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Objective: The Neutrophil–Lymphocyte Ratio (NLR) has been proposed as an inflammatory biomarker in several diseases, including Fibromyalgia, with controversial results. The objectives of this study were to: (1) compare NLR values among participants with Fibromyalgia, Axial Spondyloarthritis, and healthy controls; (2) assess the relationship between NLR and disease activity; and (3) establish diagnostic and activity cut-off values. Methods: A total of 112 age and gender-matched participants were included in each group. NLR values were compared between groups, correlations with disease activity were analyzed, and cut-off values were calculated using Receiver Operating Characteristic (ROC) curves. Results: The NLR was significantly higher in Fibromyalgia patients compared with healthy controls (1.8 ± 0.5 vs. 1.4 ± 0.2; p < 0.001) and in Axial Spondyloarthritis patients compared with both Fibromyalgia patients (2.1 ± 0.3 vs. 1.8 ± 0.5; p < 0.001) and healthy controls (2.1 ± 0.3 vs. 1.4 ± 0.2; p < 0.001). Within disease groups, the NLR was also significantly higher in patients with severe Fibromyalgia (FIQ ≥ 59) compared with non-severe cases (1.9 ± 0.5 vs. 1.7 ± 0.4; p = 0.008) and in patients with high/very high Axial Spondyloarthritis activity compared with those with low/inactive disease (2.3 ± 0.3 vs. 1.9 ± 0.2; p < 0.001). ROC analysis identified the NLR cut-off values of 1.54 for Fibromyalgia diagnosis, 1.64 for severe disease, 1.61 for Axial Spondyloarthritis diagnosis and 1.95 for high/very high disease activity. Conclusions: The NLR may serve as a cost-effective, rapid, and accessible biomarker for establishing diagnosis and disease activity in Axial Spondyloarthritis and, to a lesser extent, in Fibromyalgia. Further research is needed to validate these findings and explore NLR’s role alongside other inflammatory markers.

Tumor necrosis factor alpha (TNF-α) blockers are recognized as a risk factor for reactivation of granulomatous infections. Leishmaniasis has been associated with the use of these drugs, although few cases have been reported. We performed a retrospective observational study including patients with confirmed leishmaniasis acquired in the Mediterranean basin that were under TNF-α blockers therapy at the moment of the diagnosis. Patients diagnosed in our hospital from 2008 to 2018 were included. Moreover, a systematic review of the literature was performed and cases fulfilling the inclusion criteria were also included. Forty-nine patients were analyzed including nine cases from our series. Twenty-seven (55.1%) cases were male and median age was 55 years. Twenty-five (51%) patients were under infliximab treatment, 20 (40.8%) were receiving adalimumab, 2 (4.1%) etanercept, one (2%) golimumab and one (2%) a non-specified TNF-α blocker. Regarding clinical presentation, 28 (57.1%) presented as cutaneous leishmaniasis (CL), 16 (32.6%) as visceral leishmaniasis (VL) and 5 (10.2%) as mucocutaneous leishmaniasis (MCL). All VL and MCL patients were treated with systemic therapies. Among CL patients, 13 (46.4%) were treated with a systemic drug (11 received L-AmB, one intramuscular antimonials and one miltefosine) while 14 (50%) patients were given local treatment (13 received intralesional pentavalent antimonials, and one excisional surgery). TNF-α blockers were interrupted in 32 patients (65.3%). After treatment 5 patients (10.2%) relapsed. Four patients with a CL (3 initially treated with local therapy maintaining TNF-α blockers and one treated with miltefosine) and one patient with VL treated with L-AmB maintaining TNF-α blockers. This data supports the assumption that the blockage of TNF-α modifies clinical expression of leishmaniasis in endemic population modulating the expression of the disease leading to atypical presentations. According to the cases reported, the best treatment strategy would be a systemic drug and the discontinuation of the TNF-α blockers therapy until clinical resolution.

AimsTo explore the clinical and radiographical characteristics of axial psoriatic arthritis (PsA) and to compare it with ankylosing spondylitis (AS) with psoriasis.MethodsCross-sectional study from the national multicentre registry REGISPONSER where participants fulfilled the European Spondyloarthropathy Study Group spondyloarthritis criteria at entry. Clinical, laboratory and radiographical characteristics between patients classified as axial PsA and AS with psoriasis by their rheumatologist are compared according to HLA-B27 status.ResultsOf 2367 patients on REGISPONSER, n=405 had PsA, of whom 27% (n=109) had axial involvement as per the treating rheumatologist. 30% (n=26/86) of axial PsA were HLA-B27 positive. In the AS group, 9% (127/1422) had a history of psoriasis and were more frequently male, with longer diagnostic delay and more anterior uveitis than those with axial PsA who had more peripheral involvement and nail disease. Patients with HLA-B27-negative axial PsA reported less inflammatory pain and structural damage compared with AS with psoriasis. By contrast, HLA-B27-positive axial PsA shared clinical characteristics similar to AS and psoriasis although with a lower BASRI score. In the multivariable analysis, patients with AS and psoriasis were independently associated with HLA-B27 positivity (OR 3.34, 95% CI 1.42 to 7.85) and lumbar structural damage scored by BASRI (OR 2.14, 95% CI 1.4 to 3.19).ConclusionThe more prevalent axial PsA phenotype is predominantly HLA-B27 negative and presents different clinical and radiological manifestations when compared with AS with psoriasis. There is great heterogeneity in what rheumatologists consider axial PsA from a clinical and imaging perspective, highlighting the need for research into possible genetic drivers and a consensus definition.

