Clinical and experimental rheumatology, Jan 5, 2015
Cryopyrin-associated periodic syndromes (CAPS) are dominantly-inherited autoinflammatory diseases... more Cryopyrin-associated periodic syndromes (CAPS) are dominantly-inherited autoinflammatory diseases. The uncontrolled IL-1β overproduction observed in these patients is the rational basis to treat them with anti-IL-1 drugs. The objective of this study was to evaluate the efficacy and safety of treatment with the long-lasting fully humanised anti-IL-1β monoclonal antibody canakinumab in a Spanish cohort of patients with CAPS. Clinical and laboratory data of CAPS patients carrying a heterozygous germline NLRP3 mutation were obtained. The initial treatment scheme with canakinumab was 150 mg/8 weeks administered subcutaneously in adult patients and 2 mg/kg/8 weeks in paediatric patients. Eight unrelated patients were enrolled. Canakinumab was the first anti-IL-1 drug used in three of them; five were already receiving anakinra. The clinical response to the initial canakinumab scheme was positive in all patients, and was quickly observed in the first 24-72 hours. Four required increasing th...
Autoinflammatory diseases (AID) are usually diagnosed during the pediatric age. However, adult-on... more Autoinflammatory diseases (AID) are usually diagnosed during the pediatric age. However, adult-onset disease or diagnosis during adulthood has been occasionally described. To assess the clinical and genetic characteristics of adult patients diagnosed with an AID in an adult referral center for AID. We retrospectively evaluated clinical and genetic features of adult patients (≥16years) diagnosed with an AID or referred after AID diagnosis to the Clinical Unit of AID, at the Department of Autoimmune Diseases, Hospital Clínic of Barcelona, from 2008 to 2014. During the study period, a genetic study for suspected AID was requested to 90 patients at the Department of Autoimmune Diseases. A final diagnosis of monogenic AID was achieved in 17 patients (19% of patients tested). Five additional cases were diagnosed with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome and 10 patients with AID were referred from other adult departments. Finally, a total of 32 patients with AID were finally diagnosed or monitored in our Clinical Unit. These included 12 (37.5%) familial Mediterranean fever, 6 (18.8%) tumour necrosis factor-receptor associated periodic syndrome, 8 (25%) cryopirin-associated periodic syndromes (Muckle-Wells syndrome [MWS] or overlap familial cold-associated periodic syndrome/MWS), 1 (3.1%) mevalonate kinase deficiency, and 5 (15.6%) PFAPA. Clinical evidence of disease-onset during childhood and adulthood was observed in 15 (47%) and 17 (53%) patients, respectively. Overall, the final diagnosis was obtained after a delay of a mean of 12years (range 0-47years). Compared to children, adult patients with AID in our series presented more frequently with non-severe manifestations and none of them developed amyloidosis during follow-up. Adult patients also carried higher proportion of low-penetrance mutations or polymorphisms and all genetic variants were presented in heterozygosis or as heterozygous compounds. Adult disease-onset or delayed diagnosis of AID during adulthood is associated with milder disease phenotypes, and seem to be driven by mild genotypes, with predominant presence of low-penetrance mutations or polymorphisms.
The Journal of allergy and clinical immunology, Jan 26, 2015
Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving e... more Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving extremely high serum concentrations of the proinflammatory alarmin myeloid-related protein (MRP) 8/14 (S100A8/S100A9 and calprotectin). We sought to characterize the genetic cause and clinical spectrum of Hz/Hc. Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene sequencing was performed in 14 patients with Hz/Hc, and their clinical phenotype was compared with that of 11 patients with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. PSTPIP1-pyrin interactions were analyzed by means of immunoprecipitation and Western blotting. A structural model of the PSTPIP1 dimer was generated. Cytokine profiles were analyzed by using the multiplex immunoassay, and MRP8/14 serum concentrations were analyzed by using an ELISA. Thirteen patients were heterozygous for a missense mutation in the PSTPIP1 gene, resulting in a p.E250K mutation, and 1 carried a mutation ...
Assembly of the NLRP3 inflammasome activates caspase-1 and mediates the processing and release of... more Assembly of the NLRP3 inflammasome activates caspase-1 and mediates the processing and release of the leaderless cytokine IL-1β and thereby serves a central role in the inflammatory response and in diverse human diseases. Here we found that upon activation of caspase-1, oligomeric NLRP3 inflammasome particles were released from macrophages. Recombinant oligomeric protein particles composed of the adaptor ASC or the p.D303N mutant form of NLRP3 associated with cryopyrin-associated periodic syndromes (CAPS) stimulated further activation of caspase-1 extracellularly, as well as intracellularly after phagocytosis by surrounding macrophages. We found oligomeric ASC particles in the serum of patients with active CAPS but not in that of patients with other inherited autoinflammatory diseases. Our findings support a model whereby the NLRP3 inflammasome, acting as an extracellular oligomeric complex, amplifies the inflammatory response.
