M. Turina

Fc gamma receptor-TLR cross-talk elicits pro-inflammatory cytokine production by human M2 macrophages

M2 macrophages suppress inflammation in numerous disorders, including tumour formation, infection and obesity. However, the exact role of M2 macrophages in the context of several other diseases is still largely undefined. We here show that human M2 macrophages promote inflammation instead of suppressing inflammation on simultaneous exposure to complexed IgG (c-IgG) and TLR ligands, as occurs in the context of diseases such as rheumatoid arthritis (RA). c-IgG-TLR ligand co-stimulation of M2 macrophages selectively amplifies production of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 and promotes Th17 responses, which all play a critical role in RA pathology. Induction of pro-inflammatory cytokines on c-IgG co-stimulation mainly depends on Fc gamma receptor IIa (FcγRIIa), which selectively amplifies cytokine gene transcription and induces caspase-1 activation. These data indicate that FcγR-TLR cross-talk may be targeted for treatment to attenuate inflammation in RA, by restoring the anti-inflammatory function of M2 macrophages.

Calprotectin serum level is an independent marker for radiographic spinal progression in axial spondyloarthritis

In previous works, we demonstrated that markers of systemic inflammation (elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) are independently associated with radiographic spinal progression over 2 years in axial spondyloarthritis (axSpA) in the German spondyloarthritis inception cohort (GESPIC).1 We also found previously that calprotectin, which is secreted during monocyte infiltration into inflamed tissues, and thus, directly reflects a potentially important pathophysiological mechanism in SpA,2 ,3 and which was found to be associated with structural joint damage in psoriatic arthritis4 and in rheumatoid arthritis,5 is clearly elevated in SpA as compared to healthy controls, and decreases rapidly and consistently upon effective treatment,2 although in another work, no differences in serum calprotectin between ankylosing spondylitis patients and healthy controls could be found.6 We aimed here to assess whether serum calprotectin levels are predictive for progression of structural damage in the spine in axSpA. Seventy-six patients (mean age 38.0±11.5 years, mean symptom duration 4.6±2.8 years, 66% males, 82% HLA-B27-positives) with definite axSpA (n=63 fulfilling the modified New York criteria for ankylosing spondylitis and n=13 patients with axSpA not fulfilling the radiographic part …

Residual disease activity in psoriatic arthritis: discordance between the rheumatologist’s opinion and minimal disease activity measurement

Objective To assess how many PsA patients with an acceptable disease state according to the treating rheumatologist have quiescent disease defined as minimal disease activity (MDA). Methods This cross-sectional study included 250 PsA patients. To assess current clinical practice as closely as possible, acceptable disease state was not determined by predefined activity measures, but instead was defined by asking rheumatologists to refer those patients whom they considered sufficiently treated. Patients were evaluated for current disease activity including clinical assessments and patient reported outcomes (PROs). Results One-third (88/250) of the patients with acceptable disease state according to the rheumatologist did not fulfil MDA (MDA-). The presence of tender joints and patient pain and global disease activity scores most frequently contributed to not fulfilling MDA (not achieved in 83, 82 and 80%, respectively). However, also objective signs of disease activity were higher in the MDA- than MDA+ patient group: a swollen joint count >1 occurred in 35% vs 7% (P < 0.001), enthesitis >1 in 14% vs 3% (P = 0.002) and Psoriasis Area and Severity Index >1 in 43% vs 26% (P = 0.002). Residual disease was more frequent in females, elder patients and those with a raised BMI, independent of the treatment schedule, and negatively influenced PROs of function and quality of life. Conclusion One-third of the PsA patients with acceptable disease state according to the treating rheumatologist did not fulfil the MDA criteria and had residual disease activity on both subjective and objective disease activity measurements. As residual disease activity was associated with worse PROs, future strategy trials should evaluate if treatment adjustments are beneficial for this patient group.

Clinical and Imaging Signs of Spondyloarthritis in First-Degree Relatives of HLA-B27-Positive Ankylosing Spondylitis Patients: The Pre-Spondyloarthritis (Pre-SpA) Cohort Study

To investigate whether seemingly healthy first‐degree relatives of patients with ankylosing spondylitis (AS) have clinical, laboratory, or imaging features of spondyloarthritis (SpA).

