Rheumatoid Arthritis: Buch MH

Goëb V, Buch MH, Vital EM, Emery P. · Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds, Leeds LS7 4SA, UK. · Curr Opin Rheumatol. · Pubmed #19342956 No free full text.

Abstract: PURPOSE OF REVIEW: To describe the mechanisms of action of abatacept (CTLA4-Ig) and summarize the evidence of its efficacy and safety in rheumatoid arthritis (RA) and other rheumatic diseases such as juvenile idiopathic arthritis (JIA). RECENT FINDINGS: Several studies have demonstrated the clinical efficacy (disease activity, quality of life, prevention of structural damage) of abatacept in patients with RA who have failed to respond to standard disease-modifying antirheumatic drugs (DMARDs) and antitumour necrosis factor-alpha biologic agents. Selective modulation of T-cell costimulation may also be an alternative therapy for children with JIA who are resitant to conventional DMARDs or biologics. SUMMARY: T-cell activation is critical to the onset and maintenance of RA. Abatacept (CTLA4-Ig), the first selective T-cell costimulation modulator has shown to be effective in RA and JIA. Recent 2-year data from the 'AIM' trial suggests an increased and sustained effect of blocking of T cell signalling on the inhibition of RA structural damage progression over time. Abatacept's safety profile in combination with DMARDs also seems to be favourable but should be avoided in combination with other biologics.

Buch MH, Vital EM, Emery P. · Academic Unit of Musculoskeletal Disease, University of Leeds, Chapeltown Road, Leeds, LS7 4SA, UK. · Arthritis Res Ther. · Pubmed #19007425 links to  free full text

Abstract: T-cell biology has regained importance in the pathogenesis of rheumatoid arthritis. Despite the significant improvements associated with the introduction of tumor necrosis factor-alpha blockade, reasonable proportions of failures and suboptimal responses have been reported, necessitating a search for alternative targeted therapies. This has included drug therapy designed to interrupt T-cell activation via the co-stimulation pathway. Abatacept is a recombinant fusion protein that blocks the co-stimulatory signal mediated by the CD28-CD80/86 pathway, which is required for T-cell activation. Several clinical trials have confirmed the safety and efficacy of this drug in the treatment of rheumatoid arthritis. This review summarizes the clinical data supporting this line of treatment and considers the safety and efficacy data from phase II and III trials.

Buch MH, Boyle DL, Rosengren S, Saleem B, Reece RJ, Rhodes LA, Radjenovic A, English A, Tang H, Vratsanos G, O'Connor P, Firestein GS, Emery P. · Academic Unit of Musculoskeletal Disease, University of Leeds, Leeds, UK. · Ann Rheum Dis. · Pubmed #18772191 links to  free full text

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

Buch MH, Reece RJ, Quinn MA, English A, Cunnane G, Henshaw K, Bingham SJ, Bejarano V, Isaacs J, Emery P. · Academic Unit of Musculoskeletal Disease, University of Leeds, Leeds, UK. · Rheumatology (Oxford). · Pubmed #18660510 No free full text.

Abstract: OBJECTIVES: Clinical response to TNF-alpha blockade in the treatment of RA is heterogeneous. The study aims were to determine whether pre-treatment synovial cytokine expression predicted infliximab response and whether synovial changes after therapy correlated with response. METHODS: Fifty-one patients had arthroscopic biopsies of the knee joint prior to infliximab (3 mg/kg) treatment. Synovial tissue cell numbers (CD68 and CD3 positive) and cytokine expression (TNF-alpha, lymphotoxin-alpha, IL-1alpha, -beta and receptor antagonist, and IL-6) pre-treatment was assessed using semi-quantitative immunohistochemistry. Changes in these parameters were assessed 16 weeks after infliximab in 32 patients who underwent repeat arthroscopic biopsy. RESULTS: Of the total patients, 47% (n = 24) achieved an ACR20 response; 53% (n = 27) did not. Baseline synovial TNF-alpha, IL-1alpha and -beta expression did not differ between the two groups. No differences in baseline TNF-alpha levels were observed with ACR levels of response (ACR20 and ACR50/70 groups). Post-treatment biopsies (17 ACR responders, 15 ACR non-responders) revealed significant reductions in sub-lining layer TNF-alpha expression in both response and non-response groups with significant reduction in vascularity and membrane proliferation scores. The worst ACR non-responders (<20% CRP suppression) demonstrated no reduction in any of the parameters. CONCLUSION: Pre-treatment synovial TNF-alpha or IL-1 expression does not predict TNF blockade response. Both ACR response and non-response was associated with reduction in synovial TNF-alpha-level expression. Suppression in TNF-alpha levels was not observed in the worst non-responders. The improvements (including in vascularity), independent of ACR clinical response, are compatible with the reduced structural damage documented in all groups of patients independent of response.

