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Objective Granulomatosis with polyangiitis (GPA) is an ANCA-associated vasculitis. The 2022 ACR/EULAR-endorsed classification criteria for GPA was derived using data only from adult patients. We aimed to assess the performance of the ACR/EULAR classification criteria for GPA in paediatric patients and compare it with the EULAR/Pediatric Rheumatology International Trials Organization (PRINTO)/Pediatric Rheumatology European Society (PReS)-endorsed Ankara 2008 criteria for GPA. Methods Retrospective data of paediatric patients with GPA in 20 centres from 9 countries were evaluated. The diagnosis of GPA was made according to the expert opinion. The sensitivity, specificity, positive predictive value, and negative predictive value of the criteria sets were evaluated. Results The study included 77 patients with GPA and 108 controls [IgA vasculitis (n  = 44), Takayasu's arteritis (n  = 20), microscopic polyangiitis (n  = 16), polyarteritis nodosa (n  = 14), Behçet's disease (n  = 12), eosinophilic granulomatosis with polyangiitis (n  = 1) and Cogan's syndrome (n  = 1)] with a median age of 17.8 and 15.2 years, respectively. Among patients with GPA, constitutional symptoms (85.7%) and ENT involvement (79.2%) were the most common presentations. In the GPA group, 73 patients fulfilled the Ankara 2008 criteria and 69 the ACR/EULAR classification criteria. Sensitivities of the Ankara 2008 criteria and the ACR/EULAR classification criteria were 94.8% and 89.6%, while specificities were 95.3% and 96.3%, respectively. No significant difference was found between sensitivities and specificities of both classification criteria (P  = 0.229 and P  = 0.733, respectively). Conclusion In children, both the ACR/EULAR and EULAR/PRINTO/PReS Ankara 2008 classification criteria for GPA perform well and similarly. [ABSTRACT FROM AUTHOR]

Background Three different histological scores—histopathologic classification (Berden), Renal Risk Score (RRS) and the Mayo Clinic Chronicity Score (MCCS)—for anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (ANCA-GN) were compared to evaluate their association with patient and kidney prognosis of ANCA-GN. Methods Patients aged >18 years with at least 1 year of follow-up and biopsy-proven ANCA-GN entered this retrospective study. Renal biopsies were classified according to Berden's classification, RRS and MCCS. The first endpoint was end-stage kidney disease (ESKD), defined as chronic dialysis or estimated glomerular filtration rate <15 mL/min/1.73 m2. The second endpoint was ESKD or death. Results Of 152 patients 84 were males, with median age of 63.8 years and followed for 46.9 (interquartile range 12.8–119) months, 59 (38.8%) reached the first endpoint and 20 died. The Kaplan–Meier curves showed that Berden and RRS were associated with first (Berden: P  = .004, RRS: P  < .001) and second (Berden: P  = .001, RRS: P  < .001) endpoint, MCCS with the first endpoint only when minimal + mild vs moderate + severe groups were compared (P  = .017), and with the second endpoint (P  < .001). Among the clinical/histological presentation features, arterial hypertension [odds ratio (OR) = 2.75, confidence interval (95% CI) 1.50–5.06; P  = .0011], serum creatinine (OR = 1.17, 95% CI 1.09–1.25; P  < .0001), and the percentage of normal glomeruli (OR = 0.97, 95% CI 0.96–0.99; P  = .009) were the independent predictors of ESKD at multivariate analysis. When the three scores were included in multivariate analysis, RRS (OR = 2.21, 95% CI 1.15–4.24; P  = .017) and MCCS (OR = 2.03, 95% CI 1.04–3.95; P  = .037) remained predictive of ESKD, but Berden (OR = 1.17, 95% CI 0.62–2.22; P  = .691) did not. Conclusion RRS and MCCS scores were independent predictors of kidney survival together with high serum creatinine and arterial hypertension at diagnosis, while Berden classification was not. [ABSTRACT FROM AUTHOR]

ANCA-associated vasculitides (AAV), classified into granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis represent a group of disorders characterized by necrotizing vasculitis of small vessels, endothelial injury and tissue damage. The outcomes and prognosis of AAV have undergone significant changes with the introduction of glucocorticoids (GCs) and other immunosuppressants (cyclophosphamide, azathioprine, methotrexate, and mycophenolate mofetil). The enhanced understanding of pathogenesis has subsequently led to the incorporation into clinical practice of drugs targeting specific therapeutic targets. After an extensive literature search of Pubmed, Medline, Embase of the most recent evidence, we provide an overview of available treatments, highlighting how newer drugs have integrated into standard protocols. Our review also explores potential new therapeutic targets, including B cell depletion and inhibition, T cell inhibition, complement inhibition, and IL-5 and IgE inhibition. There is hope that the new treatment targets currently under study in AAV may enable a faster and more lasting clinical response, ensuring the reduction of possible side effects from therapies. Moreover, numerous aspects necessitate further exploration in the future, such as tailoring of GCs, integration of GCs-sparing agents, efficacy of combination therapy, optimal maintenance therapy, to reduce organ-damage and improve quality of life. [ABSTRACT FROM AUTHOR]

