Rheumatoid Arthritis: Panayi G

Emery P, Panayi G, Sturrock R, Williams B. · No affiliation provided · Rheumatology (Oxford). · Pubmed #10534539 links to  free full text

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Panayi G, Corrigall V. · Academic Department of Rheumatology, King's College London, Guy's Hospital, London SE1 9RT, UK. · Autoimmun Rev. · Pubmed #15309771 No free full text.

This publication has no abstract.

Choy E, Panayi G. · Department of Rheumatology, GKT School of Medicine, King's College, London. · Clin Exp Rheumatol. · Pubmed #10589353 No free full text.

Abstract: Second-line agents are used commonly for the treatment of rheumatoid arthritis (RA). They suppress inflammation and ameliorate symptoms but often fail to substantially improve long-term disease outcome. Their use in RA was discovered serendipitously and their modes of action were largely unknown. Recent researches have identified some of their mechanisms of action. Most of them have antiinflammatory properties and some are immunomodulators. Traditionally, second-line agents are used as monotherapy, but recent evidence suggests that combination treatment with two or more drugs may be more efficacious. However, the choice of agents in combination therapy is not based on their mechanisms of action. We review current knowledge on the modes of action of second-line agents and assess whether such understanding may offer a rational basis for combination therapy.

Baslund B, Tvede N, Danneskiold-Samsoe B, Larsson P, Panayi G, Petersen J, Petersen LJ, Beurskens FJ, Schuurman J, van de Winkel JG, Parren PW, Gracie JA, Jongbloed S, Liew FY, McInnes IB. · Rigshospitalet, Copenhagen, Denmark. · Arthritis Rheum. · Pubmed #16142748 links to  free full text

Abstract: OBJECTIVE: Interleukin-15 (IL-15) is a proinflammatory, innate response cytokine that mediates pleiotropic effector function in rheumatoid arthritis (RA) inflammatory synovitis. Our objective was to study the ability of HuMax-IL15, a human IgG1 anti-IL-15 monoclonal antibody, to neutralize exogenous and endogenous IL-15 activity in vitro and to perform a phase I-II dose-escalation trial with HuMax-IL15 in patients with active RA. METHODS: Mononuclear cells from blood and synovial fluid (SF) of RA patients were isolated and cultured in vitro under experimental conditions involving the addition of HuMax-IL15. HuMax-IL15 was administered to 30 RA patients who received no other disease-modifying antirheumatic drugs in a 12-week, dose-ascending, placebo-controlled, double-blind, phase I-II proof-of-concept study. RESULTS: In vitro studies showed that HuMax-IL15 suppressed proliferation and induced apoptosis in an IL-15-dependent cell line, BDB2, and was capable of suppressing the release of interferon-gamma by synovial fluid mononuclear cell (SFMC) cultures induced by exogenous IL-15. Furthermore, HuMax-IL15 F(ab')2 fragments suppressed exogenous IL-15-induced CD69 expression in RA peripheral blood mononuclear cells and SFMCs, which indicates that HuMax-IL15 can specifically neutralize several biologic effects of IL-15 in synovial tissue in vitro. In a phase I-II clinical trial, HuMax-IL15 was well tolerated clinically, with no significant effects on T lymphocyte subset and natural killer cell numbers. Substantial improvements in disease activity were observed according to the American College of Rheumatology criteria for 20% improvement (63% of patients), 50% improvement (38%), and 70% improvement (25%). CONCLUSION: These clinical data suggest for the first time that IL-15 could represent a novel therapeutic target in RA.

Wong M, Oakley SP, Young L, Jiang BY, Wierzbicki A, Panayi G, Chowienczyk P, Kirkham B. · Guy's and St Thomas' Hospital, London, UK. · Ann Rheum Dis. · Pubmed #18930987 links to  free full text

