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Background Lupus nephritis (LN) is a major and severe organ involvement in systemic lupus erythematosus (SLE), whose diagnosis and treatment necessitate to perform kidney biopsy, which is an invasive procedure. Non-invasive urine biomarkers are an active area of investigation to support LN diagnosis and management. Objective To investigate the role of urinary galectin-3 binding protein (u-Gal-3BP) as a candidate biomarker of renal disease in biopsy proven LN. Patients and methods Levels of u-Gal-3BP were investigated in a cross-sectional fashion by ELISA in 270 subjects: 86 LN patients, 63 active SLE patients with no kidney involvement, 73 SLE patients with inactive disease and 48 age and sex-matched population-based controls (PBC). Moreover, urine samples were analysed separately by ELISA for additional markers of kidney pathology: neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), kidney injury molecule-1 (KIM-1) and galectin-3 (Gal-3). The concentrations of all studied molecules were normalized to urine creatinine levels. In 10 patients, post-treatment levels of the biomarkers were measured. Results Normalized u-Gal-3BP levels were higher in LN patients compared to the other groups ( p < .0001). Comparing different LN classes, u-Gal-3BP levels were higher among patients with proliferative (class III/IV) and membranous (class V) as compared to mesangial (class II) forms ( p = .04). In proliferative forms, u-Gal-3BP levels correlated with the activity index in renal biopsies (r = 0.42, p = .004). Moreover, in a subset of 10 patients with repeated kidney biopsy and urine sampling before and after induction treatment, a significant decrease of u-Gal-3BP was observed ( p = .03) . Among the other markers, KIM-1 was also able to discriminate LN from the other groups, while NGAL, OPN and Gal-3 could not in this cohort. Conclusion Given its ability to discriminate LN patients from active non-renal and inactive SLE patients, the observed correlation with the activity index in renal biopsies, and its levels declining following treatment, u-Gal-3BP shows promise as a non-invasive urinary biomarker to help detecting and to monitor renal involvement in SLE patients and should be validated in larger cohorts.

ObjectiveLupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE). The pathogenesis is incompletely understood and diagnostic biomarkers are scarce. We investigated interleukin (IL) 16 as a potential biomarker for LN in a well-characterised cohort of patients with SLE.MethodsWe measured urinary (u-) and plasma (p-) levels of IL-16 in predefined patient groups using ELISA: LN (n=84), active non-renal SLE (n=63), inactive non-renal SLE (n=73) and matched population controls (n=48). The LN group included patients with recent biopsy-confirmed proliferative (PLN, n=47), mesangioproliferative (MES, n=11) and membranous (MLN, n=26) LN. Renal expression of IL-16 was investigated by immunohistochemistry. Associations between IL-16 measurements and clinical parameters and the diagnostic value for LN were explored.Resultsp-IL-16 was detected in all investigated cases and high p-IL-16 levels were observed in patients with active SLE. u-IL-16 was detected (dt-u-IL-16) in 47.6% of patients with LN, while only up to 17.8% had dt-u-IL-16 in other groups. In the LN group, 68% of patients with PLN had dt-u-IL-16, while the proportions in the MLN and MES groups were lower (11.5% and 45.5%, respectively). The highest u-IL-16 levels were detected in the PLN group. In the regression model, u-IL-16 levels differentiated PLN from other LN patient subgroups (area under the curve 0.775–0.896, pConclusionsWe demonstrate that detectable u-IL-16 can differentiate patients with PLN from those with less severe LN subtypes and active non-renal SLE. Our findings suggest that u-IL-16 could be used as a screening tool at suspicion of severe LN. Furthermore, the high IL-16 levels in plasma, urine and kidney tissue imply that IL-16 could be explored as a therapeutic target in SLE.

B cell abnormalities are common in systemic lupus erythematosus (SLE), and include expansion of double negative (DN) and age-associated-like B cells (ABC-like). We aimed to investigate rituximab (RTX) effects on DN and ABC-like B-cell subsets and, when possible, also secondary effects on T cells. Fifteen SLE patients, fulfilling the ACR 1982 criteria, starting RTX and followed longitudinally up to two years, were analyzed for B- and T- lymphocyte subsets using multicolor flow cytometry. DN were defined as IgD-CD27- and ABC-like as CD11c+CD21- within the DN gate. Additional phenotyping was performed adding CXCR5 in the B-cell panel. Cellular changes were further analyzed in the context of the generation of anti-drug antibodies (ADA) against RTX and clinical information. The SLE patients were mainly females (86.6%), of median age 36.7 (29.8-49.4) years and disease duration of 6.1 (1.6-11.8) years. Within the DN subset, ABC-like (IgD-CD27-CD11c+CD21-) B cell frequency reduced from baseline median level of 20.4% to 11.3% (p=0.03), at early follow-up. The DN B cells were further subdivided based on CXCR5 expression. Significant shifts were observed at the early follow-up in the DN2 sub-cluster (CD11c+CXCR5-), which reduced significantly (-15.4 percentage points, p=0.02) and in the recently described DN3 (CD11c-CXCR5-) which increased (+13 percentage points, p=0.03). SLE patients treated with RTX are at high risk of developing ADA. In our cohort, the presence of ADA at 6 months was associated with lower frequencies of DN cells and to a more pronounced expansion of plasmablasts at early follow-up. The frequency of follicular helper T cells (T

