RESUMEN

Microscopic polyangiitis (MPA) is a rare autoimmune disease characterized by the inflammation and necrosis of small vessels, primarily affecting kidneys and lungs. It is classified as an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) due to the presence of ANCA. MPA can manifest as diffuse alveolar hemorrhage (DAH) and rapidly progressive glomerulonephritis. In contrast, rheumatoid arthritis (RA) is an inflammatory disease that mainly targets the synovial joints. The coexistence of these two conditions presents significant diagnostic challenges, highlighting the need for further research and understanding. We report a case of a 58-year-old male with a past medical history of RA, chronic bronchitis, tobacco use, and recent Legionella pneumonia who presented with acute dyspnea. The patient was intubated for acute hypoxemic respiratory failure. Laboratory workup revealed anemia, hyponatremia, and acute kidney injury. Urinalysis showed hematuria and proteinuria. A CT scan of the chest exhibited bilateral extensive patchy infiltrates. He was transfused with one packed red blood cell (PRBC) unit. Hemoglobin decreased below 6 g/dL after transfusion. A bronchoscopy revealed erythema throughout the tracheobronchial tree, and blood on bronchial alveolar lavage suggested DAH. High-dose steroids were started. Subsequent laboratory results were positive for rheumatoid factor (RF), perinuclear ANCA (p-ANCA), anti-myeloperoxidase (anti-MPO), and antinuclear antibody (ANA). The kidney biopsy demonstrated focal crescentic necrotizing glomerulonephritis pauci-immune type, confirming MPA. RA pathogenesis involves immune dysregulation and activation of various cells, leading to the release of cytokines. Antibodies such as RF and anti-cyclic citrullinated peptide (anti-CCP) can be detected up to 10 years before the clinical manifestation of RA. Recent studies have revealed a predominance of MPA in AAV while coexisting with RA. The underlying mechanism of its occurrence remains unclear. Our patient had recurrent respiratory symptoms and renal dysfunction before hospitalization. MPA-RA overlap syndrome is potentially treatable and clinicians should maintain a high index of suspicion when encountering patients with preexisting RA. Timely initiation of immunosuppressive therapy at early stages is essential to prevent renal and pulmonary complications. ANCA serology should be assessed in these cases.

RESUMEN

The frozen elephant trunk (FET) technique, initially developed as a one-stage procedure to treat extensive thoracic aortic aneurysms, has since been adapted to address acute and chronic aortic dissections by closing entry tears and expanding the true lumen. It has become widely adopted due to its effectiveness in managing aortic diseases. We present the case of a 39-year-old female with microscopic polyangiitis (MPA) who developed recurrent type B aortic dissection accompanied by rapid expansion. The patient, a compromised host with multiple comorbidities such as glomerulonephritis, chronic renal failure, alveolar hemorrhage, and acute pancreatitis, required urgent surgical intervention. Given the complexity of her condition and the high risks associated with direct surgery, a staged approach was selected. The first stage involved using a novel FET prosthesis, the FROZENIX Partial ET (FPET), inserted via median sternotomy, followed by a left thoracotomy for non-deep hypothermic circulatory arrest (non-DHCA) descending aortic replacement. The surgery led to favorable outcomes without any major complications or sequelae. FPET offers distinct advantages in this complex scenario. Its design features a 2 cm stent-free distal section, which reduces the risk of distal stent graft-induced new entries (dSINEs) and simplifies anastomosis during the second stage of surgery. For patients with severe comorbidities and anatomical challenges that make the thoracic endovascular aortic repair (TEVAR) unsuitable, a staged open surgical approach is a viable alternative, mitigating the risks linked to DHCA. This case underscores the utility of a staged surgical approach using FPET in managing complicated chronic type B aortic dissection in patients with significant comorbidities. The FPET prosthesis facilitates effective lesion control while minimizing the risk of dSINEs and streamlining subsequent surgical procedures, presenting a promising strategy for similar complex cases.