Abstract: OBJECTIVES: Patients with rheumatoid arthritis (RA) have increased cardiovascular mortality. Tumour necrosis factor alpha (TNFalpha)-blocking therapy has been shown to reduce RA disease activity measures and joint damage progression. Some observational studies suggest that TNFalpha blockade reduces mortality and incidence of first cardiovascular events. The mechanisms contributing to these outcomes are unclear. This study assessed the effects of infliximab treatment on vascular stiffness and structure in patients with RA. METHODS: A post hoc analysis of longitudinal data from a randomised placebo controlled study evaluated the effect of infliximab on vascular assessments. 26 patients received intravenous infliximab (3 mg/kg) at weeks 0, 2, 6 and every 8 weeks thereafter to week 54. Patients were followed up to 56 weeks of infliximab therapy with assessments of RA disease activity, cardiovascular risk factors, vascular stiffness (pulse wave velocity (PWV)), carotid intima media thickness (CIMT) and carotid artery plaque (CAP). Univariate analyses of changes over time by repeated measures analysis of variance (ANOVA) were followed by multivariate time-series regression analysis (TSRA) if changes were seen. RESULTS: PWV was significantly lower (better) after 56 weeks of treatment with infliximab (ANOVA p<0.01, TSRA p<0.01). However, CIMT (ANOVA p = 0.50) and CAP (chi(2) = 4.13, p = 0.88) did not change over the study period. Multiple cardiovascular risk measures did not change with treatment and did not correlate with changes in measures of vascular structure. CONCLUSIONS: Arterial stiffness improves with infliximab treatment in RA. This change may help explain the improved cardiovascular disease survival in patients with RA receiving TNFalpha-blocking therapy.

Woods AM, Thompson SJ, Wooley PH, Panayi G, Klavinskis LS. · King's College London School of Medicine at Guy's, St. Thomas' Hospital, London, UK. · Arthritis Rheum. · Pubmed #16329091 links to  free full text

Abstract: OBJECTIVE: To develop a passively targeted, patient-compliant, intranasal interleukin-10 (IL-10) gene therapy delivery system and to investigate its therapeutic benefit in experimental collagen-induced arthritis, a model of rheumatoid arthritis. METHODS: Arthritis was induced in DBA/1 mice and monitored following intranasal administration of an IL-10 plasmid (pG-IL-10) or the empty vector 2 days (days -2 and 19) prior to collagen injection (prophylactic group, as a single dose after collagen boost on day 21 (early therapy group, or as a single dose upon acquisition of a disease score of 3 (late therapy group. IL-10-induced alterations in cytokine secretion and proliferation by spleen and lymph node cells were assessed on days 31 and 65 and correlated with histologic changes and bone erosions assessed on day 65. RESULTS: Intranasal delivery of pG-IL-10 significantly delayed arthritis onset and reduced disease severity in the prophylactic group and early therapy group, reduced cellular infiltration and bone loss in the early therapy group, and reduced T cell proliferation in response to collagen on days 31 and 65 in these two groups, with a significant reduction in tumor necrosis factor alpha production on day 65. Within the late therapy group, disease progression was arrested for the rest of the study. The intranasally administered pG-IL-10 targeted monocytes and macrophages and showed dissemination to inflamed joints and draining lymph nodes in vivo. Importantly, systemic levels of IL-10 (in serum) were transient (peaking on day 2) and undetectable by day 4. CONCLUSION: Intranasal IL-10 gene delivery significantly reduces bone destruction, shows evidence of reducing joint inflammation, and may be mediated by high local levels of IL-10 produced by transfected monocytes trafficking to inflamed joints and draining lymph nodes.

Nissim A, Winyard PG, Corrigall V, Fatah R, Perrett D, Panayi G, Chernajovsky Y. · Bones and Joint Research Unit, Barts and The London, University of London, London, UK. · Arthritis Rheum. · Pubmed #16329077 links to  free full text

