Regulatory T Cells in Autoimmune Vasculitis.

Blood vessels are indispensable for host survival and are protected from inappropriate inflammation by immune privilege. This protection is lost in patients with autoimmune vasculitides, a heterogeneous group of diseases causing damage to arteries, arterioles, and capillaries. Vasculitis leads to vascular wall destruction and/or luminal occlusion, resulting in hemorrhage and tissue ischemia. Failure in the quantity and quality of immunosuppressive regulatory T cells (Treg) has been implicated in the breakdown of the vascular immune privilege. Emerging data suggest that Treg deficiencies are disease-specific, affecting distinct pathways in distinct vasculitides. Mechanistic studies have identified faulty CD8+ Tregs in Giant Cell Arteritis (GCA), a vasculitis of the aorta and the large aortic branch vessels. Specifically, aberrant signaling through the NOTCH4 receptor expressed on CD8+ Treg cells leads to rerouting of intracellular vesicle trafficking and failure in the release of immunosuppressive exosomes, ultimately boosting inflammatory attack to medium and large arteries. In Kawasaki's disease, a medium vessel vasculitis targeting the coronary arteries, aberrant expression of miR-155 and dysregulated STAT5 signaling have been implicated in undermining CD4+ Treg function. Explorations of mechanisms leading to insufficient immunosuppression and uncontrolled vascular inflammation hold the promise to discover novel therapeutic interventions that could potentially restore the immune privilege of blood vessels and pave the way for urgently needed innovations in vasculitis management.

2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Polyarteritis Nodosa.

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.

The ratio of CD163-positive macrophages to Iba1-positive macrophages is low in the intima in the early stage of cutaneous arteritis.

The etiology of polyarteritis nodosa (PAN) and localized PAN, including cutaneous arteritis (CA), remains unknown; however, initial endothelial damage has been implicated. The intima of the vasculitis lesions is predominantly infiltrated by innate-like bystander-activated CD8 T cells, in addition to the macrophages. Macrophages are among the major inflammatory cells involved in innate immunity and are classified into M1 and M2 subtypes. M1-type macrophages kill pathogens and cause inflammation, while M2-type macrophages promote the repair of tissues. Macrophage subtypes infiltrating in PAN and localized PAN vasculitis lesions have not yet been investigated. Innate immune response to a triggering factor on the endothelial cell surface may initiate CA pathogenesis. Thus, many M1-type macrophages may infiltrate in the intima during early CA. We assessed this hypothesis by immunohistochemical observation of macrophage phenotypes and polarization. Twenty-seven skin biopsy specimens from patients with CA were retrieved. Based on histology, we classified CA into four phases. The phenotypes of infiltrating macrophages in CA were evaluated by immunohistochemistry using antibodies against Iba-1, a pan-macrophage marker, and CD163, an M2-type macrophage marker. Our results showed that the ratio of CD163-positive M2-type macrophages to Iba1-positive macrophages was lower in the intima in the early stage of CA than in the later stage. In the media to adventitia, there was no significant difference in the ratios between these stages. These findings indicate that innate immunity is involved in the intima in the early stage of CA, suggesting that a trigger for CA might exist in endothelial cells.

Choroidal vascularity index as a biomarker of systemic inflammation in childhood Polyarteritis Nodosa and adenosine deaminase-2 deficiency.

