Publications by authors named "Marco Gattorno"

223 Publications

Neutrophil Extracellular Traps-DNase Balance and Autoimmunity.

Cells 2021 Oct 5;10(10). Epub 2021 Oct 5.

Division of Nephrology, Dialysis and Transplantation, IRCCS Istituto Giannina Gaslini, GenoaLargo Gaslini, 16148 Genoa, Italy.

Neutrophil extracellular traps (NETs) are macromolecular structures programmed to trap circulating bacteria and viruses. The accumulation of NETs in the circulation correlates with the formation of anti-double-stranded (ds) DNA antibodies and is considered a causative factor for systemic lupus erythematosus (SLE). The digestion of DNA by DNase1 and DNases1L3 is the rate- limiting factor for NET accumulation. Mutations occurring in one of these two DNase genes determine anti-DNA formation and are associated with severe Lupus-like syndromes and lupus nephritis (LN). A second mechanism that may lead to DNase functional impairment is the presence of circulating DNase inhibitors in patients with low DNase activity, or the generation of anti-DNase antibodies. This phenomenon has been described in a relevant number of patients with SLE and may represent an important mechanism determining autoimmunity flares. On the basis of the reviewed studies, it is tempting to suppose that the blockade or selective depletion of anti-DNase autoantibodies could represent a potential novel therapeutic approach to prevent or halt SLE and LN. In general, strategies aimed at reducing NET formation might have a similar impact on the progression of SLE and LN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells10102667DOI Listing
October 2021

A Novel LC-MS/MS-Based Method for the Diagnosis of ADA2 Deficiency from Dried Plasma Spot.

Molecules 2021 Sep 21;26(18). Epub 2021 Sep 21.

Chromatography and Mass Spectrometry Section, Central Laboratory of Analysis, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy.

Adenosine Deaminase 2 Deficiency (DADA2) (OMIM: 607575) is a monogenic, autoinflammatory disease caused by the loss of functional homozygous or heterozygous mutations in the ADA 2 gene (previously CECR1, Cat Eye Syndrome Chromosome Region 1). A timely diagnosis is crucial to start Anti-TNF therapies that are efficacious in controlling the disease. The confirmation of DADA2 is based on DNA sequencing and enzymatic assay. It is, thus, very important to have robust and reliable assays that can be rapidly utilized in specialized laboratories that can centralize samples from other centers. In this paper, we show a novel enzymatic assay based on liquid chromatography-tandem mass spectrometry that allows the accurate determination of the ADA2 enzyme activity starting from very small amounts of plasma spotted on filter paper (dried plasma spot). The method allows significantly distinguishing healthy controls from affected patients and carriers and could be of help in implementing the diagnostic workflow of DADA2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules26185707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469151PMC
September 2021

Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients.

Genes (Basel) 2021 Aug 24;12(9). Epub 2021 Aug 24.

UOSD Laboratory of Genetics and Genomics of Rare Diseases, IRCCS Istituto Giannina Gaslini, 16148 Genoa, Italy.

Inborn errors of immunity (IEI) include a large group of inherited diseases sharing either poor, dysregulated, or absent and/or acquired function in one or more components of the immune system. Next-generation sequencing (NGS) has driven a rapid increase in the recognition of such defects, though the wide heterogeneity of genetically diverse but phenotypically overlapping diseases has often prevented the molecular characterization of the most complex patients. Two hundred and seventy-two patients were submitted to three successive NGS-based gene panels composed of 58, 146, and 312 genes. Along with pathogenic and likely pathogenic causative gene variants, accounting for the corresponding disorders (37/272 patients, 13.6%), a number of either rare (probably) damaging variants in genes unrelated to patients' phenotype, variants of unknown significance (VUS) in genes consistent with their clinics, or apparently inconsistent benign, likely benign, or VUS variants were also detected. Finally, a remarkable amount of yet unreported variants of unknown significance were also found, often recurring in our dataset. The NGS approach demonstrated an expected IEI diagnostic rate. However, defining the appropriate list of genes for these panels may not be straightforward, and the application of unbiased approaches should be taken into consideration, especially when patients show atypical clinical pictures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes12091299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469131PMC
August 2021

[Anti-interleukin-1 agents: a new class of drugs for recurrent pericarditis. A practical guide for cardiologists].

G Ital Cardiol (Rome) 2021 Oct;22(10):833-843

Università di Milano, Dipartimento di Scienze Cliniche e Biomediche "Sacco", Ospedale Fatebenefratelli, Milano.

Anti-interleukin (IL)-1 agents have been developed for the treatment of autoinflammatory diseases characterized by overproduction of IL-1. Idiopathic recurrent pericarditis with inflammatory phenotype (fever, leukocytosis, and elevation of C-reactive protein) has similar features and responds well to this treatment. At present, in Italy, prescription of anakinra is possible for idiopathic recurrent pericarditis with corticosteroid dependence and colchicine resistance. Anakinra is a recombinant antagonist of IL-1 receptor and blocks either IL-1α (released from pericardial cells) or IL-1β (derived for inflammatory cells, during pericarditis). Anakinra is prescribed at the dose of 2 mg/kg/day subcutaneously up to 100 mg/day subcutaneously for at least 3 to 6 months with subsequent tapering. Anakinra allows a quick control of symptoms after 1-2 doses and a fast and safe tapering and withdrawal of corticosteroids. Colchicine can be used together with anakinra. The most common side effect is represented by local skin injection site reactions after 1-2 weeks of therapy. These reactions are usually transient and can be treated by anti-histamines and topical corticosteroids. Less common side effects include elevation of transaminases (4-5%), cutaneous or respiratory infections (2-3%), and leukopenia (1-3%). Side effects are rarely responsible for permanent discontinuation of therapy. The aim of the present review is to provide a practical guide on the use of these drugs for cardiologists, who are often not familial with this new therapy for pericarditis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1714/3666.36514DOI Listing
October 2021

Long-term efficacy and safety of canakinumab in patients with mevalonate kinase deficiency: results from the randomised Phase 3 CLUSTER trial.

