A C Rawstron

Leeds Teaching Hospitals NHS Trust, Leeds, England, United Kingdom

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Publications (64)362.6 Total impact

  • Annals of the rheumatic diseases 03/2014; · 8.11 Impact Factor
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    ABSTRACT: Monoclonal gammopathy of undetermined significance (MGUS), a pre-malignant clone of plasma cells producing a monoclonal paraprotein, is present in ~2% of individuals >50 years. The increased risk of multiple myeloma (MM) in the relatives of individuals with MGUS is consistent with MGUS being a marker of inherited genetic susceptibility to MM. Common SNPs at 2p23.3(rs6746082), 3p22.1(rs1052501), 3q26.2(rs10936599), 6p21.33(rs2285803), 7p15.3(rs4487645), 17p11.2(rs4273077) and 22q13.1(rs877529) have recently been shown to influence MM risk. To examine the impact of these 7 SNPs on MGUS we analyzed two case-control series totaling 492 cases and 7,306 controls. Each SNP independently influenced MGUS risk with statistically significant associations (P<0.02) for rs1052501, rs2285803, rs4487645, rs4273077. SNP associations were independent with risk increasing with a larger number of risk alleles carried (per allele odds ratio=1.18; P<10(-7)). Collectively these data are consistent with a polygenic model of disease susceptibility to MGUS and provide support for genetic variation influencing MM risk through predisposition to MGUS.
    Blood 01/2014; · 9.78 Impact Factor
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    ABSTRACT: Since clinical non-response to 2×1000 mg rituximab has previously been found to be associated with incomplete B cell depletion, we determined, in a randomised controlled proof of concept study, whether patients with initial incomplete B cell depletion would benefit from an additional infusion of rituximab at week 4. Patients with active rheumatoid arthritis despite methotrexate received a first infusion of rituximab 1000 mg and were tested for persistent B cells using highly sensitive flow cytometry on day 15. All received a second infusion of 1 g (according to license), but patients with persistent B cells were subsequently randomised double-blind to receive, 2 weeks later, either a third infusion of 1000 mg rituximab or placebo. Clinical response was determined by European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) criteria. Baseline characteristics were balanced between groups. Treatment with 3×1000 mg rituximab resulted in significantly greater depletion (lower B cell and plasmablast numbers between 8 and 28 weeks) paralleled by significantly better EULAR and ACR20 response rates at 40 weeks (p=0.035 and p=0.027, respectively) and 52 weeks (p=0.021 and p=0.043, respectively) compared with 2×1000 mg. Immunoglobulin titres remained stable in both arms, and adverse event rates were balanced. In rituximab-treated patients with incomplete B cell depletion (predictive of poor response), an extra 1000 mg infusion of rituximab at 4 weeks produced both better depletion and clinical responses than placebo with no worsening of safety. Degree of depletion is an important, but modifiable, determinant of response.
    Annals of the rheumatic diseases 01/2014; · 8.11 Impact Factor
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    ABSTRACT: To evaluate the efficacy and safety of two different targeted approaches-abatacept or tocilizumab-after rituximab therapy in rheumatoid arthritis, and to explain observed difference in efficacy using blood and synovial studies of interleukin 6 (IL-6) and B cells in patients receiving rituximab therapy. Consecutive series of patients who had discontinued rituximab therapy owing to inefficacy or toxicity were treated with abatacept (n=16) or tocilizumab (n=35). Clinical response and reasons for discontinuation were evaluated. Serial blood and synovial samples were obtained from a group of 57 and 25 rituximab-treated patients, respectively, and were analysed for B cells and IL-6 using flow cytometry, immunohistochemistry and quantitative real-time PCR. In the abatacept group, mean (SEM) Disease Activity Score in 28 joints calculated using the erythrocyte sedimentation rate (DAS28-ESR) reduced from 5.69 (0.42) at baseline to 4.94 (0.44) at 6 months (p=0.12). In the tocilizumab group: mean (SEM) DAS28- ESR reduced from 5.75 (0.21) at baseline to 3.28 (0.26) at 6 months (p<0.001). This was paralleled by a significant swollen joint count reduction in the tocilizumab (5.47 (0.70) to 2.70 (0.61), p=0.033), but not abatacept (6.23 (1.3) to 4.15 (1.2), p=0.26), group. In the synovium, despite complete depletion of B cells in 19/22 patients, IL-6 mRNA expression was not significantly reduced after rituximab. Blood B cell numbers remained low 12 months after rituximab. Serum IL-6 was raised at baseline and significantly higher in rituximab clinical non-responders (p=0.035) than responders. A significant reduction in serum IL-6 was seen in rituximab clinical responders (p=0.005) but not in non-responders (p=0.237). In patients with rheumatoid arthritis for whom rituximab therapy failed despite adequate B cell depletion, IL-6-directed therapy might be a more logical and effective treatment choice than T cell costimulation blockade. Further controlled studies investigating other possible mechanisms are needed to validate these initial findings.