Buch MH, Bingham SJ, Bryer D, Emery P. · Academic Section of Musculoskeletal Disease, Chapel Allerton Hospital, Leeds LS7 4SA, UK. · Rheumatology (Oxford). · Pubmed #17478470 links to  free full text

Abstract: OBJECTIVE: Patients may cease therapy with anti-tumour necrosis factor (TNF) agents due to inefficacy at 12 weeks (termed primary non-response) or later. Until now, the extent of this later secondary non-response has not been clearly defined. We followed-up a substantial single-centre cohort to determine kinetics of this secondary loss of response. The licensed dose of 3 mg/kg was used throughout. METHODS: Prospective data collection since anti-TNF therapy introduction in 1999 formed the basis of the analysis. Patients with rheumatoid arthritis who received infliximab as their first biologic agent, with at least 2 yrs follow-up were included. All relevant clinical data to calculate DAS-28 score and EULAR response were collected at 3, 6, 9, 12, 18 and 24 months. Reasons for cessation in those patients achieving a EULAR response at 3 months (secondary failures) were determined. RESULTS: Of a total of 309 patients commenced on infliximab, 290 received this as their first biologic agent.; 195 commenced > or = 2 yrs ago. Efficacy data to identify EULAR responders at 3 months was available in 174 patients. Sixty-seven per cent achieved a 'moderate' or 'good' EULAR response; 25% failed to achieve a response, 8% developed toxicity within the first 12 weeks. Of the primary responders, over 55% subsequently ceased therapy in the first year, the predominant reason was a secondary loss of response; other reasons included high disease activity despite achieving a definable response, toxicity, and intercurrent illness. Subsequent loss of response in the second year was less pronounced. CONCLUSIONS: This study of patients treated in clinical practice with infliximab demonstrated that secondary non-response occurred in around half the patients in the first year. The data highlight the need to continue development of other therapies as well as investigation of the underlying causes of this loss of response.

Buch MH, Bingham SJ, Bejarano V, Bryer D, White J, Reece R, Quinn M, Emery P. · University of Leeds, Leeds, UK. · Arthritis Rheum. · Pubmed #17394231 links to  free full text

Abstract: OBJECTIVE: The role of alternative tumor necrosis factor (TNF) antagonist therapies in the context of failure of initial TNF antagonist therapy in patients with rheumatoid arthritis (RA) has yet to be clearly defined. The goal of this study was to determine the efficacy of etanercept in patients who failed to respond to infliximab. METHODS: Ninety-five patients with RA who failed to respond to infliximab and methotrexate were treated with etanercept (with continuation of concomitant methotrexate). Thirty-four patients never achieved a response to infliximab (primary nonresponse), 38 had an initial response to infliximab but relapsed (secondary nonresponse), and 23 demonstrated toxicity. Disease Activity Score in 28 joints (DAS28), European League Against Rheumatism (EULAR) response, and American College of Rheumatology (ACR) response were determined after 12 weeks of etanercept. RESULTS: After 12 weeks of etanercept, 38% of patients achieved an ACR 20% response (ACR20) on etanercept. Of these, 24% and 15% achieved ACR50 and ACR70 responses, respectively. In the primary infliximab nonresponse group, 42%, 30%, and 15% achieved ACR20, ACR50, and ACR70 responses, respectively; the percentages for the secondary nonresponse group were 34%, 21%, and 14%, respectively. Significant DAS28 reductions were observed in the entire cohort and nonresponse subtype groups. Sixty-one percent of the cohort achieved either a moderate or good EULAR score (67% of primary and 56% of secondary infliximab failures). No toxicity was observed in patients who stopped infliximab due to intolerance; 19 of 23 continued etanercept after week 12. CONCLUSION: This study confirms that etanercept is effective in patients who fail to respond to infliximab and suggests a higher response in patients who have never had a response to infliximab.

Buch MH, Emery P. · Leeds Teaching Hospital, Leeds, UK. · Nat Clin Pract Rheumatol. · Pubmed #16932704 No free full text.

