ObjectiveSuccessful uptake of biosimilars in rheumatology is limited by lack of real-world evidence regarding effectiveness of biosimilar-to-biosimilar switching. We investigated infliximab biosimilars CT-P13-to-GP1111 switching among patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA).MethodsObservational cohort study from the DANBIO registry. Patients were classified as originator-naïve or originator-experienced. Retention rates of 1-year GP1111 treatment were explored (Kaplan-Meier). We identified baseline factors (at the time of switch) associated with withdrawal of GP1111 (multivariable Cox-regression analyses with HRs including originator treatment history). Changes in subjective and objective measures of disease activity 4 months before and after the switch were assessed in individual patients.ResultsOf 1605 patients (685 RA, 314 PsA and 606 AxSpA, median disease duration was 9 years, 37% in Clinical Disease Activity Index/Ankylosing Spondylitis Disease Activity Score remission), 1171 were originator-naïve. Retention rates at 1-year were 83% (95% CI: 81% to 85%) and 92% (95% CI: 90% to 95%) for the originator-naïve and originator-experienced, respectively. GP1111 retention rates were higher in originator-experienced compared to originator-naïve with RA (HR=0.4 (95% CI: 0.2 to 0.7)) and PsA (HR=0.2 (95% CI: 0.1 to 0.8)), but not significantly for AxSpA: HR=0.6 (95% CI: 0.3 to 1.2). Lower disease activity was associated with higher retention. Changes in disease activity preswitch and postswitch were close to zero.ConclusionThis real-world observational study of more than 1600 patients with inflammatory arthritis showed high 1-year retention following a nationwide infliximab biosimilar-to-biosimilar switch. Retention was higher in originator-experienced and in patients with low disease activity, suggesting outcomes to be affected by patient-related rather than drug-related factors.

Objectives In 2018, a nationwide mandatory switch from originator to biosimilar adalimumab was conducted in Denmark. The available biosimilar was GP2017 (Hyrimoz) in Eastern regions and SB5 (Imraldi) in Western regions. We aimed to assess the comparative effectiveness of GP2017 versus SB5 in patients with rheumatoid arthritis (RA)/psoriatic arthritis (PsA)/axial spondyloarthritis (AxSpA). Methods Observational cohort study based on the DANBIO registry with geographical cluster pseudo-randomisation, analysed by emulating a randomised clinical trial. Main outcome was adjusted 1-year treatment retention (Cox regression). Furthermore, 6 months' remission rates (logistic regression), reasons for withdrawal and back-switching to originator were investigated (overall and stratified by indication). Results Overall, of 1570 eligible patients, 1318 switched and were included (467 RA/321 PsA/530 AxSpA); 623 (47%) switched to GP2017, 695 (53%) to SB5. Baseline characteristics of the two clusters were largely similar, but some differences in registration practice were observed. The combined 1-year retention rate for the two biosimilars was 89.5%. Compared with SB5, estimated risk of withdrawal for GP2017 was lower (HR 0.60; 95% CI 0.42 to 0.86) and 6 months' remission rate was higher (OR 1.72; 95% CI 1.25 to 2.37). Stratified analyses gave similar results (statistically significant for RA). During 1 year, 8.5% and 12.9% withdrew GP2017 and SB5, respectively (primarily lack of effect and adverse events), of whom 48 patients (3.6%) back-switched. Conclusion This head-to-head comparison of GP2017 versus SB5 following a mandatory switch from the originator indicated differences in effectiveness in routine care. This may reflect a true difference, but other explanations, for example, differences in excipients, differences between clusters and residual confounding cannot be ruled out.

