Johan A Karlsson

Treatment response to a second or third TNF-inhibitor in RA: results from the South Swedish Arthritis Treatment Group Register

OBJECTIVESnTo study treatment response rates of RA patients undergoing second- and third-line anti-TNF therapy and to identify baseline predictors of response to second-line treatment.nnnMETHODSnRA patients monitored in a prospective, observational study, having switched anti-TNF therapy once (first-time switchers, n = 337) or twice (second-time switchers, n = 36)--i.e. following failures with one antibody- and one receptor-type agent--between March 1999 and December 2006, were studied. Treatment responses at 3 months were assessed by the ACR and European League Against Rheumatism (EULAR) response criteria. Predictive potentials for response to second-line treatment of demographics, baseline disease activity measures, disease and treatment characteristics were analysed using logistic regression.nnnRESULTSnACR20 response was met by 51% of first-time and 35% of second-time switchers. Corresponding ACR50 rates were 27 and 18%; EULAR overall rates (EULAR good or moderate response) 71 and 58%; EULAR good rates 25 and 9% and 28-joint disease activity score (DAS28) remission rates 16 and 6%. Identified baseline predictors of response to second-line treatment were lower age and HAQ scores, elevated DAS28 values and having ceased the former anti-TNF treatment due to adverse events rather than inefficacy. No variable was predictive for all examined response criteria.nnnCONCLUSIONSnResponse rates of first-time anti-TNF switchers are somewhat below those of anti-TNF naïve RA patients, while the markedly inferior response rates of second-time switchers suggest other therapeutic options to be considered in this situation. Identified baseline predictors of response may be useful indicators to second-line anti-TNF therapy, but vary depending on the response criteria set studied.

Cost-effectiveness of infliximab versus conventional combination treatment in methotrexate-refractory early rheumatoid arthritis: 2-year results of the register-enriched randomised controlled SWEFOT trial

Objective To estimate the incremental cost-effectiveness of infliximab versus conventional combination treatment over 21u2005months in patients with methotrexate-refractory early rheumatoid arthritis. Methods In this multicentre, two-arm, parallel, randomised, active-controlled, open-label trial, rheumatoid arthritis patients with <1u2005year symptom duration were recruited from 15 rheumatology clinics in Sweden between October 2002 and December 2005. After 3–4u2005months of methotrexate monotherapy, patients not achieving low disease activity were randomised to addition of infliximab or sulfasalazine+hydroxychloroquine (conventional treatment group). Costs of drugs, healthcare use, and productivity losses were retrieved from nationwide registers, while EuroQol 5-Dimensions utility was collected quarterly. Results Of 487 patients initially enrolled, 128 and 130 were randomised to infliximab and conventional treatment, respectively. The infliximab group accumulated higher drug and healthcare costs (€27u2005487 vs €10u2005364; adjusted mean difference €16u2005956 (95% CI 14u2005647 to 19u2005162)), while productivity losses did not differ (€33u2005804 vs €29u2005220; €3961 (95% CI −3986 to 11u2005850)), resulting in higher societal cost compared to the conventional group (€61u2005291 vs €39u2005584; €20u2005916 (95% CI 12u2005800 to 28u2005660)). Mean accumulated quality-adjusted life-years (QALYs) did not differ (1.10 vs 1.12; adjusted mean difference favouring infliximab treatment 0.01 (95% CI −0.07 to 0.08)). The incremental cost-effectiveness ratios for the infliximab versus conventional treatment strategy were €2u2005404u2005197/QALY from the societal perspective and €1u2005948u2005919/QALY from the healthcare perspective. Conclusions In early, methotrexate-refractory rheumatoid arthritis, a treatment strategy commencing with addition of infliximab, as compared to sulfasalazine+hydroxychloroquine, was not cost-effective over 21u2005months at willingness to pay levels generally considered acceptable. Trial registration number: NCT00764725.

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.

Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in early rheumatoid arthritis: 2-year quality-of-life results of the randomised, controlled, SWEFOT trial

Objective To compare EuroQol 5-Dimensions (EQ-5D) utility and quality-adjusted life-years (QALYs) in patients with early, methotrexate (MTX) refractory rheumatoid arthritis (RA), randomised to addition of infliximab (IFX) or sulfasalazine and hydroxychloroquine (SSZ+HCQ). Methods RA-patients with symptoms <1 year were enrolled between 2002 and 2005 at 15 Swedish centres. After 3–4u2005months of MTX monotherapy, patients with a remaining DAS28>3.2 were randomised to addition of IFX or SSZ+HCQ and followed for 21u2005months. EQ-5D profiles were collected every 3u2005months. Between-group comparisons of utility change and accumulated QALYs were performed, using last observation carried forward (LOCF) following protocol breach. Missing data were imputed by linear interpolation or LOCF. Sensitivity analyses applying baseline observation carried forward (BOCF) or restricted to completers were conducted. Results Of 487 patients initially enrolled, 128 and 130 were randomised to IFX or SSZ+HCQ, respectively. Mean utility in the IFX and SSZ+HCQ groups increased from 0.52 (SD 0.27) and 0.55 (SD 0.27) at randomisation to 0.66 (SD 0.25) and 0.63 (SD 0.27) at 21u2005months (adjusted mean difference favouring IFX 0.04; 95% CI −0.01, 0.09; p=0.15). Average accumulated QALYs were 1.10 (SD 0.37) and 1.07 (SD 0.42) in the IFX and SSZ+HCQ groups, respectively (adjusted mean difference favouring IFX 0.07; 95%CI −0.01, 0.14; p=0.07). BOCF analysis showed similar results, while differences were reversed, though remained statistically non-significant among completers. Dropout rates in the IFX/SSZ+HCQ groups were 30%/43% (p=0.01). Conclusions Comparing addition of IFX or SSZ+HCQ to MTX in active early RA, no statistically significant differences in utility or QALY gain could be detected over 21u2005months. Trial registration Registered in WHO database at the Karolinska University Hospital, number CT20080004.

