A specific diagnostic metabolome signature in adult IgA vasculitis.

INTRODUCTION: IgA vasculitis diagnosis relies primarily on clinical features and is confirmed by pathological findings. To date, there is no reliable noninvasive diagnostic biomarker. OBJECTIVE: We aimed to explore the baseline serum metabolome of adult patients with IgA vasculitis to identify potential diagnostic biomarkers. METHODS: We performed a study comparing the serum metabolome of patients with IgA vasculitis to that of patients with inflammatory condition, namely spondyloarthritis. Serum analyses were performed by high-performance liquid chromatography-mass spectrometry. RESULTS: Fifty-five patients with IgA vasculitis and 77 controls with spondyloarthritis (age- and sex-matched) were included in this study. The median age of IgA vasculitis patients was 53 years. Two-thirds of patients were female (n = 32). At the time of vasculitis diagnosis, 100% of patients had skin involvement and 69% presented with glomerulonephritis (n = 38). Joint and digestive involvement were observed in 56% (n = 31) and 42% (n = 23) of patients. Four discriminative metabolites between the two groups were identified: 1-methyladenosine, L-glutamic acid, serotonin, and thymidine. The multivariate model built from the serum metabolomes of patients with IgA vasculitis and spondyloarthritis revealed an accuracy > 90%. As this model was significant according to the permutation test (p < 0.01), independent validation showed an excellent predictive value of the test set: sensitivity 98%; specificity 98%, positive predictive value 97% and negative predictive value 98%. CONCLUSION: To our knowledge, this study is the first to use the metabolomic approach for diagnostic purposes in adult IgA vasculitis, highlighting a specific diagnostic metabolome signature.

Impact of gender on baseline presentation and outcome in adult IgA vasculitis.

OBJECTIVES: Adult IgA vasculitis (IgAV) is more common in males, but the potential impact of gender remains unclear. We aimed to describe the impact of gender on presentation and outcome in adult IgAV. METHODS: We retrospectively analysed data from a multicentre retrospective cohort of 260 patients (IGAVAS). Comparisons were made according to gender status. RESULTS: Data from 259 patients (95 females and 164 males) were analysed. Compared with females, baseline presentation in males was similar for cutaneous involvement (100% vs 100%, p= 1.0), joint involvement (60% vs 63%, p= 0.7), gastrointestinal involvement (57% vs 45%, p= 0.093) and glomerulonephritis (73% vs 64%, p= 0.16). Glomerulonephritis was more severe at baseline in males than in females, with a lower median estimated glomerular filtration rate (eGFR) (90 [IQR 59-105] vs 97 ml/min/1.73m2 [76-116], p= 0.015) and increased median proteinuria (0.84 vs 0.58 g/day, p= 0.01). There were no differences in histological findings in patients who had a kidney biopsy. Methylprednisolone was more frequently used in males (40% vs22%, p= 0.015), as were immunosuppressants, especially cyclophosphamide 24% vs 6%, p= 0.0025) and azathioprine (10% vs 2%, p= 0.038). Analysis of treatment response showed that males had more frequent refractory disease (30% vs 13%, p= 0.004). Long-term outcomes (mortality and progression to chronic kidney failure) did not differ. CONCLUSION: Kidney involvement in IgAV appears to more severe in males, which is supported by more intensive treatment contrasting with a lower response rate. This study raises the question of gender as a new prognostic factor in adult IgAV.

New insights into epidemiological data and impact of the COVID-19 pandemic on IgA vasculitis in children and adults: a French nationwide cohort.

IgA vasculitis (IgAV) is a small size vasculitis for which epidemiologic data are strikingly lacking, especially about the adult form. Additionally, the COVID-19 pandemic seems to have profoundly modified the incidence of this disease. Here, we aimed to establish some relevant epidemiological data in both pediatric and adult IgAV. We performed an observational study using a national database called "BNDMR" on IgAV, which gathers patients managed in the French network of experts on rare diseases. We primarily performed descriptive statistics over the 2010-2022 period. Then, we compared the North-South geographical areas, the seasonality, and the impact of COVID-19 with that of other patients reported in the same centers. We collected data from 1988 IgAV patients. The sex ratio was 1.57 for adults and 1.05 for children. The annual incidence in 2021 was 0.06 for 100,000 adults and 0.50 for 100,000 children. Compared with other diseases reported into the BNDMR, IgAV was more common in the South than in the North of France (OR 4.88 [4.17-5.74] in adults and OR 1.51 [1.35-1.68] in children). IgAV was also observed more frequently in winter and autumn. Strikingly, we observed a decrease in incidence during the COVID-19 pandemic period in children (OR 0.62 [0.47-0.81]). Our study provides both new insights and confirmations of IgAV epidemiological data: winter and autumn seasonality, more pronounced male predominance in adults, decreasing incidence of pediatric IgAV during the COVID-19 pandemic and increasing incidence in the South of France.