Predictive immunomonitoring - The COST ENTIRE initiative

Themain role of the immune system is to protect an individual from threats coming from the environment (i.e. infections), as well as those coming from the individual itself (i.e. tumors and autoimmunity). However, due to its enormous variability and plasticity, the immune system may also exhibit deleterious effects under numerous circumstances. Inflammation is a phenomenon accompanying both beneficial and detrimental immune responses. Induction of inflammation is a complex process that helps the immune system to eliminate threats and restore homeostasis in the body. However, chronic inflammation often leads to damage of the cells and tissues leading to a group of diseases known as IMIDs. IMIDs constitute a major medical and social problem globally where up to 10% of the population suffers from these diseases [1]. Understanding the pathogenesis of these diseases has allowed therapeutic targeting of molecules that are critical in the initiation/maintenance of inflammation or in immunosuppression. After the initial success of using tumor necrosis factor (TNF) antagonists in the treatment of a patient with rheumatoid arthritis, treatment attempts have been performed in other IMIDs by blocking TNF [2], other pro-inflammatory mediators (i.e. IL-1, IL-6) [3,4], or by targeting molecules that have important functions in immune responses such as immune cell trafficking [5]. In addition, application of cytokines for the treatment of certain diseases, or using antibodies that lead to the depletion of certain cell subpopulations has been successful [6,7]. The application of biological therapies radically changed the natural disease course ofmany IMIDs and improved quality of life of patients and their families. Despite the major clinical efficacy of many biologicals, however, these drugs are still not a universal solution for all IMID patients. Indeed, biologicals were not beneficial for all patients suffering from a particular disease. For example, TNF antagonists have beneficial effects in 60% of the RA patients, but only achieve low disease activity in 30%. In some cases biological drugs turned out to have adverse effects by deregulating immune responses [8]. These drugs are contraindicated in certain patients and can increase the risk for serious infections and/or

Serum inflammatory biomarkers fail to identify early axial spondyloarthritis: results from the SpondyloArthritis Caught Early (SPACE) cohort

Introduction Decreasing the diagnostic delay in axial spondyloarthritis (axSpA) remains a major challenge. Here, we assessed the value of serum inflammatory biomarkers to distinguish early axSpA from other pathologies in a large cohort of patients referred with early back pain. Methods Serum c reactive protein (CRP), erythrocyte sedimentation rate (ESR) and calprotectin were determined in the SPondyloArthritis Caught Early (SPACE) cohort (n=310), an early back pain inception cohort. Additionally, explorative serum biomarkers derived from the literature (interleukin-27 (IL-27), human β-defensin-2 (hBD-2) and lipcolin-2 (LCN-2)) were determined by ELISA in full-blown patients with ankylosing spondylitis (AS) (n=21) and healthy controls (n=20). Results Serum CRP and ESR levels were not elevated in early axSpA versus ‘control’ back pain patients. Serum calprotectin was elevated in early axSpA versus controls (p=0.01) but failed to identify early axSpA at the individual level (positive predictive value of 38.7%). As to explorative biomarkers, serum levels of IL-27 were not detectable, and hBD-2 and LCN-2 serum levels were not elevated in full-blown AS versus healthy controls (p=0.572, p=0.562, respectively). Therefore, these markers were not further determined in the SPACE cohort. Conclusions None of the candidate serum inflammatory markers were useful as diagnostic markers in the early phase of axSpA.

OP0156 Targeting Synovial Mast Cells in Spondyloarthritis: A Proof-Of-Concept Study with Nilotinib A Tyrosine Kinase Inhibitor

