Objective. To determine the efficacy of fluoroscopically guided corticosteroid injection for hip osteoarthritis (OA) in a randomized, double-blind, placebocontrolled trial.Methods. Fifty-two patients with symptomatic hip OA were randomly allocated to receive placebo (10 mg bipuvicaine, 2 ml saline) (n ‫؍‬ 21) or corticosteroid treatment (10 mg bipuvicaine, 40 mg triamcinolone hexacetonide) (n ‫؍‬ 31). Patients were followed up for 1, 2, 3, and 6 months. The primary outcome measure was the pain improvement response, defined as a 20% decrease in the Western Ontario and McMaster Universities OA Index (WOMAC) pain score (on 5 100-mm visual analog scales [VAS]) (WOMAC20) from baseline to 2 months postinjection. Secondary outcomes were a 50% decrease in the WOMAC pain score (WOMAC50), changes in other WOMAC subscale scores, patient's global assessment of health (on a 100-mm VAS), and Short Form 36 (SF-36) quality of life indices. Analyses were based on the intent-to-treat principle.Results. The mean WOMAC pain score fell 49.2% (decreasing from 310.1 mm to 157.4 mm) at 2 months postinjection in patients receiving corticosteroid, compared with a decrease of 2.5% (from 314.3 mm to 306.5 mm) in the placebo group (P < 0.0001). The proportion of WOMAC20 responders at 2 months' followup was significantly higher in the corticosteroid group (67.7%) compared with the placebo group (23.8%) (P ‫؍‬ 0.004); similar proportions of WOMAC50 responders were observed between groups (61.3% in the corticosteroid group versus 14.3% in the placebo group; P ‫؍‬ 0.001). Response differences were maintained at 3 months' followup (58.1% responders in the corticosteroid group versus 9.5% responders in the placebo group; P ‫؍‬ 0.004). Significant differences in the WOMAC stiffness and physical function scores (P < 0.0001), patient's global health scores (P ‫؍‬ 0.005), and SF-36 physical component scores (P ‫؍‬ 0.04) were observed, with patients in the corticosteroid group showing greater improvements. There were no differences in the frequency of adverse events between groups.Conclusion. This placebo-controlled trial confirms that corticosteroid injection can be an effective treatment of pain in hip OA, with benefits lasting up to 3 months in many cases. Future studies should address questions related to the benefits of repeated steroid injection and the effects of this treatment on disease modification.Osteoarthritis (OA) affects all vertebrates, and the prevalence of the disease increases exponentially with age. Estimates of the prevalence of hip OA in humans range from 2% at age 35 years to 35% at age 85 years or older (1), and autopsies have shown that cartilage degeneration can be detected in patients as early as the second decade of life (2). A disease prevalence estimate of 3% among North Americans older than age 55 years has been commonly quoted, but this may well be an underestimate of the true burden of hip OA in the general population (3,4). The prevalence of the disease has significant fiscal implications, since it has

ObjectivesTo investigate whether following a treat-to-target (T2T)-strategy in daily clinical practice leads to more patients with rheumatoid arthritis (RA) meeting the remission target.MethodsRA patients from 10 countries starting/changing conventional synthetic or biological disease-modifying anti-rheumatic drugs were assessed for disease activity every 3 months for 2 years (RA BIODAM (BIOmarkers of joint DAMage) cohort). Per visit was decided whether a patient was treated according to a T2T-strategy with 44-joint disease activity score (DAS44) remission (DAS44 <1.6) as the target. Sustained T2T was defined as T2T followed in ≥2 consecutive visits. The main outcome was the achievement of DAS44 remission at the subsequent 3-month visit. Other outcomes were remission according to 28-joint disease activity score-erythrocyte sedimentation rate (DAS28-ESR), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI) and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean definitions. The association between T2T and remission was tested in generalised estimating equations models.ResultsIn total 4356 visits of 571 patients (mean (SD) age: 56 (13) years, 78% female) were included. Appropriate application of T2T was found in 59% of the visits. T2T (vs no T2T) did not yield a higher likelihood of DAS44 remission 3 months later (OR (95% CI): 1.03 (0.92 to 1.16)), but sustained T2T resulted in an increased likelihood of achieving DAS44 remission (OR: 1.19 (1.03 to 1.39)). Similar results were seen with DAS28-ESR remission. For more stringent definitions (CDAI, SDAI and ACR/EULAR Boolean remission), T2T was consistently positively associated with remission (OR range: 1.16 to 1.29), and sustained T2T had a more pronounced effect on remission (OR range: 1.49 to 1.52).ConclusionIn daily clinical practice, the correct application of a T2T-strategy (especially sustained T2T) in patients with RA leads to higher rates of remission.

