Diagnosis and management of ANCA-associated vasculitis.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis consists of two main diseases, granulomatosis with polyangiitis and microscopic polyangiitis, and remains among the most devastating and potentially lethal forms of autoimmune inflammatory disease. Granulomatosis with polyangiitis and microscopic polyangiitis are characterised by a necrotising vasculitis that can involve almost any organ, and have generally been studied together. The diseases commonly affect the kidneys, lungs, upper respiratory tract, skin, eyes, and peripheral nerves. Granulomatous inflammation and multinucleated giant cells are key pathological hallmarks of granulomatosis with polyangiitis, but are absent in microscopic polyangiitis. Many immune system events are essential to disease aetiopathogenesis, such as activation of the alternative complement pathway, neutrophil activation via complement receptors, and the influx of inflammatory cells, including monocytes and macrophages. These cells perpetuate inflammation and lead to organ damage. During the 21st century, the management of ANCA-associated vasculitis has moved away from reliance on cytotoxic medications and towards targeted biological medications for both the induction and maintenance of disease remission. Earlier diagnosis, partly the result of more reliable ANCA testing, has led to improved patient outcomes and better survival. Reductions in acute disease-related mortality have now shifted focus to long-term morbidities related to ANCA-associated vasculitis and their treatments, such as chronic kidney disease and cardiovascular disease. Therapeutic approaches in both clinical trials and clinical practice still remain too reliant on glucocorticoids, and continued efforts to reduce toxicity from glucocorticoids remain a priority in the development of new treatment strategies.

Significance of clinical-immunological patterns and diagnostic yield of biopsies in microscopic polyangiitis and granulomatosis with polyangiitis.

BACKGROUND: Microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are the two major antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). OBJECTIVES: To characterize a homogenous AAV cohort and to assess the impact of clinicopathological profiles and ANCA serotypes on clinical presentation and prognosis. Clinical differences in GPA patients according to ANCA serotype and the diagnostic yield for vasculitis of biopsies in different territories were also investigated. RESULTS: This retrospective study (2000-2021) included 152 patients with AAV (77 MPA/75 GPA). MPA patients (96.1% myeloperoxidase [MPO]-ANCA and 2.6% proteinase 3 [PR3]-ANCA) presented more often with weight loss, myalgia, renal involvement, interstitial lung disease (ILD), cutaneous purpura, and peripheral nerve involvement. Patients with GPA (44% PR3-ANCA, 33.3% MPO, and 22.7% negative/atypical ANCA) presented more commonly with ear, nose, and throat and eye/orbital manifestations, more relapses, and higher survival than patients with MPA. GPA was the only independent risk factor for relapse. Poor survival predictors were older age at diagnosis and peripheral nerve involvement. ANCA serotypes differentiated clinical features in a lesser degree than clinical phenotypes. A mean of 1.5 biopsies were performed in 93.4% of patients in different territories. Overall, vasculitis was identified in 80.3% (97.3% in MPA and 61.8% in GPA) of patients. CONCLUSIONS: The identification of GPA presentations associated with MPO-ANCA and awareness of risk factors for relapse and mortality are important to guide proper therapeutic strategies in AAV patients. Biopsies of different affected territories should be pursued in difficult-to-diagnose patients based on their significant diagnostic yield.

Acute glomerulonephritis.

Glomerulonephritis is a heterogeneous group of disorders that present with a combination of haematuria, proteinuria, hypertension, and reduction in kidney function to a variable degree. Acute presentation with full blown nephritic syndrome or rapidly progressive glomerulonephritis is uncommon and is mainly restricted to patients with post-infectious glomerulonephritis, anti-neutrophil cytoplasmic antibodies-associated vasculitis, and anti-glomerular basement membrane disease. Most frequently, patients present with asymptomatic haematuria and proteinuria with or without reduced kidney function. All glomerulonephritis disorders can show periods of exacerbation, but disease flairs characteristically occur in patients with IgA nephropathy or C3 glomerulopathy. The gold standard for the diagnosis of a glomerulonephritis is a kidney biopsy, with a hallmark glomerular inflammation that translates into various histopathological patterns depending on the location and severity of the glomerular injury. Traditionally, glomerulonephritis was classified on the basis of the different histopathological patterns of injury. In the last few years, substantial progress has been made in unravelling the underlying causes and pathogenetic mechanisms of glomerulonephritis and a causal approach to the classification of glomerulonephritis is now favoured over a pattern-based approach. As such, glomerulonephritis can be broadly classified as immune-complex glomerulonephritis (including infection-related glomerulonephritis, IgA nephropathy, lupus nephritis, and cryoglobulinaemic glomerulonephritis), anti-neutrophil cytoplasmic antibodies-associated (pauci-immune) glomerulonephritis, anti-glomerular basement membrane glomerulonephritis, C3 glomerulopathy, and monoclonal immunoglobulin-associated glomerulonephritis. We provide an overview of the clinical presentation, pathology, and the current therapeutic approach of the main representative disorders in the spectrum of glomerulonephritis.

