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1.
Artigo em Inglês | MEDLINE | ID: mdl-33181346

RESUMO

BACKGROUND: TNF receptor-associated periodic syndrome (TRAPS) is a rare autoinflammatory disease caused by dominant mutation of the TNFRSF1A gene. Data regarding long-term treatment outcomes is lacking. OBJECTIVE: To assess correlations of genotype-phenotypes in TRAPS patients, 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 INSAID classification in group A (pathogenic or likely pathogenic variants), B (VUS or not classified variants), and C (benign or likely benign variants) and screened for Eurofever criteria. RESULTS: In group A (127/226 patients, 56%), all fulfilled Eurofever criteria and 20/127 patients (16%) developed AA amyloidosis. In group B (78/226 patients, 35%), 40/78 patients (51%) did not fulfill Eurofever criteria, displaying a lower incidence of abdominal pain (p<0.02) and higher efficacy rate of on-demand NSAIDs (p<0.02) and colchicine (p<0.001). Group C (21/226 patients, 9%) presented a milder disease (p<0.02) and none fulfilled Eurofever criteria. Anti-interleukin (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 seven women with history of failure to conceive had successful pregnancies. CONCLUSION: Anti-IL-1 drugs are the best maintenance treatment in TRAPS patients. The diagnosis of TRAPS should be considered very carefully in patients of group B not fulfilling Eurofever criteria and C, and colchicine may be preferable as first maintenance treatment.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33217613

RESUMO

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 SAVI patients. METHODS: Assessment of clinical, radiological, and immunologic data from 21 patients (17 families). RESULTS: Patients carried heterozygous substitutions in STING1 previously described in SAVI, mainly the p.V155M. Most patients were symptomatic from infancy but late onset in adulthood occurred in one 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 one infant mimicked a combined immune deficiency. Extended features reminiscent of other interferonopathies were also found e.g. intracranial calcification, glaucoma, 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 benefice of ruxolitinib in SAVI unless the treatment is started early in the course of the disease underlying the need for early diagnosis. Tolerance was reasonably good. CONCLUSION: This largest worldwide cohort of SAVI patients precise core features and extends the clinical and immunological phenotype of the disease, displaying overlap with other monogenic interferonopathies.

3.
Arthritis Rheumatol ; 2020 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-32892503

RESUMO

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 paediatric care providers given the typical early age of disease onset. We aim to describe the clinical phenotypes and treatment response of adults as well as paediatric DADA2 patients in India. METHODS: We conducted a retrospective analysis of DADA2 patients diagnosed at various rheumatology centres across India. The clinical characteristics, diagnostic findings and treatment response of all the subjects were analysed. RESULTS: We confirmed 33 cases of DADA2 between April 2017 and March 2020. Unlike previous studies, nearly half of the cases presented during adulthood. All symptomatic patients exhibited features of vasculitis while constitutional symptoms and anaemia were more common in paediatric patients. Cutaneous and neurologic involvement were common and 18 subjects had at least one stroke. In addition, we expand the clinical spectrum of DADA2 by describing novel features including pancreatic infarction, focal myocarditis and diffuse alveolar haemorrhage. Tumour necrosis factor inhibitors (TNFi) were initiated for 25 patients. All measured 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 two deaths were reported. CONCLUSIONS: We present the first case series of DADA2 patients from India. We highlight the presentation of DADA2 in adults and raise awareness of this syndrome for both adult and paediatric care providers.

4.
J Clin Immunol ; 40(7): 1026-1037, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32803625

RESUMO

Primary immunodeficiencies (PIDs) are heterogeneous disorders, characterized by variable clinical and immunological features. National PID registries offer useful insights on the epidemiology, diagnosis, and natural history of these disorders. In 1999, the Italian network for primary immunodeficiencies (IPINet) was established. We report on data collected from the IPINet registry after 20 years of activity. A total of 3352 pediatric and adult patients affected with PIDs are registered in the database. In Italy, a regional distribution trend of PID diagnosis was observed. Based on the updated IUIS classification of 2019, PID distribution in Italy showed that predominantly antibody deficiencies account for the majority of cases (63%), followed by combined immunodeficiencies with associated or syndromic features (22.5%). The overall age at diagnosis was younger for male patients. The minimal prevalence of PIDs in Italy resulted in 5.1 per 100.000 habitants. Mortality was similar to other European registries (4.2%). Immunoglobulin replacement treatment was prescribed to less than one third of the patient cohort. Collectively, this is the first comprehensive description of the PID epidemiology in Italy.