Objective. Previous studies suggested that distinct phenotypes of eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome) could be determined by the presence or absence of antineutrophil cytoplasmic antibodies (ANCA), reflecting predominant vasculitic or eosinophilic processes, respectively. This study explored whether ANCA-based clusters or other clusters can be identified in EGPA. Methods. This study used standardized data of 15 European centers for patients with EGPA fulfilling widely accepted classification criteria. We used multiple correspondence analysis, hierarchical cluster analysis, and a decision tree model. The main model included 10 clinical variables (musculoskeletal [MSK], mucocutaneous, ophthalmological, ENT, cardiovascular, pulmonary, gastrointestinal, renal, central, or peripheral neurological involvement); a second model also included ANCA results. Results. The analyses included 489 patients diagnosed between 1984 and 2015. ANCA were detected in 37.2% of patients, mostly perinuclear ANCA (85.4%) and/or antimyeloperoxidase (87%). Compared with ANCA-negative patients, those with ANCA had more renal (P < 0.001) and peripheral neurological involvement (P = 0.04), fewer cardiovascular signs (P < 0.001), and fewer biopsies with eosinophilic tissue infiltrates (P = 0.001). The cluster analyses generated 4 (model without ANCA) and 5 clusters (model with ANCA). Both models identified 3 identical clusters of 34, 39, and 40 patients according to the presence or absence of ENT, central nervous system, and ophthalmological involvement. Peripheral neurological and cardiovascular involvement were not predictive characteristics. Conclusion. Although reinforcing the known association of ANCA status with clinical manifestations, cluster analysis does not support a complete separation of EGPA in ANCA-positive and -negative subsets. Collectively, these data indicate that EGPA should be regarded as a phenotypic spectrum rather than a dichotomous disease. [ABSTRACT FROM AUTHOR]

Objectives Rituximab has become the cornerstone of induction treatment in ANCA-associated vasculitis (AAV). B-cell depletion may increase the risk of hypogammaglobulinemia, potentially leading to severe infections. This study aims to assess factors associated with hypogammaglobulinemia in AAV patients treated with rituximab. Methods This retrospective cohort study included AAV patients treated with rituximab induction in 14 European centres. Severe adverse events (SAEs) were defined as episodes requiring hospitalization or intravenous antibiotics, malignancies, or death. Linear and logistic regression were used to identify predictors of IgG levels and of the risk of hypogammaglobulinemia, defined as IgG ≤7 g/l at 6 months. Results The study included 227 patients. IgG levels at 6 months were lower than baseline (P  < 0.001). Patients requiring intravenous antibiotics during the first 6 months had lower IgG levels at 6 months (P  = 0.004). Age [β (95% CI): −0.23 (−0.38, −0.08) per 10 years, P  = 0.003], oral glucocorticoid dose at induction [β (95% CI): −0.37 (−0.51, −0.24) per sqrt-transformed mg prednisone, P  < 0.001] and concomitant use of intravenous glucocorticoid pulses [β (95% CI): −0.88 (−1.73, −0.02), P  = 0.044] were associated with IgG levels at 6 months. Hypogammaglobulinemia was identified in 97 (42.7%) patients. In multivariable logistic regression, factors associated with the risk of hypogammaglobulinemia were age [OR (95% CI): 1.46 (1.15, 1.86) per 10 years, P  = 0.002] and oral glucocorticoid dose at induction [OR (95% CI): 1.52 (1.23, 1.89) per 10 mg prednisone, P  < 0.001]. Conclusions In AAV patients treated with rituximab, hypogammaglobulinemia at 6 months after induction is common, and lower IgG levels are associated with serious infections. The risk of hypogammaglobulinemia in these patients increases with age and higher glucocorticoid doses. [ABSTRACT FROM AUTHOR]

Idiopathic membranous nephropathy (IMN) is a pathologically defined disorder of the glomerulus, primarily responsible for nephrotic syndromes (NS) in nondiabetic adults. The underlying molecular mechanisms are still not completely clarified. To explore possible molecular and functional signatures, an optimised mass spectrometry (MS) method based on next-generation data-independent acquisition combined with ion-mobility was applied to serum of patients affected by IMN (n = 15) or by other glomerulopathies (PN) (n = 15). The statistical comparison highlighted a panel of 57 de-regulated proteins with a significant increase in lipoprotein-related proteins (APOC1, APOB, APOA1, APOL1 and LCAT) and a substantial quantitative alteration of key serpins (including A4, D1, A7, A6, F2, F1 and 1) possibly associated with IMN or NS and podocyte stress. A critical dysregulation in metabolisms of lipids (e.g., VLDL assembly and clearance) likely to be related to known hyperlipidemia in IMN, along with involvement of non-classical complement pathways and a putative enrolment of ficolin-2 in sustaining the activation of the lectin-mediated complement system have been pinpointed. Moreover, mannose receptor CD206 (MRC1-down in IMN) and biotinidase (BTD-up in IMN) are able alone to accurately distinguish IMN vs. PN. To conclude, our work provides key proteomic insights into the IMN complexity, opening the way to an efficient stratification of MN patients. [ABSTRACT FROM AUTHOR]

AA amyloidosis may complicate several chronic inflammatory conditions. From a clinical point of view, causality between inflammatory pathology and AA amyloidosis can be assumed because of the data described in the literature; some of the best known include rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, and chronic infections. Singles cases of inflammatory diseases have been found at AA amyloidosis. Causality becomes more plausible if at least two different cases with AA amyloidosis are both found to have the same rare inflammatory disease. We describe the case of a patient with primary sclerosing cholangitis (PSC) with development of AA amyloidosis conditioning a nephrotic syndrome, likely secondary to failure to control the chronic inflammatory process. Only two cases in the literature describe the association of this rare disease and the appearance of AA amyloidosis. The treatment of AA amyloidosis consists in treating the underlying inflammatory disorder; to date, few effective treatments are available for PSC. Therefore, and in view of the limited data in the literature, we believe it is important to describe its association. [ABSTRACT FROM AUTHOR]