Objective: The effects of a dose-reduction intervention of biological disease-modifying anti-rheumatic drugs (bDMARDs) in patients in remission were analysed with epidemiology and health economics strategies. The aims were to analyse changes in bDMARD dosage, evaluate potential disease worsening, and estimate cost reduction. Method: This uncontrolled single-centre observational study analysed bDMARD-treated patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and spondyloarthritis (SpA). bDMARD expenditure constituted a proxy for bDMARD doses, which enabled group-level analysis. Interrupted time-series regression was used to analyse changes in treatment cost due to the dose reduction. Disease activity and treatment durations were monitored to investigate disease worsening. Results: In total, 997 biological treatment cases were analysed. This involved 527 bDMARD patients, where an unknown fraction of patients was given reduced doses. Disease activity of RA and PsA patients decreased from 2001 to 2009 and remained stable after that, while disease activity for SpA patients was unchanged, indicating no disease worsening from the intervention. The dose tapering resulted in decreased bDMARD expenditure, indicating a decrease in bDMARD consumption, which led to an accumulated cost reduction of 4 178 000 EUR. Conclusions: The results suggest that dose reduction can be safely performed in patients in treatment remission on a group level without compromising treatment efficacy. Subcutaneous bDMARDs, including abatacept, adalimumab, and etanercept, were observed to be well suited to customizing dosage. This study highlights the potential for individualized and personalized rheumatic medicine by providing dose reduction to individual patients, while monitoring disease activity.

OBJECTIVES:To estimate the prevalence of Danish RA patients currently on biologic monotherapy and compare the effectiveness and drug adherence of biologic therapies applied as monotherapy.METHODS:All RA patients registered in the Danish biologics database (DANBIO) as receiving biologic DMARD (bDMARD) treatment as monotherapy without concomitant conventional synthetic DMARDs (csDMARDs) during the study period 1 May, 2011 through 30 April 2013 were eligible for inclusion. All patient files were checked to ensure that they were in accordance with the treatment registration in DANBIO. Descriptive statistics for prevalence, effectiveness and drug adherence of bDMARD monotherapy were calculated.RESULTS:Of the 775 patients on bDMARD monotherapy, adalimumab (21.3%), etanercept (36.6%) and tocilizumab (15.3%) were the most prevalent biologic agents administered. At the 6-month follow-up, the overall crude clinical disease activity index remission rate in patients still on a biologic drug was 22%, the 28-joint DAS remission rate was 41% and the response rate of those with a 50% improvement in ACR criteria was 28%. At the 6-month follow-up, the drug adherence rates were similar for the different bDMARDs, with the exception of infliximab, which had significantly poorer drug adherence (P < 0.001). The overall drug adherence (except for infliximab) was approximately 70% after 2 years.CONCLUSION:Nearly one in five (19%) biologic treatments for RA was prescribed in Denmark as monotherapy, of which 70% were on monotherapy from bio-initiation and 30% were on monotherapy after cessation of a concomitant csDMARD. Acceptable drug adherence and remission rates were achieved with bDMARDs. With the exception of infliximab, no statistically significant differences were observed between anti-TNFs and biologics with other modes of action.

Melanocortin signalling in leucocyte subsets elicits anti-inflammatory and immune tolerance inducing effects in animal experimental inflammation. In man, however, the effects of melanocortin signalling in inflammatory conditions have scarcely been examined. We explored the differential reactions of melanocortin 1-5 receptors (MC1-5R) gene expressions in pathogenetic leucocyte subsets in rheumatoid arthritis (RA) to treatment with TNF-α inhibitor adalimumab. Seven patients with active RA donated blood at start and at 3-month treatment. CD4+ T helper (h) lymphocytes (ly), CD8+ T cytotoxic (c) ly, CD19+ B ly and CD14+ monocytes were isolated, using immunomagnetic beads, total RNA extracted and reverse transcription quantitative polymerase chain reaction (RT-qPCR) performed. Fold changes in MC1-5R, Th1-, inflammatory- and regulatory cytokine gene expressions were assessed for correlation. Six patients responded to adalimumab treatment, while one patient was non-responder. In all lymphocyte subtypes, MC1-5R gene expressions decreased in responders and increased in the non-responder. In responders, decrease in MC2R, MC3R and MC4R gene expressions in CD8+ Tc and CD19+ B ly was significant. Fold change in MC1-5R and IFNγ gene expressions correlated significantly in CD8+ Tc ly, while fold change in MC1R, MC3R and MC5R and IL-1β gene expressions correlated significantly in CD4+ Th ly. Our results show regulation of MC2R, MC3R and MC4R gene expressions in CD8+ Tc ly and CD19+ B ly. The correlations between fold change in different MCRs and disease driving cytokine gene expressions in CD8+ Tc ly and CD4+ Th ly point at a central immune modulating function of the melanocortin system in RA.