Rheumatology (Oxford) 2021 Sep 23. Epub 2021 Sep 23.

Department of Pediatrics, University Medical Center Utrecht, Utrecht, the Netherlands.

Objectives: To evaluate the long-term efficacy and safety of canakinumab in patients with mevalonate kinase deficiency (MKD) during the open label extension (weeks 41-113) of the randomised controlled CLUSTER trial.

Methods: During a 72-week period, patients received open-label canakinumab 150 or 300 mg, every 4 or 8 weeks. The disease activity was evaluated every 8 weeks using physician global assessment (PGA) and counting the number of flares. Concentrations of C reactive protein (CRP) and serum amyloid A (SAA) protein were measured. The safety was studied by determination and classification of observed adverse events. The safety and efficacy were analysed separately in three subgroups of patients receiving a cumulative dose of less than <35 mg/kg, ≥35-<70 mg/kg or ≥ 70 mg/kg.

Results: Of the 74 patients who started the CLUSTER study, 66 entered Epoch 4 and 65 completed it. During the 72-week period, 42 (64%) patients experienced no flares, while 13 (20%) had one flare, as compared with a median of 12 flares per year reported at baseline. Low PGA scores were seen at the end of the study for all groups with >90% reporting minimal disease activity or none at all. Median CRP concentrations were consistently equal or lower than 10 mg/l, while median SAA concentrations remained only slightly above the normal range of 10 mg/l. The study showed no new or unexpected adverse events.

Conclusion: Canakinumab proved effective to control disease activity and prevent flares in MKD during the 72-week study period. No new safety concerns were reported.

Clinical Trial Registration Number: NCT02059291.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/keab696DOI Listing
September 2021

Anti-interleukin-1 agents for pericarditis: a primer for cardiologists.

Eur Heart J 2021 Sep 16. Epub 2021 Sep 16.

Center for the Diagnosis and Treatment of Pericardial Diseases, Section of Cardiovascular Imaging, Department of Cardiovascular Medicine, Heart, Vascular, and Thoracic Institute, Cleveland Clinic, USA.

Anti-interleukin (IL)-1 agents have been developed for the treatment of autoinflammatory and rheumatic conditions, where overproduction of IL-1 is an important pathophysiologic process. IL-1α and IL-1β are the most studied members of the IL-1 family of cytokines and have the strongest proinflammatory effects. A naturally occurring antagonist (IL-1Ra) mitigates their proinflammatory effects. Overproduction of both IL-1α (released by inflamed/damaged pericardial cells) and IL-1β (released by inflammatory cells) is now a well-recognized therapeutic target in patients with recurrent idiopathic pericarditis. Currently, there are three available anti-IL-1 agents: anakinra (recombinant human IL-1Ra), rilonacept (a soluble decoy receptor 'trap', binding both IL-1α and IL-1β), and canakinumab (human monoclonal anti-IL-1β antibody). For patients with corticosteroid-dependent and colchicine-resistant recurrent pericarditis with evidence of systemic inflammation, as evidenced by elevated C-reactive protein, the efficacy and safety of anakinra (2 mg/kg/day up to 100 mg/day subcutaneously usually for at least 6 months, then tapered) and rilonacept (320 mg subcutaneously for the first day followed by 160 mg subcutaneously weekly) have been clearly demonstrated in observational studies and randomized controlled clinical trials. Severe side effects are rare and discontinuation rates are very low (<4%). The most common reported side effect is injection site reactions (>50% of patients). In this article, we describe the historical and pathophysiological background and provide a comprehensive review of these agents, which appear to be the most significant advance in medical therapy of recurrent pericarditis in the last 5 years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehab452DOI Listing
September 2021

Type I interferon activation in RAS-associated autoimmune leukoproliferative disease (RALD).

Clin Immunol 2021 Oct 26;231:108837. Epub 2021 Aug 26.

Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Istituto Giannina Gaslini, Genoa, Italy; DINOGMI, Università di Genova, Genoa, Italy. Electronic address:

RAS-associated autoimmune leukoproliferative disease (RALD) is a rare immune dysregulation syndrome caused by somatic gain-of-function mutations of either NRAS or KRAS gene in hematopoietic cells. We describe a 27-year-old patient presenting at 5 months of age with recurrent infections and generalized lymphadenopathy who developed a complex multi-organ autoimmune syndrome with hypogammaglobulinemia, partially controlled with oral steroids, hydroxichloroquine, mofetil mycophenolate and IVIG prophylaxis. Activation of type I interferon pathway was observed in peripheral blood. Since 18 years of age, the patient developed regenerative nodular hyperplasia of the liver evolving into hepatopulmonary syndrome. Whole exome sequencing analysis of the peripheral blood DNA showed the NRAS p.Gly13Asp mutation validated as somatic. Our report highlights the possibility of detecting somatic NRAS gene mutations in patients with inflammatory immune dysregulation and type I interferon activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clim.2021.108837DOI Listing
October 2021

Lentiviral correction of enzymatic activity restrains macrophage inflammation in adenosine deaminase 2 deficiency.

