L.E. Kristensen

National EQ-5D tariffs and quality-adjusted life-year estimation: comparison of UK, US and Danish utilities in south Swedish rheumatoid arthritis patients

Objective To study how the choice of national EQ-5D tariff may affect utility and incremental quality-adjusted life-year (QALY) estimates. Methods South Swedish rheumatoid arthritis patients in an observational study, starting and continuing anti-tumour necrosis factor (TNF) monotherapy (n=54) or anti-TNF plus methotrexate (n=215) for 1 year during May 2002 to April 2009, were included. EQ-5D questionnaires were completed at baseline, 3, 6 and 12 months. Utilities and accumulated QALY were compared using the UK, US and Danish EQ-5D tariffs. Utilities for all 243 possible EQ-5D health states were also compared. Results US utilities were generally higher than UK, with Danish falling in between. A substantial 1-year mean utility improvement was seen in both study groups using all tariffs (UK 0.28 vs 0.29; US 0.18 vs 0.19; Danish 0.20 vs 0.22). Adjusting for baseline differences between groups, the incremental QALY gain of combined treatment was 0.09 using the UK tariff, while 0.06 according to both US and Danish tariffs. Inter-tariff disagreement in utility and accumulated QALY varied irregularly across the range of utilities. Conclusions Applying different national EQ-5D tariffs to the same data may result in substantially different incremental QALY estimates, crucial knowledge when interpreting cost-utility analyses. Studies using different tariffs cannot be directly compared.

THU0154 Adverse effects of glucocorticoid therapy in rheumatoid arthritis (RA): A systematic review and meta-analysis of randomized controlled trials

Background Arguments against glucocorticoid (GC) use are dominated by fear of adverse effects, mainly based on experience with long-term and/or high-dose GC. Whether this concern is relevant for the lengths of treatment and doses in the EULAR recommendations for GC therapy in RA (1) remains to be clarified. Objectives To assess: the risk of adverse effects of GC therapy in randomized controlled trials (RCTs) of GC in RA; the risk of Adverse Events (AE)-associated withdrawals; and withdrawal due to any cause. Methods A systematic literature search followed by evidence synthesis and meta-analysis of RCTs, where the compared interventions included any difference in GC dosing, independent of type of administration, type of GC, or study duration. Risk ratios (RR) with 95% confidence intervals (CI) were calculated. The quality of the evidence (a measure of confidence in the estimates) was assessed as recommended by the GRADE Working Group (2). Outcomes comprised those found most worrisome by EULAR Rheumatologists and patients (3). Results Of 2821 references identified 524 were reviewed in detail and 59 (66 randomized comparisons with a total of 4831 patients) were found eligible for inclusion. Median study duration: 24 weeks (range: 1-104); median prednisone equivalent dose difference (more vs. less) of 6.2 mg/day (IQ range 2.0 -13.9). The empirical evidence suggests, with varying confidence in the estimates, that the risks of the most worrisome adverse effects are not increased (Table). Renal dysfunction was increased; however confidence in the estimate was low due to (i) few incidences observed (the number of patients did not reach the optimal information size) and (ii) the indirectness as some studies used concomitant cyclosporine therapy. Outcomes Number of comparisons Number of patients RR [95% CI] Quality of the Evidence Diabetes 17 1530 1.26 [0.58, 2.73] Moderate Osteoporosis 11 1114 1.41 [0.79, 2.53] Low Cardiovascular disease 19 1944 0.91 [0.60, 1.38] Moderate Hypertension 21 2178 1.24 [0.83, 1.86] Moderate Infections 20 2296 0.90 [0.78, 1.04] Moderate Renal Dysfunction 15 2044 1.56 [1.09, 2.22] Low Weight gain 17 1897 1.21 [0.98, 1.48] Low Cushingoid changes 17 1534 1.09 [0.73, 1.61] Low Withdrawal from study 52 4471 0.77 [0.65, 0.92] Low Withdrawal due to AE 40 3573 1.23 [0.96, 1.57] Moderate Conclusions This meta-analysis of trials does not support the notion of an increased risk for a wide range of side effects traditionally associated GC, when the GC is used at low to moderate doses over a median of 24 weeks. Patients receiving more GC were less likely to withdraw from studies compared to controls. Acknowledgements This study was supported by a grant from Danish Medicines Agency, MundiPharma, and unrestricted grants from The Oak Foundation. References Hoes JN, et al. Ann Rheum Dis 2007 Dec;66(12):1560-7. Balshem H, et al. J Clin Epidemiol 2011; 64(4):401-6. van der Goes MC, et al. Ann Rheum Dis 2010; 69(6):1015-21. Disclosure of Interest S. Tarp Grant/Research support from: MundiPharma, E. Bartels Grant/Research support from: Mundipharma, J. Kirwan Grant/Research support from: Nitec, Mundipharma, Horizon, D. Furst Grant/Research support from: NItec,Pfizer, M. Boers Grant/Research support from: Nitec, MundiPharma, Horizon, T. Woodworth: None Declared, H. Bliddal Grant/Research support from: MundiPharma, B. Danneskiold-Samsøe: None Declared, L. Kristensen Grant/Research support from: NorPharma, S. Thirstrup: None Declared, M. Rasmussen: None Declared, R. Christensen Grant/Research support from: MundiPharma

