Increased gene expression of B cell-activating factor of tumor necrosis factor family, in remitting antineutrophil cytoplasmic antibody-associated vasculitis patients.

AIM: To study the expression of B cell-activating factor of tumor necrosis factor family (BAFF) and A proliferation-inducing ligand (APRIL) genes in active and remitting patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and healthy controls and their correlation with disease activity. METHODS: This was a prospective case-control study. Gene expressions of BAFF and APRIL were studied in 32 patients with AAV (16 each with active disease and in remission) and 30 healthy age and sex matched controls by real-time polymerase chain reaction. RESULTS: Out of 32 AAV patients, 26 had granulomatosis with polyangiitis (GPA) and 6 had microscopic polyangiitis (MPA). Mean ages of patients in active (12 GPA and 4 MPA) and remission (14 GPA and 2 MPA) groups were 39.4 ± 17.2 and 44.6 ± 16.1 years, respectively. BAFF gene expression was significantly higher in both the active AAV group and remission AAV group compared to controls (P < .01). The BAFF expression was significantly higher in AAV patients in remission compared to active AAV patients (P = .003). In contrast, APRIL expression did not differ between AAV patients and controls (P = .829). However, APRIL had significantly higher expression in remission as compared to active patients (P = .048). There was no significant correlation of both BAFF and APRIL expression with disease activity markers (erythrocyte sedimentation rate, C-reactive protein, platelets and Birmingham Vasculitis Activity Score version 3). CONCLUSION: BAFF gene is significantly expressed in patients with AAV. Among AAV patients, there is a significantly higher expression of BAFF and APRIL in remitting state of the disease as compared to active state. There is no significant change in APRIL gene expression in patients with AAV as compared to controls. This makes a case for anti-BAFF therapy in future for AAV patients in northern India.

Serum progranulin as a predictive marker for high activity of antineutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: This study investigated whether serum progranulin could act as a predictive marker for high disease activity of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Fifty-eight AAV patients were included in this study. Clinical and laboratory data were obtained at blood collection. The Short-Form 36-Item Health Survey Physical and Mental Component Summaries (SF-36 PCS and SF-36 MCS), Birmingham Vasculitis activity score (BVAS), Five-Factor Score (FFS), and Vasculitis Damage Index (VDI) were assessed as AAV-specific indices. Whole blood was collected and serum samples were isolated and stored at -80°C. Serum progranulin concentration was quantified by ELISA kits. RESULTS: The median age of patients was 63.0 years (19 men). The median BVAS was 11.0, and the median serum progranulin level was 49.0 ng/ml. Serum progranulin was significantly correlated with BVAS, FFS, erythrocyte sedimentation rate, C-reactive protein level, SF-36 PCS, haemoglobin, and serum albumin. Severe AAV was arbitrarily defined as the highest tertile of BVAS (BVAS ≥16). When the cut-offs of serum progranulin were set as 55.16 ng/ml and 43.01 ng/ml for severe AAV, AAV patients with serum progranulin ≥55.16 and 43.01 ng/ml had significantly higher risks of severe AAV than those without (relative risk (RR) 4.167 and 4.524, respectively). CONCLUSIONS: Progranulin might play an anti-inflammatory role in AAV pathogenesis and serum progranulin could be used as a predictive marker for high activity of AAV.

Interstitial lung disease with myeloperoxidase-antineutrophil cytoplasmic antibody-associated vasculitis in elderly patients.

Anti-neutrophil cytoplasmic antibodies-associated vasculitis (AAV) occurs in elderly people, and patients with anti-myeloperoxidase autoantibodies (MPO-ANCA)-positive AAV are often complicated with interstitial lung disease (ILD). This study aimed to evaluate the age-related clinical features of elderly patients with MPO-ANCA-positive AAV-ILD. This study retrospectively investigated 63 patients with MPO-ANCA-positive AAV-ILD, all of whom were 65 years or older at diagnosis. Clinical characteristics, causes of death and survival rates among three groups stratified by age (65-74 years, n = 29; 75-79 years, n = 18; over 80 years, n = 16) were compared. This study also examined the association with severe infections in these patients. Among the three age groups, there were significant differences in sex (P = 0.032), serum Krebs von den Lungen-6 (P < 0.01), and total ground-glass opacity score (P = 0.011). The causes of death were mainly severe infections and complications of ILD. Kaplan-Meier curve analysis showed a significantly lower 5-year survival rate in the oldest group (P < 0.01). Regarding severe infections in these patients, the 5-year cumulative incidence of severe infections was higher in the patients receiving steroid pulse therapy (P = 0.034). The clinical characteristics of MPO-ANCA-positive AAV-ILD differ with age in elderly patients, with age being an important poor prognostic factor in these patients. The administration of steroid pulse therapy is a significant risk factor of severe infection in MPO-ANCA-positive elderly patients with AAV-ILD.