BACKGROUND/PURPOSE: To assess EDI-OCT (enhanced depth imaging optical coherence tomography) of choroid for inflammatory signs in children with polyarteritis nodosa (PAN) and adenosine deaminase-2 deficiency (DADA-2). METHODS: In this cross-sectional study conducted between June 2017 and September 2018, we evaluated children diagnosed with PAN (n = 11) and DADA-2 (n = 4) and an age- and sex-matched control group (n = 15). Demographic and laboratory data were retrospectively analyzed from patient charts. Disease activity was assessed using the pediatric vasculitis activity score (PVAS). Choroidal images were obtained with spectral domain-OCT to measure choroidal thickness (ChT) at 5 points (750 and 1500 µm from the foveal center in the temporal and nasal quadrants and beneath the fovea), and to calculate the total subfoveal choroidal area (TCA), luminal area (LA), stromal area (SA), and the choroidal vascularity index (CVI). RESULTS: The median (min-max) age was 8 (4-16) years in PAN patients, 6 (5-16) years in DADA-2 patients and 8 (8-10) years in control group at the OCT visit (p = 0.214). The ChT at 3 points and the TCA, LA, and SA were higher in children with both PAN and DADA-2 patients compared to those of the control group (p < 0.0001, p = 0.049, p = 0.007, p = 0.007, p = 0.006, p = 0.033, respectively). The CVI was similar in both groups. No association was observed between the OCT findings, PVAS, and the erythrocyte sedimentation rate, and serum leukocyte and C-reactive protein levels. CONCLUSION: Similar CVI scores were obtained from PAN and DADA2 patients under treatment and from healthy controls. Increased subfoveal ChT without any other signs of ocular involvement may suggest choroidal thickening as a sign of mild subclinical inflammation.

Advances in Therapies and Imaging for Systemic Vasculitis.

Vasculitis is a systemic disease characterized by immune-mediated injury of blood vessels. Current treatments for vasculitis, such as glucocorticoids and alkylating agents, are associated with significant side effects. Furthermore, the management of both small and large vessel vasculitis is challenging because of a lack of robust markers of disease activity. Recent research has advanced our understanding of the pathogenesis of both small and large vessel vasculitis, and this has led to the development of novel biologic therapies capable of targeting key cytokine and cellular effectors of the inflammatory cascade. In parallel, a diverse range of imaging modalities with the potential to monitor vessel inflammation are emerging. Continued expansion of combined structural and molecular imaging using positron emission tomography with computed tomography or magnetic resonance imaging may soon provide reliable longitudinal tracking of vascular inflammation. In addition, the emergence of radiotracers able to assess macrophage activation and immune checkpoint activity represents an exciting new frontier in imaging vascular inflammation. In the near future, these advances will allow more precise imaging of disease activity enabling clinicians to offer more targeted and individualized patient management.

Infliximab for the treatment of refractory polyarteritis nodosa.

Polyarteritis nodosa (PAN) is a necrotizing vasculitis predominantly affecting medium and small size arteries. Cyclophosphamide, a drug with narrow therapeutic range and poor safety profile, constitutes the treatment of choice for PAN vasculitis with major organ involvement. To describe our clinical experience in treating refractory PAN with infliximab (a TNF inhibitor), a drug with good tolerability and better safety profile than cyclophosphamide. Twenty-six PAN patients were admitted to our rheumatology unit between 2006 and 2017, of whom nine patients, with severe and refractory disease, were treated with infliximab after failure of standard treatment. We describe herein the patients' characteristics, clinical manifestations, severity and response to infliximab treatment and review the current literature. Complete remission was defined as the absence of features of active disease and withdrawal of prednisone therapy. Significant improvement was defined as clinical improvement and prednisone dose reduction of at least 50% or a 50% reduction in immune modulatory medications other than prednisone. After 4 months of treatment, 8/9 (89%) patients achieved significant improvement, with two of them achieving complete remission. We suggest that anti-TNF agents, and in particular infliximab, are relatively safe and efficacious treatment options in refractory PAN. A randomized controlled trial should be done in order to objectively evaluate infliximab in PAN.

Systemic vasculitis involving the breast: a case report and literature review.