Management of antineutrophil cytoplasmic antibody-associated vasculitis: a changing tide.

PURPOSE OF REVIEW: Antineutrophil cytoplasmic antibody associated vasculitis (AAV) is a group of autoimmune disorders of small blood vessels. While outcomes in AAV have improved with the use of glucocorticoids (GC) and other immunosuppressants, these treatments are associated with significant toxicities. Infections are the major cause of mortality within the first year of treatment. There is a move towards newer treatments with better safety profiles. This review reflects on recent advances in the treatment of AAV. RECENT FINDINGS: The role of plasma exchange (PLEX) in AAV with kidney involvement has been clarified with new BMJ guideline recommendations following the publication of PEXIVAS and an updated meta-analysis. Lower dose GC regimens are now standard of care. Avacopan (C5a receptor antagonist) was noninferior to a regimen of GC therapy and is a potential steroid-sparing agent. Lastly, rituximab-based regimens were noninferior to cyclophosphamide in two trials for induction of remission and superior to azathioprine in one trial of maintenance of remission. SUMMARY: AAV treatments have changed tremendously over the past decade with a drive towards targeted PLEX use, increased rituximab use and lower GC dosing. Striking a crucial balance between morbidity from relapses and toxicities from immunosuppression remains a challenging path to navigate.

Coexistence of cryoglobulinemia and ANCA-associated vasculitis in a chronic brucellosis patient -a case report and literature review.

BACKGROUND: The renal involvement of brucellosis is not common. Here we reported a rare case of chronic brucellosis accompanied by nephritic syndrome, acute kidney injury, the coexistence of cryoglobulinemia and antineutrophil cytoplasmic autoantibodies (ANCA) associated vasculitis (AAV) superimposed on iliac aortic stent implantation. The diagnosis and treatment of the case are instructive. CASE PRESENTATION: A 49-year-old man with hypertension and iliac aortic stent implantation was admitted for unexplained renal failure with signs of nephritic syndrome, congestive heart failure, moderate anemia and livedoid change in the left sole with pain. His past history included chronic brucellosis and he just underwent the recurrence and completed the 6 weeks of antibiotics treatment. He demonstrated positive cytoplasmic/proteinase 3 ANCA, mixed type cryoglobulinemia and decreased C3. The kidney biopsy revealed endocapillary proliferative glomerulonephritis with a small amount of crescent formation. Immunofluorescence staining revealed only C3-positive staining. In accordance with clinical and laboratory findings, post-infective acute glomerulonephritis superimposed with AAV was diagnosed. The patient was treated with corticosteroids and antibiotics and sustained alleviation of renal function and brucellosis was achieved during the course of a 3-month follow-up. CONCLUSIONS: Here we describe the diagnostic and treatment challenge in a patient with chronic brucellosis related glomerulonephritis accompanied by the coexistence of AAV and cryoglobulinemia. Renal biopsy confirmed the diagnosis of postinfectious acute glomerulonephritis overlapping with ANCA related crescentic glomerulonephritis, which was not ever reported in the literature. The patient showed a good response to steroid treatment which indicated the immunity-induced kidney injury. Meanwhile, it is essential to recognize and actively treat the coexisting brucellosis even when there are no clinical signs of the active stage of infection. This is the critical point for a salutary patient outcome for brucellosis associated renal complications.

Avacopan for the Treatment of Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis.