Background In rheumatoid arthritis (RA), the activation of T and B cell clones specific for self-antigens leads to the chronic inflammation of the synovium. Here, we perform an in-depth quantitative analysis of the seven chains that comprise the adaptive immune receptor repertoire (AIRR) in RA. Results In comparison to controls, we show that RA patients have multiple and strong differences in the B cell receptor repertoire including reduced diversity as well as altered isotype, chain, and segment frequencies. We demonstrate that therapeutic tumor necrosis factor inhibition partially restores this alteration but find a profound difference in the underlying biochemical reactivities between responders and non-responders. Combining the AIRR with HLA typing, we identify the specific T cell receptor repertoire associated with disease risk variants. Integrating these features, we further develop a molecular classifier that shows the utility of the AIRR as a diagnostic tool. Conclusions Simultaneous sequencing of the seven chains of the human AIRR reveals novel features associated with the disease and clinically relevant phenotypes, including response to therapy. These findings show the unique potential of AIRR to address precision medicine in immune-related diseases.

Background Blocking of the Tumor Necrosis Factor (TNF) activity is a successful therapeutic approach for 50–60% of rheumatoid arthritis (RA) patients. However, there are yet no biomarkers to stratify patients for anti-TNF therapy. Rheumatoid factor (RF) and anti-cyclic-citrullinated antibodies (anti-CCP) have been evaluated as biomarkers of response but the results have shown limited consistency. Anti-carbamylated protein (anti-CarP) and anti-peptidylarginine deiminase type 4 (anti-PAD4) antibodies have been much less studied. Despite being linked to common immune processes, the interaction between these markers has not been evaluated yet. Our aim was to analyze the interaction between these four antibodies in relation to the response to anti-TNF therapy. Methods For this objective, a prospective cohort of n  = 80 RA patients starting anti-TNF therapy was recruited. Serum determinations at baseline were performed for RF, anti-CCP, anti-CarP and anti-PAD4 antibodies using enzyme-linked immunosorbent assays (ELISA). The clinical response to anti-TNF therapy was determined at week 12 using the change in DAS28 score. Association was performed using multivariate linear regression adjusting for baseline DAS28, sex and age. Results The interaction between pairs of antibodies was tested by the addition of an interaction term. We found two highly significant antibody interactions associated with treatment response: anti-CarP with anti-PAD4 ( p  = 0.0062), and anti-CCP with RF ( p  = 0.00068). The latter antibody interaction was replicated in an independent retrospective cohort of RA patients ( n  = 199, p  = 0.04). Conclusions The results of this study suggest that antibody interaction effects are important factors in the response to anti-TNF therapy in RA.

TNF alpha blockade agents like infliximab are actually the treatment of choice for those rheumatoid arthritis (RA) patients who fail standard therapy. However, a considerable percentage of anti-TNF alpha treated patients do not show a significant clinical response. Given that new therapies for treatment of RA have been recently approved, there is a pressing need to find a system that reliably predicts treatment response. We hypothesized that the analysis of whole blood gene expression profiles of RA patients could be used to build a robust predictor to infliximab therapy. We performed microarray gene expression analysis on whole blood RNA samples from RA patients starting infliximab therapy (n = 44). The clinical response to infliximab was determined at week 14 using the EULAR criteria. Blood cell populations were determined using flow cytometry at baseline, week 2 and week 14 of treatment. Using complete cross-validation and repeated random sampling we identified a robust 8-gene predictor model (96.6% Leave One Out prediction accuracy, P = 0.0001). Applying this model to an independent validation set of RA patients, we estimated an 85.7% prediction accuracy (75-100%, 95% CI). In parallel, we also observed a significantly higher number of CD4+CD25+ cells (i.e. regulatory T cells) in the responder group compared to the non responder group at baseline (P = 0.0009). The present 8-gene model obtained from whole blood expression efficiently predicts response to infliximab in RA patients. The application of the present system in the clinical setting could assist the clinician in the selection of the optimal treatment strategy in RA.

