OBJECTIVE: To explore effects of weight loss and maintenance on serum cartilage biomarkers denaturation neoepitope for Collagen2 (Coll2-1) and Fibulin3 fragment (Fib3-2), as well as correlations between Coll2-1 and Fib3-2 and symptomatic improvement, in a knee osteoarthritis (KOA) population.

DESIGN: 192 obese KOA patients followed a 16 week weight loss intervention and 52 weeks weight maintenance (ClinicalTrials.gov identifier: NCT00655941). Assessments were at 0, 8, 16 and 68 weeks. Serum Coll2-1 and Fib3-2 were determined with ELISA, and symptoms by the Knee Osteoarthritis Outcome Score (KOOS) questionnaire. Changes from week 0 and association between changes from baseline in body weight and Coll2-1, Fib3-2, and the 5 KOOS domains were assessed at all time points.

RESULTS: Coll2-1 changes from baseline showed a decrease at week 8 (P = 0.0002), no change at week 16 (P = 0.49), and an increase at week 68 (P = 0.036). Fib3-2 showed an increase from baseline at week 8 (P = 0.0015) and 16 (P < 0.0001), but none at week 68 (P = 0.23). No statistically significant correlations were found between changes in body weight and Coll2-1 and Fib3-2 at any time point (r < 0.05; P > 0.49). At all time-points there were significant positive correlations between changes from baseline in Coll2-1 and in KOOSSports/Recreation (week 8, 16, 68: r = 0.17; P = 0.03; r = 0.16; P = 0.04; and r = 0.17; P = 0.04, respectively).

CONCLUSION: The clinical improvement after a substantial weight loss and weight maintenance in KOA patients was not associated with decrease in markers of cartilage breakdown Coll2-1 or Fib3-2, even with indications of a slightly negative effect.

INTRODUCTION: Computerized pneumatic cuff pressure algometry (CPA) using the DoloCuff is a new method for pain assessment. Intra- and inter-rater reliabilities have not yet been established. Our aim was to examine the inter- and intrarater reliabilities of DoloCuff measures in healthy subjects.

METHODS: Twenty healthy subjects (ages 20 to 29 years) were assessed three times at 24-hour intervals by two trained raters. Inter-rater reliability was established based on the first and second assessments, whereas intrarater reliability was based on the second and third assessments. Subjects were randomized 1:1 to first assessment at either rater 1 or rater 2. The variables of interest were pressure pain threshold (PT), pressure pain tolerance (PTol), and temporal summation index (TSI). Reliability was estimated by a two-way mixed intraclass correlation coefficient (ICC) absolute agreement analysis. Reliability was considered excellent if ICC > 0.75, fair to good if 0.4 < ICC < 0.75, and poor if ICC < 0.4. Bias and random errors between raters and assessments were evaluated using 95% confidence interval (CI) and Bland-Altman plots.

RESULTS: Inter-rater reliability for PT, PTol, and TSI was 0.88 (95% CI: 0.69 to 0.95), 0.86 (95% CI: 0.65 to 0.95), and 0.81 (95% CI: 0.42 to 0.94), respectively. The intrarater reliability for PT, PTol, and TSI was 0.81 (95% CI: 0.53 to 0.92), 0.89 (95% CI: 0.74 to 0.96), and 0.75 (95% CI: 0.28 to 0.91), respectively.

CONCLUSION: Inter-rater reliability was excellent for PT, PTol, and TSI. Similarly, the intrarater reliability for PT and PTol was excellent, while borderline excellent/good for TSI. Therefore, the DoloCuff can be used to obtain reliable measures of pressure pain parameters in healthy subjects.

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.

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.

BACKGROUND: Lymphomas comprise a heterogeneous group of malignant diseases with highly variable prognosis. Rheumatoid arthritis (RA) is associated with a twofold increased risk of both Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). It is unknown whether treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) affect the risk of specific lymphoma subtypes.

METHODS: Patients never exposed to (bionaïve) or ever treated with bDMARDs from 12 European biologic registers were followed prospectively for the occurrence of first ever histologically confirmed lymphoma. Patients were considered exposed to a bDMARD after having received the first dose. Lymphomas were attributed to the most recently received bDMARD.

RESULTS: Among 124 997 patients (mean age 59 years; 73.7% female), 533 lymphomas were reported. Of these, 9.5% were HL, 83.8% B-cell NHL and 6.8% T-cell NHL. No cases of hepatosplenic T-cell lymphoma were observed. Diffuse large B-cell lymphoma (DLBCL) was the most frequent B-cell NHL subtype (55.8% of all B-cell NHLs). The subtype distributions were similar between bionaïve patients and those treated with tumour necrosis factor inhibitors (TNFi). For other bDMARDs, the numbers of cases were too small to draw any conclusions. Patients with RA developed more DLBCLs and less chronic lymphocytic leukaemia compared with the general population.

CONCLUSION: This large collaborative analysis of European registries has successfully collated subtype information on 533 lymphomas. While the subtype distribution differs between RA and the general population, there was no evidence of any modification of the distribution of lymphoma subtypes in patients with RA treated with TNFi compared with bionaïve patients.

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.

OBJECTIVE: To investigate the effect of a neuro-muscular exercise (NEMEX) therapy program compared with instructions in optimized analgesics and anti-inflammatory drug use (PHARMA), on measures of knee-joint load in people with mild to moderate knee osteoarthritis (OA). We hypothesized that knee joint loading during walking would be reduced by NEMEX and potentially increased by PHARMA.

DESIGN: Single-blind, randomized controlled trial (RCT) comparing NEMEX therapy twice a week with PHARMA. Participants with mild-to-moderate medial tibiofemoral knee OA were randomly allocated (1:1) to one of two 8-week treatments. Primary outcome was change in knee load during walking (Knee Index, a composite score from all three planes based on 3D movement analysis) after 8 weeks of intervention. Secondary outcomes were frontal plane peak knee adduction moment (KAM), Knee Injury and Osteoarthritis Outcome Scores (KOOS) and functional performance tests.

RESULTS: Ninety three participants (57% women, 58 ± 8 years with a body mass index [BMI] of 27 ± 4 kg/m(2) (mean ± standard deviation [SD])) were randomized to NEMEX group (n = 47) or PHARMA (n = 46); data from 44 (94%) and 41 (89%) participants respectively, were available at follow-up. 49% of the participants in NEMEX and only 7% in PHARMA demonstrated good compliance. We found no difference in the primary outcome as evaluated by the Knee Index -0.07 [-0.17; 0.04] Nm/%BW HT. Secondary outcomes largely supported this finding.

CONCLUSIONS: We found no difference in the primary outcome; knee joint load change during walking from a NEMEX program vs information on the recommended use of analgesics and anti-inflammatory drugs. ClinicalTrials.gov Identifier: NCT01638962 (July 3, 2012). Ethical Committee: S-20110153.