Background Polymyalgia rheumatica (PMR) is a systemic inflammatory disorder with unknown etiology and overlapping symptoms with giant cell arthritis and late-onset rheumatoid arthritis (RA). To date, no proteomics studies have been performed on PMR patients, and the number of biomarker studies remain limited. Objectives The primary aim of this study was to thoroughly investigate the corticosteroid treatment serum proteome of PMR with a focus on acute-phase reactions, complement system, and cytokines. Methods Filter-aided sample preparation for mass spectrometry, cell free DNA (cfDNA) assay, and 10plex cytokine assay were applied to PMR serum samples from the same patients before and after treatment, DMARD-naïve RA patients, and healthy controls. Results The core serum proteomes of the four groups were remarkably similar, and consisted of >200 proteins, which included acute-phase reactants, coagulation and complement proteins (figure), immunoglobulins, and apolipoproteins, and several more. Acute Phase Serum Amyloid A (SAA1) was differentially less abundant after PMR treatment, and CRP (after adjusting for two patients with low baseline CRP). cfDNA were more abundant in both groups of PMR compared to healthy controls. Complement factors were narrowly distributed and not affected by PMR treatment. The individual serum proteome of each PMR patient provided more than 100 differentially abundant proteins, and highlights the heterogeneity of patients. Conclusions We have established the core serum proteome of PMR in response to treatment, and compared it with RA and healthy controls. The results suggest a functional role of SSA1, and increased cfDNA in the pathogenesis of PMR indicates the activation of NETs. Disclosure of Interest None declared

The role of the endogenous, proresolving melanocortin system is still essentially unexplored in human auto-immune diseases. Melanocortin receptor (MCR) 1-5 genes and proteins are expressed in several leukocyte subsets and MCR1-3 and MCR5 mRNAs have been found in CD56+ natural killer (NK) cells from healthy humans. CD56+ NK cells may be decisive in the induction of auto-immunity and their cytokine profile assists in the direction of naïve CD4+ T cells into specific effector or regulatory T cell subsets. We explored the possibilities of affecting CD56+ NK cell function through MCR1-5. Thus, we determined the response of MCR1-5 gene expression in active rheumatoid arthritis (RA) to TNFα inhibition (I) with adalimumab. CD56+ NK cells from RA patients treated with adalimumab were separated by immune-magnetic beads before and after three months of adalimumab treatment. Total RNA was extracted and mRNAs for MCR1-5 and a panel of cytokines were measured by qRT-PCR. All MCR genes, including MCR4, not previously described in NK cells -, were expressed in CD56+ NK cells in active RA and reacted to adalimumab by down-regulation. In addition, the gene expression of cytokines important for CD56+ NK cell activity, i.e. especially TNFα and IFNγ were down-regulated. NK cell activity in RA may thus be modulated by MCR signalling. The response of MCR15 gene expressions in NK cells to adalimumab reinforces this perception. We propose that MCR signalling in NK cells may represent a new endogenous pathway to counteract autoimmune inflammation in RA. Citation: Marlene Andersen, Michael Kruse Meyer, Ivan Nagaev, Olga Nagaeva, Jarl Erik Sylvester Wikberg, Lucia Mincheva-Nilsson, Grethe Neumann Andersen (2017). Regulated Melanocortin Receptor 1-5 Gene Expressions in CD56+ NK Cells from Two Rheumatoid Arthritis Patients Treated with Adalimumab Page 2 of 6 www.scientonline.org J Immunol Infect Inflam Dis Volume 2 • Issue 1 • 007 where they are involved in energy homeostasis and control of libido. Of peripheral human cells, the expression of MCR4 has been demonstrated in melanocytes, keratinocytes [9] and dendritic cells, In which MCR4 participate in the control of cell adhesion and antigen presentation [10]. MCR5 was primarily found in exocrine glands, controlling secretion. The ligands of the MCRs are the melanocortins, a family of hormone peptides, derived from a common precursor protein: pro-opio-melanocortin (POMC). POMC is cleaved into α-, βand γmelanocyte stimulating hormone (MSH) and ACTH and several other peptides including β-endorphin. POMC was originally found in the pituitary, from where melanocortins are released into the blood stream. Recently, POMC mRNA has been detected in several leukocyte subsets, e.g. helper and cytotoxic T cells, B cells, monocytes and NK cells [6]. The synthesis of the melanocortins in various peripheral tissues and cells is stimulated by pro-inflammatory TNFα and inhibited by TGFβ [11]. Hypothetically therefore, in leukocytes, the melanocortins may act in an autocrine and paracrine manner to reduce inflammatory cytokine production and leukocyte trafficking [12]. Alpha-MSH may even direct the immune reaction by inducing regulatory T-lymphocyte differentiation [7]. Furthermore, α-MSH decreases antibody production by plasma cells [13]. In monocytes, α-MSH predominantly inhibits the nuclear translocation of NFκB, which controls the transcription of multiple inflammatory mediators such as TNFα [14]. NK cells are large granular lymphocytes with cytotoxic and cytokine producing potentials, which constitute 5-25 % of peripheral blood lymphocytes [15]. They express multitudes of receptors enabling the identification and lysis of stressed, infected, or tumour cells and are part of the innate immune system. Interestingly, accumulating evidence points at NK cells as important in autoimmunity due to their capacity to direct the adaptive immune response by cytokine release [16]. The low frequency of NK cells in the circulation has made their isolation challenging and limited the number of reports on their function. The role of NK cells in RA is still controversial and it is not established whether NK cells contribute to disease development or act to protect from tissue damage. In active RA, the circulating number of CD56+NK cells is reduced, but increase in patients responding to bDMARDs such as etanercept [17], tocilizumab [18] and rituximab [19]. A very low number of NK cells is characteristic of active disease in rheumatoid factor (RF) and anti-cyclic citrullinated protein antibody (ACPA) positive patients [20] and predicts a poorer response to bDMARD [18]. Not only the number, but also phenotypic characteristics of NK cells such as IFNγ expression [21], perforin A and granzyme contents are restored by bDMARDs [18]. Still, there are many question marks concerning the function of NK cells in RA. Although some NK functions have been elucidated, the question whether NK cells are friends or foes in RA remains [21]. Considering this, we examined the gene expression of MCR1-5, the activation of which has anti-inflammatory, tolerance inducing and pro-resolving properties in other leukocyte subsets. To evaluate the regulation of MCR1-5 gene expressions in NK cells in RA, we examined the reaction of MCR1-5 gene expressions to TNFα inhibition with adalimumab in the context of changes in Th1, inflammatory and regulatory cytokine gene expressions. Patients and Methods The study was approved by the ethics committee of Northern Jutland, Denmark (N-20100060). All patients gave their informed consent both orally and in writing.