    Annals of the rheumatic diseases 01/2014; · 8.11 Impact Factor
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    ABSTRACT: Background: B cell depletion is widely used in SLE. Relapse is common, but time to relapse is highly variable, with a subset of patients with very long responses accompanied by delayed repopula- tion of post-germinal centre B lineage cells[1]. In RA, some initial non- responders to rituximab responded to a repeat cycle of treatment given at 6 months. Ocrelizumab is a humanised anti-CD20 Objective: Evaluate the outcome of repeat cycles of rituximab in SLE responders and non-responders Methods: 51 patients received a first cycle (C1) of 2 x 1000mg rituximab with 2x 100mg methylprednisolone and prednisolone 60mg od days 1-7 and 30mg od days 8-14. Clinical response was assessed by BILAG criteria. B cell depletion and repopulation were monitored by 6-colour flow cytometry. Likely Human Anti-Chimaeric Antibody syn- drome (HACA) was defined by <50% B cell depletion (frequently accompanied by infusion reaction lasting >24h after a second or later infusion of rituximab). A second cycle of rituximab (C2) was administered on clinical relapse. Ocrelizumab was used in patients with evidence of HACA. Results: After C1 45/51 patients responded clinically and features of likely HACA were not observed in any patient. 28 patients have received C2: 4 at 6 months (C1 non-responders); and 24 on relapse (C1 responders). Of 4 C1 non-responders, 4/4 also had non response to C2 with features of HACA. Of 24 C1 responders, 5/24 had non-response to C2, also with clinical features of HACA. Patients who lost response in C2 had significantly longer time to retreatment than those who continued to respond: median (IQR) 164(86-259) vs. 50(42-90) weeks. 1 C1 non-responder and 3 patients who lost response in C2 were treated with 2x1000mg ocrelizumab. All had complete depletion of B cells after ocrelizumab. All 3 patients with loss of response in C2 responded clinically. The patients with C1 non-response had normal- isation of autoantibody titres but died due to complications of SLE less than 8 weeks after treatment. Conclusions: Time to relapse after rituximab in SLE is highly variable. Although initial responses were good, some patients with longer-last- ing responses did not respond to retreatment. This appears to be due to development of HACA due to very poor B cell depletion and pro- longed infusion reaction. Retreatment of first-cycle non-responders did not appear to be effective in SLE, in contrast to RA. This also appears to be due to HACA. Humanised anti-CD20 can overcome deteriorating B cell response in repeat cycles of rituximab.