THU0597 Work Disability in Ankylosing Spondylitis and Non-Radiographic Axial Spondyloarthritis Before and After Start of Anti-Tnf Therapy: A Swedish Observational Study

Background The overall work disability in AS patients benefit from anti-TNF treatment.1 Patients with nr-axSpA have comparable clinical phenotypes and burden of disease, requiring treatment irrespective of the presence of radiographic damage.2 It could be hypothesized that the two conditions reflect different aspects of one disease progression. Objectives To compare baseline characteristics and work disability before and after anti-TNF treatment start between patients with AS and nr-axSpA. Methods Within the South Swedish Arthritis Treatment Group register we identified 103 AS and 75 nr-axSpA patients (the latter fulfilling the ASAS criteria for axial spondyloarthritis without radiographic sacroiliitis on plain x-ray) aged 17-62 years starting anti-TNF treatment 2004-2011. Patients were linked by personal identification numbers to Swedish social insurance agency registry data on work disability. Total work disability (sick leave plus disability pension), sick leave, and disability pension are presented one year before to two years after anti-TNF initiation (by quarters of a year). Population references are included to exclude potential secular trends in work disability. Results Patients with nr-axSpA were younger (median 35 vs 40y p=0.014), had shorter disease duration (median 5.8 vs. 10.2y p=0.003), and less concomitant DMARDs (76 vs 47% p<0.001) at anti-TNF initiation. No statistically significant baseline differences were observed regarding sex (p=0.547) or VAS pain (p=0.907). The year before anti-TNF initiation the AS group displayed more work disability than the patients with nr-axSpA (mean 50.5 vs 37.4 days p<0.007), primarily due to a greater proportion of patients with AS having some level of disability pension (29 vs. 9%, p=0.001). After treatment start mean work disability decreased more for patients with nr-axSpA than AS, again mostly explained by a greater proportion within the AS group receiving disability pension, and hence less likely to decrease their work disability. Conversely, mean disability pension days increased more among AS patients after treatment initiation (p<0.001). The observed between-group differences after treatment start remained when adjusting for age, sex, and year of anti-TNF initiation. Conclusions Patients with nr-axSpA had less disability pension, indicating less permanently reduced work disability, than their AS counterparts. Whether this is related to the hypothesis that nr-axSpA and AS represent different phases of a disease progression remains to be further explored. References Kristensen LE, Petersson IF, Geborek P, Jöud A, Saxne T, Jacobsson LTH, m.fl. Sick leave in patients with ankylosing spondylitis before and after anti-TNF therapy: a population-based cohort study. Rheumatology (Oxford). februari 2012;51(2):243–9. Rudwaleit M, Haibel H, Baraliakos X, et al. The early disease stage in axial spondylarthritis: results from the German Spondyloarthritis Inception Cohort. Arthritis Rheum 2009;60:717–27. Disclosure of Interest A. Jöud Paid instructor for: Pfizer, T. Olofsson: None declared, L. Jacobsson Paid instructor for: Pfizer, UCB, and Abbvie, J. A. Karlsson: None declared, H. Bliddal Paid instructor for: Pfizer, UCB, Abbvie, Celgene, Bristol-Myers Squibb, and MSD, L. E. Kristensen Paid instructor for: Pfizer, UCB, Abbvie, Celgene, Bristol-Myers Squibb, and MSD

Patient-Reported Outcomes Are More Important Than Objective Inflammatory Markers for Sick Leave in Biologics-Treated Patients With Rheumatoid Arthritis

To study the impact of common noncomposite disease activity measures on sick leave in biologics‐treated patients with rheumatoid arthritis (RA).

