S. Breda

Risk of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing biologic treatment: Extending perspective from old to newer drugs

Hepatitis B virus (HBV) reactivation in rheumatoid arthritis (RA) patients undergoing biological therapy is not infrequent. This condition can occur in patients with chronic hepatitis B as well as in patients with resolved HBV infection. Current recommendations are mainly focused on prevention and management strategies of viral reactivation under tumor necrosis factor-α inhibitors or chimeric monoclonal antibody rituximab. In recent years, growing data concerning HBV reactivation in RA patients treated with newer biological drugs like tocilizumab and abatacept have cumulated. In this review, epidemiology, pathogenesis and natural history of HBV infection have been revised first, mainly focusing on the role that specific therapeutic targets of current biotechnological drugs play in HBV pathobiology; finally we have summarized current evidences from scientific literature, including either observational studies and case reports as well, concerning HBV reactivation under different classes of biological drugs in RA patients. Taking all these evidences into account, some practical guidelines for screening, vaccination, prophylaxis and treatment of HBV reactivation have been proposed.

Inhibition of Notch1 promotes hedgehog signalling in a HES1-dependent manner in chondrocytes and exacerbates experimental osteoarthritis

Objectives Notch ligands and receptors have recently been shown to be differentially expressed in osteoarthritis (OA). We aim to further elucidate the functional role of Notch signalling in OA using Notch1 antisense transgenic (Notch1 AS) mice. Methods Notch and hedgehog signalling were analysed by real-time PCR and immunohistochemistry. Notch-1 AS mice were employed as a model of impaired Notch signalling in vivo. Experimental OA was induced by destabilisation of the medial meniscus (DMM). The extent of cartilage destruction and osteophyte formation was analysed by safranin-O staining with subsequent assessment of the Osteoarthritis Research Society International (OARSI) and Mankin scores and µCT scanning. Collagen X staining was used as a marker of chondrocyte hypertrophy. The role of hairy/enhancer of split 1 (Hes-1) was investigated with knockdown and overexpression experiments. Results Notch signalling was activated in human and murine OA with increased expression of Jagged1, Notch-1, accumulation of the Notch intracellular domain 1 and increased transcription of Hes-1. Notch1 AS mice showed exacerbated OA with increases in OARSI scores, osteophyte formation, increased subchondral bone plate density, collagen X and osteocalcin expression and elevated levels of Epas1 and ADAM-TS5 mRNA. Inhibition of the Notch pathway induced activation of hedgehog signalling with induction of Gli-1 and Gli-2 and increased transcription of hedgehog target genes. The regulatory effects of Notch signalling on Gli-expression were mimicked by Hes-1. Conclusions Inhibition of Notch signalling activates hedgehog signalling, enhances chondrocyte hypertrophy and exacerbates experimental OA including osteophyte formation. These data suggest that the activation of the Notch pathway may limit aberrant hedgehog signalling in OA.

Switching from Intravenous to Subcutaneous Formulation of Abatacept: Different Results in a Series of 21 Patients

To the Editor: We read with interest the article by Reggia, et al 1, a monocentric study analyzing the efficacy and safety of switching from intravenous (IV) to subcutaneous (SC) formulation of abatacept (ABA) in patients with rheumatoid arthritis. The authors report a relatively high risk of disease relapse (27%) occurring in a mean of 11 weeks after switching to SC administration. The study did not find any significant predictive factor for a switch failure. The concern that patients with a higher body mass index could receive lower cumulative doses compared to weight-tiered monthly infusions, leading to a significant influence on treatment efficacy, was not confirmed by this study, or by previous dose-finding trials and … Address correspondence to Dr. S. Monti; E-mail: sara.saramonti{at}gmail.com

AB0226 One Year Experience of A Bdmard Spacing Protocol in Real Life Rheumatoid Arthritis Patients