The association between ear involvement and clinical features and prognosis in ANCA-associated vasculitis.

OBJECTIVE: The concept of otitis media with ANCA-associated vasculitis (OMAAV) was recently proposed by the study group of the Japan Otological Society. However, little is known about the effect of ear involvement on the clinical features and prognosis of AAV. We investigate this issue in this study. METHODS: We retrospectively examined 36 patients diagnosed with OMAAV and 44 patients diagnosed with AAV without ear involvement (non-OMAAV) at Ehime University Hospital from 2013 to 2018. We collected serological findings including ANCA type and titer, C-reactive protein (CRP), serum creatinine level, organ involved at initial diagnosis, treatment, remission, disease relapse, and mortality from medical records. We investigated whether clinical features and outcomes differed between the OMAAV and non-OMAAV groups. RESULTS: Age, ANCA titer, and CRP at initial diagnosis were not significantly different between the two groups, and the rate of intravenous cyclophosphamide (IVCY) use also did not differ. The proportions of patients with concurrent eye involvement, facial palsy (FP), and hypertrophic pachymeningitis (HCP) were significantly higher in the OMAAV than in the non-OMAAV group (p = 0.005, 0.005 and 0.049, respectively), while both renal and peripheral nerve involvement were significantly less common in OMAAV patients (p = 0.04). Among the 30 patients with renal involvement, serum creatinine level at diagnosis was significantly lower in the OMAAV group (p = 0.04). The mortality rate was 8.3% in OMAAV and 6.8% in non-OMAAV cases, but this difference was not significant. The rate of relapse was 33.3% in OMAAV and 13.6% in non-OMAAV cases; this difference was significant (p = 0.04). CONCLUSIONS: Serological measurements of disease activity did not differ between the groups. Eye involvement, FP, and HCP, however, were significantly more common in AAV with ear involvement. In addition, renal involvement was less common and renal impairment was milder in AAV with ear involvement. These findings can be considered clinical features. The relapse rate was significantly higher in AAV with ear involvement.

Temporal Arteritis Revealing Antineutrophil Cytoplasmic Antibody-Associated Vasculitides: A Case-Control Study.

OBJECTIVE: Temporal arteritis (TA) is a typical manifestation of giant cell arteritis (GCA). Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are rarely revealed by TA manifestations, leading to a risk of misdiagnosis of GCA and inappropriate treatments. This study was undertaken to describe the clinical, biologic, and histologic presentations and outcomes in cases of TA revealing AAV (TA-AAV) compared to controls with classic GCA. METHODS: In this retrospective case-control study, the characteristics of patients with TA-AAV were compared to those of control subjects with classic GCA. Log-rank test, with hazard ratios (HRs) and 95% confidence intervals (95% CIs), was used to assess the risk of treatment failure. RESULTS: Fifty patients with TA-AAV (median age 70 years) were included. Thirty-three patients (66%) presented with atypical symptoms of GCA (ear, nose, and throat involvement in 32% of patients, and renal, pulmonary, and neurologic involvement in 26%, 20%, and 16% of patients, respectively). Blood samples were screened for ANCAs at the time of disease onset in 33 patients, and results were positive in 88%, leading to a diagnosis of early TA-AAV in 20 patients. The diagnosis of AAV was delayed a median interval of 15 months in 30 patients. Compared to controls with GCA, patients with TA-AAV were younger (median age 70 years versus 74 years), were more frequently men (48% versus 30%), and had high frequencies of atypical manifestations and higher C-reactive protein levels (median 10.8 mg/dl versus 7.0 mg/dl). In patients with TA-AAV, temporal artery biopsy (TAB) showed fibrinoid necrosis and small branch vasculitis in 23% of patients each, whereas neither of these characteristics was evident in controls with GCA. Treatment failure-free survival was comparable between early TA-AAV cases and GCA controls, whereas those with delayed TA-AAV had a significantly higher risk of treatment failure compared to controls (HR 3.85, 95% CI 1.97-7.51; P < 0.0001). CONCLUSION: TA-AAV should be considered diagnostically in cases of atypical manifestations of GCA, refractoriness to glucocorticoid treatment, or early relapse. Analysis of TAB specimens for the detection of small branch vasculitis and/or fibrinoid necrosis could be useful. Detection of ANCAs should be performed in cases of suspected GCA with atypical clinical features and/or evidence of temporal artery abnormalities on TAB.