Monoclonal Antibody Engineering and Design to Modulate FcRn Activities: A Comprehensive Review.

Understanding the biological mechanisms underlying the pH-dependent nature of FcRn binding, as well as the various factors influencing the affinity to FcRn, was concurrent with the arrival of the first recombinant IgG monoclonal antibodies (mAbs) and IgG Fc-fusion proteins in clinical practice. IgG Fc-FcRn became a central subject of interest for the development of these drugs for the comfort of patients and good clinical responses. In this review, we describe (i) mAb mutations close to and outside the FcRn binding site, increasing the affinity for FcRn at acidic pH and leading to enhanced mAb half-life and biodistribution, and (ii) mAb mutations increasing the affinity for FcRn at acidic and neutral pH, blocking FcRn binding and resulting, in vivo, in endogenous IgG degradation. Mutations modifying FcRn binding are discussed in association with pH-dependent modulation of antigen binding and (iii) anti-FcRn mAbs, two of the latest innovations in anti-FcRn mAbs leading to endogenous IgG depletion. We discuss the pharmacological effects, the biological consequences, and advantages of targeting IgG-FcRn interactions and their application in human therapeutics.

COVID-19 Vaccination as a Trigger of IgA Vasculitis: A Global Pharmacovigilance Study.

OBJECTIVE: IgA vasculitis (IgAV) can occur after vaccination. We aimed to assess a potential safety signal on the association between coronavirus disease 2019 (COVID-19) vaccines and IgAV. METHODS: Cases of IgAV involving COVID-19 vaccines were retrieved in VigiBase. Disproportionate reporting was assessed using the Bayesian information component (IC) with all other drugs and vaccines as control groups. RESULTS: Three hundred thirty patients with de novo IgAV from 24 countries were included, mostly from the United States (193/330, 58%). Fifty percent (163/328) were female and median age was 32 years (IQR 15-59), of which 33% (84/254) were young (1-17 yrs). Median time to onset of IgAV was 7 days (IQR 2-16; n = 256) and 85% (280/330) of patients were vaccinated with mRNA vaccines. Seriousness was reported in 188/324 (58%) cases. Sixty-five percent (95/147) recovered and 1% (2/147) died. A positive rechallenge was reported for 3 of 4 patients (75%). A total of 996 cases of IgAV were identified with other vaccines. There was a small significant increase in IgAV reporting with COVID-19 vaccines compared with all other drugs (IC 0.22, 95% credible interval [CrI] 0.04 to 0.35). No disproportionality signal was found between COVID-19 vaccines and other vaccines (IC -1.42, 95% CrI -1.60 to -1.28). There was no significant difference between mRNA vaccines and viral vector COVID-19 vaccines. Men and children had a significant overreporting of IgAV compared with women and adults, respectively. CONCLUSION: This study provides reassuring results regarding the safety of COVID-19 vaccines in the occurrence of IgAV compared to other vaccines.

Towards better indications for kidney biopsy in adult IgA vasculitis: a clinical-laboratory and pathology correlation study.

BACKGROUND: Indications for kidney biopsy in adult IgA vasculitis (IgAV) remain debated and there are very few studies on this subject. The aim of this study was to establish a correlation between renal histological and clinical-laboratory data. METHODS: A retrospective multicenter study was conducted using three databases from French hospitals, gathered between 1977 and 2020. The study included 294 adult patients with IgAV who had undergone kidney biopsy assessed according to the prognostic "Pillebout classification". Different statistical models were used to test the correlations between histological and clinical-laboratory data: Cochran Armitage, ANOVA, Kruskal-Wallis and logistic regression. RESULTS: The patients were primarily men (64%), with a mean age of 52 years. The main organs and tissues involved were: dermatological 100%, digestive 48% and rheumatological 61%. All had features of kidney involvement. The median serum creatinine was 96 µmol/L serum albumin 35 g/L, and C-reactive protein 28 mg/L. Of the patients, 86% (n = 254) had hematuria and median proteinuria was 1.8 g/day. The only statistically significant correlation between the pathological stages and the clinical-laboratory data was the presence of hematuria (p = 0.03, 66% class I to 92% class IV). In multivariate analysis, only albuminemia was associated with extracapillary proliferation (p = 0.02; OR 0.94) and only age was associated with stages 3-4 (p = 0.03; OR 1.02). CONCLUSION: Our study suggests that there is no strict baseline correlation between renal pathology and clinical-laboratory data. Given the current knowledge, it seems relevant to recommend a kidney biopsy in the presence of significant and persistent proteinuria or unexplained kidney function decline.