Background Current guidelines about rheumatoid arthritis (RA) management might admit tapering schedules of biologic disease modifiying drugs (bDMARDs) when disease activity control has been achieved and maintained, in line with growing scientific evidences [1]. Great heterogeneity in target populations, end-points, study designs, therapeutic protocols, criteria for bDMARD discontinuation and resumption globally prevents from univocal interpretation of study results [2]. Real life data might provide additional information on the topic, which could be better extended to routine care. Objectives To analyze the impact of a bDMARD down-titration strategy (spacing) on clinical and sub-clinical disease activity control over time (12 months) in real life RA patients attending a single Italian Rheumatologic Unit. Methods RA patients with at least 1 year of bDMARDs treatment and a well-controlled disease (at least low disease activity/LDA according to DAS28 criteria for at least 6 months) were offered to undergo a spacing (doubling the inter-administration period) of their ongoing bDMARD (anti-TNF, Abatacept/ABA, Tocilizumab/TCZ) medication. When present, concomitant conventional synthetic DMARDs (csDMARDs) and/or low dosage (less than 7,5 mg/d prednisone-equivalent) oral corticosteroid (CS) were admitted and maintained: Group A= CS-on patients; Group B= CS-off patients. Disease activity was monitored every 2 months through DAS28 in order to detect any clinical relapse (>LDA): relapsing Group A patients immediately resumed original bDMARD schedule, relapsing Group B patients started firstly low dose CS (5 mg/d) while keeping on bDMARD spacing. At the same time-points, ultrasonographic (US) assessment (Gray Scale/GS and power Doppler/PD scores) was performed on dorsal view of bilateral hands and wrists. Clinical and US results were analyzed either globally and by CS-co-medication, as to detect any bDMARD sparing effect. Results Thirty-seven RA patients consented to the bDMARD spacing. Most patients were on anti-TNF agents (4 TCZ, 1 ABA) in association with csDMARDs (7/37 csDMARD free), and without CS co-medication (30/37 CS free). At time of spacing overall clinical (mean DAS28±sd 1,92±0,59), lab (median ESR [IQR] 10,50 [7–16] mm/h, median CRP [IQR] 0,14 [0,10–0,49] mg/dL) and US parameters (median GS score [IQR] 9 [6–13,5], median PD score [IQR] 0 [0–0]) were consistent with disease control; more than half patients had negative prognostic factors. Globally, trends over time of either clinical and US parameters did not significantly differ between groups, regardless of CS co-administration. Nevertheless, over the first year of observation more CS-off than CS-on patients experienced disease relapse (12 versus 4 patients, respectively, p=0,99); this occurred sooner in CS-off patients, too (mainly in the first 6 months of follow up). Conclusions The feasibility of bDMARDs step-down schedules in RA patients should be clarified in real life setting, as well as in clinical trials. bDMARD spacing might be a possible choice, especially when low dosage CS are co-administered: their eventual bDMARD sparing effect should be confirmed with larger and longer observations, together with complete evaluations about cost-effectiveness and risk-to-benefit profiles. References Smolen JS, et al. Ann Rheum Dis 2014;73:492–509. Yoshida K, et al. AnnRheumDis 2014;73:595–599. Disclosure of Interest None declared

AB0788 Treating Axial-Spa to Target: Prevalence of Ankylosing Spondylitis Disease Activity Score (ASDAS) Inactive Disease in a Cohort of Patients Treated with Anti-TNFα Agents

Background Treating disease to target is emerging as the recommended strategy also in the management of axial-SpA (axSpA) (1). Reaching remission, defined as inactive disease (ID), constitutes the ideal target in clinical practice. Objectives Using the new composite disease activity index “Ankylosing Spondylitis Disease Activity Score” (ASDAS) (2) we assessed the prevalence of ID in a cohort of patients with axSpA treated with anti-TNFα agents. Potential patient- and disease-related factors influencing the status of ID were analyzed. Methods The study population was selected from outpatients with axSpA treated with anti-TNFα attending our Rheumatology Department. Disease activity was evaluated in terms of BASDAI and ASDAS-CRP during the latest follow up visit. ID was defined as ASDAS-CRP<1.3 (2). Statistical analysis was performed with STATA. Results General characteristics of the 53 enrolled patients are presented in Table 1. A BASDAI <4 was recorded for 70% of the study population, while only 31% showed ID according to ASDAS-CRP (Figure 1). As expected, a strict correlation between the two disease activity indices was confirmed (Spearmans r =0.76; p<0.0001). Multivariate logistic regression demonstrated an inverse correlation of ID status with NSAIDs intake (OR 0.15; CI95% 0.45-0.54). ID achievement resulted independent from sex, disease duration, BASMI,DMARDs, type of anti-TNFα agent. Conclusions In our cohort of axSpA treated with biological agents, only one third achieved ID according to ASDAS-CRP. Even with the limitations of the small sample size, ID does not correlate with the principle patient- and disease-related features but is inversely associated with NSAIDs intake. Further studies are needed to optimize the targeted treatment of axSpA and to identify potential predictive factors of ID. References Smolen JS, et al. Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of an international task force. Ann Rheum Dis 2014; 73:6–16. Machado P, et al. Ankylosing Spondylitis Disease Activity Score (ASDAS): defining cut-off values for disease activity states and improvement scores. Ann Rheum Dis 2011; 70:47–53. Disclosure of Interest None declared

