The dynamics of response as measured by multiple composite outcome tools in the TIght COntrol of inflammation in early Psoriatic Arthritis (TICOPA) trial

Background: We aimed to evaluate the dynamics of treatment response with different composite measures in the TIght COntrol of inflammation in early Psoriatic Arthritis (TICOPA) trial. Methods: Participants with early disease-modifying antirheumatic drug-naïve psoriatic arthritis (PsA) were randomised 1:1 to either tight control (TC; 4 weekly review with therapy escalation if criteria not met) or standard care (SC; 12 weekly review). We calculated modified versions of the Psoriatic ArthritiS Disease Activity Score (PASDAS), Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) Composite scorE (GRACE) and Composite Psoriatic Disease Activity Index (CPDAI) at baseline and 12 weekly to 48 weeks by blinded assessor. For missing data, we used the last observation carried forward. Comparison between groups was made by analysis of covariance and comparison of area under the curve (AUC). Results: 206 people were randomised to TC (n=101) or SC (n=105). Significant differences between treatment groups were seen (p<0.0001 for all composite measures). AUC analysis demonstrated a significant difference between groups for the PASDAS but not GRACE and CPDAI. For participants with oligoarthritis, a significant difference between groups was seen for each measure, although the significance levels were greatly diminished (PASDAS, p=0.04; GRACE p=0.01; CPDAI p=0.04). For oligoarthritis using AUC analysis, none of the measures could distinguish between groups. Conclusions: Composite measures of disease activity were able to distinguish between TICOPA treatment arms, although differences were diminished for those with oligoarthritis. Further data are needed to inform the preferred composite measure for use as the primary outcome in PsA trials

A Home Exercise Programme Is No More Beneficial than Advice and Education for People with Neurogenic Claudication: Results from a Randomised Controlled Trial

Objective: To compare the effectiveness of a physiotherapy programme with a control treatment of advice and education in patients with neurogenic claudication symptoms. Design: Pragmatic randomised controlled clinical trial. Setting: Primary care-based musculoskeletal service. Patients: Adults aged 50 or over with neurogenic claudication symptoms causing limitation of walking. Interventions: Condition-specific home exercises combined with advice and education, or advice and education alone. Main outcome measures: The primary outcome was the difference in improvement of symptom severity scores on the Swiss Spinal Stenosis Scale at eight weeks. Secondary outcomes included measures of physical function, pain and general well-being at eight weeks and 12 months. Results: There was no significant difference between groups in the Swiss Spinal Stenosis symptom severity scale at eight weeks (t = 0.47, p = 0.643): mean change (SD) control group -0.18 (0.47), treatment group -0.10 (0.66), difference (95% CI) 0.08 (-0.19, 0.35); baseline-adjusted difference 0.06 (-0.19, 0.31)]. An unplanned subgroup analysis suggested that for patients with the top 25% of baseline symptom severity scores, the physiotherapy exercise programme resulted in an improvement in the primary outcome, and modest but consistently better secondary outcomes at both time-points compared to the control group. The effectiveness in different subgroups requires further direct evaluation. Conclusions: In the treatment of patients with neurogenic claudication symptoms, a physiotherapist-prescribed home exercise programme is no more effective than advice and education

The effect of targeted treatment on people with patellofemoral pain: A pragmatic, randomised controlled feasibility study

