Gene expression profiling in the synovium identifies a predictive signature of absence of response to adalimumab therapy in rheumatoid arthritis

To identify markers and mechanisms of resistance to adalimumab therapy, we studied global gene expression profiles in synovial tissue specimens obtained from severe rheumatoid arthritis (RA) patients before and after initiation of treatment

Minimization of free radical damage by metal catalysis of multivitamin/multimineral supplements

Multivitamin/multimineral complexes are the most common dietary supplements. Unlike minerals in foods that are incorporated in bioorganic structures, minerals in dietary supplements are typically in an inorganic form. These minerals can catalyze the generation of free radicals, thereby oxidizing antioxidants during digestion. Here we examine the ability of a matrix consisting of an amino acid and non-digestible oligosaccharide (AAOS) to blunt metal-catalyzed oxidations. Monitoring of ascorbate radical generated by copper shows that ascorbate is oxidized more slowly with the AAOS matrix than with copper sulfate. Measurement of the rate of oxidation of ascorbic acid and Trolox® by catalytic metals confirmed the ability of AAOS to slow these oxidations. Similar results were observed with iron-catalyzed formation of hydroxyl radicals. When compared to traditional forms of minerals used in supplements, we conclude that the oxidative loss of antioxidants in solution at physiological pH is much slower when AAOS is present

Maternal Dietary Supplementation with Oligofructose-Enriched Inulin in Gestating/Lactating Rats Preserves Maternal Bone and Improves Bone Microarchitecture in Their Offspring

This study received financial support from Abbott Nutrition, a commercial company, and coauthors PBV, MM, JMLP and RR are employees of Abbott Nutrition. There are two patents related with the data presented (EP 2502507 A1 and EP 2745706 A1).Some of these results were presented in the 7th World Congress of DOHaD (2011) and in the World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Disease (WCO-IOF-ESCEO) (2014).Nutrition during pregnancy and lactation could exert a key role not only on maternal bone, but also could influence the skeletal development of the offspring. This study was performed in rats to assess the relationship between maternal dietary intake of prebiotic oligofructose-enriched inulin and its role in bone turnover during gestation and lactation, as well as its effect on offspring peak bone mass/architecture during early adulthood. Rat dams were fed either with standard rodent diet (CC group), calcium-fortified diet (Ca group), or prebiotic oligofructose-enriched inulin supplemented diet (Pre group), during the second half of gestation and lactation. Bone mineral density (BMD) and content (BMC), as well as micro-structure of dams and offspring at different stages were analysed. Dams in the Pre group had significantly higher trabecular thickness (Tb.Th), trabecular bone volume fraction (BV/TV) and smaller specific bone surface (BS/BV) of the tibia in comparison with CC dams. The Pre group offspring during early adulthood had an increase of the lumbar vertebra BMD when compared with offspring of CC and Ca groups. The Pre group offspring also showed significant increase versus CC in cancellous and cortical structural parameters of the lumbar vertebra 4 such as Tb.Th, cortical BMD and decreased BS/BV. The results indicate that oligofructose-enriched inulin supplementation can be considered as a plausible nutritional option for protecting against maternal bone loss during gestation and lactation preventing bone fragility and for optimizing peak bone mass and architecture of the offspring in order to increase bone strength.This study was funded by Abbott Nutrition R&D, and co-authors PBV, MM, JMLP and RR receive salary from Abbott Nutrition

Opposing effects of monomeric and pentameric C-reactive protein on endothelial progenitor cells