Objective.Compelling evidence supports a treat-to-target (T2T) strategy for optimal outcomes in rheumatoid arthritis (RA). There is limited knowledge regarding the factors that impede implementation of T2T, particularly in a setting where adherence to T2T is protocol-specified. We aimed to assess clinical factors that associate with failure to adhere to T2T.Methods.Patients with RA from 10 countries who were starting or changing conventional synthetic disease-modifying antirheumatic drugs and/or starting tumor necrosis factor inhibitors were followed for 2 years. Participating physicians were required per protocol to adhere to the T2T strategy. Factors influencing adherence to T2T low disease activity (T2T-LDA; 44-joint count Disease Activity Score ≤ 2.4) were analyzed in 2 types of binomial generalized estimating equations models: (1) including only baseline features (baseline model); and (2) modeling variables that inherently vary over time as such (longitudinal model).Results.A total of 571 patients were recruited and 439 (76.9%) completed 2-year followup. Failure of adherence to T2T-LDA was noted in 1765 visits (40.5%). In the baseline multivariable model, a high number of comorbidities (OR 1.10, 95% CI 1.02–1.19), smoking (OR 1.32, 95% CI 1.08–1.63) and high number of tender joints (OR 1.03, 95% CI 1.02–1.04) were independently associated with failure to implement T2T, while anticitrullinated protein antibody/rheumatoid factor positivity (OR 0.63, 95% CI 0.50–0.80) was a significant facilitator of T2T. Results were similar in the longitudinal model.Conclusion.Lack of adherence to T2T in the RA BIODAM cohort was evident in a substantial proportion despite being a protocol requirement, and this could be predicted by clinical features. [Rheumatoid Arthritis (RA) BIODAM cohort; ClinicalTrials.gov: NCT01476956].

Cardizem SR and Bi-Tildiem were both approved in their respective countries on the basis of clinical trials demonstrating efficacy and safety in the treatment of angina pectoris. In this cross-over randomized study, we assessed whether these two sustained-release formulations of diltiazem have equivalent pharmacokinetic and pharmacodynamic profiles. Twenty-four young healthy male volunteers were hooked to Holters and ambulatory blood pressure monitors for 24 h to establish baseline systolic blood pressure (SBP), diastolic blood pressure (DBP), sinus rate and PR intervals. They then received a single dose of 120 mg of diltiazem from one formulation. The pharmacodynamic measurements were recorded for a further 24 h and blood samples were collected over 36 h for evaluation of diltiazem in plasma by a high-performance liquid chromatogrpahic (HPLC) method. The procedures were repeated with the alternate formulation after a 7 d wash-out. Pharmacokinetics showed statistically significant (p < 0.01) differences in AUC0-12 with means (+/- SD) of 519.2(+/- 172.8) and 429.6(+/- 147.2) ng h ml-1, AUC0-36 of 835.6(+/- 281.6) and 730.9 (+/- 271.5) ng h ml-1 and Cmax of 89.1(+/- 30.3) and 61.1(+/- 21.2) ng ml-1 for Cardizem SR and Bi-Tildiem, respectively. The only pharmacodynamic parameter showing a statistically significant difference in change from baseline between the two formulations was DBP with mean (+/- SD) change in AUC0-12 of -13.6(+/- 20.8) and +8.4(+/- 31.7) mm Hg h (p = 0.0135) and in AUC0-24 of -33.0(+/- 43.7) and -0.3(+/- 59.2) mm Hg h (p = 0.0463) for Cardizem SR and Bi-Tildiem, respectively. These findings suggest that assessment of efficacy of sustained-release formulations of diltiazem by bioequivalence could be misleading. They also confirm that a single dose of diltiazem does not elicit a significant pharmacodynamic response in healthy volunteers. Equivalence for such formulations should therefore be demonstrated by pharmacodynamic evaluation or clinical studies in a patient population.