FRI0467 Work Disability in Early Systemic Sclerosis: A Longitudinal Population-Based Cohort Study

Background Work is a major component of daily life for most adults. People work to make a living, but work also creates routines and structure in everyday life. Studies to date indicate that the prevalence of work disability is high in early and late systemic sclerosis (SSc) (1-4). Therefore, in order to identify patients with needs for early interventions, e.g. medical treatment and rehabilitation, more knowledge about patterns of work disability and its relationship to disease activity in early disease is needed. Objectives To study work disability with reference to levels of sick leave and disability pension in early SSc. Methods SSc patients living in the southern part of Sweden with onset of their first non-Raynaud symptom between 2003 and 2009 and with a follow-up of 36 months were included in a longitudinal study. Thirty-two patients (26 female, 24 with limited SSc), median age 47.5 years (IQR 43-53), were identified. Work disability was calculated in 30-day-intervals from 12 months prior disease onset until 36 months after, presented as the prevalence of work disability per year (0–3) and as period prevalence of mean net days per month (±SD). Comparisons were made between patients with different disease severity and sociodemographic characteristics, and between patients and a reference group from the general population. Results Seventy-eight percent had no work disability one year prior disease onset, which decreased to 47% after 3 years. The relative risk for work disability in SSc patients compared to reference group was 0.95 (95% CI 0.39–2.33) at diagnosis, and increased to 2.41 (1.28–4.55) after 3 years. There were no significant correlations between work disability and disease severity, but between work disability and years at workplace rs=-.72 (p=0.002), education rs=-.51 (p=0.004), and sickness absence the month before disease onset rs=.58 respectively (p=0.001). Conclusions Considerable increase in work disability was noted 3 years after disease onset. Short education, fewer years at workplace, and sickness absence before disease onset may be risk factors for sustained work disability and these patients should be selected for early rehabilitation intervention. References Quimet JM, Pope JE, Gutmanis I, Koval J. Work disability in scleroderma is greater than in rheumatoid arthritis and is predicted by high HAQ scores. The open Rheumatology Journal 2008; 2:44-52. Sandqvist G, Scheja A, Eklund M. Working ability in relation to disease severity,everyday occupations and wellbeing in women with limited systemic sclerosis. Rheumatology (Oxford) 2008; 47:1708-11. Hudson M, Steel R, Lu Y, Thombs BD;Canadian scleroderma research group, Baron M. Work disability in systemic sclerosis. J Rhuematol 2009;36:2481-6. Sharif R, Mayes MD, Nicassio PM, Gonzales EB, Estrada-Y-Martin RM, Nair DK, Reveille JD, Arnett FC, Assassi S, for the GENISOS Study Group. Determinants of work disability in patients with systemic sclerosis: A longitudinal study of the GENISOS cohort. Semin Arthritis Rheum 2011;41:38-47. Disclosure of Interest None declared

THU0095 Is Nephrolithiasis an Unrecognized Extra-Articular Manifestation in Ankylosing Spondylitis? A Prospective Population-Based National Cohort Study with Matched General Population Comparator Subjects