Background Resistin (RETN) was described in 2001 as an adipokine secreted by murine adipocytes resulting in insulin resistance. However, in man, adipocyte synthesis of RETN is controversial, while monocyte RETN production is well established (1). Curiously, RETN synthesis and its regulation in pathogenic immune cell subsets have not been examined in rheumatoid arthritis (RA), although blood RETN levels correlate to disease activity. In RA, -a risk factor for coronary artery disease (CAD), RETN might contribute to atherosclerosis. E.g. macrophage secreted RETN in atheromas, facilitates cholesterol uptake and plaque instability. Considering this, an in depth understanding of the regulation and effects of RETN synthesis in pathogenic immune cell subsets may provide clues to the aetiology of CAD, known to be associated with factors (high CRP, RF and ACPA), characterizing active RA. Objectives The aim of our investigation was to explore whether RETN gene transcription in pathogenic cell subsets of innate and adaptive immunity is detectable and if present, amenable to TNFα inhibition (I) and correlated to important cytokines in RA. Methods We examined the reaction of RETN gene transcription to TNFαI in CD14+ monocytes, CD4+ T helper (Th) lymphocytes (ly), CD8+ T cytotoxic (Tc) ly, and CD19+ B ly in RA patients, responding to adalimumab. Leukocyte subsets from 7 RA patients were isolated by Dynabeads before and 3 months after start of TNFαI. Total RNA was extracted and mRNAs for RETN and a panel of disease driving Th1, inflammatory and regulatory cytokines were measured by real-time qRT-PCR. Results RETN gene transcription was present in al cell subsets and in CD14+ monocytes and CD4+ Th ly responded to TNFαI with a significant decrease. In CD14+ monocytes the RETN gene was transcribed to a significantly higher degree than in lymphocyte subsets of the adaptive immune system both before and during TNFαI. In active RA, prior to TNFαI, RETN and TGFβ mRNA levels correlated significantly in CD4+ Th ly (P=0.03), while in CD14+ monocytes fold change in TGFβ and RETN mRNAs due to TNFαI correlated highly significantly (P=0.01). Furthermore, RETN and IL-8 mRNA levels tended to correlate (P=0.06) in CD14+ monocytes prior to TNFαI. Conclusions We here report regulated RETN gene transcription in human CD4+ Th ly as well as in CD14+ monocytes. Our results point at wider functions for RETN. Thus we found TNFαI regulated RETN gene transcription in CD4+Th ly in RA, indicating a possible immune response directing role. In this aspect, our results are in concert with increased RETN mRNA correlating to CD4+Th17 ly number in human cecum. The idea of RETN pleiotropic actions is further supported by the correlation to TGFβ transcription. RETN and TGFβ share a pathway for their synthesis and fibrogenic ability (2), on top TGFβ also has a prominent role in immune tolerance. The relation to IL-8 indicates influence on neutrophil trafficking (1). References Nagaev I et al. Human resistin is an immune-derived proinflammatory cytokine targeting both leukocytes and adipocytes. PLoS One 2006 Dec 20;1:e30. Chemaly R et al. Differential patterns of replacement and reactive fibrosis in pressure and volume overload are related to the propensity for ischaemia and involve resistin. J Physiol 2013;59:5337–55 Disclosure of Interest None declared

Background Although biological agents may manage rheumatoid arthritis (RA), curative treatment is still the ”holy grail”. Induction of auto-antigen specific immune tolerance might offer a solution and obviate the need for life-long immunosuppression. Melanocortins are small peptides with considerable immune tolerance inducing, inflammation resolving and tissue preserving qualities (1). In animal experimental, autoimmune conditions, melanocortins have been demonstrated to bind differentially to melanocortin receptor (MCR) 1–5 on immune cells and to transform auto-reactive CD4+ T helper (Th) lymphocytes (ly) as well as sensitized CD8+ T cytotoxic (Tc) ly into regulatory T (Treg) ly and thus clear cell-mediated auto-immunity and delayed type hypersensitivity. In contrast to the situation in organ transplantation, clinical application of Treg therapy in human autoimmune disease is still non-existing, primarily because of a lack of in depth understanding. Objectives To explore if the pro-resolving melanocortin system may offer a pathway to immune tolerance induction, we examined whether the melanocortin system is present and responsive in pathogenic immune cell subsets in RA. To this end, we related changes due to TNFα inhibition (I) in MCR1–5 mRNA levels to changes in Th1 signature-, inflammatory and regulatory cytokine mRNA levels. Methods CD4+ Th, CD8+ Tc ly, CD19+ B-ly and CD14+ monocytes from seven patients with definite RA were isolated by Dynabeads before and three months after the start of TNFαI. Total RNA was extracted and mRNAs for MCR1–5 and a panel of disease driving Th1, inflammatory and regulatory cytokines were measured by real-time qRT-PCR. Fold changes in MCR1–5 gene levels were correlated to changes in cytokine gene levels. Results MCR1–5 gene expressions were reduced in al examined cell types, significantly so in CD8+ Tc ly and CD19+ B ly in RA patients responding to TNFαI. In addition, Th1 and inflammatory cytokine mRNA levels were reduced in all cell types in responders. In a non-responding patient MCR1–5 gene expressions as well as Th1 and inflammatory cytokine gene levels increased substantially. The changes in MCR1–5 gene expressions in CD8+ Tc cells correlated significantly to changes in the Th1 cytokine IFNγ gene level in this cell type. Furthermore, we found significant correlations between changes in MCR 1, 3, 5- and change in IL-1β gene levels in CD4+ Th ly. Conclusions Our results point at a responsive melanocortin system in immune cells in RA. Moreover, its regulation seems intimately connected to the disease driving Th1 response, that is IFNγ production by CD8+ Tc ly. Our results are underlined by the recently reported importance of IFNγ producing CD8+ Tc ly in early RA. Thus our findings indicate that the melanocortin pathway lies open to treatment of auto-reactive effector T ly from RA patients with MCR type specific synthetic ligands in vivo or in vitro to induce Treg transformation. Future curative induction of auto-antigen specific immune tolerance in RA may therefore involve the melanocortin system. References Ahmed TJ, Montero-Melendez T, Peretti M, Pitzalis C. Curbing Inflammation through endogenous pathways: Focus on melanocortin peptides. Int J Inflamm 2013;2013:985815. Disclosure of Interest None declared

Rheumatoid arthritis (RA) is caused by complex interactions between immune cells and sustained by Th1 response cytokines. Resistin [resistance to insulin; (RETN)] is an inflammatory cytokine, first discovered in murine adipocytes. In man, RETN is mainly secreted by monocytes. The distinct role of RETN in the immune reaction is uncertain; however, RETN has pro-inflammatory, profibrotic and possibly tolerogenic properties. The aim was to assess the reaction of RETN gene expression to TNF-alpha inhibition (I) in pathogenetic immune cell subsets in RA, in the context of Th1, inflammatory and regulatory cytokine gene expressions. Accordingly, we measured RETN, IFN-gamma, TNF-beta, IL-1 beta, TNF-alpha, TGF-beta and IL-10 gene expressions in CD14(+) monocytes, CD4(+) T helper (Th) lymphocytes (ly), CD8(+) T cytotoxic (Tc) ly and CD19(+) B ly in active RA before and 3 months after start of TNF-alpha I. Leucocyte subsets were separated by specific monoclonal antibody-covered beads, RNA extracted and levels of RETN, Th1 response, inflammatory and regulatory cytokine mRNAs measured by quantitative reverse transcription-polymerase chain reaction technique. We found that TNF-alpha I caused a significant downregulation of RETN gene expression in CD14(+) monocytes and CD4(+) Th ly and was unchanged in CD8(+) Tc ly and CD19(+) B ly. Both in active RA and during TNF-alpha I, RETN mRNA levels were significantly higher in CD14(+) monocytes than in all other examined cell types. In monocytes, fold change in RETN and TGF-beta gene expressions upon TNF-alpha I correlated significantly. Our findings indicate that RETN has pro-inflammatory as well as proresolving roles in active RA.