We investigated the cause of hereditary periodic fever syndrome in a Spanish child with recurrent... more We investigated the cause of hereditary periodic fever syndrome in a Spanish child with recurrent long episodes of fever, migratory skin rash, myalgia, arthralgia, conjunctivitis and abdominal pain. Infectious and autoimmune causes were ruled out. No familial history was reported. Analysis of the tumour necrosis factor receptor superfamily 1A (TNFRSF1A) gene identified a missense mutation (G36E) on exon 3. The absence of this variant in the patient's parents and in controls identified it as a de novo disease-associated mutation. Clinical symptoms disappeared with administration of etanercept; however, levels of acute-phase reactants remained increased and could not be stabilised by the addition of colchicine. We believe that this patient gained some symptomatic relief with etanercept therapy, although not enough to completely avoid the risk of amyloidosis. Thus it is debatable whether etanercept alone or combined with other drugs, is the treatment of choice for patients with tumour necrosis factor receptor-associated periodic syndrome. Since there is variability in treatment responses among different patients with tumour necrosis factor receptor-associated periodic syndrome, we suggest that a systematic evaluation of acute-phase reactants, especially SAA-1, could be useful in maintaining or modifying a given therapeutic approach in these patients.
Hereditary periodic fever syndromes (HPFS) are rare genetic diseases characterized by recurrent e... more Hereditary periodic fever syndromes (HPFS) are rare genetic diseases characterized by recurrent episodes of inflammation. Little information is available concerning HPFS in Latin American Hispanic population. The purpose of this study was to determine the clinical and genetic features of HPFS in Chilean population. A multicenter retrospective study of Hispanic Chilean patients with genetically confirmed HPFS was performed. We included 13 patients, 8 with familial Mediterranean fever (FMF) and 5 with TNF receptor-associated periodic syndrome (TRAPS), evaluated at rheumatology or pediatric rheumatology clinics between January 2007 and December 2010. Median age of symptoms onset was 8 years (range 1-35) and 8 years (range 0.3-21) for FMF and TRAPS, respectively. Median duration of fever was 3 days (range 2.5-15) for FMF and 21 days (range 9.5-30) for TRAPS. Genotyping of the MEFV gene in FMF patients revealed a homozygous M694V missense mutation in one patient, and heterozygous missense mutations in seven patients: M694V (n = 3), E148Q, R717H, A744S, and A511V. Sequencing of the TNFRSF1A gene in TRAPS patients revealed heterozygous missense mutations in four patients: T50M, C30R, R92Q, and IVS3+30:G→A, and a two-base pair deletion (IVS2-17_18del2bpCT) in one patient. Mutation in MEFV R717H and mutations in TNFRSF1A IVS2-17_18del2bpCT and IVS3+30:G→A are novel and have not been described previously. This study reports the largest series of genetically confirmed HPFS in Latin America, and adds evidence regarding the clinical and genetic characteristics of patients with FMF and TRAPS in Hispanic population. Mutations identified in MEFV and TNFRSF1A genes include defects reported in other ethnicities and novel mutations.
Objective. Chronic infantile neurologic, cutaneous, articular syndrome (CINCA), also known as neo... more Objective. Chronic infantile neurologic, cutaneous, articular syndrome (CINCA), also known as neonatal-onset multisystem inflammatory disease (NOMID), is a severe, early-onset autoinflammatory disease characterized by an urticaria-like rash, arthritis/ arthropathy, variable neurologic involvement, and dysmorphic features, which usually respond to interleukin-1 blockade. CINCA/NOMID has been associated with dominant Mendelian inherited NLRP3 mutations. However, conventional sequencing analyses detect true disease-causing mutations in only ϳ55-60% of patients, which suggests the presence of genetic heterogeneity. We undertook the current study to assess the presence of somatic, nongermline NLRP3 mutations in a sporadic case of CINCA/NOMID.