OBJECTIVE: To review the safety and efficacy of avacopan for the treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. DATA SOURCES: A systematic review of the literature was performed using the terms avacopan OR tavneos OR CCX168 OR ANCA-associated vasculitis in PubMed and Google Scholar. Articles between January 2016 and January 2023 were considered for inclusion. Bibliographies and ClinicalTrials.gov were also searched for completion. STUDY SELECTION AND DATA EXTRACTION: Relative English language and human studies related to pharmacology, clinical trials, and safety were included. DATA SYNTHESIS: The 52-week ADVOCATE and 12-week CLEAR clinical trials evaluated the safety and efficacy of avacopan. The remission rate was 65.7% and 54.9% in the avacopan and placebo group, respectively, in the ADVOCATE trial. The Birmingham Vasculitis Activity Score improved by ≥50% in 86.4% of avacopan treated patients and 70% of prednisone treated patients in the CLEAR trial. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: Glucocorticoids in combination with cyclophosphamide, azathioprine, and/or rituximab have been a mainstay of ANCA-associated vasculitis treatment. However, short- and long-term medication-related adverse effects risk negative outcomes for patients. Avacopan may provide equivalent to better treatment with fewer side effects due to a reduction, if not elimination, of glucocorticoids. CONCLUSIONS: Avacopan used in isolation or combination is safe and effective for ANCA-associated vasculitis.

De Novo ANCA-Negative Pauci-Immune Crescentic Glomerulonephritis After COVID-19 mRNA Vaccination: A Case Report.

To prevent the spread of the coronavirus disease 2019 (COVID-19) pandemic, vaccines have been authorized for emergency use and implemented worldwide. We present a case of de novo glomerulonephritis (GN) after use of the COVID-19 mRNA vaccine BNT162b2. A 48-year-old man with no relevant medical history was referred for sudden and persistent worsening of renal insufficiency 1.5 months after the second vaccine dose. He had arthralgia and skin rash a week after vaccination. Abdominal pain and diarrhea started 2 weeks later, and he was admitted to the hospital for enteritis treatment. Colonoscopy showed multiple ulcerations and petechiae suggestive of vasculitis in the terminal ileum. After prednisolone therapy, his gastrointestinal symptoms improved, but his renal function continued to deteriorate. Based on kidney biopsy findings and nephrotic-range proteinuria (5,306 mg/24 hours), he was diagnosed with anti-neutrophil cytoplasmic autoantibody (ANCA)-negative pauci-immune crescentic GN (CrGN). He received high-dose steroid pulse therapy and oral cyclophosphamide, and then, gradually underwent steroid tapering, with improvement in proteinuria and renal function over several weeks. Several cases of GN suspected to be related to COVID-19 vaccines have been reported. To our knowledge, this is the first case report of ANCA-negative pauci-immune crescentic CrGN with extrarenal involvement after COVID-19 mRNA vaccination. Our finding expands the spectrum of COVID-19 vaccine-associated GN.

[Granulomatosis with polyangiitis: what's new?] / Granulomatose avec polyangéite : quoi de neuf ?

Within the group of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides, granulomatosis with polyangiitis (GPA) is the most frequent. The incidence is around 10 to 20 cases/million/year. Clinical manifestations are varied, with ENT, lungs and kidneys most frequently involved. ANCA are pathogenic by triggering neutrophil activation, which leads to vascular damage. Detection of ANCA is most helpful in establishing the diagnosis, but serology may be negative in GPA limited to the airways. Diagnostic work-up and therapy require a multidisciplinary approach. Treatment includes an induction and maintenance phase, combining corticosteroids and immunosuppressive drugs. It aims at limiting the risk of relapses, which is important in GPA, and at reducing corticosteroids toxicity.

La granulomatose avec polyangéite (GPA) fait partie des vasculites associées aux anticorps anti-cytoplasme des polynucléaires neutrophiles (ANCA). La maladie touche principalement la sphère ORL, les poumons et les reins. Son incidence est de 10 à 20 cas/million/année. Les ANCA sont pathogéniques en induisant une activation des polynucléaires neutrophiles, entraînant des lésions endothéliales. Le diagnostic est facilité par la détection des ANCA, qui peuvent cependant être absents dans les formes ORL limitées. La prise en charge est multidisciplinaire. Le traitement comprend une phase d'induction et une autre de maintien de la rémission, associant corticostéroïdes et immunosuppresseurs. L'objectif du traitement est de limiter le risque important de rechute et de réduire la toxicité des corticostéroïdes.

Long-term survival after treatment for primary anal cancer- results from the Swedish national ANCA cohort study.