Background Immunopathological studies on synovitis recently identified the mast cell as potential novel therapeutic target in spondyloarthritis (SpA).[1] Mast cells can be targeted by inhibiting the signalling of c-Kit, which is one of the targets of the tyrosine kinase inhibitor nilotinib. Objectives To evaluate the immunomodulating and clinical effects of nilotinib in the treatment of SpA. Methods 28 patients with active peripheral and/or axial SpA were included in a randomized, double-blind, placebo-controlled clinical trial. Patients were treated 1:1 with nilotinib or placebo for 12 weeks, followed by an open label extension for another 12 weeks. Paired synovial tissue biopsies, serum sampling and assessment of clinical symptoms were performed serially. Results In peripheral SpA (n=13) synovial inflammation was markedly reduced after 12 weeks of nilotinib treatment as evidenced by histopathology (decrease in number of infiltrating CD68+ and CD163+ macrophages and mast cells). Compared to placebo the mRNA expression of c-Kit as mast cell marker (p=0.037) and of pro-inflammatory cytokines such as IL-6 (p=0.024) were reduced. The improvement of synovial inflammation was paralleled by a decrease in serum biomarkers of inflammation such as C-reactive protein (CRP) from 9.2 (IQR 1.7-33.1) to 5.2 (IQR 1.7-25.1) mg/L (p=0.024) and calprotectin from 359.9 (IQR 183.3-484.9) to 287.9 (IQR 116.7-457.1) ng/mL (p=0.055). Also clinical parameters such as patients global assessment of disease activity (week 0: 52 (IQR 43-65) vs week 12: 21 (IQR 0-51) mm; p=0.031) and Ankylosing Spondylitis Disease Activity Score (ASDAS) (week 0: 2.2 (IQR 1.2-3.0) vs week 12: 1.1 (IQR 0.7-2.4); p=0.031) showed improvement upon 12 weeks of nilotinib but not placebo treatment, and this improvement was further augmented at week 24. In sharp contrast to peripheral SpA, neither serum biomarkers of inflammation nor clinical parameters improved upon nilotinib treatment in axial SpA. During the trial one serious adverse event occurred, which was considered unrelated to the study drug. There were no unexpected safety signals in comparison with published large scale data on nilotinib in chronic myeloid leukemia (CML). Conclusions This small proof-of-concept study supports the concept that mast cells can contribute to synovial inflammation in SpA and that tyrosine kinase inhibition targeting these cells has a biological and clinical immunomodulatory effect in peripheral but not axial SpA. These results support further clinical evaluation of nilotinib in larger clinical trials in pure peripheral SpA, as well as evaluation of other drugs targeting mast cells in SpA. References Noordenbos T, et al. Interleukin-17-positive mast cells contribute to synovial inflammation in spondylarthritis. Arthritis Rheum 2012;64:99-109. Acknowledgements We thank Novartis for the supply of the study medication for this investigator initiated and independent study. Disclosure of Interest J. Paramarta: None declared, M. Turina: None declared, T. Noordenbos: None declared, T. Heijda: None declared, I. Blijdorp: None declared, N. Yeremenko: None declared, D. Baeten Grant/research support: AbbVie, Centocor, Janssen-Cilag, MSD, Novartis, and Pfizer, Consultant for: AbbVie, BMS, Boehringer Ingelheim, Centocor, Janssen, MSD, Novartis, Pfizer, and UCB DOI 10.1136/annrheumdis-2014-eular.2823

Lessons to be learned from serum biomarkers in psoriasis and IBD - the potential role in SpA.

ABSTRACT Introduction: Early diagnosis, monitoring of disease activity, prediction of treatment response, and structural outcome remain major challenges in spondyloarthritis (SpA). Biomarkers could play a role in addressing these challenges, but in SpA there is a lack of suitable biomarkers. Areas covered: As SpA is clinically and pathophysiologically closely related to psoriasis and inflammatory bowel disease (IBD), we reviewed in literature, the value of serum biomarkers in these conditions with the aim to find potential candidates for assessing SpA. Expert commentary: Candidates of interest were antimicrobial peptides, including serum human beta defensin-2 (hBD-2) and lipocalin-2 (LCN-2), and class-1 MHC molecule beta2-microglobulin. Since these biomarkers are relevant in psoriasis and/or IBD from a pathophysiological point of view, and may play a role in the pathogenesis of SpA, we recommend further exploration of their value as biomarker in the diagnosis and prognosis of SpA.

