Impact of FCGR2A R131H, FCGR3A F158V and FCGR3B NA1/NA2 polymorphisms on response to Fc-containing TNF inhibitors in Tunisian rheumatoid arthritis patients.

OBJECTIVES: Single nucleotid polymorphisms (SNPs) of Fc-gamma receptors (FcgRs), by inducing a variation of their affinity to the Fc-region of immunoglobulins, might influence the efficacy of Fc-containing biologics prescribed in rheumatoid arthritis (RA). Our aim was to investigate associations of FCGR2A, FCGR3A and FCGR3B SNPs with TNF-inhibitors (TNFi)' response in Tunisian RA patients. METHODS: A cross-sectional, observational and analytic multicentric cohort study was conducted in a group of 47 Tunisian RA patients treated with (etanercept [ETA], adalimumab [ADL] and infliximab [IFX]). Treatment outcome was evaluated after 6 months. R131H-FCGR2A, F158V-FCGR3A and NA1/NA2-FCGR3B SNPs were genotyped. RESULTS: The analytic study including all types of TNFi showed that FCGR3A-F/F low-affinity receptor was associated with a greater decrease of DAS28, while FCGR3B-NA1/NA1 high-affinity receptor was associated with a lower decrease of DAS28 in ADL group. Furthermore, both of high affinity receptors FCGR3B-NA1/NA1 and FCGR3A-V/V were more prevalent in non-responders to ADL, according to EULAR criteria. CONCLUSIONS: Identifying reliable biomarkers of response to biologics in RA is necessary to improve responsiveness, preserve joints' functions and structure, and reduce treatment's cost. Our study showed that FCGR3A and FCGR3B polymorphisms might have an impact on TNFis' response in RA Tunisian patients since bad response was more frequent in homozygous carriers of high affinity alleles FCGR3A-V and FCGR3B-NA1.

Assessment of the influence of Fc-γ receptor polymorphisms on biologics' pharmacokinetics in Tunisian rheumatoid arthritis patients.

AIMS: This study aims to determine whether a modification in Fc-γ receptors' (FcgRs) affinity to Fc portion, caused by single nucleotide polymorphisms such as rs1801274-R131H FcgRIIa, rs396991-F158V FcgRIIIa and NA1/NA2-FcgRIIIb, might impact clearance of therapeutic monoclonal antibodies and thus serum drug levels and the development of anti-drug antibodies. METHODS: A cross sectional, multicentral and noninterventional study was conducted in Tunisian RA patients treated with rituximab (RTX), etanercept (ETA), infliximab (IFX) and adalimumab (ADL). Serum drug level (SDL) of the different biologics and ADA against them were measured. All patients were genotyped for the 3 FcgR single nucleotide polymorphisms. RESULTS: A total of 81 patients were included: 47 were under tumour necrosis factor inhibitors (18 ETA, 13 ADL and 16 IFX), and 34 were under RTX. Regardless of the type of biotherapy, SDL was in therapeutic range, in 35 patients (43.2%), of whom only 1 was treated with RTX. Fourteen patients (22.2%) developed ADA, but none of the patients treated with ETA had detectable ADA levels. There was no association between SDL positivity and FcgR polymorphisms. However, the high affinity FcgR2A 131 H/H receptor was statistically more prevalent in patients with detectable ADA treated with ADL, IFX and RTX (P = .018). The same result was obtained in the monoclonal antibody tumour necrosis factor inhibitor subgroup (n = 29, P = .022) as well as in patients treated only with IFX (n = 16, P = .029). CONCLUSION: Our work supports the hypothesis of an impact of FcgR single nucleotide polymorphisms on biologics' immunogenicity, particularly FcgR R131H polymorphism, but further studies with larger cohorts need to be undertaken to confirm these results.

Intra-articular hip neurofibromas in von Recklinghausen's disease.

Neurofibromatosis is a genetic disorder with osteo-articular manifestations. The intra-articular location of neurofibroma is scarce.

SFRP5 Enhances Wnt5a Induced-Inflammation in Rheumatoid Arthritis Fibroblast-Like Synoviocytes.