The podocyte injury, and consequent proteinuria, that characterize the pathology of idiopathic membranous nephropathy (IMN) is mediated by an autoimmune reaction against podocyte antigens. In particular, the activation of pathways leading to abundant renal deposits of complement is likely to involve the binding of mannose-binding lectin (MBL) to aberrant glycans on immunoglobulins. To obtain a landscape of circulatory IgG Fc glycosylation characterizing this disease, we conducted a systematic N-glycan profiling study of IgG1, 2, and 4 by mass spectrometry. The cohort included 57 IMN patients, a pathological control group with nephrotic syndrome (PN) (n = 20), and 88 healthy control subjects. The effect of sex and age was assessed in all groups and controlled by rigorous matching. Several IgG Fc glycan traits were found to be associated with IMN. Interestingly, among them, only IgG4-related results were specific for IMN and not for PN. Hypo-galactosylation of IgG4, already shown for IMN, was observed to occur in the absence of core fucose, in line with a probable increase of pro-inflammatory IgG. In addition, elevated levels of fucosylated IgG4, along with low levels of hybrid-type glycans, were detected. Some of these IgG4 alterations are likely to be more pronounced in high PLA2R (phospholipase A2 receptor) patients. IgG Fc glycosylation patterns associated with IMN warrant further studies of their role in disease mechanisms and may eventually enrich the diagnostic spectrum regarding patient stratification. [ABSTRACT FROM AUTHOR]

Vulnerable subjects, including systemic lupus erythematosus (SLE) patients, have been prioritised to receive anti-SARS-CoV-2 vaccines. Few data about the safety of these vaccines in SLE are available. The aim of our study is to investigate the safety of anti-SARS-CoV-2 vaccines in SLE. We included 452 SLE patients, referring to seven tertiary centres, who were immunised. A total of 119 (26%) reported side effects (SE) after the first and/or the second shot (the most frequent SE were fever, local reaction, fatigue, and arthralgia). Patients with constitutional symptoms and those on an immunosuppressive regimen (especially belimumab) showed more SE. In addition, 19 (4%) had a flare after the immunisation (flares classified by organ involvement: six musculoskeletal with constitutional symptoms, four renal, three cardio-respiratory, three haematological, two mucocutaneous). None of the patients needed hospitalisation and none died. Moreover, 15 required a transient increase in corticosteroids and four were treated with steroid pulses. One patient required an additional rituximab course. Anti-dsDNA, moderate/high DAS before vaccine, and belimumab were found more frequently in patients with disease flare. Anti-SARS-CoV-2 vaccines are safe in SLE patients, and they should be recommended in these patients, as the potential benefits widely outweigh the risk of SE. Treatment adjustment might be considered with the aim of minimising SE risk and flare. [ABSTRACT FROM AUTHOR]

Objectives The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with SLE remains unclear and data on clinical manifestations after infection are lacking. The aim of this multicentre study is to describe the effect of SARS-CoV-2 in SLE patients. Methods SLE patients referring to four Italian centres were monitored between February 2020 and March 2021. All patients with SARS-CoV-2 infection were included. Disease characteristics, treatment, disease activity and SARS-CoV-2-related symptoms were recorded before and after the infection. Results Fifty-one (6.14%) SLE patients were included among 830 who were regularly followed up. Nine (17.6%) had an asymptomatic infection and 5 (9.8%) out of 42 (82.6%) symptomatic patients developed interstitial pneumonia (no identified risk factor). The presence of SLE major organ involvement (particularly renal involvement) was associated with asymptomatic SARS-CoV-2 infection (P  = 0.02). Chronic corticosteroid therapy was found to be associated with asymptomatic infection (P  = 0.018). Three SLE flares (5.9%) were developed after SARS-CoV-2 infection: one of them was characterized by MPO-ANCA-positive pauci-immune crescentic necrotizing glomerulonephritis and granulomatous pneumonia. Conclusions SARS-CoV-2 infection determined autoimmune flares in a small number of patients. Our data seem to confirm that there was not an increased risk of SARS-CoV-2 in SLE. Patients with asymptomatic SARS-CoV-2 infections were those having major SLE organ involvement. This may be explained by the high doses of corticosteroids and immunosuppressive agents used for SLE treatment. [ABSTRACT FROM AUTHOR]

