Philip O'Connor

An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis

OBJECTIVE Achieving remission is the aim of treatment in rheumatoid arthritis (RA). This should represent minimal arthritis activity and ensure optimal disease outcome. However, we have previously demonstrated a high prevalence of imaging-detected synovial inflammation in RA patients who were in clinical remission. The purpose of this study was to evaluate the long-term significance of subclinical synovitis and its relationship to structural outcome. METHODS We studied 102 RA patients receiving conventional treatment who had been judged by their consultant rheumatologist to be in remission, as well as 17 normal control subjects. Subjects underwent clinical, laboratory, functional, and quality of life assessments over 12 months. In addition to standard radiography of the hands and feet, imaging of the hands and wrists was performed with musculoskeletal ultrasonography (US) and conventional 1.5 T magnetic resonance imaging (MRI) at baseline and 12 months, using validated acquisition and scoring techniques. RESULTS Despite their being in clinical remission, 19% of the patients displayed deterioration in radiographic joint damage over the study period. Scores on musculoskeletal US synovial hypertrophy, power Doppler (PD), and MRI synovitis assessments in individual joints at baseline were significantly associated with progressive radiographic damage (P=0.032, P<0.001, and P=0.002, respectively). Furthermore, there was a significant association between the musculoskeletal US PD score at baseline and structural progression over 12 months in totally asymptomatic metacarpophalangeal joints (P=0.004) and 12 times higher odds of deterioration in joints with increased PD signal (odds ratio 12.21, P<0.001). CONCLUSION Subclinical joint inflammation detected by imaging techniques explains the structural deterioration in RA patients in clinical remission who are receiving conventional therapy. Our findings reinforce the utility of imaging for the accurate evaluation of disease status and the prediction of structural outcome.

Efficacy of etanercept in the treatment of the entheseal pathology in resistant spondylarthropathy: a clinical and magnetic resonance imaging study.

OBJECTIVE To determine the effect of tumor necrosis factor alpha (TNFalpha) blockade with etanercept on the clinical manifestations of resistant spondylarthropathy (SpA) and on axial and peripheral entheseal lesions using magnetic resonance imaging (MRI). METHODS We performed a descriptive longitudinal study of 10 SpA patients, all of whom had active inflammatory back pain and peripheral involvement. Patients were treated with 25 mg subcutaneous etanercept twice weekly for 6 months. Clinical assessments included entheseal count, visual analog scale (VAS) scores for spinal pain during the day and night, VAS scores for entheseal pain, the Bath Ankylosing Spondylitis Functional Index (BASFI), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and the Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire. MRI scans of sacroiliac (SI) joints, the lumbar spine, and affected peripheral joints were performed using a 1.5T scanner employing T1-weighted, T2-weighted fat-suppressed (FS), and T1-weighted FS postgadolinium sequences at baseline and at 6 months. Enthesitis and associated osteitis were scored semiquantitatively in pre- and posttreatment scans. RESULTS There was a statistically significant improvement in all clinical and functional parameters (P = 0.008 for VAS spinal pain score during the day and for VAS spinal pain score during the night, P = 0.008 for the BASFI, and P = 0.005 for the BASDAI) as well as in quality of life (P = 0.005 for the ASQoL) at 6 months. Nine patients had a total of 44 MRI-detectable entheseal lesions. These were seen in the SI joints in 6 patients (n = 15 lesions), in the lumbar or cervical spine in 9 patients (n = 22 lesions), and in peripheral joints in 5 patients (n = 7 lesions). Overall, 86% of MRI-detected entheseal lesions either regressed completely or improved. No new lesions developed. CONCLUSION These findings suggest that TNFalpha blockade with etanercept is markedly effective in controlling the clinical manifestations of SpA that is resistant to disease-modifying antirheumatic drugs. This is associated with marked improvement of enthesitis and associated osteitis pathology as determined by MRI.

EULAR recommendations for the use of imaging of the joints in the clinical management of rheumatoid arthritis

Objective To develop evidence-based recommendations on the use of imaging of the joints in the clinical management of rheumatoid arthritis (RA). Methods The task force comprised an expert group of rheumatologists, radiologists, methodologists and experienced rheumatology practitioners from 13 countries. Thirteen key questions on the role of imaging in RA were generated using a process of discussion and consensus. Imaging modalities included were conventional radiography, ultrasound, MRI, CT, dual-emission x-ray absorptiometry, digital x-ray radiogrammetry, scintigraphy and positron emission tomography. Research evidence was searched systematically for each question using MEDLINE, EMBASE and Cochrane CENTRAL. The experts used the evidence obtained from the relevant studies to develop a set of 10 recommendations. The strength of recommendation was assessed using a visual analogue scale. Results A total of 6888 references was identified from the search process, from which 199 studies were included in the systematic review. Ten recommendations were produced encompassing the role of imaging in making a diagnosis of RA, detecting inflammation and damage, predicting outcome and response to treatment, monitoring disease activity, progression and remission. The strength of recommendation for each proposition varied according to both the research evidence and expert opinion. Conclusions Ten key recommendations for the role of imaging in the management of RA were developed using research-based evidence and expert opinion.