Background: Targeted treatment, matched according to specific clinical criteria e.g. hip muscle weakness, may result in better outcomes for people with patellofemoral pain (PFP). However, to ensure the success of future trials, a number of questions on the feasibility of a targeted treatment need clarification. The aim of the study was to explore the feasibility of matched treatment (MT) compared to usual care (UC) management for a subgroup of people with PFP determined to have hip weakness and to explore the mechanism of effect for hip strengthening. Methods: In a pragmatic, randomised controlled feasibility study, 24 participants with PFP (58% female; mean age 29 years) were randomly allocated to receive either MT aimed specifically at hip strengthening, or UC over an eight-week period. The primary outcomes were feasibility outcomes, which included rates of adherence, attrition, eligibility, missing data and treatment efficacy. Secondary outcomes focused on the mechanistic outcomes of the intervention, which included hip kinematics. Results: Conversion to consent (100%), missing data (0%), attrition rate (8%) and adherence to both treatment and appointments ( > 90%) were deemed successful endpoints. The analysis of treatment efficacy showed that the MT group reported a greater improvement for the Global Rating of Change Scale (62% vs. 9%) and the Anterior Knee Pain Scale (-5.23 vs. 1.18) but no between-group differences for either average or worst pain. Mechanistic outcomes showed a greatest reduction in peak hip internal rotation angle for the MT group (13.1% vs. -2.7%). Conclusion: This feasibility study indicates that a definitive randomised controlled trial investigating a targeted treatment approach is achievable. Findings suggest the mechanism of effect of hip strengthening may be to influence kinematic changes in hip function in the transverse plane

Patellofemoral morphology is not related to pain using three-dimensional quantitative analysis in an older population: data from the Osteoarthritis Initiative

Objectives: Current structural associations of patellofemoral pain (PFP) are based on 2D imaging methodology with inherent measurement uncertainty due to positioning and rotation. This study employed novel technology to create 3D measures of commonly described patellofemoral joint imaging features and compared these features in people with and without PFP in a large cohort. Methods: We compared two groups from the Osteoarthritis Initiative: one with localized PFP and pain on stairs, and a control group with no knee pain; both groups had no radiographic OA. MRI bone surfaces were automatically segmented and aligned using active appearance models. We applied t-tests, logistic regression and linear discriminant analysis to compare 13 imaging features (including patella position, trochlear morphology, facet area and tilt) converted into 3D equivalents, and a measure of overall 3D shape. Results: One hundred and fifteen knees with PFP (mean age 59.7, BMI 27.5 kg/m², female 58.2%) and 438 without PFP (mean age 63.6, BMI 26.9 kg/m², female 52.9%) were included. After correction for multiple testing, no statistically significant differences were found between groups for any of the 3D imaging features or their combinations. A statistically significant discrimination was noted for overall 3D shape between genders, confirming the validity of the 3D measures. Conclusion: Challenging current perceptions, no differences in patellofemoral morphology were found between older people with and without PFP using 3D quantitative imaging analysis. Further work is needed to see if these findings are replicated in a younger PFP population

Obesity and rates of clinical remission and low MRI inflammation in rheumatoid arthritis

Objectives: Obesity has been proposed as a risk factor for refractory rheumatoid arthritis (RA). We evaluated the impact of obesity on achieving clinical and imaging definitions of low disease activity. Methods: This study evaluated 470 patients with RA from GO-BEFORE and GO-FORWARD randomised clinical trials. Included patients had blinded clinical disease activity measures and MRI at baseline, 24 and 52 weeks. Synovitis, osteitis and total inflammation scores were determined using the RA MRI scoring system. Multivariable logistic regression analyses compared odds of achieving Disease Activity Score using 28 joints and C-reactive protein (DAS28-CRP) remission, low component measures, or low MRI inflammation measures at 24 weeks in patients with obesity versus no obesity. Results: At 24 weeks, patients with obesity were significantly less likely to achieve DAS28(CRP) remission (OR 0.47; 95% CI 0.24 to 0.92, p=0.03). In contrast, patients with obesity had similar odds of achieving low synovitis (OR 0.94; 95% CI 0.51 to 1.72, p=0.84) and inflammation scores (OR 1.16; 95% CI 0.61 to 2.22, p=0.64) and greater odds of achieving low osteitis scores (OR 2.06; 95% CI 1.10 to 3.84, p=0.02) versus normal weight patients. Conclusions: Patients with RA and obesity have lower rates of DAS28 remission but similar rates of low MRI activity compared with patients without obesity, suggesting that obesity and its associated comorbidities can bias clinical disease activity measures. Trial registration number: NCT00361335 and NCT00264550; Post-results

