Tanja Schjødt Jørgensen

Association of Exercise Therapy and Reduction of Pain Sensitivity in Patients With Knee Osteoarthritis: A Randomized Controlled Trial

Exercise has beneficial effects on pain in knee osteoarthritis (OA), yet the underlying mechanisms are unclear. The purpose of this study was to investigate the effects of exercise on pressure–pain sensitivity in patients with knee OA.

Association of exercise therapy and reduction of pain sensitivity in patients with knee osteoarthritis

Exercise has beneficial effects on pain in knee osteoarthritis (OA), yet the underlying mechanisms are unclear. The purpose of this study was to investigate the effects of exercise on pressure–pain sensitivity in patients with knee OA.

Effectiveness and drug adherence of biologic monotherapy in routine care of patients with rheumatoid arthritis: a cohort study of patients registered in the Danish biologics registry

OBJECTIVES To estimate the prevalence of Danish RA patients currently on biologic monotherapy and compare the effectiveness and drug adherence of biologic therapies applied as monotherapy. METHODS All RA patients registered in the Danish biologics database (DANBIO) as receiving biologic DMARD (bDMARD) treatment as monotherapy without concomitant conventional synthetic DMARDs (csDMARDs) during the study period 1 May, 2011 through 30 April 2013 were eligible for inclusion. All patient files were checked to ensure that they were in accordance with the treatment registration in DANBIO. Descriptive statistics for prevalence, effectiveness and drug adherence of bDMARD monotherapy were calculated. RESULTS Of the 775 patients on bDMARD monotherapy, adalimumab (21.3%), etanercept (36.6%) and tocilizumab (15.3%) were the most prevalent biologic agents administered. At the 6-month follow-up, the overall crude clinical disease activity index remission rate in patients still on a biologic drug was 22%, the 28-joint DAS remission rate was 41% and the response rate of those with a 50% improvement in ACR criteria was 28%. At the 6-month follow-up, the drug adherence rates were similar for the different bDMARDs, with the exception of infliximab, which had significantly poorer drug adherence (P < 0.001). The overall drug adherence (except for infliximab) was approximately 70% after 2 years. CONCLUSION Nearly one in five (19%) biologic treatments for RA was prescribed in Denmark as monotherapy, of which 70% were on monotherapy from bio-initiation and 30% were on monotherapy after cessation of a concomitant csDMARD. Acceptable drug adherence and remission rates were achieved with bDMARDs. With the exception of infliximab, no statistically significant differences were observed between anti-TNFs and biologics with other modes of action.

Altered Visual and Feet Proprioceptive Feedbacks during Quiet Standing Increase Postural Sway in Patients with Severe Knee Osteoarthritis

Objective The objective was to investigate how postural control in knee osteoarthritis (KOA) patients, with different structural severities and pain levels, is reorganized under different sensory conditions. Methods Forty-two obese patients (BMI range from 30.1 to 48.7 kg*m−2, age range from 50 to 74 years) with KOA were evaluated. One minute of quiet standing was assessed on a force platform during 4 different sensory conditions, applied 3 times at random: Eyes open (EO) and eyes closed (EC) standing on firm and soft (foam) surfaces (EO-soft and EC-soft). Centre of pressure (Cop) standard deviation, speed, range and Cop mean position in both directions (anterior-posterior and medial-lateral) were extracted from the force platform data. Structural disease severity was assessed from semiflexed standing radiographs and graded by the Kellgren and Lawrence (KL) score. Pain intensity immediately before the measurements was assessed by numeric rating scale (range: 0–10). Results The patients were divided into “less severe” (KL 1 and 2, n = 24) and “severe” (KL>2, n = 18) group. The CoP range in the medial-lateral direction was larger in the severe group when compared with the less severe group during EC-soft condition (P<0.01). Positive correlation between pain intensity and postural sway (range in medial-lateral direction) was found during EC condition, indicating that the higher the pain intensity, the less effective is the postural control applied to restore an equilibrium position while standing without visual information. Conclusion The results support that: (i) the postural reorganization under manipulation of the different sensory information is worse in obese KOA patients with severe degeneration and/or high pain intensity when compared with less impaired patients, and (ii) higher pain intensity is related to worse body balance in obese KOA patients.