C-reactive protein (CRP) has been linked to the pathogenesis of atherosclerosis. The dissociation of native, pentameric (p)CRP to monomeric (m)CRP on the cell membrane of activated platelets has recently been demonstrated. The dissociation of pCRP to mCRP may explain local pro-inflammatory reactions at the site of developing atherosclerotic plaques. As a biomarker, pCRP predicts cardiovascular adverse events and so do reduced levels and function of circulating endothelial progenitor cells (EPCs). We hypothesised that mCRP and pCRP exert a differential effect on EPC function and differentiation. EPCs were treated with mCRP or pCRP for 72 h, respectively. Phenotypical characterisation was done by flow cytometry and immunofluorescence microscopy, while the effect of mCRP and pCRP on gene expression was examined by whole-genome gene expression analysis. The functional capacity of EPCs was determined by colony forming unit (CFU) assay and endothelial tube formation assay. Double staining for acetylated LDL and ulex lectin significantly decreased in cells treated with pCRP. The length of tubuli in a matrigel assay with HUVECs decreased significantly in response to pCRP, but not to mCRP. The number of CFUs increased after pCRP treatment. RNA expression profiling demonstrated that mCRP and pCRP cause highly contradictory gene regulation. Interferon-responsive genes (IFI44L, IFI44, IFI27, IFI 6, MX1, OAS2) were among the highly up-regulated genes after mCRP, but not after pCRP treatment. In conclusion, EPC phenotype, genotype and function were differentially affected by mCRP and pCRP, strongly arguing for differential roles of these two CRP conformations. The up-regulation of interferon-inducible genes in response to mCRP may constitute a mechanism for the local regulation of EPC function

Secukinumab, an Interleukin-17A Inhibitor, in Ankylosing Spondylitis

Background Secukinumab is an anti–interleukin-17A monoclonal antibody that has been shown to control the symptoms of ankylosing spondylitis in a phase 2 trial. We conducted two phase 3 trials of secukinumab in patients with active ankylosing spondylitis. Methods In two double-blind trials, we randomly assigned patients to receive secukinumab or placebo. In MEASURE 1, a total of 371 patients received intravenous secukinumab (10 mg per kilogram of body weight) or matched placebo at weeks 0, 2, and 4, followed by subcutaneous secukinumab (150 mg or 75 mg) or matched placebo every 4 weeks starting at week 8. In MEASURE 2, a total of 219 patients received subcutaneous secukinumab (150 mg or 75 mg) or matched placebo at baseline; at weeks 1, 2, and 3; and every 4 weeks starting at week 4. At week 16, patients in the placebo group were randomly reassigned to subcutaneous secukinumab at a dose of 150 mg or 75 mg. The primary end point was the proportion of patients with at least 20% improvement in Assessment of Spondyloarthritis International Society (ASAS20) response criteria at week 16. Results In MEASURE 1, the ASAS20 response rates at week 16 were 61%, 60%, and 29% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P<0.001 for both comparisons with placebo); in MEASURE 2, the rates were 61%, 41%, and 28% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P<0.001 for the 150-mg dose and P=0.10 for the 75-mg dose). The significant improvements were sustained through 52 weeks. Infections, including candidiasis, were more common with secukinumab than with placebo during the placebo-controlled period of MEASURE 1. During the entire treatment period, pooled exposure-adjusted incidence rates of grade 3 or 4 neutropenia, candida infections, and Crohn’s disease were 0.7, 0.9, and 0.7 cases per 100 patient-years, respectively, in secukinumab-treated patients. Conclusions Secukinumab at a subcutaneous dose of 150 mg, with either subcutaneous or intravenous loading, provided significant reductions in the signs and symptoms of ankylosing spondylitis at week 16. Secukinumab at a subcutaneous dose of 75 mg resulted in significant improvement only with a higher intravenous loading dose. (Funded by Novartis Pharma; ClinicalTrials.gov numbers, NCT01358175 and NCT01649375.

The posterior interosseous nerve and the radial tunnel syndrome: an anatomical study.