    The 10th International Congress on SLE - LUPUS 2013; 04/2013
  • Annals of the rheumatic diseases 11/2012; · 8.11 Impact Factor
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    ABSTRACT: Detection of minimal residual disease (MRD) in chronic lymphocytic leukaemia (CLL) is becoming increasingly important as treatments improve. An internationally harmonised four-colour (CLR) flow cytometry MRD assay is widely used but has limitations. The aim of this study was to improve MRD analysis by identifying situations where a less time-consuming CD19/CD5/κ/λ analysis would be sufficient for detecting residual CLL, and develop a six-CLR antibody panel that is more efficient for cases requiring full MRD analysis. In 784 samples from CLL patients after treatment, it was possible to determine CD19/CD5/κ/λ thresholds that identified cases with detectable MRD with 100% positive predictive value (PPV). However, CD19/CD5/κ/λ analysis was unsuitable for predicting iwCLL/NCI response status or identifying cases with no detectable MRD. For the latter cases requiring a full MRD assessment, a six-CLR assay was designed comprising CD19/CD5/CD20 with (1) CD3/CD38/CD79b and (2) CD81/CD22/CD43. There was good correlation between four-CLR and six-CLR panels in dilution studies and clinical samples, with 100% concordance for detection of residual disease at the 0.01% (10(-4)) level (n=59) and good linearity even at the 0.001-0.01% (10(-5)-10(-4)) level. A six-CLR panel therefore provides equivalent results to the four-CLR panel but it requires fewer reagents, fewer cells and a much simpler analysis approach.Leukemia advance online publication, 5 October 2012; doi:10.1038/leu.2012.216.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2012; · 10.16 Impact Factor
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    ABSTRACT: Most consensus leukemia & lymphoma antibody panels consist of lists of markers based on expert opinions, but they have not been validated. Here we present the validated EuroFlow 8-color antibody panels for immunophenotyping of hematological malignancies. The single-tube screening panels and multi-tube classification panels fit into the EuroFlow diagnostic algorithm with entries defined by clinical and laboratory parameters. The panels were constructed in 2-7 sequential design-evaluation-redesign rounds, using novel Infinicyt software tools for multivariate data analysis. Two groups of markers are combined in each 8-color tube: (i) backbone markers to identify distinct cell populations in a sample, and (ii) markers for characterization of specific cell populations. In multi-tube panels, the backbone markers were optimally placed at the same fluorochrome position in every tube, to provide identical multidimensional localization of the target cell population(s). The characterization markers were positioned according to the diagnostic utility of the combined markers. Each proposed antibody combination was tested against reference databases of normal and malignant cells from healthy subjects and WHO-based disease entities, respectively. The EuroFlow studies resulted in validated and flexible 8-color antibody panels for multidimensional identification and characterization of normal and aberrant cells, optimally suited for immunophenotypic screening and classification of hematological malignancies.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2012; 26(9):1908-75. · 10.16 Impact Factor
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    ABSTRACT: In chronic lymphocytic leukemia (CLL), TP53 deletion/mutation is strongly associated with an adverse outcome and resistance to chemotherapy-based treatment. In contrast, TP53 defects are not associated with resistance to the anti-CD52 monoclonal antibody alemtuzumab or methylprednisolone. In an attempt to improve the treatment of TP53-defective CLL, a multicenter phase II study was developed to evaluate alemtuzumab and methylprednisolone in combination. Thirty-nine patients with TP53-deleted CLL (17 untreated and 22 previously treated) received up to 16 weeks of treatment with alemtuzumab 30 mg three times a week and methylprednisolone 1.0 g/m(2) for five consecutive days every 4 weeks. Antimicrobial prophylaxis consisted of cotrimoxazole, itraconazole, and aciclovir (or valganciclovir for asymptomatic cytomegalovirus viremia). The primary end point was response as assigned by an end-point review committee. Secondary end points were safety, progression-free survival (PFS) and overall survival (OS). The overall response rate, complete response rate (including with incomplete marrow recovery), median PFS, and median OS were 85%, 36%, 11.8 months, and 23.5 months, respectively, in the entire cohort and 88%, 65%, 18.3 months, and 38.9 months, respectively, in previously untreated patients. Grade 3 to 4 hematologic and glucocorticoid-associated toxicity occurred in 67% and 23% of patients, respectively. Grade 3 to 4 infection occurred in 51% of the overall cohort and in 29% of patients less than 60 years of age. Treatment-related mortality was 5%. Alemtuzumab plus methypredisolone is the most effective induction regimen hitherto reported in TP53-deleted CLL. The risk of infection is age related and, in younger patients, seems only marginally higher than that associated with rituximab, fludarabine, and cyclophosphamide.