Blood Adv 2021 08;5(16):3174-3187

San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Adenosine deaminase 2 deficiency (DADA2) is a rare inherited disorder that is caused by autosomal recessive mutations in the ADA2 gene. Clinical manifestations include early-onset lacunar strokes, vasculitis/vasculopathy, systemic inflammation, immunodeficiency, and hematologic defects. Anti-tumor necrosis factor therapy reduces strokes and systemic inflammation. Allogeneic hematopoietic stem/progenitor cell (HSPC) transplantation can ameliorate most disease manifestations, but patients are at risk for complications. Autologous HSPC gene therapy may be an alternative curative option for patients with DADA2. We designed a lentiviral vector encoding ADA2 (LV-ADA2) to genetically correct HSPCs. Lentiviral transduction allowed efficient delivery of the functional ADA2 enzyme into HSPCs from healthy donors. Supranormal ADA2 expression in human and mouse HSPCs did not affect their multipotency and engraftment potential in vivo. The LV-ADA2 induced stable ADA2 expression and corrected the enzymatic defect in HSPCs derived from DADA2 patients. Patients' HSPCs re-expressing ADA2 retained their potential to differentiate into erythroid and myeloid cells. Delivery of ADA2 enzymatic activity in patients' macrophages led to a complete rescue of the exaggerated inflammatory cytokine production. Our data indicate that HSPCs ectopically expressing ADA2 retain their multipotent differentiation ability, leading to functional correction of macrophage defects. Altogether, these findings support the implementation of HSPC gene therapy for DADA2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020003811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405196PMC
August 2021

Effect of anakinra on mortality in patients with COVID-19: a systematic review and patient-level meta-analysis.

Lancet Rheumatol 2021 Oct 9;3(10):e690-e697. Epub 2021 Aug 9.

Rheumatology Department, Groupe Hospitalier Paris Saint-Joseph, Paris, France.

Background: Anakinra might improve the prognosis of patients with moderate to severe COVID-19 (ie, patients requiring oxygen supplementation but not yet receiving organ support). We aimed to assess the effect of anakinra treatment on mortality in patients admitted to hospital with COVID-19.

Methods: For this systematic review and individual patient-level meta-analysis, a systematic literature search was done on Dec 28, 2020, in Medline (PubMed), Cochrane, medRxiv, bioRxiv, and the ClinicalTrials.gov databases for randomised trials, comparative studies, and observational studies of patients admitted to hospital with COVID-19, comparing administration of anakinra with standard of care, or placebo, or both. The search was repeated on Jan 22, 2021. Individual patient-level data were requested from investigators and corresponding authors of eligible studies; if individual patient-level data were not available, published data were extracted from the original reports. The primary endpoint was mortality after 28 days and the secondary endpoint was safety (eg, the risk of secondary infections). This study is registered on PROSPERO (CRD42020221491).

Findings: 209 articles were identified, of which 178 full-text articles fulfilled screening criteria and were assessed. Aggregate data on 1185 patients from nine studies were analysed, and individual patient-level data on 895 patients were provided from six of these studies. Eight studies were observational and one was a randomised controlled trial. Most studies used historical controls. In the individual patient-level meta-analysis, after adjusting for age, comorbidities, baseline ratio of the arterial partial oxygen pressure divided by the fraction of inspired oxygen (PaO/FiO), C-reactive protein (CRP) concentrations, and lymphopenia, mortality was significantly lower in patients treated with anakinra (38 [11%] of 342) than in those receiving standard of care with or without placebo (137 [25%] of 553; adjusted odds ratio [OR] 0·32 [95% CI 0·20-0·51]). The mortality benefit was similar across subgroups regardless of comorbidities (ie, diabetes), ferritin concentrations, or the baseline PaO/FiO. In a subgroup analysis, anakinra was more effective in lowering mortality in patients with CRP concentrations higher than 100 mg/L (OR 0·28 [95% CI 0·17-0·47]). Anakinra showed a significant survival benefit when given without dexamethasone (OR 0·23 [95% CI 0·12-0·43]), but not with dexamethasone co-administration (0·72 [95% CI 0·37-1·41]). Anakinra was not associated with a significantly increased risk of secondary infections when compared with standard of care (OR 1·35 [95% CI 0·59-3·10]).

Interpretation: Anakinra could be a safe, anti-inflammatory treatment option to reduce the mortality risk in patients admitted to hospital with moderate to severe COVID-19 pneumonia, especially in the presence of signs of hyperinflammation such as CRP concentrations higher than 100 mg/L.

Funding: Sobi.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2665-9913(21)00216-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352496PMC
October 2021

Intravenous immunoglobulin for corticosteroid-resistant intestinal Henoch-Schönlein purpura: worth a controlled trial against corticosteroids?

Rheumatology (Oxford) 2021 08;60(8):3868-3871

Pediatrics and Pediatric Emergency Unit, The Children Hospital, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.

Objectives: Henoch-Schönlein purpura (HScP) may present in children with severe, occasionally refractory, gastrointestinal (GI) involvement. The use of corticosteroids (CSs) is commonplace in the management of the disease, but to date no standardized protocol is available and, although rare, resistance to CS therapy may be challenging to clinicians. IVIG has been proposed as an effective alternative to CSs, but to date no controlled trial has been conducted to ascertain their real efficacy. We share our personal experience of successful IVIG treatment in two cases of GI HScP, comparing it with similar experiences reported in literature.

Methods: Retrospective clinical data collection, comparison with available literature.

Results: We describe two children with severe HScP GI vasculitis refractory to high-dose intravenous CSs that responded rapidly to IVIG administration, with complete recovery within a few days. Patient characteristics and response to IVIG administration were comparable to those of other previously reported cases.

Conclusion: Our observation confirms that IVIG may be useful in the treatment of CS-resistant HScP-related GI vasculitis in children, and highlights the need for more structured research, including a randomized trial against CSs, in order to ascertain their real effectiveness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/keaa743DOI Listing
August 2021

Syndrome of Undifferentiated Recurrent Fever (SURF): An Emerging Group of Autoinflammatory Recurrent Fevers.