Arthritis is a common clinical feature of systemic lupus erythematosus (SLE) and is usually non-erosive as opposed to rheumatoid arthritis (RA). While RA synovial pathology has been extensively studied, little is known about the pathophysiology of lupus arthritis. Here, we aimed to explore the cytokine and cellular compartments in synovial fluids of SLE patients with arthritic manifestations. Acellular synovial fluid and paired serum samples from SLE patients (n=17) were analyzed with cytokine bead array for T helper associated cytokines. From two SLE patients, synovial fluid mononuclear cells (SFMC) were analyzed by multiparameter flow cytometry to dissect T cell, B cell, monocyte and dendritic cell phenotypes. SLE-derived SFMC were further stimulated in vitro to measure their capacity for producing IFN and IL-17A. All patients fulfilled the ACR 1982 classification criteria for SLE. Clinical records were reviewed to exclude the presence of comorbidities such as osteoarthritis or overlap with RA. IL-17A and IL-6 levels were high in SLE synovial fluid. A clear subset of the synovial CD4+ T cells expressed CCR6+, a marker associated with Th17 cells. IL-17-production was validated amongst CD4+CCR6+ T cells following in vitro stimulation. Furthermore, a strong IFN production was observed in both CD4+ and CD8+ cells. Our study shows high IL-17A and IL-6 levels in synovial fluids of patients with lupus arthritis. The Th17 pathway have been implicated in several aspects of SLE disease pathogenesis and our data points to Th17 involvement also for lupus arthritis.

Summary Arthritis is a common clinical feature of systemic lupus erythematosus (SLE) and is usually non‐erosive, as opposed to rheumatoid arthritis (RA). While RA synovial pathology has been extensively studied, little is known about the pathophysiology of lupus arthritis. Here, we aimed to explore the cytokine and cellular compartments in synovial fluids of SLE patients with arthritic manifestations. Acellular synovial fluid and paired serum samples from SLE patients (n = 17) were analyzed with cytokine bead array for T helper‐associated cytokines. From two SLE patients, synovial fluid mononuclear cells (SFMC) could also be captured and were analyzed by multiparameter flow cytometry to dissect T cell, B cell, monocyte and dendritic cell phenotypes. SLE‐derived SFMC were further stimulated in vitro to measure their capacity for producing interferon (IFN)‐γ and interleukin (IL)‐17A. All patients fulfilled the ACR 1982 classification criteria for SLE. Clinical records were reviewed to exclude the presence of co‐morbidities such as osteoarthritis or overlap with RA. IL‐17A and IL‐6 levels were high in SLE synovial fluid. A clear subset of the synovial CD4+ T cells expressed CCR6+, a marker associated with T helper type 17 (Th17) cells. IL‐17A‐production was validated among CD4+CCR6+ T cells following in‐vitro stimulation. Furthermore, a strong IFN‐γ production was observed in both CD4+ and CD8+ cells. Our study shows high IL‐17A and IL‐6 levels in synovial fluids of patients with lupus arthritis. The Th17 pathway has been implicated in several aspects of SLE disease pathogenesis and our data also point to Th17 involvement for lupus arthritis., IL‐17A and IL‐6 are elevated in synovial fluid of SLE arthritis patients. The Th17 pathway have been implicated in several aspects of SLE disease pathogenesis and our data points to Th17 involvement also for lupus arthritis.

ObjectivesPatients with chronic inflammatory diseases are often treated with immunosuppressants and therefore are of particular concern during the SARS-CoV-2 pandemic. Serological tests will improve our understanding of the infection and immunity in this population, unless the tests give false positive results. The aim of this study was to evaluate the specificity of SARS-Cov-2 serological assays with samples from patients with chronic inflammatory diseases collected before April 2019, thus defined as negative.MethodsSamples from patients with multiple sclerosis (MS, n=10), rheumatoid arthritis (RA, n=47) with or without rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide antibodies (anti-CCP2) and RF +/- systemic lupus erythematosus (SLE, n=10), were tested with 17 commercially available lateral flow assays (LFA), two ELISA kits and one in-house developed multiplex bead-based assay.ResultsSix LFA and the in-house IgG assay gave the correct negative results for all samples. However, the majority of assays (n=13), gave false positive signal with samples from patients with RA and SLE. This was most notable in RF positive RA samples. MS samples did not give any false positive in any of the assays.ConclusionThe majority of the verified serological assays were sensitive to interfering antibodies in samples from patients with chronic inflammatory diseases and therefore may have poor specificity in this context. For these patients, the risk of false positivity should be considered when interpreting results of the SARS-CoV-2 serological assays.

OP0018 (2020) A MULTICENTER RANDOMIZED STUDY IN EARLY RHEUMATOID ARTHRITIS TO COMPARE ACTIVE CONVENTIONAL THERAPY VERSUS THREE BIOLOGICAL TREATMENTS: 24 WEEK EFFICACY RESULTS OF THE NORD-STAR TRIAL M. L. Hetland1, E. A. Haavardsholm1, A. Rudin1, D. Nordström1, M. Nurmohamed1, B. Gudbjornsson1, J. Lampa1, K. Hørslev-Petersen1, T. Uhlig1, G. Gröndal1, M. Ǿstergaard1, M. Heiberg1, J. Twisk1, S. Krabbe1, K. Lend1, I. Olsen1, J. Lindqvist1, A. K. H. Ekwall1, K. L. Grøn1, M. C. Kapetanovic1, F. Faustini1, R. Tuompo1, T. Lorenzen1, G. Cagnotto1, E. Baecklund1, O. Hendricks1, D. Vedder1, T. Sokka-Isler1, T. Husmark1, M. K. A. Ljosa1, E. Brodin1, T. Ellingsen1, A. Soderbergh1, M. Rizk1, Å. Reckner1, P. Larsson1, L. Uhrenholt1, S. A. Just1, D. Stevens1, T. B. Laurberg1, G. Bakland1, R. Van Vollenhoven1 1Denmark, Finland, Iceland, Netherlands, Norway, Sweden Background: The optimal first-line treatment of patients (pts) with early rheumatoid arthritis (RA) is yet to be established. Objectives: The primary aim was to assess and compare the proportion of pts who achieved remission with active conventional therapy (ACT) and with three different biologic therapies after 24 wks. Secondary aims were to assess and compare other efficacy measures. Methods: The investigator-initiated NORD-STAR trial (NCT01491815) was conducted in the Nordic countries and Netherlands. In this multicenter, randomized, open-label, blinded-assessor study pts with treatment-naïve, early RA with DAS28>3.2, and positive RF or ACPA, or CRP >10mg/L were randomized 1:1:1:1. Methotrexate (25 mg/week after one month) was combined with: 1) (ACT): oral prednisolone (tapered quickly); or : sulphasalazine, hydroxychloroquine and mandatory intra-articular (IA) glucocorticoid (GC) injections in swollen joints

