F. Benaglio

Serum levels of CXCL13 are associated with ultrasonographic synovitis and predict power Doppler persistence in early rheumatoid arthritis treated with non-biological disease-modifying anti-rheumatic drugs.

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.

Subclinical remodelling of draining lymph node structure in early and established rheumatoid arthritis assessed by power Doppler ultrasonography

OBJECTIVE To investigate the suitability of power Doppler ultrasonography (PD-US) for the assessment of lymph node (LN) status in RA, evaluating the existence of structural and dynamic modifications in well-characterized stages of the disease. METHODS Ten patients with active disease and five patients in clinical remission underwent complete clinical and PD-US examination of hands, wrists, axillary and cervical LNs on the same day. Synovitis and PD were graded 0-3. LN assessment included maximum short axis, cortical hypertrophy (CH) and PD signal distribution. All patients with active disease were re-evaluated prospectively 3 months after initiation of therapy. RESULTS PD-US signs of axillary LN remodelling were observed in 7 out of 10 patients with active disease despite the absence of clinical lymphoadenopathy. Subclinical alterations were detected in both early untreated RA and in established disease. Characteristic structural changes consisted of hypertrophy of the LN cortex and PD signal amplification in cortical and hilar regions. Cervical LNs in active disease and axillary LNs in clinical remission were unaffected. LN PD amplification returned to normal ranges in patients with baseline alterations re-evaluated 3 months after therapy with TNF-α blocking agents and/or MTX. CONCLUSION 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.

Power Doppler ultrasonographic assessment of the joint-draining lymph node complex in rheumatoid arthritis: a prospective, proof-of-concept study on treatment with tumor necrosis factor inhibitors.

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.

20 years of experience with tumour necrosis factor inhibitors: what have we learned?

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 patients 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.

THU0099 The 2010 classification criteria and a more aggressive treatment strategy improve clinical outcomes in seropositive but not seronegative rheumatoid arthritis

Background Current guidelines recommend an early and intensive treatment in patients diagnosed with rheumatoid arthritis (RA), and the 2010 ACR/EULAR Classification Criteria were developed with the aim of allowing earlier diagnosis and treatment (1,2). Recent studies highlighted some differences in disease activity between seropositive and seronegative RA patients at disease onset (3). Objectives To investigate whether the application of the 2010 ACR/EULAR Classification Criteria and a more aggressive treatment strategy improve clinical outcomes in patients with early RA irrespective of the autoantibody status. Methods 584 early, treatment-naïve RA patients were recruited in the years 2005–2014. RA diagnosis was made according to the ACR 1987 criteria in 2005–2010 (n=360, cohort 1987), and to the 2010 ACR/EULAR criteria in 2011–2014 (n=224, cohort 2010). Patients were classified in autoantibody (Ab)-negative (negative rheumatoid factor (RF) and/or anticitrullinated peptide antibody (ACPA) and Ab-positive (RF and/or ACPA positive). Methotrexate (MTX) was used at the initial dosage of 10 mg/week in cohort 1987, and 15 mg/week in cohort 2010, and progressively increased if low disease activity (LDA) (DAS28≤3.2) was not met. The frequency and predictors of LDA and clinical remission (DAS28<2.6) over 6 months were assessed by Cox regression. Results In Ab-negative patients, LDA and clinical remission were achieved in 62.8% and 37.2% of the cases, and the 2010 cohort did not show significantly improved outcomes (HR [95% CI] 0.86 [0.611.23] for LDA

A5.13 Power-doppler ultrasound assessment of the joint-draining lymph node complex in rheumatoid arthritis

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A5.14 Serum CXCL13 is a non-invasive synovitis marker holding non-redundant information compared with acute phase reactants and autoantibodies in patients with rheumatoid arthritis

1.04 [0.651.69] for remission) (Figure 1A,B). In contrast, in Ab-positive patients, the application of the 2010 classification criteria and higher dosages of MTX were associated with increased frequency of LDA after adjustment for confounders (age, sex, prednisone, baseline DAS28

SAT0540 Power Doppler Ultrasound Imaging of The Joint-Draining Lymph Node Complex in Rheumatoid Arthritis

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SAT0087 Serum Levels of CXCL13 Refine The Predictive Ability of Autoantibodies To Identify Unstable Remission in Early Rheumatoid Arthritis

HR [95% CI] 1.39 [1.012]) (Figure 1C). Clinical remission was achieved in 41.3% of the cases, compared to 29.6% in the 1987 cohort (p=0.17) (Figure 1D). Conclusions Early diagnosis and a more aggressive treatment strategy with MTX lead to significantly improved outcomes in autoantibody positive RA. The management of seronegative patients remains suboptimal. References Smolen JS et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis 2016. Aletaha D et al. 2010 rheumatoid arthritis classification criteria: an ACR/EULAR collaborative initiative. Ann Rheum Dis 2010. Nordberg LB et al. Patients with seronegative RA have more inflammatory activity compared with patients with seropositive RA in an inception cohort of DMARD naive patients classified according to 2010 ACR/EULAR criteria. Ann Rheum Dis 2017. Disclosure of Interest None declared

A8.29 Outcome and predictors of relapse in early rheumatoid arthritis patients achieving DMARDs-induced stable remission during drug-free follow-up

Background and objectives The afferent lymphatic system and the draining lymph node (LN)act as complementary check-points through progressive steps of the inflammatory and resolution processes. We have previously shown in a proof-of-concept study that LN Power Doppler ultrasound (PDUS) allows detection of qualitative changes in rheumatoid arthritis (RA). In this study we developed a quantification approach for PDUS assessment of the inflammatory node and investigated its clinical and pathologic significance. Materials and methods Forty RA patients refractory to conventional DMARDs were evaluated through complete clinical and PDUS examination in hands/wrists and axillary LN. Twenty healthy individuals were recruited as controls. Thirty-one patients starting anti-TNF treatment were followed-up prospectively at weeks 4 and 24. Axillary LN were investigated by digital image analysis and semi-quantitatively focusing on volumetric measures, vascular perfusion and micro-structure of the lymphocyte-rich cortex. Patient-related US indices for each parameter were constructed for correlative, response-to-treatment and predictive analyses. Results LN perfusion and morpho-structural features demonstrated specific quantitative increase in RA LN leading to distinct sonotypes differentiating patients from controls. LN PDUS parameters showed however a high degree of heterogeneity with values exceeding the threshold of controls restricted to 42.5% of the cases. No differences in LN status were observed in relation to autoantibody positivity. LN indices showed instead a link with peripheral joint inflammation as inferred by the significant correlation (at systemic and ipsilateral level) between LN and peripheral joint PD (r = 0.35, p = 0.03). At week 24, 61.3% of the patients were EULAR responders. Patients with different treatment outcomes did not show any significant difference in baseline clinical features and joint US. In contrast, the LN PD index was significantly lower in non-responders (median [IQR] 0 [0–0.5] vs 2 [1–4.75], p = 0.007). Lack of changes of LN PD above the threshold of controls (PD index≤2) was the only predictor of failure to achieve response with an OR of 9.9 (p = 0.04). Conclusions Synchronised and longitudinal PDUS monitoring of joint inflammation and LN reactivity is an achievable goal in patients with RA. Lack of draining LN involvement in patients with active disease seems to associate with a less favourable anti-TNF treatment response.