Rheumatoid Arthritis: McInnes IB

Brennan FM, McInnes IB. · Kennedy Institute of Rheumatology, Imperial College London, London, UK. · J Clin Invest. · Pubmed #18982160 links to  free full text

Abstract: A large number of cytokines are active in the joints of patients with rheumatoid arthritis (RA). It is now clear that these cytokines play a fundamental role in the processes that cause inflammation, articular destruction, and the comorbidities associated with RA. Following the success of TNF-alpha blockade as a treatment for RA, other cytokines now offer alternative targets for therapeutic intervention or might be useful as predictive biomarkers of disease. In this Review, we discuss the biologic contribution and therapeutic potential of the major cytokine families to RA pathology, focusing on molecules contained within the TNF-alpha, IL-1, IL-6, IL-23, and IL-2 families.

Emery P, McInnes IB, van Vollenhoven R, Kraan MC. · Academic Unit of Musculoskeletal Disease, Leeds University, Leeds LS7 4S, UK. · Rheumatology (Oxford). · Pubmed #18094000 No free full text.

Abstract: Inflammation is the major factor driving the progression of structural damage in rheumatoid arthritis (RA); therefore, it is critical to achieve rapid suppression of inflammation to maximize disease control. The severity of inflammation and progression of joint damage varies from patient to patient. Some patients have the propensity to change slowly over time and then progress in a more rapid and dynamic fashion. In those where inflammation is more severe, extensive damage can occur within only a few years of disease onset. The progress of joint destruction, as assessed radiographically, results in a decline in functional capacity and quality of life. Consequently, the challenge for clinicians is to identify and treat those patients who develop rapid, progressive disease. Several biological markers and clinical indicators have been identified to help predict or establish which of the patients have rapidly progressing disease or who are at most risk for rapid progression. Early diagnosis of patients with rapidly progressing RA enables immediate and intensive intervention (e.g. with biologic therapy) and a greater opportunity to change the course of disease.

McInnes IB, Schett G. · Centre for Rheumatic Diseases, Glasgow Biomedical Research Centre, University of Glasgow, 120 University Place, Glasgow G12 8TA, UK. · Nat Rev Immunol. · Pubmed #17525752 No free full text.

Abstract: Cytokines regulate a broad range of inflammatory processes that are implicated in the pathogenesis of rheumatoid arthritis. In rheumatoid joints, it is well known that an imbalance between pro- and anti-inflammatory cytokine activities favours the induction of autoimmunity, chronic inflammation and thereby joint damage. However, it remains less clear how cytokines are organized within a hierarchical regulatory network, and therefore which cytokines may be the best targets for clinical intervention a priori. Here, we discuss the crucial effector function of cytokines in the immunological processes that are central to the pathogenesis of rheumatoid arthritis.

Asquith DL, McInnes IB. · Glasgow Biomedical Research Centre, Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, UK. · Curr Opin Rheumatol. · Pubmed #17414950 No free full text.

Abstract: PURPOSE OF REVIEW: The utility of cytokines as therapeutic targets in rheumatoid arthritis has been unequivocally demonstrated by the success of tumour necrosis factor blockade in clinical practice. Partial and non-responses to tumour necrosis factor blocking agents, however, together with the increasing clinical drive to remission induction, requires that further therapeutic targets be identified. RECENT FINDINGS: Numerous cytokine activities with pathogenetic potential have now been demonstrated in rheumatoid arthritis synovial membrane, including members of the IL-1 superfamily and the IL-12 superfamily. Continued efforts are ongoing to target IL-6 and IL-15 in clinical trials with promising data emerging. There is particular interest in the biology of IL-17 and of the recently described IL-32 as critical effector mediators. SUMMARY: Novel cytokine activities are emerging on an ongoing basis. There remain difficulties in ascribing the optimal regulatory hierarchy for given moieties on the basis of existing preclinical model systems. This in turn poses novel challenges in determining which cytokines represent the best therapeutic targets.