Objective: Mepolizumab proved to be an efficacious treatment for eosinophilic granulomatosis with polyangiitis (EGPA) at a dose of 300 mg every 4 weeks in the randomized, controlled MIRRA trial. In a few recently reported studies, successful real‐life experiences with the approved dose for treating severe eosinophilic asthma (100 mg every 4 weeks) were observed. We undertook this study to assess the effectiveness and safety of mepolizumab 100 mg every 4 weeks and 300 mg every 4 weeks in a large European EGPA cohort. Methods: We included all patients with EGPA treated with mepolizumab at the recruiting centers in 2015–2020. Treatment response was evaluated from 3 months to 24 months after initiation of mepolizumab. Complete response to treatment was defined as no disease activity (Birmingham Vasculitis Activity Score [BVAS] = 0) and a prednisolone or prednisone dose (or equivalent) of ≤4 mg/day. Respiratory outcomes included asthma and ear, nose, and throat (ENT) exacerbations. Results: Two hundred three patients, of whom 191 received a stable dose of mepolizumab (158 received 100 mg every 4 weeks and 33 received 300 mg every 4 weeks) were included. Twenty‐five patients (12.3%) had a complete response to treatment at 3 months. Complete response rates increased to 30.4% and 35.7% at 12 months and 24 months, respectively, and rates were comparable between mepolizumab 100 mg every 4 weeks and 300 mg every 4 weeks. Mepolizumab led to a significant reduction in BVAS score, prednisone dose, and eosinophil counts from 3 months to 24 months, with no significant differences observed between 100 mg every 4 weeks and 300 mg every 4 weeks. Eighty‐two patients (40.4%) experienced asthma exacerbations (57 of 158 [36%] who received 100 mg every 4 weeks; 17 of 33 [52%] who received 300 mg every 4 weeks), and 31 patients (15.3%) experienced ENT exacerbations. Forty‐four patients (21.7%) experienced adverse events (AEs), most of which were nonserious AEs (38 of 44). Conclusion: Mepolizumab at both 100 mg every 4 weeks and 300 mg every 4 weeks is effective for the treatment of EGPA. The 2 doses should be compared in the setting of a controlled trial. [ABSTRACT FROM AUTHOR]

Objectives Circulating anti-ENO1 and anti-H2A IgG2 have been identified as specific signatures of LN in a cross-over approach. We sought to show whether the same antibodies identify selected population of patients with LN with potentially different clinical outcomes. Methods Here we report the prospective analysis over 36 months of circulating IgG2 levels in patients with newly diagnosed LN (n =91) and SLE (n =31) and in other patients with SLE recruited within 2 years from diagnosis (n =99). Anti-podocyte (ENO1), anti-nucleosome (DNA, histone 2 A, histone 3) and anti-circulating proteins (C1q, AnnexinA1-ANXA1) IgG2 antibodies were determined by home-made techniques. Results LN patients were the main focus of the study. Anti-ENO1, anti-H2A and anti-ANXA1 IgG2 decreased in parallel to proteinuria and normalized within 12 months in the majority of patients while anti-dsDNA IgG2 remained high over the 36 months. Anti-ENO1 and anti-H2A had the highest association with proteinuria (Heat Map) and identified the highest number of patients with high proteinuria (68% and 71% respectively) and/or with reduced estimated glomerula filtration rate (eGFR) (58% for both antibodies) compared with 23% and 17% of anti-dsDNA (agreement analysis). Anti-ENO1 positive LN patients had higher proteinuria than negative patients at T 0 and presented the maximal decrement within 12 months. Conclusions Anti-ENO1, anti-H2A and anti-ANXA1 antibodies were associated with high proteinuria in LN patients and Anti-ENO1 also presented the maximal reduction within 12 months that paralleled the decrease of proteinuria. Anti-dsDNA were not associated with renal outcome parameters. New IgG2 antibody signatures should be utilized as tracers of personalized therapies in LN. Trial registration The Zeus study was registered at https://clinicaltrials.gov (study number: NCT02403115). [ABSTRACT FROM AUTHOR]

Objectives Serum anti-dsDNA and anti-nucleosome IgGs have been proposed as signatures for SLE and LN in limited numbers of patients. We sought to show higher sensitivity and specificity of the same antibodies with the IgG2 isotype and included IgG2 antibodies vs specific intracellular antigens in the analysis. Methods A total of 1052 SLE patients with (n = 479) and without (n = 573) LN, recruited at different times from the beginning of symptoms, were included in the study. Patients with primary APS (PAPS, n = 24), RA (RA, n = 24) and UCTD (UCTD, n = 96) were analysed for comparison. Anti-nucleosome (dsDNA, Histone2A, Histone3), anti-intracellular antigens (ENO1), anti-annexin A1 and anti-C1q IgG2 were determined by non‐commercial techniques. Results The presence in the serum of the IgG2 panel was highly discriminatory for SLE/LN vs healthy subjects. Serum levels of anti-dsDNA and anti-C1q IgG2 were more sensitive than those of IgGs (Farr radioimmunoassay/commercial assays) in identifying SLE patients at low–medium increments. Of more importance, serum positivity for anti-ENO1 and anti-H2A IgG2 discriminated between LN and SLE (ROC T0–12 months), and high levels at T0–1 month were detected in 63% and 67%, respectively, of LN, vs 3% and 3%, respectively, of SLE patients; serum positivity for each of these was correlated with high SLEDAI values. Minor differences existed between LN/SLE and the other rheumatologic conditions. Conclusion Nephritogenic IgG2 antibodies represent a specific signature of SLE/LN, with a few overlaps with other rheumatologic conditions. High levels of anti-ENO1 and anti-H2A IgG2 correlated with SLE activity indexes and were discriminatory between SLE patients limited to the renal complication and other SLE patients. Trial registration The Zeus study was registered at https://clinicaltrials.gov , NCT02403115. [ABSTRACT FROM AUTHOR]

