Synovial CXCL13 appears to be a marker of a more severe pattern of RA disease, characterized by increased lymphocyte activation and bone remodelling beyond the level of conventional markers of inflammation.

IntroductionBiological markers specifically reflecting pathological processes may add value in the assessment of inter-individual variations in the course of rheumatoid arthritis (RA). The current study was undertaken to investigate whether baseline serum levels of the chemokine CXCL13 might predict clinical and ultrasonographic (US) outcomes in patients with recent-onset RA.MethodsThe study included 161 early RA patients (disease duration < 12 months) treated according to a disease activity score (DAS) driven step-up protocol aiming at DAS < 2.4. Clinical disease activity measures were collected at baseline, 2, 4, 6, 9 and 12 months, and US examination of the hands was performed at baseline, 6 and 12 months. Grey-Scale (GS) and Power Doppler (PD) synovitis were scored (0 to 3), with overall scores as the sum of each joint score. CXCL13 levels were measured at baseline by enzyme-linked immunosorbent assay and evaluated in relation to the achievement of low disease activity (LDA, DAS < 2.4) and US residual inflammation (PD ≤ 1) at 12 months.ResultsBaseline levels of CXCL13 were significantly higher in RA compared to healthy controls (n = 19) (P = 0.03) and correlated with measures of synovitis, such as the swollen joint count (R 0.28, P < 0.001), the US-GS (R 0.27, P = 0.003) and US-PD (R 0.26, P = 0.005) score. Although CXCL13 did not predict the likelihood of achieving clinical LDA at 12 months within a structured treat-to-target protocol, elevated levels of CXCL13 were associated with more frequent increases of methotrexate dosage (P < 0.001). Using adjusted analyses, the highest levels of CXCL13 (> 100 pg/ml) were the only independent predictor of residual imaging inflammation (P = 0.005), irrespective of initial US-PD scores, disease activity status, acute phase reactants and autoantibodies. Among the patients in clinical LDA at 12 months, US-PD scores ≤ 1 were less frequently achieved in the high baseline CXCL13 (> 100 pg/ml) group, with an adjusted OR = 0.06 (95% CI 0.01 to 0.55, P = 0.01).ConclusionsCXCL13 emerges as a new biological marker in early RA, accurate in assessing the severity of synovitis and the persistence of US-PD activity over time in response to conventional treatments.

Draining LNs in RA are subjected to subclinical intra-parenchymal changes and vascular flow modulation detectable by PD-US. Sonographic signs of LN involvement associate with disease activity and are reversible upon treatment. These data point at LN reactivity as a dynamic component of RA inflammatory cascade and an attractive platform to be explored in prognostic and response to therapy evaluations.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease of unknown aetiology, leading to progressive damage of bone and cartilage with functional impairment and disability. Whilst the synovial membrane represents the epicentre of the immune-inflammatory process, there is growing evidence indicating the potential involvement of additional anatomical compartments, such as the lung, bone marrow, and secondary lymphoid tissues. Draining lymph nodes represent the elective site for tissue immune-surveillance, for the generation of adaptive immune responses and a candidate compartment for the maintenance of peripheral tolerance. Despite the precise role of the juxta- and extra-articular lymph node stations in the pathogenesis of RA remaining poorly defined, several lines of research exploiting new technological approaches are now focusing on their assessment as a potential new source of pathobiologic information, biomarkers, and complementary therapeutic targets. In this review we present an updated overview of the main concepts driving lymph node research in RA, highlighting the most relevant findings, current hypothesis, and translational perspectives.

TNF inhibitors are biologic DMARDs approved for the treatment of active RA in mid-1990s. They still represent a valuable therapeutic option to control the activity, disability and radiographic progression of the disease. In the context of TNF inhibitors, there are currently several molecules and different administration routes that provide optimal treatment personalization, allowing us to respond to a patient's needs in the best possible way. The increasing use of TNF inhibitors has not only improved the management of RA, but it has also helped in our understanding of the pathogenetic mechanisms of the disease. This review focuses on the basis of this targeted therapy and on the knowledge gained from their use about therapeutic effects and adverse events. Effectiveness analysed from drug registries and safety issues are presented together with recent data on infections (in particular, Mycobacterium tuberculosis and hepatitis B), cancer (lymphoma, skin cancers) and cardiovascular risk.

BackgroundEmerging research on the mechanisms of disease chronicity in experimental arthritis has included a new focus on the draining lymph node (LN). Here, we combined clinical-serological analyses and power Doppler ultrasound (PDUS) imaging to delineate noninvasively the reciprocal relationship in vivo between the joint and the draining LN in patients with rheumatoid arthritis (RA).MethodsForty consecutive patients refractory to conventional synthetic disease-modifying anti-rheumatic drugs were examined through parallel PDUS of the hand–wrist joints and axillary LNs and compared with 20 healthy subjects. A semiquantitative score for LN gray-scale (GS) parameters (nodal hypertrophy and cortical structure) and LN PD signal was developed. A 6-month follow-up study with serial sonographic assessments was then performed on initiation of tumor necrosis factor (TNF) inhibitors.ResultsPDUS analysis of RA axillary LNs revealed the existence of marked inter-individual heterogeneity and of quantitative differences compared with healthy individuals in both GS and PD characteristics. RA LN changes were plastic, responsive to anti-TNF treatment, and displayed a degree of concordance with synovitis activity in peripheral joints. However, low LN PD signal at baseline despite active arthritis was strongly associated with a poor clinical response to TNF blockade.ConclusionsPDUS analysis of the draining LN in RA allows capture of measurable inter-individual differences and dynamic changes linked to the underlying pathologic process. LN and joint sonographic assessments are nonredundant approaches that may provide independent perspectives on peripheral disease and its evolution over time.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1142-7) contains supplementary material, which is available to authorized users.