    Journal of Clinical Oncology 04/2012; 30(14):1647-55. · 18.04 Impact Factor
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    ABSTRACT: Rituximab appears to be effective in many studies of systemic lupus erythematosus (SLE), with variable initial clinical response and time to relapse. However, results of a randomized controlled trial of rituximab were negative. This study was undertaken to evaluate the effectiveness of rituximab in SLE, using highly sensitive flow cytometry (HSFC), which can define B cell numbers 50-100 times lower than conventional techniques and predicts responses in rheumatoid arthritis. Thirty-nine patients with active SLE were started on a standard regimen of rituximab with intravenous and oral steroids. Clinical response and relapse were defined using the British Isles Lupus Assessment Group (BILAG) index with criteria for major clinical response, partial clinical response, and nonresponse. HSFC, including analysis of B cell subsets, was performed. There was a significant reduction from baseline in global BILAG score at all time points analyzed (P<0.0001), and major clinical response and partial clinical response rates were 51% and 31%, respectively. Time to relapse was highly variable. Fifty percent of the patients relapsed after 6-18 months (earlier relapse); the remainder relapsed at a slower rate (later relapse). B cell depletion and repopulation were variable and were predictive of these clinical outcomes. There was a persistent B cell presence in 21 patients after 2 infusions of rituximab, which included all 7 patients with no response (P=0.012 versus patients with complete depletion of B cells). Memory B cell (P=0.02) and plasmablast (P<0.001) repopulation after 26 weeks was markedly faster in patients with earlier relapse versus patients with later relapse. Our findings indicate that rituximab is effective in SLE, and clinical responses are supported by close correlation with B cell numbers. HSFC is a valuable tool in the assessment and prediction of response in SLE.
    Arthritis & Rheumatology 05/2011; 63(10):3038-47. · 7.48 Impact Factor
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    ABSTRACT: Studies comparing 500 mg rituximab and 1,000 mg rituximab doses in rheumatoid arthritis have yielded conflicting data on clinical outcomes, but in all of these studies a subgroup of patients has had excellent responses at the lower dose. Historically, it was considered that rituximab uniformly depleted B cells at both doses. Using highly sensitive assays, we have shown that B cell depletion is variable and predictive of clinical response. Using the same techniques, we undertook the present study to test the hypothesis that the level of B cell depletion, rather than the rituximab dose, determines clinical response. Nineteen patients were treated with two 500-mg infusions of rituximab, and 61 patients were treated with two 1,000-mg infusions of rituximab. Highly sensitive flow cytometry was performed at 0, 2, 6, 14, and 26 weeks. European League Against Rheumatism (EULAR) response rates at 6 months were compared between patients with and those without complete depletion at each dose. The median B cell count was numerically higher at all time points following therapy in the 500 mg rituximab group. Twenty-five percent of patients in the 500 mg rituximab group had complete depletion at 2 weeks, compared with 49% of those in the 1,000 mg rituximab group. Complete depletion at 2 weeks after treatment with 500 mg rituximab was associated with lower baseline preplasma cell counts (P = 0.047). Most patients responded after either dose, but response was related to B cell depletion. Notably, in the 500 mg rituximab group all patients with complete depletion had a EULAR good response (P = 0.011). This pilot study suggests that the degree of B cell depletion, rather than the dose of rituximab, determines clinical response. It may be possible to predict which patients will respond to lower-dose rituximab, and this may allow more cost-effective treatment.
    Arthritis & Rheumatology 03/2011; 63(3):603-8. · 7.48 Impact Factor
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    ABSTRACT: Histological transformation, typically to diffuse large B-cell lymphoma (DLBCL) is reported to occur in 5%-10% of patients with WM and recent studies have highlighted a possible aetiological role for the nucleoside analogues. It is however becoming increasingly clear that histological transformation is a complex phenomenon and may include clonally unrelated disorders. In order to highlight this pathological heterogeneity we describe 5 patients with diverse histological progression events. These included EBV-associated events namely DLBCL, peripheral T-cell lymphoma and spontaneously resolving mucocutaneous ulcer. A further 2 patients demonstrated a localised plasma cell rich lesion simulating plasmacytoma and a de novo DLBCL arising in an unrelated B-cell clone. It is clear therefore that detailed pathological assessments are required in all suspected cases of transformation and that the pathological heterogeneity demonstrated by this study needs to be taken into account when potential aetiological factors are being assessed.
