Rheumatoid Arthritis: Brown AK

Keen HI, Brown AK, Wakefield RJ, Conaghan PG. · Academic Unit of Musculoskeletal Disease, Department of Rheumatology, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK. · Rheum Dis Clin North Am. · Pubmed #16287592 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic and progressive inflammatory disorder primarily affecting the synovium and is characterized by destruction of bone and cartilage. Early diagnosis and treatment of RA can improve disease outcomes substantially. Magnetic resonance imaging and musculoskeletal ultrasonography may facilitate early diagnosis and aid the targeting of intensive therapy. Magnetic resonance imaging and musculoskeletal ultrasonography also are able to monitor temporal changes in disease activity (ie, synovitis) and damage (ie, erosions). These imaging modalities are likely to be increasingly used in the management of early rheumatoid arthritis to ensure the best patient outcomes, although more work is required to determine their optimal roles.

Brown AK, Wakefield RJ, Conaghan PG, Karim Z, O'Connor PJ, Emery P. · Academic Unit of Musculoskeletal Disease, Department of Rheumatology, University of Leeds, Leeds General Infirmary, UK. · Clin Exp Rheumatol. · Pubmed #15552510 No free full text.

Abstract: Imaging techniques such as musculoskeletal ultrasonography (MUS) and magnetic resonance imaging (MRI) are playing an increasingly important role in the assessment of patients with inflammatory arthritis. Such modalities are now used routinely in the evaluation of joint, tendon and soft tissue inflammation and bone damage in many early arthritis clinics. They have the ability to directly visualise, characterise and quantify the earliest inflammatory changes and have proved not only to be useful additional complimentary clinical tools to improve the speed and accuracy of diagnosis, direct appropriate treatment, monitor response to therapy, measure disease progression and outcome but also continue to contribute to our understanding of disease pathogenesis. These imaging methods may therefore offer a significant advantage as they endorse the principles of early diagnosis and optimal targeted therapy essential to providing the most favourable long term outcome for patients with inflammatory arthritis. This article reviews the current evidence supporting the role of MUS and MRI in the assessment of patients with inflammatory arthritis.

Wakefield RJ, Kong KO, Conaghan PG, Brown AK, O'Connor PJ, Emery P. · Academic Department of Musculoskeletal Medicine, General Infirmary at Leeds, Leeds, United Kingdom. · Clin Exp Rheumatol. · Pubmed #14969049 No free full text.

Abstract: Advances in ultrasound (US) and magnetic resonance imaging (MRI) techniques have provided new methods for evaluating early rheumatoid arthritis (RA). Their diagnostic properties in terms of detecting primary pathology of RA (i.e., erosions, bone changes, synovitis, tenosynovitis, and effusion) are reviewed. High-resolution US plays a significant role in therapeutic and diagnostic procedures. MRI also assists in the understanding of RA pathogenesis and joint mechanics.

Brown AK, Quinn MA, Karim Z, Conaghan PG, Peterfy CG, Hensor E, Wakefield RJ, O'Connor PJ, Emery P. · Chapel Allerton Hospital, University of Leeds, Leeds, UK. · Arthritis Rheum. · Pubmed #17133543 links to  free full text

Abstract: OBJECTIVE: More timely and effective therapy for rheumatoid arthritis (RA) has contributed to increasing rates of clinical remission. However, progression of structural damage may still occur in patients who have satisfied remission criteria, which suggests that there is ongoing disease activity. This questions the validity of current methods of assessing remission in RA. The purpose of this study was to test the hypothesis that modern joint imaging improves the accuracy of remission measurement in RA. METHODS: We studied 107 RA patients receiving disease-modifying antirheumatic drug therapy who were judged by their consultant rheumatologist to be in remission and 17 normal control subjects. Patients underwent clinical, laboratory, functional, and quality of life assessments. The Disease Activity Score 28-joint assessment and the American College of Rheumatology remission criteria, together with strict clinical definitions of remission, were applied. Imaging of the hands and wrists using standardized acquisition and scoring techniques with conventional 1.5T magnetic resonance imaging (MRI) and ultrasonography (US) were performed. RESULTS: Irrespective of which clinical criteria were applied to determine remission, the majority of patients continued to have evidence of active inflammation, as shown by findings on the imaging assessments. Even in asymptomatic patients with clinically normal joints, MRI showed that 96% had synovitis and 46% had bone marrow edema, and US showed that 73% had gray-scale synovial hypertrophy and 43% had increased power Doppler signal. Only mild synovial thickening was seen in 3 of the control subjects (18%), but no bone marrow edema. CONCLUSION: Most RA patients who satisfied the remission criteria with normal findings on clinical and laboratory studies had imaging-detected synovitis. This subclinical inflammation may explain the observed discrepancy between disease activity and outcome in RA. Imaging assessment may be necessary for the accurate evaluation of disease status and, in particular, for the definition of true remission.