Background and objectivesNewly identified B-cell related markers beyond autoantibodies may help better stratifying and predicting the heterogeneous outcome of rheumatoid arthritis (RA). The aim of this study was to investigate whether serum levels of the B-cell chemoattractant CXCL13 can implement information provided by traditional laboratory markers in patient with early RA.Materials and methodsThe pathological correlates of CXCL13, acute phase reactants and autoantibodies were determined in 60 RA patients with paired serum and synovial tissue samples. Baseline associations, responsiveness to change and predictive validity for response to therapy were assessed in a prospective cohort of 213 early RA patients undergoing treatment with methotrexate aiming at low disease activity (LDA).ResultsIn paired serum and synovial samples, CXCL13 covaried with tissue levels of the chemokine (rho 0.56, p = 0.01) and was the only laboratory marker able to discriminate high degrees of B-cell infiltration (AUROC [95% CI] 0.74 [0.61 to 0.85]). Serum CXCL13 showed lower correlation with disease activity and lower responsiveness to change after 2 months of therapy compared with acute phase reactants. Levels were increased in anti-citrullinated protein antibody-positive (ACPA) subjects, approximatively half of whom had high CXCL13 (3rd tertile, >106 pg/ml), and correlated with rheumatoid factor (RF) titres. High CXCL13 alone independently predicted failure to achieve LDA after 12 months of therapy with an adjusted OR (95% CI) of 2.87 (1.42 to 5.82) (p = 0.003), a high negative predictive value (NPV) (79.9%, 95% CI 72.1% to 86.3%) but a quite low positive predictive value (PPV) (50.7%, 95% CI 38.4% to 63%). Combining high CXCL13 with autoantibody positivity (ACPA and/or RF) significantly increased the PPV (61%, 95% CI 44.5% to 75.8%) without affecting the NPV (77.2%, 95% CI 69.9% to 83.4%).ConclusionsIn early RA patients treated with conventional synthetic disease-modifying anti-rheumatic drugs, serum CXCL13 appears a novel lymphoid-linked biomarker holding non-redundant information with respect to acute phase reactants and autoantibodies, and able to stratify patients into different prognostic subgroups.

Background The B cell chemoattractant CXCL13 has recently emerged as a new candidate biomarker of disease activity capable of identifying patients with persistent synovitis and worst radiographic outcomes in early rheumatoid arthritis (RA). However, whether CXCL13 reflects underlying disease processes or simply represents another non-specific marker of inflammation is currently unknown. Objectives To analyse the clinico-pathologic significance of serum CXCL13 in comparison to routine laboratory markers of disease activity and severity in patients with RA. Methods Baseline serum levels of CXCL13 were measured by colorimetric ELISA in 205 consecutive early untreated RA patients with disease duration <12 months (median 3 months, IQR 2-5.5). Disease activity was assessed by a comprehensive set of subjective, semi-objective and objective clinical features. Changes in CXCL13 levels were evaluated in 87 patients after 2 months of treatment with methotrexate and low-dose prednisone. An additional study population of 60 RA patients (n=22 with disease duration <12 months) in whom paired serum and synovial samples were collected on the same day was used to assess the pathologic correlates of circulating CXCL13. Results In cross-sectional analyses at baseline, CXCL13 was moderately correlated with the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) (rho 0.35 and 0.36 respectively, p<0.001). Similarly to acute phase reactants, CXCL13 correlated with overall disease activity as measured by the DAS28, in particular with physician-derived measures, as well as with ultrasonographic scores for Gray Scale and Power Doppler signals. In contrast to ESR and CRP, no correlation was found with patient-derived measures and functional status. Although increased CXCL13 levels were found in patients with anti-citrullinated protein antibodies (ACPA), high CXCL13 and ACPA were not synonymous. CXCL13 in the 3rd tertile (>100 pg/ml) was found in 27.9% of ACPA(−) patients, and, in turn, 53.4% of ACPA(+) patients had CXCL13 <100 pg/ml. Similar results were observed for rheumatoid factor. After 2 months of treatment, CXCL13 levels were not significantly changed from baseline, as opposite to the significant reduction of acute phase reactants (standardised response mean 0.04, 0.52 and 0.66 for CXCL13, ESR and CRP respectively). In paired serum and tissue samples, circulating CXCL13 was significantly correlated with synovial CXCL13 protein (n=60 patients, rho 0.30, p=0.04) and mRNA (n=19 patients, rho 0.56, p=0.02) expression. Similarly to ESR and CRP, serum CXCL13 was related to synovial inflammatory features such as the degree of sublining macrophage infiltration (rho 0.34, p=0.01). Serum CXCL13, but not acute phase reactants, showed further correlation with specific histopathologic and molecular synovial parameters such as the presence and density of large B cell aggregates (rho 0.28, p=0.03), expression levels of the B cell enzyme activation induced cytidine deaminase (AID) (rho 0.4, p=0.046), and the receptor activator o...