Objectives: Short-term predictive endpoints of chronic kidney disease (CKD) are needed in lupus nephritis (LN). We tested response to therapy at 1 year.Methods: We considered patients with LN who underwent renal biopsy followed by induction therapy between January 1970 and December 2016. LN was assessed using the International Society of Nephrology/Renal Pathology Society (2003) criteria and the National Institute of Health (NIH) activity and chronicity index. The renal outcome was CKD. Response was defined according to EULAR/European League Against Rheumatism/European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations: complete: proteinuria <0.5 g/24 hours, (near) normal estimated glomerular filtration rate (eGFR); partial: ≥50% proteinuria reduction to subnephrotic levels, (near) normal eGFR; and no response: all the other cases. Logistic regression analysis was employed for 12-month response and Cox regression for CKD prediction.Results: We studied 381 patients (90.5% Caucasians). After 12-month therapy, 58%, 26% and 16% of patients achieved complete, partial and no response, respectively, according to EULAR/ERA-EDTA. During a median follow-up of 10.7 (IQR: 4.97-18.80) years, 53 patients developed CKD. At 15 years, CKD-free survival rate was 95.2%, 87.6% and 55.4% in patients with complete, partial and no response at 12 months, respectively (p<0.0001). CKD-free survival rates did not differ between complete and partial responders (p=0.067). Serum creatinine (HR: 1.485, 95% CI 1.276 to 1.625), eGFR (HR 0.967, 95% CI 0.957 to 0.977) and proteinuria at 12 months (HR 1.234, 95% CI 1.111 to 1.379) were associated with CKD, yet no reliable cut-offs were identified on the receiver operating characteristic curve. In multivariable analysis, no EULAR/ERA-EDTA response at 12 months (HR 5.165, 95% CI 2.770 to 7.628), low C4 (HR 1.053, 95% CI 1.019 to 1.089) and persistent arterial hypertension (HR 3.154, 95% CI 1.500 to 4.547) independently predicted CKD.Conclusions: Lack of EULAR/ERA-EDTA response at 12 months predicts CKD. [ABSTRACT FROM AUTHOR]

Objective: Neutrophil extracellular traps (NET) expose modified antigens for autoantibodies in vasculitis. Little is known about levels and removal pathways of NET in systemic lupus erythematosus (SLE), especially in lupus nephritis (LN). We determined circulating levels and defined NET removal in large subsets of patients with incident SLE (iSLE), some of whom had new-onset nephritis.Methods: Serum levels of NET (ELISA), DNase1/DNase1L3 (ELISA), and DNase activity (functional assay) were determined in 216 patients with iSLE [103 had incident LN (iLN)], in 50 patients with other primary glomerulonephritis, and in healthy controls. Ex vivo NET production by neutrophils purified from a random selection of patients was quantified as elastase/DNA release and by immunofluorescence techniques.Results: Serum NET levels were very high in iSLE/iLN compared to all groups of controls and correlated with anti-dsDNA, C3-C4, and proteinuria; iLN had the highest levels. DNase activity was decreased in iLN compared to SLE (20% had one-half DNase activity) despite similar serum levels of DNase1/DNase1L3. In these cases, pretreatment of serum with protein A restored DNase efficiency; 1 patient was homozygous for a c.289_290delAC variant of DNASE1L3. Ex vivo NET production by neutrophils purified from LN, SLE, and normal controls was similar in all cases.Conclusion: Patients with iLN have increased circulating NET and reduced DNase activity, the latter being explained by the presence of inhibitory substances in circulation and/or by rare DNase1L3 mutations. Accumulation of NET derives from a multifactorial mechanism, and is associated and may contribute to disease severity in SLE, in particular to renal lesions. (Clinical trial registration: The Zeus study was registered at ClinicalTrials.gov, study number NCT02403115). [ABSTRACT FROM AUTHOR]

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis associated with asthma, anti-neutrophil cytoplasmic antibodies (ANCA) positivity, and tissue eosinophilia. Objective: To describe the presenting clinical features, significant biochemical alterations, and also potential pathogenic factors in adult patients diagnosed in our Center over a period of >20 years. Method: A retrospective study of EGPA patients diagnosed from 1994 to 2019 at ASST Grande Ospedale Metropolitano Niguarda Ca' Granda, Milan (Italy), which was performed according to the 1990 American College of Rheumatology criteria and Chapel Hill Consensus Conference definition. A dataset was compiled, registering demographic and clinical features, biochemical analysis at onset, and also the therapies received 3 months prior to EGPA diagnose. Statistical analyses were subsequently conducted dividing patients in 2 groups based on ANCA positivity and comparing them. Results: Two groups were clearly identified by ANCA serology and specific organ involvement in accordance with literature reports; however, our data underline for the first time the association between anti-leukotriene receptor antagonists (LTRAs) and ANCA positivity. The group of previously treated patients presents an OR of 6.42 to be ANCA positive. This finding could be attributed to an imbalanced stimulation of leukotriene receptors, inducing both mast cells activation and an increased neutrophil extracellular traps release from neutrophils. Conclusion: Despite the limitations of this retrospective study, the association between LTRAs and ANCA antibodies elucidates the mechanism by which innate immunity is directly involved in tolerance breakdown and autoantibodies production. Validation of our results with targeted studies could clarify the differences between ANCA-positive and ANCA-negative patients with important consequences on the use of some drug classes in the treatment of EGPA and asthmatic subjects. [ABSTRACT FROM AUTHOR]

The European Eosinophilic Granulomatosis with Polyangiitis (EGPA) study group first gathered in Firenze in December 2018. The discussion was centred around the clinical and therapeutic needs in EGPA which still remain unmet. Indeed, EGPA is a puzzling and rare disease which shares clinical features with other anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAVs) and hypereosinophilic syndromes (HESs). Some of the recommendations published in 2015 are based on data derived from EGPA-related diseases, rather than from EGPA itself, and therefore need to be updated. Thus, the aim of the meeting was to stimulate ongoing research, to promote collaborative European studies and to define the main issues on which future studies should be focused. Current fields of research on EGPA include potential serological biomarkers of disease activity and of specific organ involvement, possible links between different genetic variants and clinical phenotypes, and new therapeutic perspectives. Herein, we give an overview of the meeting with the goal to stimulate an international collaboration and new points of discussion. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate changes in demographic, clinical and histological presentation, and prognosis of lupus nephritis (LN) over time.Patients and Methods: We studied a multicentre cohort of 499 patients diagnosed with LN from 1970 to 2016. The 46-year follow-up was subdivided into three periods (P): P1 1970-1985, P2 1986-2001 and P3 2002-2016, and patients accordingly grouped based on the year of LN diagnosis. Predictors of patient and renal survival were investigated by univariate and multivariate proportional hazards Cox regression analyses. Survival curves were compared using the log-rank test.Results: A progressive increase in patient age at the time of LN diagnosis (p<0.0001) and a longer time between systemic lupus erythematosus onset and LN occurrence (p<0.0001) was observed from 1970 to 2016. During the same period, the frequency of renal insufficiency at the time of LN presentation progressively decreased (p<0.0001) and that of isolated urinary abnormalities increased (p<0.0001). No changes in histological class and activity index were observed, while chronicity index significantly decreased from 1970 to 2016 (p=0.023). Survival without end-stage renal disease (ESRD) was 87% in P1, 94% in P2% and 99% in P3 at 10 years, 80% in P1 and 90% in P2 at 20 years (p=0.0019). At multivariate analysis, male gender, arterial hypertension, absence of maintenance immunosuppressive therapy, increased serum creatinine, and high activity and chronicity index were independent predictors of ESRD.Conclusions: Clinical presentation of LN has become less severe in the last years, leading to a better long-term renal survival. [ABSTRACT FROM AUTHOR]

The wide employment of oral anticoagulants and the introduction of new anticoagulant agents highlight disparate kind of toxicities that can affect many different organ systems. Renal toxicity by oral anticoagulants is a well-known entity characterized by hematuria and the worsening of renal function associated with uncontrolled INR values. Although it is mainly a clinical diagnosis, renal biopsy may help especially in challenging cases when multiple comorbidities and underlying renal conditions exist. The mechanism of the anticoagulant-induced damage is still debated and special tissue stains (such as Perls’) could help in detecting the direct tubular toxicity induced by chronic glomerular bleeding. The employment of a diagnostic clinic-pathological flow-chart can help in the prompt detection and full characterization of these cases, improving the management of the patient. [ABSTRACT FROM AUTHOR]

Background. The optimal dosing and the efficacy of rituximab for primary membranous nephropathy (PMN) has not been established. This multicentric prospective study evaluates the efficacy and safety of low-dose rituximab (RTX) therapy in patients with PMN in clinical practice. Methods. Thirty-four consecutive patients with PMN and nephrotic syndrome were included and received RTX (375 mg/ m2) once (18 patients) or twice (16 patients). RTX was the firstline therapy for 19 (56%) and the second line for 15 (44%) patients. All patients were followed for 12 months after RTX and 24 for at least 18months (mean 23.9± 18.6 months). Results. At 12 months, 5 patients (14.7%) achieved complete response, 10 (29.4%) partial and 19 (55.8%) no response. Response occurred ~6 months after RTX. At 24 months, the clinical situation was unchanged: two non-responders achieved partial response and two responders relapsed. Responders had significantly higher baseline GFR and lower anti-PLA2R antibodies compared with non-responders. Outcome was similar between one or two doses of RTX (non-responders 55.5 versus 56%, respectively) and between patients who had received previous therapy versus those receiving RTX as first-line therapy (non-responders 40 versus 68%, respectively). In the 15 patients already treated, the response to RTX was comparable to that of previous therapies. Conclusion. Low-dose RTX obtains remission in <50% of PMN patients. Probably, higher doses and longer treatments are needed to induce andmaintain a response. The balance between the costs and benefits should guide the selection of the patient and the optimal dosage. [ABSTRACT FROM AUTHOR]

Background: The association of anti-C1q antibodies (anti- C1q) with the renal activity of lupus nephritis (LN) and the methods for their determination is still a matter of debate. Methods: In 116 serum samples of 66 patients with biopsy proven LN, we aimed: 1) to compare the results of the determination of anti-C1q obtained by a commercial kit with a clinically validated in-house ELISA; 2) to evaluate the correlation of anti-C1q with the most important immunological and clinical parameters employed in LN, i.e., antibodies to dsDNA (anti-dsDNA), C3 and C4 complement component, haemoglobin and haematuria. Results: Good correlation and agreement between the two methods (r = 0.81, p < 0.0001; contingency coefficient = 0.70, p < 0.0001, respectively) were demonstrated. No differences were observed between the two assays by ROC curves comparison. Anti-C1q levels were significantly higher in patients with active LN [44 arbitrary units (AUs)] in comparison to those with inactive LN (23 AUs, p = 0.047) and significantly correlated with anti-dsDNA (r = 0.44, p < 0.0001), complement fractions (C3: r = -0.33, p = 0.001; C4: r = -0.29, p = 0.003), haemoglobin levels (r = -0.34, p = 0.0004) and the number of urinary red blood cells (r = 0.26, p = 0.01). Conclusions: Our results suggest the validity of this commercial assay in detecting anti-C1q and confirm the association of anti-C1q with renal involvement of LN and the importance of introducing this parameter in the analytical panel for the evaluation of LN activity. [ABSTRACT FROM AUTHOR]