J Clin Med 2021 May 3;10(9). Epub 2021 May 3.

Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy.

Syndrome of undifferentiated recurrent fever (SURF) is a heterogeneous group of autoinflammatory diseases (AID) characterized by self-limiting episodes of systemic inflammation without a confirmed molecular diagnosis, not fulfilling the criteria for periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome. In this review, we focused on the studies enrolling patients suspected of AID and genotyped them with next generation sequencing technologies in order to describe the clinical manifestations and treatment response of published cohorts of patients with SURF. We also propose a preliminary set of indications for the clinical suspicion of SURF that could help in everyday clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm10091963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124817PMC
May 2021

The Association among Pyoderma Gangrenosum, Ulcerative Colitis, and Hidradenitis Suppurativa and the Syndromic Hidradenitis Suppurativa Network: A Case Report.

Skin Appendage Disord 2021 Apr 4;7(3):227-230. Epub 2021 Mar 4.

Section of Dermatology and Infectious Diseases, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.

Hidradenitis suppurativa (HS), together with other inflammatory diseases, is involved in a syndromic network where different combinations of signs and symptoms characterize the definition. The observation of the concurrent occurrence of HS, pyoderma gangrenosum (PG), and inflammatory bowel disease (IBD), in detail ulcerative colitis (UC), led the authors to describe a new association. The patient, a 36-year-old woman, who saw IBD as the first appearing condition, shortly followed by HS and PG, was referred because of a clinical situation quickly worsening. A severe aggravation of both GI symptoms and general systemic situation total led to total colectomy. Surprisingly, shortly after the radical surgical treatment of UC, the cutaneous manifestations of HS and PG with no specific treatment almost completely disappeared suggesting the existence of a common etiopathogenetic mechanism and possibly an inductor role of UC on the other disorders. The presentation of this case offers the opportunity to deal with the fact that the resolution of one of the associated conditions may lead to the clearance of one or more of the others. It confirms a pathogenetic link between them and the pivotal role of one of them, in this case colitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000513639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138252PMC
April 2021

Expanding the clinical and neuroimaging features of post-varicella arteriopathy of childhood.

J Neurol 2021 May 27. Epub 2021 May 27.

Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Objective: Post-varicella arterial ischemic stroke (AIS) is considered an uncommon cause of pediatric stroke that is considered a self-limiting, monophasic disease. However, in a subset of patients, disease recurs; the prevalence of vasculopathy or AIS recurrence, severity of clinical outcomes, and standardized therapies have not been well characterized. Herein, we determined the clinical-neuroradiological features, long-term evolution, and relationship between acute phase treatment and vasculopathy recurrence in a pediatric population with post-varicella AIS.

Methods: Clinical, laboratory, and neuroradiological features of 22 children with post-varicella AIS between 2010 and 2019 (16 males, mean age at stroke 4 years, range 1.7-10) were reviewed. Statistical analyses were performed using χ and Fisher exact tests.

Results: Of the 22 cases, mean time from varicella to stroke was 4.5 months with 3 cases presenting more than 12 months after rash; 21 (95%) were not vaccinated for varicella; 3 (13.6%) had posterior circulation involvement; and 5 (22.7%) had AIS or vasculopathy recurrence, of which 4 recurred 6.1 months to 2.8 years after initial clinical onset. Recurrence was associated with lack of antiviral treatment during the first episode (p = 0.02).

Conclusions: Post-varicella AIS can occur months after rash making diagnosis challenging. Because recurrent vasculopathy was seen predominantly in cases not treated with antiviral therapy during initial presentation, it is important to rapidly diagnose post-varicella AIS through clinical criteria and/or virological testing then treat with antivirals to prevent recurrence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-021-10606-6DOI Listing
May 2021

Curation and expansion of Human Phenotype Ontology for defined groups of inborn errors of immunity.

J Allergy Clin Immunol 2021 May 12. Epub 2021 May 12.

Department of Immunology, Great Ormond Street (GOS) Hospital for Children NHS Foundation Trust, London, United Kingdom.

Background: Accurate, detailed, and standardized phenotypic descriptions are essential to support diagnostic interpretation of genetic variants and to discover new diseases. The Human Phenotype Ontology (HPO), extensively used in rare disease research, provides a rich collection of vocabulary with standardized phenotypic descriptions in a hierarchical structure. However, to date, the use of HPO has not yet been widely implemented in the field of inborn errors of immunity (IEIs), mainly due to a lack of comprehensive IEI-related terms.

Objectives: We sought to systematically review available terms in HPO for the depiction of IEIs, to expand HPO, yielding more comprehensive sets of terms, and to reannotate IEIs with HPO terms to provide accurate, standardized phenotypic descriptions.

Methods: We initiated a collaboration involving expert clinicians, geneticists, researchers working on IEIs, and bioinformaticians. Multiple branches of the HPO tree were restructured and extended on the basis of expert review. Our ontology-guided machine learning coupled with a 2-tier expert review was applied to reannotate defined subgroups of IEIs.

Results: We revised and expanded 4 main branches of the HPO tree. Here, we reannotated 73 diseases from 4 International Union of Immunological Societies-defined IEI disease subgroups with HPO terms. We achieved a 4.7-fold increase in the number of phenotypic terms per disease. Given the new HPO annotations, we demonstrated improved ability to computationally match selected IEI cases to their known diagnosis, and improved phenotype-driven disease classification.

Conclusions: Our targeted expansion and reannotation presents enhanced precision of disease annotation, will enable superior HPO-based IEI characterization, and hence benefit both IEI diagnostic and research activities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2021.04.033DOI Listing
May 2021

Neutrophil Extracellular Traps in Systemic Lupus Erythematosus Stimulate IgG2 Production From B Lymphocytes.