RESUMEN

Microscopic polyangiitis (MPA) is predominantly characterized by rapidly progressive glomerulonephritis (RPGN) associated with myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA). Nonetheless, up to 30% of cases of ANCA-associated vasculitis (AAV) may exhibit a more indolent progression toward renal failure, an aspect less frequently discussed and understood in medical literature. This study seeks to clarify the clinical and pathological distinctions between the slowly and rapidly progressive forms of MPA, thereby enhancing understanding of their distinct pathogeneses and treatment responses. We conducted a comparative analysis of two patients diagnosed with MPA under the 2022 American College of Rheumatology/the European Alliance of Associations for Rheumatology (ACR/EULAR) classification. Evaluations included laboratory tests such as serum creatinine levels, serology for MPO-ANCA, and renal biopsies. Patient 1 exhibited a mere 1.07% decrease in estimated glomerular filtration rate (eGFR) over 6 months, significantly below the RPGN threshold, and demonstrated sclerotic glomerular pathology without active inflammation. This patient also showed lower levels of MPO-ANCA, Birmingham Vasculitis Activity Score (BVAS), and C-reactive protein. Conversely, Patient 2 experienced an 89.9% reduction in eGFR over the same timeframe, accompanied by acute systemic inflammation. The comparative clinical analysis of these cases illuminates clear differences in disease activity. Slowly progressive MPA is marked by lesser disease activity that fosters chronic inflammation, leading to a more gradual decline in renal function. Early diagnosis, facilitated by initial measurements of MPO-ANCA, can enhance disease management and improve patient outcomes.

RESUMEN

Avacopan, an orally administered C5a receptor antagonist, is effective in microscopic polyangiitis via the inhibition of neutrophil priming induced by C5a. However, the exact effect of avacopan on the production of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) is yet to be clearly established. This report presents a microscopic polyangiitis patient without major organ damage where high levels of MPO-ANCA persisted with high-dose steroid therapy and azathioprine, but the addition of avacopan led to a reduction in MPO-ANCA titres. The present case implies that avacopan-mediated inhibition of C5a may lead to a reduction in MPO-ANCA levels, thereby potentially ameliorating the pathophysiology of ANCA-associated vasculitis. Nevertheless, the impact of avacopan on MPO-ANCA production cannot be asserted solely based on this report; therefore, further examination is necessary through subgroup analysis using data from larger-scale studies.

Asunto(s)

Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Anticuerpos Anticitoplasma de Neutrófilos , Peroxidasa , Humanos , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Peroxidasa/inmunología , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Resultado del Tratamiento , Masculino , Femenino , Inmunosupresores/uso terapéutico , Anciano , Poliangitis Microscópica/tratamiento farmacológico , Poliangitis Microscópica/inmunología , Poliangitis Microscópica/diagnóstico , Poliangitis Microscópica/complicaciones , Azatioprina/uso terapéutico , Azatioprina/administración & dosificación , Compuestos de Anilina , Ácidos Nipecóticos

RESUMEN

ANCA-associated vasculitis (AAV) can affect multiple organs with severe life-threatening manifestations. Disease monitoring is difficult due to a lack of defined biomarkers. We aimed to assess the diagnostic role of serum interleukin-6 and vascular ultrasonography in AAV and subclinical atherosclerosis. The study included 20 AAV patients and two control groups of 34 patients with rheumatoid arthritis (RA) and 35 healthy controls. The levels of Il-6, carotid intima-media thickness test (CIMT), atherosclerotic plaque, and degree of stenosis were investigated. A GRACE-risk score was calculated for AAV and RA patients. The AAV patients had elevated levels of IL-6 (115 ± 23.96) compared to the RA patients (91.25 ± 42.63) and the healthy controls (15.65 ± 3.30), p < 0.001. IL-6 showed a diagnostic accuracy of 73% in distinguishing AAV from RA patients (AUC = 0.730; 95% CI 0.591 to 0834). In the AAV group, CIMT was 1.09, above the upper reference value of 0.90, p < 0.001. The AAV patients had a higher median GRACE risk score, and 60% of them had a high risk of cardiovascular events as compared to 35% of the RA patients. Sonography of extracranial vessels and serum levels of IL-6 can be used in daily clinical practice to diagnose and monitor patients with AAV.

Asunto(s)

Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Artritis Reumatoide , Aterosclerosis , Biomarcadores , Grosor Intima-Media Carotídeo , Interleucina-6 , Humanos , Interleucina-6/sangre , Femenino , Masculino , Persona de Mediana Edad , Artritis Reumatoide/sangre , Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/complicaciones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/sangre , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico por imagen , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Biomarcadores/sangre , Pronóstico , Adulto , Aterosclerosis/sangre , Aterosclerosis/diagnóstico por imagen , Aterosclerosis/etiología , Aterosclerosis/diagnóstico , Anciano , Estudios de Casos y Controles , Arterias Carótidas/diagnóstico por imagen , Valor Predictivo de las Pruebas , Ultrasonografía de las Arterias Carótidas

RESUMEN

There have been reports of COVID-19 vaccination triggering anti-nuclear cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but no robust studies have examined the link. This retrospective cohort study assessed the impact of COVID vaccination on the rate of denovo and relapsed AAV in a Sydney Local Health District from 2018 to 2022. Despite more than 95% of the population receiving vaccination, the case rate of AAV was stable. These findings do not support a relationship between COVID vaccination and AAV.

