Iron boosts anti-tumor type 1 T-cell responses and anti-PD1 immunotherapy.

Cancers only develop if they escape immunosurveillance, and the success of cancer immunotherapies relies in most cases on their ability to restore effector T-cell functions, particularly IFN-γ production. Revolutionizing the treatment of many cancers, immunotherapies targeting immune checkpoints such as PD1 can increase survival and cure patients. Unfortunately, although immunotherapy has greatly improved the prognosis of patients, not all respond to anti-PD1 immunotherapy, making it crucial to identify alternative treatments that could be combined with current immunotherapies to improve their effectiveness. Here, we show that iron supplementation significantly boosts T-cell responses in vivo and in vitro. This boost is associated with a metabolic reprogramming of T cells in favor of lipid oxidation. We also found that the "adjuvant" effect of iron led to a marked slowdown of tumor-cell growth after tumor-cell line transplantation in mice. Specifically, our results suggest that iron supplementation promotes anti-tumor responses by increasing IFN-γ production by T cells. In addition, iron supplementation considerably improves the efficacy of anti-PD1 cancer immunotherapy in mice. Finally, our study suggests that, in cancer patients, the quality and efficacy of the anti-tumor response following anti-PD1 immunotherapy may be modulated by plasma ferritin levels. In summary, our results suggest the benefits of iron supplementation on the reactivation of anti-tumor responses and support the relevance of a fruitful association between immunotherapy and iron supplementation.

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.

No evidence for systemic low-grade inflammation in adult patients with early-treated phenylketonuria: The INGRAPH study.

The question of an increased cardiovascular risk has been recently raised in adults with phenylketonuria (PKU). As low-grade systemic inflammation increases cardiovascular risk, the INGRAPH study aimed to evaluate low-grade inflammation in adult PKU patients compared to healthy controls and to determine the potential influence of Phe-controlled diet on inflammation. Twenty early-treated adult PKU patients, including a subgroup of 15 classical PKU patients, and 20 healthy volunteers were included. PKU patients and healthy subjects were matched on age, sex and body mass index class. Plasma concentrations of CRP, IFNg, IL1a, IL1b, IL2, IL6, IL10, and TNFα were measured in PKU patients and compared to controls. Plasma CRP was not different in the PKU group as compared to controls. No significant differences were observed between the two groups concerning plasma cytokines concentrations. Plasma CRP and cytokine profile were not different between "on diet" and "off diet" PKU patients. All these results were similar considering only the classical PKU subgroup. No differences were shown in plasma CRP and pro-inflammatory cytokines between adult PKU patients and healthy controls. Further studies are needed, including more patients and extensive characterization of systemic low-grade inflammation, as cardiovascular risk appears to be a new concern in adult PKU population.

Joint manifestations revealing inborn metabolic diseases in adults: a narrative review.

Inborn metabolic diseases (IMD) are rare conditions that can be diagnosed during adulthood. Patients with IMD may have joint symptoms and the challenge is to establish an early diagnosis in order to institute appropriate treatment and prevent irreversible damage. This review describes the joint manifestations of IMD that may be encountered in adults. The clinical settings considered were arthralgia and joint stiffness as well as arthritis. Unspecific arthralgias are often the first symptoms of hereditary hemochromatosis, chronic low back pain may reveal an intervertebral disc calcification in relation with alkaptonuria, and progressive joint stiffness may correspond to a mucopolysaccharidosis or mucolipidosis. Gaucher disease is initially revealed by painful acute attacks mimicking joint pain described as "bone crises". Some IMD may induce microcrystalline arthropathy. Beyond classical gout, there are also gouts in connection with purine metabolism disorders known as "enzymopathic gouts". Pyrophosphate arthropathy can also be part of the clinical spectrum of Gitelman syndrome or hypophosphatasia. Oxalate crystals arthritis can reveal a primary hyperoxaluria. Destructive arthritis may be indicative of Wilson's disease. Non-destructive arthritis may be seen in mevalonate kinase deficiency and familial hypercholesterolemia.

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.

Intravenous versus subcutaneous tocilizumab in Takayasu arteritis: multicentre retrospective study.

