Rheumatoid Arthritis: McGonagle D

Marzo-Ortega H, Emery P, McGonagle D. · No affiliation provided · J Rheumatol. · Pubmed #12180712 links to  free full text

This publication has no abstract.

McGonagle D, Tan AL. · Academic Unit of Musculoskeletal Disease, University of Leeds and Chapel Allerton Hospital, Chapeltown Road, Leeds, LS7 4SA, UK. · Arthritis Res Ther. · Pubmed #18947372 links to  free full text

Abstract: Modern imaging modalities, including magnetic resonance imaging (MRI), are valuable diagnostic and therapy monitoring tools in rheumatoid arthritis (RA). This article reviewed how these imaging modalities have greatly improved our understanding of pathogenic mechanisms in RA, namely the link between inflammation and damage. For example, traditional paradigms regarding the mechanisms of joint destruction, including the idea that synovitis and damage are uncoupled, have been challenged. As the power of MRI increases, there is a need to define normality since apparently normal joints occasionally exhibit MRI evidence of synovitis in the absence of symptoms.

Tyndall A, Walker UA, Cope A, Dazzi F, De Bari C, Fibbe W, Guiducci S, Jones S, Jorgensen C, Le Blanc K, Luyten F, McGonagle D, Martin I, Bocelli-Tyndall C, Pennesi G, Pistoia V, Pitzalis C, Uccelli A, Wulffraat N, Feldmann M. · Rheumatology, University Hospital Basel, Felix Platter Spital, Burgfelderstrasse 101, Basel, CH-4012, Switzerland. · Arthritis Res Ther. · Pubmed #17284303 links to  free full text

Abstract: Multipotent mesenchymal stromal cells isolated from bone marrow and other sites are currently being studied to determine their potential role in the pathogenesis and/or management of autoimmune diseases. In vitro studies have shown that they exhibit a dose-dependent antiproliferative effect on T and B lymphocytes, dendritic cells, natural killer cells and various B cell tumour lines--an effect that is both cell contact and soluble factor dependent. Animal models of autoimmune disease treated with multipotent mesenchymal stromal cells have mostly exhibited a positive clinical response, as have a limited number of patients suffering from acute graft versus host disease. This review summarizes the findings of a 1-day meeting devoted to the subject with the aim of coordinating efforts.

McGonagle D. · Academic Unit Musculoskeletal Diseases, University of Leeds, Calderdale Royal Hospital, Salterhebble, Halifax HX3 0PW, UK. · Ann Rheum Dis. · Pubmed #15708939 links to  free full text

Abstract: The distinct radiographic features of psoriatic arthritis (PsA) help confirm it as a distinct entity from rheumatoid arthritis and highlight some unique non-synovial based disease imaging features. The advent of magnetic resonance imaging and a better understanding of joint microanatomy including the complexity of joint entheses provide a unifying anatomical and biomechanical concept that links disease at the apparently disparate sites of involvement in PsA, including the synovium, the enthesis, the bone and the periosteum. These findings suggest a reason for the localisation of disease to skeletal sites that are subject to repeated mechanical stressing.

van der Heijde D, Braun J, McGonagle D, Siegel J. · Department of Internal Medicine, Division of Rheumatology, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands. · Ann Rheum Dis. · Pubmed #12381508 links to  free full text

Abstract: Emerging treatment options in ankylosing spondylitis (AS) are giving new hope to patients with this chronic and potentially disabling disease. Clinical development of new treatments requires that rigorous and well controlled trials be conducted to demonstrate safety and efficacy. A number of classification systems have been developed in recent years as a result of enhanced understanding of the pathogenesis of AS. Although new outcome measures have been developed and a consensus has been reached on the use of assessment instruments in clinical trials, there is still need for improvement and implementation. The ASsessments in Ankylosing Spondylitis (ASAS) Working Group has addressed some of these dilemmas by establishing a core set of domains for the evaluation of AS and by selecting specific assessment methods for each domain. They have also published improvement criteria for assessing short term improvement with symptom modifying antirheumatic drugs and are presently in the process of developing response criteria for disease controlling antirheumatic treatment. Various experts are also currently examining discrepancies and inadequacies of classification systems for AS. Imaging studies, magnetic resonance imaging, in particular, may provide better classification criteria in the near future. In addition to consensus on outcome assessment and classification of AS, lessons learnt from clinical trials in rheumatoid arthritis (RA) may serve as a template for AS. Guidance provided by the United States Food and Drug Administration (FDA) for clinical trials in RA may be of particular use. The FDA has defined the claims that sponsors can receive for RA products and the clinical trial data that would be expected to be submitted to support such claims.

