Association between sinusitis and relapse and changes in the myeloperoxidase-antineutrophil cytoplasmic antibody in microscopic polyangiitis.

Previous studies have evaluated the risk factors for relapse of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and the biomarkers of AAV for predicting relapse. However, little is known about the association between the presence of sinusitis and relapse and changes in the ANCA levels in AAV. This single-center, retrospective cohort study included 104 consecutive patients who were newly diagnosed with myeloperoxidase (MPO)-ANCA-positive microscopic polyangiitis (MPA) between 2006 and 2018 and were treated at the Aichi Medical University Hospital in Japan. The relationships between sinusitis and relapse of vasculitis and elevated MPO-ANCA levels were assessed using multivariate Cox proportional hazards models that were adjusted for clinically relevant factors. During the entire follow-up period (median, 24 months; interquartile range, 7-54 months), 93 (89.4%) patients achieved remission. After achieving remission, 38 (40.9%) patients experienced at least one relapse (13 [65.0%] in the sinusitis group; 25 [34.3%] in the non-sinusitis group). Sinusitis was identified as a significant predictor of relapse (adjusted hazard ratio: 2.41, 95% confidence interval [CI]: 1.19-4.88; P = 0.015). Furthermore, sinusitis was more likely to be associated with elevated MPO-ANCA levels (adjusted hazard ratio: 2.59, 95% CI: 1.14-5.92; P = 0.024). In conclusion, sinusitis was associated with a higher risk of relapse and elevated MPO-ANCA levels in MPA patients, suggesting that careful management may be required to reduce the risk of relapse in patients with sinusitis. Further studies are needed to elucidate the optimal treatment strategy for these patients.

Pathogenesis and therapeutic interventions for ANCA-associated vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) affects systemic small vessels and is accompanied by the presence of ANCAs in the serum. This disease entity includes microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis and drug-induced AAV. Similar to other autoimmune diseases, AAV develops in patients with a predisposing genetic background who have been exposed to causative environmental factors. The mechanism by which ANCAs cause vasculitis involves ANCA-mediated excessive activation of neutrophils that subsequently release inflammatory cytokines, reactive oxygen species and lytic enzymes. In addition, this excessive activation of neutrophils by ANCAs induces formation of neutrophil extracellular traps (NETs). Although NETs are essential elements in innate immunity, excessive NET formation is harmful to small vessels. Moreover, NETs are involved not only in ANCA-mediated vascular injury but also in the production of ANCAs themselves. Therefore, a vicious cycle of NET formation and ANCA production is considered to be involved in the pathogenesis of AAV. In addition to this role of NETs in AAV, some other important discoveries have been made in the past few years. Incorporating these new insights into our understanding of the pathogenesis of AAV is needed to fully understand and ultimately overcome this disease.

Hypoalbuminaemia in antineutrophil cytoplasmic antibody-associated vasculitis: incidence and significance.

OBJECTIVES: Hypoalbuminaemia has been proved to be a biomarker of poor prognosis in many diseases. The objective of this study was to investigate the significance of hypoalbuminaemia in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Data of 117 AAV patients were analysed retrospectively. The relationship between hypoalbuminaemia and disease severity were studied. The influence of albumin on the pathogenetic role of ANCA was investigated in vitro. RESULTS: Among all patients, 52 had light hypoalbuminaemia (30g/L<=albumin<35g/L) and 40 had nephrotic hypoalbuminaemia (albumin <30g/L). Patients with hypoalbuminaemia had higher inflammation levels and more severe kidney injury than patients without hypoalbuminaemia, but no significant difference of the urinary protein levels were found between patients with nephrotic and light hypoalbuminaemia. Multivariate analysis showed serum albumin correlated with age (r=-0.566, p=0.018), C-reactive protein (r=-0.521, p=0.032) and haemoglobin (r=0.512, p=0.036). Patients with nephrotic hypoalbuminaemia had higher incidence of infection, end stage renal disease and all cause mortality during treatment than patients with light hypoalbuminaemia or normal serum albumin. In vitro study indicated albumin could inhibit the binding between ANCA and neutrophils in a concentration dependent manner. Albumin also inhibited the ANCA-induced respiratory burst and neutrophil extracellular traps formation. CONCLUSIONS: Serum albumin have an inhibitory effect on the binding between ANCA and its antigen. The incidence of hypoalbuminaemia in AAV with kidney involvement is high but is not caused by heavy proteinuria. Hypoalbuminaemia is correlated with the high inflammation level and poor prognosis of AAV. Therapy targeting hypoalbuminaemia might benefit patients with AAV.