Background Several factors known to increase the risk of NL are at play in AS patients, namely clinical and subclinical bowel inflammation, altered calcium metabolism due to inflammatory cytokines, bone-remodeling and spinal immobility. Objectives To estimate the rates of nephrolithiasis (NL) in Swedish patients with a diagnosis of ankylosing spondylitis (AS) compared to matched comparator subjects from the general Swedish population. Methods This is a prospective population-based national cohort study based on linkage of data from The Swedish Patient Register, The Swedish Register of Total Population and Population Changes, The Swedish Cause of Death Register, The Swedish Register of Education and The Swedish Biologics Register (2001-2009). The rate of NL in AS patients was compared to population comparator subjects matched on age, sex, and date of study entry. Cox regression models were used to calculate Hazard Ratios (HR) with adjustment for comorbidities and anti-TNF treatment. Results A total of 8,572 AS patients and 39,639 matched general population comparators were included in the study contributing 49,258 person-years (py) respectively 223,985 py. Mean age at study entry was 46 years (inter quartile range 36-56 years) and 65% were male. The univariate HR of NL in AS patients compared to general population comparators was 2.44 (95%CI 2.09 to 2.84). Predictors of NL within the AS group included anti-TNF treatment (HR 1.6; 95%CI 1.2 to 2.1), prior diagnosis of IBD (HR 2.3; 95%CI 1.7 to 3.3) and prior diagnosis of NL (HR 16.4;95%CI 11.5 to 23.4). After adjustment for these confounders AS patients still had a significantly increased risk of NL diagnosis (HR 2.08; 95%CI 1.77 to 2.44) and for AS patients with anti-TNF treatment this risk was even higher (HR 3.02;95%CI 2.32 to 3.93) when compared to general population subjects. As can be seen in the figure, male sex was associated with a significantly higher risk of NL in both AS patients and general population comparators. Conclusions The risk of NL in AS patients is more than two-fold increased and seems to correlate with disease severity of AS. NL is suggested as a novel extra-articular manifestation in AS patients. IBD, previous history of NL, and male sex were identified as other predictors of NL in the AS population. Acknowledgements We are indebted to all colleagues and staff at our university departments, especially Pernilla Nilsson and Jonas Eriksson. This study was supported by grants from Lund University, The Skane region, Österlund and Kock Foundations, and Reumatikerförbundet. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.3826

FRI0196 Costs in Relation to Disability, Disease Activity and Health-Related Quality of Life in Rheumatoid Arthritis

Background RA is associated with high societal costs. While disability predicts costs in RA, little is known about the relations between costs and disease activity or health-related quality of life. Objectives To study the associations between costs, disability, disease activity, and health-related quality of life. Methods RA patients receiving anti-TNF therapy in southern Sweden (n=2504; median disease duration 11y) were monitored between July 2005 and December 2010. At each visit (n=15732) HAQ, DAS28 and EQ-5D scores were collected, while costs of anti-rheumatic drugs, healthcare use and productivity losses were calculated from 30 days before to 30 days after the visit using nationwide registers. Associations between the clinical measures and healthcare (all patients, applying individual means) and work loss costs (patients <65y; n=1806) were studied by linear regression, adjusting for demographics and disease characteristics, and by Spearman correlation. Confidence intervals were estimated by non-parametric bootstrapping. Due to the inclusion criteria, anti-TNF cost varied little between patients and was excluded from the analyses. Results Over 60 days, the mean (SD) healthcare cost of patients with ongoing anti-TNF therapy was €3189 (1290), encompassing an anti-TNF cost of €2470 (502; 77%). In patients <65y, the mean work loss cost amounted to €4235 (3450). By linear regression, both healthcare (excl. anti-TNF) and work loss costs were most closely related to HAQ scores, while the association with work loss costs was also higher for EQ-5D than DAS28. Spearman results were similar, but did not detect a closer correlation of healthcare costs with HAQ than DAS28. Healthcare (excl. anti-TNF) costs: B = €440 (95%CI 324-557), 143 (85-201) and -652 (-948 to -355) for each 1.0 difference in HAQ, DAS28 and EQ-5D, respectively (p=0.030 for HAQ vs. DAS28 and p=0.027 for HAQ vs. EQ-5D by comparison of standardised B); rS=0.23, 0.18 and -0.16 for HAQ, DAS28 and EQ-5D, respectively (p=0.085 for HAQ vs. DAS28 and p=0.020 for HAQ vs EQ-5D). Work loss costs: B = €2574 (95%CI 2342-2807), 794 (668-919) and -4817 (-5392 to -4243) (p<0.01 for HAQ vs. DAS28/EQ-5D, p=0.027 for EQ-5D vs. DAS28); rS=0.52, 0.32 and -0.40 (p<0.001 for HAQ vs. DAS28/EQ-5D, p=0.008 for EQ-5D vs. DAS28). Figure 1 Conclusions In RA, work loss costs are more closely related to disability than to disease activity or health-related quality of life. HAQ disability is also a better marker of healthcare costs than health-related quality of life, while disease activity was not consistently inferior to HAQ in this regard. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1466