Benjamin M, McGonagle D. · Anatomy Unit, School of Biosciences, Cardiff University, UK. · J Anat. · Pubmed #11760883 links to  free full text

Abstract: The 2 major categories of idiopathic inflammatory arthritis are rheumatoid arthritis and the seronegative spondyloarthropathies. Whilst the synovium is the primary site of joint disease in the former, the primary site in the latter is less well defined. However, it has recently been proposed that enthesitis-associated changes in the spondyloarthropathies are primary and that all other joint manifestations are secondary. Nevertheless, some of the sites of disease localisation have not been adequately explained in terms of enthesitis. This article summarises current knowledge of the structure, function, blood supply, innervation, molecular composition and histopathology of the classic enthesis (i.e. the bony attachment of a tendon or ligament) and introduces the concept of 'functional' and articular 'fibrocartilaginous' entheses. The former are regions where tendons or ligaments wrap-around bony pulleys, but are not attached to them, and the latter are synovial joints that are lined by fibrocartilage rather than hyaline cartilage. We describe how these 3 types of entheses relate to other, and how all are prone to pathological changes in spondyloarthropathy. We propose that the inflammatory responses characteristic of spondyloarthropathies are triggered at these seemingly diverse sites, in genetically susceptible individuals, by a combination of anatomical factors which lead to higher levels of tissue microtrauma, and the deposition of microbes.

Conaghan P, Edmonds J, Emery P, Genant H, Gibbon W, Klarlund M, Lassere M, McGonagle D, McQueen F, O'Connor P, Peterfy C, Shnier R, Stewart N, Ostergaard M. · Rheumatology Research Unit, University of Leeds, UK. · J Rheumatol. · Pubmed #11361206 No free full text.

Abstract: Complementing the 3 papers that precede it, this paper explains the rationale for the activities of an OMERACT working party on magnetic resonance imaging (MRI) evaluation of rheumatoid arthritis (RA), sets out provisional recommendations for the acquisition and scoring of MRI of the hand and wrist in RA, and delineates some of the many residual problems that need to be addressed.

McGonagle D, Conaghan PG, Wakefield R, Emery P. · Rheumatology and Rehabilitation Research Unit, University of Leeds, 36 Clarendon Road, Leeds, LS2 9NZ, UK. · Best Pract Res Clin Rheumatol. · Pubmed #11358417 No free full text.

Abstract: Radiography is the most widely utilized imaging modality for early rheumatoid arthritis, determination of radiographic progression remaining a crucial part of the evaluation of therapy. Conventional radiography is, however, insensitive for showing bone damage in early disease and is totally unsuitable for assessing synovial inflammation. The recognition of these limitations has led to intense interest in the multiplanar imaging capabilities of magnetic resonance imaging in rheumatoid arthritis and to an increasing use of ultrasonography for assessing synovitis and bone damage. This chapter discusses the role of radiography in early rheumatoid arthritis and the emerging use and role of magnetic resonance imaging and ultrasonography in evaluating synovitis and bone damage. The relationship between synovitis and bone damage is also addressed in the light of recent magnetic resonance imaging observations.

Conaghan PG, McGonagle D, Wakefield R, Emery P. · Rheumatology and Rehabilitation Unit, University of Leeds, UK. · Clin Exp Rheumatol. · Pubmed #10589355 No free full text.

Abstract: Conventional radiology (CR) is a major tool for the diagnosis and assessment of early arthritis. However, CR does not image the primary pathology of rheumatoid arthritis (RA), i.e. the synovium, and is insensitive for radiological erosions. New techniques, particularly magnetic resonance imaging (MRI) and ultrasonography (US) have shown their potential to improve on the sensitivity of CR. This article reviews the current status of this approach in early disease.

McGonagle D, Tan AL, Madden J, Taylor L, Emery P. · Academic Unit of Musculoskeletal Disease, Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, UK. · Rheumatology (Oxford). · Pubmed #18390581 No free full text.

Abstract: OBJECTIVES: This study assessed the utility of rituximab for the therapy of RA in a non-academic environment in a group of cases where anti-TNF was either not available or relatively contraindicated. METHODS: Thirty-nine patients with active RA who had failed at least one DMARD received two rituximab infusions 2 weeks apart. Seventeen patients received two 1000 mg doses, and 22 received the 500 mg regimen. The 28-joint disease activity index (DAS28) and European League against Rheumatism (EULAR) response criteria were recorded at baseline, 3, 6, 9 and 12 months. RF and ANA were recorded at baseline and at 6 and 12 months. RESULTS: There was a significant improvement in the DAS28 at all time points, and EULAR response was observed in 29 of 33 patients (87.9%) at 3 months, 25 of 33 patients (75.8%) at 6 months, 22 of 29 patients (75.9%) at 9 months and 23 of 30 patients (76.7) at 12 months. Improvement was also noted in CRP, and both RF and ANA were generally reduced after treatment. Patients who were on the higher regimen of two 1000 mg doses appeared to respond slightly better compared with the lower dose regimen. CONCLUSIONS: Rituximab is well tolerated in everyday clinical practice and may represent a good short-term treatment option where anti-TNF therapy is either unavailable or relatively contraindicated.