Front Med (Lausanne) 2021 12;8:635436. Epub 2021 Apr 12.

Laboratory of Molecular Nephrology, Division of Nephrology and Transplantation, Scientific Institute for Research, Hospitalization and Health Care (IRCCS) Giannina Gaslini Institute, Genoa, Italy.

Circulating autoantibodies of IgG2 isotype predominate in Systemic Lupus Erythematosus (SLE) and concur to the development of the renal lesions characteristic of Lupus Nephritis (LN). Anti-dsDNA and anti-histones IgG2, together with anti-podocyte proteins (i.e., α-enolase) are the major autoantibodies in serum and renal glomeruli of LN patients. The mechanisms underlying autoantibody formation and isotype switching in SLE and LN are unknown. A major issue is how DNA/histones are externalized from cell nucleus, driving the autoimmune response. Neutrophil Extracellular Traps (NETs) have been recently identified as crucial players in this context, representing the main source of DNA and nucleosome proteins. A second key point is what regulates IgG2 isotype switching: in mouse models, T-bet transcription factor has been described as essential for IgG2a class switch. We hypothesized that, in SLE, NET formation is the key mechanism responsible for externalization of autoantigens (i.e., dsDNA, histones 2,3, and α-enolase) and that T-bet is upregulated by NETs, driving, in this way, immunoglobulin class switch recombination (CSR), with production of IgG2 autoantibodies. The data here presented show that NETs, purified from SLE patients, stimulate IgG2 isotype class switch possibly through the induction of T-bet. Of note, we observed a prominent effect of NETs on the release of soluble IgG2 in SLE patients', but not in healthy donors' B cells. Our results add important knowledge on the mechanisms of IgG2 class switch in SLE and contribute to further elucidate the role of NETs in LN pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmed.2021.635436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072216PMC
April 2021

The challenge of early diagnosis of autoimmune lymphoproliferative syndrome in children with suspected autoinflammatory/autoimmune disorders.

Rheumatology (Oxford) 2021 Apr 28. Epub 2021 Apr 28.

Center for Autoinflammatory diseases and Immunodeficiencies, IRCCS G. Gaslini.

Objectives: To test the usefulness of an extended panel of lymphocyte subsets (LS) in combination with Oliveira's diagnostic criteria for the identification of autoimmune lymphoproliferative syndrome (ALPS) in children referred to a pediatric rheumatology center.

Methods: patients referred from 2015 to 2018 to our Rheumatology Unit for an autoimmune or autoinflammatory condition were retrospectively analyzed. Oliveira's required criteria (chronic lymphoproliferation and elevated DNT) were applied as first screening. Flow cytometry study included double negative CD4-CD8-TCR αβ+T lymphocytes (DNT), CD25+CD3+, HLA-DR+CD3+T cells, B220+T cells, and CD27+B cells. Data were analyzed with an univariate logistic regression analysis, followed by a multivariate analysis. Sensitivity and specificity of the Oliveira's required criteria were calculated.

Results: 264 patients were included in the study and classified as: i) autoimmune diseases (26); ii) juvenile idiopathic arthritis (JIA) (35) iii) monogenic systemic autoinflammatory disease (SAID) (27); iv) PFAPA syndrome (100); v) systemic undefined recurrent fever (SURF) (45); vi) undetermined-SAID (14); vii) ALPS (17). Oliveira's required criteria displayed a sensitivity of 100% and specificity of 79%. When compared with other diseases the TCRαβ+B220+ lymphocytes were significantly increased in ALPS patients. The multivariate analysis revealed 5 clinical/laboratory parameters positively associated to ALPS: splenomegaly, female gender, arthralgia, elevated DNT and TCRαβ+B220+lymphocytes.

Conclusions: Oliveira's required criteria are useful for the early suspicion of ALPS. TCRαβ+B220+ lymphocytes should be added in the diagnostic work-up of patients referred to pediatric rheumatology unit for a suspected autoimmune or autoinflammatory condition, providing a relevant support in the early diagnosis of ALPS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/keab361DOI Listing
April 2021

Anti-interleukin 1 agents for the treatment of recurrent pericarditis: a systematic review and meta-analysis.

Heart 2021 Mar 18. Epub 2021 Mar 18.

Department of Biomedical and Clinical Sciences, Fatebenefratelli Hospital, University of Milan, Milano, Italy.

Aims: Corticosteroid-dependent and colchicine-resistant recurrent pericarditis (RP) is a challenging management problem, in which conventional anti-inflammatory therapy (nonsteroidal anti-inflammatory drugs, colchicine, corticosteroids) is unable to control the disease. Recent data suggest a potential role for anti-interleukin-1 (IL-1) agents for this condition. This study was designed to assess the safety and efficacy of anti-IL-1 agents in this setting.

Methods: We performed a systematic review and meta-analysis of randomised controlled trials and observational studies assessing pericarditis recurrences and drug-related adverse events in patients receiving anti-IL-1 drugs for pericarditis.

Results: The meta-analysis assessed 7 studies including 397 pooled patients with RP. The median age was 42 years, 60% were women and the aetiology was idiopathic in 87%. After a median follow-up of 14 months (IQR,12-39), patients receiving anti-IL-1 agents (anakinra or rilonacept) had a significantly reduction in pericarditis recurrences (incidence rate ratio 0.06, 95% CI 0.03 to 0.14), compared with placebo and/or standard medical therapy. Anti-IL-1 agents were associated with increased risk of adverse events compared with placebo (risk ratio (RR) 5.38, 95% CI 2.08 to 13.92): injection-site reactions occurred in 15/41 (36.6%) vs none (RR 14.98, 95% CI 2.09 to 107.09), infections occurred in 13/51 (25.5%) vs 3/41 (7.3%; RR 3.65, 95% CI 1.23 to 10.85). Anti-IL-1 agents were not associated with increased risk of severe adverse events.