OBJECTIVES: In this large multicentre study, we compared the effectiveness and safety of tocilizumab intravenous versus subcutaneous (SC) in 109 Takayasu arteritis (TAK) patients. METHODS: We conducted a retrospective multicentre study in referral centres from France, Italy, Spain, Armenia, Israel, Japan, Tunisia and Russia regarding biological-targeted therapies in TAK, since January 2017 to September 2019. RESULTS: A total of 109 TAK patients received at least 3 months tocilizumab therapy and were included in this study. Among them, 91 and 18 patients received intravenous and SC tocilizumab, respectively. A complete response (NIH <2 with less than 7.5 mg/day of prednisone) at 6 months was evidenced in 69% of TAK patients, of whom 57 (70%) and 11 (69%) patients were on intravenous and SC tocilizumab, respectively (p=0.95). The factors associated with complete response to tocilizumab at 6 months in multivariate analysis, only age <30 years (OR 2.85, 95% CI 1.14 to 7.12; p=0.027) and time between TAK diagnosis and tocilizumab initiation (OR 1.18, 95% CI 1.02 to 1.36; p=0.034). During the median follow-up of 30.1 months (0.4; 105.8) and 10.8 (0.1; 46.4) (p<0.0001) in patients who received tocilizumab in intravenous and SC forms, respectively, the risk of relapse was significantly higher in TAK patients on SC tocilizumab (HR=2.55, 95% CI 1.08 to 6.02; p=0.033). The overall cumulative incidence of relapse at 12 months in TAK patients was at 13.7% (95% CI 7.6% to 21.5%), with 10.3% (95% CI 4.8% to 18.4%) for those on intravenous tocilizumab vs 30.9% (95% CI 10.5% to 54.2%) for patients receiving SC tocilizumab. Adverse events occurred in 14 (15%) patients on intravenous route and in 2 (11%) on SC tocilizumab. CONCLUSION: In this study, we confirm that tocilizumab is effective in TAK, with complete remission being achieving by 70% of disease-modifying antirheumatic drugs-refractory TAK patients at 6 months.

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.

Adverse effect of Pneumocystis Jirovecii infection associated with rituximab therapy for autoimmune disease are more frequently reported in older vs. younger patient.

INTRODUCTION: Rituximab is a chimeric anti-CD20 antibody commonly used to treat patients with autoimmune diseases. Such diseases mainly affect young people, but older patients may also be concerned. So far, very little data exist concerning the safety of rituximab in older patients with autoimmune diseases. METHODS: This study was intended to describe the adverse reaction profile of rituximab in patients over 75 years of age treated for autoimmune diseases and to compare such profile to those observed in patients below 75 years of age. Adverse reactions related to rituximab were reported to the French Pharmacovigilance Network. From such reports, a descriptive analysis as well as a disproportionality analysis were performed to identify safety signals. RESULTS: 1096 reports of rituximab-related adverse reactions reported in France between 2006 and 2019, were included in the study, such as 127 in the older group (>75 years) and 969 in the younger group (<75 years). Infusion reactions were less frequently reported than other adverse drug reaction in older patients (11 vs. 27%, P<0.001). By contrast, a higher rate of opportunistic infection due to Pneumocystis jirovecii was reported in the older subject group (3.9 vs. 0.6%, P<0.001), along with neutropenia (22.8 vs. 9.3%, P<0.0001). These results were confirmed by the disproportionality analysis. CONCLUSION: Pneumocystis jirovecii infection was significatively more reported in older patients treated by Rituximab which probably reflects a higher incidence in this population. The use of anti-pneumocystis prophylaxis should be considered in this population.

Pleuropulmonary Manifestations of Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic (VEXAS) Syndrome.

BACKGROUND: The vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a newly identified autoinflammatory disorder related to somatic UBA1 mutations. Up to 72% of patients may show lung involvement. RESEARCH QUESTION: What are the pleuropulmonary manifestations in VEXAS syndrome? STUDY DESIGN AND METHODS: One hundred fourteen patients were included in the French cohort of VEXAS syndrome between November 2020 and May 2021. Each patient included in the study who had an available chest CT scan was discussed in an adjudication multidisciplinary team and classified as showing potentially pleuropulmonary-specific involvement of VEXAS syndrome or others. RESULTS: Fifty-one patients had a CT scan available for review and 45 patients (39%) showed pleuropulmonary abnormalities on chest CT scan that were considered related to VEXAS syndrome after adjudication. Most patients were men (95%) with a median age 67.0 years at the onset of symptoms. Among these 45 patients, 44% reported dyspnea and 40% reported cough. All 45 patients showed lung opacities on chest CT scan (including ground-glass opacities [87%], consolidations [49%], reticulation [38%], and septal lines [51%]) and 53% of patients showed pleural effusion. Most patients showed improvement with prednisone, but usually required > 20 mg/d. The main clinical and biological features as well the median survival did not differ between the 45 patients with pleuropulmonary involvement and the rest of the cohort, suggesting that the prevalence of pleuropulmonary involvement might have been underdiagnosed in the rest of the cohort. INTERPRETATION: Pulmonary manifestations are frequent in VEXAS syndrome, but rarely are at the forefront. The initial outcome is favorable with prednisone and does not seem to lead to pulmonary fibrosis.

The diagnostic challenge of patients with anti-U1-RNP antibodies.

