Increased renal damage in hypocomplementemic patients with ANCA-associated vasculitis: retrospective cohort study.

INTRODUCTION: The complement system has an important role in the pathogenesis of vasculitis associated with antineutrophilic cytoplasmic antibody (AAV) mainly at the level of the kidneys because patients with complement deposits on the glomerular basal membrane present more aggressive disease compared with those with pauci-immune vasculitis. AIM: To analyze the association of hypocomplementemia with the clinical manifestations, laboratory data, renal histology, progress to renal insufficiency, and mortality of patients with AAV. METHODS: Retrospective cohort study (2000-2007) included 93 patients with AAV. Hypocomplementemia is defined as having C3 values lower than 80 mg/dL or C4 values below 15 mg/dL. Demographic, statistical, clinical, hematological, serological, and histopathological characteristics of all the patients with and without diagnosis of hypocomplementemia were compared. In order to evaluate variable independence, a logistic regression analysis was used. RESULTS: Ninety-three patients were studied of whom 63 (67.7%) had complement dosage at the moment of AAV diagnosis. Seven patients (11.1%) presented hypocomplementemia and a greater kidney involvement compared with normocomplementemic patients. Thirty renal biopsies were analyzed and 4 (13.3%) showed immunocomplex (IC) or complement deposits by an immunofluorescence test (IFT). Patients with "non-pauci-immune" AAV also presented terminal chronic renal disease (TCRD). CONCLUSION: There is an association between low complement and the degree of renal damage in patients with AAV. Patients with renal biopsies confirming IC and/or complement deposits showed more aggressive renal disease. Key Points • The complement system has an important role in the pathogenesis of vasculitis associated to antineutrophilic cytoplasmic antibody. • The studies in murine models confirming the complement activation by alternative pathway and particularly the receptor C5a (C5aR) is necessary for the development of glomerulonefritis. • Complement deposit observed in the renal biopsies of patients diagnosed with AAV was correlated to greater kidney damage, greater proteinuria and major disease activity compared to patients diagnosed with typical pauci-immune vasculitis. • The presence of hypocomplementemia at the onset of the disease was also associated with a greater organ involvement, poor prognosis and greater mortality.

Airway Biopsy Results From Patients With Suspected Granulomatosis With Polyangiitis (2005-2015): Clinicopathological Correlation and Proposal of an Algorithm to Improve Diagnosis.

OBJECTIVES: The aim of this study was to review the histologic diagnostic yield of airway biopsies with a suspected granulomatosis with polyangiitis (GPA) diagnosis at a single center devoted to respiratory diseases using previously published criteria. A secondary aim was to apply the algorithm proposed by the European Medicines Agency to determine whether more biopsies were confidently identified as having GPA diagnoses. METHODS: From a total of 132 airway biopsies (2005-2015), 50 were randomly selected for second review by an expert pathologist, and previously published criteria were applied. Thereafter, antineutrophil cytoplasm autoantibody testing results and the European Medicines Agency algorithm were applied. RESULTS: Repeat review and application of the published criteria resulted in an increase from 16 to 25 diagnoses of GPA. This increased to 35 of 50 when antineutrophil cytoplasm autoantibody results and the European Medicines Agency algorithm were applied. Interobserver correlation was 57.5% among pathologists (κ = 0.19), which was likely due to missing clinical information and inadequate tissue samples. Patients with generalized disease were 2.6 times more likely to obtain diagnostic GPA airway biopsy results than those with limited disease (airway only). CONCLUSIONS: An increase in the diagnostic yield of this malady could be attained by following an algorithm that incorporates carefully retrieved clinical, endoscopic, and serologic data, coupled with systematic histopathologic sample review.