Conclusions: In patients with RP, anti-IL-1 agents (anakinra and rilonacept) are efficacious for prevention of recurrences, without severe adverse events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/heartjnl-2020-318869DOI Listing
March 2021

Hemolysis and Neurologic Impairment in PAMI Syndrome: Novel Characteristics of an Elusive Disease.

Pediatrics 2021 03;147(3)

Pediatric Hematology/Oncology Department, Istituto di Ricovero e Cura a Carattere Scientifico, Istituto G. Gaslini, Genova, Italy.

PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome is a rare early-onset autoinflammatory disease associated with various hematologic findings, including chronic neutropenia and pancytopenia. We report a unique case of PAMI syndrome in a toddler with transfusion-dependent hemolytic anemia, hepatosplenomegaly, failure to thrive, developmental delay, and multiple malformations. Because of acute inflammatory-driven decompensation, anakinra was started with dramatic improvement of both the hematologic and neurologic involvement. A customized next-generation sequencing panel later identified a de novo pathogenic variant in the gene, confirming the diagnosis. Our case illustrates the broad spectrum of phenotypes associated with PAMI syndrome, which should be considered in any case of unexplained cytopenias associated with autoinflammatory stigmata. It is also one of the few reports of neurologic involvement in -associated inflammatory diseases. Increased awareness of this rare disease and early performance of genetic testing can correctly diagnose PAMI syndrome and prevent disease complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1542/peds.2020-0784DOI Listing
March 2021

Efficacy of early anti-inflammatory treatment with high doses of intravenous anakinra with or without glucocorticoids in patients with severe COVID-19 pneumonia.

J Allergy Clin Immunol 2021 04 6;147(4):1217-1225. Epub 2021 Feb 6.

IRCCS G. Gaslini, Genoa, Italy. Electronic address:

Background: IL-1 plays a pivotal role in the inflammatory response during cytokine storm syndromes.

Objective: Our aim was to analyze the efficacy and safety of early anti-inflammatory treatment (AIT) with intravenous anakinra with or without glucocorticoids in coronavirus disease 2019 (COVID-19) pneumonia.

Methods: We performed a retrospective single-center cohort study of patients admitted for COVID-19 pneumonia from February 26 to April 29, 2020, to assess the efficacy of early AIT with intravenous anakinra (100 mg every 8 hours for 3 days, with tapering) alone or in combination with a glucocorticoid (intravenous methylprednisolone, 1-2 mg/kg daily, with tapering). The standard of care (SOC) treatment was hydroxychloroquine and/or azithromycin with or without antivirals and anticoagulants. Late rescue AIT with anakinra or tocilizumab was also evaluated. Treatment effect on overall survival was assessed by a propensity score-adjusted Cox model.

Results: A total of 128 patients were analyzed; 63 patients received early AIT (30 received anakinra alone and 33 received anakinra plus a glucocorticoid) at admission, and 65 patients did not receive early AIT and were used as controls; of the latter 65 patients, 44 received the SOC treatment alone and 21 received the SOC treatment plus late rescue AIT. After adjustment for all the unbalanced baseline covariates, early AIT reduced the hazard of mortality by 74% (adjusted hazard ratio [HR] = 0.26; P < .001). The effect was similar in patients receiving anakinra alone (adjusted HR = 0.28; P = .04) and anakinra plus a glucocorticoid (adjusted HR = 0.33; P = .07). Late rescue treatment did not show a significant advantage over SOC treatment alone (adjusted HR = 0.82; P = .70).

Conclusions: This study suggests, on a larger series of patients with COVID-19 pneumonia, the potential efficacy and safety of the early use of high doses of intravenous anakinra with or without glucocorticoids.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2021.01.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865089PMC
April 2021

The Challenge of Managing Children With Periodic Fever Syndromes in the Era of COVID-19.

Front Pediatr 2020 6;8:620621. Epub 2021 Jan 6.

Center for Autoinflammatory Diseases and Immunodeficiencies, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Giannina Gaslini, Genoa, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fped.2020.620621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815684PMC
January 2021

Actin Remodeling Defects Leading to Autoinflammation and Immune Dysregulation.

Front Immunol 2020 7;11:604206. Epub 2021 Jan 7.

Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

A growing number of monogenic immune-mediated diseases have been related to genes involved in pathways of actin cytoskeleton remodeling. Increasing evidences associate cytoskeleton defects to autoinflammatory diseases and primary immunodeficiencies. We reviewed the pathways of actin cytoskeleton remodeling in order to identify inflammatory and immunological manifestations associated to pathological variants. We list more than twenty monogenic diseases, ranging from pure autoinflammatory conditions as familial Mediterranean fever, mevalonate kinase deficiency and PAPA syndrome, to classic and novel primary immunodeficiencies as Wiskott-Aldrich syndrome and DOCK8 deficiency, characterized by the presence of concomitant inflammatory and autoimmune manifestations, such as vasculitis and cytopenia, to severe and recurrent infections. We classify these disorders according to the role of the mutant gene in actin cytoskeleton remodeling, and in particular as disorders of transcription, elongation, branching and activation of actin. This expanding field of rare immune disorders offers a new perspective to all immunologists to better understand the physiological and pathological role of actin cytoskeleton in cells of innate and adaptive immunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.604206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817698PMC
June 2021

Haploidentical α/β T-cell and B-cell depleted stem cell transplantation in severe mevalonate kinase deficiency.