Marzo-Ortega H, McGonagle D, Rhodes LA, Tan AL, Conaghan PG, O'Connor P, Tanner SF, Fraser A, Veale D, Emery P. · Consultant Rheumatologist, Academic Unit of Musculoskeletal Disease, Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, UK. · Ann Rheum Dis. · Pubmed #17185324 No free full text.

Abstract: BACKGROUND: Psoriatic arthritis (PsA) is commonly associated with bone pathology, including entheseal new bone formation and osteolysis. On MRI, areas of active clinical involvement are represented by bone oedema and synovitis. Aim: To assess the impact of infliximab on bone oedema in PsA as shown by MRI. METHODS: 18 patients with joint swelling, psoriasis and seronegativity for rheumatoid factor received four infusions of infliximab, 3 mg/kg, in combination with methotrexate. MRI of the affected hand (12 patients) or knee joints (6 patients) was performed before and after treatment. The primary outcome was the assessment of bone oedema and synovitis at 20 weeks as shown by MRI. Secondary outcomes included the American College of Rheumatology (ACR) response criteria, psoriasis skin scores (Psoriasis Area and Severity Index (PASI)) and a quality of life measure (Psoriatic Arthritis Quality of Life (PsAQoL)). RESULTS: At baseline, bone oedema was seen in 50% of patients (seven hands and two knees) in 30% of scanned joints, and this improved or resolved in all cases in the hand joints (p = 0.018) and in one knee joint at 20 weeks. Synovitis was found to be reduced in 90% of cases on MRI. Likewise, a significant improvement in all clinical outcomes, including PASI (p = 0.003) and PsAQoL (p = 0.006) was seen at week 20. 65% (n = 11) of the patients achieved an ACR response, of whom 45% had ACR70 or above and 54% had ACR20 or ACR50. CONCLUSIONS: Infliximab treatment is associated with dramatic improvements in MRI-determined bone oedema in PsA in the short term. It remains to be determined whether infliiximib treatment is the cause for prevention of new bone formation, bone fusion or osteolysis in PsA as shown by radiography.

Conaghan PG, O'Connor P, McGonagle D, Astin P, Wakefield RJ, Gibbon WW, Quinn M, Karim Z, Green MJ, Proudman S, Isaacs J, Emery P. · University of Leeds and Leeds General Infirmary, Leeds, UK. · Arthritis Rheum. · Pubmed #12528105 links to  free full text

Abstract: OBJECTIVE: To simultaneously image bone and synovium in the individual joints characteristically involved in early rheumatoid arthritis (RA). METHODS: Forty patients with early, untreated RA underwent gadolinium-enhanced magnetic resonance imaging (MRI) of the second through fifth metacarpophalangeal joints of the dominant hand at presentation, 3 months, and 12 months. In the first phase (0-3 months), patients were randomized to receive either methotrexate alone (MTX) or MTX and intraarticular corticosteroids (MTX + IAST) into all joints with clinically active RA. The MTX-alone group received no further corticosteroids until the second phase (3-12 months), when both groups received standard therapy. RESULTS: In the first phase, MTX + IAST reduced synovitis scores more than MTX alone. There were significantly fewer joints with new erosions on MRI in the former group compared with the latter. During the second phase, the synovitis scores were equivalent and a similar number of joints in each group showed new erosions on MRI. In both phases, there was a close correlation between the degree of synovitis and the number of new erosions, with the area under the curve for MRI synovitis the only significant predictor of bone damage progression. In individual joints, there was a threshold effect on new bone damage related to the level of synovitis; no erosions occurred in joints without synovitis. CONCLUSION: In early RA, synovitis appears to be the primary abnormality, and bone damage occurs in proportion to the level of synovitis but not in its absence. In the treatment of patients with RA, outcome measures and therapies should focus on synovitis.

Bingham SJ, Snowden J, McGonagle D, Richards S, Isaacs J, Morgan G, Emery P. · Rheumatology and Rehabilitation Research Unit, University of Leeds, UK. · J Rheumatol Suppl. · Pubmed #11642498 No free full text.

Abstract: We assessed the safety and efficacy of autologous stem cell transplantation (ASCT) using T cell depleted grafts in the treatment of severe rheumatoid arthritis. Methods included mobilization 2 g/m2 cyclophosphamide (Cy) and granulocyte-colony stimulating factor; graft manipulation of positive CD34+ and negative T cell selection; and conditioning by 200 mg/kg Cy. All 6 patients improved according to American College of Rheumatology response criteria (one patient ACR70, 2 ACR50, 3 ACR20), but relapsed at 1.5-9 months when they began cyclosporine A (CSA). Five improved (one patient ACR remission, 2 ACR70, one ACR50, one improved but did not satisfy ACR response criteria). No serious complications occurred during ASCT or up to 30 months' followup. There was prolonged reduction in CD4+ T cells. ASCT is safe and has short term efficacy. T cell purging does not prevent relapse. Five patients responded to CSA when their disease had previously been refractory, suggesting an immunomodulatory effect. No serious infectious complications occurred despite prolonged reduction in CD3+CD4+ lymphocytes.