Systemic vasculitis involving the breast is a rare clinical condition and may mimic breast cancer or mastitis clinically or radiographically. Here, we report a case of polyarteritis nodosa (PAN) with breast involvement and perform a literature review of published cases of systemic vasculitis affecting the breast to better understand this disorder. We report a case of PAN affecting the right breast in a young woman. A retrospective review was performed by searching Medline, Embase, Web of Science, the Cochrane Library, and Scopus for cases of systemic vasculitis involving the breast written in English up to June 1st, 2018. A 27-year-old woman presented with a painful mass in the right breast was diagnosed as PAN by the biopsy. She was treated with prednisone and methotrexate for 6 months, at which time her condition had stabilized and inflammatory markers had normalized. A total of 66 cases were identified, with granulomatosis with polyangiitis (GPA), giant cell arteritis (GCA), and PAN as the main types. The typical manifestation was mass (79.2%, 53/67) in the breast, and all diagnoses were made by the pathology of the breast biopsy. Glucocorticoid and immunosuppressant were the main therapies, and 74.6% (50/67) patients achieved remission during follow-up. Our case and a literature review of 66 cases of systemic vasculitis involving the breast reveal the importance of tissue biopsy to obtain a definitive diagnosis, because the vasculitis subtype strongly influences prognosis.

Four distinct clinical phenotypes of vasculitis affecting medium-sized arteries.

Objective: Within the spectrum of polyarteritis nodosa (PAN), cutaneous PAN (cPAN) is further classified into mild cPAN and severe cPAN which presents with ulcers, necrosis, or neuritis. As distinguishing between severe cPAN and systemic PAN can be difficult, this study evaluated the clinical characteristics of patients with necrotizing arteritis of medium-sized arteries. Methods: Forty-one patients diagnosed with necrotizing arteritis of medium-sized arteries between 2008 and 2017 at our institution were enrolled in this study. Clinical background, laboratory findings, treatments, and rates of relapse and death were evaluated. Results: Thirty-six patients were classified as having cPAN (mild, 15; ulcer, nine; neuritis, eight; both, four), and five cases manifested systemic vasculitis. Clinical characteristics of mild cPAN included female predominance (84.6%) and younger age (median 31 years); those of systemic PAN included older age (median 71 years) and higher levels of inflammatory markers. Severe cPAN manifested with intermediate phenotypes. The median doses of prednisolone used to treat mild cPAN, severe cPAN, and systemic PAN were 20.0, 40.0, and 40.0 mg/day, respectively. Immunosuppressants were used in 20.0% of mild cPAN, 90.5% of severe cPAN, and 80.0% of systemic PAN patients. Although the mortality rates were indistinguishable, the relapse rates of severe cPAN (ulcer type) were significantly higher than those of other types (88.9%). Conclusion: The clinical characteristics of mild cPAN, severe cPAN (ulcer type), severe cPAN (neuritis type), and systemic PAN were distinct from each other. In particular, patients with severe cPAN (ulcer type) had higher relapse rates, indicating the importance of combination therapy.

Serum lysosomal-associated membrane protein-2 levels are increased in small and medium-vessel vasculitis, especially in polyarteritis nodosa.

OBJECTIVES: Lysosomal-associated membrane protein-2 (LAMP-2) is a highly glycosylated type I glycoprotein ex- pressed on the membranes of neutrophils, endothelial cells and other cells, which are closely linked to subsets of systematic vasculitis. The aim of this study was to investigate whether serum LAMP-2 can be used as a biomarker in small and medium vessel vasculitis (SMVV). METHODS: Serum samples from 39 patients with SMVV (including ANCA-associated vasculitis (AAV) and polyarteritis nodosa (PAN)) confirmed by angiography and/or biopsy and 78 healthy controls (HC) were collected. Serum LAMP-2 levels were determined by enzyme-linked immunosorbent assay. RESULTS: Serum LAMP-2 levels in SMVV patients were increased compared with HC (p<0.001). Serum LAMP-2 levels were significantly different between patients with active stage and those with inactive stage (p=0.024). Patients with renal involvement had higher LAMP-2 levels than patients with non-renal involvement at presentation (p=0.022). Furthermore, serum LAMP-2 levels were correlated with Birmingham Vasculitis Activity Score (BVAS), C-reactive protein (CRP), hypersensitive CRP (Hs-CRP), serum creatinine (Scr) and 24-hour proteinuria (all p<0.05). Among SMVV subsets, serum LAMP-2 levels were signi cantly higher in PAN compared with AAV (p=0.003). In PAN patients, serum LAMP-2 levels were correlated with BVAS and Hs-CRP (all p<0.05). CONCLUSIONS: Serum LAMP-2 levels can reflect the disease activity and renal involvement of SMVV. Furthermore, serum LAMP-2 levels were significantly higher in PAN compared with AAV, and associated with disease activity. LAMP-2 might be a potential biomarker for SMVV, especially in PAN.