Saleem B, Brown AK, Keen H, Nizam S, Freeston J, Karim Z, Quinn M, Wakefield R, Hensor E, Conaghan PG, Emery P. · University of Leeds, Chapel Allerton Hospital, Leeds, UK. · Arthritis Rheum. · Pubmed #19565512 No free full text.

Abstract: OBJECTIVE: For patients with rheumatoid arthritis (RA) in remission who are receiving disease-modifying antirheumatic drugs (DMARDs), radiographic progression correlates with imaging-detected synovitis as measured by power Doppler activity. In contrast, patients with disease in remission who are receiving the combination of tumor necrosis factor (TNF) blockade with methotrexate (MTX) (combination treatment) have reduced radiographic damage for the equivalent clinical state. We undertook this study to determine whether the difference in radiographic outcome is a result of more complete suppression of imaging-detected synovitis. METHODS: One hundred patients with RA in remission (Disease Activity Score in 28 joints [DAS28] <2.6) for at least 6 months while receiving either combination treatment (n = 50) or DMARDs (n = 50) were matched for clinical variables. Ultrasound of metacarpophalangeal joints 1-5 and the wrist joints was performed. Remission according to imaging results was defined as a score of 0 for both grey scale synovitis and power Doppler activity. RESULTS: In patients receiving combination treatment or DMARDs (median DAS28 1.65 versus 1.78, median disease duration 120 months versus 90 months, and median duration of remission 13 months versus 18 months), the proportion with remission according to imaging results was not significantly different (10% versus 16%, respectively). The combination treatment group had more grey scale synovitis (P < 0.001) but similar power Doppler activity (48% versus 60%, respectively; P = 0.229) in any joint as compared with the DMARD group. Results were not affected by stratification for duration of disease or remission. CONCLUSION: In RA patients with disease in remission, imaging-detected synovitis persists, with power Doppler activity seen in >/=48% of the patients regardless of therapy. These results suggest that superior radiographic outcomes in patients treated with the combination of TNF blockade and MTX may not be due to complete suppression of imaging-detected synovitis.

Kiely PD, Brown AK, Edwards CJ, O'Reilly DT, Ostör AJ, Quinn M, Taggart A, Taylor PC, Wakefield RJ, Conaghan PG. · Department of Rheumatology, St Georges Healthcare NHS Trust, London, UK. · Rheumatology (Oxford). · Pubmed #19401359 No free full text.

Abstract: OBJECTIVE: RA has a substantial impact on both patients and healthcare systems. Our objective is to advance the understanding of modern management principles in light of recent evidence concerning the condition's diagnosis and treatment. METHODS: A group of practicing UK rheumatologists formulated contemporary management principles and clinical practice recommendations concerning both diagnosis and treatment. Areas of clinical uncertainty were documented, leading to research recommendations. RESULTS: A fundamental concept governing treatment of RA is minimization of cumulative inflammation, referred to as the inflammation-time area under the curve (AUC). To achieve this, four core principles of management were identified: (i) detect and refer patients early, even if the diagnosis is uncertain: patients should be referred at the first suspicion of persistent inflammatory polyarthritis and rheumatology departments should provide rapid access to a diagnostic and prognostic service; (ii) treat RA immediately: optimizing outcomes with conventional DMARDs and biologics requires that effective treatment be started early-ideally within 3 months of symptom onset; (iii) tight control of inflammation in RA improves outcome: frequent assessments and an objective protocol should be used to make treatment changes that maintain low-disease activity/remission at an agreed target; (iv) consider the risk-benefit ratio and tailor treatment to each patient: differing patient, disease and drug characteristics require long-term monitoring of risks and benefits with adaptations of treatments to suit individual circumstances. CONCLUSION: These principles focus on effective control of the inflammatory process in RA, but optimal uptake may require changes in service provision to accommodate appropriate care pathways.

Brown AK, Conaghan PG, Karim Z, Quinn MA, Ikeda K, Peterfy CG, Hensor E, Wakefield RJ, O'Connor PJ, Emery P. · Leeds Institute of Molecular Medicine, University of Leeds, and Chapel Allerton Hospital, Leeds, UK. · Arthritis Rheum. · Pubmed #18821687 No free full text.

Abstract: 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.

Burgoyne CH, Field SL, Brown AK, Hensor EM, English A, Bingham SL, Verburg R, Fearon U, Lawson CA, Hamlin PJ, Straszynski L, Veale D, Conaghan P, Hull MA, van Laar JM, Tennant A, Emery P, Isaacs JD, Ponchel F. · Academic Unit of Musculoskeletal Disease, University of Leeds, Leeds, UK. · Ann Rheum Dis. · Pubmed #17644540 No free full text.