Abstract: OBJECTIVE: Collagen-induced arthritis is a commonly accepted model of rheumatoid arthritis (RA). However, it has been difficult to substantiate the involvement of autoimmunity to type II collagen (CII) in the pathogenesis of RA. The aim of this investigation was to determine if CII, modified by reactive oxidant species present within the inflamed joint, could generate neoantigenic epitopes. METHODS: Oxidants that play a role in acute and chronic inflammation and are present in the rheumatoid joint (hydroxyl radical, hypochlorous acid, and peroxynitrite) were used for modification of native CII. In addition, CII was glycated with ribose, since nonenzymatic oxidative reactions by glycation are evident in RA. Modifications were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and 3-dimensional fluorescence followed by enzyme-linked immunosorbent assay (ELISA) and Western blotting, using, as probes, sera from patients with RA and from patients with other inflammatory and noninflammatory joint diseases. RESULTS: Only 1 RA serum sample showed strong binding to native CII. In contrast, binding to modified CII was increased in 14 of 31 RA sera, of which 7 were strong binders and 7 were moderate binders. Among the non-RA serum samples, only 1 yielded a strong reaction to modified CII and 5 of 41 were moderate binders. Samples that showed the strongest binding to modified CII in ELISA also showed strong binding to various fragmented or aggregated forms of CII in Western blots, as well as strong binding to fragmented CII present in RA synovial fluid. CONCLUSION: When modified by conditions found within the inflamed joint, CII acts as an autoantigen in RA.

Bennett AN, Peterson P, Zain A, Grumley J, Panayi G, Kirkham B. · Department of Rheumatology, Thomas Guy House, Guy's Hospital, St Thomas Street, London SE1 9RT, UK. · Rheumatology (Oxford). · Pubmed #15870150 links to  free full text

Abstract: OBJECTIVE: To assess the efficacy and safety of the fully human recombinant monoclonal anti-TNF antibody adalimumab in routine clinical practice, including comparison of patients with and without previous anti-TNF exposure. METHODS: We prospectively studied the outcome of 70 rheumatoid arthritis patients treated with adalimumab in normal clinical practice. The primary outcome measures were Disease Activity Score 28 (DAS28), EULAR (European League Against Rheumatism) response and Health Assessment Questionaire (HAQ). RESULTS: Seventy-seven per cent achieved a EULAR response (26% good, 51% moderate) and 19% were in remission. The mean decrease in DAS28 was 2.1 (6.3-4.2; P<0.001). The mean decrease in HAQ score was 0.34 (2.07-1.73; P<0.001), 66% achieving a clinically significant decrease of greater than 0.22. Twenty-three per cent stopped treatment because of side-effects (7%) or failure to respond (16%). Of the 26 patients who had previously tried 29 biologicals, 65% responded to adalimumab. There was no significant difference in the change in mean DAS (P = 0.69) or HAQ (P = 0.88) between groups with and without previous anti-TNF exposure. Of the 13 patients with previous secondary failure to infliximab, 77% responded to adalimumab. Patients with previous secondary failure had significantly better improvement in DAS (P = 0.023) than patients with previous primary failure. CONCLUSION: Our clinical experience confirms that adalimumab is effective and safe in the treatment of RA. It also shows adalimumab is effective in patients with previous biological failures, particularly patients with secondary failure to infliximab.

Lee L, Buckley C, Blades MC, Panayi G, George AJ, Pitzalis C. · Guy's, King's, and St Thomas' School of Medicine, London, UK. · Arthritis Rheum. · Pubmed #12209516 links to  free full text

Abstract: OBJECTIVE: To identify homing peptides specific for human synovium that could be used as targeting devices for delivering therapeutic/diagnostic agents to human joints. METHODS: Human synovium and skin were transplanted into SCID mice. A disulfide-constrained 7-amino acid peptide phage display library was injected intravenously into the animals and synovial homing phage recovered from synovial grafts. Following 3-4 cycles of enrichment, DNA sequencing of homing phage clones allowed the identification of specific peptides that were synthesized by a-fluorenylmethyloxycarbonyl chemistry and used in competitive in vivo assays and immunohistochemistry analyses. RESULTS: We isolated synovial homing phages displaying specific peptides that distinctively bound to synovial but not skin or mouse microvascular endothelium (MVE). They retained their tissue homing specificity in vivo, independently from the phage component, the original pathology of the transplanted tissue, and the degree of human/murine graft vascularization. One such peptide (CKSTHDRLC) maintained synovial homing specificity both when presented by the phage and as a free synthetic peptide. The synthetic peptide also competed with and inhibited in vivo the binding of the parent phage to the cognate synovial MVE ligand. CONCLUSION: This is the first report describing peptides with homing properties specific for human synovial MVE. This was demonstrated using a novel approach targeting human tissues, transplanted into SCID mice, directly by in vivo phage display selection. The identification of such peptides opens the possibility of using these sequences to construct joint-specific drug delivery systems that may have considerable impact in the treatment of arthritic conditions.

