Sustained improvements in MRI outcomes with abatacept following the withdrawal of all treatments in patients with early, progressive rheumatoid arthritis

Objectives: To assess structural damage progression with subcutaneous abatacept (ABA) in the Assessing Very Early Rheumatoid arthritis Treatment (AVERT) trial following abrupt withdrawal of all rheumatoid arthritis (RA) medication in patients achieving Disease Activity Score (DAS)-defined remission or low disease activity. Methods: Patients with early, active RA were randomised to ABA plus methotrexate (ABA/MTX) 125 mg/week, ABA 125 mg/week or MTX for 12 months. All RA treatments were withdrawn after 12 months in patients with DAS28 (C reactive protein (CRP)) <3.2. Adjusted mean changes from baseline in MRI-based synovitis, osteitis and erosion were calculated for the intention-to-treat population. Results: 351 patients were randomised and treated: ABA/MTX (n=119), ABA (n=116) or MTX (n=116). Synovitis and osteitis improved, and progression of erosion was statistically less with ABA/MTX versus MTX at month 12 (−2.35 vs −0.68, −2.58 vs −0.68, 0.19 vs 1.53, respectively; p<0.01 for each) and month 18 (−1.34 vs −0.49 −2.03 vs 0.34, 0.13 vs 2.0, respectively; p<0.01 for erosion); ABA benefits were numerically intermediate to those for ABA/MTX and MTX. Conclusions: Structural benefits with ABA/MTX or ABA may be maintained 6 months after withdrawal of all treatments in patients who have achieved remission or low disease activity

The relationship between specific tissue lesions and pain severity in persons with knee osteoarthritis

SummaryIntroductionPain is the most common symptom in knee osteoarthritis (OA), a leading cause of chronic disability, and a major source of the disability attributable to OA in general. Pain severity in knee OA is variable, ranging from barely perceptible to immobilizing. The knee lesions that contribute to pain severity have received little attention.ObjectiveTo examine whether worse pathology of specific knee tissues – i.e. cartilage, bone (attrition, cysts, bone marrow lesions, and osteophytes), menisci (tears and subluxation), ligaments, and synovium (synovitis/effusion) – is associated with more severe knee pain.MethodsOne hundred and forty-three individuals were recruited from the community with primary (idiopathic) knee OA, with definite tibiofemoral osteophytes in at least one knee, and at least some difficulty with knee-requiring activity. Knee magnetic resonance (MR) images were acquired using coronal T1-weighted spin-echo (SE), sagittal fat-suppressed dual-echo turbo SE, and axial and coronal fat-suppressed, T1-weighted 3D-fast low angle shot (FLASH) sequences. The whole-organ magnetic resonance imaging (MRI) scoring (WORMS) method was used to score knee tissue status. Since summing tissue scores across the entire joint, including regions free of disease, may dilute the ability to detect a true relationship between that tissue and pain severity, we used the score from the worst compartment (i.e. with the poorest cartilage morphology) as our primary approach. Knee pain severity was measured using knee-specific, 100mm visual analogue scales. In analyses to evaluate the relationship between knee pain severity and lesion score, median quantile regression was used, adjusting for age and body mass index (BMI), in which a 95% CI excluding 0 is significant.ResultsThe increase in median pain from median quantile regression, adjusting for age and BMI, was significant for bone attrition (1.91, 95% confidence interval (CI) 0.68, 3.13), bone marrow lesions (3.72, 95% CI 1.76, 5.68), meniscal tears (1.99, 95% CI 0.60, 3.38), and grade 2 or 3 synovitis/effusion vs grade 0 (9.82, 95% CI 0.38, 19.27). The relationship with pain severity was of borderline significance for osteophytes and cartilage morphology and was not significant for bone cysts or meniscal subluxation. Ligament tears were too infrequent for meaningful analysis. When compared to the pain severity in knees with high scores for both bone attrition and bone marrow lesions (median pain severity 40mm), knees with high attrition alone (30mm) were not significantly different, but knees with high bone marrow lesion without high attrition scores (15mm) were significantly less painful.ConclusionIn persons with knee OA, knee pain severity was associated with subarticular bone attrition, bone marrow lesions, synovitis/effusion, and meniscal tears. The contribution of bone marrow lesions to pain severity appeared to require the presence of bone attrition

Potential role of the posterior cruciate ligament synovio-entheseal complex in joint effusion in early osteoarthritis: a magnetic resonance imaging and histological evaluation of cadaveric tissue and data from the Osteoarthritis Initiative