Update on systemic vasculitides.

Management of systemic vasculitis has been revolutionised over the last decade with the introduction of targeted biological agents. With an increase in both the prevalence and the recognition of vasculitis as well as the high cost of these agents, it is important to ensure their most optimal utilisation. The goals of vasculitis therapy include the induction and maintenance of remissions, preventing relapses, reducing the toxicity of therapy with the aim of reducing morbidity and mortality as well as improving the quality of life of those afflicted. This review focuses on the recent advances in the diagnosis, surveillance and treatment of these conditions.

pANCA-vasculitis associated with rectal adenocarcinoma.

We report the case of a 69-year-old male patient who was admitted for fever, dry cough, recurrent sinusitis with epistaxis, anorexia with weight loss of 20 kg over a 3-month period, myalgia, and mononeuritis multiplex. He was diagnosed with pANCA/anti-MPO associated vasculitis and rectal adenocarcinoma. The tumor was treated by surgical resection. Recurrence of vasculitis occurred during steroid tapering which prompted us to add Mycophenolate mofetyl. A complete remission was achieved. We conclude that in the present case the vasculitis was an independent disease, not a paraneoplastic phenomenon. We discuss the value of different ANCA serologies for diagnostics and follow-up, the epidemiology of vasculitis associated with malignancy, and the concept of vasculitis as a paraneoplastic syndrome.

Hematuria duration does not predict kidney function at 1 year in ANCA-associated glomerulonephritis.

OBJECTIVES: Hematuria is considered a marker of active renal disease in ANCA-associated glomerulonephritis (ANCA-GN) with induction immunosuppression often continued until hematuria has resolved. We aim to determine whether longer hematuria duration is associated with lower estimated glomerular filtration rate (eGFR) at 1 year. METHODS: We conducted a retrospective study of 55 patients with biopsy-proven ANCA-GN. Linear regression models were constructed to determine predictors of eGFR at 1 year. The primary exposure was hematuria (>5 rbc/hpf) duration, defined as <90 days vs. ≥ 90 days following renal biopsy. Covariates included age, gender, ANCA type, baseline eGFR, and baseline proteinuria. RESULTS: Mean age at diagnosis was 58 years (53% male, 80% Caucasian, 38% PR3-ANCA, and 45% MPO-ANCA). At baseline, all patients had hematuria, 95% had proteinuria, and mean serum creatinine was 3.1 [standard deviation (SD) = 2.3]mg/dL. Overall, 93% were treated with steroids in combination with either cyclophosphamide or rituximab. Mean hematuria duration was 92 (SD = 77) days with 34 (62%) patients having hematuria resolution within 90 days. Older age and lower baseline eGFR were associated with lower eGFR at 1 year (p = 0.03 and p < 0.001, respectively). Hematuria resolution (<90 days vs. ≥ 90 days) was not predictive of eGFR at 1 year (p = 0.93). CONCLUSIONS: In ANCA-GN, hematuria duration does not predict eGFR at 1 year. Our findings provide support that among individuals who are otherwise considered to be in clinical remission, the persistence of hematuria should not delay transition from induction to maintenance immunosuppression.

Endothelium-neutrophil interactions in ANCA-associated diseases.

The two salient features of ANCA-associated vasculitis (AAV) are the restricted microvessel localization and the mechanism of inflammatory damage, independent of vascular immune deposits. The microvessel localization of the disease is due to the ANCA antigen accessibility, which is restricted to the membrane of neutrophils engaged in ß2-integrin-mediated adhesion, while these antigens are cytoplasmic and inaccessible in resting neutrophils. The inflammatory vascular damage is the consequence of maximal proinflammatory responses of neutrophils, which face cumulative stimulations by TNF-α, ß2-integrin engagement, C5a, and ANCA by the FcγRII receptor. This results in the premature intravascular explosive release by adherent neutrophils of all of their available weapons, normally designed to kill IgG-opsonized bacteria after migration in infected tissues.

[Granulomatosis with polyangiitis (Wegener's granulomatosis)]. / Granulomatose avec polyangéite (maladie de Wegener).