AB0401 Anxiety and Depression in Patients with Rheumatoid Arthritis Treated with Biological Drugs: Prevalence and Relationship with Disease Activity

Background Many patients with rheumatoid arthritis (RA) experience anxiety and depression, with higher presence of these disorders in those with poorer outcome [1]. Previous experiences found relationships with psychological status and disease activity in patients with active disease [2,3]. Further evidences are needed to asses the impact on residual RA activity during treatment. Objectives To register the prevalence of anxious (ANX) and depressive (DEP) disorders in RA patients treated with bDMARDs with stable disease and therapy and to evaluate their connection with disease activity. Methods We assessed the presence of ANX and DEP disorders with the HADS questionnaire [4] in patients with RA treated according the EULAR 2013 recommendations with bDMARDs [5]. We registered disease activity using DAS28 score during the same day of questionnaire compiling. Patients with major changes in their DMARD therapy during the previous six months, with known diagnosis of anxiety-depressive syndrome, fibromyalgia, or treated with antidepressant drugs were excluded. The variables of interest were compared between groups with Kruskall-Wallis test. Results We assessed 200 patients, female 171 (85%), with an overall median (IQR) age and disease duration of 62,35 (54,09 – 76,03) years and 11,24 (7,29 – 19,46) years respectively. At least one ANX or DEP disorder was present in 93 (46.5%) patients. In patients with ANX, DEP and with ANX*DEP disorders values of pain VAS, DAS28, GH, PGA, number of painful joints on 28 (TND28), HAQ were higher than those in HEALTY group (p<0,01). Prednisone dosage was higher among patients with ANX or DEP disorders. Number of swollen joints on 28 (SWJ28) CRP and ESR were not different among groups. There was a moderate correlation between HADS scores and DAS28, pain VAS, PGA, GH and TND28. Conclusions There is a high prevalence of ANX and DEP disorders in patients with RA. Patients with those disorders have higher level of residual disease based on higher subjective variables, while objective variables (SWJ28 and laboratory indexes) remain unmodified. The higher steroid doses in patients with ANX or DEP are probably due to higher disease activity measured with DAS28. References Matcham F et al, Rheumatology (Oxford) 2013. Traki L et al, Clin Rheumatol 2014. Cordingley L et al, Arthritis Care Res (Hoboken) 2014. Zigmond AS et al, Acta Psychiatr Scand 1983. Smolen JS et al, Annals Rheum Dis 2014. Disclosure of Interest None declared

AB0426 Biologic Spacing in Rheumatoid Arthritis Patients in Persistent Disease Activity Control: A Real Life Experience