Serum 25-hydroxyvitamin D levels in patients with Granulomatosis with Polyangiitis: association with respiratory infection

OBJECTIVES: To determine the possible association of serum 25-hydroxyvitamin D (25OHD) levels with disease activity and respiratory infection in granulomatosis with polyangiitis patients during two different periods: winter/spring and summer/autumn. METHODS: Thirty-two granulomatosis with polyangiitis patients were evaluated in the winter/spring, and the same patients (except 5) were evaluated in summer/autumn (n=27). The 25OHD levels were measured by radioimmunoassay. Disease activity was assessed by the Birmingham Vasculitis Activity Score Modified for Wegener's Granulomatosis (BVAS/WG) and antineutrophil cytoplasmic antibody (ANCA) positivity. Respiratory infection was defined according the Centers for Disease Control and Prevention criteria. RESULTS: 25OHD levels were lower among patients in winter/spring than in summer/autumn (32.31±13.10 vs. 38.98±10.97 ng/mL, p=0.04). Seven patients met the criteria for respiratory infection: 5 in winter/spring and 2 in summer/autumn. Patients with respiratory infection presented lower 25OHD levels than those without infection (25.15±11.70 vs. 36.73±12.08 ng/mL, p=0.02). A higher frequency of low vitamin D levels (25OHD<20 ng/mL) was observed in patients with respiratory infection (37.5% vs. 7.8, p=0.04). Serum 25OHD levels were comparable between patients with (BVAS/WG≥1 plus positive ANCA) and without disease activity (BVAS/WG=0 plus negative ANCA) (35.40±11.48 vs. 35.34±13.13 ng/mL, p=0.98). CONCLUSIONS: Lower 25OHD levels were associated with respiratory infection but not disease activity in granulomatosis with polyangiitis patients. Our data suggest that hypovitaminosis D could be an important risk factor for respiratory infection in granulomatosis with polyangiitis patients.

Gingival granulomatosis with polyangiitis (Wegener's granulomatosis) as a primary manifestation of the disease.

Granulomatosis with polyangiitis (GPA) is a potentially lethal disease characterized by systemic necrotizing vasculitis, which affects small- and medium-sized blood vessels and is often associated with serum cytoplasmic antineutrophil cytoplasmic antibody. The upper and lower respiratory tract and kidney are the most involved sites, but oral lesions can be identified in 6-13% of the cases, whereas in only 2% of the cases, oral manifestations represent the first signal of the disease usually as gingival swellings or unspecific ulcerations. Without treatment, the mainstay of which is the combination of immunosuppressants and systemic corticosteroids, GPA may run a fatal course. In this report we describe an original case of GPA affecting a 75-year-old female patient referred to our service due to a gingival swelling with 3-month duration. Although the patient was correctly diagnosed and promptly treated, she died 3 months after the initial diagnosis.

Granulomatosis with polyangiitis according to geographic origin and ethnicity: clinical-biological presentation and outcome in a French population.

Objectives: Granulomatosis with polyangiitis (GPA) mainly affects white Europeans, but rarely GPA may also affect non-Europeans. This study aimed to describe GPA clinical-biological presentation and outcome in black sub-Saharan Africans and Afro-Caribbeans and in North Africans. Methods: Among 914 GPA patients included in the French Vasculitis Study Group database, geographic origin and ethnicity were known for 760. Clinical-biological presentations and outcomes of white Europeans vs black sub-Saharans and Afro-Caribbeans and vs North Africans were analysed. Results: Among the 760 patients, 689 (91%) were white Europeans, 33 (4.3%) were North Africans and 22 (2.9%) were sub-Saharans (n = 8) or Afro-Caribbeans (French West Indies, n = 14). Black sub-Saharans and Afro-Caribbeans, compared with white Europeans, were significantly younger at GPA diagnosis (P = 0.003), had more frequent central nervous system involvement (P = 0.02), subglottic stenosis (P = 0.002) and pachymeningitis (P = 0.009), and tended to have more frequent chondritis and retroorbital tumour. Median serum creatinine levels and Birmingham Vasculitis Activity Score were significantly lower in sub-Saharans and Afro-Caribbeans (P = 0.002 and P = 0.003, respectively). In contrast, in comparison with white Europeans, North Africans had only less frequent arthralgias (P = 0.004). Time to relapse was shorter for black sub-Saharans and Afro-Caribbeans compared with white Europeans [adjusted HR = 1.96 (95% CI: 1.09, 3.51) (P = 0.02)], and did not differ for North Africans. In contrast, overall survival was not significantly different according to ethnicity. Conclusion: Our findings indicated different GPA clinical presentations in white Europeans and sub-Saharans and Afro-Caribbeans, with black patients having more frequent severe granulomatous manifestations. In addition, time to relapse was significantly shorter for black sub-Saharans and Afro-Caribbeans compared with white Europeans.