Granulomatosis with polyangiitis (GPA), is the recently proposed, new alternative name for Wegener's granulomatosis. It defines a systemic small-vessels vasculitis, characterized by frequent involvement of upper and lower respiratory tract. The presence of cytoplasmic-type ANCA with anti-proteinase 3 specificity is observed in more than 90% of patients with GPA but is not mandatory for the definition of the disease, which is based on clinical criteria and presence of granulomas on the tissue biopsy. Necrotizing glomerulonephritis is observed in more than 50% of patients, and has important prognostic value, requiring urgent therapeutic intervention. Classical immunosuppressive schemes used in GPA combine high-dose corticosteroids and cyclophosphamide, but recent trials have shown that rituximab offers a similar efficacy with probably less cytotoxic side-effects. The best maintenance treatment is not yet defined, but the prevention of relapses remains the main therapeutic challenge in this vasculitis.

[Pathophysiology of ANCA-associated vasculitides]. / Physiopathologie des vascularites ANCA-positives.

ANCA-associated vasculitides comprise granulomatosis with polyangiitis (GPA) (formerly names Wegener's granulomatosis), Churg-Strauss syndrome (SCS) (which will be renamed GPA and eosinophilia) and microscopic polyangiitis (MPA). Immune cells (dendritic and non dendritic cells) and inflammatory cells (neutrophils, monocytes, macrophages) and resident cells (endothelial cells, fibroblasts) are implicated in the pathophysiology of ANCA-associated vasculitides. One of the targets of ANCA, myeloperoxydase, is only present in the azurophil granules of neutrophils, whereas the other target of these antibodies, proteinase 3, is also present at the internal face of cytoplasmic membrane of neutrophils, as well as at their surface. Anti-myeloperoxydase ANCA are pathogenicin vitroandin vivo, whereas the pathogenicity of anti-proteinase 3 ANCA has only been demonstrated in vitro and recent studies suggest a pathogenic role of ANCA anti-PR3 in mouse model. Two phenotypes of GPA can be distinguished: a granulomatous form, localized to the respiratory tract with Th1 immune response features, and a vasculitic form with Th2 immune response features. Recently, an increase in TH17 lymphocytes at the acute phase and a defect in T regulatory cells at the chronic phase have been identified in GPA. The role of B-lymphocytes in the pathogenesis of ANCA-associated vasculitides is now well documented by the effectiveness of rituximab in the treatment of this condition.

Anti-neutrophil cytoplasmic antibodies stimulate release of neutrophil microparticles.

The mechanisms by which anti-neutrophil cytoplasmic antibodies (ANCAs) may contribute to the pathogenesis of ANCA-associated vasculitis are not well understood. In this study, both polyclonal ANCAs isolated from patients and chimeric proteinase 3-ANCA induced the release of neutrophil microparticles from primed neutrophils. These microparticles expressed a variety of markers, including the ANCA autoantigens proteinase 3 and myeloperoxidase. They bound endothelial cells via a CD18-mediated mechanism and induced an increase in endothelial intercellular adhesion molecule-1 expression, production of endothelial reactive oxygen species, and release of endothelial IL-6 and IL-8. Removal of the neutrophil microparticles by filtration or inhibition of reactive oxygen species production with antioxidants abolished microparticle-mediated endothelial activation. In addition, these microparticles promoted the generation of thrombin. In vivo, we detected more neutrophil microparticles in the plasma of children with ANCA-associated vasculitis compared with that in healthy controls or those with inactive vasculitis. Taken together, these results support a role for neutrophil microparticles in the pathogenesis of ANCA-associated vasculitis, potentially providing a target for future therapeutics.

Recent aspects of vasculitis and future direction.

Vasculitis is pathologically identified as specific cellular inflammation, vessel destruction, and tissue necrosis. Current classifications of vasculitis such as the Chapel Hill Classification (CHCC) and American College of Rheumatology (ACR) guidelines are not sufficiently adequate for clinicians to diagnose vasculitis. The biomarkers that are currently in clinical use such as PR3-ANCA and MPO-ANCA, only help in diagnosing small vessel vasculitis and their sensitivity and specificity are not sufficient. However, recent developments related to the pathogenesis and etiopathogenesis of vasculitis have the potential to contribute to new and improved biomarkers. The determination of diverse roles of ANCA and synergistic effects of infection, genetic, environmental factors and drugs on pathogenesis is quite important. The demonstration of a new autoantibody directed to hLAMP-2 and the resemblance to some microbial structures, in addition to the determination of the possible roles of hepatitis B and C on vasculitis are important findings. These hints may lead to new biomarker developments, providing a better method to diagnose vasculitis. The evidence on T cell immunity as circulatory and lesional will likely contribute to the development of new drugs for vasculitis.