Blau syndrome and early-onset sarcoidosis are NOD2 gene-associated chronic autoinflammatory disea... more Blau syndrome and early-onset sarcoidosis are NOD2 gene-associated chronic autoinflammatory diseases characterized by skin rash, arthritis, and/or eye involvement, with noncaseating granulomata as their pathologic hallmark. This study was undertaken to describe the expanded clinical phenotype, treatment outcomes, and NOD2 gene mutation analysis in a Spanish cohort with pediatric granulomatous arthritis, a chronic disease resembling Blau syndrome/early-onset sarcoidosis. Clinical, laboratory, and treatment data on the 12 patients in the cohort were obtained through direct interviews. NOD2 gene analysis was performed in a central laboratory, by bidirectional sequencing. Cytokine levels were measured using the human Flex-Set cytokine bead array. The classic Blau syndrome/early-onset sarcoidosis triad of skin rash, arthritis, and recurrent uveitis was identified in 5 patients (41.7%), whereas 7 patients (58.3%) presented with fewer than 3 of the classic features. Novel atypical manifestations such as persistent fever and myocardiopathy were also observed. NOD2 analysis revealed 1 heterozygous mutation in each patient, and familial studies confirmed its full penetrance. Of the 12 cases, 58.3% were sporadic, due to de novo mutations. Four different missense mutations on exon 4 were detected. Two of them (R334W and R334Q) were recurrent mutations and were found in 77.8% of the Spanish families, whereas the other 2 (C495Y and R587C) were novel. In the patient who received anakinra treatment, all clinical inflammatory symptoms improved and plasma cytokine levels normalized. These findings indicate that the expanding clinical heterogeneity of the disease (that is, the presentation of incomplete forms of the classic triad and atypical manifestations) and the high prevalence of sporadic cases should alert clinicians to the possible genetic basis of the condition and support the inclusion of DNA analysis as a diagnostic test. The positive response to anakinra observed in 1 patient suggests a new potential therapeutic approach that merits further investigation, and suggests that the pathogenesis of pediatric granulomatous arthritis may involve interleukin-1-mediated events.
Objective To report on the demographic data from the fi rst 18 months of enrollment to an interna... more Objective To report on the demographic data from the fi rst 18 months of enrollment to an international registry on autoinfl ammatory diseases in the context of the Eurofever project. Methods A web-based registry collecting baseline and clinical information on autoinfl ammatory diseases and related conditions is available in the member area of the PRINTO web-site. Anonymised data were collected with standardised forms.
Clinical and experimental rheumatology, Jan 5, 2015
Cryopyrin-associated periodic syndromes (CAPS) are dominantly-inherited autoinflammatory diseases... more Cryopyrin-associated periodic syndromes (CAPS) are dominantly-inherited autoinflammatory diseases. The uncontrolled IL-1β overproduction observed in these patients is the rational basis to treat them with anti-IL-1 drugs. The objective of this study was to evaluate the efficacy and safety of treatment with the long-lasting fully humanised anti-IL-1β monoclonal antibody canakinumab in a Spanish cohort of patients with CAPS. Clinical and laboratory data of CAPS patients carrying a heterozygous germline NLRP3 mutation were obtained. The initial treatment scheme with canakinumab was 150 mg/8 weeks administered subcutaneously in adult patients and 2 mg/kg/8 weeks in paediatric patients. Eight unrelated patients were enrolled. Canakinumab was the first anti-IL-1 drug used in three of them; five were already receiving anakinra. The clinical response to the initial canakinumab scheme was positive in all patients, and was quickly observed in the first 24-72 hours. Four required increasing th...
Autoinflammatory diseases (AID) are usually diagnosed during the pediatric age. However, adult-on... more Autoinflammatory diseases (AID) are usually diagnosed during the pediatric age. However, adult-onset disease or diagnosis during adulthood has been occasionally described. To assess the clinical and genetic characteristics of adult patients diagnosed with an AID in an adult referral center for AID. We retrospectively evaluated clinical and genetic features of adult patients (≥16years) diagnosed with an AID or referred after AID diagnosis to the Clinical Unit of AID, at the Department of Autoimmune Diseases, Hospital Clínic of Barcelona, from 2008 to 2014. During the study period, a genetic study for suspected AID was requested to 90 patients at the Department of Autoimmune Diseases. A final diagnosis of monogenic AID was achieved in 17 patients (19% of patients tested). Five additional cases were diagnosed with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome and 10 patients with AID were referred from other adult departments. Finally, a total of 32 patients with AID were finally diagnosed or monitored in our Clinical Unit. These included 12 (37.5%) familial Mediterranean fever, 6 (18.8%) tumour necrosis factor-receptor associated periodic syndrome, 8 (25%) cryopirin-associated periodic syndromes (Muckle-Wells syndrome [MWS] or overlap familial cold-associated periodic syndrome/MWS), 1 (3.1%) mevalonate kinase deficiency, and 5 (15.6%) PFAPA. Clinical evidence of disease-onset during childhood and adulthood was observed in 15 (47%) and 17 (53%) patients, respectively. Overall, the final diagnosis was obtained after a delay of a mean of 12years (range 0-47years). Compared to children, adult patients with AID in our series presented more frequently with non-severe manifestations and none of them developed amyloidosis during follow-up. Adult patients also carried higher proportion of low-penetrance mutations or polymorphisms and all genetic variants were presented in heterozygosis or as heterozygous compounds. Adult disease-onset or delayed diagnosis of AID during adulthood is associated with milder disease phenotypes, and seem to be driven by mild genotypes, with predominant presence of low-penetrance mutations or polymorphisms.