Connell L, McInnes IB. · Centre for Rheumatic Diseases, University of Glasgow, Glasgow Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER, Scotland, UK. · Best Pract Res Clin Rheumatol. · Pubmed #16980211 No free full text.

Abstract: With the advent of biological therapies, considerable advances have been achieved in the treatment of inflammatory arthritis. These have arisen primarily from studies elucidating mechanisms of pathophysiology and are best exemplified in the wide use of tumour necrosis factor (TNF) blockade in several rheumatic diseases. The identification of additional pro-inflammatory factors in rheumatic diseases and an understanding of their effector function, now offers major possibilities for the generation of novel therapeutics. To address unmet clinical need, such interventions will ideally fulfil several of the following criteria: (1) control of inflammation, (2) modulation of underlying immune dysfunction - promoting the re-establishment of immune tolerance, (3) protection of targeted tissues such as bone and cartilage - this should encompass promoting healing of previously damaged tissues, (4) preservation of host immune capability - to avoid profound immune suppression and (5) amelioration of co-morbidity associated with underlying inflammatory arthritis. This short review will consider those novel cytokine activities that represent optimal utility as therapeutic targets. Since we wish to reflect the current predominant research effort, we will focus primarily on rheumatoid arthritis (RA) based studies.

McInnes IB, Liew FY. · Centre for Rheumatic Diseases, University of Glasgow, UK. · Nat Clin Pract Rheumatol. · Pubmed #16932625 No free full text.

Abstract: Success achieved so far in the blockade of tumor necrosis factor and interleukin (IL)-1 in rheumatoid arthritis exemplifies the feasibility and potential therapeutic application of antagonizing cytokine signaling. Despite these advances, there remains a considerable unmet clinical need in this field. A number of preclinical development programs are ongoing to target a variety of cytokines that are central to immune regulation and tissue-matrix destruction in rheumatoid arthritis. Evidence indicates that IL-6 antagonists might represents a useful approach and preliminary data similarly identify IL-15 as an intriguing target. Numerous additional cytokines are under investigation at the preclinical stage, including IL-12-IL-23, IL-17 and IL-18. As therapeutic goals move from disease control towards remission induction, development of the capacity for cytokine targeting to modify the underlying immune dysregulation remains a major priority.

Anderson EJ, McGrath MA, Thalhamer T, McInnes IB. · Division of Immunology, Infection and Inflammation, Centre for Rheumatic Diseases, University of Glasgow, Glasgow, Scotland, UK. · Springer Semin Immunopathol. · Pubmed #16738954 No free full text.

This publication has no abstract.

Bresnihan B, Baeten D, Firestein GS, Fitzgerald OM, Gerlag DM, Haringman JJ, McInnes IB, Reece RJ, Smith MD, Ulfgren AK, Veale DJ, Tak PP, Anonymous00383. · Department of Rheumatology, St. Vincent's University Hospital, Dublin, Ireland. · J Rheumatol. · Pubmed #16331792 No free full text.

Abstract: Synovial tissue analysis has considerable potential for future randomized controlled trials (RCT). The synovial membrane is the target tissue in treatment strategies of rheumatoid arthritis and other arthropathies. Effective modulation of synovitis is critical when attempting to control symptoms and signs, to prevent joint damage, and to maintain function. In RCT, the systematic evaluation of changes in synovial tissue after commencing treatment enables identification of an early therapeutic effect, using relatively small numbers of patients. This special interest group is working on establishing the evidence to have this endpoint meet the OMERACT filter criteria.

McInnes IB, Gracie JA. · Centre for Rheumatic Diseases, Glasgow Royal Infirmary, 10 Alexandra Parade, Glasgow, G31 2ER, Scotland. · Curr Pain Headache Rep. · Pubmed #16282041 No free full text.