McGonagle D, Pease C, Marzo-Ortega H, O'Connor P, Gibbon W, Emery P. · Rheumatology Department, University of Leeds, United Kingdom. · J Rheumatol. · Pubmed #11508586 No free full text.

Abstract: OBJECTIVE: Joint inflammation in polymyalgia rheumatica is regarded primarily as a disease of the synovial cavities and bursae, but the adjacent capsules and soft tissues have not been evaluated using sensitive imaging methods. We used fat suppression magnetic resonance imaging (MRI) to determine anatomical sites of inflammatory change in the shoulders of patients with early polymyalgia rheumatica (PMR) and a control group of patients with rheumatoid arthritis (RA). METHODS: Fourteen patients with PMR and 14 with RA (a total of 20 shoulders in each group) were evaluated. T2 SPIR (fat suppressed) coronal oblique MRI sequences of the shoulders were performed. Scans were assessed for sites of joint effusion, bursitis, tenosynovitis, bone edema, and extracapsular soft tissue edema. Statistical analysis was performed using Fisher's test. RESULTS: Nine of 14 patients (10/20 joints) with PMR but only 2/14 (2/20 joints) with RA had prominent edema at extracapsular sites adjacent to the joint capsule or in the soft tissues (p = 0.02). Both groups had a comparable degree of joint effusion (18 PMR, 17 RA), bursitis (18 PMR, 16 RA), and tenosynovitis (3 PMR, 2 RA). CONCLUSION: The only significant difference between the 2 groups was the presence of inflammatory change outside the joint cavity in patients with PMR. This may contribute to the diffuse nature of symptoms in PMR and have implications for its pathogenesis.

Ostergaard M, Klarlund M, Lassere M, Conaghan P, Peterfy C, McQueen F, O'Connor P, Shnier R, Stewart N, McGonagle D, Emery P, Genant H, Edmonds J. · Department of Rheumatology and Danish Research Centre of Magnetic Resonance, Hvidovre Hospital, University of Copenhagen. · J Rheumatol. · Pubmed #11361204 No free full text.

Abstract: Magnetic resonance imaging (MRI) allows direct visualization of inflammation and destruction in rheumatoid arthritis (RA) joints. However, MRI scoring methods have not yet been standardized or appropriately validated. Our aim was to examine interreader agreement for a simple system of scoring RA changes on MRI among 5 centers that had not undertaken intergroup calibration. MRI of RA wrist and metacarpophalangeal (MCP) joints were scored by experienced readers in 5 centers in different countries. In substudy 1, 5 sets of 2nd-5th MCP joints from UK [Technique A: 1.5 T, coronal and axial T1 and T2 spin-echo, -/+ fat saturation (FS), -/+ iv gadolinium (Gd)] were scored for synovitis (score 0-3) and bone lesions (0-3). In substudy 2, we evaluated 19 sets of 2nd-5th MCP joints [10 sets from UK (Technique A) and 9 sets from the US (Technique B: 1.5 T; coronal T1 spin-echo and T2* gradient-echo + FS, no Gd)] and 19 wrist joints [9 from the US (Technique B) and 10 from Denmark (Technique C: 1.0 T; coronal and axial T1 spin-echo, no FS, -/+ Gd)]. Synovitis (0-3), bone lesions (0-3), and joint space narrowing (JSN, 0-3) were scored in each MCP joint and in 3 different regions of the wrist. Bone erosions and lesions in each bone were scored 0-5. Substudy 1 served to test and redesign the score sheets. In substudy 2, the scores of synovitis and bone lesions by the 5 groups were the same or differed by only one grade in 73% and 85% of joints, respectively. On MRI that included 2 imaging planes and iv Gd (Techniques A and C), these rates were 86% (synovitis) and 97% (bone lesions). Corresponding intraclass correlation coefficients (quadratic weighted kappas) were 0.44-0.68, mean 0.58 (synovitis), and 0.44-0.69, mean 0.62 (bone lesion), i.e., in the moderate to good range. Unweighted kappa values were in the low to moderate range, generally lowest for JSN (< 0.20), better for synovitis and bone erosions, and best for bone lesions, being generally highest for MRI with 2 planes pre- and post-Gd and in MCPjoints compared with wrists. These preliminary results suggest that the basic interpretation of MRI changes in RA wrist and MCP joints is relatively consistent among readers from different countries and medical backgrounds, but that further training, calibration, and standardization of imaging protocols and grading schemes will be necessary to achieve acceptable intergroup reproducibility in assessing synovitis and bone destruction in RA multicenter studies.