Objective Rituximab-mediated late-onset neutropenia (LON) has been described in various diseases. We investigated its occurrence, consequences and contributing factors in patients with systemic lupus erythematosus (SLE). Methods Rituximab-treated patients from the Karolinska University Hospital ( n = 107) were surveyed. LON was defined as an absolute neutrophil count Results Thirty-two patients (29.9%) developed LON after a median time of 201.5 days. Thirteen patients were admitted to the hospital; 10 due to fever. Three patients developed critical conditions. BAFF levels increased from baseline (median: 0.62 ng/ml) to the post-treatment evaluation (median: 1.16 ng/ml; p 8). No association with neutropenia prior to rituximab treatment was documented. Conclusion Post-rituximab LON was a common complication. Although the phenomenon was predominantly self-limiting, several patients developed severe conditions. Distinct roles of BAFF and APRIL are implicated: BAFF may contribute to LON development, whereas high APRIL levels may be predictive. Rituximab-treated SLE patients should be monitored for neutrophil counts, fever and infections.

Background: Musculoskeletal involvement is a common clinical feature of systemic lupus erythematosus (SLE), that can be present either at the onset or in later disease course. SLE related arthritis is usually non-erosive and non-deforming as opposed to rheumatoid arthritis (RA). While RA synovial pathology has been extensively studied, little is known about the pathophysiology of arthritis in SLE. Objectives: to explore the cellular compartments in synovial fluid of SLE patients with arthritic manifestations. Methods: paired synovial fluid (SF) samples from large joint aspiration and peripheral blood samples (PBMC) obtained at the same time point from five SLE patients were analyzed by multicolor flow cytometry. The patients fulfilled the ACR 1982 classification criteria for SLE [1]. Clinical records were reviewed in order to exclude the presence of comorbidities such osteoarthritis or overlap with RA. Three different lineage-specific panels for B cells, T cells (cytotoxic and helper) were developed. Results: The overall frequency of CD4+ and CD8+ T cells was similar across the SF and PBMC samples. Among the CD4+ T cells, those co-expressing CCR4, showed a much higher frequency in the SF compared to the peripheral blood in 4 out of 5 patients (mean percentage 8.9±7.0% vs 2.1±1.6%, p=ns). In addition, in 4 out of 5 patients we could identify an increased frequency of CD4+ expressing CCR6+, a marker for Th17 cells in SF as compared to PBMC (mean percentage 35±16.6% vs 12.7±8.9%, respectively, p=ns). In all patients, a higher frequency of EOMES+ Granzyme A + CD4+ T cells was observed in SF when compared to PBMC (9.2±2.5% vs 4.5±2.5%, p=0.03). Moreover, in all patients, we could observe a higher proportion of regulatory T cells (FOXP3+/CD25+) in the SF (21.5±15.4% vs 8.4±7.8%, p=ns). No relevant differences were observed in the Th1 compartment (CXCR3+). CD19+ cells (B-lymphocytes) were scarcely present in the SF of SLE patients as opposed to the peripheral blood. Conclusion: Although SLE is usually considered to be a B cell driven disease, its common clinical features like arthritis could be driven in situ by T cells, namely subtypes of CD4+ (helper) cells such as TH17 cells and CD4+ T cells with cytotoxic profile. Further confirmation of the present findings is needed. Reference [1] Tan, E.M., et al., The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum, 1982. 25(11 Disclosure of Interests: Francesca Faustini Consultant for: I have participated to an advisoryborad for Pfizer Sweden in one occasion during 2018, Speakers bureau: I have been speaker for an internal education meeting for Novartis Sweden in one occasion during 2018, Natalie Sippl: None declared, Karine Chemin: None declared, Iva Gunnarsson: None declared, Vivianne Malmstrom: None declared

COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Acute respiratory distress syndrome (ARDS), observed in most critically ill cases with SARS-CoV-2, is a life-threatening inflammatory lung injury.1 It necessitates hospitalisation, oxygen supplementation and in some cases mechanical ventilation, and is associated with high mortality rates, reaching around 40%.2 It is the effects of an over-reacting immune system, rather than the viral load, which are believed to cause ARDS. A cytokine storm characterised by proinflammatory cytokines, such as interleukin (IL)-1 and IL-6, together with hypercoagulability is seen in a majority of hospitalised patients. Elevated D-dimer, lactate dehydrogenase and fibrinogen and clinical thromboembolic manifestations, such as pulmonary emboli, are common features of severe COVID-19. Zhang et al 3 recently reported significant coagulopathy with multiple infarctions accompanied by prothrombotic antiphospholipid antibodies in three cases of COVID-19. Endothelial damage, …