Rheumatology (Oxford) 2021 Oct;60(10):4850-4854

Centro Malattie Auto-infiammatorie e Immunodeficienze, Istituto G. Gaslini, Genova, Italy.

Objective: Mevalonic aciduria represents the most severe form of mevalonate kinase deficiency (MKD). Patients with mevalonic aciduria have an incomplete response even to high doses of anti-cytokine drugs such as anakinra or canakinumab and stem cell transplantation (SCT) represents a possible therapy for this severe disease.

Methods: We report the first two children affected by severe MKD who received haploidentical α/β T-cell and B-cell depleted SCT. Both patients received a treosulfan-based conditioning regimen and one received a second haploidentical-SCT for secondary rejection of the first.

Results: Both patients obtained a stable full donor engraftment with a complete regression of clinical and biochemical inflammatory signs, without acute organ toxicity or acute and chronic GvHD. In both, the urinary excretion of mevalonic acid remained high post-transplant in the absence of any inflammatory signs.

Conclusion: Haploidentical α/β T-cell and B-cell depleted SCT represents a potential curative strategy in patients affected by MKD. The persistence of urinary excretion of mevalonic acid after SCT, probably related to the ubiquitous expression of MVK enzyme, suggests that these patients should be carefully monitored after SCT to exclude MKD clinical recurrence. Prophylaxis with anakinra in the acute phase after transplant could represent a safe and effective approach. Further biological studies are required to clarify the pathophysiology of inflammatory attacks in MKD in order to better define the therapeutic role of SCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/keaa912DOI Listing
October 2021

Defining colchicine resistance/intolerance in patients with familial Mediterranean fever: a modified-Delphi consensus approach.

Rheumatology (Oxford) 2021 08;60(8):3799-3808

Division of Paediatric Rheumatology, Department of Paediatrics and Autoinflammation Reference Center Tuebingen, University Hospital Tuebingen, Tuebingen, Germany.

Objectives: Colchicine is the main treatment for FMF. Although a number of individuals with FMF are intolerant/resistant to colchicine, there is no standard definition of colchicine resistance/intolerance. We developed a set of evidence-based core statements defining colchicine resistance/intolerance in patients with FMF that may serve as a guide for clinicians and health authorities.

Methods: A set of statements was identified using a modified-Delphi consensus-based approach. The process involved development of an initial colchicine resistance/intolerance-related questionnaire derived from a systematic literature review. The questionnaire, which was completed by an international panel of 11 adult and paediatric rheumatologists with expertise in FMF, was analysed anonymously. The results informed draft consensus statements that were discussed by a round-table expert panel, using a nominal group technique to agree on the selection and wording of the final statements.

Results: Consensus among the panel was achieved on eight core statements defining colchicine resistance/intolerance in patients with FMF. A definition of resistance was agreed upon that included recurrent clinical attacks (average one or more attacks per month over a 3-month period) or persistent laboratory inflammation in between attacks. Other core statements recognize the importance of assessing treatment adherence, and the impact of active disease and intolerance to colchicine on quality of life.

Conclusion: Based on expert opinion, a set of evidence-based core statements defining colchicine resistance/intolerance in patients with FMF were identified to help guide clinicians and health authorities in the management of patients with FMF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/keaa863DOI Listing
August 2021

Overview of STING-Associated Vasculopathy with Onset in Infancy (SAVI) Among 21 Patients.

J Allergy Clin Immunol Pract 2021 02 18;9(2):803-818.e11. Epub 2020 Nov 18.

Pediatric Pulmonology Department and Reference Center for Rare Lung Disease RespiRare, Trousseau University Hospital, AP-HP Sorbonne Université, Paris, France.

Background: Gain-of-function mutations in STING1 underlie a type I interferonopathy termed SAVI (STING-associated vasculopathy with onset in infancy). This severe disease is variably characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease (ILD).

Objective: To describe a cohort of patients with SAVI.

Methods: Assessment of clinical, radiological and immunological data from 21 patients (17 families) was carried out.

Results: Patients carried heterozygous substitutions in STING1 previously described in SAVI, mainly the p.V155M. Most were symptomatic from infancy, but late onset in adulthood occurred in 1 patient. Systemic inflammation, skin vasculopathy, and ILD were observed in 19, 18, and 21 patients, respectively. Extensive tissue loss occurred in 4 patients. Severity of ILD was highly variable with insidious progression up to end-stage respiratory failure reached at teenage in 6 patients. Lung imaging revealed early fibrotic lesions. Failure to thrive was almost constant, with severe growth failure seen in 4 patients. Seven patients presented polyarthritis, and the phenotype in 1 infant mimicked a combined immunodeficiency. Extended features reminiscent of other interferonopathies were also found, including intracranial calcification, glaucoma and glomerular nephropathy. Increased expression of interferon-stimulated genes and interferon α protein was constant. Autoantibodies were frequently found, in particular rheumatoid factor. Most patients presented with a T-cell defect, with low counts of memory CD8+ cells and impaired T-cell proliferation in response to antigens. Long-term follow-up described in 8 children confirmed the clinical benefit of ruxolitinib in SAVI where the treatment was started early in the disease course, underlying the need for early diagnosis. Tolerance was reasonably good.

Conclusion: The largest worldwide cohort of SAVI patients yet described, illustrates the core features of the disease and extends the clinical and immunological phenotype to include overlap with other monogenic interferonopathies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaip.2020.11.007DOI Listing
February 2021

INSAID Variant Classification and Eurofever Criteria Guide Optimal Treatment Strategy in Patients with TRAPS: Data from the Eurofever Registry.

J Allergy Clin Immunol Pract 2021 02 9;9(2):783-791.e4. Epub 2020 Nov 9.