5.
Pediatr Rheumatol Online J ; 18(1): 67, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32819369

RESUMO

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.

6.
Eur J Immunol ; 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32707604

RESUMO

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.

7.
Pediatr Rheumatol Online J ; 18(1): 55, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32650789

RESUMO

BACKGROUND: FBLIM1 gene has been recently demonstrated to be involved in the pathogenesis of bone sterile inflammation. The aim of the study is to evaluate the prevalence of FBLIM1 gene variants in a cohort of 80 Italian patients with Chronic Non-bacterial Osteomyelitis (CNO). METHODS: The coding regions of FBLIM1 gene were sequenced in a cohort of 80 patients with CNO using DNA extracted from blood lymphocytes, and PCR products were sequenced. Only rare (global MAF < 2%), coding variants detected were considered. Clinical evaluation of patients with rare variants and those without was performed. Fisher's exact test was used to compare categorical and ordinal data, and Student's t-test was used to analyze continuous data. RESULTS: Eighteen out of 80 patients (~ 22%) presented at least one rare coding variant in FBLIM1. Eight patients presented a variant never associated before with CNO. All patients presented classical features of CNO and no statistical difference between patients with presence of FBLMI1 variants and those without were found in terms of clinical manifestation, treatment, and outcome. CONCLUSION: Considering the high frequency of rare variants in our CNO cohort, our data seem to confirm a possible role of FBLIM1 in the pathogenesis of CNO suggesting that CNO is a disorder of chronic inflammation and imbalanced bone remodeling.

8.
Pediatr Rheumatol Online J ; 18(1): 56, 2020 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-32653009

RESUMO

BACKGROUND: Hyperferritinemic syndromes are systemic inflammatory disorders characterized by a dysfunctional immune response, which leads to excessive activation of the monocyte-macrophage system with hypercytokinemia and may pursue a rapidly fatal course. CASE PRESENTATION: We describe two patients of 11 and 9 years of age with hyperferritinemic syndromes, one with impending macrophage activation syndrome (MAS) and one with overt MAS, who were refractory or intolerant to conventional therapies, but improved dramatically with canakinumab. CONCLUSIONS: Our report indicates that canakinumab may be efficacious in the management of hyperferritinemic syndromes, including MAS.

9.
Artigo em Inglês | MEDLINE | ID: mdl-32618445

RESUMO

Type I interferonopathies are a clinically heterogeneous group of inherited disorders of the innate immune system characterized by constitutive activation of the type I interferon-signaling pathway. Cutaneous vasculopathy, lipodystrophy, interstitial lung disease and brain calcifications are the typical manifestations characterizing affected patients. The pathogenic mechanism commonly underlying these disorders is the abnormal activation of immune pathways involved in recognition of non-self-oligonucleotides. These natural defenses against virus consent humans to survive the infections. Target therapies capable of inhibiting type I interferon signaling pathway seems effective in these patients, albeit with possible incomplete responses and severe side effects.

10.
Pediatr Rheumatol Online J ; 18(1): 51, 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32546242

RESUMO

BACKGROUND: Recurrent pericarditis (RP) is a complication (15-30%) of acute pericarditis with an unknown etiology. Treatment regimen consists of a combination of non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine, with the addition of corticosteroids in resistant or intolerant cases. In the last decade anakinra was shown as an effective treatment in patients with colchicine resistant and steroid-dependent RP, initially in anecdotal reports in children and more recently in a randomized trial. Canakinumab is a monoclonal antibody selectively blocking IL-1ß and its use is only anecdotally reported to treat pericarditis. We report two pediatric patients with refractory recurrent pericarditis, who presented an optimal response to anakinra treatment but prompt relapse after switch to canakinumab. CASE PRESENTATION: The first patient is a girl with Recurrent Pericarditis started in April 2015, after heart surgery. NSAIDs and oral steroids were started, with prompt relapse after steroid suspension. The child showed a steroid-dependent RP; anakinra was therefore started with excellent response, but discontinued after 2 weeks for local reactions. In July 2016 therapy with canakinumab was started. She experienced four relapses during canakinumab therapy despite dosage increase and steroid treatment. In January 2018 a procedure of desensitization from anakinra was performed, successfully. Anakinra as monotherapy is currently ongoing, without any sign of flare. The second patient is a girl with an idiopathic RP, who showed an initial benefit from NSAIDs and colchicine. However, 10 days after the first episode a relapse occurred and therapy with anakinra was established. Two months later, while being in complete remission, anakinra was replaced with canakinumab due to patient's poor compliance to daily injections. She experienced a relapse requiring steroids 10 days after the first canakinumab injection. Anakinra was subsequently re-started with complete remission, persisting after 24 months follow-up. CONCLUSIONS: We describe two cases of failure of the treatment with anti-IL-1ß monoclonal antibodies in steroid- dependent idiopathic RP. This anecdotal and preliminary observation suggests a different efficacy of the two IL-1 blockers in the management of RP and support a possible pivotal role of IL-1α in the pathogenesis of this condition.