Ingegnoli F, Blades M, Manzo A, Wahid S, Perretti M, Panayi G, Pitzalis C. · Cattedra di Reumatologia, Università degli Studi di Milano, Istituto Ortopedico G. Pini, Italia. · Reumatismo. · Pubmed #12105681 links to  free full text

Abstract: OBJECTIVE: Adhesion mechanisms play a central role in the recruitment of leukocytes which characteristically infiltrate rheumatoid synovium. Therefore, we adapted an animal model, in which human rheumatoid synovium was transplanted into severe combined immunodeficient (SCID) mice, to study the effects of Tumor Necrosis Factor-alpha (TNF-alpha) in modulatine leukocyte migration and to investigate the chemotactic potential of Stromal Derived Factor-1 alpha (SDF-1 alpha). MATERIALS AND METHODS: Human synovium samples, obtained from patients undergoing joint replacement, were divided into two parts. One was analysed by immunohistology and the other was implanted subcutaneously into SCID mice under general anaesthesia. Four weeks post-transplantation, grafts were injected with optimal dose of SDF-1, TNF-alpha or saline (negative control). At the same time, animals were injected iv with fluorescently labelled cells. 48 hours later mice were sacrificed and grafts removed for cryo-hystology. The number of cells migrating to the grafts was determined by UV-microscopy and the results expressed as cells per high power field. RESULTS AND CONCLUSIONS: In these studies we provide the evidence that: 1) the animal model, in which human tissues are grafted into SCID mice, can be used to study cell migration under controlled experimental conditions; 2) direct intragraft injection of TNF-alpha increases lymphocytes migration and up-regulates the expression of human adhesion molecules (CAMs) and 3) SDF-1 alphainjected intragraft increases the migration of the pro-myelo-monocytic U937 cells to synovial transplants, even more efficiently than TNF-alpha, but without modifications of CAMs' expression.

Huizinga TW, Keijsers V, Yanni G, Hall M, Ramage W, Lanchbury J, Pitzalis C, Drossaers-Bakker WK, Westendorp RG, Breedveld FC, Panayi G, Verweij CL. · Department of Rheumatology and. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. · Rheumatology (Oxford). · Pubmed #11085795 links to  free full text

Abstract: OBJECTIVE: Constitutive differences between individuals in cytokine production may determine the variation in the course of inflammatory arthritis. METHODS: The association between interleukin 10 (IL-10) production and joint destruction was studied by comparing IL-10 mRNA content in synovial biopsies from seven patients with destructive joint disease and six patients with non-destructive joint disease. The IL-10 mRNA content was 0.4 +/- 0.6 arbitrary units in erosive joints compared with 2.3 +/- 1.2 arbitrary units in non-erosive joints (P: < 0.03, Mann-Whitney U:-test). As this difference suggested that IL-10 production was associated with joint destruction, we tested whether the IL-10 locus determined the extent of joint damage. RESULTS: Innate differences in IL-10 production are locus-dependent. In line with these data, we showed that innate differences in IL-10 protein production were also present as differences in IL-10 mRNA levels. We tested if polymorphisms in the promoter of IL-10 were associated with the extent of joint damage. DISCUSSION: In a cohort study of female rheumatoid arthritis patients followed for 12 yr, the extent of joint destruction differed significantly between patients with different IL-10 genotypes. In patients with the -1082AA genotype who were studied prospectively, the mean increase in radiographic damage score (modified Sharp score of X-rays of hands and feet) during the first 6 yr was 9 +/- 9 per yr vs 19 +/- 16 per yr for patients with the genotype -1082GG (P: < 0.02). In line with these data, cultures of endotoxin-stimulated whole blood from 158 donors showed that the presence of the allele associated with less joint destruction correlated with slightly higher IL-10 production. CONCLUSIONS: Both the immunogenetic and the synovial biopsies suggest that a variation in IL-10 production is associated with joint destruction.

Bennett AN, Wong M, Zain A, Panayi G, Kirkham B. · No affiliation provided · Rheumatology (Oxford). · Pubmed #15870147 links to  free full text

This publication has no abstract.