Asunto(s)

Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Coronavirus , Granulomatosis con Poliangitis , Poliangitis Microscópica , Humanos , Estudios Retrospectivos , Vacunas contra la COVID-19 , Anticuerpos Anticitoplasma de Neutrófilos

RESUMEN

Based on the efficacy of intravenous immunoglobulin (IVIg) for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), we developed a recombinant single-chain-fragment variable clone, VasSF, therapeutic against AAV in a mouse model (SCG/Kj mice). VasSF is thought to bind to vasculitis-associated apolipoprotein A-II (APOA2) as a target molecule. VasSF is a promising new drug against AAV, but difficulties in the yield and purification of VasSF remain unresolved. We produced monomers of new VasSF molecules by modifying the plasmid structure for VasSF expression and simplifying the purification method using high-performance liquid chromatography. We compared the therapeutic effects between 5-day continuous administration of the monomers, as in IVIg treatment, and single shots of 5-day-equivalent doses. We also evaluated the life-prolonging effect of the single-shot treatment. Two-dimensional western blots were used to examine the binding of VasSF to APOA2. Our improved manufacturing method resulted in a 100-fold higher yield of VasSF than in our previous study. Monomerization of VasSF stabilized its efficacy. Single shots of a small amount (1/80 000 of IVIg) produced sufficient therapeutic effects, including decreased glomerular crescent formation, a decreasing trend of serum ANCA against myeloperoxidase (MPO-ANCA), decreases in multiple proinflammatory cytokines, and a trend toward prolonged survival. Two-dimensional western blots confirmed the binding of VasSF to APOA2. The newly produced pure VasSF monomers are stable and therapeutic for AAV with a single low-dose injection, possibly by removing vasculitis-associated APOA2. Thus, the new VasSF described herein is a promising drug against AAV.

Asunto(s)

Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Anticuerpos Anticitoplasma de Neutrófilos , Animales , Ratones , Inmunoglobulinas Intravenosas/uso terapéutico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/genética , Peroxidasa

RESUMEN

INTRODUCTION: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are rare autoimmune diseases triggering inflammation of small vessels. This real-world analysis was focused on the most common AAV forms, granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), to describe patients' demographic and clinical characteristics, therapeutic management, disease progression, and the related economic burden. METHODS: A retrospective analysis was conducted on administrative databases of a representative sample of Italian healthcare entities, covering approximately 12 million residents. Between January 2010 and December 2020, adult GPA patients were identified by payment waiver code or hospitalization discharge diagnosis, and MPA patients by payment waiver code with or without hospitalization discharge diagnosis. Clinical outcomes were evaluated through AAV-related hospitalizations, renal failure onset, and mortality. Economic analysis included healthcare resource utilization deriving from drugs, hospitalizations, and outpatient specialist services. The related mean direct costs year/patient were also calculated in patients stratified by presence/absence of glucocorticoid therapy and type of inclusion criterion (hospitalization/payment waiver code). RESULTS: Overall, 859 AAV patients were divided into GPA (n = 713; 83%) and MPA (n = 146; 17%) cohorts. Outcome indicators highlighted a clinically worse phenotype associated with GPA compared to MPA. Cost analysis during follow-up showed tendentially increased expenditures in glucocorticoid-treated patients versus untreated (overall AAV: €8728 vs. €7911; GPA: €9292 vs. €9143; MPA: €5967 vs. €2390), mainly driven by drugs (AAV: €2404 vs. €874; GPA: €2510 vs. €878; MPA: €1881 vs. €854) and hospitalizations. CONCLUSION: Among AAV forms, GPA resulted in a worse clinical picture, higher mortality, and increased costs. This is the first real-world pharmaco-economic analysis on AAV patients stratified by glucocorticoid use on disease management expenditures. In both GPA and MPA patients, glucocorticoid treatment resulted in higher healthcare costs, mostly attributable to medications, and then hospitalizations, confirming the clinical complexity and economic burden for management of patients with autoimmune diseases under chronic immunosuppression.