Background Actually, as suggested from current therapeutic guidelines, tapering of biologic agents (bDMARDs) seems a feasible option in subsets of rheumatoid arthritis (RA) patients in persistent clinical disease control [1]. However definite step-down schedules are far to be fully elucidated due to the heterogeneity of available data in controlled trials. Data on real life contests are even fewer. Objectives To analyze the feasibility of bDMARD spacing in maintaining clinical disease control in real life RA patients in persistent low disease activity (LDA) or remission. To monitor sub-clinical signs of disease activity during bDMARDs tapering. Methods RA patients in persistent clinical disease control (at least LDA according to DAS28 score for at least 6 months) underwent current bDMARD (anti-TNF/no anti-TNF agents for at least 1 year) spacing (doubling of the inter-administration time); concomitant co-medications (conventional synthetic DMARDs/csDMARDs and/or low dose oral corticosteroids/CS) were carried on at stable dosages. Clinical and ultrasonographic (US) assessments were performed bi-monthly over initial 6 months period in order to define clinical relapse (> LDA) and to monitor clinical and sub-clinical signs of inflammation (Gray scale, GS, and power Doppler, PD scores detected on hand and wrist US examination). Results about first 4 months of follow up are yet available for preliminary analysis. Results Globally, 35 patients met the criteria and agreed to the spacing. Most of them had an established disease (mean duration ± sd 11,92±7,80 years) with markers of poor prognosis (57% seropositive patients, 60% patients with erosive disease). They were generally on their first anti-TNF bDMARD therapy (30 anti-TNF, 4 tocilizumab, 1 abatacept) together with csDMARDs co-medication (29/35 patients); they were mostly CS free (28/35 cs-free patients; 7 patients on low dose oral CS). Over 4 months of observation DAS28 score did not significantly change (mean value ± sd from 1,92±0,59 to 1,89±0,63, p not significant), as happened for GS score (median [IQR] from 9 [8-12] to 11 [9-13], p not significant). Median PD score [IQR] significantly increase over time, from 0 [0-0] at baseline examination to 1,5 [0-4] (p=0,01) at 4 months. In 4 months, globally 2 patients relapsed. Conclusions Biologic DMARDs spacing might be a possible therapeutic option in real life RA patients in persistent disease control: despite the substantial increase in PD score, few patients clinically relapsed in the first months of observation. For a complete evaluation, risk-to-benefit issues should involve long-term clinical, functional and structural outcomes, along with safety and financial issues too. Predictive factors need to be fully elucidated to target patients who might benefit more from this strategy. References Smolen JS, et al. Ann Rheum Dis 2014;73:492–509. Disclosure of Interest None declared

FRI0502 Osteoporosis and Fracture Risk in Outpatients with Systemic Sclerosis

Background Osteoporosis (OP) is a frequent complication of a number of chronic inflammatory diseases. Only Rheumatoid Arthritis (RA) is included in the FRAX algorythm to calculate fracture risk but also Systemic Sclerosis (SSc) displays many disease-specific OP risk factors (chronic inflammation, malnutrition, steroid use, etc.) Objectives To determine OP frequency and fracture risk by FRAX in outpatients with SSc Methods After consent, in outpatients with SSc (le Roy criteria) of a University Hospital, bone mineral density (BMD) was calculated by Dual Energy X-Ray Absorptiometry (DEXA) at the femoral neck and lumbar spine and FRAX was obtained by the calculation tool (http://www.shef.ac.uk/FRAX). A routine SSc evaluation (according to EUSTAR) was performed as well. Age- and BMI-matched early AR (ACR/EULAR 2010 criteria) patients and healthy controls (HC) were enrolled as well. Results Seventy-one SSc patients (3:68 M:F, age 66±9yrs, 57:14 limited:diffuse cutaneous, median disease duration 8.5, 2.4-14.7yrs, median disease activity 1, 0.25-2), 44 AR (11:33 M:F, age 62±12yrs, median DAS28 4.42, 3.94-5) and 29 healthy controls (all F, 60.1±10.7yrs) were enrolled. OP was detected in 42/71 (59%) SSc patients. Disease duration was significantly higher in SSc-OP patients (10.5, 4.3-16.6 vs 5.5, 1.6-9.8, p<0.01) and it was also significantly associated to OP (OR 1.4, 1.1-1.7, p<0.01), even when corrected at a multivariable analysis for other disease-specific features (skin and gastrointestinal involvement, autoantibody subset, median mRSS, disease activity) and OP risk factors (steroid use, smoke, BMI, chronic renal insufficiency). OP in RA patients was significantly lower than in SSc (9/44, 20%, p<0.001). Mean femoral BMD was 0.58 (0.53-0.7) in SSc vs 0.72 (0.64-0.82) in RA and 0.7 (0.51-0.75) in HC (p<0.0001), lumbar mean BMD 0.82 (0.75-0.9) in SSc vs 0.92 (0.81-1) in RA and 0.89 (0.67-0.99) in hc (p=NS). FRAX for major fracture was not significantly different between disease groups (low in 47% and 50%, medium in 28% and 40%, high in 25% and 10% of SSc and RA respectively) while it was significantly different for SSc vs HC (p<0.001) and for AR vs HC (p<0.01). A diagnosis of SSc was significantly associated to OP (OR=13.2, 4-42.4), even when corrected for steroid use. Conclusions We have detected a very high OP frequency in our SSc patients, significantly higher than a control early AR cohort and significantly associated to disease duration. Routine DEXA evaluation and risk factors for OP should always be considered and treated when possible in every SSc patient, especially after 5 years of disease duration. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5172