Proudman SM, Conaghan PG, Richardson C, Griffiths B, Green MJ, McGonagle D, Wakefield RJ, Reece RJ, Miles S, Adebajo A, Gough A, Helliwell P, Martin M, Huston G, Pease C, Veale DJ, Isaacs J, van der Heijde DM, Emery P. · University of Leeds, UK. · Arthritis Rheum. · Pubmed #10943871 links to  free full text

Abstract: OBJECTIVE: To determine whether a regimen of methotrexate, cyclosporin A, and corticosteroids introduced at onset in poor-prognosis rheumatoid arthritis (RA) can produce a significant improvement in outcome compared with standard monotherapy with sulfasalazine (SSZ). METHODS: Eighty-two consecutive patients presenting with new, untreated RA of less than 12 months' duration who fulfilled criteria for poor long-term outcome were randomized to receive either combination therapy (n = 40) or SSZ alone (n = 42). The primary outcome measures were remission and American College of Rheumatology (ACR) criteria for 20% improvement at 48 weeks. RESULTS: After 48 weeks, the numbers of patients who met the ACR criteria for 20% improvement were not significantly different between the two groups (combination 58% versus SSZ 45%), and similar numbers of patients had persisting clinical remission (approximately 10% both groups). During the first 3 months, there were significantly greater reductions in parameters of disease activity in the combination group. By 24 weeks, the swollen and tender joint counts, C-reactive protein levels, and erythrocyte sedimentation rates had fallen significantly in both groups, with a greater improvement in the swollen and tender joint count in the combination group. At 48 weeks, the radiographic damage score had increased by a median of 1 (range 0-42.5) in the combination group and 1.25 (range 0-72.5) in the SSZ group (P = 0.28; although there were significant differences in the scores for the right hand). There were significantly fewer withdrawals due to lack of efficacy in the combination group than in the SSZ group (1 of 40 versus 10 of 42; P = 0.007). In the combination group, dose reduction was needed in 22.5% because of hypertension and in 22.5% because of elevated creatinine levels. Over 48 weeks, serum creatinine increased in both groups, but particularly in the combination arm. CONCLUSION: In poor-prognosis RA patients, "aggressive" combination therapy led to more rapid disease suppression but did not result in significantly better ACR response or remission rates. This suggests that in poor-prognosis disease, an approach based on identifying patients with poor treatment responses before extra therapy is added ("step-up" approach) may be more appropriate than the use of combination therapy in all patients from the outset.

McGonagle D, Tan AL, Møller Døhn U, Ostergaard M, Benjamin M. · University of Leeds, and Chapel Allerton Hospital, Leeds, UK. · Arthritis Rheum. · Pubmed #19333927 No free full text.

Abstract: OBJECTIVE: The microanatomic basis for formation of erosions in inflammatory arthritis is incompletely understood but is thought to be related to bare areas and the associated cartilage-synovium junction. The purpose of this study was to test the hypothesis that erosion-prone sites are associated with microdamage in macroscopically normal joints. METHODS: Histologic evaluation of erosion-prone sites was performed on 20 collateral ligaments (CLs) from the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of 5 normal cadavers. In addition, the MCP joints (n = 17) and PIP joints (n = 3) of 20 patients with rheumatoid arthritis (RA) were assessed by computed tomography (CT) to ascertain whether the topography of erosion formation in patients with RA corresponded to the cadaveric findings. RESULTS: Absence of a bare area was noted in cadaveric tissue at the periligamentous erosion-prone regions, especially in the distal MCP joints and both distal and proximal PIP joints. Nevertheless, these sites exhibited soft-tissue pathologic features and bony microdamage/cyst formation. Other significant findings included the presence of pannus without inflammatory changes in the regions in which a bare area was absent, and the replacement of bare area regions with fibrovascular synovial tissue in joints without inflammatory changes. The sites of cadaveric tissue microdamage corresponded to CT-determined erosion formation in the MCP and PIP joints of patients with RA, in whom erosions adjacent to the CLs were more common than dorsal or volar erosions. CONCLUSION: Periarticular erosion formation may not necessarily depend on the presence of a bare area and has a propensity to occur adjacent to ligaments in which bone microdamage is common. These findings suggest that periligamentous locations prone to microdamage may critically influence the topography of erosion formation in inflammatory arthritis.

Marzo-Ortega H, Tanner SF, Rhodes LA, Tan AL, Conaghan PG, Hensor EM, Radjenovic A, O'Connor P, Emery P, McGonagle D. · Academic Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, Chapel Allerton Hospital, Leeds LS74SA, UK. · Scand J Rheumatol. · Pubmed #19177263 No free full text.

