Pyrin Inflammasome Activation Defines Colchicine-Responsive SURF Patients from FMF and Other Recurrent Fevers.

Syndrome of undifferentiated recurrent fever (SURF) is characterized by recurrent fevers, a lack of confirmed molecular diagnosis, and a complete or partial response to colchicine. Despite the clinical similarities to familial Mediterranean fever (FMF), the underlying inflammatory mechanisms of SURF are not yet understood. We here analyzed the in vitro activation of the pyrin inflammasome in a cohort of SURF patients compared to FMF and PFAPA patients. Peripheral blood mononuclear cells (PBMC) were collected from SURF (both colchicine-treated and untreated), FMF, PFAPA patients, and healthy donors. PBMC were stimulated ex vivo with Clostridium difficile toxin A (TcdA) and a PKC inhibitor (UCN-01), in the presence or absence of colchicine. The assembly of the pyrin inflammasome was evaluated by measuring the presence of apoptosis-associated Speck-like protein containing caspase recruitment domain (ASC) specks in monocytes using flow cytometry. IL-1ß secretion was quantified using an ELISA assay. No differences in TcdA-induced activation of pyrin inflammasome were observed among FMF, PFAPA, and healthy donors. Untreated SURF patients showed a reduced response to TcdA, which was normalized after colchicine treatment. In contrast to FMF, SURF patients, similar to PFAPA patients and healthy donors, did not exhibit pyrin inflammasome activation in response to UCN-01-mediated pyrin dephosphorylation. These data demonstrate that in vitro functional analysis of pyrin inflammasome activation can differentiate SURF from FMF and PFAPA patients, suggesting the involvement of the pyrin inflammasome in the pathophysiology of SURF.

Monitoring of Adverse Events and Safety in Autoinflammatory Diseases: Real-Life Data from the Eurofever Registry.

OBJECTIVES: The study is aimed to evaluate the impact of safety events in the Eurofever registry for Autoinflammatory diseases. METHODS: This was a retrospective and longitudinal observational multicentre study. Data were retrieved from the international registry Eurofever, starting patients' enrolment since 2009. All moderate, severe, or very severe AEs reported by treating physician in Eurofever were analyzed regardless of a possible suspected causal relationship to any therapies and according to the latest release of the Medical Dictionary for Regulatory Activities. RESULTS: Complete information on safety were available in 2464 patients enrolled in the registry. In 1499 of them retrospective data encompassing the period from disease onset to enrolment were available, whereas 965 consecutive patients entered in the longitudinal part of the study. A total of 479 AEs have been reported in 275 patients. Eighty-two AEs were reported as serious and 99 were drug-related according to the physicians. Infections or infestations (94; 19.6%), gastrointestinal disorders (66; 13.8%), nervous system disorders (41; 8.6%) and systemic disorders or administration site reactions (35; 7.3%) were the most frequent reported events. The highest absolute number of drug-related AEs were related to biologic DMARDs (40/99 reports, 40,4%) and colchicine (31/99 reports, 31.3%). CONCLUSIONS: Present study shows the importance of a longitudinal and homogeneous registration of the AEs in rare conditions, with a particular focus on the safety profile of the treatments used in these conditions.

COVID-19 Vaccination in Patients with Inborn Errors of Immunity Reduces Hospitalization and Critical Care Needs Related to COVID-19: a USIDNET Report.