Asunto(s)

Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Poliangitis Microscópica , Adulto , Humanos , Estudios Retrospectivos , Glucocorticoides , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Poliangitis Microscópica/terapia , Costos de la Atención en Salud

RESUMEN

We describe a rare case of concurrent eosinophilic granulomatosis with polyangiitis and mixed connective tissue disease in a 27-year-old man who presented with pulmonary, renal, cardiac, and skin manifestations. We confirmed the diagnosis based on clinical, histopathological, and serological criteria. We treated the patient with corticosteroids, methotrexate, cyclophosphamide, and hydroxychloroquine, achieving early remission. The coexistence of both conditions in the same patient is extremely rare and has only been reported in a few cases worldwide. We also review the literature on these two rare autoimmune diseases' coexistence, pathogenesis, diagnosis, and management. Our case emphasizes recognizing overlapping autoimmune conditions in patients with complex clinical features and employing a comprehensive diagnostic approach and tailored treatment strategies. Further research is needed to understand these patients' epidemiology, prognosis, and optimal therapy. Early diagnosis and aggressive immunosuppression are crucial for achieving remission and preventing organ damage. We also identified the knowledge gaps and research needs in this field.

RESUMEN

Microscopic polyangiitis (MPA) is an autoimmune disease, characterized by ANCA in blood and necrotizing inflammation of small and medium-sized vessels, one of the three clinical phenotypes of ANCA-associated vasculitis (AAV). Autophagy has been confirmed to be involved in the pathogenesis of AAV. AKT1 is one of the autophagy-regulated proteins. Its single nucleotide polymorphisms (SNPs) are associated with multiple immune-related diseases, but there are rarely studies in AAV. The incidence rate of AAV has a notable geographic difference, and MPA is predominant in China. The aim of this study was to investigate the association between AKT1 SNP and MPA risk. Genotypes of 8 loci in AKT1 were evaluated by multiplex polymerase chain reaction (PCR) and high-throughput sequencing in 416 people, including 208 MPA patients and 208 healthy volunteers from Guangxi in China. Additionally, data of 387 healthy volunteers from China were obtained from the 1000Genomes Project on public database. Differences were observed between the loci (rs2498786, rs2494752, and rs5811155) genotypes in AKT1 and MPA risk (P = 7.0 × 10-4, P = 3.0 × 10-4, and P = 5.9 × 10-5, respectively). A negative association was detected in the Dominant model (P = 1.2 × 10-3, P = 2.0 × 10-4 and P = 3.6 × 10-5, respectively). A haplotype (G-G-T) was associated with MPA risk negatively (P = 7.0 × 10-4). This study suggests that alleles (rs2498786 G, rs2494752 G and rs5811155 insT) are protective factors for MPA and alleles (rs2494752 G and rs5811155 insT) for MPO-ANCA in patients with MPA. There is a haplotype (G-G-T), which is a protective factor for MPA. It suggests that the role of AKT1 in MPA/AAV needs further study to provide more intervention targets for MPA/AAV.

Asunto(s)

Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Poliangitis Microscópica , Humanos , Poliangitis Microscópica/genética , Polimorfismo de Nucleótido Simple/genética , Anticuerpos Anticitoplasma de Neutrófilos/genética , Pueblos del Este de Asia , China/epidemiología , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/genética , Proteínas Proto-Oncogénicas c-akt/genética

RESUMEN

Cyclophosphamide (CYC) is an immunosuppressive medication used to treat life-threatening complications of various rheumatic diseases like vasculitis and systemic lupus erythematosus. A rare side effect of this medication is pneumonitis, which occurs in less than 1% of patients. We describe a case of an 83-year-old woman with a past medical history of microscopic polyangiitis, who presented with progressive dyspnea at rest, exacerbated on exertion, and associated with orthopnea that was attributed to CYC-induced pneumonitis. Three months before this presentation, the patient was diagnosed with antineutrophil cytoplasmic antibodies (ANCA)-positive pauci-immune crescentic and necrotizing glomerulonephritis and started on CYC. On admission, a computed tomography (CT) chest showed worsening bilateral ground-glass opacities in a mosaic distribution and inter and intralobular septal thickening, not present on the CT performed three months prior. The patient underwent an extensive workup, which included an echocardiogram, bronchoscopy with bronchoalveolar lavage, and viral respiratory panel to rule out infectious and cardiac pathologies. She was started on empiric treatment with antibiotics and diuretics, however, despite these interventions, she continued with respiratory distress. A multidisciplinary team convened, and the diagnosis of CYC-induced lung injury was entertained. The CYC was discontinued, and the patient was started on prednisone with significant improvement in symptoms. This case highlights the importance of recognizing CYC as a rare cause of interstitial pneumonitis. When considering CYC-induced lung toxicity, other etiologies, such as opportunistic infections, cardiac etiologies, and diffuse alveolar hemorrhage, should be ruled out.