Few studies have correlated serum biomarkers with renal histology, the gold standard for renal activity, in lupus nephritis (LN). We tested a panel of autoantibodies and complement at the time of kidney biopsy and after treatment. Anti-dsDNA, anti-nucleosome, anti-ribosome P, and anti-C1q antibodies and C3/C4 were measured in 107 patients with LN at the time of renal biopsy and after 6–12 months and were correlated with clinical/histological parameters. At multivariate analysis, high titers of anti-C1q antibodies or of anti-dsDNA antibodies (P=0.005, OR = 8.67, CI: 2.03–37.3) were the independent predictors that discriminate proliferative from nonproliferative LN. All the immunological parameters, except anti-ribosome, showed a significant correlation with activity index but not with chronicity index. Only anti-C1q showed a significant correlation with the amount of proteinuria (R=0.2, P=0.03). None of the immunological parameters were predictive of remission at 6 and 12 months. We found that anti-C1q alone or in combination with anti-dsDNA emerged as the most reliable test in differentiating proliferative and nonproliferative LN. Anti-C1q was the only test correlated with the clinical presentation of LN. After treatment, the titre of the autoantibodies was significantly reduced, but none was predictive of remission. [ABSTRACT FROM AUTHOR]

In this study we assess the presence of antibodies against infectious agents as well as for a variety of autoantibodies in an attempt to establish associations between various vasculitides and infections in order to shed light on the etiopathogenesis of these diseases and perhaps implicate a potential cure. Sera from patients with Wegener's granulomatosis (WG), polyarteritis nodosa, microscopic polyangiitis, Churg Strauss, and giant cell arteritis were compared to healthy control sera. Serum samples were assessed, using the Bio-Rad BioPlex 2200, for the presence of Toxoplama gondii, cytomegalovirus (CMV), Epstein–Barr virus (EBV), Treponema pallidum, and Saccharomyces cerevisiae. Hepatitis B virus (HBV), hepatitis C virus (HCV), and anti- Helicobacter pylori antibodies were assessed by ELISA. In addition, sera were tested for a panel of antibodies associated with thrombophilia as well as various autoantibodies. The prevalence of antibodies toward HCV and H. pylori was significantly higher among patients with WG. IgG antibodies toward T. gondii and IgM antibodies toward CMV were significantly more common among WG patients than among controls. WG patients exhibited more antibodies toward EBV viral capsid antigen IgG and EBV early antigen IgG compared to sera from healthy controls. In WG, positive associations were disclosed between CMV IgG antibodies and the presence of gastrointestinal manifestations and renal involvement, and there was a higher Birmingham vasculitis activity score in association with elevated titers of EBV viral capsid antigen IgG antibodies. Otorhinolaryngeal manifestations were more common in those with positive IgG antibodies for EBV early antigen. Our results unveil novel associations between WG and various infectious agents, including HCV, H. pylori, T. gondii, CMV, and EBV. In addition to putative roles in initiation and exacerbation of the vasculitic process, it seems that these infectious agents also modulate the clinical phenotype of the disease. [ABSTRACT FROM AUTHOR]

Anti-C1q antibodies are found in a variety of diseases, in addition to systemic lupus erythematosus (SLE), and in 3–5% of normal individuals. In particular, anti-C1q antibodies are detected at a high titer in 100% of patients with hypocomplementemic urticarial vasculitis and in 30–48% of SLE patients. Their titer correlates with active renal disease with a sensitivity of 44–100% and a specificity of 70–92%. An increase in anti-C1q antibody titer has been suggested to be able to predict renal flares in lupus nephritis so that monitoring anti-C1q might be valuable for the clinical management of SLE patients as a noninvasive biological marker. Recently our group studied 228 patients affected by lupus nephritis and found that the association of anti-C1q, C3, and C4, in a multivariate analysis, provided the best prediction of renal flares, particularly in patients with focal and diffuse proliferative lupus nephritis and in the absence of antiphospholipid antibodies. [ABSTRACT FROM AUTHOR]

The complement (C') cascade is an important part of the innate immunity. It acts through three major pathways: classical (CP), alternative (AP) and mannose-binding-lectin (MP). C' reduction is a key feature in systemic lupus erythematosus (SLE), for its pathogenesis and for disease relapse. The aims of our study are to correlate C' variations with disease activity and verify the presence of C' deficiencies. We tested for three C' pathways 52 sera from 20 patients affected by SLE. A significant correlation between the ECLAM score and the degree of activation of the CP (Mann-Whitney; P= 0.001) was recorded, while the correlation with anti-dsDNA antibodies did not reach statistical significance (Mann-Whitney; P > 0.05). In conclusion, the ELISA assay can be considered well suited for testing SLE samples. We detected a significant link between the phases of lupus activity and the reduction of the CP. [ABSTRACT FROM AUTHOR]