Objective: The purpose of this study was to assess the clinical feasibility and effectiveness of manual mobilization of the hands of patients with rheumatoid arthritis (RA). Methods: A total of 320 individual hand joints were evaluated after recruiting an experimental research group of 12 participants with RA and, for clinical comparability, 8 participants with hand osteoarthritis (OA). One hand per participant was randomized to receive weekly low-grade (I-II) Kaltenborn manual mobilization, using passive sustained stretch of the metacarpophalangeal (MCP) joints II to V by licensed manual therapists. After 2 weeks, the randomized treated hand was crossed over to control (untreated) during weeks 3 to 4 and vice versa. Final assessment was at 2 months, which was 1 month after the last treatment at week 4. Primary hand outcomes included pain by visual analog scale, tender or swollen joint count, and presence of Doppler signal or synovial fluid and radiographic joint space by musculoskeletal ultrasound. Results: In the RA group, both the initially randomized treated hand and the contralateral hand improved significantly from baseline to crossover to follow-up at 2 months (pain outcomes and Doppler signal, P < .050; synovial fluid and MCP joint space, P ≤ .001). Hand pain and MCP joint space also improved significantly in OA. There were no dropouts or reported adverse events in either the RA or OA group. Conclusion: In this study, manual mobilization of the hands of patients with RA was shown to be feasible, safe, and effective to integrate into specialized healthcare.

Background Comprehensive simultaneous quantification of bone erosion and enthesiophytes in the joints of patients with psoriatic arthritis (PsA) has not been performed. Herein, we aimed to compare the extent of bone erosion and enthesiophytes in patients with PsA, psoriasis (PSO) and healthy controls, assess the influence of age and disease duration on the development of erosions and enthesiophytes and define their impact on physical function. Methods Patients with PsA or with PSO and controls were analysed by high-resolution peripheral quantitative computed tomography (HR-pQCT). The extent of bone erosions and enthesiophytes was assessed and plotted according to different categories of age, duration of PSO and duration of PsA, respectively. In addition, demographic and disease-specific data, including physical function (health assessment questionnaire) were collected. Results A total of 203 patients were analysed; 101 had PsA, 55 had PSO and 47 were healthy individuals. Patients with PsA had significantly more and larger erosions (p = 0.002/p = 0.003) and enthesiophytes (p

OBJECTIVES To investigate whether MRI allows the detection of osteosclerosis as a sign of repair of bone erosions compared with high-resolution peripheral quantitative computed tomography (HR-pQCT) as a reference and whether the presence of osteosclerosis on HR-pQCT is linked to synovitis and osteitis on MRI. METHODS A total of 103 RA patients underwent HR-pQCT and MRI of the dominant hand. The presence and size of erosions and the presence and extent (grades 0-2) of osteosclerosis were assessed by both imaging modalities, focusing on MCP 2 and 3 and wrist joints. By MRI, the presence and grading of osteitis and synovitis were assessed according to the Rheumatoid Arthritis MRI Score (RAMRIS). RESULTS Parallel evaluation was feasible by both modalities on 126 bone erosions. Signs of osteosclerosis were found on 87 erosions by HR-pQCT and on 22 by MRI. False-positive results (MRI(+)CT(-)) accounted for 3%, while false-negative results (MRI(-)CT(+)) accounted for 76%. MRI sensitivity for the detection of osteosclerosis was 24% and specificity was 97%. The semi-quantitative scoring of osteosclerosis was reliable between MRI and HR-pQCT [intraclass correlation coefficient 0.917 (95% CI 0.884, 0.941), P < 0.001]. The presence of osteosclerosis on HR-pQCT showed a trend towards an inverse relationship to the occurrence and extent of osteitis on MRI [χ(2)(1) = 3.285; ϕ coefficient = -0.124; P = 0.070] but not to synovitis [χ(2)(1) = 0.039; ϕ coefficient = -0.14; P = 0.844]. CONCLUSION MRI can only rarely detect osteosclerosis associated with bone erosions in RA. Indeed, the sensitivity compared with HR-pQCT is limited, while the specificity is high. The presence of osteitis makes osteosclerosis more unlikely, whereas the presence of synovitis is not related to osteosclerosis.

ObjectivesTo search for structural bone changes in the joints of psoriasis patients without psoriatic arthritis (PsA).Methods55 psoriasis patients without any current or past symptoms of arthritis or enthesitis and 47 healthy controls were examined by high-resolution peripheral quantitative CT scans of the metacarpophalangeal joints. Number, size and exact localisation of erosions and enthesiophytes were recorded by analysing axial scans of the metacarpal heads and phalangeal bases and were confirmed in additional coronal and/or sagittal sections. In addition, we collected demographic and clinical data including subtype, duration and severity of psoriasis.ResultsPsoriasis patients showed a larger and significantly increased number of enthesiophytes (total number 306; mean±SD/patient 5.62±3.30) compared with healthy controls (total number 138; mean±SD/patient 3.04±1.81, pConclusionsPsoriasis patients without PsA show substantial signs of enthesiophyte formation compared with healthy controls. These changes represent new bone formation at mechanically exposed sites of the joint and substantiate the concept of the existence of a ‘Deep Koebner Phenomenon’ at enthesial sites in psoriasis patients.