RESUMEN

Background: Disease relapse remains a major problem in the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In European populations, HLA-DPB1*04:01 is associated with both susceptibility and relapse risk in proteinase 3-ANCA positive AAV. In a Japanese population, we previously reported an association between HLA-DRB1*09:01 and DQB1*03:03 with susceptibility to, and DRB1*13:02 with protection from, myeloperoxidase-ANCA positive AAV (MPO-AAV). Subsequently, the association of DQA1*03:02, which is in strong linkage disequilibrium with DRB1*09:01 and DQB1*03:03, with MPO-AAV susceptibility was reported in a Chinese population. However, an association between these alleles and risk of relapse has not yet been reported. Here, we examined whether HLA-class II is associated with the risk of relapse in MPO-AAV. Methods: First, the association of HLA-DQA1*03:02 with susceptibility to MPO-AAV and microscopic polyangiitis (MPA) and its relationship with previously reported DRB1*09:01 and DQB1*03:03 were examined in 440 Japanese patients and 779 healthy controls. Next, the association with risk of relapse was analyzed in 199 MPO-ANCA positive, PR3-ANCA negative patients enrolled in previously reported cohort studies on remission induction therapy. Uncorrected P values (Puncorr) were corrected for multiple comparisons in each analysis using the false discovery rate method. Results: The association of DQA1*03:02 with susceptibility to MPO-AAV and MPA was confirmed in a Japanese population (MPO-AAV: Puncorr=5.8x10-7, odds ratio [OR] 1.74, 95% confidence interval [CI] 1.40-2.16, MPA: Puncorr=1.1x10-5, OR 1.71, 95%CI 1.34-2.17). DQA1*03:02 was in strong linkage disequilibrium with DRB1*09:01 and DQB1*03:03, and the causal allele could not be determined using conditional logistic regression analysis. Relapse-free survival was shorter with nominal significance in carriers of DRB1*09:01 (Puncorr=0.049, Q=0.42, hazard ratio [HR]:1.87), DQA1*03:02 (Puncorr=0.020, Q=0.22, HR:2.11) and DQB1*03:03 (Puncorr=0.043, Q=0.48, HR:1.91) than in non-carriers in the log-rank test. Conversely, serine carriers at position 13 of HLA-DRß1 (HLA-DRß1_13S), including DRB1*13:02 carriers, showed longer relapse-free survival with nominal significance (Puncorr=0.010, Q=0.42, HR:0.31). By combining DQA1*03:02 and HLA-DRß1_13S, a significant difference was detected between groups with the highest and lowest risk for relapse (Puncorr=0.0055, Q=0.033, HR:4.02). Conclusion: HLA-class II is associated not only with susceptibility to MPO-AAV but also with risk of relapse in the Japanese population.

Asunto(s)

Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Poliangitis Microscópica , Humanos , Anticuerpos Anticitoplasma de Neutrófilos , Peroxidasa/genética , Pueblos del Este de Asia , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/genética , Mieloblastina

RESUMEN

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) compromise a rare group of necrotizing small to medium vessel vasculitides that constitute three distinct disorders: granulomatosis with polyangiitis (GPA) (formerly known as Wegener's granulomatosis), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA) (formerly known as Churg-Strauss syndrome). AAV is characterized by the usual presence of circulating autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). These antibodies can activate neutrophils and the complement system resulting in vessel wall inflammation and damage. The clinical presentation of AAV varies from non-severe (non-life threatening) to severe often with potentially life-threatening multi-organ involvement. Early recognition and diagnosis are crucial. In the past two decades, advances in understanding the pathophysiology of AAV have led to development of new treatments and resulted in significant improvement in general outcomes and survival rates. This narrative review will focus on GPA and MPA. We will highlight clinical manifestations, diagnosis, disease monitoring, and treatment strategies in patients with AAV.