BACKGROUND: Squamous cell carcinoma of the anus is increasing in incidence but remains a rare disease with good 3- and 5-year recurrence free and overall survival rates of 63%-86%. The treatment includes chemoradiotherapy, mainly with 5-fluoruracil (5FU) and mitomycin. The aim of this study was to describe long-term (up to 9 years after treatment) oncological outcome and the types of treatments given, in a Swedish national cohort of patients diagnosed with anal cancer between 2011 and 2013. METHOD: Patients were identified in the Swedish Cancer Registry. Patients still alive were contacted and asked for consent. Clinical data were retrieved from National Patient Register at the Swedish National Board of Health and Welfare and from medical records. Unadjusted and adjusted analyses were performed for overall survival. RESULTS: Three hundred and eighty-eight patients were included in the study of which 338 patients (87%) received treatment with a curative intent. Follow up was 85 months (0-113 months) for patients treated with curative intent (information missing in one patient) 7.5 months (0-55) for patients with treated with a palliative intent. Curative treatment varied and consisted of both chemoradiotherapy and radiotherapy (46-64 Gy) alone. 5-FU, mitomycin and cisplatin were the most used chemotherapy agents. Five-year overall survival for patients treated with curative intent was 73%. In an adjusted analysis 5-FU and mitomycin is associated with a lower mortality than 5-FU and cisplatin but the association was weaker (HR 1.61 (95% CI: 0.904; 2.85) than in the unadjusted analysis. CONCLUSIONS: In this national cohort overall five-year survival was 73% for patients treated with curative intent. As reported by others our results indicate that 5-FU and mitomycin C should be the preferred chemotherapy in treatment for cure.

Population pharmacokinetic and dose optimization of mycophenolic acid in children with anti-neutrophilic cytoplasmic antibody-associated nephritis.

PURPOSE: Anti-neutrophilic cytoplasmic antibody (ANCA)-associated vasculitis is a rare autoimmune disease. Mycophenolic acid (MPA) is widely used for ANCA-associated nephritis (AAN) but with large pharmacokinetic variability. This study aims to investigate clinical factors impacting MPA disposition in pediatric AAN. METHODS: We retrospectively collected 391 MPA concentrations from 25 children diagnosed with AAN. A population pharmacokinetic model was developed to explore the potential effects of demographics and biochemical covariates on MPA. Monte Carlo simulations were performed to optimize dosage regimen. RESULTS: MPA pharmacokinetics best fitted a two-compartment model with first-order absorption and linear elimination. The pharmacokinetic parameters for Ka, CL/F, Vc/F, Vp/F, and Q/F were 0.45 h-1, 9.86 L/h, 19.69 L, 408.32 L, and 23.01 L/h. Dosage form significantly affected drug absorption. CL/F significantly decreased with increasing cystatin C, while decreasing with myeloperoxidase. Cystatin C was superior to serum creatinine in predicting apparent clearance of MPA. A dose regimen of 650 mg/m2 twice daily was required to achieve target exposure in children with normal renal function and no inflammation. The combined effects of myeloperoxidase concentration and renal function resulted in a sixfold range of MPA dose. CONCLUSION: This was the first study of MPA population pharmacokinetic model in children with AAN. Myeloperoxidase was not only a biomarker of AAN, but also an inflammatory factor to impact drug CL. The influence of renal function and underlying diseases on drug metabolism should be fully considered in personalized medication for AAN.

How the Availability of Anti-C5a Agents Could Change the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

BACKGROUND: Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a cluster of potentially life-threatening disorders, often involving the kidney with a necrotizing crescentic glomerulonephritis with scanty deposition of immunoglobulins and complement. Historically the role of complement has been considered ancillary. Recently, an anti-myeloperoxidase (MPO) AAV model in complement-deficient mice has shown an involvement for the complement cascade in the development of the renal injuries. Further animal studies showing that in contrast to mice deficient for factor B and C5 animals deficient for C4 were susceptible to AAV development by injection of anti-MPO antibodies emphasized the specific involvement of the alternative pathway. Consonantly, the C5a receptor (Cd88) blockade was found to protect mice from MPO-AAV. CCX168, i.e., avacopan, a powerful inhibitor of C5a receptor that can be administered orally, was shown to reduce the proinflammatory effects of C5a and abolish the activation of neutrophils, their migration and adherence to endothelium, and the vascular endothelial cell retraction that increases permeability. SUMMARY: Avacopan was found to be safe in healthy volunteers given a wide range of doses in a phase 1 clinical trial. The phase 2 trial CLEAR assessed the possibility to decrease dose or entirely replace glucocorticosteroids in the standard-of-care therapy of AAV. Avacopan, added to CYC or RTX either in combination with GCs or not, shortened the time to remission in patients with either newly diagnosed or relapsing AAV. The phase 3 ADVOCATE study compared the ability of an avacopan-associated regimen to induce and sustain remission in AAV patients versus a conventional GC-associated scheme. Remission at week 26 was observed in 72.3% of patients given avacopan and in 70.1% of those given prednisone. Sustained remission at week 52 (second primary endpoint) was obtained in 65.7% of patients given avacopan and in 54.9% receiving prednisone. The avacopan-associated regimen was noninferior at week 26 and superior at week 52 in sustaining remission as compared to the GC-based scheme. KEY MESSAGES: The results of the ADVOCATE trial opened new prospects for the treatment of AAV and also other immune-mediated diseases with renal involvement. The possible position of avacopan in a routine clinical setting and its possible indications in specific subsets of patients with AAV are extensively discussed.