Abstract: OBJECTIVES: The aim of this study was to determine whether magnetic resonance imaging (MRI)-related entheseal changes including osteitis and extracapsular oedema could be used to differentiate between metacarpophalangeal (MCP) joint involvement in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). METHODS: Twenty patients (10 each with early RA and PsA) had dynamic contrast-enhanced MRI (DCE-MRI) of swollen MCP joints. Synovitis and tenosynovitis was calculated using quantitative analysis including the degree and kinetics of enhancement of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA). Periarticular bone erosion and bone oedema were scored using the Outcome Measures in Rheumatology Clinical Trials (OMERACT) proposals. Entheseal-related features including extracapsular soft tissue enhancement or regions of diffuse bone oedema were also evaluated. RESULTS: MRI was not able to differentiate at the group level between both cohorts on the basis of entheseal-related disease but a subgroup of PsA patients had diffuse extracapsular enhancement (30%) or diffuse bone oedema (20%). The RA patient group had a greater degree of MCP synovitis (p<0.0001) and tenosynovitis than PsA patients (p<0.0001). There were no significant differences in either the total number of erosions (p = 0.315) or the presence of periarticular bone oedema (p = 0.105) between the groups. CONCLUSION: Although conventional MRI shows evidence of an enthesitis-associated pathology in the MCP joints in PsA, this is not sufficiently common to be of diagnostic utility.

Dass S, Rawstron AC, Vital EM, Henshaw K, McGonagle D, Emery P. · University of Leeds, and Leeds Teaching Hospitals National Health Service Trust, Leeds, UK. · Arthritis Rheum. · Pubmed #18821683 No free full text.

Abstract: OBJECTIVE: In rheumatoid arthritis (RA), B cell depletion occurs in all patients treated with rituximab, but the clinical responses to rituximab are variable. A highly sensitive assay was used to test the hypothesis that B cell depletion is variable, and that incomplete depletion leads to a poorer outcome. METHODS: Sixty patients with active RA unresponsive to anti-tumor necrosis factor agents received two 1-gram infusions of rituximab. B cell numbers were measured by highly sensitive flow cytometry before and after each infusion and at 3-month intervals thereafter. A reduction in B cell levels below 0.0001x10(9)/liter was defined as complete depletion (compared with 0.05x10(9)/liter by conventional cytometry). Clinical responses were measured using the European League Against Rheumatism (EULAR) criteria. RESULTS: At 6 months, 92% of patients had a moderate-to-good clinical response according to the EULAR criteria. B cells were detected in 63% of patients after the first infusion of rituximab (median level 0.0009x10(9)/liter [range<0.0001-0.0015x10(9)/liter), and these patients had poorer clinical outcomes than patients with complete depletion. At 9 months, 82% of patients with complete depletion had a moderate-to- good EULAR response, compared with 43% of those with partial depletion (P=0.01). At 12 months, 59% of complete responders had a moderate-to-good EULAR response, compared with 21% of those with partial depletion (P=0.01). Patients in whom B cells were depleted only after the second infusion did no better than those in whom depletion was never complete and had poorer clinical outcomes than those in whom depletion was initially complete. CONCLUSION: This study is the first to show, using a highly sensitive analysis, that rituximab therapy is associated with variable diminution in B cell numbers. A lack of complete depletion of B cells after 1 infusion was associated with a poorer outcome.

Bejarano V, Quinn M, Conaghan PG, Reece R, Keenan AM, Walker D, Gough A, Green M, McGonagle D, Adebajo A, Jarrett S, Doherty S, Hordon L, Melsom R, Unnebrink K, Kupper H, Emery P, Anonymous00360. · University of Leeds, Leeds, UK. · Arthritis Rheum. · Pubmed #18821658 No free full text.

Abstract: OBJECTIVE: To compare work disability and job loss in early rheumatoid arthritis (RA) patients receiving adalimumab plus methotrexate (adalimumab + MTX) versus MTX alone. METHODS: In this multicenter, randomized, controlled trial, patients with RA for <2 years who had never taken MTX and who self-reported work impairment were randomized to adalimumab + MTX or placebo + MTX for 56 weeks. Primary outcome was job loss of any cause and/or imminent job loss at or after week 16. Secondary outcomes included disease activity, function (Health Assessment Questionnaire [HAQ] score), and RA quality of life (RAQoL) questionnaire score. Work was evaluated with work diaries and the RA Work Instability Scale. RESULTS: Although job loss during the 56-week study was significantly lower with adalimumab + MTX (14 of 75 patients) compared with MTX alone (29 of 73 patients; P=0.005), the primary end point was not met (12 of 75 versus 20 of 73 patients; P=0.092), likely owing to early drop out in the MTX group. There were significant improvements in American College of Rheumatology 20% response criteria, 28-joint Disease Activity Score, DeltaHAQ, DeltaRAQoL, and working time lost in the adalimumab + MTX group. Twenty-four serious adverse events were reported in 17 participants, with no differences between groups. CONCLUSION: Adalimumab + MTX reduced job loss and improved productivity in early RA when compared with MTX alone, which supports the early use of anti-tumor necrosis factor therapy and suggests its cost efficacy.