BACKGROUND: The CDC and ACIP recommend COVID-19 vaccination for patients with inborn errors of immunity (IEI). Not much is known about vaccine safety in IEI, and whether vaccination attenuates infection severity in IEI. OBJECTIVE: To estimate COVID-19 vaccination safety and examine effect on outcomes in patients with IEI. METHODS: We built a secure registry database in conjunction with the US Immunodeficiency Network to examine vaccination frequency and indicators of safety and effectiveness in IEI patients. The registry opened on January 1, 2022, and closed on August 19, 2022. RESULTS: Physicians entered data on 1245 patients from 24 countries. The most common diagnoses were antibody deficiencies (63.7%). At least one COVID-19 vaccine was administered to 806 patients (64.7%), and 216 patients received vaccination prior to the development of COVID-19. The most common vaccines administered were mRNA-based (84.0%). Seventeen patients were reported to seek outpatient clinic or emergency room care for a vaccine-related complication, and one patient was hospitalized for symptomatic anemia. Eight hundred twenty-three patients (66.1%) experienced COVID-19 infection. Of these, 156 patients required hospitalization (19.0%), 47 required ICU care (5.7%), and 28 died (3.4%). Rates of hospitalization (9.3% versus 24.4%, p < 0.001), ICU admission (2.8% versus 7.6%, p = 0.013), and death (2.3% versus 4.3%, p = 0.202) in patients who had COVID-19 were lower in patients who received vaccination prior to infection. In adjusted logistic regression analysis, not having at least one COVID-19 vaccine significantly increased the odds of hospitalization and ICU admission. CONCLUSION: Vaccination for COVID-19 in the IEI population appears safe and attenuates COVID-19 severity.

The HyperPed-COVID international registry: Impact of age of onset, disease presentation and geographical distribution on the final outcome of MIS-C.

OBJECTIVES: The aim of the study was to establish an international multicenter registry to collect data on patients with Multisystem Inflammatory Syndrome in Children (MIS-C), in order to highlight a relationship between clinical presentation, age of onset and geographical distribution on the clinical outcome. STUDY DESIGN: Multicenter retrospective study involving different international societies for rare immunological disorders.1009 patients diagnosed with MIS-C between March and September 2022, from 48 centers and 22 countries were collected. Five age groups (<1, 1-4, 5-11, 12-16, >16 years) and four geographic macro-areas, Western Europe, Central-Eastern Europe, Latin America, Asian-African resource-limited countries (LRC), were identified. RESULTS: Time to referral was significantly higher in LRC. Intensive anti-inflammatory treatment, including biologics, respiratory support and mechanic ventilation were more frequently used in older children and in European countries. The mortality rate was higher in very young children (<1 year), in older patients (>16 years of age) and in LRC. Multivariate analysis identified the residence in LRC, presence of severe cardiac involvement, renal hypertension, lymphopenia and non-use of heparin prophylaxis, as the factors most strongly associated with unfavorable outcomes. CONCLUSIONS: The stratification of patients by age and geographic macro-area provided insights into the clinical presentation, treatment and outcome of MIS-C. The mortality and sequelae rates exhibited a correlation with the age and geographical areas. Patients admitted and treated in LRC displayed more severe outcomes, possibly due to delays in hospital admission and limited access to biologic drugs and to intensive care facilities.

Early anakinra treatment improves cardiac outcome of multisystem inflammatory syndrome in children, regardless of disease severity.

OBJECTIVE: The main aim of this study was to define the best treatment option for multisystem inflammatory syndrome in children (MIS-C) and to analyse the role of anakinra. METHODS: This is a multicentre retrospective cohort study. Patients were treated according to the attending physician's decision. The patients were divided into four groups on the basis of the first treatment at time of admittance: (i) IVIG, (ii) IVIG and methylprednisolone (≤2 mg/kg/day), (iii) IVIG with high-dose methylprednisolone (>2 mg/kg/day) and (iv) anakinra with or without IVIG and/or methylprednisolone. Primary outcomes were defined as the presence of at least one of the following features: death, the failure of initial treatment, meaning the need for additional treatment for clinical worsening and cardiac involvement at the end of follow-up. RESULTS: Two hundred thirty-nine patients were recruited. At univariate analysis, persistent heart involvement at discharge was more frequent in those not receiving anakinra as initial treatment (3/21 vs 66/189; P = 0.047). After comparisons between the four treatment regimens, adjusting for the propensity score, we observed that early treatment with anakinra was associated with a lower probability of developing persistent heart disease at the end of follow-up (odds ratio: 0.6; 95% CI: 0.4-1.0). CONCLUSION: We report that early treatment with anakinra is safe and very effective in patients with severe MIS-C. In addition, our study suggests that early treatment with anakinra is the most favourable option for patients with a higher risk of developing a severe disease outcome.

A Novel LC-MS/MS Method for Therapeutic Drug Monitoring of Baricitinib in Plasma of Pediatric Patients.