Nutrition Risk Index Score at Diagnosis Can Effectively Predict Poor Prognosis in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVES: This study investigated whether the nutritional risk index (NRI) score at diagnosis might be useful for anticipating poor prognosis, in particular, all-cause mortality and end-stage renal disease (ESRD) in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: The medical records of 242 immunosuppressive drug-naïve patients with AAV were retrospectively reviewed. Data at diagnosis and poor prognosis and medications during follow-up were assessed. The NRI score was calculated by 1.519 × serum albumin (g/L) + 41.7 × present (kg)/ideal body weight (kg). RESULTS: The median age at diagnosis of patients with AAV (131 microscopic polyangiitis, 62 granulomatosis with polyangiitis, and 49 eosinophilic granulomatosis with polyangiitis) was 60 years (85 male). During follow-up, twenty-nine patients (12.0%) died after a period of 35.9 months, and 42 patients (17.4%) had ESRD for a period of 30.0 months. Using the receiver operator characteristic curve, the cutoffs of the NRI scores for all-cause mortality and ESRD were calculated as NRI ≤ 101.95 (sensitivity, 46.5%; specificity, 89.7%) and NRI ≤ 99.85 (sensitivity, 57.0%; specificity, 83.3%). In the multivariable Cox hazard model analyses, age (hazard ratio [HR], 1.035), five-factor score (HR, 1.623), and the NRI score ≤ 101.95 (HR, 4.262) were independent predictors of all-cause mortality, whereas, five-factor score (HR, 1.516), hypertension (HR, 1.906), and the NRI score ≤ 99.85 (HR, 3.623) were independent predictors of ESRD occurrence during follow-up in patients with AAV. CONCLUSIONS: The NRI score at diagnosis may be a useful index to anticipate all-cause mortality and ESRD occurrence during follow-up in patients with AAV.

[ANCA-Associated Vasculitides]. / ANCA-assozierte Vaskulitis.

ANCA-Associated Vasculitides Abstract. The according to their immunoserological markers (anti-neutrophil cytoplasmic antibodies - ANCA) named ANCA-associated vasculitides (AAV) are classified following the Chapel Hill nomenclature (2012). Microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA) are categorized according to clinical, histological, and imaging findings. GPA and EGPA mainly differ from MPA in the presence of granulomatous inflammation within the airways. All three are rare autoimmune diseases and their prevalences show geographical differences. Despite their rarity, recognition of the typical symptoms is very important. A timely diagnosis is crucial, as without immunosuppressive treatment the prognosis with respect to preservation of organ function and survival is poor. New treatments with potentially fewer side effects have been introduced in recent years. Amongst those Rituximab plays an important role and has largely replaced cyclophosphamide. Now the aim of therapeutic approaches is to reduce patient exposure to steroids. Because the side effects of therapy and especially steroids are the main causes of AAV morbidity besides the disease itself.

[Eosinophilic Granulomatosis with Polyangiitis with Pulmonary and Cardiac Involvement]. / Eosinophile Granulomatose mit Polyangiitis mit pulmonaler und kardialer Beteiligung.