Obesity and rates of clinical remission and low MRI inflammation in rheumatoid arthritis

Objectives: Obesity has been proposed as a risk factor for refractory rheumatoid arthritis (RA). We evaluated the impact of obesity on achieving clinical and imaging definitions of low disease activity. Methods: This study evaluated 470 patients with RA from GO-BEFORE and GO-FORWARD randomised clinical trials. Included patients had blinded clinical disease activity measures and MRI at baseline, 24 and 52 weeks. Synovitis, osteitis and total inflammation scores were determined using the RA MRI scoring system. Multivariable logistic regression analyses compared odds of achieving Disease Activity Score using 28 joints and C-reactive protein (DAS28-CRP) remission, low component measures, or low MRI inflammation measures at 24 weeks in patients with obesity versus no obesity. Results: At 24 weeks, patients with obesity were significantly less likely to achieve DAS28(CRP) remission (OR 0.47; 95% CI 0.24 to 0.92, p=0.03). In contrast, patients with obesity had similar odds of achieving low synovitis (OR 0.94; 95% CI 0.51 to 1.72, p=0.84) and inflammation scores (OR 1.16; 95% CI 0.61 to 2.22, p=0.64) and greater odds of achieving low osteitis scores (OR 2.06; 95% CI 1.10 to 3.84, p=0.02) versus normal weight patients. Conclusions: Patients with RA and obesity have lower rates of DAS28 remission but similar rates of low MRI activity compared with patients without obesity, suggesting that obesity and its associated comorbidities can bias clinical disease activity measures. Trial registration number: NCT00361335 and NCT00264550; Post-results

Design of a Phase 4 Randomized, Double-Blind, Placebo-Controlled Trial Assessing the ImPact of Residual Inflammation Detected via Imaging TEchniques, Drug Levels, and Patient Characteristics on the Outcome of Dose TaperIng of Adalimumab in Clinical Remission Rheumatoid ArThritis (RA) Patients (PREDICTRA)

Introduction: The current American College of Rheumatology and European League Against Rheumatism treatment recommendations advise tapering biological disease-modifying antirheumatic drug (bDMARD) therapy in patients with rheumatoid arthritis (RA) who achieve stable clinical remission while receiving bDMARDs. However, not all patients maintain remission or low disease activity after tapering or discontinuation of bDMARDs. The aim of the ImPact of Residual Inflammation Detected via Imaging TEchniques, Drug Levels and Patient Characteristics on the Outcome of Dose TaperIng of Adalimumab in Clinical Remission Rheumatoid ArThritis (RA) study, or PREDICTRA, is to generate data on patient and disease characteristics that may predict the clinical course of a fixed dose-tapering regimen with the bDMARD adalimumab. Methods and analysis: PREDICTRA is an ongoing, multicentre, phase IV, randomised, double-blind, parallel-group study of adalimumab dose tapering controlled by withdrawal in participants with RA who achieved stable clinical remission while receiving adalimumab. The study includes a screening period, a 4-week lead-in period with open-label adalimumab 40 mg every other week and a subsequent 36-week double-blind period during which participants are randomised 5:1 to adalimumab 40 mg every 3 weeks (taper arm) or placebo (withdrawal arm). The primary explanatory efficacy variables are lead-in baseline hand and wrist MRI-detected synovitis and bone marrow oedema scores, as well as a composite of both scores; the dependent variable is the occurrence of flare up to week 40. Additional efficacy variables, safety, pharmacokinetics, biomarkers and immunogenicity will also be assessed, and an ultrasound substudy will be conducted. Ethics and dissemination: The study is conducted in accordance with the International Conference on Harmonisation guidelines, local laws and the ethical principles of the Declaration of Helsinki. All participants are required to sign a written informed consent statement before the start of any study procedures