Background Musculoskeletal symptoms are considered as one of the most frequent extra-intestinal manifestation in Inflammatory Bowel Disease (IBD) patients with a prevalence of up to 40% involving axial and/or peripheral joints. Data on the prevalence of musculoskeletal disease, in particular of SpA are limited and vary considerably due to different criteria the studies have used to define musculoskeletal disease in IBD patients. Objectives To define the prevalence of axial and peripheral spondyloarthritis (SpA) according to Assessment of Spondyloarthritis International Society (ASAS) in patients with Crohn9s disease (CD) and ulcerative colitis (UC). Methods The SPICE cohort (Spondyloarthritis in Inflammatory Bowel Disease Cohort Erlangen) comprises prospectively recruited colonoscopy- proven Crohn9s Disease (CD) or Ulcerative Colitis (UC) patients, who received a pre-defined and standardized musculoskeletal assessment by the rheumatologist. Duration and activity of gastrointestinal and rheumatic disease (axial and peripheral) was documented and fulfillment of ASAS classification criteria for axial and peripheral SpA was tested. Results 102 IBD patients (62 with CD and 40 with UC) with a median (IQR) disease of 11.0 (18.0) years were assessed. 38.2% fulfilled ASAS criteria for SpA with no difference between CD and UC. ASAS axial SpA criteria were fulfilled by 12%, ASAS peripheral SpA criteria by 31.4% of the IBD patients. Inflammatory back pain was present in 24.5% with MRI signs of sacroiliitis in 48% of IBD patients with inflammatory back pain. Disease activity according to ASDAS-CRP was moderate to high in 91% of the patients with axial SpA. Peripheral arthralgia was present in 71.6%, while arthritis was found in 18.6% of the IBD patients. Conclusions Both major forms of IBD show a similar burden of musculoskeletal disease. More than one third of inflammatory bowel disease patients show axial or peripheral SpA according to ASAS criteria. Peripheral SpA is more commonly found than axial SpA. References Harbord M, Annese V, Vavricka SR, et al. The first European evidence-based consensus on extra-intestinal manifestations in inflammatory bowel disease. J Crohn Colitis 2016; 239–254. Karreman MC, Luime JJ, Hazes JMW, Weel AEAM. The prevalence and incidence of axial and peripheral spondyloarthritis in inflammatory bowel disease: a systematic literature review and meta-analysis. J Crohn Colitis 2016; 1–12. Disclosure of Interest None declared

Objective Anticitrullinated protein antibodies (ACPA) are a major risk factor for bone loss in rheumatoid arthritis (RA). We have recently shown that ACPA directly induce bone loss by stimulating osteoclast differentiation. As ACPA precede the clinical onset of RA by years, we hypothesised that ACPA positive healthy individuals may already show skeletal changes. Methods We performed a comparative micro-CT analysis of the bone microstructure in the metacarpophalangeal joints of ACPA positive and ACPA negative healthy individuals without clinical signs of arthritis. Results ACPA positive (n=15) and negative (n=15) healthy individuals were not different in age (48.2±4.1 vs 51.4±3.8 years, p=0.57) or gender (eight women and two men in both groups). Bone mineral density was significantly reduced in ACPA positive individuals (mean±SEM 280±11 mg/cm 3 ) compared with controls (327±6). Bone loss was based on cortical bone changes, with significant (p=0.044) reduction in cortical thickness in the ACPA positive group (mean±SEM 0.22±0.03 mm) compared with controls (0.32±0.03 mm). Areas of cortical porosity were significantly (p=0.0005) more widespread in ACPA positive (mean±SEM 7.4±1.4%) than in ACPA negative individuals (1.0±0.3%). Discussion Structural bone damage starts before the clinical onset of arthritis in subjects with ACPA. These findings revise the concept that bone damage is an exclusive consequence of synovitis in patients with RA.

Objective To define the anatomic distribution of the earliest inflammatory and structural changes in individuals with anti-citrullinated protein antibody (ACPA+) positivity but no signs of arthritis. Methods ACPA+ individuals ( N = 20) and healthy controls ( N = 13) received simultaneous gadolinium-enhanced magnetic resonance imaging (MRI) and high-resolution peripheral quantitative computed tomography (HR-pQCT) of the hands. MRI sequences were scored for synovitis, osteitis, and bone erosions according to the RAMRIS method as well as for presence, localization, and extent of tenosynovitis. Bone erosions were validated by HR-pQCT scanning and related to the inflammatory changes found in the MRI. Results Tenosynovitis was the most prevalent inflammatory pathology, affecting 80% of ACPA+ individuals but none of the controls. Tenosynovitis at two or more anatomical sites was associated with later development of RA. Synovitis (65%) and osteitis (35%) were present in ACPA+ individuals as well, but at a lower frequency than tenosynovitis. MRI bone erosions were found in 65% of the individuals and additionally confirmed by HR-pQCT. Presence of MRI osteitis was the inflammatory pathology most strongly associated with bone erosions. Conclusion Tenosynovitis is highly prevalent in ACPA+ individuals without arthritis and associated with later development of RA. Small erosions, often linked to osteitis, are also found in ACPA+ individuals without arthritis.

Background and Aims: To investigate the macro- and microstructural changes of bone in patients with inflammatory bowel disease [IBD] and to define the factors associated with bone loss in IBD. Methods: A total of 148 subjects, 59 with Crohn’s disease [CD], 39 with ulcerative colitis [UC], and 50 healthy controls were assessed for the geometric, volumetric and microstructural properties of bone using high-resolution peripheral quantitative computed tomography. In addition, demographic and disease-specific characteristics of IBD patients were recorded. Results: IBD patients and controls were comparable in age, sex, and body mass index. Total \[ p = 0.001], cortical [ p < 0.001], and trabecular volumetric bone mineral density [BMD\] \[ p = 0.03\] were significantly reduced in IBD patients compared with healthy controls. Geometric and microstructural analysis revealed significantly lower cortical area [ p = 0.001] and cortical thickness [ p < 0.001] without differences in cortical porosity, pore volume, or pore diameter. CD showed a more severe bone phenotype than UC: cortical bone loss was observed in both diseases, but CD additionally showed profound trabecular bone loss with reduced trabecular BMD [p = 0.008], bone volume [ p = 0.008], and trabecular thickness [ p = 0.009]. Multivariate regression models identified the diagnosis of CD, female sex, lower body mass index, and the lack of remission as factors independently associated with bone loss in IBD. Conclusion: IBD patients develop significant cortical bone loss, impairing bone strength. Trabecular bone loss is limited to CD patients, who exhibit a more severe bone phenotype compared with UC patients.