A 62-year-old patient with bronchial asthma and chronic rhinosinusitis underwent inguinal hernia surgery. After the operation, sudden circulatory arrest occurred, requiring cardiopulmonary resuscitation. Coronary angiography revealed a 99 % proximal stenosis of right coronary artery (RCA) with unsuspicious and smooth coronary vessel walls. In the further course, several similar events occurred, but without pathological findings in the coronary angiography. Initially, echocardiography showed slightly reduced left ventricular ejection fraction of 45 %. Chest radiography revealed bilateral pulmonary infiltrates, and white blood cell count showed severe eosinophilia (37 %). Serological antibody testing including ANA, ENA and c-/p-ANCA was negative. Myeloproliferative pathologies were excluded by bone marrow puncture. The patient suffered from emerging dyspnea, weakness, and ongoing weight loss. A methylprednisolone pulse of 250 mg/d for 3 days remained without significant effect, so that the patient was eventually referred to our university hospital due to ongoing clinical deterioration. On admission, the patient suffered from weakness, progressive muscular atrophy, and dyspnea on exertion. Physical examination revealed a right-sided peroneal paralysis. Bronchial lavage detected severe eosinophil alveolitis (37 %), and laboratory findings showed elevated cardiac enzymes and NT-proBNP (Troponin-T > 700 ng/l, NT-proBNP > 10.000 ng/l). Echocardiography revealed a dramatic deterioration of cardiac function (LVEF 16 %). Interdisciplinary discussion between pulmonologists and cardiologists lead to the diagnosis of ANCA-negative eosinophilic granulomatosis with polyangiitis (EGPA) with pulmonary and cardiac involvement. Initiation of immunosuppressive therapy with methylprednisolone 1000 mg/d for 3 days followed by cyclophosphamide therapy (6 pulses, administered every 4 weeks) led to substantial symptomatic improvement, complete regression of pulmonary infiltrates and marked recovery of cardiac function (LVEF 47 %). CONCLUSION: Serological detection of elevated ANCAs is not necessary for diagnosis of EGPA. Only 30 - 70 % of patients are positive for these, particularly if neurological and/or renal rather than cardiac and/or pulmonary involvement is present. This may be a pitfall in establishing the correct diagnosis. Induction therapy with cyclophosphamide is the preferred treatment for steroid-refractory EGPA with life-threatening organ involvement.

Clinical trials in antineutrophil cytoplasmic antibody-associated vasculitis: what we have learnt so far, and what we still have to learn.

The prognosis of the antineutrophil cytoplasmic antibody associated vasculitides (AAV), microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic GPA (EGPA), has been fundamentally improved over the last five decades by the use of glucocorticoids and immunosuppressants, turning them from consistently fatal diseases into chronic conditions. The long-term course is now largely determined by the frequency of disease flares and by accruing damage caused by disease activity and treatment-related comorbidities. This review summarizes the evidence derived from clinical trials performed during the last 30 years and the remaining clinical unmet needs that new studies aim to address. In MPA and GPA, ongoing studies assess (i) different strategies to reduce cumulative glucocorticoid doses currently used for induction and maintenance of remission, (ii) the efficacy of new drugs and (iii) the optimal duration of immunosuppression and the use of biomarkers to individualize therapy. Prospective randomized trials also target disease-associated cardiovascular risk and infections. The first prospective controlled trials specifically designed for EGPA have recently been launched and could lead to new therapeutic options for patients diagnosed with this rare disease. This is an exciting time for researchers in the field of AAV, and for patients as collaborative efforts raise the hope of developing new therapies and more individualized approaches to the management of the diseases, maximizing efficacy while minimizing treatment toxicities.

Is there a role for TNFα blockade in ANCA-associated vasculitis and glomerulonephritis?