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Buch MH, Seto Y, Bingham SJ, Bejarano V, Bryer D, White J, Emery P. · University of Leeds, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK. · Arthritis Rheum. · Pubmed #15641046 links to  free full text

Abstract: OBJECTIVE: Nonresponse to anti-tumor necrosis factor alpha in patients with rheumatoid arthritis (RA) is poorly understood. The aims of this study were to define nonresponse patterns using infliximab and C-reactive protein (CRP) profiles, to assess the predictive power of a CRP response for outcome, and to correlate these findings with subsequent response to etanercept. METHODS: We studied 207 patients with resistant RA who were started on treatment with infliximab. After 12 weeks, the American College of Rheumatology 20% improvement criteria (ACR20) were used to classify patients as responders (ACR20 response or greater) or nonresponders (NRs). The NRs were further subdivided into 3 groups according to the CRP response at weeks 2, 6, and 12. Within the NR group, those with a suppressed CRP at week 12 continued taking infliximab for a further 12 weeks; those without a CRP response were switched to etanercept, and the ACR response at 12 weeks was calculated. RESULTS: At week 12, 54% of patients achieved an ACR20 response, and 46% failed to achieve a response. Of the NRs, 63% demonstrated a significant reduction in the CRP level at week 12, 59% of whom achieved an ACR20 response at week 24 on continuation of infliximab. Of the patients who did not demonstrate a significant reduction in the CRP level after the first infusion, 86% failed to show a biochemical or ACR20 response by week 12. Twenty-four percent of the NRs had a temporary reduction in the CRP level, and 13% of the NRs showed no CRP reduction. Seventy-five percent of these NRs switched to etanercept, and 68% of this group achieved an ACR20 response at week 12 (51% achieved an ACR50 response), with a CRP response in 63%. CONCLUSION: Infliximab NRs comprise subtypes with distinct CRP patterns. Failure to suppress the CRP at week 2 identified the majority of patients who were NRs at week 12. CRP suppression at week 12 in the NRs was associated with a late clinical improvement with infliximab treatment (24 weeks), whereas failure to suppress the CRP at week 12 was associated with a good response on switching to etanercept.

Bingham SJ, Buch MH, Kerr MA, Emery P, Valadäo Barcelos AT. · Leeds General Infirmary, Leeds, UK. · Arthritis Rheum. · Pubmed #15593202 links to  free full text

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Buch MH, Conaghan PG, Quinn MA, Bingham SJ, Veale D, Emery P. · Academic Unit of Musculoskeletal Disease, 1st Floor, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK. · Ann Rheum Dis. · Pubmed #15033655 links to  free full text

Abstract: BACKGROUND: The combination of methotrexate and the anti-tumour necrosis factor alpha (TNFalpha) antibody infliximab is a very effective treatment for rheumatoid arthritis (RA). However, a proportion of patients are not responsive to this treatment. Inefficacy may represent a TNFalpha independent disease or insufficient drug at the site of action. CASE REPORT: A patient with RA resistant to repeated high dose infliximab infusions and intra-articular infliximab into an inflamed knee is described. No beneficial clinical effect was observed. Pre-injection arthroscopic biopsy of the study knee demonstrated TNFalpha staining but also confirmed the presence of lymphotoxin alpha (LTalpha or TNFbeta) on immunohistochemistry. Subsequent treatment with etanercept (which blocks LTalpha as well as TNFalpha) resulted in clinical remission of disease. CONCLUSION: This case suggests that resistance to TNF blockade may occur when TNFalpha is not the dominant inflammatory cytokine and suggests that LTalpha may have a pathogenic role in RA.

Buch MH, Bingham SJ, Seto Y, McGonagle D, Bejarano V, White J, Emery P. · University of Leeds, Leeds, UK. · Arthritis Rheum. · Pubmed #15022311 links to  free full text

Abstract: OBJECTIVE: In patients with rheumatoid arthritis (RA) treated with tumor necrosis factor alpha (TNF alpha)- blocking therapy, there is heterogeneity of response. This raises the possibility that in certain circumstances, cytokines such as interleukin-1 (IL-1) may dominate the drive toward joint inflammation. This study was undertaken to investigate whether blocking the action of IL-1 with an IL-1 receptor antagonist (IL-1Ra) is efficacious in patients with disease that did not respond to TNF alpha blockade. METHODS: We identified 26 RA patients whose disease had failed to respond to TNF alpha-blocking therapy, defined as failure to achieve or sustain a 20% improvement in disease activity according to the criteria of the American College of Rheumatology (ACR20 response). These patients were then treated with anakinra (100 mg/day subcutaneously) for 12 weeks, and their levels of response were assessed. RESULTS: After 3 months of anakinra therapy, only 2 of 26 patients (8%) achieved an ACR20 response; none achieved an ACR50 or ACR70 response. A rise in the mean C-reactive protein level and an increase in the mean swollen joint count were noted during the study period. CONCLUSION: This study demonstrates that patients with disease that fails to respond to TNF alpha blockade also do not respond to IL-1Ra. These data do not provide evidence of a dominant role for IL-1 in patients who do not respond to TNF alpha blockade, but they do not exclude a role for other proinflammatory mediators.