Abstract: OBJECTIVES: An abnormal CD4+ T cell subset related to inflammation exposure (inflammation-related cells, IRC) has been identified in rheumatoid arthritis (RA). Patients with inflammatory and non-inflammatory diseases were used to examine the relationship between inflammation and this T cell subset in vivo. METHODS: Blood was collected from healthy controls and patients with RA (active disease or in clinical remission), Crohn's disease and osteoarthritis. IRC and chemokine receptors were quantified by flow cytometry. Thymic activity and apoptotic factors were measured by real-time polymerase chain reaction. Circulating cytokines were measured by enzyme-linked immunosorbent assay. CXCR4 and SDF1 in synovial biopsies were measured using immunohistochemistry. RESULTS: IRC were identified in patients with RA (p<0.0001) and Crohn's disease (p = 0.005), but not in those with osteoarthritis. In RA in remission, IRC persisted (p<0.001). In remission, hyperproliferation of IRC was lost, chemokine receptor expression was significantly lowered (p<0.007), Bax expression dropped significantly (p<0.001) and was inversely correlated with IRC (rho = -0.755, p = 0.03). High IRC frequency in remission was associated with relapse within 18 months (OR = 6.4, p<0.001) and a regression model predicted 72% of relapse. CONCLUSIONS: These results suggest a model in which, despite the lack of systemic inflammation, IRC persist in remission, indicating that IRC are an acquired feature of RA. They have, however, lost their hyper-responsiveness, acquired a potential for survival, and no longer express chemokine receptors. IRC persistence in remission confirms their important role in chronic inflammation as circulating precursors of pathogenic cells. This was further demonstrated by much higher incidence of relapse in patients with high IRC frequency in remission.

Karim Z, Quinn MA, Wakefield RJ, Brown AK, Green MJ, Hensor EM, Conaghan PG, Emery P. · Academic Unit of Musculoskeletal Medicine, Chapel Allerton Hospital, Leeds, UK. · Ann Rheum Dis. · Pubmed #17127687 No free full text.

Abstract: BACKGROUND: Hand pain with stiffness is a common clinical presentation to early arthritis clinics, with outcome varying from resolution to the development of rheumatoid arthritis. OBJECTIVE: To assess the response and predictors of response to intramuscular methylprednisolone (MP) and hydroxychloroquine (HCQ) using a standardised treatment protocol. METHODS: Patients with inflammatory hand pain (IHP), defined as predominantly hand pain and morning stiffness of at least 30 min duration, received a standardised assessment prior to receiving intramuscular MP. Response (primary outcome) at 4 weeks was a 50% improvement in symptoms as perceived by the patient; responders who relapsed received repeat intramuscular MP and HCQ. RESULTS: 102 patients were recruited, of which 21% were rheumatoid factor (RF) positive, 23% had clinical synovitis, 25% had raised C-reactive protein level and 55% had ultrasound-detected synovitis. 73% responded, with associated significant reductions in morning stiffness, Health Assessment Questionnaire, painful and tender joint counts, and visual analogue scores (p < or = 0.006 for all). Ultrasound-detected synovitis (p<0.001) and RF (p = 0.04), but not clinical synovitis (p = 0.74), were significantly associated with response to intramuscular MP. 86% who remained on HCQ long term reported a benefit. CONCLUSIONS: Patients with IHP have significant improvement in symptoms and function following intramuscular MP. Further placebo-controlled trials are required to assess the role of intramuscular MP and ultrasonography in managing this patient group.

Lawson CA, Brown AK, Bejarano V, Douglas SH, Burgoyne CH, Greenstein AS, Boylston AW, Emery P, Ponchel F, Isaacs JD. · Academic Unit of Musculoskeletal Disease, IMMECR, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK. · Rheumatology (Oxford). · Pubmed #16571607 links to  free full text

Abstract: OBJECTIVE: Our aim was to test the hypothesis that there is a deficit in the CD4+CD25high regulatory T-cell population in early rheumatoid arthritis (RA), either in size or functional activity. METHODS: Peripheral blood mononuclear cells were examined from subjects with early active RA who had received no previous disease-modifying therapy (n = 43), from individuals with self-limiting reactive arthritis (n = 14), from subjects with stable, well-controlled RA (n = 82) and from healthy controls (n = 72). The frequencies of CD4+CD25high T-cells were quantified using flow cytometry, and function was assessed by the ability to suppress proliferation of CD4+CD25- T-cells. Paired blood and synovial fluid was analysed from a small number of RA and reactive arthritis patients. RESULTS: There was a smaller proportion of CD4+CD25high T-cells in the peripheral blood of early active RA patients (mean 4.25%) than in patients with reactive arthritis or in controls (mean 5.90 and 5.30%, respectively, P = 0.001 in each case). Frequencies in stable, well-controlled RA (mean 4.63%) were not significantly different from early active RA or controls. There were no differences in suppressor function between groups. Higher frequencies of CD4+CD25high T-cells were found in synovial fluid than blood in both RA and reactive arthritis. CONCLUSIONS: These data demonstrate a smaller CD4+CD25high regulatory T-cell population in peripheral blood of individuals with early active RA prior to disease-modifying treatment. This may be a contributory factor in the susceptibility to RA and suggests novel approaches to therapy.