Tumour necrosis factor alpha (TNFα) is a cytokine that is pivotal in the inflammatory response. Blockade of TNFα has been shown to be effective in a number of human autoimmune diseases, including rheumatoid arthritis, raising the question of whether this approach may be effective in inflammatory kidney disease, such as ANCA-associated vasculitis (AAV). In AAV, there is considerable evidence for the role of TNFα in the pathophysiology of disease, including increased expression of TNFα mRNA in leucocytes and in renal tissue. Importantly, TNFα can induce leucocyte cell membrane expression of the autoantigens involved in vasculitis [proteinase 3 and myeloperoxidase (MPO)], thus priming cells for the effects of ANCA. In rodent models of anti-GBM disease (nephrotoxic nephritis), TNFα enhances glomerular injury and TNFα blockade using soluble TNFα receptor or anti-TNFα antibody ameliorates disease. Mice deficient in TNFα are protected from nephrotoxic nephritis and this effect is dependent mainly on intrinsic renal cells. A mouse model of anti-MPO antibody-induced glomerulonephritis is enhanced by LPS, and this effect is blocked by anti-TNFα antibody. In a rat model of AAV induced by MPO (experimental autoimmune vasculitis), anti-TNFα antibody improves renal pathology and also reduces leucocyte transmigration, as shown by intravital microscopy. In clinical studies, the Wegener's Granulomatosis Etanercept Trial (WGET) showed no benefit of additional etanercept versus standard therapy. However, there are several reasons why the results of the WGET study do not rule out the use of anti-TNFα antibody in acute renal AAV, including the study design and the considerable biological differences between the effects of etanercept and anti-TNFα antibody. There are several clinical studies demonstrating a response to anti-TNFα antibody in patients with AAV refractory to conventional treatment, and in some of these, the addition of anti-TNFα antibody was the only change in treatment. We suggest that further investigation of TNFα blockade in AAV is warranted.

Successful treatment of Bordetella bronchiseptica pneumonia by minocycline in anti-neutrophil cytoplasmic antibodies-associated vasculitis patient.

Bordetella bronchiseptica is a bacterial pathogen usually isolated from animals and rarely causes human infections. There are, however, some reports that B. bronchiseptica causes human respiratory infections in immunocompromised patients or those with underlying respiratory diseases, although there is a lack of treatment guidelines. An 80-year-old woman was admitted to our hospital to treat anti-neutrophil cytoplasmic antibodies-associated vasculitis. On the 16th day after admission, she complained of a productive cough with right pleuritic pain and had low-grade fever. After chest CT scans, we diagnosed pneumonia. Gram stain of her sputum revealed moderate levels of gram-negative coccobacilli, which was later identified as B. bronchiseptica by mass spectrometry. According to the result of minimum inhibitory concentration, we successfully treated the pneumonia with minocycline. This case suggests that B. bronchiseptica pneumonia can be treated by minocycline if the minimum inhibitory concentration is less than 0.25 µg/mL.

Prospective study of complications and sequelae of glucocorticoid therapy in ANCA-associated vasculitis.

OBJECTIVE: Glucocorticoids (GC) are a cornerstone in treating antineutrophil cytoplasmic antibodies-associated vasculitides (AAV), however, they add to morbidity and mortality. To date, GC toxicity in AAV has rarely been systematically investigated. METHODS: Patients with a confirmed AAV were included in this monocentric prospective study. GC toxicity was assessed by structured interviews, clinical examination and electronic medical record analysis. The Glucocorticoid Toxicity Index (GTI) consisting of the Aggregate Improvement Score (GTI-AIS) and the Cumulative Worsening Score (GTI-CWS) was assessed at two time points (t1 baseline, t2 6 months later). We used regression analyses to assess the relationship between GTI and GC exposure, toxicity, and disease activity, and a receiver operating characteristic analysis to calculate a GC threshold dose beyond which toxicity is expected to occur. RESULTS: We included 138 patients with AAV. The median cumulative GC dose was 9014.0 mg. The most frequent adverse events were skin atrophy, osteoporosis and myopathy. GC exposure and toxicity were significantly correlated (p<0.001). GTI-AIS was significantly higher in active disease compared with patients in remission (p<0.001). GTI-CWS scored significantly higher in long-standing diseases (p=0.013) with high cumulative GC doses (p=0.003). Patients with a cumulative GC dose of 935 mg or more showed an 80% likelihood for a clinically meaningful change in GTI scoring. CONCLUSION: The GTI is capable of capturing GC toxicity in AAV and identifies patients at increased risk for GC side effects. Our data support efforts to limit GC exposure in patients with AAV.

A projected cost-utility analysis of avacopan for the treatment of antineutrophil cytoplasmic antibody-associated vasculitis in Spain.