BackgroundA Treat-to-Target approach (T2T), treating patients with RA towards a target, either remission or low disease activity (T2T-REM or T2T-LDA) is nowadays recommended. However it has never been assessed whether such a strategy in daily clinical practice really leads to more patients meeting that target.MethodsBIODAM is a 2-year prospective cohort including patients in daily practice with RA from 10 countries, who were started or changed on DMARD and/or anti-TNF treatment and were followed-up every 3 months. Participating physicians were required to practice T2T per protocol. Per visit was decided whether a patient was treated according to T2T or not. T2T-REM was considered met: i) if a patient had already a disease activity score below the target (DAS28-CRP<2.6); or ii) if treatment was intensified (by increasing dosage or adding drugs) upon a DAS28≥2.6. T2T-LDA was computed using the benchmark for low disease activity (LDA) (DAS28<3.2) (T2T-LDA). The main outcome was the presence or absence of ACR/EULAR-boolean remission 3 months after T2T-REM or T2T-LDA. Another outcome analysed was sustained remission (present >6 months). The relationship between T2T and ACR/EULAR Boolean remission 3 months later (or sustained remission) was investigated using generalized estimating equations with auto-regression.ResultsIn total 3084 visits of 539 patients (mean (SD) age: 56 (13) years, 76% female, disease duration 6 (8) years). In 68% of the visits, T2T-REM was applied (in 79% of the visits T2T-LDA was applied). ACR/EULAR-boolean remission was reached in 15% of the visits. Appropriate application of T2T-REM led to a 50% higher likelihood of ACR/EULAR-boolean remission 3 months later than not applying T2T-REM. Both T2T-REM and T2T-LDA strategies led to lower disease activity (with an exception of DAS28 remission or DAS28-LDA). Only 9% of the treatment intensifications followed upon a DAS28 between 2.6 and 3.2, and 79% of the intensifications were applied upon a DAS>3.2. Following T2T strategies led to higher achievement of sustained remission (table).ConclusionsA treat-to-target approach, even with a modest benchmark (DAS28 = 3.2), works and leads to a higher achievement of (sustained) ACR/EULAR-remission. Our study illustrates the importance of acting upon the data that is routinely collected in a clinical encounter. Rheumatologists should be encouraged to follow a treat-to-target approach in order to improve the outcome of their patients.Disclosure of InterestNone declared

Objective.The Outcome Measures in Rheumatology Soluble Biomarker Working Group initiated an international, multicenter, prospective study, the Rheumatoid Arthritis (RA) BIODAM cohort, to generate resources for the clinical validation of candidate biomarkers predictive of radiographic progression. This first report describes the cohort, clinical outcomes, and radiographic findings.Methods.Patients with RA from 38 sites in 10 countries starting or changing conventional synthetic disease-modifying antirheumatic drugs and/or starting tumor necrosis factor inhibitors were followed for 2 years. Participating physicians were required to adhere to a treat-to-target strategy. Biosamples (serum, urine) were acquired every 3 months, radiography of hands and feet every 6 months, and ultrasound of hands and feet every 3 months in a subset. Primary endpoint was radiographic progression by the Sharp/van der Heijde score.Results.A total of 571 patients were recruited and 439 (76.9%) completed 2-year followup. At baseline, the majority was female (76%), mean age 55.7 years, and mean disease duration 6.5 years. Patients had a mean of 8.4 swollen and 13.6 tender joints, 44-joint count Disease Activity Score (DAS44) 3.8, 77.7% rheumatoid factor–positive or anticitrullinated protein antibody–positive. Percentage of patients in DAS and American College of Rheumatology remission at 2 years was 52.2% and 27.1%, respectively. Percentage of patients with radiographic progression (> 0.5) at 1 and 2 years was 38.2% and 59.9%, respectively.Conclusion.The RA BIODAM prospective study succeeded in generating an extensive list of clinical, imaging (2343 radiographs), and biosample (4638 sera) resources that will be made available to expedite the identification and validation of biomarkers for radiographic damage endpoints. (Clinicaltrials.gov: NCT01476956, clinicaltrials.gov/ct2/show/NCT01476956)