Anti-U1-RNP antibodies are necessary for the diagnosis of mixed connective tissue disease (MCTD), but they are also prevalent in other connective tissue diseases, especially systemic lupus erythematosus (SLE), from which distinction remains challenging. We aimed to describe the presentation and outcome of patients with anti-U1-RNP antibodies and to identify factors to distinguish MCTD from SLE. We retrospectively applied the criteria sets for MCTD, SLE, systemic sclerosis (SSc) and rheumatoid arthritis (RA) to all patients displaying anti-U1-RNP antibodies in the hospital of Caen from 2000 to 2020. Thirty-six patients were included in the analysis. Eighteen patients (50%) satisfied at least one of the MCTD classifications, 11 of whom (61%) also met 2019 ACR/EULAR criteria for SLE. Twelve other patients only met SLE without MCTD criteria, and a total of 23 patients (64%) met SLE criteria. The most frequent manifestations included Raynaud's phenomenon (RP, 91%) and arthralgia (67%). We compared the characteristics of patients meeting only the MCTD (n = 7), SLE (n = 12), or both (n = 11) criteria. Patients meeting the MCTD criteria were more likely to display SSc features, including sclerodactyly (p < 0.01), swollen hands (p < 0.01), RP (p = 0.04) and esophageal reflux (p < 0.01). The presence of scleroderma features (swollen hands, sclerodactyly, gastro-oesophageal reflux), was significantly associated with the diagnosis of MCTD. Conversely, the absence of those manifestations suggested the diagnosis of another definite connective tissue disease, especially SLE.

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.

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.

[Adult IgA vasculitis]. / Vascularite à IgA de l'adulte.

ADULT IGA VASCULITIS. IgA vasculitis previously named rheumatoid purpura is a rare systemic vasculitis in adults involving small vessels and associated with the presence of immunoglobulin A deposits. IgA vasculitis is often triggerd by infections, taking medication and vaccination. It is characterised by the presence of vascular purpura associated with joint (arthralgia), gastrointestinal (abdominal pain) and sometimes renal involvement (glomerulonephritis). Gastrointestinal involvement can be lifethreatening (bowel perforation), while the longterm prognosis is shaped by the renal involvement (renal failure). In most cases, the disease has a good outcome and only symptomatic treatment is recommended. In more severe forms, corticosteroids, combined with another immunosuppressant or biotherapy, may be discussed on a casebycase basis.

VASCULARITE À IGA DE L'ADULTE. La vascularite à IgA, anciennement appelée purpura rhumatoïde, est une vascularite systémique liée à la présence de dépôts d'immunoglobulines A dans les vaisseaux de petit calibre. Elle fait souvent suite à un facteur déclenchant, comme une infection du tractus respiratoire, la prise d'un médicament ou une vaccination. Elle est caractérisée par la présence d'un purpura vasculaire associé à une atteinte articulaire (arthralgies typiquement des chevilles), gastrointestinale (douleurs abdominales) et parfois rénale (glomérulonéphrite). Le pronostic vital peut être engagé par l'atteinte gastrointestinale (risque de perforation digestive), alors que le pronostic à long terme est lié à l'atteinte rénale (risque d'insuffisance rénale chronique). La maladie évolue généralement favorablement, et seul un traitement symptomatique est conseillé. Dans les formes plus sévères, des corticostéroïdes, associés à un immunosuppresseur ou une biothérapie, peuvent être discutés au cas par cas.

Disease patterns and specific trajectories of anti-MDA5-related disease: a multicentre retrospective study of 70 adult patients.

Introduction: This study aimed to provide an updated analysis of the different prognostic trajectories of patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibodies. Methods: Among a cohort of 70 patients, baseline characteristics and phenotypes, treatments and outcomes were analyzed. A Cox proportional hazards model was used to identify factors associated with poor outcomes, i.e., death or progressive disease at the last follow-up. Results: Among the 70 patients, 45 were women, and 54 were Caucasian. A dermatologic involvement was observed in 58 (83%) patients, including 40 with MDA5 vasculopathy-related skin lesions. Muscular involvement was observed in 39 (56%) patients. Interstitial lung disease (ILD) was observed at baseline in 52 (74%) patients, including 23 (44%) who developed rapidly progressive (RP) ILD. Seven (10%) patients showed thromboembolic complications within the first weeks of diagnosis, and eight (11%) other patients developed a malignancy (4 before the diagnosis of anti-MDA5 disease). Poor outcomes were observed in 28 (40%) patients, including 13 (19%) deaths. Among the 23 patients with RP-ILD, 19 (79%) showed poor outcomes, including 12 (63%) who died. In multivariate analyses, RP-ILD (hazard ratio (HR), 95% CI: 8.24 [3.21-22], p<0.0001), the occurrence of thromboembolic events (HR: 5.22 [1.61-14.77], p=0.008) and the presence of any malignancy (HR: 19.73 [6.67-60], p<0.0001) were the three factors independently associated with poor outcomes. Discussion: This new independent cohort confirms the presence of different clinical phenotypes of anti-MDA5 diseases at baseline and the poor prognosis associated with RP-ILD. Thromboembolic events and malignancies were also identified as prognostic factors.