@article {10549, title = {ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study.}, journal = {Ann Rheum Dis}, volume = {76}, year = {2017}, month = {2017 Oct}, pages = {1648-1656}, abstract = {

OBJECTIVES: To analyse the prevalence of mutations in patients diagnosed with early onset livedo reticularis and/or haemorrhagic/ischaemic strokes in the context of inflammation or polyarteritis nodosa (PAN). Forty-eight patients from 43 families were included in the study.

METHODS: Direct sequencing of was performed by Sanger analysis. Adenosine deaminase 2 (ADA2) enzymatic activity was analysed in monocyte isolated from patients and healthy controls incubated with adenosine and with or without an ADA1 inhibitor.

RESULTS: Biallelic homozygous or compound heterozygous mutations were detected in 15/48 patients. A heterozygous disease-associated mutation (p.G47V) was observed in two affected brothers. The mean age of onset of the genetically positive patients was 24 months (6 months to 7 years). Ten patients displayed one or more cerebral strokes during their disease course. Low immunoglobulin levels were detected in six patients. Thalidomide and anti-TNF (tumour necrosis factor) blockers were the most effective drugs. Patients without mutations had a later age at disease onset, a lower prevalence of neurological and skin manifestations; one of these patients displayed all the clinical features of adenosine deaminase 2deficiency (DADA2) and a defective enzymatic activity suggesting the presence of a missed mutation or a synthesis defect.

CONCLUSIONS: DADA2 accounts for paediatric patients diagnosed with PAN-like disease and strokes and might explain an unrecognised condition in patients followed by adult rheumatologist. Timely diagnosis and treatment with anti-TNF agents are crucial for the prevention of severe complications of the disease. Functional assay to measure ADA2 activity should complement genetic testing in patients with non-confirming genotypes.

}, keywords = {Adenosine Deaminase, Adolescent, Age of Onset, Case-Control Studies, Child, Child, Preschool, DNA Mutational Analysis, Female, Heterozygote, Homozygote, Humans, Immunoglobulins, Immunosuppressive Agents, Infant, Intercellular Signaling Peptides and Proteins, Italy, Livedo Reticularis, Male, Pedigree, Polyarteritis Nodosa, Stroke, Thalidomide, Tumor Necrosis Factor-alpha, Young Adult}, issn = {1468-2060}, doi = {10.1136/annrheumdis-2016-210802}, author = {Caorsi, Roberta and Penco, Federica and Grossi, Alice and Insalaco, Antonella and Omenetti, Alessia and Alessio, Maria and Conti, Giovanni and Marchetti, Federico and Picco, Paolo and Tommasini, Alberto and Martino, Silvana and Malattia, Clara and Gallizi, Romina and Podda, Rosa Anna and Salis, Annalisa and Falcini, Fernanda and Schena, Francesca and Garbarino, Francesca and Morreale, Alessia and Pardeo, Manuela and Ventrici, Claudia and Passarelli, Chiara and Zhou, Qing and Severino, Mariasavina and Gandolfo, Carlo and Damonte, Gianluca and Martini, Alberto and Ravelli, Angelo and Aksentijevich, Ivona and Ceccherini, Isabella and Gattorno, Marco} } @article {10555, title = {Intra-articular corticosteroids versus intra-articular corticosteroids plus methotrexate in oligoarticular juvenile idiopathic arthritis: a multicentre, prospective, randomised, open-label trial.}, journal = {Lancet}, volume = {389}, year = {2017}, month = {2017 03 04}, pages = {909-916}, abstract = {

BACKGROUND: Little evidence-based information is available to guide the treatment of oligoarticular juvenile idiopathic arthritis. We aimed to investigate whether oral methotrexate increases the efficacy of intra-articular corticosteroid therapy.

METHODS: We did this prospective, open-label, randomised trial at ten hospitals in Italy. Using a concealed computer-generated list, children younger than 18 years with oligoarticular-onset disease were randomly assigned (1:1) to intra-articular corticosteroids alone or in combination with oral methotrexate (15 mg/m; maximum 20 mg). Corticosteroids used were triamcinolone hexacetonide (shoulder, elbow, wrist, knee, and tibiotalar joints) or methylprednisolone acetate (ie, subtalar and tarsal joints). We did not mask patients or investigators to treatment assignments. Our primary outcome was the proportion of patients in the intention-to-treat population who had remission of arthritis in all injected joints at 12 months. This trial is registered with European Union Clinical Trials Register, EudraCT number 2008-006741-70.