Background: The goal of our study was to evaluate the diagnostic performance of the anti-cyclic citrullinated peptide 2 (anti-CCP2) assay in patients with autoimmune and inflammatory disorders. Methods: We tested the specificity and sensitivity of anti-CCP2 antibodies measured by ELISA in 787 patients with rheumatoid arthritis (RA), 1024 patients with other autoimmune/inflammatory rheumatic disease and 401 subjects without autoimmune rheumatic disease. The optimal cut-off value was defined as the value with the highest diagnostic accuracy (receiver operating characteristic curve analysis). Interval-specific likelihood ratios (LRs) were calculated for each range bounded by defined anti-CCP2 values. Results: To distinguish between patients with RA and controls, the cut-off value with the highest diagnostic accuracy for anti-CCP2 was 2.8 U/mL. Comparing the optimal cut-off value for anti-CCP2 to that recommended by the manufacturer (5.0 U/mL), an increase in prevalence between the proportions of test-positive patients was found for RA, undifferentiated connective tissue disease and undifferentiated arthritis. Evaluating interval-specific LRs for the selected ranges bound by two anti-CCP2 values, in RA and diseased controls, the LRs were 0.40 for values 30.0 U/mL. Conclusions: The cut-off value of 2.8 U/mL for anti-CCP2 has the highest diagnostic accuracy. A value of anti-CCP2 >15 U/mL is associated with an increase in the likelihood of RA disease. Clin Chem Lab Med 2010;48:829–34.

Objective:To investigate the role of the HS1,2 enhancer polymorphisms as a new candidate marker for rheumatoid arthritis (RA) and to define the possible association with autoantibody positivity and clinical outcome.Methods:Genomic DNA was obtained from two cohorts of patients with RA (100 with early RA (ERA) and 114 with longstanding RA (LSRA)) and from 248 gender-matched controls from the same geographical area. Clinical and immunological characteristics were recorded for all the patients.Results:The percentage of the 2/2 genotype was higher in patients with ERA (27.0%), and in patients with LSRA (34.2%), than in controls (14.9%) (ERA: OR = 2.11 (95% CI 1.20 to 3.70) vs controls; LSRA: OR = 2.96 (95% CI 1.76 to 5.00) vs controls). A lower representation of allele *3 was present in patients with ERA (2.0%) than in controls (6.0%; OR = 0.32 (95% CI 0.11 to 0.91)). No significant associations were found between polymorphisms and autoantibodies positivity.Conclusion:The HS1,2A allele *2 associates with early and longstanding RA.

Objectives To search for subclinical inflammatory joint disease in patients with psoriasis without psoriatic arthritis (PsA), and to determine whether such changes are associated with the later development of PsA. Methods Eighty-five subjects without arthritis (55 with psoriasis and 30 healthy controls) received high field MRI of the hand. MRI scans were scored for synovitis, osteitis, tenosynovitis and periarticular inflammation according to the PsAMRIS method. Patients with psoriasis additionally received complete clinical investigation, high-resolution peripheral quantitative CT for detecting erosions and enthesiophytes and were followed up for at least 1 year for the development of PsA. Results 47% of patients with psoriasis showed at least one inflammatory lesion on MRI. Synovitis was the most prevalent inflammatory lesion (38%), while osteitis (11%), tenosynovitis (4%) and periarticular inflammation (4%) were less frequent. The mean (±SD) PsAMRIS synovitis score was 3.0±2.5 units. Enthesiophytes and bone erosions were not different between patients with psoriasis with or without inflammatory MRI changes. The risk for developing PsA was as high as 60% if patients had subclinical synovitis and symptoms related to arthralgia, but only 13% if patients had normal MRIs and did not report arthralgia. Conclusions Prevalence of subclinical inflammatory lesions is high in patients with cutaneous psoriasis. Arthralgia in conjunction with MRI synovitis constitutes a high-risk constellation for the development of PsA.

Objective To investigate the effect of intensive lowering of serum uric acid (SUA) levels by pegloticase on the resolution of tophi in patients with refractory gout. Methods Descriptive study in patients with refractory gout receiving pegloticase treatment. SUA levels were measured before and after each infusion. Dual-energy CT (DECT) scans were taken from all patients before the first infusion and after the last infusion. Computerised tophus volumes were calculated for the baseline and follow-up assessments and compared with each other. Results 10 patients with refractory gout and baseline mean SUA level of 8.1 mg/dL were enrolled. Patients were treated for a mean of 13.3 weeks. Pegloticase effectively reduced tophi in all patients showing a decrease in volume by 71.4%. Responders, showing reduction of SUA level below 6 mg/dL during at least 80% of the treatment time, were virtually cleared from tophi (−94.8%). Dependent on their anatomical localisation, resolution of tophi showed different dynamics, with articular tophi showing fast, and tendon tophi slow, resolution. Conclusions Tophi are highly sensitive to pegloticase treatment, particularly when located at articular sites. Debulking of disease and a tophus-free state can be reached within a few months of pegloticase treatment. DECT allows for comprehensively assessing tophus burden and monitoring treatment responses.