    Clinical lymphoma, myeloma & leukemia 02/2011; 11(1):176-9.
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    ABSTRACT: BackgroundB cell depletion using rituximab appears effective in systemic lupus erythematosus (SLE) in open label case series, but initial response, effect on autoantibody titres and time to relapse are highly variable.Objective To investigate relationships between clinical response, B cell subsets and autoantibody titres during rituximab therapy for SLE.Materials and methods41 patients with active SLE received a standard regime of rituximab with intravenous and oral steroids. Clinical response and relapse were defined using BILAG with criteria for response, non-response and relapse. Naïve(CD19+CD27-CD38+/-), memory(CD19+CD27+CD38+/-) and plasmablast(CD19+CD27++CD38++) numbers were measured by flow cytometry evaluating 500 000 events at baseline, after each infusion of rituximab and then three monthly. BILAG and B cell numbers were compared between patient groups using non-parametric tests and anti-dsDNA and immunoglobulin titres were log transformed and compared using t tests.ResultsThere was significant reduction in global BILAG (p
    Annals of The Rheumatic Diseases - ANN RHEUM DIS. 01/2011; 70(2).
  • Leukemia Research - LEUK RES. 01/2011; 35.
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    ABSTRACT: Antibody-drug conjugates (ADCs) are potent cytotoxic drugs linked to antibodies through chemical linkers, and allow specific targeting of drugs to neoplastic cells. The expression of CD22 is limited to B-cells, and we show that CD22 is expressed on the vast majority of non-Hodgkin's lymphomas (NHLs). An ideal target for an ADC for the treatment of NHL would have limited expression outside the B-cell compartment and be highly effective against NHL. We generated an ADC consisting of a humanized anti-CD22 antibody conjugated to the anti-mitotic agent maytansine with a stable linker (anti-CD22-MCC-DM1). Anti-CD22-MCC-DM1 was broadly effective in in vitro killing assays on NHL B-cell lines. We did not find a strong correlation between in vitro potency and CD22 surface expression, internalization of ADC or sensitivity to free drug. We show that anti-CD22-MCC-DM1 was capable of inducing complete tumor regression in NHL xenograft mouse models. Further, anti-CD22-MCC-DM1 was well tolerated in cynomolgus monkeys and substantially decreased circulating B-cells as well as follicle size and germinal center formation in lymphoid organs. These results suggest that anti-CD22-MCC-DM1 has an efficacy, safety and pharmacodynamic profile that support its use as a treatment for NHL.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 09/2010; 24(9):1566-73. · 10.16 Impact Factor
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    ABSTRACT: A proportion of patients with rheumatoid arthritis (RA) have disease that fails to respond to an initial cycle of rituximab. Using highly sensitive flow cytometry (HSFC), it has been shown that most patients who do not exhibit a response, as measured using the European League Against Rheumatism (EULAR) criteria, have persistent circulating B cell levels at week 2 after initial treatment with rituximab. This study was undertaken to examine whether an additional cycle of rituximab would improve B cell depletion and clinical response in patients whose disease did not respond to the initial cycle. Patients with RA (n = 158) were treated with a first cycle of rituximab (2 infusions of 1 gm each). Clinical responses were assessed using EULAR criteria, and patients were categorized as either first-cycle responders or first-cycle nonresponders. Baseline characteristics of first-cycle nonresponders (n = 38) and first-cycle responders (n = 65) with complete data were compared. First-cycle nonresponders (n = 25) were treated with a second cycle of rituximab at least 6 months after the first cycle. HSFC was performed at baseline, immediately prior to the second infusion (week 2), 1 month after the second infusion (week 6), and then every 3 months for each cycle of rituximab. Complete B cell depletion was defined as being <0.0001 x 10(9) cells/liter. At baseline, the number of preplasma cells was significantly higher in first-cycle nonresponders than in first-cycle responders (P = 0.003). Following the first infusion of the first cycle of rituximab, only 9% of first-cycle nonresponders (3 of 34) exhibited complete depletion of B-lineage cells, compared with 37% of first-cycle responders (22 of 59) (P = 0.007). Following the first infusion of the second cycle of rituximab, 38% of first-cycle nonresponders exhibited complete depletion. Twenty-six weeks after the second cycle, there was a significant improvement in the Disease Activity Score in 28 joints, with 72% of patients exhibiting a EULAR response. RA patients whose disease did not respond to an initial cycle of rituximab have higher circulating preplasma cell numbers at baseline and incomplete depletion. Our findings indicate that an additional cycle of rituximab administered prior to total B cell repopulation enhances B cell depletion and clinical responses.
