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Abstract Number: 1225

Clinical Presentation and Cytokine Production Abnormalities in a Cohort of Patients Carrying NLRP12 GENE Variants

Antonella Insalaco1, Luigi Raganelli2, Manuela Pardeo2, Virginia Messia2, Denise Pires Marafon2, Francesca Romana Lepri3, Elisa Pisaneschi3, Claudia Bracaglia4, Valeria Gerloni5, Rebecca Nicolai2, Elisabetta Cortis6, Fabrizio De Benedetti Sr.4 and Giusi Prencipe4, 1Department of Pediatric Medicine,, Division of Rheumatology, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy, 2Division of Rheumatology, Department of Pediatric Medicine, Ospedale Pediatrico Bambino Gesù, IRCCS, Roma, Italy, 3Cytogenetics, Ospedale Pediatrico Bambino Gesù, IRCCS, Roma, Italy, 4Department of Pediatric Medicine, Division of Rheumatology, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy, 5Pediatric Rheumatology Unit, Department of Rheumatology, Istituto Ortopedico Gaetano Pini, Milano, Italy, 6Division of Pediatric, Santa Maria della Stella Hospital, Orvieto, Italy

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Autoinflammatory Disease

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Session Information

Session Title: Miscellaneous Rheumatic and Inflammatory Diseases

Session Type: Abstract Submissions (ACR)

Background/Purpose: The NLRP12 related autoinflammatory disorder (NLRP12-RD) is a rare autosomal dominant disease,caused by mutations in the NLRP12 gene.Clinical manifestations are extremely heterogeneous.We describe clinical features and inflammatory response of a cohort of patients carrying different NLRP12 variants,some of which not yet described as being associated with NLRP12-RD.Methods: Twelve caucasian patients(6 males)carrying NLRP12 variants were identified.Blood samples obtained from 9/12 NLRP12 patients and from 7 active Juvenile idiopathic arthritis(JIA) patients were stimulated ex vivo with 1 mg/ml of Zymosan for 22h.Whole blood RNA analysis was also performed,using a human immune array(TaqMan® Human Immune Array from Applied Biosystems),containing 92 genes typically involved in the immune response Results: The median age at symptoms onset was 11,4 months(IQR 4,6–35,2)and the median of disease duration was 6,8 years(IQR 4,1–11).Sequencing of NLRP12 gene in the 12 patients revealed 5 heterozygous mutations:F402L(n=6),G448A(n=1),H304Y(n=1),R1030G(n=1) and G39V(n=1).Two patients were homozygous for NLRP12 variants:F402L and G39V.In 6/12 variants of NLRP3 were also found:Q703K(n=4) and V198M(n=2).All patients had symptoms consistent with a recurrent inflammatory syndrome:11/12 presented recurrent episodes of skin lesions,11/12 arthralgia,10/12 recurrent fever episodes,8/12 arthritis,10/12 headache,11/12 fatigue,5/12 conjunctivitis,7/12 recurrent abdominal pain and lymphadenopathy,5/12 oral aphthosis,4/12 thoracic pain and 2/12 sensorineural deafness. During the attacks 5/12 patients showed increased acute phase reactants.In 5/12 patients anakinra was administered because of the severity of phenotype and the persistence of elevated acute phase reactants.In 2 of these 5 patients lack of efficacy led withdrawal of anakinra and introduction of tocilizumab with good response.In vitro cytokine release studies,performed in 9 patients,showed that the production of IL-6 and TNF-α was significantly higher in patients carrying the NLRP12 variants compared to patients with JIA (IL-6:2841±1682 ng/ml and 1496±982.4 ng/ml versus 498.8±338.7 ng/ml and 226.6±111.8 ng/ml respectively;p=0.0002 and p=0.007)and even higher in homozygous patients;no significant difference in IL-1β production was found(2134 ± 1026 ng/ml versus 1527±930.3 ng/ml, p=0.29).Whole blood RNA samples collected from 5 NLRP12 patients were compared to 6 whole blood RNA samples collected from healthy controls comparable for age.At basal level,we did not find significant differences in the expression of 92 genes evaluated. Conclusion: Our data in vitro and in vivo suggest that these NLRP12 variants are pathogenic.The role played by the concomitant presence of the NLRP3 variants remains to be clarified,though an effect in modifying the disease phenotype cannot be excluded.Our data also confirm the clinical and functional heterogeneity of NLRP12 related disorder,a condition often misunderstood.Furthermore,although the small number of patients treated,our data suggest that inhibition of IL-6 may be effective in NLRP12-related disorder.


Disclosure:

A. Insalaco,
None;

L. Raganelli,
None;

M. Pardeo,
None;

V. Messia,
None;

D. Pires Marafon,
None;

F. R. Lepri,
None;

E. Pisaneschi,
None;

C. Bracaglia,
None;

V. Gerloni,

AbbVie, Novartis,

2;

R. Nicolai,
None;

E. Cortis,
None;

F. De Benedetti Sr.,

Novartis, Novimmune, Hoffmann-La Roche, SOBI, AbbVie,

2,

AbbVie Novartis, Novimmune, Hoffmann-La Roche, SOBI ,

5;

G. Prencipe,
None.

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