Asunto(s)

Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Síndrome de Churg-Strauss , Granulomatosis con Poliangitis , Poliangitis Microscópica , Humanos , Granulomatosis con Poliangitis/diagnóstico , Granulomatosis con Poliangitis/terapia , Síndrome de Churg-Strauss/diagnóstico , Síndrome de Churg-Strauss/terapia , Anticuerpos Anticitoplasma de Neutrófilos , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/terapia , Mieloblastina , Peroxidasa

RESUMEN

Microscopic polyangiitis (MPA) is a type of antineutrophil cytoplasmic antibody (ANCA)-related vasculitis. Autophagy-related gene 7 (ATG7) protects against complicated disorder states in model organisms, but the way ATG7 dysfunction contributes to MPA remains elusive. This investigation assessed the impacts of ATG7 single-nucleotide polymorphisms (SNPs) on microscopic polyangiitis (MPA) in China. A total of 211 controls and 214 MPA patients were recruited and analyzed. Polymerase chain reaction (PCR) and high-throughput sequencing were adopted to detect the ATG7 SNPs (rs75492008, rs2594966, rs6442260 and rs8154), and stratification analysis, different genetic models and differences in allele and genotype frequencies were evaluated. Haplotype evaluation was performed after linkage disequilibrium (LD) analyses, and interactions between alleles were assessed. Generalized multifactor dimensionality reduction (GMDR) was adopted to analyze SNP-SNP interactions among the four ATG7 SNPs and phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and unc-nc-like autophagy activating kinase 1 (ULK1) SNPs previously studied by our team. Relationships between ATG7 polymorphisms, disease activity biomarkers and therapeutic effects in MPA were analyzed. Sex stratification analysis of the rs2594966 GG genotype with codominant and recessive models showed OR=3.42, 95% CI [1.19-9.80], P=0.041 and OR=3.31, 95% CI [1.23-8.90], P=0.012, respectively. Haplotype G-G-C-T was related to an increased MPA risk (OR=1.5, 95% CI [0.999-2.266], P=0.029). Permutation testing of GMDR suggested that ATG7 rs6442260 and rs8154, PIK3CA rs1607237, and ULK1 rs4964879 might interact with each other in MPA development (P<0.05). Among 214 MPA patients, 79 available complete follow-up clinical datasets were gathered from September 2009 to October 2020, showing that rs75492008 and rs4964879 affect the correlation between C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) in MPA activity. Patients with rs8154 TT and rs1607237 CC genotypes had better clinical treatment effects (P<0.05). Gene polymorphisms may be related to MPA in China, exhibiting correlation with MPA activity indicators, treatment and prognosis.

RESUMEN

Microbiota has been associated with autoimmune diseases, with nasal Staphylococcus aureus being implicated in the pathogenesis of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). Little is known about the role of oral microbiota in AAV. In this study, levels of IgG antibodies to 53 oral bacterial species/subspecies were screened using immunoblotting in plasma/serum in pre-symptomatic AAV-individuals (n = 85), matched controls, and established AAV-patients (n = 78). Saliva microbiota from acute-AAV and controls was sequenced from 16s rDNA amplicons. Information on dental status was extracted from a national register. IgG levels against oral bacteria were lower in established AAV versus pre-AAV and controls. Specifically, pre-AAV samples had, compared to controls, a higher abundance of periodontitis-associated species paralleling more signs of periodontitis in established AAV-patients than controls. Saliva microbiota in acute-AAV showed higher within-sample diversity but fewer detectable amplicon-sequence variants and taxa in their core microbiota than controls. Acute-AAV was not associated with increased abundance of periodontal bacteria but species in, e.g., Arthrospira, Staphylococcus, Lactobacillus, and Scardovia. In conclusion, the IgG profiles against oral bacteria differed between pre-AAV, established AAV, and controls, and microbiota profiles between acute AAV and controls. The IgG shift from a pre-symptomatic stage to established disease cooccurred with treatment of immunosuppression and/or antibiotics.