Clinical and imaging efficacy of infliximab in HLA–B27–Positive patients with magnetic resonance imaging–determined early sacroiliitis

OBJECTIVE To evaluate the efficacy of infliximab in HLA-B27-positive patients with magnetic resonance imaging (MRI)-determined early sacroiliitis, using both clinical and MRI assessments. METHODS Forty patients with recent-onset inflammatory back pain, as assessed by the Calin criteria, HLA-B27 positivity, clinical disease activity as measured by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), pain and morning stiffness, and magnetic resonance imaging (MRI)-determined sacroiliac joint bone edema were randomized in a double-blind manner to receive infliximab 5 mg/kg or placebo at 0, 2, 6, and 12 weeks. MRI scans were performed at baseline and 16 weeks and scored by 2 observers (blinded to both the order of the scans and to treatment group), using the Leeds scoring system. Clinical assessments included the BASDAI, the Bath Ankylosing Spondylitis Functional Index (BASFI), the Ankylosing Spondylitis Quality of Life (ASQoL) instrument, the ASsessment in Ankylosing Spondylitis International Working Group criteria (ASAS) for improvement, and markers of inflammation. RESULTS The mean reduction in the total MRI score from week 0 to week 16 was significantly greater in infliximab-treated patients compared with placebo-treated patients (P = 0.033). On average, significantly more lesions resolved in the infliximab group (P < 0.001), while significantly more new lesions developed in the placebo group (P = 0.004). Significantly greater improvement in the infliximab group versus the placebo group was also observed for changes from week 0 to week 16 in the BASDAI (P = 0.002), BASFI (P = 0.004), and ASQoL (P = 0.007) scores. Responses according to the ASAS criteria for 40% improvement, the ASAS criteria for 20% improvement in 5 of 6 domains, and ASAS partial remission were achieved by 61%, 44%, and 56% of infliximab-treated patients, respectively. Infliximab was well tolerated, and no serious adverse events were observed. CONCLUSION Infliximab was an effective therapy for early sacroiliitis, providing a reduction in disease activity by week 16. This study is the first to show that infliximab is effective for reducing clinical and imaging evidence of disease activity in patients with MRI-determined early axial spondylarthritis.

THE RELATIONSHIP BETWEEN SYNOVITIS AND BONE CHANGES IN EARLY UNTREATED RHEUMATOID ARTHRITIS A Controlled Magnetic Resonance Imaging Study

OBJECTIVE The interrelationship between synovitis and bone damage in rheumatoid arthritis (RA) is a subject of controversy. Using magnetic resonance imaging (MRI), this study followed the bone changes in early RA and determined their relationship to synovitis. METHODS Thirty-one patients with early RA who had swelling of the metacarpophalangeal (MCP) joints and 31 healthy control subjects with no clinical evidence of arthritis underwent MRI of the second through fifth MCP joints of the dominant hand by use of a 1.5T scanner. Coronal T1-weighted and T2-fat suppressed (FS) sequences were performed to evaluate bone edema, and gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) pulse sequences were obtained to evaluate synovitis. Bony abnormalities were described as bone edema (low signal on T1-weighted sequences and intermediate/high signal on T2 FS sequences adjacent to the bone cortex) or as bone cysts (circular juxtacortical abnormalities with low signal on T1-weighted images and with very high signal on T2 FS sequences). Contrast and noncontrast MRI films were scored in a blinded manner, and Fishers exact probability test was used to determine differences between groups. RESULTS Twenty-one of the 31 RA patients (68%) had bone edema, which was seen in 43 of 124 joints (35% of joints) and 3 of the 31 control subjects had bone edema seen in 3 of 124 joints (2% of joints) (P < 0.0001). Thirty RA patients (97%) had Gd-DTPA-confirmed MCP joint synovitis, and bone edema was seen in 40 of the 75 joints with Gd-DTPA-proven synovitis (53%), but in only 3 of 49 without (6%) (P < 0.0001). CONCLUSION MCP joint bone edema is present in the majority of patients with RA at presentation, but is seen only occasionally in normal control subjects. The fact that bone edema occurred rarely in the absence of synovitis in patients with RA suggests that bony changes in RA are secondary to synovitis.

Enthesitis in spondyloarthropathy.

Inflammation at the insertions of ligaments, tendons, or joint capsules to bone, which is termed enthesitis, is a characteristic feature of spondyloarthropathy. Because of the relative inaccessibility of the enthesis, the inflammatory, microbiologic, and immunologic events at that site have been poorly defined. Recent magnetic resonance imaging studies have drawn attention to the ubiquitous nature of enthesitis in spondyloarthropathies, especially adjacent to synovial joints. This may have implications for the mechanisms of synovitis in spondyloarthropathies. Magnetic resonance imaging studies also suggest that enthesitis lesions may be extensive, which could explain the diffuse nature of bone changes seen in some patients with spondyloarthropathies. The importance of enthesitis as a skeletal phenomenon in spondyloarthropathies has gained further support from transgenic models in which either tumor necrosis factor-alpha or bone morphogenetic protein-6 overexpression result in entheseal-associated polyarthropathy.