Wakefield RJ, O'Connor PJ, Conaghan PG, McGonagle D, Hensor EM, Gibbon WW, Brown C, Emery P. · Chapel Allerton Hospital, Leeds, UK. · Arthritis Rheum. · Pubmed #17907233 links to  free full text

Abstract: OBJECTIVE: To investigate the frequency and distribution of finger tenosynovitis in patients with early, untreated rheumatoid arthritis (RA) using gray-scale ultrasound (US) and magnetic resonance imaging (MRI). METHODS: Fifty patients underwent US and MRI of metacarpophalangeal (MCP) joints 2-5. Twenty healthy controls underwent US only. Flexor and extensor involvement was documented for each joint. Intrareader reliability (IRR) was calculated by rereading static images. RESULTS: Flexor tenosynovitis was found in 57 (28.5%) of 200 joints in 24 (48%) of 50 patients on US compared with 128 (64%) of 200 joints in 41 (82%) of 50 patients on MRI. Periextensor tenosynovitis was found in 14 (7%) joints in 9 (18%) patients on US compared with 80 (40%) joints in 36 (72%) patients on MRI. No controls had imaging tenosynovitis. Using MRI as the gold standard, the sensitivity, specificity, and negative and positive predictive values for US were 0.44, 0.99, 0.49, and 0.98, respectively, for flexor tenosynovitis and 0.15, 0.98, 0.63, and 0.86 for extensor tenosynovitis, respectively. The IRR was 0.85 and 0.8 for US and MRI, respectively. The most frequently involved joints on US and MRI were the second and third MCP joints. CONCLUSION: This is the first study to compare US and MRI for the detection of tenosynovitis in the fingers of patients with early untreated RA. Tenosynovitis was found to be common using both modalities, with MRI being more sensitive. A negative US scan does not exclude inflammation and an MRI should be considered. Further work is recommended to standardize definitions and image acquisition for both US and MRI images.

Marzo-Ortega H, Rhodes LA, Tan AL, Tanner SF, Conaghan PG, Hensor EM, O'Connor P, Radjenovic A, Pease CT, Emery P, McGonagle D. · University of Leeds, and Chapel Allerton Hospital, Leeds, UK. · Arthritis Rheum. · Pubmed #17907197 links to  free full text

Abstract: OBJECTIVE: The anatomic basis for joint disease localization in polymyalgia rheumatica (PMR) is poorly understood. This study used contrast-enhanced and fat suppression magnetic resonance imaging (MRI) to evaluate the relationship between synovial and extracapsular inflammation in PMR and early rheumatoid arthritis (RA). METHODS: Ten patients with new-onset PMR and 10 patients with early RA underwent dynamic contrast-enhanced MRI and conventional MRI of affected metacarpophalangeal (MCP) joints. Synovitis and tenosynovitis were calculated based on the number of enhancing voxels, initial rate of enhancement, and maximal enhancement of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA). Periarticular bone erosion and bone edema were scored according to the OMERACT (Outcome Measures in Rheumatology Clinical Trials) scoring system in both groups. The degree of extracapsular Gd-DTPA enhancement was assessed in both conditions using semiquantitative scoring. RESULTS: No significant differences were seen in the volume of synovitis (P = 0.294), degree of flexor tenosynovitis (P = 0.532), periarticular erosions (P = 0.579), or degree of bone edema (P = 0.143) between RA and PMR joints. However, despite comparable degrees of synovitis, the proportion of MCP joints showing extracapsular enhancement was higher in the PMR group (100%) than in the RA group (50%) (P = 0.030). One PMR patient, but none of the RA patients, had bone edema at the capsular insertion. CONCLUSION: Despite degrees of synovitis and tenosynovitis comparable with those in RA, PMR-related hand disease is associated with prominent extracapsular changes, suggesting that inflammation in these tissues is more prominent than joint synovitis, which is common in both conditions. This suggests that the anatomic basis for joint disease localization differs between RA and PMR.

Rhodes LA, Conaghan PG, Radjenovic A, Grainger AJ, Emery P, McGonagle D. · Academic Unit of Medical Physics, University of Leeds, Wellcome Wing, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK. · Ann Rheum Dis. · Pubmed #16100340 links to  free full text

Abstract: BACKGROUND: Qualitative differences in synovitis between the cartilage-pannus junction (CPJ) region and the adjoining suprapatellar pouch (SPP) have been reported in rheumatoid arthritis and the spondyloarthropathies. OBJECTIVE: To determine if the distribution of synovitis is the same in osteoarthritis (OA) using sensitive measures of inflammation derived from dynamic, contrast enhanced magnetic resonance imaging (DEMRI). METHODS: 20 subjects with established OA of the knee were recruited. Conventional MR images together with the DEMRI measurements were obtained. Areas of synovitis at the CPJ region and at a distant site in the SPP were calculated; differences in CPJ and SPP synovitis were determined using DEMRI parameters: the initial rate of contrast enhancement (IRE) and maximal enhancement (ME). RESULTS: The area of synovitis was significantly greater adjacent to the CPJ than in the SPP. IRE and ME measures were greater at the CPJ than the SPP. CONCLUSIONS: The magnitude of synovitis at the CPJ is not disease-specific and applies across the spectrum of degenerative disease as well as inflammatory diseases.