RESUMEN

OBJECTIVE: The breakdown of immune tolerance mediated by the reduced regulatory T (Treg) cell contributes to autoimmune diseases, which can be recovered by the short-term and low-dose interleukin 2 (IL-2). However, the role of Treg cells in microscopic polyangiitis (MPA) and the efficacy of short-term and low-dose IL-2 for MPA remain unclear. Therefore, we performed a retrospective study to explore the role of Treg cells and evaluate the efficacy of short-term and low-dose IL-2 therapy in MPA. METHODS: 52 MPA were collected as research objects, and 15 of them voluntarily received short-term and low-dose IL-2 subcutaneous injection combined with conventional therapy. 60 volunteers were recruited as health controls (HC) according to the inclusion and exclusion criteria. The number of circulating CD4 + T cell subsets was detected by flow cytometry. RESULTS: Patients with MPA had reduced circulating Treg cells than HCs (P < 0.001), and the level of Treg cells were reduced in MPA-activity and ANCA-positive group (P = 0.018 and P = 0.008 respectively). The patients with lower Treg cells had the higher incidence of the organ involvement (P = 0.006). The level of Treg cells in MPA was doubled after the short-term and low-dose IL-2 combined with conventional therapy (P = 0.001), and the disease activity indicators such as ESR and CRP were improved (P < 0.05) with no apparent side effects. CONCLUSION: Patients with MPA had reduced circulating Treg cells, especially the MPA-activity and ANCA-positive patients. And the patients with lower Treg cells were more likely to exhibit the organ involvement. Short-term and low-dose IL-2 therapy increased the reduced Treg cells and promoted the remission of the disease at a certain extent with well tolerance.

Asunto(s)

Poliangitis Microscópica , Linfocitos T Reguladores , Anticuerpos Anticitoplasma de Neutrófilos , Humanos , Interleucina-2/uso terapéutico , Poliangitis Microscópica/tratamiento farmacológico , Estudios Retrospectivos

RESUMEN

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is a destructive small vessel vasculitis affecting multiple organs. Renal involvement often leads to end-stage renal disease and increases mortality. Prompt diagnosis and initiation of adequate immunosuppressive therapy are critical for the best patient and kidney outcomes. However, considerable heterogeneity in symptoms and severity across the patients frequently hinder the diagnosis and management. The objective of this review is to emphasize the heterogeneity of the ANCA-associated vasculitis, facilitate the recognition and give guidance to the therapeutical possibilities. We present epidemiologic and risk factors, pathogenesis, and provide comprehensive clinical features of the disease. This article also focuses on the currently available therapeutic options and emerging cellular and molecular targets for the management of systemic and especially renal disease. We conducted extensive literature research published on PubMed and Google Scholar. We systematically reviewed, analyzed, and assembled databases, covering a broad spectrum of aspects of the disease. We compared and summarized the recommendations of two recent guidelines on ANCA-associated vasculitis. The incidence of ANCA-associated vasculitis, hence glomerulonephritis shows a steady increase. Familiarity with the presenting symptoms and laboratory abnormalities are necessary for rapid diagnosis. Early initiation of treatment is the key aspect for favorable patient and renal outcomes. A better understanding of the pathogenesis constantly leads to more targeted and therefore more efficient and less toxic treatment.

RESUMEN

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises a group of small vessel vasculitides grouped by commonalities of clinical manifestations and ANCA testing. Skin findings are not uncommon, although there is considerable overlap and many times nonspecificity. In general, patients with skin findings tend to have more significant systemic illness, and skin lesions most often develop simultaneously or following onset of systemic symptoms. There are clinical and pathological clues of help in the differentiation of skin findings in these disorders. Purpura of various forms with leukocytoclastic vasculitis is common to all AAV. Granulomatosis with polyangiitis (GPA) comprises the largest number of patients with an AAV. Upper airway, oral, ear, and facial lesions, with or without granuloma, are more commonly seen in this AAV. Pyoderma gangrenosum-like lesions, including facial location, while not common are most closely associated with GPA. Eosinophilic granulomatosis with polyangiitis (EGPA) as its name implies is more closely associated with eosinophilic, allergic, or asthmatic conditions. Papular lesions of the extensor extremities showing extravascular granulomatous changes are characteristic but not specific for EGPA. Microscopic polyangiitis (MPA) is more closely associated with livedoid skin changes, and vascular inflammation tends to be deeper in the skin than with the other AAV. Extravascular granulomas are not expected. While the skin findings in AAV can be nonspecific and overlapping, combining careful full skin examination with histopathologic study of selected lesions is critical to making the correct diagnosis and in ruling out other similar diseases not ANCA related. The aim of this article is to encourage increased participation by dermatologists and dermatopathologists in the care of these patients.

