OLT1177, a ß-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation.

Activation of the NLRP3 inflammasome induces maturation of IL-1ß and IL-18, both validated targets for treating acute and chronic inflammatory diseases. Here, we demonstrate that OLT1177, an orally active ß-sulfonyl nitrile molecule, inhibits activation of the NLRP3 inflammasome. In vitro, nanomolar concentrations of OLT1177 reduced IL-1ß and IL-18 release following canonical and noncanonical NLRP3 inflammasome activation. The molecule showed no effect on the NLRC4 and AIM2 inflammasomes, suggesting specificity for NLRP3. In LPS-stimulated human blood-derived macrophages, OLT1177 decreased IL-1ß levels by 60% and IL-18 by 70% at concentrations 100-fold lower in vitro than plasma concentrations safely reached in humans. OLT1177 also reduced IL-1ß release and caspase-1 activity in freshly obtained human blood neutrophils. In monocytes isolated from patients with cryopyrin-associated periodic syndrome (CAPS), OLT1177 inhibited LPS-induced IL-1ß release by 84% and 36%. Immunoprecipitation and FRET analysis demonstrated that OLT1177 prevented NLRP3-ASC, as well as NLRP3-caspase-1 interaction, thus inhibiting NLRP3 inflammasome oligomerization. In a cell-free assay, OLT1177 reduced ATPase activity of recombinant NLRP3, suggesting direct targeting of NLRP3. Mechanistically, OLT1177 did not affect potassium efflux, gene expression, or synthesis of the IL-1ß precursor. Steady-state levels of phosphorylated NF-κB and IkB kinase were significantly lowered in spleen cells from OLT1177-treated mice. We observed reduced IL-1ß content in tissue homogenates, limited oxidative stress, and increased muscle oxidative metabolism in OLT1177-treated mice challenged with LPS. Healthy humans receiving 1,000 mg of OLT1177 daily for 8 d exhibited neither adverse effects nor biochemical or hematological changes.

A novel assessment tool for clinical care of patients with autoinflammatory disease: juvenile autoinflammatory disease multidimensional assessment report.

OBJECTIVES: To develop and test a new multidimensional questionnaire for assessment of children with auto-inflammatory disease (AID) such as FMF, PFAPA, HIDS, TRAPS in standard clinical care. METHODS: The juvenile auto-inflammatory disease multidimensional assessment report (JAIMAR) includes 16 parent or patient-centered measures and four dimensions that assess functional status, pain, therapeutic compliance and health-related quality of life (physical, social, school, emotional status) with disease outcome. It is proposed for use as both a proxy-report and a patient self-report, with the suggested age range of 8-18 years for use as a self-report. RESULTS: 250 children with FMF were included in the study. Total of 179 forms were filled up by parents and patients, and 71 forms were filled up by parents having children less than 8 years. Completing and scoring the JAIMAR can be done in 15 minutes. For the JAIMAR's dimensions, the Cronbach's alpha coefficient for internal consistency was between 0.507-0.998. There was a significant and a positive correlation between the test-retest scale scores (ICC=0.607-0.966). Concerning construct validity, all factors loadings were above 0.30. For the criterion validity, the correlation level between each dimension and the related scale ranged from medium (r=0.329, p<0.0001) to large (r=0.894, p<0.0001). The parents' proxy-reported and children's self-reported data were outstandingly concordant (r=0.770-0.989). CONCLUSIONS: The development of the JAIMAR introduces a new and multi-dimensional approach in paediatric rheumatology practice. It is a new tool for children with auto-inflammatory dis-ease and it may help enhance their quality of care.

A preliminary score for the assessment of disease activity in hereditary recurrent fevers: results from the AIDAI (Auto-Inflammatory Diseases Activity Index) Consensus Conference.

BACKGROUND: The systemic autoinflammatory disorders (SAID) share many clinical manifestations, albeit with variable patterns, intensity and frequency. A common definition of disease activity would be rational and useful in the management of these lifelong diseases. Moreover, standardised disease activity scores are required for the assessment of new therapies in constant development. The aim of this study was to develop preliminary activity scores for familial Mediterranean fever, mevalonate kinase deficiency, tumour necrosis factor receptor-1-associated periodic syndrome and cryopyrin-associated periodic syndromes (CAPS). METHODS: The study was conducted using two well-recognised consensus formation methods: the Delphi technique and the nominal group technique. The results from a two-step survey and data from parent/patient interviews were used as preliminary data to develop the agenda for a consensus conference to build a provisional scoring system. RESULTS: 24 of 65 experts in SAID from 20 countries answered the web questionnaire and 16 attended the consensus conference. There was consensus agreement to develop separate activity scores for each disease but with a common format based on patient diaries. Fever and disease-specific clinical variables were scored according to their severity. A final score was generated by summing the score of all the variables divided by the number of days over which the diary was completed. Scores varied from 0 to 16 (0-13 in CAPS). These scores were developed for the purpose of clinical studies but could be used in clinical practice. CONCLUSION: Using widely recognised consensus formation techniques, preliminary scores were obtained to measure disease activity in four main SAID. Further prospective validation study of this instrument will follow.

Dynamic contrast-enhanced magnetic resonance imaging in the assessment of disease activity in patients with juvenile idiopathic arthritis.

OBJECTIVE: To determine the capability and reliability of dynamic contrast-enhanced MRI (DCE-MRI) in the assessment of disease activity in juvenile idiopathic arthritis (JIA). METHODS: DCE-MRI of the clinically more affected wrist or hip joints was undertaken in 21 patients, coupled with standard clinical assessment and biochemical analysis. Synovial inflammation was assessed by computing the maximum level of synovial enhancement (ME), the maximum rate of enhancement (MV) and the rate of early enhancement (REE) from the enhancement curves generated from region of interest independently delineated by two readers in the area of the ME. Correlations between dynamic parameters and clinical measures of disease activity, and static MRI synovitis score were investigated. RESULTS: In patients with wrist arthritis, REE correlated with the wrist swelling score (r(s) = 0.72), ESR (r(s) = 0.69), pain assessment scale (r(s) = 0.63) and childhood HAQ (r(s) = 0.60). In patients with hip arthritis, ME correlated with the hip limitation of motion (r(s) = 0.69). Static MRI synovitis score based on post-gadolinium enhancement correlated with MV (r(s) = 0.63) in patients with wrist arthritis and with ME (r = 0.68) in those with hip arthritis. The inter-reader agreement assessed by intra-class correlation coefficient (ICC) for ME, MV and REE (ICC = 0.98, 0.97 and 0.84, respectively) was excellent. CONCLUSIONS: DCE-MRI represents a promising method for the assessment of disease activity in JIA, especially in patients with wrist arthritis. As far as we know, this study is the first to demonstrate the feasibility, reliability and construct validity of DCE-MRI in JIA. These results should be confirmed in large-scale longitudinal studies in view of its further application in therapeutic decision making and in clinical trials.