Background:High-specificity biomarkers that can differentiate PsA and AS patients from healthy people, as well as RA patients, would be extremely helpful for early diagnosis and treatment of these two diseases. Based on the hypothesis that each disease state may cause specific changes to the metabolome, metabolomics is becoming a powerful tool for biomarker discovery. In this work, we applied a high-performance chemical isotope labeling (CIL) LC-MS platform to search for biomarker candidates of PsA and AS in human serum samples.Objectives:We aimed to identify metabolite biomarkers with high specificity for PsA and AS.Methods:Serum samples were collected from 331 subjects, including 100 healthy controls, 48 PsA patients, 52 AS patients and 131 RA patients. The average age of each group was: 52.6 (control), 50.7 (PsA), 51.8 (AS) and 53.1 (RA) years. After pre-treatment, each sample was incubated with12C-dansyl chloride, which can label the amine/phenol-containing metabolites. The reference sample for relative quantification was prepared by mixing all individual samples and then labeled by13C-dansyl chloride. With this normalization, the individual samples and the reference sample were mixed at an equal amount. Finally, we used an LC-QTOF-MS platform to analyze the mixtures and measure the12C/13C peak pairs.Results:We detected 1,149 peak pairs commonly existing in the serum samples. Using our dansyl-library of 700 dansyl-labeled standards and a prediction library, which contains the predicted retention times and mass values of 3,431 dansylated human metabolites, we identified 134 and 141 peak pairs, respectively. The relative concentrations are calculated from the intensity ratios of12C/13C peak pairs. We first visualized the entire amine/phenol-submetabolome for all phenotypes using the partial least squares discriminant analysis (PLS-DA). We found that the most significant between-group separation was between healthy controls and all the patients. No significant sex or age effect was observed. Furthermore, among the three diseases, PsA and AS samples were closely clustering, while the RA group was well separated from them. Therefore, we chose a two-step diagnosis approach that first differentiates PsA patients from controls/RA patients and then filters out the AS patients wrongly classified as PsA in the first step. The same strategy was conducted for AS. Stipulating a fold change larger than 1.5 with the false discovery rate lower than 5%, we found 74 metabolites having significantly higher or lower concentrations in the PsA group compared to the control or the RA group. We selected two of these significant metabolites to build a classification model based on the linear support vector machine (SVM) method, and the area-under-the-curve (AUC) value of the resulting receiver operating characteristic (ROC) curve was 0.929 (95% confidence interval: 0.899-0.956). Similarly, 37 metabolites could differentiate AS samples from RAs and controls. A proposed diagnostic panel containing four metabolites demonstrated an AUC value of 0.890 (0.843-0.934). For the last step, distinguishing between PsA and AS, there were 15 significantly increased metabolites and 9 lowered ones. The biomarker panel consisting of the top three metabolites also achieved good discriminatory power with AUC = 0.827 (0.717-0.919).Conclusion:Isotope-labeling-LC-MS-based metabolomics has revealed biomarker candidates that can specifically differentiate PsA or AS patients from control populations.Disclosure of Interests:Wei Han: None declared, Xiaohang Wang: None declared, Liang Li: None declared, Stephanie Wichuk: None declared, Edna Hutchings: None declared, Rana Dadashova: None declared, Joel Paschke: None declared, Walter P Maksymowych Grant/research support from: Received research and/or educational grants from Abbvie, Novartis, Pfizer, UCB, Consultant of: WPM is Chief Medical Officer of CARE Arthritis Limited, has received consultant/participated in advisory boards for Abbvie, Boehringer, Celgene, Eli-Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, UCB, Speakers bureau: Received speaker fees from Abbvie, Janssen, Novartis, Pfizer, UCB.

BackgroundWhile, a Treat-to-Target strategy (T2T), treating patients with rheumatoid arthritis (RA) towards a certain target (eg. clinical remission; T2T-REM), is highly recommended, several patients in clinical remission often have residual synovitis on ultrasound-imaging (US). This may result in silent radiographic progression and clinical flare. It is arguable whether targeting US-synovitis may result in “deeper” remission in clinical practice.ObjectivesTo assess whether using US in a T2T strategy leads to more patients meeting clinical remission than using only clinical information.MethodsPatients with RA who started or changed csDMARD and/or anti-TNF treatment followed in centers with expertise in US and participating in BIODAM (2-year multicenter prospective observational cohort) were included. Clinical and US data [by the US7-score that includes 7 joints of the clinically dominant hand and foot for synovitis and tenosynovitis on gray-scale US (GSUS) and power-doppler US (PDUS) and erosions on GSUS] were collected every 3 months. Per visit was decided whether the patient was treated according to the clinical definition of T2T with remission as benchmark (T2T-CLIN-REM). Though not mandatory, US-data could also be used for this purpose. T2T-CLIN-REM was considered correctly applied if: either i) a patient already had a disease activity score below the remission target (i.e. ACR/EULAR boolean remission) or ii) if not, treatment was intensified. A T2T strategy taking also US data into account (T2T-CLIN-US-REM) was considered correctly applied if: either i) both clinical and US remission (all joints included in the US7-score with GSUS synovitis <2 and PDUS synovitis=0) were present; or ii) if not, the treatment was intensified. The main outcome was ACR/EULAR boolean remission. The effect of adding US to T2T (T2T-CLIN-US-REM) on clinical remission 3 months later compared to a clinical remission benchmark only (T2T-CLIN-REM) was analyzed using generalized estimating equations with auto-regression.ResultsIn total 963 visits of 130 patients were included. T2T-CLIN-US-REM was correctly followed in 33% of the visits, T2T-CLIN-REM in 14%, and any of these in 52%. Remission according to the ACR/EULAR-boolean definition was achieved in 19.6% of the visits. Compared to the conventional T2T-CLIN-REM strategy, using a combined clinical and US benchmark for T2T led to a lower – instead of higher - likelihood of ACR/EULAR-boolean remission 3 months later [OR (95% CI): 0.39 (0.24; 0.63] (table).ConclusionsOur results, from a non-randomized study, did not suggest an advantage of using US of 7 joints in addition to clinical examination as a T2T benchmark as compared to clinical examination alone in getting RA patients into clinical remission.Disclosure of InterestNone declared