Diagnosis and management of ADA2 deficient polyarteritis nodosa.

Deficiency of ADA2 (DADA2) is a recently described systemic inflammatory vasculopathy caused by mutations in the CERC1 gene that often, but not always, clinically resembles polyarteritis nodosa (PAN). The condition was originally characterized by livedoid rash, systemic inflammation, variable hypogammaglobulinemia, and early-onset stroke. The phenotypic spectrum has expanded to include patients with immunodeficiency syndromes and bone marrow dysfunction, which are not typical features of PAN. Exploration into the pathogenesis and treatment options of DADA2 has added to our understanding of this condition, but more studies are needed. The purpose of this article is to review the various clinical phenotypes of DADA2, and raise awareness among rheumatologists to consider DADA2 when evaluating patients presenting with PAN-like disease.

Biologics for childhood systemic vasculitis.

Recent advances have allowed better understanding of vasculitis pathogenesis and led to more targeted therapies. Two pivotal randomized controlled trials, RITUXVAS and rituximab in ANCA-associated vasculitis (RAVE), provide high-quality evidence demonstrating rituximab (RTX) is efficacious in inducing remission in adult ANCA-associated vasculitis (AAV) patients compared with cyclophosphamide (CYC). RAVE also demonstrated superiority of RTX to oral CYC for induction of remission in relapsing disease. Disappointingly, the RTX regimen was not associated with reduction in early serious adverse events. At least nine randomized trials are in progress, aiming to further delineate optimal dosing and duration of RTX therapy in AAV. In particular, the 6-month interim results of the PEPRS trial provide encouraging data specific to children. Due to special concerns related to growth, preservation of fertility, and potential for high cumulative medication doses, children with AAV should be considered as candidates for RTX even as a first-line remission induction therapy. Two randomized clinical trials have defined the role of infliximab in Kawasaki disease (KD), which appears to be as an alternative to a second infusion of intravenous immunoglobulin (IVIG) for treatment-resistant disease. Support for other biologics in the treatment of AAV or for biologics in the treatment of other vasculidities is largely lacking due to either unimpressive trial results or lack of trials. Except for the KD trials and the PEPRS, trials enrolling children remain scant. This review touches on the key trials and case series with biologics in the treatment of vasculitis that have influenced practice and shaped current thinking.

Biomarkers in vasculitis.

PURPOSE OF REVIEW: Biomarkers are considered to be helpful in diagnosing, monitoring, predicting treatment response, and prognosis in clinical practice and as outcomes in clinical trials. In this article, we review the recent literature on new biomarkers and the expanding use of older ones in vasculitic conditions. RECENT FINDINGS: In antineutrophil cytoplasmic antibody-associated vasculitis patients antineutrophil cytoplasmic antibody type may be useful as a predictor of relapse and response to rituximab. Moreover, serial measurements of proteinase-3 titer may help to predict relapse. Urinary soluble CD163 levels are promising for identifying active renal vasculitis. Imaging modalities such as positron emission tomography, computerized angiography tomography, and temporal artery ultrasound maintain their role in diagnosis and disease assessment in large vessel vasculitis. Fecal calprotectin is a useful marker of active gastrointestinal involvement in Behçet's syndrome. SUMMARY: The publications reviewed here potentially may help to move the field of biomarkers in vasculitis management. However, more work toward understanding the underlying pathophysiology and effects of an intervention on the disease process are needed before true biomarkers can be realized. Further studies with appropriate control groups, using good definitions for disease states such as activity and remission are needed to guide our use of these markers correctly in the management of our patients.

In vasculitis of small muscular arteries, activation of vessel-infiltrating CD8 T cells seems to be antigen-independent.