BACKGROUND: Janus kinase inhibitors are antirheumatic immunosuppressive drugs that target intracellular Janus kinases (JAKs). Baricitinib is a selective and reversible orally administered JAK1/JAK2 inhibitor approved for treating rheumatoid arthritis, atopic dermatitis, and alopecia areata in adult patients. Expanded access to baricitinib has been approved for treating pediatric patients affected by rare Mendelian autoinflammatory diseases with type I interferon-mediated damage. Knowledge of the pharmacokinetic properties and target plasma levels of baricitinib in pediatric patients is limited. In this study, a novel LC-MS/MS method for measuring baricitinib in plasma, validated according to the ICH M10 guidelines, is presented. METHODS: Sample preparation was performed by adding 10 µL of IS working solution (150 ng/mL) and 200 µL of MeOH to each plasma sample. Chromatographic separation was conducted using a Thermo Scientific Accucore Polar Premium column (50 mm × 2.1 mm, i.d. 2.6 m). This method was applied to 7 real anonymous plasma samples obtained from pediatric patients treated with baricitinib at IRCCS Istituto Giannina Gaslini (Genoa, Italy). Patients of both sexes had a median age of 14 years (range, 10-17 years). RESULTS: The LC-MS/MS method resulted linear over wide concentration ranges (1.024-100 ng/mL) and was accurate and reproducible in the absence of matrix effects, allowing for robust, specific, and rapid quantification of baricitinib from a low amount of plasma (50 µL). The plasma concentration of baricitinib in the samples of the patients, expressed as mean ± SD, was 11.25 ± 10.86 ng/mL. CONCLUSIONS: This novel LC-MS/MS method is suitable for the therapeutic drug monitoring of baricitinib and can help guide therapy optimization in pediatric patients.

Epidemiological and clinical evolution of multisystem inflammatory syndrome in children throughout the SARS-CoV-2 pandemic in a tertiary Italian children's hospital.

Multisystem inflammatory syndrome in children (MIS-C) is a potentially life-threatening disease temporally linked to SARS-CoV-2 whose incidence and clinical presentation may have been altered by the different SARS-CoV-2 variants and by vaccination. METHODS: We retrospectively collected the data of all MIS-C cases admitted to the Gaslini Children's Hospital, the hub for SARS-CoV-2 related diseases in Liguria region, Italy, from 01 October 2020, to 30 November 2022, evaluating the ratio between MIS-C cases and (1) COVID-19 paediatric cases in our region, (2) emergency department admissions and (3) emergency department febrile patients. We also compared MIS-C incidence in pre- post-vaccination periods. RESULTS: We observed a significant global decline in the incidence of MIS-Cover the four variant periods and after the starting of vaccination whereas clinical features, therapeutic management and severity did not significantly vary. CONCLUSIONS: In our setting, we demonstrated a significant decrease of MIS-C incidence according to the predominant variant and including not vaccinated children. Regardless of variant type, the patients showed similar phenotypes and severity throughout the pandemic. SARS-CoV-2 variants as well as immune protection after previous infections and/or vaccination may have interacted by playing different roles and reducing the incidence of MIS-C.

Pediatric Recurrent Pericarditis: Appropriateness of the Standard of Care and Response to IL-1 Blockade.

OBJECTIVE: To analyze, in a cohort of pediatric patients with recurrent pericarditis undergoing anti-interleukin (IL)-1 treatment: the agent and dosing used as first-line treatment, the long-term efficacy of IL-1 blockers, the percentage of patients achieving a drug-free remission, and the presence of variables associated with drug-free remission. STUDY DESIGN: Data were collected from patients' charts. The annualized relapse rate (ARR) was used for evaluation of treatment efficacy, and bivariate logistic regression analysis was used for variables associated with drug-free remission. RESULTS: Fifty-eight patients, treated between 2008 and 2018, were included in the study (mean follow-up. 2.6 years). Of the 56 patients treated with first-line drugs, 14 not responsive patients were underdosed. Fifty-seven patients were treated with anakinra: the ARR before and during daily treatment was 3.05 and 0.28, respectively (P < .0001); an increase to 0.83 was observed after the reduction/withdrawal of treatment (P < .0001). The switch from anakinra to canakinumab (5 patients) was associated to an increase of the ARR (0.49 vs 1.46), but without statistical significance (P = .215). At last follow-up, only 9 of the 58 patients had withdrawn all treatments. With the limits of a retrospective study and the heterogeneity between the patients enrolled in the study, a shorter duration of treatment with anakinra was the only variable associated with drug-free remission. CONCLUSIONS: This study shows that most pediatric patients with recurrent pericarditis needing IL-1 blockade received an inadequate treatment with first-line agents. The effectiveness of anakinra is supported by this study, but few patients achieved drug-free remission. The different rate of response to anakinra and canakinumab may suggest a possible role of IL-1α in the pathogenesis of recurrent pericarditis.