Risk of serious adverse effects of biological and targeted drugs in patients with rheumatoid arthritis: a systematic review meta-analysis

Objectives. To determine possible differences in serious adverse effects among the 10 currently approved biological and targeted synthetic DMARDs (b/ts-DMARDs) for RA. Methods. Systematic review in bibliographic databases, trial registries and websites of regulatory agencies identified randomized trials of approved b/ts-DMARDs for RA. Network meta-analyses using mixed-effects Poisson regression models were conducted to calculate rate ratios for serious adverse events (SAEs) and deaths between each of the 10 drugs and control (i.e. no b/ts-DMARD treatment), based on subjects experiencing an event in relation to person-years. Confidence in the estimates was assessed by applying the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE). Results. A total of 117 trials (47 615 patients) were included. SAEs were more common with certolizumab compared with abatacept (rate ratio = 1.58, 95% CI: 1.18, 2.14), adalimumab (1.36, 95% CI: 1.02, 1.81), etanercept (1.60, 95% CI: 1.18, 2.17), golimumab (1.45, 95% CI: 1.00, 2.08), rituximab (1.63, 95% CI: 1.16, 2.30), tofacitinib (1.44, 95% CI: 1.03, 2.02) and control (1.45, 95% CI: 1.13, 1.87); and tocilizumab compared with abatacept (1.30, 95% CI: 1.03, 1.65), etanercept (1.31, 95% CI: 1.04, 1.67) and rituximab (1.34, 95% CI: 1.01, 1.78). No other comparisons were statistically significant. Accounting for study duration confirmed our findings for up to 6 months’ treatment but not for longer-term treatment (6–24 months). No differences in mortality between b/ts-DMARDs and control were found. Based on the GRADE approach, confidence in the estimates was low due to lack of head-to-head comparison trials and imprecision in indirect estimates. Conclusion. Despite low confidence in the estimates, our analysis found potential differences in rates of SAEs. Our data suggest caution should be taken when deciding among available drugs. Systematic review registration number. PROSPERO CRD42014014842.

Societal costs and patients' experience of health inequities before and after diagnosis of psoriatic arthritis: a Danish cohort study

Objectives To comprehensively study the comorbidities, healthcare and public transfer (allowance) costs in patients with psoriatic arthritis (PsA) before and after diagnosis. Methods Nationwide cohort study, using data from Danish registries from January 1998 through December 2014. A total of 10 525 patients with PsA and 20 777 matched general population comparator (GPC) subjects were included. Societal costs, employment status and occurrence of comorbidities in patients with PsA both before and after diagnosis were compared with GPC subjects. Results At baseline, patients with PsA had significantly more comorbidities, including cardiovascular disease (OR 1.70 95% CI 1.55 to 1.86), respiratory diseases (OR 1.73 95% CI 1.54 to 1.96) and infectious diseases (OR 2.03 95% CI 1.69 to 2.42) compared with GPC subjects. At all time points, patients with PsA had higher total healthcare and public transfer costs; they also had lower income (p<0.001) and incurred a net average increased societal cost of €10 641 per patient-year compared with GPC subjects following diagnosis. The relative risk (RR) for being on disability pension 5 years prior to PsA diagnosis was 1.36 (95% CI 1.24 to 1.49) compared with GPC subjects. The RR increased to 1.60 (95% CI 1.49 to 1.72) at the time of diagnosis and was 2.69 (95% CI 2.40 to 3.02) 10 years after diagnosis, where 21.8% of the patients with PsA received disability pension. Conclusions Our findings are suggestive of health inequity for patients with PsA and call for individual preventive measures and societal action.

EQ-5D utility, response and drug survival in rheumatoid arthritis patients on biologic monotherapy: A prospective observational study of patients registered in the south Swedish SSATG registry