The detection and measurement of antibodies to double-stranded (ds) DNA is important in the diagnosis and monitoring of patients with systemic lupus erythematosus (SLE). Several methods are available for their determination but none of them is completely satisfactory. Usually, purified dsDNA from different sources is used as antigen in the solid (enzyme-linked immunosorbent assay, ELISA) or liquid phase (Farr assay). Alternatively, anti-dsDNA antibodies can be demonstrated by immunofluorescence, using the haemoflagellate Crithidia luciliae (CLIFT). We have developed a new oligonucleotide-based anti-dsDNA ELISA in which dsDNA, constituted of a 5′photobiotinylated nucleic acid probe and its highly specific complementary oligonucleotide, is formed onto the solid-phase. To do that, a 40 bp probe is coated on the microplate wells via streptavidin–biotin bond and the in vitro (in solid-phase) developed hybrid between probe and its complementary helix used as capturing antigen. The assay has proved to be specific and the several experiments performed to ascertain the absence of single-stranded DNA (ssDNA) contamination and/or non specific binding to plastic, streptavidin, probe (without complementary chain) have all excluded any significant interference. To evaluate the clinical performance of this new assay, 114 serum samples from 68 SLE patients and 85 samples from 85 disease controls, in addition to 30 blood donors, were studied. The results were compared with commercial ELISAs, Farr assay and indirect immunofluorescence. The sensitivity and specificity were 66.2 and 96.4%, respectively, comparable and even better than those of the commercially available anti-dsDNA kits. Anti-dsDNA antibody levels, measured with the oligonucleotide–ELISA, correlated with SLE clinical activity determined using the European Consensus Lupus Activity Measurement (ECLAM) ( r = 0.59, p < 0.0001). In conclusion, this assay has proved to be reproducible, and the results correlate well with other standard anti-dsDNA assays. The features of this new assay make it promising for clinical use. [ABSTRACT FROM AUTHOR]

Recently, anti-C1q autoantibodies have been proposed as a useful marker in systemic lupus erythematosus (SLE) since their occurrence correlates with renal involvement and, possibly, with nephritic activity. We aimed to evaluate the prevalence of anti-C1q antibodies in patients with SLE, with and without renal involvement, and to correlate these markers' presence and levels with the activity of the disease and nephropathy. We studied 61 patients with SLE, 40 of whom had biopsy-proven lupus nephritis; 35 patients with other connective tissue diseases; and 54 healthy controls. In addition, 18 lupus nephritis patients were followed up during the disease time course. Anti-C1q antibodies were measured using "homemade" ELISA with high salt concentration (1 M sodium chloride). High anti-C1q antibody titers (> 55 AU) were present in 27 of 61 (44%) SLE patients and in 4% and 0% of normal blood donors and pathologic controls, respectively. Anti-C1q antibodies were found in 60% of patients with lupus nephritis compared with only 14% of SLE patients without nephropathy (P < 0.05). Moreover, patients who were positive for anti-C1q antibodies had a higher European Consensus Lupus Activity Measurement (ECLAM) score (4.35 vs. 2.2); 89% of patients with active lupus nephritis showed high titers of anti-C1q antibodies compared with 0% of patients with inactive nephritis. Anti-C1q and anti-dsDNA antibodies agreed in 79% of cases. Our results confirm that anti-C1q antibodies are present in a significant percentage of SLE patients, and that their presence and levels correlate with disease activity—in particular, during renal flare-ups. [ABSTRACT FROM AUTHOR]

The value of anti-neutrophil cytoplasmic antibody (ANCA) detection for monitoring disease activity in ANCA-associated systemic vasculitis (AASV) remains controversial. The aim of our work was to rate the performance of a new automated fluorescence PR3 and MPO-ANCA immunoassay (EliA) for monitoring disease activity in AASV. We evaluated 100 serum samples from 71 AASV patients (with Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome) as well as sera from 58 pathological and 35 normal controls. In addition to PR3 and MPO-ANCA EliA, we performed indirect immunofluorescence and "homemade" PR3 and MPO-ANCA ELISA tests. In AASV patients, ANCA levels were correlated with disease activity, according to the Birmingham Vasculitis Activity Score (BVAS). We derived cutoff limits from receiver operating characteristic (ROC) curve analysis comparing AASV with pathological controls. Our results showed that EliA and ELISA had comparable sensitivity (76%) and specificity (95%). The analysis of active versus inactive status and correlation with ANCA levels showed a clear difference between BVAS Group I (score ≤ 4) and BVAS Group II (scores > 4) (AUC = 0.86 vs. 0.72; relative risk [RR] = 2.4; P < 0.0001) for PR3-ANCA, but not for MPO-ANCA (AUC = 0.94 vs. 0.87; RR = 1.48; P = 0.46). Serial serum samples from 16 patients were examined in detail. For the majority of patients, for both PR3 and MPO-ANCA, change in titer was strongly associated with change in BVAS score. Our data showed a good correlation between ANCA titer (especially for PR3) and AASV disease activity. We recommend that ANCA titer be used to monitor AASV disease activity with the caveat that a few exceptions, in particular with MPO-ANCA, are possible. [ABSTRACT FROM AUTHOR]