Spontaneous NLRP3 inflammasome-driven IL-1-ß secretion is induced in severe COVID-19 patients and responds to anakinra treatment.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may result in a severe pneumonia associated with elevation of blood inflammatory parameters, reminiscent of cytokine storm syndrome. Steroidal anti-inflammatory therapies have shown efficacy in reducing mortality in critically ill patients; however, the mechanisms by which SARS-CoV-2 triggers such an extensive inflammation remain unexplained. OBJECTIVES: To dissect the mechanisms underlying SARS-CoV-2-associated inflammation in patients with severe coronavirus disease 2019 (COVID-19), we studied the role of IL-1ß, a pivotal cytokine driving inflammatory phenotypes, whose maturation and secretion are regulated by inflammasomes. METHODS: We analyzed nod-like receptor protein 3 pathway activation by means of confocal microscopy, plasma cytokine measurement, cytokine secretion following in vitro stimulation of blood circulating monocytes, and whole-blood RNA sequencing. The role of open reading frame 3a SARS-CoV-2 protein was assessed by confocal microscopy analysis following nucleofection of a monocytic cell line. RESULTS: We found that circulating monocytes from patients with COVID-19 display ASC (adaptor molecule apoptotic speck like protein-containing a CARD) specks that colocalize with nod-like receptor protein 3 inflammasome and spontaneously secrete IL-1ß in vitro. This spontaneous activation reverts following patient's treatment with the IL-1 receptor antagonist anakinra. Transfection of a monocytic cell line with cDNA coding for the ORF3a SARS-CoV-2 protein resulted in ASC speck formation. CONCLUSIONS: These results provide further evidence that IL-1ß targeting could represent an effective strategy in this disease and suggest a mechanistic explanation for the strong inflammatory manifestations associated with COVID-19.

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

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.

An Update on Familial Mediterranean Fever.

(1) Background: Familial Mediterranean Fever (FMF) is the prototypal autoinflammatory disease, characterized by recurrent bursts of neutrophilic inflammation. (2) Methods: In this study we look at the most recent literature on this condition and integrate it with novel information on treatment resistance and compliance. (3) Results: The canonical clinical presentation of FMF is in children with self-limited episodes of fever and polyserositis, associated with severe long-term complications, such as renal amyloidosis. It has been described anecdotally since ancient times, however only recently it has been characterized more accurately. We propose an updated overview on the main aspects of pathophysiology, genetics, diagnosis and treatment of this intriguing disease. (4) Conclusions: Overall, this review presents the all the main aspects, including real life outcome of the latest recommendation on treatment resistance of FMF, a disease, that not only helped understanding the pathophysiology of the auto inflammatory process but also the functioning of the innate immune system itself.

Complications of severe acute respiratory syndrome coronavirus 2 infection in children.

PURPOSE OF REVIEW: Although during the initial stages of COVID-19 pandemic, the pediatric population seemed to be less affected, a number of SARS-CoV-2-related manifestations emerged over time, the principal of which is the multisystem inflammatory syndrome in children (MIS-C). Here we provide an update on the main pediatric disorders associated with SARS-CoV-2 infection. RECENT FINDINGS: MIS-C is novel postinfectious manifestation with clinical features similar to Kawasaki disease and characterized by intense systemic inflammation affecting multiple organs. Many children required intensive care therapy because of circulatory shock, usually of myocardial origin. Appropriate treatment with immunomodulatory therapies led to favorable outcomes in most patients, with recovery of overall health and cardiac dysfunction. In addition to MIS-C, a variety of other complications of COVID-19 in children have been described, including thrombotic events, neurologic manifestations, and chilblain-like lesions. There is still uncertainty about the true prevalence of long COVID in children and its distinction from pandemic-related complaints. SUMMARY: The experience gained so far with MIS-C and the other SARS-CoV-2-related complications in children and adolescents will facilitate accurate diagnosis and appropriate treatment. Further studies are needed to elucidate the pathophysiology of MIS-C and to determine the real impact of long-COVID in the pediatric age group.