Objective: To investigate the possibility of drug-free remission in patients with psoriatic arthritis (PsA) in continuous remission. Methods: Prospective observational study in disease-modifying antirheumatic drug (DMARD)-treated PsA patients in continuous disease remission (no musculoskeletal symptoms, no or minimal skin/nail disease) for at least 6 months. Demographic, disease-specific and ultrasound parameters were assessed at baseline. DMARDs (traditional or biologic) were discontinued at the initial visit, and patients were followed for a maximum of 6 months for recurrence of disease. Results: 26 patients (methotrexate monotherapy: N=14; tumour necrosis factor inhibitors: N=12) with a mean age of 55.2 years, absence of musculoskeletal symptoms and minimal skin disease (mean Psoriasis Area Severity Index (PASI): 0.21) were enrolled. Incidence of recurrence of disease was high (N=20, 76.9%) and occurred rapidly (74.50±51.72 days) after treatment discontinuation. Male PsA patients were significantly more likely to lose remission. Long disease duration, more severe skin involvement and the presence of synovial hypertrophy by ultrasonographic examination at baseline decreased the likelihood for drug-free remission. Reinitiation of DMARDs promptly restored remission in all PsA patients with recurrence of disease. Conclusions: This study shows that the chance to reach drug-free remission in PsA patients is low. Discontinuation of DMARD therapy cannot be recommended in patients with PsA.

Chronic hepatitis C virus (HCV) infection is frequent worldwide and causes hepatic damage as well as a wide spectrum of extrahepatic manifestations. This capacity of the infection to determine several extrahepatic comorbidities was demonstrated early after discovery of the infectious agent and appears to be related to its ability to infect immune cells, namely B cells. This can lead to their abnormal activation and end in an autoimmune or lymphoproliferative disease. The strict link between HCV and mixed cryoglobulinemia (MC) is well known. In addition, it is clear that many symptoms of rheumatologic interest can be present in the setting of chronic HCV infection, such as arthralgias and fatigue. In some cases, as in sicca syndrome, MC manifests as a true infectious-related autoimmune disease. Here we review the main rheumatic symptoms that can occur during MC (HCV chronic infection) and discuss the principles underlying their clinical management.

OBJECTIVE: The PTPN22 rs2476601 polymorphism is associated with rheumatoid arthritis (RA); nonetheless, the association is weaker or absent in some southern European populations. The aim of the study was to evaluate the association between the PTPN22 rs2476601 polymorphism and RA in Italian subjects and to compare our results with those of other European countries, carrying out a meta-analysis of European data. METHODS: A total of 396 RA cases and 477 controls, all of Italic ancestry, were genotyped for PTPN22 rs2476601 polymorphism. Patients were tested for autoantibodies positivity. The meta-analysis was performed on 23 selected studies. RESULTS: The PTPN22 T1858 allele was significantly more frequent in RA patients compared to controls (5.7% vs. 3.7%, p = 0.045). No clear relationship arose with the autoantibodies tested. The 1858T allele frequency in Italian RA patients was lower than the one described in northern European populations and similar to the frequency found in Spain, Turkey, Greece, Tunisia. A clear-cut North-South gradient arose from the analysis. CONCLUSIONS: The PTPN22 T1858 allele is associated with RA in the Italian population. A North-South gradient of the allele frequency seems to exist in Europe, with a lower prevalence of the mutation in the Mediterranean area.

BACKGROUND AND PURPOSE Rheumatoid arthritis (RA) is a chronic inflammatory multisystem disease with articular and extra-articular manifestations. Intracranial manifestations of RA are rare. Purpose of this article is to report on a rarely described leptomeningeal involvement in RA, and on its neuroimaging features, including diffusion-weighted imaging (DWI). METHODS The authors describe the case of a 74-year-old woman with a 5-year history of RA presenting with progressive left-side weakness and hypoesthesia. The patient underwent laboratory investigation and brain contrast-enhanced MRI, also with DWI, before undergoing brain biopsy. RESULTS Neuroimaging revealed abnormal high T2-signal in right frontal and parietal lobes, restricted diffusion in the subarachnoid space, and diffuse thick linear leptomeningeal contrast-enhancement. These findings were interpreted as rheumatoid leptomeningitis, and brain biopsy confirmed this diagnosis. CONCLUSIONS In summary, rheumatoid meningitis is a rare neurological complication of RA, but it should be considered in the proper clinical setting when patient presentation and laboratory results fail to support the other differential diagnostic possibilities proposed by the MR imaging findings.

Background Refractory gout is a serious medical condition, which leads to massive deposition of uric acid crystals in the body resulting in the formation of tophi. A new highly effective treatment modality based on the administration of recombinant PEGylated uricase (pegloticase) allows to approach such patients. Pegloticase cleaves uric acid and leads to a profound drop in serum uric acide levels. How this decrease in uric acid in the body affects the resolution of existing tophi is not yet adequately characterized. Objectives To investigate the effect of intensive lowering of serum uric acid levels by pegloticase on the resolution of tophi in patients with refractory gout. Methods Descriptive study in patients with refractory gout receiving pegloticase treatment. Serum uric acid levels were measured before and after each infusion. Dual energy computed tomography scans were taken from all patients before the first infusion and after the last infusion. Computerized tophus volumes were calculated for the baseline and follow up assessments and compared with each other. Results Ten patients with refractory gout and baseline mean serum uric acid level of 8.1 mg/dL were enrolled. Pegloticase effectively reduced tophi in all patients showing a decrease in volume by 71.4%. Responders, showing reduction of serum uric acid level below 6 mg/dl during at least 80% of the treatment time, were virtually cleared from tophi (-94.8%). Dependent on their anatomical localization, resolution of tophi showed different dynamics, with articular tophi showing fast and tendon tophi slow resolution. Conclusions Tophi are highly sensitive to pegloticase treatment, particularly when located at articular sites. Debulking of disease and a tophus-free state can be reached within a few months of pegloticase treatment. DECT allows for comprehensively assessing tophus burden and monitoring treatment responses. Disclosure of Interest None declared