OP0189 Long term work disability in anti-TNF therapy treated patients with psoriatic arthritis: A population-based cohort study

Background Reduced work ability leading to sick leave is a common consequence of psoriatic arthritis (PsA). TNF-antagonist therapy has been a major advance in treating several aspects of PsA. Little is known about the impact of TNF treatment on long term work disability in PsA. Objectives To study proportions of long term sick leave and disability pension before and after TNF-antagonist therapy in PsA patients. Methods Using the population-based South Swedish Arthritis Treatment Group register, we identified 191 PsA patients (median age 43years, range 18-58y, 55% men), who between Jan 2003 and Dec 2007 (allowing for a complete 4 year follow-up period) started treatment with adalimumab, etanercept, or infliximab. We linked data to the payment register by the Swedish Social Insurance Agency and calculated the proportion on any sick leave in 30-day-intervals from 12 months before treatment start until 3 years after. For each PsA patient we randomly selected 4 reference subjects from the general population matched for age, sex, area of residence, and date of inclusion. Results At treatment initiation 67% of the PsA patients were either on sick leave or received disability pension of any degree from part time thru full time. During the first 12 months after treatment start this fraction dropped to 58%, and remained at 57% after 3 years (p<0.001). Comparing PsA patients to the general population, the relative risk of being work disabled at treatment start, 12 months, and 3 years after treatment start was 4.2 (95% CI 3.4, 5.1), 3.7 (3.0, 4.5), and 3.4 (2.7, 4.2), respectively. Patients withdrawing from therapy during the follow-up period compared to patients sustaining treatment had the same baseline risk of being work disabled (69 vs 64%), but a 50% increased risk after the 3 year observational period (73 vs 53%; relative risk 1.5 [95% CI] 1.2, 1.8 for comparison between withdrawers to sustainers). Conclusions There is a decline in work disability during the first 12 months after initiation of TNF-antagonist treatment in PsA patients not explained by societal factors or secular trends. This decline was sustained for the following 3 years. Patients withdrawing from therapy have a 50% increased risk of being work disabled than patients remaining on therapy. Disclosure of Interest L. Kristensen Consultant for: Abbott, BMS, Pfizer, MSD, Mundipharma, M. Englund: None Declared, P. Geborek: None Declared, M. Neovius: None Declared, J. Askling: None Declared, L. Jacobsson Consultant for: Abbott, BMS, Pfizer, MSD, I. Petersson Consultant for: Abbott, Pfizer, MSD

SAT0130 Defining the Optimal Biological Monotherapy in Rheumatoid Arthritis (RA): Network Meta-Analysis of Randomized Trials