Asunto(s)

Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Síndrome de Churg-Strauss , Granulomatosis con Poliangitis , Enfermedades de la Piel , Humanos , Anticuerpos Anticitoplasma de Neutrófilos , Granulomatosis con Poliangitis/complicaciones , Granulomatosis con Poliangitis/diagnóstico , Síndrome de Churg-Strauss/complicaciones , Síndrome de Churg-Strauss/diagnóstico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Granuloma , Enfermedades de la Piel/etiología , Enfermedades de la Piel/complicaciones

RESUMEN

Microscopic polyangiitis (MPA), a systemic necrotizing vasculitis of small vessels, is primarily associated with necrotizing and crescentic glomerulonephritis and pulmonary capillaritis. Neurological involvement, particularly of the central nervous system (CNS) is scarcely observed. The diversity of CNS symptoms could puzzle the diagnosis causing delays in treatment and potentially having a considerable effect on patient's quality of life or even death. The aim of this case report is to highlight the unusual manifestation of MPA in order to raise awareness of this orphaned disease among pediatricians or even pediatric rheumatologists and neurologists. Case Report: Herein we report the case of a 13-year-old Thai girl diagnosed with MPA presented with rapidly progressive glomerulonephritis (RPGN). Renal biopsy was performed demonstrated crescentic glomerulonephritis with negative immunofluorescence and positive titer of myeloperoxidase (MPO) antibody. Pulse methylprednisolone (MP) and cyclophosphamide (CYC) as well as plasmapheresis were initiated. Despite treatment with prednisolone (45 mg/day) and monthly CYC for two doses, she experienced a brief generalized tonic-clonic seizure during the follow-up period. The potential differential diagnosis of new-onset neurological manifestation contains infection owing to the immunocompromised status of the patient and CNS vasculitis as a result of the disease itself. Lumbar puncture was performed, and cerebrospinal fluid analysis demonstrated pleocytosis with negative infectious panel. Contrast magnetic resonance imaging studies of the brain showed multifocal patchy T2/FLAIR-hyperintense lesions in the cerebral as well as cerebellum regions, and irregular narrowing along the V4 segment of the right vertebral artery was demonstrated in magnetic resonance angiography. In the presence of CNS vasculitis, pulse MP and CYC were provided. The symptom of nervous system has progressively improved. Conclusion: In our case, MPA revealed RPGN with neurological manifestation. Despite the fact that it is scarcely reported, CNS vasculitis is one of the organ-threatening symptoms. To improve patient morbidity and mortality, multidisciplinary care teams with prompt diagnosis and treatment are highly recommended.

RESUMEN

BACKGROUND: Microscopic polyangiitis (MPA) is an autoimmune disease characterized by frequent kidney involvement. Imbalance of intestinal flora has been found implicated in multiple immune-mediated disorders. However, the profiling and the role of the gut microbiome in MPA remains unclear. METHODS: We performed 16S rRNA amplicon sequencing on fecal samples from 71 MPA patients with kidney involvement (35 at incipient active stage, 36 at remissive stage) and 34 healthy controls (HCs). Microbial diversity and abundance were compared among the three cohorts. The correlation between altered microbes and clinical indices were investigated. Two random forest models based on the profiling of the gut microbiome were constructed for the diagnosis of MPA. RESULTS: Two α-diversity indices, including Simpson and Shannon index, were decreased in MPA patients (P<0.001), especially in those with active disease (P=0.001). ß-diversity analysis showed biased microbial composition among the three groups. Genus Actinomyces and Streptococcus were more abundant in both MPA cohorts than those in HCs, while genus Subdoligranulum, Eubacterium hallii, Ruminococcaceae UCG013, Eubacterium ventriosum, Dorea and Butyricicoccus were more abundant in HCs than those in both MPA cohorts. All the 6 genera with decreased abundance belong to short-chain fatty acids (SCFA)-producing taxons. Besides, 1 and 2 operational taxonomic units (OTUs) were enriched in patients with active MPA who needed dialysis at sampling and in patients who progressed to end-stage renal disease during follow up, respectively. Furthermore, the model for diagnosis of MPA incorporated 6 OTU markers and achieved an AUC of 93.45% (95% CI, 88.15-98.74%). Similarly, the model for predicting disease activity incorporated 11 OTU markers and achieved an AUC of 90.71% (95% CI, 82.49-98.94%). CONCLUSIONS: Alteration of intestinal flora existed in MPA patients with kidney involvement and was characterized by increased abundance of genus Actinomyces and Streptococcus and decreased abundance of 6 SCFA-producing genera. Gut microbial profiling combined with machining-learning methods showed potentials for diagnosing MPA and predicting disease activity.