PP115-MON SERUM PREALBUMIN IS A PREDICTOR OF MORTALITY IN SYSTEMIC SCLEROSIS OUTPATIENTS

PP115-MON SERUM PREALBUMIN IS A PREDICTOR OF MORTALITY IN SYSTEMIC SCLEROSIS OUTPATIENTS E. Cereda1, V. Codullo2, C. Klersy3, S. Breda2, A. Crippa1, M.L. Rava1, M. Orlandi1, C. Bonardi1, L. Quarleri1, S. Cappello1, R. Caporali2, R. Caccialanza1. 1Nutrition and Dietetics Service, Fondazione IRCCS Policlinico San Matteo, 2Division of Rheumatology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 3Biometry and Clinical Epidemiology Service, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

SAT0217 Anti- RO/SSA Antibodies in Systemic Sclerosis: Frequency and Clinical Associations in a Monocentric Referral Cohort

Background Systemic Sclerosis (SSc) is an autoimmune connective tissue disease (CTD) characterized by the presence of several autoantibodies that correlate with diagnostic and prognostic aspects of the disease. Besides those autoantibodies (anti-centromere, ACA; anti-topoisomerase I, anti-topo 1) which are specific to SSc, other reactivities shared with other CTDs can be detected whose clinical associations are less investigated. Anti-Ro/SSA antibodies have been associated with sicca syndrome and recently with the occurrence of pulmonary fibrosis and presence of anti-topo I Objectives To analyse the frequency of anti-Ro/SSA in patients with SSc and to explore their clinical, laboratory and instrumental associations. Methods After collecting patients’ informed consent, all patients included in the cohort of our centre from 2000 who satisfied LeRoy’s criteria for SSc were followed according to EUSTAR recommendations. We recorded data about cutaneous involvement (limited, lc, or diffuse cutaneous, dc), modified Rodnan Skin score, Raynaud phenomenon, digital ulcers, gastrointestinal tract (G-I), lung and peripheral vascular involvement (dyspnea with NYHA class, HRCT, Doppler echocardiography) at baseline and during the follow-up. Antinuclear antibodies (ANA) and specific subsets were analysed using standard methods (indirect immunofluorescence and Elia). Statistical evaluation was performed using software SPSS for Mac. Results Serum samples from 407 patients were analysed: M:F 50:357, mean age at disease onset ± SD was 57.6±3.72yrs, disease duration± SD was 4.6±6.7 yrs, lc:dc 335:61, ANA+ 369 (91%), ACA 195 (48%), anti-topo 83 (20%). Anti-Ro/SSA antibodies were detected in 50 (12%) patients: they were concomitant with ACA in 21/50 (42%) patients, with anti-topo1 in 7/50 (14%), with anti-RNP in 1/50 (2%). In 21/50 (42%) anti-Ro/SSA antibodies were associated with no other specificity. No significant differences between the anti-Ro+ve and anti-Ro-ve group were found for cutaneous or gastrointestinal involvement and presence of Raynaud’s phenomenon. At baseline the frequency of significant dyspnea (NYHA≥2) was significantly higher in patients with anti-Ro antibodies (58%vs37%, p=0.03), independently of the presence of anti-topo-1. Accordingly, but with no significant difference, in the anti-Ro+ group there was a higher frequency of HRCT alterations ((honey-combing (HC) and ground glass 28%vs19% and 20%vs16% respectively); % DLCO reduction (-29(-71-+63)%VS-22(-90-+65)%); estimated systolic pulmonary artery pressure on echocardiography (25(18-33)mmHg vs 20 (16-30)mmHg) and % of overlap with Sjögren syndrome (33%vs11%). The same associations were confirmed in patients with anti-Ro antibodies positivity only, with a significantly higher presence of HC at HRCT (64%vs30%, p<0.01) and higher DLCO % reduction (-39(-71-+7)% vs -23(-90-+65)%, p<0.05). After a mean follow up of 9.2±2.6 years, the presence of antiRo/SSA did not influence survival (94% vs 93% in the rest of the cohort). Conclusions In SSc patients, anti-Ro antibodies are frequent and significantly associated with respiratory symptoms already at disease onset. This correlation supports the utility of anti-Ro in the prognostic stratification of organ involvement, regardless of the presence of other autoantibodies. References Disclosure of Interest None Declared