Serum 25-hydroxyvitamin D levels in patients with Granulomatosis with Polyangiitis: association with respiratory infection.

OBJECTIVES: To determine the possible association of serum 25-hydroxyvitamin D (25OHD) levels with disease activity and respiratory infection in granulomatosis with polyangiitis patients during two different periods: winter/spring and summer/autumn. METHODS: Thirty-two granulomatosis with polyangiitis patients were evaluated in the winter/spring, and the same patients (except 5) were evaluated in summer/autumn (n=27). The 25OHD levels were measured by radioimmunoassay. Disease activity was assessed by the Birmingham Vasculitis Activity Score Modified for Wegener's Granulomatosis (BVAS/WG) and antineutrophil cytoplasmic antibody (ANCA) positivity. Respiratory infection was defined according the Centers for Disease Control and Prevention criteria. RESULTS: 25OHD levels were lower among patients in winter/spring than in summer/autumn (32.31±13.10 vs. 38.98±10.97 ng/mL, p=0.04). Seven patients met the criteria for respiratory infection: 5 in winter/spring and 2 in summer/autumn. Patients with respiratory infection presented lower 25OHD levels than those without infection (25.15±11.70 vs. 36.73±12.08 ng/mL, p=0.02). A higher frequency of low vitamin D levels (25OHD<20 ng/mL) was observed in patients with respiratory infection (37.5% vs. 7.8, p=0.04). Serum 25OHD levels were comparable between patients with (BVAS/WG≥1 plus positive ANCA) and without disease activity (BVAS/WG=0 plus negative ANCA) (35.40±11.48 vs. 35.34±13.13 ng/mL, p=0.98). CONCLUSIONS: Lower 25OHD levels were associated with respiratory infection but not disease activity in granulomatosis with polyangiitis patients. Our data suggest that hypovitaminosis D could be an important risk factor for respiratory infection in granulomatosis with polyangiitis patients.

Juvenile idiopathic arthritis and Wegener's granulomatosis--causal or casual acquaintances?

We report two cases of long-term juvenile idiopathic arthritis which developed recurrent subglottic stenosis secondary to localized Wegener's granulomatosis. In both cases, the biopsies taken from the affected region shown granulomatous vasculitis with multinucleated giant cells. Both patients presented positive serology for antineutrophil cytoplasmic antibodies by immunofluorescence (c-ANCA) and ELISA (PR3). The involvement or other organs was ruled out at the time of Wegener's granulomatosis diagnosis and during follow-up. To our knowledge, this is the first report of the association between juvenile idiopathic arthritis and a localized form of Wegener's granulomatosis.

C-ANCA-positive IgG fraction from patients with Wegener's granulomatosis induces lung vasculitis in rats.

The aim of the present study was to analyse in rats the ability of C-ANCA-positive IgG fraction in triggering inflammatory response on pulmonary tissue. Wistar rats (n = 18) were injected via the the internal jugular vein with 20 mg of total C-ANCA-positive IgG fraction isolated from serum of three different Wegener's granulomatosis patients obtained before therapy. Similarly, control rats were treated with IgG fraction from two rheumatoid arthritis patients (n = 7), IgG from six normal human sera (n = 15) or saline (n = 18), respectively. Animals were sacrificed after 24h of injection for histological analysis of the lungs. Vasculitis and inflammatory infiltrate were consistently absent in rats injected with rheumatoid arthritis IgG or saline and in 14/15 of normal IgG treated animals. In contrast, marked vasculitis was observed in all 18 animals injected with C-ANCA-positive IgG fraction. The histological features were characterized by the presence of a perivascular pleomorphic cellular sheath, particularly around small vessels, endothelial adherence and diapedesis of polymorphonuclear leucocytes and presence of granuloma-like lesions. A dose-response relationship was observed between protein concentration of C-ANCA IgG sample and the intensity of the inflammatory response in the animals. In addition, IgG fraction with undetectable C-ANCA, obtained from one patient in remission after treatment, was not able to reproduce the pulmonary tissue alterations induced by its paired IgG that was positive for C-ANCA taken before therapy. The experimental model described herein may be useful to characterize more effectively the pathogenic mechanism of C-ANCA in Wegener's disease.