Hematopoietic Stem Cell Transplantation in ARPC1B Deficiency.

Mutations in the ARPC1B isoform component of human actin-related protein 2/3 complex have been recently associated with an inborn error of immunity characterized by combined immunodeficiency, allergies, autoinflammation, and platelet abnormalities. Currently, indications on the management of this novel disease and information on its outcome are lacking. We report the first case series of 7 children with a homozygous mutation in ARPC1B gene who underwent allogeneic-HSCT (allo-HSCT). All patients presented an early clinical onset, characterized by recurrent infections, failure to thrive and gastrointestinal bleeding episodes complicated with neonatal hemorrhagic enteritis in 3 cases, and macrophage activating syndrome in 2. Allo-HSCT was performed at the median age of 1.83 years after a myeloablative conditioning regimen in all cases. Engraftment occurred in all patients with full donor chimerism in 6 out of 7. The clinical course after engraftment was uneventful in 3 out of 7 children; 2 patients developed a grade 1-2 acute graft-versus-host disease (GvHD), and 1 patient a grade 1 chronic-GvHD. JC virus-related progressive multifocal leukoencephalopathy was diagnosed in one patient 13 months after haploidentical-HSCT and successfully managed with donor-derived viral-specific T-cell infusion. Only one patient had a fatal outcome 3 months after HSCT because of sepsis, after veno-occlusive disease, and transplant-associated microangiopathy. At a median follow-up of 19 months (range 3-110), 6 out of 7 patients are alive and disease-free. The severity of the clinical phenotype at diagnosis and the high survival rate, with limited transplant-related morbidity, strongly support the indication to allo-HSCT for patients with this diagnosis.

Dysregulation in B-cell responses and T follicular helper cell function in ADA2 deficiency patients.

Adenosine deaminase 2 deficiency (DADA2) is an autoinflammatory disease characterized by inflammatory vasculopathy, early strokes associated often with hypogammaglobulinemia. Pure red cell aplasia, thrombocytopenia, and neutropenia have been reported. The defect is due to biallelic loss of function of ADA2 gene, coding for a protein known to regulate the catabolism of extracellular adenosine. We therefore investigated immune phenotype and B- and T-cell responses in 14 DADA2 patients to address if ADA2 mutation affects B- and T-cell function. Here, we show a significant decrease in memory B cells, in particular class switch memory, and an expansion of CD21low B cells in DADA2 patients. In vitro stimulated B lymphocytes were able to secrete nonfunctional ADA2 protein, suggesting a cell intrinsic defect resulting in an impairment of B-cell proliferation and differentiation. Moreover, CD4+ and CD8+ T cells were diminished; however, the frequency of circulating T follicular helper cells was significantly increased but they had an impairment in IL-21 production possibly contributing to an impaired B cell help. Our findings suggest that ADA2 mutation could lead to a B-cell intrinsic defect but also to a defective Tfh cell function, which could contribute to the immunodeficient phenotype reported in DADA2 patients.