    Arthritis & Rheumatology 05/2010; 62(5):1273-9. · 7.48 Impact Factor
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    ABSTRACT: Chronic lymphocytic leukemia (CLL) and the other low-grade non-Hodgkin lymphomas are among the most common lymphoid malignancies. Recent studies suggest that more than 4% of the general population over age 40 harbor a population of clonal B cells with the phenotype of either CLL or another B-cell malignancy, a condition now designated monoclonal B-cell lymphocytosis (MBL). Although all cases of CLL appear to be preceded by MBL, the majority of individuals with MBL will not develop a hematologic malignancy. The biologic characteristics and clinical implications of MBL appear to differ based on whether it is identified during the diagnostic evaluation of lymphocytosis or incidentally discovered through screening of individuals with normal lymphocyte counts as part of research studies using highly sensitive detection methods. In this paper, we provide a state of the art review on the prevalence, nomenclature, biology, natural history and clinical management of MBL.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 03/2010; 24(3):512-20. · 10.16 Impact Factor
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    ABSTRACT: A relatively high number of different subsets of B-cells are generated through the differentiation of early B-cell precursors into mature B-lymphocytes in the bone marrow (BM) and antigen-triggered maturation of germinal center B-cells into memory B-lymphocytes and plasmablasts in lymphoid tissues. These B-cell subpopulations, which are produced in the BM and lymphoid tissues, recirculate through peripheral blood (PB), into different tissues including mucosa and the BM, where long-living plasma cells produce antibodies. These circulating PB B-cells can be classified according to their maturation stage into i) immature/transitional, ii) naïve, and iii) memory B-lymphocytes, and iv) plasmablasts/plasma cells. Additionally, unique subsets of memory B-lymphocytes and plasmablasts/plasma cells can be identified based on their differential expression of unique Ig-heavy chain isotypes (e.g.: IgM, IgD, IgG, IgA). In the present paper, we review recent data reported in the literature about the distribution, immunophenotypic and functional characteristics of these cell subpopulations, as well as their distribution in PB according to age and seasonal changes. Additional information is also provided in this regard based on the study of a population-based cohort of 600 healthy adults aged from 20 to 80 years, recruited in the Salamanca area in western Spain. Detailed knowledge of the distribution and traffic of B-cell subsets through PB mirrors the immune status of an individual subject and it may also contribute to a better understanding of B-cell disorders related to B-cell biology and homeostasis, such as monoclonal B-cell lymphocytosis (MBL).
    Cytometry Part B Clinical Cytometry 01/2010; 78 Suppl 1:S47-60. · 2.23 Impact Factor
  • Annals of The Rheumatic Diseases - ANN RHEUM DIS. 01/2010; 69(2).
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    Arthritis & Rheumatology 07/2009; 60(6):1867; author reply 1867-8. · 7.48 Impact Factor

Publication Stats

2k Citations
362.60 Total Impact Points

Institutions

  • 2004–2012
    • Leeds Teaching Hospitals NHS Trust
      Leeds, England, United Kingdom
  • 2011
    • The University of York
      York, England, United Kingdom
  • 2010
    • Mayo Foundation for Medical Education and Research
      • Division of Hematology
      Scottsdale, AZ, United States
  • 1997–2010
    • University of Leeds
      • • Leeds Institute of Molecular Medicine (LIMM)
      • • School of Medicine
      Leeds, England, United Kingdom