Objective: This study explored posterior cruciate ligament (PCL) synovio-entheseal complex (SEC) microanatomy to determine whether it may participate in the early osteoarthritis (OA) disease process. Methods: SEC microanatomy and OA features were evaluated in 14 non-arthritic cadaveric knees (mean age = 69.9) using magnetic resonance imaging (MRI) and histology. MRI images of 49 subjects selected from the progression cohort of the Osteoarthritis Initiative (OAI) were evaluated by a musculoskeletal radiologist using an original semi-quantitative method for features associated with OA at the PCL tibial enthesis. Statistical analysis was performed using chi-square and Wilcoxon signed-rank tests to evaluate associations between SEC configuration and OA features. Results: The PCL formed a SEC-like structure encompassing bone- and ligament-lining intra-articular cartilages to which the posterior root of the medial meniscus contributed. Degenerative features at the PCL-SEC included: neovascularisation (44%), enthesis chondrocyte clustering (44%), collagen matrix fissuring at the enthesis (56%) and in the PCL itself (67%), tidemark duplication (44%), bone remodelling (44%) and microscopic inflammatory changes (33%). In the OAI cohort, SEC-related pathology included bone marrow lesions (BMLs) (69%) and osteophytosis (94%) at locations that corresponded to SEC-related cartilages. Posterior joint recess effusion (49%) was linked to MRI abnormalities at PCL-SEC cartilages (χ2 = 7.27, P = 0.007). Conclusions: The PCL has a prominent SEC configuration that is associated with microscopic OA changes in aged clinically non-diseased joints. MRI determined knee OA commonly exhibited pathological features at this site which was associated with adjacent joint effusion. Thus, the PCL-SEC could play a hitherto unappreciated role in the early OA disease process

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

Assessment of the radioanatomic positioning of the osteoarthritic knee in serial radiographs: comparison of three acquisition techniques

SummaryObjectiveRecent studies using various standardized radiographic acquisition techniques have demonstrated the necessity of reproducible radioanatomic alignment of the knee to assure precise measurements of medial tibiofemoral joint space width (JSW). The objective of the present study was to characterize the longitudinal performance of several acquisition techniques with respect to long-term reproducibility of positioning of the knee, and the impact of changes in positioning on the rate and variability of joint space narrowing (JSN).MethodsEighty subjects were randomly selected from each of three cohorts followed in recent studies of the radiographic progression of knee osteoarthritis (OA): the Health ABC study (paired fixed-flexion [FF] radiographs taken at a 36-month interval); the Glucosamine Arthritis Intervention Trial (GAIT) (paired metatarsophalangeal [MTP] radiographs obtained at a 12-month interval), and a randomized clinical trial of doxycycline (fluoroscopically assisted semiflexed anteroposterior (AP) radiographs taken at a 16-month interval).Manual measurements were obtained from each radiograph to represent markers of radioanatomic positioning of the knee (alignment of the medial tibial plateau and X-ray beam, knee rotation, femorotibial angle) and to evaluate minimum JSW (mJSW) in the medial tibiofemoral compartment. The effects on the mean annualized rate of JSN and on the variability of that rate of highly reproduced vs variable positioning of the knee in serial radiographs were evaluated.ResultsParallel or near-parallel alignment was achieved significantly more frequently with the fluoroscopically guided positioning used in the semiflexed AP protocol than with either the non-fluoroscopic FF or MTP protocol (68% vs 14% for both FF and MTP protocols when measured at the midpoint of the medial compartment; 75% vs 26% and 34% for the FF and MTP protocols, respectively, when measured at the site of mJSW; P<0.001 for each). Knee rotation was reproduced more frequently in semiflexed AP radiographs than in FF radiographs (66% vs 45%, P<0.01). In contrast, the FF technique yielded a greater proportion of paired radiographs in which the femorotibial angle was accurately reproduced than the semiflexed AP or MTP protocol (78% vs 59% and 56%, respectively, P<0.01 for each). Notably, only paired radiographs with parallel or near-parallel alignment exhibited a mean rate of JSN (±SD) in the OA knee that was more rapid and less variable than that measured in all knees (0.186±0.274mm/year, standardized response to mean [SRM]=0.68 vs 0.128±0.291mm/year, SRM=0.44).ConclusionThis study confirms the importance of parallel radioanatomic alignment of the anterior and posterior margins of the medial tibial plateau in detecting JSN in subjects with knee OA. The use of radiographic methods that assure parallel alignment during serial X-ray examinations will permit the design of more efficient studies of biomarkers of OA progression and of structure modification in knee OA