Rheumatoid arthritis (RA) is the most frequent autoimmune disease involving the joints. Although anti-TNF therapies have proven effective in the management of RA, approximately one third of patients do not show a significant clinical response. The objective of this study was to identify new genetic variation associated with the clinical response to anti-TNF therapy in RA. We performed a sequential multi-omic analysis integrating different sources of molecular information. First, we extracted the RNA from synovial biopsies of 11 RA patients starting anti-TNF therapy to identify gene coexpression modules (GCMs) in the RA synovium. Second, we analyzed the transcriptomic association between each GCM and the clinical response to anti-TNF therapy. The clinical response was determined at week 14 using the EULAR criteria. Third, we analyzed the association between the GCMs and anti-TNF response at the genetic level. For this objective, we used genome-wide data from a cohort of 348 anti-TNF treated patients from Spain. The GCMs that were significantly associated with the anti-TNF response were then tested for validation in an independent cohort of 2,706 anti-TNF treated patients. Finally, the functional implication of the validated GCMs was evaluated via pathway and cell type epigenetic enrichment analyses. A total of 149 GCMs were identified in the RA synovium. From these, 13 GCMs were found to be significantly associated with anti-TNF response ( < 0.05). At the genetic level, we detected two of the 13 GCMs to be significantly associated with the response to adalimumab ( = 0.0015) and infliximab ( = 0.021) in the Spain cohort. Using the independent cohort of RA patients, we replicated the association of the GCM associated with the response to adalimumab ( = 0.0019). The validated module was found to be significantly enriched for genes involved in the nucleotide metabolism ( = 2.41e-5) and epigenetic marks from immune cells, including CD4+ regulatory T cells ( = 0.041). These findings show the existence of a drug-specific genetic basis for anti-TNF response, thereby supporting treatment stratification in the search for response biomarkers in RA.

Anti-TNF therapies have been highly efficacious in the management of rheumatoid arthritis (RA), but 25-30% of patients do not show a significant clinical response. There is increasing evidence that genetic variation at the Fc receptor FCGR2A is associated with the response to anti-TNF therapy. We aimed to validate this genetic association in a patient cohort from the Spanish population, and also to identify new genes functionally related to FCGR2A that are also associated with anti-TNF response. A total of 348 RA patients treated with an anti-TNF therapy were included and genotyped for FCGR2A polymorphism rs1081274. Response to therapy was determined at 12 weeks, and was tested for association globally and independently for each anti-TNF drug (infliximab, etanercept and adalimumab). Using gene expression profiles from macrophages obtained from synovial fluid of RA patients, we searched for genes highly correlated with FCGR2A expression. Tag SNPs were selected from each candidate gene and tested for association with the response to therapy. We found a significant association between FCGR2A and the response to adalimumab (P=0.022). Analyzing the subset of anti-CCP positive RA patients (78%), we also found a significant association between FCGR2A and the response to infliximab (P=0.035). DHX32 and RGS12 were the most consistently correlated genes with FCGR2A expression in RA synovial fluid macrophages (P<0.001). We found a significant association between the genetic variation at DHX32 (rs12356233, corrected P=0.019) and a nominally significant association between RGS12 and the response to adalimumab (rs4690093, uncorrected P=0.040). In the anti-CCP positive group of patients, we also found a nominally significant association between RGS12 and the response to infliximab (rs2857859, uncorrected P=0.042). In the present study we have validated the FCGR2A association in an independent population, and we have identified new genes associated with the response to anti-TNF therapy in RA.

Transient CD20 B-cell depletion with rituximab is an effective treatment for rheumatoid arthritis (RA). However, there is a subgroup of patients that do not show significant clinical response to rituximab and for these patients, other modes of treatment are preferred. Finding biomarkers for drug response in RA has immense potential for improving treatment and lowering healthcare costs for treating RA patients by facilitating the optimization of their pharmacotherapy. In the present study, we report on gene expression profiles of three different blood cell types in rituximab responders and nonresponder RA patients identifying new candidate genes associated with rituximab response. Transcriptional profiles of whole-blood, CD4 T cells and B cells were analyzed from nine female patients (mean age 53 ±± 11 years) with active RA disease (DAS28 > 5.1), starting rituximab therapy using Illumina (CA, USA) gene-expression microarrays. Whole-blood RNA was extracted using the PAXgene™™ system (PreAnalytix, Hombrechtikon, Switzerland) whilst the lymphocyte RNA was obtained following cell isolation using negative selection. Flow cytometry analysis was performed to determine whole blood subpopulations, as well as the lymphocyte isolation purity. A whole-genome expression profiling was performed on the RNA samples prepared from the three blood cell populations using the Illumina Human 6 Beadchip array system version 1 (Illumina). From the group of statistically significant genes showing differential expression in rituximab responders compared with nonresponder RA patients, we selected a group of candidate genes that were subsequently validated in the same RNA samples using TaqMan real-time PCR assays. Several genes were identified whose level of expression is associated significantly with the response to rituximab in all three blood cell types evaluated (multiple-test corrected p-value < 0.05). Real-time PCR-validated genes include (1.6-fold downregulated in responders) and (1.4-fold upregulated in responders) genes in whole blood and (1.3-fold upregulated in responders) in CD4 T cells. The present study is the first gene expression microarray analysis reporting on biomarkers of the clinical response to rituximab in RA in blood cells. Following validation in larger cohorts, the identified genes may serve as biomarkers for treatment choice in RA.