Approach to the pediatric patient with Graves' disease: when is definitive therapy warranted?

Pediatric Graves' disease accounts for 10-15% of thyroid disorders in patients less than 18 yr of age. The onset of symptoms may be insidious and subsequently associated with a delay in diagnosis. Decreased concentration and poor school performance are frequent complaints and can be quite frustrating for the patient and family. Severe ophthalmopathy is uncommon. The diagnosis is established by the findings of an increased heart rate and goiter in the setting of a suppressed TSH and elevated T(3) and/or T(4). The majority of pediatric patients are initially placed on antithyroid medications and maintained on these medications for prolonged periods of time in hopes of achieving remission. Unfortunately, for many children and adolescents remission is unattainable, ultimately occurring in only 15-30% of patients. Several recent studies have suggested that the age of the patient, the degree of thyrotoxicosis at diagnosis, the initial response to therapy, and the level of TSH receptor antibodies serve as reasonable predictors of remission and relapse. However, a consensus on the utility of these markers has not been reached. The present clinical case describes an adolescent with Graves' disease and highlights the negative impact that prolonged medical therapy can have on quality of life and school performance; it reviews pertinent data on the diagnosis, comorbidities, and treatment options; and it identifies gaps in knowledge for when definitive therapy should be pursued. The case serves as a reminder that earlier discussion and decision for definitive therapy should be more commonplace in caring for our pediatric patients with Graves' disease.

Experimental models of vasculitis and glomerulonephritis induced by antineutrophil cytoplasmic autoantibodies.

Antineutrophil cytoplasmic autoantibodies (ANCA) are closely associated with systemic small vessel vasculitis characterized by segmental vessel wall necrotizing inflammation and a paucity of immunoglobulin deposition. Clinically, in vitro and experimental animal model observations indicate a direct pathogenic role for ANCA. This review focuses on the results of experiments utilizing a mouse model of ANCA disease induced by transfer of mouse anti-MPO IgG or anti-MPO lymphocytes into recipient mice, which causes small vessel vasculitis and glomerulonephritis that closely mimics human disease. Evidence for the following conclusion about this model, and by implication about human ANCA disease, will be summarized as follows: (1) anti-MPO IgG is sufficient even in the absence of functional T cells to cause disease and anti-MPO T lymphocytes are not sufficient to cause acute injury; (2) neutrophils are required; (3) ANCA antigens in bone marrow-derived cells are sufficient targets; (4) increased circulating pro-inflammatory cytokines and microbial products exacerbate disease, and concurrent viral infection exacerbates and modulates the phenotype of disease; (5) Fcγ receptor engagement is required for disease induction, and Fcγ receptor repertoire modulates the phenotype of disease, especially pulmonary disease; (6) activation of the alternative pathway of complement is required, complement is activated by factors released by neutrophils stimulated by ANCA IgG and engagement of C5a receptors is a primary event in complement-mediated amplification; and (7) genetic background has a marked influence on the severity and outcome of disease, and modified gene expression in bone marrow-derived cells is the primary basis for genetically determined differences in disease susceptibility. Investigations using this animal model of ANCA disease have provided important insights into the cellular, molecular and genetic factors involved in the pathogenesis of ANCA disease which are likely to lead to the identification of improved markers of disease activity and response to therapy, as well as more effective and less toxic therapies.

Carbimazole-induced agranulocytosis: does antineutrophil cytoplasmic antibody have a role?

Carbimazole is a drug that is widely used for hyperthyroid disorders, such as Graves' disease. Agranulocytosis is a rare idiosyncratic adverse reaction to the drug which is potentially fatal. This report describes a patient with a history of successfully treated pyoderma gangrenosum, who developed agranulocytosis 3 weeks after commencement of carbimazole for Graves' disease. It may give credence to the theory that implicates antineutrophil cytoplasmic antibodies in the pathogenesis of agranulocytosis induced by antithyroid drugs.

Churg-Strauss syndrome: evolving concepts.