Changes in the anticitrullinated peptide antibody response in relation to therapeutic outcome in early rheumatoid arthritis: results from the SWEFOT trial

Objective To determine the relationship between changes in antibody levels towards citrullinated peptides derived from different candidate autoantigens and therapeutic outcome in early rheumatoid arthritis (RA). Methods Baseline and 3-month serum samples from 316 patients with early RA enrolled in the Swedish Farmacotherapy (SWEFOT) trial were analysed for antibodies against cyclic citrullinated peptides (CCP) and citrullinated peptides derived from vimentin (cVim), fibrinogen (cFib) and α-enolase (CEP-1). At 3-month follow-up, methotrexate monotherapy-inadequate responders were randomised to add-on therapy with sulfasalazine and hydroxychloroquine or infliximab. In these patients, anticitrullinated peptide antibodies (ACPA) were also assessed at 12 and 24u2005months. The proportion of antibody-positive patients and relative changes in antibody levels were compared across ACPA specificities and related to therapeutic response and radiographic progression. Results During the 2-year follow-up, the proportion of patients testing positive declined significantly regarding antibodies to cVim, cFib and CEP-1, while anti-CCP antibody occurrence remained stable over time. Turning anti-cVim antibody negative was most common, and anti-cVim antibody seroreversion during the first threeu2005months associated with significantly less 2-year radiographic progression compared with patients who remained positive. Median antibody levels of all tested ACPAs declined uniformly during initial methotrexate therapy and following response to add-on therapy, with no significant relation to treatment regimen or radiographic progression. Conclusions The influence of early antirheumatic therapy on ACPA seroreversions was markedly different across specificities, and early disappearance of anti-cVim antibodies associated with better radiological outcome. Thus, these data suggest that the disappearance of particular ACPA reactivities may be beneficial in early RA. Trial registration number WHO database at the Karolinska institute: CT20080004; and clinicaltrials.gov: NCT00764725.

Is swollen to tender joint count ratio a new and useful clinical marker for biologic drug response in rheumatoid arthritis? Results from a Swedish cohort.

To study the impact of swollen to tender joint count ratio (STR) and other baseline characteristics on treatment response to a first course of anti–tumor necrosis factor (anti‐TNF) therapy in rheumatoid arthritis (RA) patients.

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

SAT0352 Comparison of Nonradiographic Axial Spondyloarthritis and Ankylosing Spondylitis Patients – Baseline Characteristics and Development of Clinical Variables during Three Years of Anti-TNF Therapy in Clinical Practice

Background The relationship between nonradiographic axial Spondyloarthritis (nr-axSpA) and Ankylosing Spondylitis (AS) is currently debated. In Sweden, anti-TNF agents were often used to treat patients with nr-axSpA, even before this phenotype was formally characterised by the 2009 ASAS criteria. Objectives To compare clinical and laboratory patterns between patients with nr-axSpA and AS during three years of anti-TNF treatment. Methods Patients with nr-axSpA (n=99) or AS (n=238), starting anti-TNF therapy at a Rheumatology university department in southern Sweden, were monitored between 1999 and 2013. Diagnoses were based on data collected at anti-TNF initiation, applying the 2009 ASAS criteria for nr-axSpA and the modified New York criteria for AS. Visits were routinely scheduled at 0, 3, 6, 12, 24 and 36 months. Study dropout was defined as ceasing anti-TNF therapy, whithout starting another anti-TNF agent within three months. Baseline differences between the nr-axSpA and AS patients were studied by χ2 and Mann-Whitney U-test, while differences in the three year development of VAS global, VAS pain, EQ-5D, doctorsevaluation of disease activity (on a 5-grade Likert scale), CRP and ESR were assessed by repeated ANOVA (including all timepoints), adjusting for sex, age, disease duration and the presence of peripheral arthritis. Last observation carried forward was applied from study dropout and to impute missing data. For EQ-5D, due to a higher proportion of missing data (37%), lacking values at 0 and 3 months were first imputed by linear regression. Analyses restricted to observed data were also conducted. Results More men were identified in the AS group (nr-axSpA/AS: 62/76%; p=0.009), and significant (p<0.05) baseline differences were also seen in age (nr-axSpA/AS mean [SD]: 38 [13]/43 [12] years), self reported disease duration (9.1 [8.9]/16 [12] years), doctors evaluation of disease activity (1.7 [0.7]/2.0 [0.7]), CRP (8.9 [12]/23 [26] mg/l) and ESR (22 [21]/28 [23] mm/h). Study dropout was similar in both groups (nr-axSpA/AS: 27/23%; Log rank test p=0.355). From 0 to 36 months, no significant between-group differences were seen in the development of VAS global, VAS pain, EQ-5D or doctors evaluation of disease activity, regardless of analysing observed or imputed data. The pattern of CRP levels differed by both methods (observed/imputed p=0.034/0.001), while there was a discrepancy in the results regarding ESR (p=0.109/0.031; curves visually similar to those presented for CRP). Conclusions Despite baseline variables indicating a more severe and longstanding disease in the AS group, patient reported outcomes and doctors evaluation of disease activitiy developed similarly between the nr-axSpA and AS patients following the start of anti-TNF treatment and during three years of follow up. The overall CRP level was higher in the AS group, with the greatest difference seen at treatment initiation. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1838