BACKGROUND: Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) are rare autoimmune diseases characterized by inflammation of blood vessels. This study aimed to assess the cost-utility of avacopan in combination with rituximab (RTX) or cyclophosphamide (CYC) compared with glucocorticoids (GC) for the treatment of severe, active AAV in Spain. METHODS: A 9-state Markov model was designed to reflect the induction of remission and sustained remission of AAV over a lifetime horizon. Clinical data and utility values were mainly obtained from the ADVOCATE trial, and costs (€ 2022) were sourced from national databases. Quality-adjusted life years (QALYs), and incremental cost-utility ratio (ICUR) were evaluated. An annual discount rate of 3% was applied. Sensitivity analyses were performed to examine the robustness of the results. RESULTS: Avacopan yielded an increase in effectiveness (6.52 vs. 6.17 QALYs) and costs (€16,009) compared to GC, resulting in an ICUR of €45,638 per additional QALY gained. Avacopan was associated with a lower incidence of end-stage renal disease (ESRD), relapse and hospitalization-related adverse events. Sensitivity analyses suggested that the model outputs were robust and that the progression to ESRD was a driver of ICUR. CONCLUSIONS: Avacopan is a cost-effective option for patients with severe, active AAV compared to GC in Spain.

Characteristics and prognosis of acute renal failure on dialysis in ANCA vasculitis / Caractéristiques et pronostic des insuffisances rénales aiguës dialysées au cours des vascularites à ANCA

Renal involvement in ANCA (Anti Neutrophil Cytoplasmic Antigen) vasculitis is common and is associated with increased mortality with a significant risk of progression to end-stage renal disease. The aim of this study is to investigate the epidemiological, clinicopathological, therapeutic and evolutionary characteristics of patients with ANCA vasculitis with acute renal injury, and to evaluate the impact of haemodialysis in the acute phase on mortality and renal recovery. Secondary objectives are to investigate other risk factors that impact on overall and renal survival. 31 patients were included ; the mean follow-up time was 30 months. The mean age was 68.52 years, and the sex ratio 0.72. All patients had acute renal failure, with histology revealing a mixed form in 45% of cases and a sclerotic form in 12.9% of cases. Pulmonary involvement was found in 58% of cases. 71% of patients had ANCA with anti-myeloperoxydase specificity, and 25.8% anti-proteinase 3 specificity. 32.2% of patients required haemodialysis, of which 60% were weaned. As initial treatment, 58.1% of patients received cyclophosphamide and 35.5% rituximab. The relapse rate was 6.5%. Infectious and cardiovascular complications affected more than half of the patients. The mortality rate was 19.35%. Comparing the two groups of patients dialysed in the acute phase and not dialysed, it appears that the overall and renal mortality was comparable. The progression to end-stage renal failure was higher in the dialysis patients. In a multivariate study, the presence of chronic kidney disease in the history and pulmonary involvement were associated with higher mortality.

L'atteinte rénale au cours des vascularites à ANCA (anticorps anticytoplasmes des polynucléaires neutrophiles) est fréquente ; elle est associée à une surmortalité avec un risque important d'évolution vers l'insuffisance rénale terminale. L'objectif de ce travail est d'étudier les caractéristiques épidémiologiques, clinico-paracliniques, thérapeutiques et évolutives de patients atteints de vascularite à ANCA avec insuffisance rénale aiguë, et d'évaluer l'impact du recours à l'hémodialyse à la phase aiguë sur la mortalité et la récupération rénale. Les objectifs secondaires sont de rechercher d'autres facteurs de risque ayant un impact sur la survie globale et rénale. Trente et un patients ont été inclus, avec un délai moyen de suivi de 30 mois. L'âge moyen était de 68,5 ans, et le sex ratio de 0,72. Tous les patients avaient une insuffisance rénale aiguë, dont l'histologie a révélé une forme mixte dans 45 % des cas et une forme scléreuse dans 12,9 % des cas. Une atteinte pulmonaire était retrouvée dans 58 % des cas. Parmi les patients, 71 % (22) avaient des ANCA de spécificité anti-myélopéroxydase, contre 25,8 % (8) de spécificité anti-protéinase 3. Au total, 32,2 % des patients ont eu recours à l'hémodialyse, dont 60 % ont été sevrés. En traitement d'attaque, 58,1 % des patients ont reçu du cyclophosphamide et 35,5 % du rituximab. Le taux de rechutes était de 6,5 %. Les complications infectieuses et cardiovasculaires concernaient plus de la moitié des patients. Le taux de mortalité était de 19,35 %. En comparant les deux groupes des patients dialysés à la phase aiguë et non dialysés, il apparaît que la mortalité globale et rénale était comparable. L'évolution vers l'insuffisance rénale terminale était plus élevée chez les patients dialysés. En étude multivariée, la présence d'une insuffisance rénale chronique dans les antécédents et l'atteinte pulmonaire étaient associées à une surmortalité.