Objectives Biologic agents have dramatically changed treatment of rheumatoid arthritis (RA). To date only scarce head-to-head data exist especially when the biological therapies are given as monotherapy without concomitant disease modifying drugs (DMARDs). Thus the objective of the current study is to evaluate treatment response of all available biological therapies with special focus on utility (EQ-5D-3L) and drug survival of biologic DMARDs (bDMARDs) prescribed as monotherapy in RA patients in southern Sweden. Materials and methods All RA patients registered in a regional database as initiating bDMARD as monotherapy, i.e. without concomitant conventional synthetic DMARDs (csDMARDs), from 1st of January 2006 through 31st of December 2012, were included. Patients were followed from initiation of the first dose of bDMARD monotherapy treatment until withdrawal from treatment, loss of follow-up or 31st of December 2012. Descriptive statistics for utility (EQ-5D-3L), effectiveness, and drug survival of bDMARD monotherapy were calculated. Results During the study period, a total of 554 patients were registered in SSATG as initiating bDMARD monotherapy. Most of the patients were women (81%), with a mean age of 57 years. The average disease duration was more than 12 years, and on average the patients had previously been treated with approximately four different csDMARDs. Fifty-five percent of the patients were initiating their first bDMARD, 26% their second, and 19% their third or more. At baseline the average EQ-5D-3L was 0.34. Most patients had moderate to high disease activity, with a mean DAS28 of 5.0, and were substantially disabled, with an average HAQ score of 1.4. At 6 months´ follow-up, the EQ-5D-3L in patients still on the biologic drug had increased by mean 0.23 (SD 0.4) with no differences between type of bDMARD (p = 0.49). The mean change in EQ-5D-3L ranged from 0.11 (rituximab and infliximab) to 0.42 (tocilizumab). Although the changes were numerically different, no distinct pattern favored any particular bDMARD for EQ-5D-3L (p = 0.49) or other clinical outcomes. Overall, DAS28 defined remission and low disease activity were achieved in 20% and 43% of patients, respectively. Drug survival rates were statistically significantly different between bDMARDs (p = 0.01), with the highest rates observed for rituximab, followed by etanercept. After failing first course of anti-TNF, patients switching to another mode of action had significantly higher drug survival than those switching to a second course of anti-TNF therapy (p = 0.02). Conclusions Utility (EQ-5D-3L) increased after 6 months of all bDMARD treatments in monotherapy, indicating improvement of patients’ quality of life. After failure of anti-TNF treatment in monotherapy, switching to another mode of action may be associated with better drug survival than starting a second TNF-inhibitor.

Work Disability in Newly Diagnosed Patients with Primary Sjögren Syndrome

Objective. To study longterm work disability and possible predictors in newly diagnosed patients with primary Sjögren syndrome (pSS). Methods. Because we wanted to include only patients with full work availability potential, eligible patients were aged 18–62 years. Fifty-one patients (mean age 46 yrs, range 18–61 yrs, 50 women) diagnosed with pSS between January 2001 and December 2012 were included in the study. For each patient we randomly selected 4 reference subjects from the general population and matched for age, sex, and area of residence. We linked data to the Swedish Social Insurance Agency and calculated the proportion as well as net days of work disability in 30-day intervals from 12 months before pSS diagnosis until 24 months after . Results. Work disability was increased in patients with pSS in comparison to general population comparators. At diagnosis, 26% of patients were work-disabled, while 37% and 41% were disabled at 12 and 24 months after diagnosis, respectively (p < 0.05 and p < 0.05 vs baseline). Prior work disability status at diagnosis (OR 15.4, 95% CI 2.9–81.9; p = 0.001), concomitant fibromyalgia (OR 10.5, 95% CI 2.0–56.0; p = 0.006), and each additional year of age (OR 1.1, 95% CI 1.0–1.2; p = 0.009) were found to be associated with work disability 24 months after diagnosis. Conclusion. Patients with pSS showed an increased work disability, in comparison with the general population, which increased significantly during the first 2 years after diagnosis. Work disability at diagnosis, concomitant fibromyalgia, and increasing age, but not anti-SSA/anti-SSB antibodies or disease activity, were associated with longterm work disability.

The dynamics of the pain system is intact in patients with knee osteoarthritis: An exploratory experimental study

Abstract Background and aims Despite the high prevalence of knee osteoarthritis (OA) it remains one of the most frequent knee disorders without a cure. Pain and disability are prominent clinical features of knee OA. Knee OA pain is typically localized but can also be referred to the thigh or lower leg. Widespread hyperalgesia has been found in knee OA patients. In addition, patients with hyperalgesia in the OA knee joint show increased pain summation scores upon repetitive stimulation of the OA knee suggesting the involvement of facilitated central mechanisms in knee OA. The dynamics of the pain system (i.e., the adaptive responses to pain) has been widely studied, but mainly from experiments on healthy subjects, whereas less is known about the dynamics of the pain system in chronic pain patients, where the pain system has been activated for a long time. The aim of this study was to assess the dynamics of the nociceptive system quantitatively in knee osteoarthritis (OA) patients before and after induction of experimental knee pain. Methods Ten knee osteoarthritis (OA) patients participated in this randomized crossover trial. Each subject was tested on two days separated by 1 week. The most affected knee was exposed to experimental pain or control, in a randomized sequence, by injection of hypertonic saline into the infrapatellar fat pad and a control injection of isotonic saline. Pain areas were assessed by drawings on anatomical maps. Pressure pain thresholds (PPT) at the knee, thigh, lower leg, and arm were assessed before, during, and after the experimental pain and control conditions. Likewise, temporal summation of pressure pain on the knee, thigh and lower leg muscles was assessed. Results Experimental knee pain decreased the PPTs at the knee (P <0.01) and facilitated the temporal summation on the knee and adjacent muscles (P < 0.05). No significant difference was found at the control site (the contralateral arm) (P =0.77). Further, the experimental knee pain revealed overall higher VAS scores (facilitated temporal summation of pain) at the knee (P < 0.003) and adjacent muscles (P < 0.0001) compared with the control condition. The experimental knee pain areas were larger compared with the OA knee pain areas before the injection. Conclusions Acute experimental knee pain induced in patients with knee OA caused hyperalgesia and facilitated temporal summation of pain at the knee and surrounding muscles, illustrating that the pain system in individuals with knee OA can be affected even after many years of nociceptive input. This study indicates that the adaptability in the pain system is intact in patients with knee OA, which opens for opportunities to prevent development of centralized pain syndromes.