The Journal of allergy and clinical immunology, Jan 26, 2015
Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving e... more Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving extremely high serum concentrations of the proinflammatory alarmin myeloid-related protein (MRP) 8/14 (S100A8/S100A9 and calprotectin). We sought to characterize the genetic cause and clinical spectrum of Hz/Hc. Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene sequencing was performed in 14 patients with Hz/Hc, and their clinical phenotype was compared with that of 11 patients with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. PSTPIP1-pyrin interactions were analyzed by means of immunoprecipitation and Western blotting. A structural model of the PSTPIP1 dimer was generated. Cytokine profiles were analyzed by using the multiplex immunoassay, and MRP8/14 serum concentrations were analyzed by using an ELISA. Thirteen patients were heterozygous for a missense mutation in the PSTPIP1 gene, resulting in a p.E250K mutation, and 1 carried a mutation ...
Assembly of the NLRP3 inflammasome activates caspase-1 and mediates the processing and release of... more Assembly of the NLRP3 inflammasome activates caspase-1 and mediates the processing and release of the leaderless cytokine IL-1β and thereby serves a central role in the inflammatory response and in diverse human diseases. Here we found that upon activation of caspase-1, oligomeric NLRP3 inflammasome particles were released from macrophages. Recombinant oligomeric protein particles composed of the adaptor ASC or the p.D303N mutant form of NLRP3 associated with cryopyrin-associated periodic syndromes (CAPS) stimulated further activation of caspase-1 extracellularly, as well as intracellularly after phagocytosis by surrounding macrophages. We found oligomeric ASC particles in the serum of patients with active CAPS but not in that of patients with other inherited autoinflammatory diseases. Our findings support a model whereby the NLRP3 inflammasome, acting as an extracellular oligomeric complex, amplifies the inflammatory response.
We investigated the cause of hereditary periodic fever syndrome in a Spanish child with recurrent... more We investigated the cause of hereditary periodic fever syndrome in a Spanish child with recurrent long episodes of fever, migratory skin rash, myalgia, arthralgia, conjunctivitis and abdominal pain. Infectious and autoimmune causes were ruled out. No familial history was reported. Analysis of the tumour necrosis factor receptor superfamily 1A (TNFRSF1A) gene identified a missense mutation (G36E) on exon 3. The absence of this variant in the patient's parents and in controls identified it as a de novo disease-associated mutation. Clinical symptoms disappeared with administration of etanercept; however, levels of acute-phase reactants remained increased and could not be stabilised by the addition of colchicine. We believe that this patient gained some symptomatic relief with etanercept therapy, although not enough to completely avoid the risk of amyloidosis. Thus it is debatable whether etanercept alone or combined with other drugs, is the treatment of choice for patients with tumour necrosis factor receptor-associated periodic syndrome. Since there is variability in treatment responses among different patients with tumour necrosis factor receptor-associated periodic syndrome, we suggest that a systematic evaluation of acute-phase reactants, especially SAA-1, could be useful in maintaining or modifying a given therapeutic approach in these patients.