Abstract: Targeting tumor necrosis factor-a has proven of considerable value in treatment for rheumatoid arthritis, with substantial benefits achieved in a proportion of treated patients. However, a significant number of patients do not achieve sufficient improvement and as a result there remains considerable unmet clinical need. A number of cytokines have recently been described with proinflammatory activity in rheumatoid arthritis synovitis, including interleukin (IL)-6, IL-12, IL-15, and IL-18. We review recent data that support the notion that some or all of these moieties offer therapeutic potential. The possibility that some may be useful in partial responders to tumor necrosis factor blocking agents or in synergy with the latter is discussed.

Choo-Kang BS, Hutchison S, Nickdel MB, Bundick RV, Leishman AJ, Brewer JM, McInnes IB, Garside P. · Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow G11 6NT, Scotland, UK. · Trends Immunol. · Pubmed #16087401 No free full text.

Abstract: Despite expanding use of drugs blocking tumour necrosis factor (TNF), their precise mechanisms of action remain unclear. Early assumptions that they act by direct neutralization of the toxic inflammatory effects of TNF might be too simplistic because they explain neither the range of effects observed nor the varying properties of different TNF-blocking agents. Recent studies have demonstrated a key role for mast cell-derived TNF in the increase in lymph node size and the organizational complexity that accompanies a developing immune response. Regulation of this phenomenon might comprise a novel mode of action for TNF-directed therapy: by preventing this lymph node hyperplasia, TNF blockade could modulate immune responses, ameliorating pathology in autoimmune diseases, such as rheumatoid arthritis.

Smith MD, Baeten D, Ulfgren AK, McInnes IB, Fitzgerald O, Bresnihan B, Tak PP, Veale D, Anonymous00013. · Rheumatology Research Unit, Repatriation General Hospital, Adelaide, South Australia. · Ann Rheum Dis. · Pubmed #15975970 links to  free full text

Abstract: Changes in cellular infiltrate and expression of cytokines, chemokines, and cell adhesion molecules as a result of therapeutic interventions in rheumatoid arthritis can be demonstrated in the synovial membrane. However, before synovial tissue analysis can be used as an outcome measure in such studies, standardisation of the site and method of synovial tissue acquisition, methods of tissue processing, and appropriate methods of detection and measurement of cell lineage specific markers and relevant biological proteins is needed.

Sattar N, McInnes IB. · Section of Vascular Biochemistry, Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow Royal Infirmary, Scotland, UK. · Curr Opin Rheumatol. · Pubmed #15838238 No free full text.

Abstract: PURPOSE OF REVIEW: To summarise recent evidence for elevated risk of coronary heart disease (CHD) in rheumatoid arthritis (RA) and explore explanatory mechanisms and modalities that may lessen such risk. RECENT FINDINGS: Evidence for elevated CHD risk in RA is convincing. On current estimates, individuals who have had RA for several years have around a twofold higher risk for CHD compared with non-RA persons after taking account of most traditional risk factors. Such excess risk appears to be driven by systemic inflammation both directly via its deleterious effects on blood vessels (endothelial dysfunction inclusive of myocardial microvascular abnormalities) and indirectly by its accentuation of multiple risk pathways including lipid abnormalities. Established therapies that lessen RA disease activity and systemic inflammation will likely lessen CHD risk, although there remains considerable scope for more robust studies employing better measures of vascular disease (e.g., carotid intima-media thickening). Other emerging evidence indicates statins may have dual effects in RA, with a modest disease-modifying effect (requiring confirmation) and significant lipid-lowering action. The latter finding is particularly important because extrapolation of data from all statin endpoint trials suggests that the extent of low-density lipoprotein cholesterol reduction may account for most statin clinical benefit. SUMMARY: Systemic inflammation is the major driver for excess vascular comorbidity in RA. Controlling systemic inflammation should lessen vascular risk but complete, long-term suppression of articular inflammation is rarely achieved. Thus, the use of conventional CHD risk reduction strategies, in particular statins, should be considered in patients with RA with prevalent CHD or at elevated risk.