Bingham SJ, Buch MH, Tennant A, Emery P. · Rheumatology Research Unit, First Floor, Old Nurses Home, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK. · Rheumatology (Oxford). · Pubmed #14657509 links to  free full text

Abstract: OBJECTIVE: To assess the impact of escalating conventional therapy in patients with RA who satisfy BSR/NICE criteria for biologics. METHODS: A total of 308 consecutive patients referred to a tertiary centre for biological therapy between January 1999 and February 2001 were studied prospectively. They were considered by their own consultant to have failed standard therapy. Prior to biologics, conventional therapy was escalated to include combination and parenteral methotrexate treatment. Patients were assessed at 12-weekly intervals for 1 yr and therapy was changed if response was not satisfactory. The subsequently released BSR/NICE biologic eligibility criteria were applied retrospectively. Response (disease activity, disability and quality of life) to escalated therapy in those patients who did or did not satisfy current eligibility criteria were compared. RESULTS: In total, 159 satisfied BSR/NICE criteria and would have been eligible for immediate treatment with biologics [DAS28 > 5.1, failed methotrexate (20 mg/week or lower dose owing to toxicity) and one other DMARD]; however, 93 of these responded to escalated conventional therapy and did not require biologics [significant improvement (P < 0.01) in disease activity, disability and quality of life]. However, mild disease activity (DAS28 < 3.2) was only achieved in 7% of these patients at 12 months. CONCLUSIONS: Although over half the patients who satisfied standard criteria for biologics responded satisfactorily to escalated therapy, only a minority achieved mild disease activity. The savings achieved by treating with conventional therapies need to be weighed against the risk of persistent disease activity.

Jarrett SJ, Cunnane G, Conaghan PG, Bingham SJ, Buch MH, Quinn MA, Emery P. · Academic Unit of Musculoskeletal Medicine, University of Leeds, Great George Street, Leeds LS1 3EX, United Kingdom. · J Rheumatol. · Pubmed #14528531 No free full text.

Abstract: As experience with anti-tumor necrosis factor (TNF-alpha) therapy increases, there has been the expected emergence of reports on uncommon side effects. Large clinical trials identified the development of autoantibodies and postmarketing surveillance has identified problems including tuberculosis. There have been several case reports of drug-induced systemic lupus erythematosus. We describe eight patients with rheumatoid arthritis treated with anti-TNF therapies who developed presumed vasculitis, with different pathophysiologic causes. We discuss the literature and potential causal mechanisms, including disease activity, the role of autoantibodies, and shifts in T cell responses.

Morgan AW, Keyte VH, Babbage SJ, Robinson JI, Ponchel F, Barrett JH, Bhakta BB, Bingham SJ, Buch MH, Conaghan PG, Gough A, Green M, Lawson CA, Pease CT, Markham AF, Ollier WE, Emery P, Worthington J, Isaacs JD. · Rheumatology and Rehabilitation Research Unit, University of Leeds, UK. · Rheumatology (Oxford). · Pubmed #12649399 links to  free full text

Abstract: OBJECTIVES: To develop a robust assay for genotyping the FcgammaRIIIA-158V/F polymorphism and to confirm the putative association between the FcgammaRIIIA-158V allele and rheumatoid arthritis (RA). METHODS: This allelic association study examined the FcgammaRIIIA-158V/F polymorphism for association with RA. A novel single-stranded conformational polymorphism assay was used to genotype 828 RA patients and 581 controls from the UK. RESULTS: The FcgammaRIIIA-158V allele was associated with both RA (P=0.02) and nodules (P=0.04). Individuals homozygous for this higher affinity allele had a significantly increased risk of RA (OR 1.53, 95% CI 1.08-2.18) and the development of nodules (OR 2.20, 95% CI 1.20-4.01). There was no evidence of an interaction with the shared epitope. CONCLUSIONS: We have developed a novel assay to genotype the FcgammaRIIIA-158F/V polymorphism and confirmed that homozygosity for the FcgammaRIIIA-158V allele is associated with UK Caucasian RA, particularly in those individuals with nodules, suggesting FcgammaRIIIA may play a role in determining disease severity or in the development of nodules per se.

Vital EM, Dass S, Buch MH, Rawstron AC, Ponchel F, McGonagle D, Emery P. · No affiliation provided · Arthritis Rheum. · Pubmed #19479853 No free full text.

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

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Buch MH, Bryer D, Lindsay S, Rees-Evans B, Fairclough A, Emery P. · No affiliation provided · Rheumatology (Oxford). · Pubmed #16352636 links to  free full text

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Buch MH, Marzo-Ortega H, Bingham SJ, Emery P. · No affiliation provided · Rheumatology (Oxford). · Pubmed #14739466 links to  free full text

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Bingham SJ, Buch MH, Lindsay S, Pollard A, White J, Emery P. · No affiliation provided · Rheumatology (Oxford). · Pubmed #12869673 links to  free full text

This publication has no abstract.