Takayasu's arteritis coexisting with Wegener's granulomatosis in a teenager with renal insufficiency: case report.

A case of Wegener's granulomatosis (WG) coexisting with Takayasu's arteritis (TA) in a 12-year-old girl is presented. She presented with fulminant and severe renal insufficiency due to crescentic glomerulonephritis. At autopsy, aortic lesions of Takayasu's arteritis coexisted with pulmonary and renal findings of WG, and the patient's serum at autopsy had an elevated level of antineutrophil cytoplasmic antibodies (ANCA). Both forms of vasculitis have been thought to be triggered by infectious agents and it is postulated that this occurrence accounts for the coexistence of the two forms of vasculitis in this case.

[Comparison between immunofluorescence techniques and ELISA, using whole neutrophil extract and primary granules, for the detection of antineutrophil cytoplasma antibodies (ANCA)]. / Comparação entre as técnicas de imunofluorescência e ELISA com extrato total de neutrófilos e com grânulos primários para a detecção de anticorpos contra o citoplasma de neutrófilos (ANCA).

The detection of antineutrophil cytoplasmic antibodies is a very important tool for the diagnosis of systemic vasculitis. The specificity and sensitivity of these antibodies depends on the assay utilized for their detection. Therefore we have compared the immunofluorescence test (IF) with the ELISA using two different antigens: total neutrophil extract and isolated primary granules. Two patterns of fluorescence were detected by IF: the classic pattern was highly specific for Wegener's granulomatosis. In contrast the perinuclear staining correlated with renal vasculitis but was also observed in other diseases. However the IF test was unable to differentiate low-positive from atypical patterns. Such distinction could be achieved by ELISA. The use of ELISA with isolated primary granules is a good alternative for if since it has a good specificity, sensitivity and reproducibility, moreover it is a quantitative method.

Anticuerpos anti-citoplasma de polimorfonuclear neutrófilo en granulomatosis de Wegener, en otras enfermedades autoinmunes y en pacientes hemodializados / Anticytoplasm antibodies of polymorphonuclear neutrophils in Wegener's granulomatosis, other autoimmune diseases and in patients under hemodialysis

Las vasculitis sistémicas son un grupo heterogénio de enfermedades caracterizadas por infiltración inflamatoria y necrosis de la pared vascular. Anticuerpos contra citoplasma de polimorfonuclear neutrófilo (ANCA-C y ANCA-P) fueron descriptos como marcadores serológicos de algunas de estas afecciones y de ciertos tipos de glomerulonefritis. La presencia de ANCA se investigó en el suero de 182 pacientes. En 16/17 con Granulomatosis de Wegener (G.W.) (critérios ACR) se encontró ANCA, 14 de ellos con imagen C (en 10 asociada a imagem P) y en los dos restantes, imagem P solamente (p < 0,001, comparando con los otros grupos estudiados). La presencia de estos anticorpos se asoció con la atividad clínica de la enfermedad (p, 0,01). El único paciente ANCA-C positivo fuera de este grupo tenía estonosis subglótica como única manifestación clínica con histología inespecífica, ANCA-P se encontró, además, en 6 por ciento de los casos con Enfermedades del Tejido Conectivo estudiados, y en 6/66 de la Unidad de Diálisis, lo cual sugiere que un mecanismo relacionado al ANCA puede ser el responsable de la nefropatía en aproximadamente el 10//de los pacientes en hemodiálisis crónica. Los resultados obtenidos indican que la investigación de ANCA puede ser un elemento de ayuda útil para el diagnóstico y monitoreo de la actividad clínica en la G.W