Background Methotrexate (MTX) is considered the anchor drug in RA, both as monotherapy, as well as for its ability to increase the efficacy of biologic agents when used in combination [1]. Some RA patients have to discontinue DMARD therapy. Thus, it is important to define the optimal biological monotherapy in RA patients. Objectives To review the evidence for short-term efficacy and safety of biologic monotherapy in RA. The aim was to define the optimal biological monotherapy in RA patients without concomitant use of any DMARD therapy. Methods Systematic review and Network Meta-Analysis of RCTs with DMARD inadequate responders (IR) and DMARD naïve RA patients, comparing biologic agents in monotherapy with either placebo (no DMARD) or DMARD, were considered eligible for inclusion. The co-primary outcomes were the number of patients achieving an ACR50 response, and the number discontinuing therapy due to adverse events (AE) [2] preferably after 6 months (3-12 months), respectively. The network meta-analysis was based on mixed-effects logistic regression (GLMM modelled in SAS) [2]; combining statistical inference from both direct and indirect comparisons of the treatment effects between biologics. All dosages applied for all of the nine biologics. Results are reported as odds ratios (OR [95%CI]). For sensitivity, in terms of the included patients, we compared DMARD IR responder trials with DMARD Naïve trials. Results From the literature search 27 individual studies (7,938 patients) were included: abatacept [Aba:1], adalimumab [Ada:5], anakinra [Ana:2], certolizumab [Cer:2], etanercept [Eta:6], golimumab [Gol:3], infliximab [Inf:1], rituximab [Rit:1] and tocilizumab [Toc:6]. The network only included one ‘closed loop’ with biologics head-to-head: ADACTA (Toc vs. Ada) [3]. Benefit (ACR50): Ana was statistically less likely than Ada, Eta, Gol, and Toc, respectively, to have a clinical response (p<0.05). The odds for responding was statistically higher (p<0.05) for Toc compared to Aba (3.9[1.2;12.4]), Ada (2.1[1.2;3.6]), and Inf (7.7[1.8;32.4]), respectively. Finally, Eta was statistically more likely to result in a response than Inf (5.6[1.3;23.9]). Harm (Withdrawal d/t AEs): Gol seemed less likely to cause withdrawal from side effects (p<0.05) compared to Ada (0.4[0.1;0.9]), Ana (0.3[0.1;0.8]), Cer (0.3[0.1;1.0]), Inf (0.2[0.1;1.0]), and Toc (0.4[0.1;0.8]). For sensitivity, the ACR50 estimates were compared with the direct comparison of Ada vs. Toc [3]; the model apparently did not build on incoherence, as data from the ADACTA study reported a comparable effect size (OR=2.3 [1.5; 3.7]). Conclusions All biologics are not equal. In RA patients who need biologic therapy without concomitant use of DMARDs, some biologics are better than others with respect to ACR50 responses. References Smolen J, et al. Ann Rheum Dis. 2010;69(6):964-75. Singh JA, et al. CMAJ. 2009;181(11):787-96. Gabay C, et al. Lancet (Accepted, 2013) Acknowledgements Musculoskeletal Statistics Unit, The Parker Institute receives support via research grants from the Oak Foundation. Disclosure of Interest R. Christensen Grant/research support from: This particular study, including both the protocol and subsequent manuscript, has been supported by a grant from Roche; the grant was provided as an unrestricted grant to Musculoskeletal Statistics Unit, The Parker Institute., Speakers bureau: Abbott, BMS, Pfizer, Roche, MSD, Expanscience, Biogen Idec, Ipsen, Novartis, Bayer, S. Tarp: None Declared, D. Furst: None Declared, M. Østergaard: None Declared, T. Lorenzen: None Declared, M. Hansen: None Declared, J. Singh: None Declared, E. Choy: None Declared, M. Boers: None Declared, M. Suarez-Almazor: None Declared, B. Ejbjerg: None Declared, L. Kristensen: None Declared, H. Bliddal: None Declared

SAT0047 Impact of Anti-Rheumatic Treatment on Immunogenicity of Pandemic H1N1 Influenza Vaccine in Patients with Arthritis

Background A monovalent, adjuvanted, inactivated H1N1 influenza vaccine (Pandemrix) was reported as highly immunogenic resulting in seroconversion in 77-94% of adults after administration of a single dose (ref). Objectives To investigate impact of different anti-rheumatic treatments on antibody response following H1N1 vaccination in patients with rheumatoid arthritis (RA) and spondylarthropathy (SpA). Methods Patients with arthritis (n=333; mean age 58 years, 66% women) participated. Hemagglutination inhibition (HI) assay was performed on blood samples drawn prior to and after mean 8 months following vaccination. A positive immune response was defined as seroconversion i.e. ≥4-fold increase in HI titer or HI ≥40 in case ofa negative pre-vaccination serum. There were 7 treatment groups: RA on MTX; RA on anti-TNF monotherapy; RA on anti-TNF+MTX; RA on other biologics (abatacept, rituximab, tocilizumab); SpA on anti-TNF monotherapy; SpA on anti-TNF+MTX and SpA on NSAIDs/analgesics. Results The figure shows percentages of patients with positive immune responses in different treatment groups. RA patients on rituximab had significantly lower (p<0.001) and SpA on anti-TNF monotherapy significantly better response rates compared to other treatment groups (p 0.001-0.032). No significant differences were found between other groups. Image/graph Conclusions Rituximab treatment is associated with severely reduced antibody response to the pandemic H1N1 influenza vaccine. Eight months after vaccination, antibody response in SpA patients on anti-TNF monotherapy was still as good as that reported for healthy adults efter 3-4 weeks. All other treatments groups showed lower antibody response. References Broadbent AJ, Subbarao K. Current Opinion in Virology 2011 (1);4:254-262. Disclosure of Interest None Declared