Clinical and pathological characteristics of ANA/anti-dsDNA positive patients with antineutrophil cytoplasmic autoantibody-associated vasculitis.

Antineutrophil cytoplasmic autoantibodies (ANCA) associated vasculitis (AAV) consists of a group of systemic autoimmune diseases. The roles of serum anti-nuclear antibodies (ANA) and anti-double-stranded DNA (anti-dsDNA) antibodies in AAV patients remain unknown. This study investigated the prevalence of serum ANAs and anti-dsDNA antibodies in AAV patients and characterized the clinical and pathological features of these patients. A total of 218 AAV patients were enrolled. Clinical and pathological data of patients were analyzed retrospectively. Of the 218 AAV patients, 109 (50.0%) were positive for ANA, 45 (20.6%) were positive for anti-dsDNA, and 43 (19.7%) were positive for both. The AAV patients with ANA had severer kidney damage and more chronic renal histopathological changes compared to those who were negative for ANA. Specifically, patients positive for ANA had more hypertension, higher levels of urea nitrogen and serum creatinine, lower estimated glomerular filtration rate (eGFR), more end-stage renal disease (ESRD), severer proteinuria, glomerular sclerosis, tubular interstitial fibrosis and tubular atrophy, and were more likely to receive renal biopsies compared to ANA negative patients. The study found ANA and anti-dsDNA in AVV patients were not rare, ANA-positive AAV patients had severer kidney damage and more chronic renal histopathological changes compared to ANA-negative AAV patients. Renal biopsy is strongly recommended for differential diagnosis in such cases.

Pulmonary manifestations and outcomes in paediatric ANCA-associated vasculitis: a single-centre experience.

OBJECTIVES: ANCA-associated vasculitis (AAV) usually involves the renal and respiratory systems, but the paediatric literature on pulmonary manifestations and outcomes is limited. We aimed to describe pulmonary manifestations and outcomes after therapy in a cohort of paediatric AAV (pAAV) patients. METHODS: A retrospective chart review of all patients <19 years presenting to our institution with AAV between 1/2008 and 2/2018 was conducted. Patient demographics, clinical presentation, diagnostic testing, therapy and pulmonary outcomes over the first 3 years after presentation were evaluated. RESULTS: A total of 38 patients were included; all had ANCA positivity by immunofluorescence. A total of 23 had microscopic polyangiitis (MPA), 13 had granulomatosis with polyangiitis and 2 had eosinophilic granulomatosis with polyangiitis. A total of 30 (79%) had pulmonary manifestations, with cough (73%) and pulmonary haemorrhage (67%) being the most common. Abnormalities were noted in 82% of chest CT scans reviewed, with nodules and ground-glass opacities being the most common. At 6, 12 and 36 months follow-up, respectively, 61.8%, 39.4% and 29% of patients continued to show pulmonary manifestations. Five MPA patients with re-haemorrhage are described in detail. CONCLUSION: MPA was more common than granulomatosis with polyangiitis, with pulmonary involvement being common in both. MPA patients had more severe pulmonary manifestations. Chest CT revealed abnormal findings in a majority of cases. A subgroup of young MPA patients experienced repeat pulmonary haemorrhage. Treatment modality and response were comparable in different subtypes of AAV, except for this young MPA group. Additional prospective studies are needed to better understand the different phenotypes of pAAV.

ANCA-associated vasculitis.