Hereditary periodic fever syndromes (HPFS) are rare genetic diseases characterized by recurrent e... more Hereditary periodic fever syndromes (HPFS) are rare genetic diseases characterized by recurrent episodes of inflammation. Little information is available concerning HPFS in Latin American Hispanic population. The purpose of this study was to determine the clinical and genetic features of HPFS in Chilean population. A multicenter retrospective study of Hispanic Chilean patients with genetically confirmed HPFS was performed. We included 13 patients, 8 with familial Mediterranean fever (FMF) and 5 with TNF receptor-associated periodic syndrome (TRAPS), evaluated at rheumatology or pediatric rheumatology clinics between January 2007 and December 2010. Median age of symptoms onset was 8 years (range 1-35) and 8 years (range 0.3-21) for FMF and TRAPS, respectively. Median duration of fever was 3 days (range 2.5-15) for FMF and 21 days (range 9.5-30) for TRAPS. Genotyping of the MEFV gene in FMF patients revealed a homozygous M694V missense mutation in one patient, and heterozygous missense mutations in seven patients: M694V (n = 3), E148Q, R717H, A744S, and A511V. Sequencing of the TNFRSF1A gene in TRAPS patients revealed heterozygous missense mutations in four patients: T50M, C30R, R92Q, and IVS3+30:G→A, and a two-base pair deletion (IVS2-17_18del2bpCT) in one patient. Mutation in MEFV R717H and mutations in TNFRSF1A IVS2-17_18del2bpCT and IVS3+30:G→A are novel and have not been described previously. This study reports the largest series of genetically confirmed HPFS in Latin America, and adds evidence regarding the clinical and genetic characteristics of patients with FMF and TRAPS in Hispanic population. Mutations identified in MEFV and TNFRSF1A genes include defects reported in other ethnicities and novel mutations.
Objective. Chronic infantile neurologic, cutaneous, articular syndrome (CINCA), also known as neo... more Objective. Chronic infantile neurologic, cutaneous, articular syndrome (CINCA), also known as neonatal-onset multisystem inflammatory disease (NOMID), is a severe, early-onset autoinflammatory disease characterized by an urticaria-like rash, arthritis/ arthropathy, variable neurologic involvement, and dysmorphic features, which usually respond to interleukin-1 blockade. CINCA/NOMID has been associated with dominant Mendelian inherited NLRP3 mutations. However, conventional sequencing analyses detect true disease-causing mutations in only ϳ55-60% of patients, which suggests the presence of genetic heterogeneity. We undertook the current study to assess the presence of somatic, nongermline NLRP3 mutations in a sporadic case of CINCA/NOMID.
Blau syndrome and early-onset sarcoidosis are NOD2 gene-associated chronic autoinflammatory disea... more Blau syndrome and early-onset sarcoidosis are NOD2 gene-associated chronic autoinflammatory diseases characterized by skin rash, arthritis, and/or eye involvement, with noncaseating granulomata as their pathologic hallmark. This study was undertaken to describe the expanded clinical phenotype, treatment outcomes, and NOD2 gene mutation analysis in a Spanish cohort with pediatric granulomatous arthritis, a chronic disease resembling Blau syndrome/early-onset sarcoidosis. Clinical, laboratory, and treatment data on the 12 patients in the cohort were obtained through direct interviews. NOD2 gene analysis was performed in a central laboratory, by bidirectional sequencing. Cytokine levels were measured using the human Flex-Set cytokine bead array. The classic Blau syndrome/early-onset sarcoidosis triad of skin rash, arthritis, and recurrent uveitis was identified in 5 patients (41.7%), whereas 7 patients (58.3%) presented with fewer than 3 of the classic features. Novel atypical manifestations such as persistent fever and myocardiopathy were also observed. NOD2 analysis revealed 1 heterozygous mutation in each patient, and familial studies confirmed its full penetrance. Of the 12 cases, 58.3% were sporadic, due to de novo mutations. Four different missense mutations on exon 4 were detected. Two of them (R334W and R334Q) were recurrent mutations and were found in 77.8% of the Spanish families, whereas the other 2 (C495Y and R587C) were novel. In the patient who received anakinra treatment, all clinical inflammatory symptoms improved and plasma cytokine levels normalized. These findings indicate that the expanding clinical heterogeneity of the disease (that is, the presentation of incomplete forms of the classic triad and atypical manifestations) and the high prevalence of sporadic cases should alert clinicians to the possible genetic basis of the condition and support the inclusion of DNA analysis as a diagnostic test. The positive response to anakinra observed in 1 patient suggests a new potential therapeutic approach that merits further investigation, and suggests that the pathogenesis of pediatric granulomatous arthritis may involve interleukin-1-mediated events.
Objective To report on the demographic data from the fi rst 18 months of enrollment to an interna... more Objective To report on the demographic data from the fi rst 18 months of enrollment to an international registry on autoinfl ammatory diseases in the context of the Eurofever project. Methods A web-based registry collecting baseline and clinical information on autoinfl ammatory diseases and related conditions is available in the member area of the PRINTO web-site. Anonymised data were collected with standardised forms.
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Papers by Juan Aróstegui