The OMERACT Psoriatic Arthritis Magnetic Resonance Imaging Scoring System (PsAMRIS): Definitions of Key Pathologies, Suggested MRI Sequences, and Preliminary Scoring System for PsA Hands

This article describes a preliminary OMERACT psoriatic arthritis magnetic resonance image scoring system (PsAMRIS) for evaluation of inflammatory and destructive changes in PsA hands, which was developed by the international OMERACT MRI in inflammatory arthritis group. MRI definitions of important pathologies in peripheral PsA and suggestions concerning appropriate MRI sequences for use in PsA hands are also provided.

Mode of action of abatacept in rheumatoid arthritis patients having failed tumour necrosis factor blockade: a histological, gene expression and dynamic magnetic resonance imaging pilot study.

Objectives: Abatacept is the only agent currently approved to treat rheumatoid arthritis (RA) that targets the co-stimulatory signal required for full T-cell activation. No studies have been conducted on its effect on the synovium, the primary site of pathology. The aim of this study was to determine the synovial effect of abatacept in patients with RA and an inadequate response to tumour necrosis factor alpha (TNFα) blocking therapy. Methods: This first mechanistic study incorporated both dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and arthroscopy-acquired synovial biopsies before and 16 weeks after therapy, providing tissue for immunohistochemistry and quantitative real-time PCR analyses. Results: Sixteen patients (13 women) were studied; all had previously failed TNFα-blocking therapy. Fifteen patients completed the study. Synovial biopsies showed a small reduction in cellular content, which was significant only for B cells. The quantitative PCR showed a reduction in expression for most inflammatory genes (Wald statistic of p<0.01 indicating a significant treatment effect), with particular reduction in IFNγ of −52% (95% CI −73 to −15, p<0.05); this correlated well with MRI improvements. In addition, favourable changes in the osteoprotegerin and receptor activator of nuclear factor kappa B levels were noted. DCE–MRI showed a reduction of 15–40% in MRI parameters. Conclusion: These results indicate that abatacept reduces the inflammatory status of the synovium without disrupting cellular homeostasis. The reductions in gene expression influence bone positively and suggest a basis for the recently demonstrated radiological improvements that have been seen with abatacept treatment in patients with RA.

Efficacy of etanercept for treatment of Crohn’s related spondyloarthritis but not colitis

The seronegative spondyloarthropathies (SpAs) are associated both with clinical and subclinical colitis. Recently biological blockade with the tumour necrosis factor alpha (TNFα) antagonists infliximab and etanercept has been shown to be effective in the treatment of SpA. However, only infliximab is efficacious in the treatment of colitis in patients with Crohn’s SpA. We report on two patients with SpA and associated Crohn’s disease treated with etanercept whose arthritis showed an excellent response with complete resolution of spinal pathology, whereas their Crohn’s disease persisted or flared. These findings suggest that the effect of TNFα blockade in SpA differs between the joint and the bowel.

Baseline and 1-year magnetic resonance imaging of the sacroiliac joint and lumbar spine in very early inflammatory back pain. Relationship between symptoms, HLA-B27 and disease extent and persistence

Background: The precise anatomical location of pathology associated with inflammatory back pain (IBP) in early spondyloarthropathy (SpA) remains unclear. Objective: To use MRI to study the sacroiliac joint (SIJ) and lumbar spine (LS) and explore the relationship between sites and extent of inflammation and HLA-B27 status over 12 months. Methods: 54 patients with IBP; median duration 24 weeks (54% HLA-B27 positive; median Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 5.65) and 22 control subjects (11 with mechanical back pain; 11 volunteers) were recruited and 63% (n = 34) were reassessed at 1 year. Fat saturation and T1-weighted MRI was performed with images being scored for active bone marrow oedema (BMO) lesions representative of inflammation. Results: At baseline 46/54 (85%) patients had BMO (SIJs and LS) compared with 40% in the control group. The majority of affected patients had inflammation at the SIJ level (96% (n = 44); 23.5% (n = 12) LS) and 28.3% (n = 13) at both sites simultaneously. The SIJ activity score confirmed more severe inflammation (BMO grade 2 or 3: 52.2%) in the IBP group (controls = BMO grade 1: 100%; p<0.001). HLA-B27 was associated with both the severity (p = 0.009) and number of baseline SIJ lesions (p = 0.045) and with persistence (SIJ or LS) at 1 year (p = 0.02). 90% of reattenders fulfilled European Spondyloarthropathy Study Group criteria; 73.5% showed MRI inflammation despite clinical improvement (median BASDAI 5.65 to 3.05; p<0.009). Conclusion: LS and SIJ involvement may occur simultaneously in very early SpA and may be differentiated from non-inflammatory back pain by the severity of MRI lesions. HLA-B27 is associated with both the severity of osteitis and its persistence.