FINDINGS: Between July 7, 2009, and March 31, 2013, we screened 226 participants and randomly assigned 102 to intra-articular corticosteroids alone and 105 to intra-articular corticosteroids plus methotrexate. 33 (32\%) patients assigned to intra-articular corticosteroids alone and 39 (37\%) assigned to intra-articular corticosteroids and methotrexate therapy had remission of arthritis in all injected joints (p=0{\textperiodcentered}48). Adverse events were recorded for 20 (17\%) patients who received methotrexate, which led to permanent treatment discontinuation in two patients (one due to increased liver transaminases and one due to gastrointestinal discomfort). No patient had a serious adverse event.

INTERPRETATION: Concomitant administration of methotrexate did not augment the effectiveness of intra-articular corticosteroid therapy. Future studies are needed to define the optimal therapeutic strategies for oligoarticular juvenile idiopathic arthritis.

FUNDING: Italian Agency of Drug Evaluation.

}, keywords = {Adrenal Cortex Hormones, Arthritis, Juvenile, Humans, Injections, Intra-Articular, Italy, Methotrexate, Prospective Studies, Treatment Outcome}, issn = {1474-547X}, doi = {10.1016/S0140-6736(17)30065-X}, author = {Ravelli, Angelo and Dav{\`\i}, Sergio and Bracciolini, Giulia and Pistorio, Angela and Consolaro, Alessandro and van Dijkhuizen, Evert Hendrik Pieter and Lattanzi, Bianca and Filocamo, Giovanni and Verazza, Sara and Gerloni, Valeria and Gattinara, Maurizio and Pontikaki, Irene and Insalaco, Antonella and De Benedetti, Fabrizio and Civino, Adele and Presta, Giuseppe and Breda, Luciana and Marzetti, Valentina and Pastore, Serena and Magni-Manzoni, Silvia and Maggio, Maria Cristina and Garofalo, Franco and Rigante, Donato and Gattorno, Marco and Malattia, Clara and Picco, Paolo and Viola, Stefania and Lanni, Stefano and Ruperto, Nicolino and Martini, Alberto} } @article {8331, title = {Clinical Characteristics of Patients Carrying the Q703K Variant of the NLRP3 Gene: A 10-year Multicentric National Study.}, journal = {J Rheumatol}, volume = {43}, year = {2016}, month = {2016 Jun}, pages = {1093-100}, abstract = {

OBJECTIVE: The aim of our study was to analyze the clinical and functional effect of the p.Q703K (p. Q705K, c. 2107C>A) variant of the NLRP3 gene in a population of patients screened for suspected cryopyrin-associated periodic syndrome (CAPS).

METHODS: Since 2002, 580 patients underwent molecular analysis for NLRP3. Data on clinical presentation, response to treatment, and longterm followup were collected using a uniform questionnaire. The pattern of cytokine secretion after lipopolysaccharide stimulation from isolated monocytes was analyzed in 3 patients carrying the p.Q703K variant and 1 patient with a chronic infantile neurologic, cutaneous, articular syndrome phenotype carrying both the p.M406I and p.Q703K, and compared with 7 patients with CAPS with sure pathogenic variants and 6 healthy controls.

RESULTS: The p.Q703K variant was found in 57 screened patients with an overall allelic frequency of 5\%. The frequency in normal controls was 5.5\%. Clinical data at the moment of molecular analysis and at followup were available in 36 patients. Two patients displayed additional mutations of NLRP3. The mean followup was 2.5 years. Thirteen patients (39\%) had a final diagnosis different from the original suspicion of CAPS. The remaining 21 patients displayed a mild phenotype mainly characterized by recurrent episodes of urticarial rash and arthralgia. Only 8 patients were treated with anti-interleukin (IL)-1 treatment, with a complete response in 5 patients. The pattern of secretion of IL-1β and other cytokines (IL-6 and IL-1 receptor antagonist) in patients did not display the aberrancies observed in patients with CAPS and was similar to that observed in healthy controls.

CONCLUSION: The present study confirms the weak clinical and functional effect of the p.Q703K variant.

