structures composed of granule and nuclear constituents such as MPO, PR3, and histones (42). Initially thought to occur with neutrophil death and as a response to invading microbes, recent evidence suggests not all NETosis is associated with cell death (41). A form of vital NETosis, in which neutrophils retain their ability to perform phagocytic functions, has also been described (41,43).

NETs have been shown to occur in AAV in kidney biopsy specimens in the absence of a microbial infection, suggesting ANCAs may perpetuate a cycle of NET production that maintains delivery of antigen-chromatin complexes to the immune system (44). NETs have also been found in skin specimens (45,46), thrombi (47,48), and serum of patients with AAV (49), and in peripheral nerves of patients with MPA-associated neuropathy (50). While an in-depth review of NETosis is beyond the scope of this manuscript, mounting evidence suggests a pathogenic role. Levamisole-associated vasculopathy/vasculitis has been a source of evidence for this pathogenic role of NETosis (51,52). Levamisole acts via muscarinic receptors to stimulate NETosis (53). These NETs contribute to vascular pathology and have been found in the skin of patients with levamisole-induced autoimmunity, forming autoantibodies against NET components, including neutrophil elastase, PR3, MPO, and antinuclear antibodies (54). As additional evidence mounts for NETosis in vasculitis, treatments directed toward inhibiting or reducing the impact of NETs are under investigation (53-55).

Deficiency of adenosine deaminase 2 (DADA2); a monogenic vasculitis

DADA2 is a monogenic vasculitis which mimics PAN (56-59). DADA2 results from loss-of-function mutations in CECR1, the gene that encodes adenosine deaminase 2 (57). Patients often present at a young age with clinical manifestations of systemic vasculitis. These manifestations may include both skin findings (livedo reticularis, nodular vasculitis, digital necrosis, Raynaud disease, and cutaneous ulcers) and systemic findings (lacunar strokes, fever, hypertension, renal and mesenteric aneurysms) (56-61). The spectrum of clinical manifestations is wide-ranging even within the same family, suggesting variability in the penetrance of expression of DADA2 (56,57,61). Dermatologists should be aware that patients with cutaneous manifestations of PAN may have this disease (61). In addition, authors of a recent study suggest that patients who have hepatitis B-negative PAN should be screened for DADA2 (58). In the same study, patients with GPA and MPA were not found to have this genetic mutation. Treatment options are limited; TNF-inhibitors may be considered for severe disease (62). Fresh-frozen plasma has also been utilized in an attempt to restore levels of adenosine deaminase 2, but this has not been shown to be as effective (62). Because the therapeutic approach, treatment, and prognosis differ between DADA2, idiopathic PAN, and other vasculitides, it is important that clinicians are aware of this condition.

Conclusions

Recent advances have enhanced understanding of vasculitis pathogenesis, evidence-based classification, and targeted treatment approaches, with a shift away from broad immunosuppression toward therapies targeting specific inflammatory pathways. Large-scale, multi-institutional efforts are leading the way to uncover these insights.

While significant progress has been made, more research is needed. Frequently affected and easily accessible, the skin provides an important opportunity for clinical and translational research in vasculitis, speaking to the importance of dermatologic input and expertise as part of collaborative, multidisciplinary networks.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Drs. Richard D. Sontheimer, M. Kari Connolly, David F. Fiorentino, and Victoria P. Werth) for the series “Rheumatologic Skin Disease” published in Annals of Translational Medicine. The article has undergone external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-6395). The series “Rheumatologic Skin Disease” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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