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.
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.
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...
CA 125 and CA 15.3 antigens were determined by enzyme immunoassay in 78 patients with ovarian cancer for a total of 540 determinations. The antigens were also investigated in sera from 100 women with other gynaecological diseases, 82 lung cancer patients and in 39 pleural fluids of varying origin. CA 15.3 reference values were evaluated in 91 healthy women (cut-off: 25 U/ml). CA 15.3 sensitivity at diagnosis (60%) and for detecting relapse (44%) was lower than that of CA 125 (90% and 64.7%, respectively). However, CA 15.3 does not increase with aspecific mesothelial cell reaction and thus it is more specific than CA 125. Combined use of the markers during follow-up improves early detection of relapse (at least one of the two was positive in 79% of cases). Therefore both CA 15.3 and CA 125 should be routinely determined for the detection and monitoring of ovarian cancer.
The utility of the markers CEA, beta-HCG, CA-50, alpha-fetoprotein (APF), ferritin, alkaline phosphatase (AP), its isoenzyme liver-1 (APL1), gamma-glutamyltransferase (gGT), its fast migrating isoenzyme (gGT1) and 5'nucleotidase (5'N) in differentiating liver malignancies and benign involvement was evaluated in the sera of 85 patients with hepatocellular carcinoma (HCC), 157 with chronic liver disease (CLD) and 91 with liver metastases (LM) derived from different tumors. The mean concentrations of all the parameters except CEA and GGT1 were significantly different in HCC and CLD, but a broad overlap existed in the two groups, so different cut-offs were considered to assess the positive and negative predictive values and test efficiency (Eff). The best results were observed considering AFP greater than 100 IU/m (Eff0.86), ferritin greater than 800 ng/ml (Eff0.69), CA-50 greater than 100 U/ml (Eff 0.63), beta-HCG greater than 10 mU/ml (Eff 0.61), AP greater than 300 IU/ml (Eff 0.66), the presence of APL1 (Eff 0.78), 5'N greater than 25 mU/ml (Eff 0.70), gGT greater than 100 mIU/ml (Eff 0.63). Among HCC patients 17% did not secrete AFP; in 26% the protein was less than 100 IU/ml and in 36% less than 400 IU/ml. Apart from AFP the most effective marker was APL1. At the above cut-offs more than three parameters were simultaneously positive in 71% of HCC and 9.9% of CLD. CEA, CA50, AFP were the only parameters that distinguished the HCC from the LM group; in the latter, APL1 was also a very sensitive marker (87%) for neoplastic involvement of the liver.
Background The introduction of DAS-driven intensive treatment strategies in early rheumatoid arthritis (RA) has allowed the achievement of drug-induced clinical remission in a significant percentage of cases. Previous studies have also suggested the possibility, in selected patients, of remission maintenance for prolonged periods following treatment suspension. Despite these observations, three critical issues remain unsolved: 1) whether achievement of stable clinical remission and suppression of inflammation can coincide with reversal of the pathogenetic process, 2) the possibility to define parameters able to predict in which patients treatment can be suspended, 3) the primary dynamics as well as the anatomic and biologic substrate of relapse. Objectives To investigate, through a pilot assessment, the clinical outcome and ultrasonographic-synovitis dynamics of RA patients in DMARDs-induced SDAI remission, during a 12 months drug-free follow-up. Methods From December 2011, all RA patients followed at the Pavia's Early Arthritis Clinic achieving stable clinical remission and candidate to treatment suspension are referred to a dedicated Remission Clinic (RemC). Inclusion criteria for RemC referral: 1) introduction of DMARDs treatment within 12 months from symptoms' onset, 2) at least 24 months DMARDs treatment with a DAS28-driven intensive protocol, 3) stable DAS28 clinical remission (DAS28<2.6) for at least 6 months in the absence of corticosteroids. All patients allowed to drug-free follow-up at RemC are monitored at three months' intervals (for the first 12 months) through complete clinical, ultrasonographic (hands-feet-axillary lymph nodes) and immunologic screenings. Hands-feet radiographs are performed at baseline and every 12 months. Treatment with DMARDs is re-introduced in case of moderate disease activity (MDA, DAS28>3.2) or radiographic progression. Results 32 consecutive RA patients (females n=22, ACPA positive n=10) in DAS28 and SDAI remission (SDAI<3.3) at the baseline visit have been followed-up for 12 months after treatment withdrawal and monitored every 3 months. Treatment re-introduction due to MDA was required in 9/32 patients (28%) during follow-up. In 7/32 (22%) it was observed unstable remission with transient states of low disease activity, while in 16/32 patients (50%) stable DAS28 remission was maintained in all visits (T0-T12). Ultrasonographic stratification at baseline showed the absence of power Doppler signal in hands-wrists in 23/32 of patients (SDAI<3.3-PD=0). Despite the absence of clinical and sub-clinical signs of synovitis at recruitment, 5/23 (22%) patients relapsed, while in 11/18 (61%) a transient or persistent reappearance of defined PD signal (PD>1) was detected during follow-up despite the lack of requirement of DMARDs re-introduction according to study criteria. Conclusions Suspension of DMARDs with short term maintenance of good clinical status is an achievable goal after treat-to-target and tight control strategies in early RA. However, despite the presence of ...