A psychometric analysis of outcome measures in peripheral spondyloarthritis

Objectives To assess the discriminatory capacity of various outcome measures and response criteria in patients with peripheral spondyloarthritis (pSpA). Methods Data originated from two randomised controlled trials, ABILITY-2 and Tnf Inhibition in PEripheral SpondyloArthritis (TIPES). Continuous outcome measures included patients global assessment (PGA)/physicians global assessment of disease (PhGA), C-reactive protein (CRP), tender joint counts (TJC)/swollen joint counts (SJC), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and the Ankylosing Spondylitis Disease Activity Score (ASDAS). Dichotomous response criteria included Peripheral SpondyloArthritis Response Criteria (PSpARC), American College of Rheumatology (ACR), ASDAS and BASDAI response criteria. The capacity to discriminate between adalimumab and placebo groups was assessed by standardised mean differences (SMD) for continuous variables, and Pearsons χ2 for dichotomous response criteria. Results Within each trial, the composite indices for axial SpA assessment, ASDAS-CRP (SMD: −0.63 and −0.89 in ABILITY-2 and the TIPES trial, respectively) and BASDAI (SMD: −0.50 and −0.73), and the single-item measures PGA (SMD: −0.47 and −1.12) and PhGA (SMD: −0.64 and −0.87) performed better than other single-item measures, such as CRP (SMD: −0.18 and −0.53), SJC or TJC. In general, the PSpARC and ACR response criteria discriminated better than ASDAS and BASDAI response criteria. Conclusions The axial SpA-specific ASDAS-CRP and BASDAI, but also PGA and PhGA, demonstrated good discriminatory ability in patients with pSpA. The pSpA-specific pSpARC response criteria and the rheumatoid arthritis-specific ACR response criteria also discriminated well. To fully capture typical pSpA manifestations, it may be worth developing new pSpA-specific indices with better performance and face validity. Trial registration numbers ABILITY-2: NCT01064856; TIPES: EUDRACT 2008-006885-27.

OP0297 Calprotectin (S100A8/9) as Serum Biomarker for Clinical Response in Proof-Of-Concept Trials in Axial and Peripheral Spondyloarthritis

Background Biomarkers complementing clinical evaluations may help to reduce the length and size of proof-of-concept (PoC) trials aimed to obtain quick “go/no go” decisions in the clinical development of new treatments. Objectives We aimed to identify and validate serum biomarkers to predict clinical response in spondyloarthritis (SpA) PoC trials. Methods The candidate biomarkers high sensitive-C-reactive protein (hs-CRP), interleukin-6 (IL-6), pentraxin-3 (PTX-3), alpha-2-macroglobulin (alpha-2-MG), matrix metalloproteinase-3 (MMP-3), calprotectin, and Vascular Endothelial Growth Factor (VEGF) were determined by ELISA in healthy controls (n=20) and SpA patients before and after 2 weeks of infliximab (n=18) or placebo (n=19) treatment. Clinical outcome was evaluated at week 12. Results were validated in ankylosing spondylitis (AS) with infliximab and peripheral SpA with etanercept. Results Serum levels of calprotectin, hs-CRP, PTX-3, VEGF (all P<0.001) and MMP-3 (P=0.062), but not IL-6 and alpha-2-MG, were increased in SpA versus healthy controls. Treatment with infliximab, but not placebo, significantly decreased calprotectin (P<0.001) and hs-CRP (P<0.001) levels, with a similar trend for MMP-3 (P=0.063). The Standardized Response Mean (SRM), which reflects the ability to detect changes over time, was high for calprotectin (1.26), good for hs-CRP (0.96) and moderate for MMP-3 (0.52). Calprotectin and hs-CRP, but not MMP-3, were good biomarkers of treatment response in axial SpA as evaluated in 2 separate cohorts. All 3 markers reflected response to etanercept treatment in peripheral SpA with SRMs above 0.5. Conclusions Calprotectin and hs-CRP are good serum biomarkers to predict clinical response at the group level in small-scale, short term PoC trials in SpA. Disclosure of Interest M. Turina: None declared, N. Yeremenko: None declared, J. Paramarta: None declared, L. De Rycke: None declared, D. Baeten Grant/research support: AbbVie, Centocor, Janssen-Cilag, MSD, Novartis, and Pfizer, Consultant for: AbbVie, BMS, Boehringer Ingelheim, Centocor, Janssen, MSD, Novartis, Pfizer, and UCB DOI 10.1136/annrheumdis-2014-eular.2837