AB0279 A Dynamic of the Multi-Biomarker Disease Activity Score in Methotrexate Incomplete Responders is Predictive for Clinical Response to Non-Biological or Biological Therapy in Early RA

Background In our previous study (1) from the Swedish Farmacotherapy (SWEFOT) trial (2), we showed that a change of multi-biomarker disease activity (ΔMBDA) score (3) in methotrexate incomplete responders (MTX-IR) was predictive for subsequent response to non-biological triple therapy (TT; a combination of MTX with sulfasalazine and hydroxychloroquine) or to anti-tumour necrosis factor (anti-TNF) therapy. Objectives To evaluate further how ΔMBDA score could be used to predict optimal choice of second-line treatment, by investigating different cut-offs and by comparing this to using the C-reactive protein (CRP) for prediction. Methods 157 MTX-IR patients from the SWEFOT trial with complete data were grouped into those with and without big ΔMBDA (big decrease >22 and non-big decrease ≤22 respectively from baseline to Month 3) based on highest quartile. The change of CRP (ΔCRP) was studied in parallel using a cut-off based on the highest quartile (>28 & ≤28). Analysis was done by last observation carried forward. The proportion of clinical responders (DAS28 ≤3.2) across ΔMBDA groups between the two therapy arms was assessed by Breslow-Day test. Results Among patients with ΔMBDA>22, 76% responded to TT and 47% to anti-TNF, while among the others more responded to anti-TNF (55% vs 38%; cross-comparison for all 4 groups p=0.016; figure 1). When based on ΔCRP responses were 50% and 39% versus 45% and 56% (p=0.226). Conclusions In MTX-IR patients, an improvement in the MBDA scores by >22 predicts better response to subsequent Triple Therapy, and lack thereof predicts a better response to anti-TNF. The same analyses using CRP did not reveal similar results. Thus, monitoring patients during MTX treatment using the MBDA score may guide optimal therapy choice in MTX-IRs on the individual patient level. References Hambardzumyan K, Bolce R, Saevarsdottir S, et al. FRI0005 In Early RA Patients with Non-Response to Methotrexate Monotherapy the Change in Multi-Biomarker Disease Activity Score is Differentially Associated with Subsequent Response to Non-Biological versus Biological Therapy. Annals of the rheumatic diseases. 2014 June 1, 2014;73(Suppl 2):382-3. van Vollenhoven RF, Geborek P, Forslind K, et al. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial. Lancet. 2012 May 5;379(9827):1712-20. PubMed PMID: 22464340. Centola M, Cavet G, Shen Y, et al. Development of a multi-biomarker disease activity test for rheumatoid arthritis. PloS one. 2013;8(4):e60635. PubMed PMID: 23585841. Pubmed Central PMCID: 3621826. Disclosure of Interest K. Hambardzumyan: None declared, R. Bolce Shareholder of: Myriad Genetics Inc., Employee of: Crescendo Bioscience, a wholly owned subsidiary of Myriad Genetics, Inc., S. Saevarsdottir: None declared, K. Forslind: None declared, J. Karlsson: None declared, E. Sasso Shareholder of: Myriad Genetics Inc., Employee of: Crescendo Bioscience, a wholly owned subsidiary of Myriad Genetics, Inc., D. Chernoff Consultant for: Crescendo Bioscience, a wholly owned subsidiary of Myriad Genetics, Inc., C. C. Hwang Shareholder of: Myriad Genetics Inc., Employee of: Crescendo Bioscience, a wholly owned subsidiary of Myriad Genetics, Inc., R. van Vollenhoven Grant/research support from: Abb Vie, BMS, GSK, Pfizer, Roch, UCB, Consultant for: Abb Vie, Biotest, BMS, Crescendo Bioscience, GSK, Janssen, Lilly, Merck, Pfizer, Roch, UCB, Vertex

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