Background: Tissue derived fibroblast-like synoviocytes (td-FLS) are key actors in pannus formation and contribute to joint destruction and inflammation during rheumatoid arthritis (RA). Several members of the Wnt family, including Wnt5a, may contribute to RA td-FLS activation and can potentially serve as therapeutic targets. Objective: The present work aimed to investigate the expression of Wnt5a signaling elements in RA td-FLS and their potential precursors (fluid derived (fd) FLS and fibrocytes). We also studied the role of Wnt5a in RA td-FLS pro-inflammatory activity and whether the inhibitor SFRP5 could restore Wnt5a-induced synovial dysfunction in vitro. Materials and Methods: The levels of Wnt5a, SFRP5, Wnt5a receptors/coreceptors and Wnt5a pro-inflammatory targets were determined in cultured RA td-FLS, fd-FLS and fibrocytes using qPCR under basal conditions. The expression of pro-inflammatory molecules was assessed after RA td-FLS stimulation with Wnt5a and SFRP5 at different time points. Results: Our data showed that td-FLS, fd-FLS and fibrocytes from patients with RA expressed similar levels of Wnt5a and a set of Wnt5a receptors/coreceptors. We also demonstrated that Wnt5a stimulated the expression of the pro-inflammatory targets, especially IL1ß, IL8 and IL6 in RA td-FLS. Wnt5a-induced inflammation was enhanced in the presence of SFRP5. Furthermore, Wnt5a alone and in conjunction with SFRP5 inhibited the gene expression of TCF4 and the protein levels of the canonical coreceptor LRP5. Conclusion: Wnt5a pro-inflammatory effect is not inhibited but enhanced by SFRP5 in RA td-FLS. This research highlights the importance of carefully evaluating changes in Wnt5a response in the presence of SFRP5.

Spinal Osteoid Osteoma Revealed by Radiculopathy: Case Report and Literature Review.

Osteoid osteoma (OO) is a benign tumor that usually occurs in long bones of young males. We report a rare case of spinal OO in a 25-year-old woman, revealed by a sciatica. Spinal radiographs and computed tomography scan were normal, although performed at 6 months of symptom evolution. On magnetic resonance imaging, however, an important edema of the right transverse process of L5 vertebrae was depicted but was inconclusive. The diagnosis of OO was finally retained on a second computed tomography scan with thinner slices focused on the edematous area. The patient had an en-bloc excision of the tumor with complete regression of symptoms. Due to the atypical clinical presentation and the absence of common findings in imaging, the diagnosis was delayed by 12 months. Radiculopathy caused by spinal OO is a rare condition with no more than 30 cases reported in the literature. In fact, spinal OO usually presents with inflammatory back pain or painful scoliosis. This case emphasizes the importance of early suspicion and diagnostic interventions in the detection and treatment of OO.

[Comparison of two kits of anti-infliximab antibodies plasmatic measurement]. / Comparaison de deux réactifs de dosage plasmatique des anticorps anti-infliximab.

Infliximab (IFX) is a chimeric monoclonal antibody which has proven its efficacy in the treatment of inflammatory diseases. However, its efficacy can be limited by the development of anti-IFX antibodies (ATI) resulting in a therapeutic failure of IFX. ATI plasmatic monitoring is then indicated to optimize IFX treatment. The aim of this study was to validate an ELISA (enzyme linked immuno sorbent assay) method of ATI plasmatic monitoring. METHODS: Assessment of performance was based on the study of correlation and concordance (Bland Altman method) of the absorbances measured by the two readers. ELISA kit validation was made by calculating the accuracy and the exactitude. RESULTS: We collected 23 samples. Their mean age was 46 years and sex ratio M/W was 0.92. In nine cases, plasmatic AIT were positive and in 14 cases, they were not detected. Correlation between the two readers showed a correlation coefficient r2 of 99.95%. Concordance limits of the confidence interval 95% were [-112.768%-41.425%] with a bias of -35.671%. Repeatability and reproductibility were checked by a positive control and coefficients of variation were respectively of 5.574% and 14.184%. Limits of detection and quantification were respectively of 0.046 and 0.086. The positive predictive value was 0.5 and the negative predictive value was 1. The sensitivity was 100% and the specificity was 83%. CONCLUSION: The assessment of the performance of the tested microplate reader and the validation of the tested ELISA kit showed good results allowing ATI routine measurement to optimize therapeutic management of patients treated by IFX.