Twenty anatomical specimens were carefully studied in order to establish a possible connection between the posterior interosseous nerve and the radial tunnel syndrome. Our results show that the posterior interosseous nerve distal to the supinator muscle may be compressed by various structures. These include the distal border of the supinator muscle, the ramifications of the anterior and posterior interosseous vessels, and the septum between the extensor carpi ulnaris and the extensor digitorum minimi. The posterior interosseous nerve is also stressed during passive supination (elongation and rotation), and during passive pronation (compression). This suggests that the interosseous nerve distal to the supinator muscle should be explored in radial tunnel compression syndromes

F-18-fluoride PET for monitoring therapeutic response in Paget's disease of bone

A prospective study was undertaken to evaluate PET with F-18-fluoride for monitoring the response to bisphosphonates in Paget's disease of bones. Methods: Fourteen patients with a monostotic (n = 9) or a polyostotic form (n = 5) of Paget's disease were scanned at baseline and at 1 and 6 mo after the beginning of treatment. Dynamic acquisition and arterial blood sampling were used to calculate the influx constant Ki (by both the Patlak [Ki-PAT] method and the nonlinear regression [Ki-NLR] method). Kinetic modeling was compared with maximal standardized uptake values (SUVmax) and biochemical markers of bone remodeling. Results: Baseline uptake of 18F-fluoride by pagetic bones was significantly higher than in normal bones (P < 0.05). One month after the start of treatment, SUVmax, Ki-PAT, Ki-NLR, and K-1 (the unidirectional clearance of fluoride from plasma to the whole of the bone tissue) decreased significantly by 27.8%, 27.9%, 27.5%, and 23.6%, respectively. Biochemical markers were already normalized in 6 of 9 patients with monostotic disease, although all had high F-18-fluoride uptake values. Six months after the start of treatment, F-18-fluoride uptake further diminished by 22.3%-25.6%. Biochemical markers were normal in all but 2 patients, although 10 of 14 patients still showed high F-18-fluoride uptake. One patient did not respond to treatment and maintained high uptake of F-18-fluoride throughout the study. SUVmax correlated with both Ki-PAT and Ki-NLR at baseline, 1 mo, and 6 mo (P < 0.05). Moreover, the change of SUVmax between baseline and 1 mo, as well as between baseline and 6 mo, also correlated with the change of Ki-PAT and Ki-NLR (P < 0.05). Conclusion: Our results show that F-18-fluoride PET can be used to noninvasively and accurately monitor the efficacy of treatment with bisphosphonates in Paget's disease of bones. SUVmax correlates with Ki-PAT and Ki-NLR and, interestingly, varies in the same manner as kinetic indices. Therefore, the use of SUVmax could avoid the need for dynamic acquisition and arterial blood sampling and would facilitate the use of whole-body PET in a clinical setting

Functional outcome of myositis patients: can a low-dose glucocorticoid regimen achieve good functional results?

OBJECTIVE: During the last few years, in an attempt to reduce the side effects of glucocorticoid (GC) therapy, we have been treating polymyositis-dermatomyositis (PM-DM) patients with a lower starting dose of GC than is classically recommended. In order to validate this approach, we performed a functional re-evaluation of these PM-DM patients. METHODS: A comprehensive protocol evaluating muscle strength, muscle function, CK levels, persistence of spontaneous activity on electromyography, disability in daily life activities and degree of dependence was applied in 25 non-cancer-associated biopsy-proven PM-DM patients, 15 of whom had been treated with a high-dose regimen (i.e. > 0.5 mg prednisolone/kg/day) and 10 with a low-dose regimen (i.e. < or = 0.5 mg prednisolone/kg/day). RESULTS: Our results indicate that the functional outcome of PM-DM patients given a low-dose starting regimen of GC does not differ from that observed in patients given higher doses. Interestingly, vertebral fractures were less common in patients treated with lower GC doses. CONCLUSIONS: Although our analysis has certain shortcomings, including the small number of patients investigated and their uncontrolled assignment to a low-dose or a high-dose GC regimen, the results of this retrospective study suggest that a low-dose starting regimen of GC can achieve a good functional outcome in PM-DM patients, with a reduction of treatment-related disability. This approach would be welcome as a step forward should it be validated by a longitudinal study