The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a group of disorders involving severe, systemic, small-vessel vasculitis and are characterized by the development of autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). The three AAV subgroups, namely granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophilic GPA (EGPA), are defined according to clinical features. However, genetic and other clinical findings suggest that these clinical syndromes may be better classified as PR3-positive AAV (PR3-AAV), MPO-positive AAV (MPO-AAV) and, for EGPA, by the presence or absence of ANCA (ANCA+ or ANCA-, respectively). Although any tissue can be involved in AAV, the upper and lower respiratory tract and kidneys are most commonly and severely affected. AAVs have a complex and unique pathogenesis, with evidence for a loss of tolerance to neutrophil proteins, which leads to ANCA-mediated neutrophil activation, recruitment and injury, with effector T cells also involved. Without therapy, prognosis is poor but treatments, typically immunosuppressants, have improved survival, albeit with considerable morbidity from glucocorticoids and other immunosuppressive medications. Current challenges include improving the measures of disease activity and risk of relapse, uncertainty about optimal therapy duration and a need for targeted therapies with fewer adverse effects. Meeting these challenges requires a more detailed knowledge of the fundamental biology of AAV as well as cooperative international research and clinical trials with meaningful input from patients.

Clinical characteristics of patients with myalgia as the initial manifestation of small and medium-sized vasculitis: a retrospective study.

Myalgia is a common symptom in small and medium-sized systemic vasculitis, sometimes occurring as the initial or only clinical manifestation of vasculitis. This study investigated the clinical features and diagnostic process in patients presenting with myalgia as the initial symptom of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) or polyarteritis nodosa (PAN). We included 93 patients diagnosed with AAV or PAN by retrospectively reviewing their clinical records at the initial diagnosis. Clinical findings and diagnostic methods were assessed in patients with myalgia. Of 93 patients, myalgia was observed in 21 (22.6%) patients, with diagnostic classifications of microscopic polyangiitis (MPA) in 12 (52.4%), granulomatosis with polyangiitis in 2 (9.5%), eosinophilic granulomatosis with polyangiitis in 2 (9.5%), and PAN in 5 (23.8%). Myalgia was present in the lower extremities of all patients; more than 80% of patients had pain in the calf muscle. In 10 patients with myalgia, including 7 with MPA and 3 with PAN, muscle biopsy was performed because myalgia was the main symptom and no other impaired organs were suitable for biopsy. Consequently, 8 patients had necrotizing vasculitis, leading to MPA or PAN diagnosis, although muscle pathology was not evaluated in patients without myalgia. Muscle magnetic resonance imaging was useful in determining the biopsy site. Myalgia, especially in the lower limbs, may be an initial clinical sign of vasculitis, particularly in MPA or PAN patients. Moreover, the histological evidence of muscular vasculitis can contribute to a definite diagnosis especially in patients presenting with myalgia as an early symptom of AAV or PAN.

Clinical characteristics and prognostic risk factors of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV).

OBJECTIVE: The complement alternative pathway is involved in the development of AVV. Several studies showed that AVV patients with low serum complement C3 (sC3) levels tend to have a poor prognosis. The aim of this study was to determine whether low sC3 measured at AAV onset is a risk factor for survival prognosis in patients with AVV, and further identified other potential risk factors for predicting patient survival prognosis. METHODS: A retrospective analysis of 52 newly onset AAV patients was performed. The clinical parameters of the AAV patients were collected. The laboratory parameters before immunosuppressive treatment were evaluated. According to the level of sC3, the patients were divided into low sC3 group (n = 19) and normal sC3 group (n = 33). Disease outcome measures included end-stage renal disease (ESRD) or death. The clinical parameters and survival rate between the two groups were compared. Spearson correlation analysis was used to analyze the correlation between sC3 and other laboratory parameters. RESULTS: Significant differences were found regarding Birmingham Vasculitis Activity Score (BVAS), sC3, sC4, lactate dehydrogenase, blood urea nitrogen, procalcitonin (PCT), and estimated glomerular filtration rate (eGFR) between the two groups (p = 0.006, 0.000, 0.001, 0.049, 0.019, 0.000 and 0.045, respectively). The survival rate of the low sC3 group was significantly lower than that of the normal sC3 group (Log Rank Chi-square = 4.416, P = 0.036). Low sC3 was significantly associated with lower sC4 (r = 0.570, P = 0.000), lower serum albumin (r = 0.311, P = 0.025), lower eGFR (r = 0.289, P = 0.037), higher PCT (r = -0.566, P = 0.000), and higher lactate dehydrogenase (r = -0.323, P = 0.019). CONCLUSION: This retrospective study demonstrates that AAV patients with low sC3 level at diagnosis tend to have lower baseline eGFR and poorer survival prognosis than those of the normal sC3 level. Furthermore, the high procalcitonin (PCT), low serum albumin and high lactate dehydrogenase in AVV patients may be predictors of poor prognosis.