Ponchel F, Verburg RJ, Bingham SJ, Brown AK, Moore J, Protheroe A, Short K, Lawson CA, Morgan AW, Quinn M, Buch M, Field SL, Maltby SL, Masurel A, Douglas SH, Straszynski L, Fearon U, Veale DJ, Patel P, McGonagle D, Snowden J, Markham AF, Ma D, van Laar JM, Papadaki HA, Emery P, Isaacs JD. · Molecular Medicine Unit, University of Leeds, Leeds, UK. · Arthritis Res Ther. · Pubmed #15642146 links to  free full text

Abstract: We previously demonstrated prolonged, profound CD4+ T-lymphopenia in rheumatoid arthritis (RA) patients following lymphocyte-depleting therapy. Poor reconstitution could result either from reduced de novo T-cell production through the thymus or from poor peripheral expansion of residual T-cells. Interleukin-7 (IL-7) is known to stimulate the thymus to produce new T-cells and to allow circulating mature T-cells to expand, thereby playing a critical role in T-cell homeostasis. In the present study we demonstrated reduced levels of circulating IL-7 in a cross-section of RA patients. IL-7 production by bone marrow stromal cell cultures was also compromised in RA. To investigate whether such an IL-7 deficiency could account for the prolonged lymphopenia observed in RA following therapeutic lymphodepletion, we compared RA patients and patients with solid cancers treated with high-dose chemotherapy and autologous progenitor cell rescue. Chemotherapy rendered all patients similarly lymphopenic, but this was sustained in RA patients at 12 months, as compared with the reconstitution that occurred in cancer patients by 3-4 months. Both cohorts produced naive T-cells containing T-cell receptor excision circles. The main distinguishing feature between the groups was a failure to expand peripheral T-cells in RA, particularly memory cells during the first 3 months after treatment. Most importantly, there was no increase in serum IL-7 levels in RA, as compared with a fourfold rise in non-RA control individuals at the time of lymphopenia. Our data therefore suggest that RA patients are relatively IL-7 deficient and that this deficiency is likely to be an important contributing factor to poor early T-cell reconstitution in RA following therapeutic lymphodepletion. Furthermore, in RA patients with stable, well controlled disease, IL-7 levels were positively correlated with the T-cell receptor excision circle content of CD4+ T-cells, demonstrating a direct effect of IL-7 on thymic activity in this cohort.

Rhodes LA, Tan AL, Tanner SF, Radjenovic A, Hensor EM, Reece R, O'Connor P, Emery P, McGonagle D. · University of Leeds, and Leeds General Infirmary, Leeds, UK. · Arthritis Rheum. · Pubmed #15334454 links to  free full text

Abstract: OBJECTIVE: To use magnetic resonance imaging (MRI) to investigate the importance of knee joint synovitis at the cartilage-pannus junction (CPJ) in rheumatoid arthritis (RA) as compared with synovitis at a distant site in the suprapatellar pouch (SPP) and as compared with CPJ synovitis in the spondylarthropathies (SpA), and to assess the relative response of knee joint synovitis to therapy at the CPJ and SPP sites. METHODS: Dynamic contrast-enhanced MRI (DEMRI) of actively involved knee joints in 24 patients (13 with RA and 11 with SpA) was undertaken. The area of synovitis was calculated at the CPJ and SPP regions of interest in patients with RA and in patients with SpA. Differences in CPJ and SPP synovitis were determined using calculated DEMRI parameters which included the initial rate of contrast enhancement (IRE) and the maximal enhancement (ME). Changes in the synovial area at the CPJ and SPP were also measured in 10 patients with early RA, following treatment with disease-modifying antirheumatic drugs (DMARDs) (either methotrexate or leflunomide). RESULTS: In patients with RA or SpA, the area of synovitis was significantly larger immediately adjacent to the CPJ compared with a distant site at the SPP (in RA, mean synovitis area 162 mm2 at the CPJ versus 114 mm2 at the SPP [P = 0.010]; in SpA, mean synovitis area 214 mm2 at the CPJ versus 143 mm2 at the SPP [P = 0.002]), but the differences in the areas of synovitis at these sites were not significant between the RA and SpA patients. The IRE and ME values were also higher at the CPJ compared with the SPP, both in the RA patients (IRE P = 0.054, ME P = 0.018) and in the SpA patients (IRE P = 0.002, ME P = 0.001). A larger reduction in the area of synovitis was seen at the SPP compared with the CPJ following DMARD therapy in the RA patients (mean reduction 35% at the SPP [P = 0.023] and 12% at the CPJ [P not significant]). CONCLUSION: The non-disease-specific variations in synovitis and the differential responses to therapy in RA patients have implications for improving our understanding of CPJ synovitis. The results suggest that the pathophysiologic events at the CPJ reflect common anatomic, immune system, or biomechanical factors that play a role in modulating the severity of arthritis, and these events are not specific to RA since the same process was observed in other arthritides.