16.
Arthritis Rheumatol ; 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: covidwho-60433

RESUMO

Poor outcomes in COVID-19 correlate with clinical and laboratory features of cytokine storm syndrome. Broad screening for cytokine storm and early, targeted antiinflammatory therapy may prevent immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in cytokine storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID-19.

17.
Arthritis Rheumatol ; 72(7): 1059-1063, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32293098

RESUMO

Poor outcomes in COVID-19 correlate with clinical and laboratory features of cytokine storm syndrome. Broad screening for cytokine storm and early, targeted antiinflammatory therapy may prevent immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in cytokine storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/virologia , Pneumonia Viral/imunologia , Betacoronavirus , Biomarcadores , Infecções por Coronavirus/complicações , Infecções por Coronavirus/terapia , Síndrome da Liberação de Citocina/diagnóstico , Intervenção Médica Precoce , Humanos , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/terapia
18.
Clin Chem ; 66(4): 525-536, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32176780

RESUMO

BACKGROUND: Monogenic autoinflammatory diseases are caused by pathogenic variants in genes that regulate innate immune responses, and are characterized by sterile systemic inflammatory episodes. Since symptoms can overlap within this rapidly expanding disease category, accurate genetic diagnosis is of the utmost importance to initiate early inflammation-targeted treatment and prevent clinically significant or life-threatening complications. Initial recommendations for the genetic diagnosis of autoinflammatory diseases were limited to a gene-by-gene diagnosis strategy based on the Sanger method, and restricted to the 4 prototypic recurrent fevers (MEFV, MVK, TNFRSF1A, and NLRP3 genes). The development of best practices guidelines integrating critical recent discoveries has become essential. METHODS: The preparatory steps included 2 online surveys and pathogenicity annotation of newly recommended genes. The current guidelines were drafted by European Molecular Genetics Quality Network members, then discussed by a panel of experts of the International Society for Systemic Autoinflammatory Diseases during a consensus meeting. RESULTS: In these guidelines, we combine the diagnostic strength of next-generation sequencing and recommendations to 4 more recently identified genes (ADA2, NOD2, PSTPIP1, and TNFAIP3), nonclassical pathogenic genetic alterations, and atypical phenotypes. We present a referral-based decision tree for test scope and method (Sanger versus next-generation sequencing) and recommend on complementary explorations for mosaicism, copy-number variants, and gene dose. A genotype table based on the 5-category variant pathogenicity classification provides the clinical significance of prototypic genotypes per gene and disease. CONCLUSIONS: These guidelines will orient and assist geneticists and health practitioners in providing up-to-date and appropriate diagnosis to their patients.


Assuntos
Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenosina Desaminase/genética , Proteínas do Citoesqueleto/genética , Testes Genéticos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteína Adaptadora de Sinalização NOD2/genética , Guias de Prática Clínica como Assunto , Diagnóstico Pré-Natal , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética
20.
Orphanet J Rare Dis ; 15(1): 33, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000824

RESUMO

The Rare Immunodeficiency, AutoInflammatory and AutoImmune Disease (RITA) network is a European Research Network (ERN) that brings together the leading centres for rare immune disorders. On April 2018 an online survey was sent to all RITA members in order to facilitate the harmonization of data collection in rare immune disorders registries. Currently, as many as 52 different registries collect data on rare immune disorders, of whom 30 (58%) are dedicated primarily to autoimmune diseases, 15 (29%) to primary immunodeficiencies and 12 (23%) to autoinflammatory disorders. Improving data on patient safety, outcome, and quality of life measures is warranted to unfold the full potential of RITA registries.

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