Demographic and clinical characteristics of patients with ANCA-positive vasculitis in a Colombian University Hospital over a 12-year period: 2005-2017.

Vasculitides associated with anti-neutrophil cytoplasmic antibodies are heterogeneous, systemic, low prevalence and high morbidity and mortality entities. They include granulomatosis with polyangiitis, microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis. In Latin America, there are few descriptive registries of these patients. The objective of the study was to describe the demographic and clinical characteristics and in-hospital morbidity and mortality of patients with vasculitis associated with anti-neutrophil cytoplasmic antibodies in a university hospital in Colombia. This was a cross-sectional descriptive study. We performed computer searches with terms related to patients with anti-neutrophil cytoplasmic antibody-associated vasculitis, between 2005 and 2017 who met the American College of Rheumatology classification criteria for vasculitis associated with anti-neutrophil cytoplasmic antibodies, and their clinical and laboratory characteristics. One hundred and six patients with anti-neutrophil cytoplasmic antibody-associated vasculitis were included in the study. The average age was 55 years, and 57.5% were women. In 68.8% of the cases, the diagnosis was made during hospitalization, with an average hospital stay of 16.6 days (± 12.22). The distribution by type of vasculitis was: granulomatosis with polyangiitis 52%, microscopic polyangiitis 45.2% and eosinophilic granulomatosis with polyangiitis 1.8%. Alveolar hemorrhage occurred in 35% of patients; 20.7% had variable renal involvement, of which 53.8% progressed to advanced kidney disease. Treatment included glucocorticoids 91.5%, cyclophosphamide 62.2%, plasmapheresis 14.1%, and 41.5% required renal replacement therapy. In-hospital mortality was 16.5%, Sepsis was the most common cause of death. We present clinical information on a group of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis; renal involvement was the the most common type of affectation. Both the clinical and serological characteristics of our registry were similar to those described in other Latin American and European cohorts, and a lower in-hospital mortality rate was evidenced.

The association of neutrophil-to-lymphocyte ratio with all-cause mortality in Chinese patients with MPO-ANCA associated vasculitis.

Neutrophil-to-lymphocyte ratio (NLR) has been recently reported to be a promising inflammatory marker to assess systemic inflammation in many disorders. However, there are only a few studies looking at NLR in patients with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study was thus undertaken to explore the relationship between NLR at diagnosis with inflammatory response and disease activity among MPO-AAV patients in a single Chinese center. Furthermore, we evaluated whether NLR could predict the renal prognosis and patient outcome. 188 patients with MPO-AAV were included in this study. Baseline NLR was positively correlated with CRP (r = 0.404, P < 0.001) and negatively with serum levels of C3 (r = - 0.163, P = 0.035), but it had no obvious correlation with Birmingham Vasculitis Activity Score (BVAS). Patients with MPO-AAV having NLR ≥ 9.53 exhibited higher risk for all-cause mortality than those having NLR < 9.53 (P < 0.0001). However, no significant difference was found in the kidney survival between patients having NLR ≥ 9.53 and those NLR < 9.53 at diagnosis. In multivariate analysis, NLR was positively associated with all-cause mortality (P = 0.037, HR = 1.98, 95% CI 1.04-3.78). There was no association between NLR with ESRD observed using univariate analysis or multivariate analysis. This large retrospective study of MPO-AAV patients in a single Chinese center demonstrates that NLR positively correlates with CRP and negatively correlates with serum levels of C3 in Chinese patients with MPO-AAV. Importantly, higher NLR predicts increased mortality and is, therefore, a useful independent prognostic in MPO-AAV.

Hematoma intraparenquimatoso asociado a vasculitis ANCA positiva / Intraparenchymal haematoma associated with an ANCA-positive vasculitis

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