Objective:The availability of biological disease-modifying anti-rheumatic drugs (bDMARDs) has increased during the last decade, and while focus has been on treating clinical symptoms, the associated changes in the immune system remains poorly understood.Several key immunological regulators, including Interleukin (IL)-6 are intimately associated with rheumatoid arthritis disease progression.In this proof-of-concept case study we assess the immunological changes in multiple important immune cell populations to treatment with the commonly applied bDMARD tocilizumab, a humanized monoclonal antibody against the IL-6 receptor.Methods: Peripheral blood was obtained from one rheumatoid arthritis patient with poor response to conventional DMARD, before biological treatment and 4 months after.Peripheral blood mononuclear cells were extracted and separated into CD14 + , CD4 + , CD8 + , CD19 + , and CD56 + immune cells.Each cell-type was prepared through a discovery proteomics pipeline, and analyzed on a Q Exactive Plus mass spectrometer by gel-free shotgun proteomics. Results:The patient responded well to tocilizumab monotherapy, and reached clinical remission without any observed side effects.A combined total of 4,343 proteins were identified at <1% false discovery rate, hereof 3,242 proteins qualified for label free quantification.We systematically evaluated the metabolic, inflammatory and signaling pathways of each immune cell type as a result of the IL-6R inhibition.The CD14 + cells were the most responsive to therapy, and proteins involved in the JAK/STAT and MAPK signaling pathways were less abundant. Conclusion:Our data support that effective treatment of rheumatoid arthritis with tocilizumab causes decrease in the JAK/STAT and modulation of the MAPK signaling pathways, increases glucose metabolism, and reduces stress responses.

Background Enthesitis are frequently occurring in spondyloarthritis and are considered a hallmark of the disease. However, little is known of the occurrence of entheseal abnormalities in other rheumatic conditions such as rheumatoid arthritis (RA). Clinical evaluation of entheseal involvement is often difficult and ultrasound (US) has been shown to be more sensitive than clinical evaluation. Objectives To describe the occurrence of entheseal abnormalities by US in patients with RA using B-mode and Doppler US. Methods Patients with active RA according to the ACR criteria were included. All patients were examined by US using a GE LOGIQ 9 with a 14 MHz linear array transducer, a Doppler frequency of 7.5 MHz and Doppler settings adjusted to slow flow according to published recommendations. For each patient 10 entheseal sites were examined bilaterally by US: Quadriceps tendon, superior and inferior insertion of the patella tendon, Achilles tendon, proximal insertion of the plantar fascia, common extensor and flexor tendon insertion at the elbow, triceps tendon insertion on olecranon, gluteal muscle insertion onto the greater trochanter and supraspinatus tendon insertion. Each entheseal site was scored for US signs of enthesitis: bone erosion, thickened enthesis/loss of fibrillar structure, calcifications/enthesophytes and Doppler signal. Clinically, the patients were examined for swelling and tenderness of joints (66/68) and for tenderness of 33 entheseal sites, and DAS28 and a MASES index (13 entheses) and were calculated, as measures of disease activity and entheseal involvement, respectively, at time of evaluation. Results Twenty patients (18 women and 2 men, median age 54.5 (range 26-73) years and median disease duration 6 years (range 1-42)) were included. At baseline the median DAS28 was 4.69 (range 3.48-6.66) and the median entheses score (MASES) was 2 (range 0-8). Of the 400 entheseal sites examined by US, 108 (27%) showed abnormalities. A total of 148 US changes were seen of which 73 calcification/enthesophytes (49%), 60 erosions (40%) 12 thickened enthesis (8%) and 3 entheses with Doppler activity (2%). Overall, the entheseal sites of the lower limbs were the most frequently affected, 67%, versus 33% in the upper limbs. Clinically, only 14 patients had a positive MASES score but all the patients had B-mode changes, most frequently calcifications/enthesophytes and erosions and 3 patients had Doppler changes. The median number of entheses involved was 5 (range 1-9) and all patients had at least one entheseal site with abnormalities. The most frequently affected entheseal site was the trochanter region, whereas the inferior patella tendon was never involved. Conclusions Entheseal abnormalities detected by US were frequent in RA patients. Although some of these changes may be on degenerative basis, 6 patients had at least 1 thickened enthesis and 3 had Doppler activity as a sign of inflammatory activity. This indicates that enthesitis may be a component of disease also in RA patients. Disclosure of Interest None declared

Adalimumab (Humira (R)) normalizes melanocortin receptor subtype 2, 3, and 4 expression in CD8+, CD14+, and CD19+leucocyte subsets in rheumatoid arthritis