CD28 between tolerance and autoimmunity: The side effects of animal models [version 1; referees: 2 approved]

Regulation of immune responses is critical for ensuring pathogen clearance and for preventing reaction against self-antigens. Failure or breakdown of immunological tolerance results in autoimmunity. CD28 is an important co-stimulatory receptor expressed on T cells that, upon specific ligand binding, delivers signals essential for full T-cell activation and for the development and homeostasis of suppressive regulatory T cells. Many in vivo mouse models have been used for understanding the role of CD28 in the maintenance of immune homeostasis, thus leading to the development of CD28 signaling modulators that have been approved for the treatment of some autoimmune diseases. Despite all of this progress, a deeper understanding of the differences between the mouse and human receptor is required to allow a safe translation of pre-clinical studies in efficient therapies. In this review, we discuss the role of CD28 in tolerance and autoimmunity and the clinical efficacy of drugs that block or enhance CD28 signaling, by highlighting the success and failure of pre-clinical studies, when translated to humans

A Phosphatidic Acid Binding/Nuclear Localization Motif Determines Lipin1 Function in Lipid Metabolism and Adipogenesis

A polybasic motif in the metabolic regulator lipin1 is both a membrane anchor and a nuclear localization sequence required for lipin1 function in phospholipid metabolism and adipogenesis

Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors

Objectives: To assess the efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis (RA) and poor prognostic factors. Methods: In this double-blind, phase IIIb study, patients with RA for 2 years or less were randomly assigned 1 : 1 to receive abatacept (similar to 10 mg/kg) plus methotrexate, or placebo plus methotrexate. Patients were methotrexate-naive and seropositive for rheumatoid factor (RF), anti-cyclic citrullinated protein (CCP) type 2 or both and had radiographic evidence of joint erosions. The co-primary endpoints were the proportion of patients achieving disease activity score in 28 joints (DAS28)-defined remission (C-reactive protein) and joint damage progression (Genant-modified Sharp total score; TS) at year 1. Safety was monitored throughout. Results: At baseline, patients had a mean DAS28 of 6.3, a mean TS of 7.1 and mean disease duration of 6.5 months; 96.5% and 89.0% of patients were RF or anti-CCP2 seropositive, respectively. At year 1, a significantly greater proportion of abatacept plus methotrexate-treated patients achieved remission (41.4% vs 23.3%; p<0.001) and there was significantly less radiographic progression (mean change in TS 0.63 vs 1.06; p = 0.040) versus methotrexate alone. Over 1 year, the frequency of adverse events (84.8% vs 83.4%), serious adverse events (7.8% vs 7.9%), serious infections (2.0% vs 2.0%), autoimmune disorders (2.3% vs 2.0%) and malignancies (0.4% vs 0%) was comparable for abatacept plus methotrexate versus methotrexate alone. Conclusions: In a methotrexate-naive population with early RA and poor prognostic factors, the combination of abatacept and methotrexate provided significantly better clinical and radiographic efficacy compared with methotrexate alone and had a comparable, favourable safety profile

MR imaging of osteochondral grafts and autologous chondrocyte implantation

Surgical articular cartilage repair therapies for cartilage defects such as osteochondral autograft transfer, autologous chondrocyte implantation (ACI) or matrix associated autologous chondrocyte transplantation (MACT) are becoming more common. MRI has become the method of choice for non-invasive follow-up of patients after cartilage repair surgery. It should be performed with cartilage sensitive sequences, including fat-suppressed proton density-weighted T2 fast spin-echo (PD/T2-FSE) and three-dimensional gradient-echo (3D GRE) sequences, which provide good signal-to-noise and contrast-to-noise ratios. A thorough magnetic resonance (MR)-based assessment of cartilage repair tissue includes evaluations of defect filling, the surface and structure of repair tissue, the signal intensity of repair tissue and the subchondral bone status. Furthermore, in osteochondral autografts surface congruity, osseous incorporation and the donor site should be assessed. High spatial resolution is mandatory and can be achieved either by using a surface coil with a 1.5-T scanner or with a knee coil at 3 T; it is particularly important for assessing graft morphology and integration. Moreover, MR imaging facilitates assessment of complications including periosteal hypertrophy, delamination, adhesions, surface incongruence and reactive changes such as effusions and synovitis. Ongoing developments include isotropic 3D sequences, for improved morphological analysis, and in vivo biochemical imaging such as dGEMRIC, T2 mapping and diffusion-weighted imaging, which make functional analysis of cartilage possible