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

OBJECTIVES: To test the usefulness of an extended panel of lymphocyte subsets in combination with Oliveira's diagnostic criteria for the identification of autoimmune lymphoproliferative syndrome (ALPS) in children referred to a paediatric rheumatology centre. METHODS: Patients referred from 2015 to 2018 to our rheumatology unit for an autoimmune or autoinflammatory condition were retrospectively analysed. Oliveira's required criteria [chronic lymphoproliferation and elevated double-negative T (DNT)] were applied as first screening. Flow cytometry study included double-negative CD4-CD8-TCRαß+ T lymphocytes (DNT), CD25+CD3+, HLA-DR+CD3+ T cells, B220+ T cells and CD27+ B cells. Data were analysed with a univariate logistic regression analysis, followed by a multivariate analysis. Sensitivity and specificity of the Oliveira's required criteria were calculated. RESULTS: A total of 264 patients were included in the study and classified as: (i) autoimmune diseases (n = 26); (ii) juvenile idiopathic arthritis (JIA) (35); (iii) monogenic systemic autoinflammatory disease (27); (iv) periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (100); (v) systemic undefined recurrent fever (45); (vi) undetermined-systemic autoinflammatory disease (14); or (vii) ALPS (17). Oliveira's required criteria displayed a sensitivity of 100% and specificity of 79%. When compared with other diseases the TCRαß+B220+ lymphocytes were significantly increased in ALPS patients. The multivariate analysis revealed five clinical/laboratory parameters positively associated to ALPS: splenomegaly, female gender, arthralgia, elevated DNT and TCRαß+B220+ lymphocytes. CONCLUSIONS: Oliveira's required criteria are useful for the early suspicion of ALPS. TCRαß+B220+ lymphocytes should be added in the diagnostic work-up of patients referred to the paediatric rheumatology unit for a suspected autoimmune or autoinflammatory condition, providing a relevant support in the early diagnosis of ALPS.

Disparities in the prevalence of clinical features between systemic juvenile idiopathic arthritis and adult-onset Still's disease.

OBJECTIVE: To compare clinical features and treatments of patients with systemic JIA (sIJA) and adult-onset Still's disease (AOSD). METHODS: The clinical charts of consecutive patients with sJIA by International League of Association of Rheumatology criteria or AOSD by Yamaguchi criteria were reviewed. Patients were seen at a large paediatric rheumatology referral centre or at 10 adult rheumatology academic centres. Data collected included clinical manifestations, inflammation biomarkers, systemic score, macrophage activation syndrome (MAS), parenchymal lung disease, disease course, disability, death and medications administered. RESULTS: A total of 166 patients (median age at diagnosis 5 years) with sJIA and 194 patients with AOSD (median age at diagnosis 41 years) were included. The frequency of fever, rash, arthralgia, abdominal pain, MAS, parenchymal lung disease and increased acute phase reactants and ferritin were comparable between the two cohorts. Patients with sJIA had a higher prevalence of arthritis, whereas patients with AOSD had experienced leucocytosis and extra-articular organ involvement more frequently. Patients with AOSD were given more commonly low-dose corticosteroids, whereas biologic DMARDs were administered first-line more frequently in patients with sJIA. CONCLUSION: We found remarkable disparities in the prevalence of clinical manifestations between the two illnesses, which may partly depend on their classification by different criteria.

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

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.

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

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.

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

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.

Failure of first anti-TNF agent in Takayasu's arteritis: to switch or to swap?

OBJECTIVES: Biologic drugs (bDMARD), especially TNF-α-inhibitors (TNFi), are used in refractory Takayasu's arteritis (TAK) patients. Up to 23% of patients are switched to a different bDMARD because of inefficacy. No data are available on which strategy is more efficient after TNFi failure. The aim of our study is to evaluate whether a switch or swap strategy should be preferred in TAK patients failing TNFis. METHODS: TAK patients treated with a second bDMARD after the failure of the first TNFi were identified from 3 referral centres. Patients were classified as switch if treated with a different TNFi, and swap if treated with a non-TNFi bDMARD. Baseline features were evaluated. Efficacy and safety of the second bDMARD at 6 and 12 months were assessed and a comparison between switch and swap patients was made. RESULTS: Twenty-four TAK patients were identified. Eleven patients (46%) were switched and 13 patients (54%) were swapped (12 to tocilizumab, 1 to ustekinumab). Baseline features of patients in the 2 groups were comparable. At 12 months, the second bDMARD was suspended in 4 switch (36%) and in 5 swap (42%) patients. Second biologic drug survival and relapse-free survival were equivalent between the two groups at 6 and 12 months. A vascular worsening was observed in 4 switch (40%) and 2 swap (25%) patients. Severe infections, myocardial infarction, ischemic stroke or cancer were recorded in no patient. CONCLUSIONS: Our retrospective study suggests that in first-line TNFi failure TAK patients both switch and swap strategies can be considered suitable approaches.