The dynamics of response as measured by multiple composite outcome tools in the TIght COntrol of inflammation in early Psoriatic Arthritis (TICOPA) trial

Background: We aimed to evaluate the dynamics of treatment response with different composite measures in the TIght COntrol of inflammation in early Psoriatic Arthritis (TICOPA) trial. Methods: Participants with early disease-modifying antirheumatic drug-naïve psoriatic arthritis (PsA) were randomised 1:1 to either tight control (TC; 4 weekly review with therapy escalation if criteria not met) or standard care (SC; 12 weekly review). We calculated modified versions of the Psoriatic ArthritiS Disease Activity Score (PASDAS), Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) Composite scorE (GRACE) and Composite Psoriatic Disease Activity Index (CPDAI) at baseline and 12 weekly to 48 weeks by blinded assessor. For missing data, we used the last observation carried forward. Comparison between groups was made by analysis of covariance and comparison of area under the curve (AUC). Results: 206 people were randomised to TC (n=101) or SC (n=105). Significant differences between treatment groups were seen (p<0.0001 for all composite measures). AUC analysis demonstrated a significant difference between groups for the PASDAS but not GRACE and CPDAI. For participants with oligoarthritis, a significant difference between groups was seen for each measure, although the significance levels were greatly diminished (PASDAS, p=0.04; GRACE p=0.01; CPDAI p=0.04). For oligoarthritis using AUC analysis, none of the measures could distinguish between groups. Conclusions: Composite measures of disease activity were able to distinguish between TICOPA treatment arms, although differences were diminished for those with oligoarthritis. Further data are needed to inform the preferred composite measure for use as the primary outcome in PsA trials

Prospects for Therapies in Osteoarthritis

Osteoarthritis (OA) is a chronic, debilitating disease affecting millions of people worldwide. Management of OA involves pharmacological and non-pharmacological approaches. Conventional pharmacological treatments have limited efficacy and are associated with a number of side-effects, restricting the number of patients who can use them. New pharmacological therapies for managing OA are required and a number have been developed targeting different tissues in OA: bone and cartilage, synovium and nerves. However, there has been overall limited success. Disease-modifying osteoarthritis drugs (DMOADs) are a putative class of therapies aimed at improving OA structural pathologies and consequent symptoms. Recent DMOAD studies have demonstrated some promising therapies but also provided new considerations for future trials

Short-term changes on MRI predict long-term changes on radiography in rheumatoid arthritis: an analysis by an OMERACT Task Force of pooled data from four randomised controlled trials

Objective: In rheumatoid arthritis (RA), MRI provides earlier detection of structural damage than radiography (X-ray) and more sensitive detection of intra-articular inflammation than clinical examination. This analysis was designed to evaluate the ability of early MRI findings to predict subsequent structural damage by X-ray. Methods: Pooled data from four randomised controlled trials (RCTs) involving 1022 RA hands and wrists in early and established RA were analysed. X-rays were scored using van der Heijde-modified or Genant-modified Sharp methods. MRIs were scored using Outcome Measures in Rheumatology (OMERACT) RA MRI Score (RAMRIS). Data were analysed at the patient level using multivariable logistic regression and receiver operating characteristic curve analyses. Results: Progression of MRI erosion scores at Weeks 12 and 24 predicted progression of X-ray erosions at Weeks 24 and 52, with areas under the curve (AUCs) of 0.64 and 0.74, respectively. 12-week and 24-week changes in MRI osteitis scores were similarly predictive of 24-week and 52-week X-ray erosion progressions; pooled AUCs were 0.78 and 0.77, respectively. MRI changes in synovitis at Weeks 12 and 24 also predicted progression of X-ray joint damage (erosion and joint-space narrowing) at Weeks 24 and 52 (AUCs=0.72 and 0.65, respectively). Conclusions: Early changes in joint damage and inflammation detected with MRI predict changes in joint damage evident on subsequent X-rays. These findings support the use of MRI as a valid method for monitoring structural damage in short-duration RCTs