Background and objectives Early diagnosis and treat-to-target strategies in rheumatoid arthritis (RA) have allowed the achievement of remission in a significant percentage of cases. Despite the possibility of remission maintenance even after treatment suspension, three critical issues remain unsolved: 1) to what extent suppression of inflammation can coincide with reversal of the pathogenic process, 2) the parameters able to predict in which patients treatments can be suspended, 3) the dynamics of relapse. In this study we investigated the outcome and predictors of relapse in a cohort of RA patients during drug-free follow-up after remission achievement with conventional DMARDs. Materials and methods 62 RA patients achieving stable remission and candidate to DMARD suspension were recruited from our early arthritis clinic (EAC) according to the following criteria: 1) introduction of MTX within 12 months from symptoms’ onset, 2) at least 24 months of MTX treatment with a DAS28-driven protocol, 3) DAS28 < 2.6 for ≥6 months in the absence of corticosteroids. Following treatment suspension, patients were monitored at three months’ intervals through clinical-ultrasonographic (hands-feet)-radiographic and immunologic screenings (serological analyses and multicolour FACS profiles). The primary outcome was the maintenance of DAS28 < 3.2 in all visits (EAC target). Results Baseline stratification showed SDAI remission in 77.4% of the patients, SDAI remission with hands power Doppler (PD) = 0 in 50%, while the absence of detectable clinical-subclinical synovitis (SJC44 = 0, PD hands-feet = 0) in 35.5%. At 12 months from recruitment, clinical relapse was observed in 42.5% of the patients with maintenance of clinical, functional and radiographic stability in 40.7%. As inferred by cumulative survival analyses through 24 months, in patients achieving SDAI remission, high titers of ACPA (with a strengthening effect of ACPA-RF double positivity) were the strongest predictor of relapse, independent of remission duration, further baseline remission depth and ultrasonographic status (HR [95% CI] = 4.19 [1.23–14.28], p = 0.02). In ACPA(high) patients, despite the achievement of stringent clinical-ultrasonographic remission at the time of drug withdrawal, isotype switched IgG ACPA serum levels were on average unchanged compared to paired values at disease diagnosis, with recognition of active spontaneous secretion by isolated PBMC ex-vivo and a specific association with systemic increased rates of proliferation within switched memory B cells (Ki67+IgD-CD27+) (p < 0.05). Conclusions DMARD suspension/drug-holiday are possible options in a proportion of RA patients achieving stable remission. Ongoing immune activation (ACPA production with a possible cooperative function of RF) is the strongest predictor of disease reactivation in patients achieving DMARDs-induced clinical-ultrasonographic control of the inflammatory process.
BackgroundEarly diagnosis and treat-to-target strategies with conventional DMARDs in rheumatoid arthritis (RA) have allowed the achievement of remission in a significant percentage of the cases in daily clinical practice. Whether and in which patients treatments can be suspended with maintenance of health is currently unclear.ObjectivesThe aim of this study was to investigate the outcomes of methotrexate (MTX) suspension and predictors of disease recurrence in a real life single centre cohort of early RA patients followed prospectively under DMARD- and glucocorticoid-free conditions.MethodsAll RA patients included in this current prospective observational study derived from the Pavia's Early Arthritis Clinic (pEAC) and were treated according to a DAS-driven step-up protocol with MTX in monotherapy. Patients achieving stable DAS28 remission and fulfilling the following criteria were eligible for drug suspension: 1) fulfilment of the 2010 ACR/EULAR classification criteria for RA within 12 months from baseline visit; 2) MTX introduced within 12 months from symptoms' onset; 3) ≥24 months of continuative MTX; 4) DAS28 remission documented for ≥6 months in the absence of glucocorticoids. Patients were followed-up at three-months intervals through complete clinical and ultrasonographic (hands-feet) assessments. Radiographs were repeated annually. Treatment was re-introduced in case of DAS28≥3.2 in a single occasion or 3.2
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