The etiology of polyarteritis nodosa (PAN) and localized PAN is still unknown, although a T cell-mediated immune mechanism has been considered. CD8 T cells participate not only in the antigen-dependent adaptive immune system, but also in the antigen-independent innate immune system. Non-antigen-activated CD8 T cells express a unique phenotype: granzyme B (GrB) positive /CD25 negative /programmed death-1 (PD-1) negative. The aims of this study were to assess the participation of T cells, especially innate CD8 T cells, in the development of vasculitis. Twenty-eight consecutive cases of skin biopsy specimens with cutaneous vasculitis of small muscular arteries (CVSMA) were retrieved. The series comprises of 21 cases of cutaneous arteritis, three cases of PAN, and four cases of rheumatoid vasculitis. Cases of antineutrophil cytoplasmic antibody-associated vasculitis were excluded. The phenotypes of infiltrating lymphocytes in vasculitis lesions were evaluated by immunohistochemistry. In most cases of CVSMA, the number of CD8 T cells infiltrating the intima was higher than that of CD4 T cells, and significant numbers of GrB-positive cells, which represent activated CD8 T cells, were observed. However, GrB/CD25-double-positive cells, which correspond to antigen-activated T cells, were very few in a small number of cases. Cells positive for PD-1, which is also expressed on antigen-activated CD8 T cells, were not detected. We conclude that a T cell-mediated immune mechanism, involving cytotoxic CD8 T cells, may play a role in the development of CVSMA. Low expression of CD25 in activated CD8 T cells suggests that activation was antigen-independent.

Asymptomatic cutaneous polyarteritis nodosa: treatment options and therapeutic guidelines.

Cutaneous polyarteritis nodosa (CPAN) is a rare cutaneous small- to medium-vessel vasculitis of unknown etiology. Clinically it ranges in manifestation from livedo reticularis to large cutaneous ulcers and necrosis. Prognosis is favorable and progression to systemic polyarteritis nodosa is rare. There are multiple treatment options, none of which have proven to be definitively effective. Cutaneous polyarteritis nodosa has been associated with abnormal antibody testing with elevations of antiphospholipid cofactor antibody, lupus anticoagulant, anticardiolipin antibody, and anti-ß2-glycoprotein I-dependent cardiolipin antibodies, as well as elevated anti-phosphatidylserine-prothrombin complex antibody. These antibodies suggest increased risk for thrombosis and systemic diseases such as lupus or other autoimmune connective tissue disease. We present a case of asymptomatic CPAN and evaluate if treatment should be instituted for asymptomatic disease that presents with abnormal antibody findings.

Imbalanced expression of dysfunctional regulatory T cells and T-helper cells relates to immunopathogenesis in polyarteritis nodosa.

OBJECTIVES: We investigated the characteristics of circulating T-helper (Th) cells and CD4+ regulatory T cells (Tregs) in polyarteritis nodosa (PAN). METHODS: Peripheral blood samples were obtained from 14 patients with PAN. Nine patients having granulomatosis with polyangiitis (GPA) and 11 healthy individuals (HC) were enrolled as controls. Th cells and Tregs were analyzed by flow cytometry. Suppression assay of Tregs was simultaneously performed by evaluating the proliferation of conventional CD4+ T cells cocultured with Tregs. RESULTS: The frequencies of Th cells were significantly higher in PAN than in HC. In comparison with GPA, the expression of Th1 cells was higher but that of Th17 cells was lower. Additionally, significant increase in Tregs was observed in PAN, which was correlated with the expression of Th1 cells; however, defects in suppressive ability and CTLA-4 expression were observed. The Th1-cell frequency was significantly decreased after immunosuppressive therapy in PAN; however, there were no improvements in other phenotypes or in Treg function. CONCLUSION: T-helper cell expansion and Treg dysfunction are thought to be associated with the pathogenesis of PAN. Th1 cells show a response to immunosuppressive therapy; however, the persistent immune abnormalities may interfere with complete recovery in patients with PAN.