Anticuerpos anti-citoplasma de polimorfonuclear neutrófilo en granulomatosis de Wegener, en otras enfermedades autoinmunes y en pacientes hemodializados / Anticytoplasm antibodies of polymorphonuclear neutrophils in Wegeners granulomatosis, other autoimmune diseases and in patients under hemodialysis

Las vasculitis sistémicas son un grupo heterogénio de enfermedades caracterizadas por infiltración inflamatoria y necrosis de la pared vascular. Anticuerpos contra citoplasma de polimorfonuclear neutrófilo (ANCA-C y ANCA-P) fueron descriptos como marcadores serológicos de algunas de estas afecciones y de ciertos tipos de glomerulonefritis. La presencia de ANCA se investigó en el suero de 182 pacientes. En 16/17 con Granulomatosis de Wegener (G.W.) (critérios ACR) se encontró ANCA, 14 de ellos con imagen C (en 10 asociada a imagem P) y en los dos restantes, imagem P solamente (p < 0,001, comparando con los otros grupos estudiados). La presencia de estos anticorpos se asoció con la atividad clínica de la enfermedad (p, 0,01). El único paciente ANCA-C positivo fuera de este grupo tenía estonosis subglótica como única manifestación clínica con histología inespecífica, ANCA-P se encontró, además, en 6 por ciento de los casos con Enfermedades del Tejido Conectivo estudiados, y en 6/66 de la Unidad de Diálisis, lo cual sugiere que un mecanismo relacionado al ANCA puede ser el responsable de la nefropatía en aproximadamente el 10//de los pacientes en hemodiálisis crónica. Los resultados obtenidos indican que la investigación de ANCA puede ser un elemento de ayuda útil para el diagnóstico y monitoreo de la actividad clínica en la G.W (AU)

[Anticytoplasm antibodies of polymorphonuclear neutrophils in Wegener's granulomatosis, other autoimmune diseases, and in patients undergoing hemodialysis]. / Anticuerpos anti-citoplasma de polimorfonuclear neutrófilo en granulomatosis de Wegener, en otras enfermedades autoinmunes y en pacientes hemodializados.

Systemic vasculitis are an heterogeneous group of diseases characterized by inflammatory infiltration and necrosis of blood vessel walls. Antineutrophil cytoplasmic antibodies (ANCA) with different immunofluorescent patterns (C or P) have been described as serological markers of some of these diseases and some types of glomerulonephritis. The presence of ANCA by immunofluorescence on normal fixed polymorphonuclear neutrophils was investigated in 182 patients. Results are depicted in Table 1. ANCA was present in 16/17 (94%) patients with Wegener Granulomatosis (W.G.) (ACR criteria) (p < 0.001). In 14 out of the 16 (82%), the pattern was ANCA-C (associated in 10 with ANCA-P) and only ANCA-P was observed in the remaining two. The presence of ANCA was associated with active disease: 15/16 samples of active patients and 3/9 of inactive patients were ANCA positive (p < 0.01). Among the other groups, ANCA-C was detected in only one patient with isolated subglottal stenosis. The specificity of ANCA-C for W.G. was 99%. ANCA-P was also detected in 3/49 (6%) patients with connective tissue disorders and in 3/63 (5%) patients in chronic hemodialysis with exclusive or predominant renal disease of unknown etiology. Three additional ANCA positive patients with known diagnosis (2 W.G. and 1 Systemic Lupus Erythematosus) were also in hemodialysis in the same unit. Thus, an ANCA related mechanism may be involved in the pathogenesis of approximately 10% of cases undergoing this procedure. None of 45 sera submitted for the detection of antinuclear antibodies were ANCA positive. Detection of ANCA (especially C pattern) may be of help in the diagnosis of W.G. and in monitoring clinical activity of the disease.