National Amyloidosis Centre, UCL Division of Medicine, Royal Free Campus, University College London, London, United Kingdom. Electronic address:

Background: TNF receptor-associated periodic syndrome (TRAPS) is a rare autoinflammatory disease caused by dominant mutation of the TNF super family receptor 1A (TNFRSF1A) gene. Data regarding long-term treatment outcomes are lacking.

Objective: To assess correlations of genotype-phenotypes in patients with TRAPS, as defined by the International Study Group for Systemic Autoinflammatory Diseases (INSAID) classification and Eurofever criteria, with treatment responses.

Methods: Data from 226 patients with variants of the TNFRSF1A gene and enrolled in the Eurofever registry were classified according to the INSAID classification in groups A (pathogenic or likely pathogenic variants), B (variants of uncertain significance or not classified variants), and C (benign or likely benign variants) and screened for Eurofever criteria.

Results: In group A (127 of 226 patients, 56%), all fulfilled Eurofever criteria and 20 of 127 patients (16%) developed AA amyloidosis. In group B (78 of 226 patients, 35%), 40 of 78 patients (51%) did not fulfill Eurofever criteria, displaying a lower incidence of abdominal pain (P < .02) and higher efficacy rate of on-demand nonsteroidal anti-inflammatory drugs (P < .02) and colchicine (P < .001). Group C (21 of 226 patients, 9%) presented a milder disease (P < .02) and none fulfilled Eurofever criteria. Anti-IL-1 drugs were the most frequently used in patients fulfilling Eurofever criteria, with the highest efficacy rate (>85% complete response). No patients on anti-IL-1 treatments developed AA amyloidosis, and 7 women with a history of failure to conceive had successful pregnancies.

Conclusion: Anti-IL-1 drugs are the best maintenance treatment in patients with TRAPS. The diagnosis of TRAPS should be considered very carefully in patients of group B not fulfilling Eurofever criteria and group C, and colchicine may be preferable as the first maintenance treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaip.2020.10.053DOI Listing
February 2021

Deficiency of Adenosine Deaminase 2 in Adults and Children: Experience From India.

Arthritis Rheumatol 2021 02 26;73(2):276-285. Epub 2020 Dec 26.

Centro Malattie Autoinfiammatorie e Immunodeficienze, IRCCS, Istituto Giannina Gaslini, Genoa, Italy.

Objective: Deficiency of adenosine deaminase 2 (DADA2) is a potentially fatal monogenic syndrome characterized by variable manifestations of systemic vasculitis, bone marrow failure, and immunodeficiency. Most cases are diagnosed by pediatric care providers, given the typical early age of disease onset. This study was undertaken to describe the clinical phenotypes and treatment response both in adults and in children with DADA2 in India.

Methods: A retrospective analysis of pediatric and adult patients with DADA2 diagnosed at various rheumatology centers across India was conducted. Clinical characteristics, diagnostic findings, and treatment responses were analyzed in all subjects.

Results: In total, 33 cases of DADA2 were confirmed in this cohort between April 2017 and March 2020. Unlike previous studies, nearly one-half of the confirmed cases presented during adulthood. All symptomatic patients exhibited features of vasculitis, whereas constitutional symptoms and anemia were more common in pediatric patients. Cutaneous and neurologic involvement were common, and 18 subjects had experienced at least one stroke. In addition, the clinical spectrum of DADA2 was expanded by recognition of novel features in these patients, including pancreatic infarction, focal myocarditis, and diffuse alveolar hemorrhage. Treatment with tumor necrosis factor inhibitors (TNFi) was initiated in 25 patients. All of the identified disease manifestations showed marked improvement after initiation of TNFi, and disease remission was achieved in 19 patients. Two cases were complicated by tuberculosis infection, and 2 deaths were reported.

Conclusion: This report presents the first case series of patients with DADA2 from India, diagnosed by adult and pediatric care providers. The findings raise awareness of this syndrome, particularly with regard to its presentation in adults.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.41500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902299PMC
February 2021

A case report of a novel compound heterozygous mutation in a Brazilian patient with deficiency of Interleukin-1 receptor antagonist (DIRA).

Pediatr Rheumatol Online J 2020 Aug 20;18(1):67. Epub 2020 Aug 20.

Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Giannina Gaslini, Genoa, Italy.

Background: Deficiency of the natural antagonist of interleukin-1 was first described in 2009 and so far 20 patients has been reported. In Brazil just two cases have been reported both carrying the same homozygous 15 bp deletion. Blocking interleukin-1 has changed rate survival for DIRA patients. The use of anakinra and rilonacept has been reported safe and efficient, whereas the selective blockade of interleukin-1 beta, using the monoclonal antibody canakinumab has been reported in a single case only.

Case Presentation: Here we report a case of a 7 years old Brazilian boy that presented with recurrent episodes of systemic inflammation with severe disabling osteomyelitis with mild pustular skin rash. A Next Generation Sequencing gene panel allowed to detect two pathogenic mutations in the IL1RN gene, described in compound heterozygosity. Corticosteroids was effective in controlling inflammation and anti-IL1 beta blocker triggered disease flare. Complete clinical control could be achieved using IL-1 receptor antagonist.

Conclusions: DIRA is a severe, life threatening autoinflammatory condition with low numbers of patients described all over the world. The mutation p.Asp72_Ile76del in IL1RN is presented in all Brazilian DIRA patients already described and p.Q45* (rs1019766125) is a new mutation affecting the IL1RN gene. Following the pathogenesis of DIRA, blocking both subunits of interleukin one as well as antagonizing the receptor using anakinra or rilonacept seems to be effective. There is just one report using canakinumab for the treatment of DIRA and this is the first report of disease flare using this drug.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12969-020-00454-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439677PMC
August 2020
-->