Wakefield RJ, Balint PV, Szkudlarek M, Filippucci E, Backhaus M, D'Agostino MA, Sanchez EN, Iagnocco A, Schmidt WA, Bruyn GA, Bruyn G, Kane D, O'Connor PJ, Manger B, Joshua F, Koski J, Grassi W, Lassere MN, Swen N, Kainberger F, Klauser A, Ostergaard M, Brown AK, Machold KP, Conaghan PG, Anonymous00384. · Academic Unit of Musculoskeletal Disease, University of Leeds, Leeds, UK. · J Rheumatol. · Pubmed #16331793 No free full text.

Abstract: Ultrasound (US) has great potential as an outcome in rheumatoid arthritis trials for detecting bone erosions, synovitis, tendon disease, and enthesopathy. It has a number of distinct advantages over magnetic resonance imaging, including good patient tolerability and ability to scan multiple joints in a short period of time. However, there are scarce data regarding its validity, reproducibility, and responsiveness to change, making interpretation and comparison of studies difficult. In particular, there are limited data describing standardized scanning methodology and standardized definitions of US pathologies. This article presents the first report from the OMERACT ultrasound special interest group, which has compared US against the criteria of the OMERACT filter. Also proposed for the first time are consensus US definitions for common pathological lesions seen in patients with inflammatory arthritis.

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.

Tan AL, Tanner SF, Conaghan PG, Radjenovic A, O'Connor P, Brown AK, Emery P, McGonagle D. · Leeds General Infirmary, Leeds, UK. · Arthritis Rheum. · Pubmed #12746894 links to  free full text

Abstract: OBJECTIVE: To investigate the role of metacarpophalangeal (MCP) joint anatomic and biomechanical factors in the distribution of synovitis and bone erosion in early rheumatoid arthritis (RA). METHODS: Thirty-three patients with early RA with clinically diagnosed MCP joint disease and 28 healthy controls were examined by magnetic resonance imaging of the second to fifth MCP joints of the dominant hand. T1 and T2 fat-suppressed coronal sequences were obtained to assess erosion, and dynamic contrast-enhanced images were acquired to assess synovitis in all of the RA patients and in 8 of the controls. Erosions were defined as bone defects with sharp margins observed using T1-weighted imaging in 2 planes, with a cortical break seen in at least 1 plane. The location of erosions was recorded. The volume of synovitis surrounding each MCP joint (divided into 8 regions) was calculated by summation of voxels derived from the maximal enhancement parameters. The synovial volumes adjacent to MCP joint collateral ligaments were determined by correcting synovial volumes for the positions of asymmetrically placed flexor tendons. RESULTS: In patients with early RA in whom bone erosions were present, there was a propensity for involvement of the radial side of the second (P < 0.0001), third (P = 0.002), and fourth (P = 0.056) MCP joints, but not the fifth. Fifty-two of the 110 erosions (47.3%) occurred adjacent to the radial collateral ligaments of the second, third, and fourth MCP joints. The volume of synovitis was also greater on the radial side of the second (P < 0.0001) and third (P < 0.001) MCP joints. A predilection for synovitis in all of the MCP joints adjacent to the radial collateral ligaments was evident when the positional effects of the flexor tendon were considered. The position of radial collateral ligaments had an effect on erosion formation that was independent of synovitis. A predilection for radial bone damage was also evident in the controls, although lesions were 5-fold less frequent, were generally smaller, and had well-defined margins. CONCLUSION: This study shows that there is a predilection for both synovitis and bone erosion formation on the radial side of the MCP joints in early RA, and that joint inflammation appears to drive the inherent tendency for bone damage on the radial side of joints. These findings have implications regarding the pathogenesis of joint damage in RA.

Bejarano V, Conaghan PG, Proudman SM, Buch MH, Brown AK, Emery P. · No affiliation provided · Ann Rheum Dis. · Pubmed #19366897 No free full text.

This publication has no abstract.

Freeston JE, Brown AK, Hensor EM, Emery P, Conaghan PG. · No affiliation provided · Ann Rheum Dis. · Pubmed #18697780 No free full text.

This publication has no abstract.