Churg-Strauss syndrome is a rare, small-sized vessel systemic necrotizing vasculitis that was first described in the early 1950s. Its most typical presentation consists of the appearance, in a patient with late-onset asthma, of vasculitic manifestations, like fever, cutaneous purpura and mononeuritis multiplex. In such a setting, the combination of blood eosinophilia and inflammatory syndrome is highly suggestive of the diagnosis, which can be further supported by the detection of antineutrophil cytoplasmic autoantibodies (ANCN), especially P-ANCA with anti-myeloperoxidase specificity, in almost 40% of the patients, and the presence of eosinophilic granulomas and/or necrotizing vasculitis in an affected-tissue biopsy. Although these disease hallmarks are now well-known, its pathophysiological mechanisms remain to be fully understood. Several gene polymorphisms and immune dysregulations are surely implicated, ranging from direct eosinophil toxicity to T- or even B-cell dysfunctions and, altogether, suggesting the existence of different disease stages and subsets according to the predominantly involved pathway. Only half the patients initially have severe life-threatening manifestations, like cardiac involvement, which require prompt aggressive treatments based on combined corticosteroids and immunosuppressants (mainly cyclophosphamide). Other less severe disease forms can usually be controlled with corticosteroids alone. Even though this current standardized therapy quite effectively and safely obtains remission, more than three-quarters of all the patients will remain corticosteroid-dependent, mostly because of residual asthma and/or eosinophilia. Hence, progress is needed in Churg-Strauss syndrome's therapeutic management, and better understanding of the complex disease mechanisms may aid such a quest.

Clinical characteristics of myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis caused by antithyroid drugs.

CONTEXT: The clinical characteristics of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis caused by antithyroid drugs are still unclear because most reports describe only a small number of patients. OBJECTIVE: The objective was to analyze a large number of patients with MPO-ANCA-associated vasculitis to determine the time of onset, the drug and dose taken, the clinical symptoms, the relationship between the clinical symptoms and the MPO-ANCA titer, and the incidence. DESIGN: We analyzed 92 patients in whom the adverse reaction of MPO-ANCA-associated vasculitis was reported to Chugai Pharmaceutical, a company that markets antithyroid drugs. RESULTS: Of the 92 patients, 41 (44.6%) had single-organ failure, 32 (34.8%) had two-organ failure, 13 (14.1%), had three-organ failure, and two (2.2%) had four-organ failure. The number of organs involved was unknown in the other four patients (4.3%). The median time of onset was 42 months (range, 1-372 months) after starting drug treatment. The median dose at onset of MPO-ANCA-associated vasculitis was 15 mg/d (range, 2.5-45 mg/d) for methimazole and 200 mg/d (50-450 mg/d) for propylthiouracil. The severity and number of organs involved were not correlated with the MPO-ANCA titer. The incidence was between 0.53 and 0.79 patients per 10,000, and the ratio of the estimated incidences for methimazole and propylthiouracil was 1:39.2. CONCLUSIONS: The time of onset of MPO-ANCA-associated vasculitis and the dose at onset varied. The severity and number of organs involved were not correlated with the MPO-ANCA titer, indicating a need for vigilance even when the MPO-ANCA titer is only weakly positive.

Treatment of ANCA-associated systemic small-vessel vasculitis.

Much has been learnt over the last 30 years to optimize the use of immunosuppressive and glucocorticoid therapies that has allowed the publication of treatment guidelines. However, major unmet needs remain in the treatment of ANCA-associated vasculitis (AAV) and include refractory disease, only partial efficacy and toxicity of current drugs and the need for long-term regimens. Newer therapies, including mycophenolate mofetil, leflunomide and rituximab, are providing a real opportunity for improved outcomes of AAV in the future. The development of therapy has been facilitated by international clinical research networks but delayed by the complexities of studying an uncommon, multi-system disease.

ANCA-small vessel vasculitides: what have we (not yet) learned from animal models?

Anti-neutrophil cytoplasmic autoantibodies (ANCA) with a specificity for myeloperoxidase or proteinase 3 are closely associated with small vessel vasculitides (SVV). In vitro, ANCA activate primed neutrophils to release toxic substances that destroy endothelial cells, suggesting a pathogenic role for these autoantibodies in disease development. However, to study the complex interplay between ANCA, neutrophils, and the local environment in vivo, animal models are required. Here, we will review the animal models developed for ANCA-SVV and discuss how these models have been applied to study ANCA-SVV pathogenesis. In addition, some directions for future research pertaining to unresolved issues relevant for the pathogenesis and immunogenesis of ANCA-SVV are proposed.