IgA Vasculitis Following COVID-19 Vaccination: A French Multicenter Case Series Including 12 Patients.

OBJECTIVE: The worldwide coronavirus disease 2019 (COVID-19) vaccination campaign triggered several autoimmune diseases. We hereby aimed to describe IgA vasculitis (IgAV) following COVID-19 vaccination. METHODS: We conducted a national, multicenter, retrospective study in France of new-onset adult IgAV diagnosis following COVID-19 vaccination. RESULTS: In total, 12 patients with new-onset IgAV were included. Of these, 5 (41.7%) were women, and the median age was 52.5 (IQR 30.75-60.5) years. Of the 12 patients, 10 had received an mRNA vaccine and 2 had received a viral vector vaccine. The median time from vaccination to onset of symptoms was 11.5 (IQR 4.25-21.25) days. Vasculitis occurred after the first vaccine dose in most patients (n = 8). All patients had skin involvement, with skin necrosis in 4 patients. In total, 7 patients had joint involvement and 2 had arthritis. A total of 4 patients had nonsevere gastrointestinal involvement and 2 had nonsevere renal involvement. The median C-reactive protein level was 26 (IQR 10-66.75) mg/L, the median creatininemia level was 72 (IQR 65-81) µmol/L, and 1 patient had an estimated glomerular filtration rate of less than 60 mL/min at management. All patients received treatment, including 9 patients (75%) who received glucocorticoids. In total, 5 patients received a vaccine dose after developing IgAV, 1 of whom experienced a minor cutaneous relapse. CONCLUSION: The baseline presentation of IgAV following COVID-19 vaccination was mild to moderate, and outcomes were favorable. Thus, a complete COVID-19 vaccination regimen should be completed in this population. Of note, a fortuitous link cannot be ruled out, requiring a worldwide pharmacovigilance search to confirm these findings.

Immunoglobulin A Vasculitis Following COVID-19: A French Multicenter Case Series.

OBJECTIVE: Immunoglobulin A vasculitis (IgAV) usually occurs following viral respiratory tract infection. In the context of the global coronavirus disease 2019 (COVID-19) pandemic, we describe a case series of patients who developed IgAV following SARS-CoV-2 infection. METHODS: This national multicenter retrospective study included patients with IgAV following SARS-CoV-2 infection from January 1, 2020, to January 1, 2022. Patients had histologically proven IgAV and reverse transcription PCR (RT-PCR)-proven SARS-CoV-2 infection. The interval between infection and vasculitis onset had to be < 4 weeks. RESULTS: We included 5 patients, 4 of whom were women with a mean age of 45 years. Four patients had paucisymptomatic infections and 1 required a 48-hour low-flow oxygen treatment. All 5 patients had purpuric skin involvement. Arthritis was observed in 2 patients, 3 had IgA glomerulonephritis, and 2 had digestive involvement. Three renal biopsies were performed and showed mesangial IgA deposits without any extracapillary proliferation. Median C-reactive protein was 180 (range 15.1-225) mg/L, median serum creatinine level was 65 (range 41-169) µmol/L, and 2 patients had a glomerular filtration rate < 60 mL/min. Four patients received first-line treatment with glucocorticoids. All patients had a favorable progression and 2 patients experienced minor skin relapses, one after COVID-19 vaccination. CONCLUSION: This series describes the emergence of IgAV closely following COVID-19; we were not able to eliminate an incidental link between these events. Their disease outcomes were favorable. In most of our patients, the SARS-CoV-2 infection was paucisymptomatic, and we recommend RT-PCR tests to look for COVID-19 in patients without any evident triggers for IgAV.

"Ways in which the neonatal Fc-receptor is involved in autoimmunity".

Since the neonatal IgG Fc receptor (FcRn) was discovered, its role has evolved from immunoglobulin recycling and biodistribution to antigen presentation and immune complex routing, bringing it to the center of both humoral and cellular immune responses. FcRn is thus involved in the pathophysiology of immune-related diseases such as cancer, infection, and autoimmune disorders. This review focuses on the role of FcRn in autoimmunity, based on the available data from both animal models and human studies. The knowledge concerning ways in which FcRn is involved in autoimmune response has led to the development of inhibitors for the treatment of autoimmune diseases, also described here. Up to date, the literature remains scarce, shedding light on the need for further studies to fully understand the various pathophysiological roles of this unique receptor.