Background Autoimmunity develops long before the development of clinically signs of inflammation in patients with rheumatoid arthritis (RA). In this context the appearance of autoantibodies against citrullinated proteins (ACPA) may be an important step promoting the transition from autoimmunity to inflammatory disease. Objectives We hypothesized that healthy ACPA-positive individuals with no clinical signs of arthritis show subclinical soft tissue inflammation in their joints, which can be detected by magnetic resonance imaging (MRI). Methods Twelve ACPA positive healthy individuals without clinical signs of arthritis and normal acute phase reactant levels received an MRI (Siemens 1,5 Tesla Aera) examination of the dominant hand. Patients were taken from a cohort of ACPA-positive healthy individuals established at the University of Erlangen-Nuremberg. T1- and T2-weigthed MRI sequences were scored for synovitis, osteitis and bone erosions according to the OMERACT rheumatoid arthritis MRI scoring system (RAMRIS) by two independent assessors. Furthermore, the presence or absence of tenosynovitis was recorded. Results Data of twelve ACPA positive individuals [10 females (average age 49,8), 2 males (age: 54/39)] were analyzed. Mean level of CCP-antibodies were 251,7 U/ml (cut off: 10 U/ml), mean level for MCV–antibodies were 335 U/ml (cut off: 20 U/ml). Six subjects were also positive for rheumatoid factor (RF) with a mean level of 65,9 IE/ml (cut off 20 IE/ml). Synovitis (not higher than grade 1 in OMERACT Score) was seen in 7/12 subjects affecting 13% (11/84) of all assessed joints. Due to low-grade synovitis inter-reader reliability was low (κ-coefficient 0,53). Osteitis was detected in 3/12 subjects, involving 2,1% (6/276) of the evaluated bones. Osteitis was exclusively found in the carpal bones when present. Inter-reader reliability was high (κ-coefficient 1,00). Tenosynovitis of the extensor and/or flexor tendons was rather frequent and found in 7/12 subjects. Small bone erosions were seen in 9/12 subjects affecting 5,8% (16/276) of the bone surface. 75% of erosions did affect the carpal bones. Conclusions A subset of healthy ACPA-positive individuals, which are at risk for developing RA, show distinct inflammatory lesions in the MRI. The carpal joints are the preferentially affected anatomical region, whereas the MCP joints are rarely and the PIP joints never affected. Tenosynovitis was frequently present support the concept that inflammatory lesions in RA start in the tendons around the wrist. Acknowledgements *AK and MK contributed equally to this work Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3437

Background Patients with cutaneous psoriasis (PSO) are at risk of developing psoriatic arthritis (PsA) overtime. The transition from skin disease to joint involvement is only partially characterized. Advanced imaging can depict signs of subclinical joint involvement. Objectives To assess the prevalence of inflammatory MRI signs in a group of PSO patients with no history or presence of PsA, who showed bony changes (either erosions or osteophytes) on high-resolution peripheral quantitative computed tomography (HR-pQCT). Secondly, to examine whether inflammation on MRI is linked to the changes on HR-pQCT. Methods PSO patients (with no arthritis, enthesitis nor dactylitis) underwent HR-pQCT and 1.5T magnetic resonance imaging (MRI) of the dominant hand. HR-pQCT scanning was conducted on the metacarpophalangeal (MCP) joints 2 and 3. Images were analyzed for the presence of periarticular changes as erosions and osteophytes. MRI images were acquired for the whole hand. Subsequent analysis of the images focused on the detection of osteitis, synovitis, tenosynovitis of the flexor tendon, periarticular inflammation at the MCP, PIP and DIP region of the 2nd to 5th finger, according to the definitions of key pathologies provided for the PsAMRIS scoring system.1 HR-pQCT and MRI images have been analyzed by 2 independent readers, mean time interval between both imaging techniques was 42 days. The study was conducted upon approval by the local ethic committee and the National Radiation Safety Agency (BfS). Patients participated after signing informed consent. Results Images were acquired from 55 PSO patients (36.4% female) of mean age 49.5±11.5 years, mean disease duration 15.2±15.4 years and mean PASI score of 6.2±8.0. The most prevalent subtype was psoriasis vulgaris (73%), while nail psoriasis was present in 51% and scalp involvement in 29%. By HR-pQCT, 29% of the patients showed erosions, while all presented osteophytes. Of the 55 patients, 26 (47%) showed at least one of the mentioned inflammatory signs on MRI. In detail, osteitis was found in 6 out of the 55 patients (11%), while synovitis in 21 (38%); tenosynovitis and periarticular inflammation were detected each in 2 patients (4%). In the total sample, partial correlations (controlling for the influence of age and disease duration) between bony changes in HR-pQCT and osteitis as well as synovitis in MRI did not show any significant relations. Conclusions Subclinical inflammatory lesions are prevalent in the joints of patients with PSO and affect about half of the patients. These findings suggest that a substantial proportion of PSO patients are affected by joint inflammation but are not classified as PsA. Interestingly, the relation of inflammatory-MRI changes to structural-CT changes in the joints of PSO patients is rather poor at the cross-sectional level, which will necessitate longitudinal assessment of joint inflammation in PSO patients. References 1. Ostergaard M et al, J Rheumatol. 2009 Aug; 36(8): 1816-24 Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5412