}, issn = {0315-162X}, doi = {10.3899/jrheum.150962}, author = {Naselli, Aldo and Penco, Federica and Cantarini, Luca and Insalaco, Antonella and Alessio, Mariolina and Tommasini, Alberto and Maggio, Cristina and Obici, Laura and Gallizi, Romina and Cimmino, Marco and Signa, Sara and Lucherini, Orso Maria and Carta, Sonia and Caroli, Francesco and Martini, Alberto and Rubartelli, Anna and Ceccherini, Isabella and Gattorno, Marco} } @article {7780, title = {Different presentations of mevalonate kinase deficiency: a case series.}, journal = {Clin Exp Rheumatol}, volume = {33}, year = {2015}, month = {2015 May-Jun}, pages = {437-42}, abstract = {

OBJECTIVES: We aimed to raise awareness among paediatricians and physicians about this often misunderstood condition.

METHODS: We discussed the clinical profiles associated with late or wrong diagnosis of mevalonate kinase deficency (MKD) in a single centre case series.

RESULTS: We analysed the most common challenges and pitfalls that a clinician might face during the diagnostic process. Five main clinical profiles were characterised.

CONCLUSIONS: We propose a new perspective on MKD, suggesting that the presentation of this disease can vary from patient to patient.

}, keywords = {Age Factors, Bacterial Infections, Child, Child, Preschool, Diagnosis, Differential, Diagnostic Errors, Female, Genetic Predisposition to Disease, Humans, Infant, Inflammatory Bowel Diseases, Male, Mevalonate Kinase Deficiency, Phenotype, Predictive Value of Tests, Recurrence, Risk Factors, Sepsis, Vasculitis, Young Adult}, issn = {0392-856X}, author = {De Pieri, Carlo and Taddio, Andrea and Insalaco, Antonella and Barbi, Egidio and Lepore, Loredana and Ventura, Alessandro and Tommasini, Alberto} } @article {8036, title = {Next-generation sequencing and its initial applications for molecular diagnosis of systemic auto-inflammatory diseases.}, journal = {Ann Rheum Dis}, year = {2015}, month = {2015 Sep 17}, abstract = {

OBJECTIVES: Systemic auto-inflammatory disorders (SAIDs) are a heterogeneous group of monogenic diseases sharing a primary dysfunction of the innate immune system. More than 50\% of patients with SAID does not show any mutation at gene(s) tested because of lack of precise clinical classification criteria and/or incomplete gene screening. To improve the molecular diagnosis and genotype interpretation of SAIDs, we undertook the development of a next-generation sequencing (NGS)-based protocol designed to simultaneous screening of 10 genes.

METHODS: Fifty patients with SAID, already genotyped for the respective causative gene(s), were massively sequenced for the coding portions of MEFV, MVK, TNFRSF1A, NLRP3, NLRP12, NOD2, PSTPIP1, IL1RN, LPIN2 and PSMB8. Three different bioinformatic pipelines (Ion Reporter, CLC Bio Genomics Workbench, GATK-based in-house workflow) were compared.

RESULTS: Once resulting variants were compared with the expected mutation list, no workflow turned out to be able to detect all the 79 variants known in the 50 DNAs. Additional variants were also detected, validated by Sanger sequencing and compared to assess true and false positive detection rates of the three workflows. Finally, the overall clinical picture of 34 patients was re-evaluated in the light of the new mutations found.

CONCLUSIONS: The present gene panel has resulted suitable for molecular diagnosis of SAIDs. Moreover, genotype-phenotype correlation has confirmed that the interpretation of NGS data in patients with an undefined inflammatory phenotype is remarkably difficult, thus supporting the need of evidence-based and validated clinical criteria to be used concurrently with the genetic analysis for the final diagnosis and classification of patients with SAIDs.

}, issn = {1468-2060}, doi = {10.1136/annrheumdis-2015-207701}, author = {Rusmini, Marta and Federici, Silvia and Caroli, Francesco and Grossi, Alice and Baldi, Maurizia and Obici, Laura and Insalaco, Antonella and Tommasini, Alberto and Caorsi, Roberta and Gallo, Eleonora and Olivieri, Alma Nunzia and Marzano, AngeloValerio and Coviello, Domenico and Ravazzolo, Roberto and Martini, Alberto and Gattorno, Marco and Ceccherini, Isabella} }