THU0126 Added-Value of Combining Methotrexate with a Biological Agent Compared to Biological Monotherapy in Patients with Rheumatoid Arthritis: A Systematic Review and Meta-Analysis of Randomised Trials

Background Methotrexate (MTX) is considered the anchor drug in rheumatoid arthritis (RA) treatment, based on efficacy, safety, and its ability to increase the efficacy of biologic agents when used in combination. Both the “American College of Rheumatology” (ACR) and the “European League Against Rheumatism” (EULAR) recommend the use of biologic agents with concomitant MTX in RA. However, analyses from health care claims suggest that the MTX prescribed in conjunction with a biologic disease-modifying antirheumatic drug (bDMARD), is not collected at the pharmacy by more than half of the patients. Despite claims from pivotal trial data, the empirical evidence supporting combination MTX plus bDMARD in terms of the actual benefit-harm has not been evaluated extensively. Objectives To review the evidence for benefit and harm associated with combining MTX with a biologic agent in RA patients. Methods A systematic review and meta-analysis of randomised controlled trials (RCTs) was performed to identify all trials relating treatment of RA with MTX in combination with bDMARD compared to a bDMARD in monotherapy. Random-effects models were applied for meta-analyses with risk ratio and 95% confidence intervals (RR, 95%CI) and inconsistency (I2, %) estimated using Review Manager. According to the protocol the major outcomes were ACR50 for benefit and withdrawals due to adverse events (AEs) for harm (PROSPERO: CRD42014014633). Results From the 4,405 identified references, 14 trials were eligible for inclusion in the meta-analysis. The overall likelihood of responding to therapy (ie, RR according to ACR50) was 1.36 [1.24 to 1.49] - with a low degree of inconsistency (28%) - in favour of concomitant use of MTX when treating with a biologic (P<0.001). There was no reason to suspect that added value of MTX varied with the choice of bDMARD (Test for subgroup differences P=0.38): abatacept 1.27 [0.97 to 1.67], adalimumab 1.42 [1.24 to 1.61], etanercept 1.44 [1.22 to 1.69], golimumab 1.60 [1.13 to 2.27], infliximab 3.54 [1.38 to 9.08], rituximab 1.31 [0.74 to 2.32], and tocilizumab 1.24 [1.03 to 1.51]. The overall estimate of discontinuing therapy due to AEs from concomitant use of MTX was 1.17 [0.94 to 1.44] (P=0.16) compared to bDMARD in monotherapy - corresponding to a possible 17% increased risk. Conclusions This systematic review and meta-analysis of RCTs provides empirical evidence about the clinical value of combining the prescribed bDMARD with the recommended concomitant use of MTX. Combination therapy increases the probability of achieving treatment success at the level of ACR50 by approximately 40% compared to patients using biologics in monotherapy. Although the precision around the estimate of concomitant MTX use does not rule out an increased risk of clinically important harms, these findings justify the recommendation that all patients prescribed biologics should be encouraged to continue MTX therapy. Acknowledgements This study was supported by unrestricted grants from The Oak foundation, and AbbVie (Denmark). Disclosure of Interest T. S. Jørgensen Grant/research support from: has received research grants paid to institute: AbbVie and Roche, S. Tarp: None declared, D. E. Furst: None declared, A. Døssing: None declared, P. Taylor: None declared, H. Bliddal Grant/research support from: has received research grants paid to institute: AbbVie and Roche, R. Christensen Grant/research support from: has received research grants paid to institute: AbbVie and Roche