McCarey DW, Sattar N, McInnes IB. · Centre for Rheumatic Diseases, Glasgow Royal Infirmary, Glasgow, UK. · Arthritis Res Ther. · Pubmed #15743490 links to  free full text

Abstract: Pleiotropic effects are now described for the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (or statins) that might have utility in the context of chronic inflammatory autoimmune disease. Here we discuss the pharmacology and established uses of statins and in this context describe potential anti-inflammatory and immune-modulatory effects. An extensive in vitro data set defines roles for statins in modifying endothelial function, particularly with respect to adhesion molecule expression and apoptosis. Broader effects on leukocyte function have now emerged including altered adhesion molecule expression, cytokine and chemokine release and modulation of development of adaptive immune responses via altered MHC class II upregulation. In vivo data in several inflammatory models, including collagen-induced inflammatory arthritis and experimental autoimmune encephalomyelitis, suggest that such effects might have immune-modulatory potential. Finally, a recent clinical trial has demonstrated immunomodulatory effects for statins in patients with rheumatoid arthritis. Together with their known vasculoprotective effects, this growing body of evidence provides compelling support for longer-term trials of statin therapy in human disease such as rheumatoid arthritis.

McInnes IB, McCarey DW, Sattar N. · Centre for Rheumatic Diseases, Department of Vascular Biochemistry, University of Glasgow, UK. · Ann Rheum Dis. · Pubmed #15547075 links to  free full text

This publication has no abstract.

McInnes IB, Gracie JA. · Centre for Rheumatic Diseases, Glasgow Royal Infirmary, 10 Alexandra Parade, Glasgow, G31 2ER, Scotland. · Curr Rheumatol Rep. · Pubmed #15355745 No free full text.

Abstract: Targeting tumor necrosis factor-a has proven of considerable value in treatment for rheumatoid arthritis, with substantial benefits achieved in a proportion of treated patients. However, a significant number of patients do not achieve sufficient improvement and as a result there remains considerable unmet clinical need. A number of cytokines have recently been described with proinflammatory activity in rheumatoid arthritis synovitis, including interleukin (IL) -6, IL-12, IL-15, and IL-18. We review recent data that support the notion that some or all of these moieties offer therapeutic potential. The possibility that some may be useful in partial responders to tumor necrosis factor blocking agents or in synergy with the latter is discussed.

McInnes IB, Gracie JA. · Centre for Rheumatic Diseases, Glasgow Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER, UK. · Curr Opin Pharmacol. · Pubmed #15251134 No free full text.

Abstract: Interleukin (IL)-15 is a pleiotropic pro-inflammatory cytokine that is expressed in several inflammatory disorders, including rheumatoid arthritis, psoriasis and pulmonary inflammatory diseases. IL-15 promotes activation of T cells, neutrophils and macrophages, and is critical to dendritic cell function in several model systems. Recent emerging data suggest that IL-15 may serve as a useful therapeutic target across a range of disease states. Advances in the past year highlight the beneficial effect of IL-15 neutralisation in models of psoriasis and diabetes. Further evidence for IL-15 expression and effector function has emerged across a range of rheumatic disorders, including juvenile inflammatory arthritis, rheumatoid arthritis and Kawasaki disease. These data hold promise for therapeutic targeting in ongoing human studies and those in the near future.

Harnett W, McInnes IB, Harnett MM. · Department of Immunology, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, UK. · Immunol Lett. · Pubmed #15234531 No free full text.

Abstract: Arthropod-transmitted filarial nematodes can survive for in excess of a decade via modulation of the vertebrate host immune system. Although human infection can result in very severe pathology, most infected individuals show remarkably little evidence of this. Analysis of the anti-nematode response indicates that apparently pathology-free individuals have an anti-inflammatory immunological phenotype and it has been suggested that this favours maintenance of host good health. It is considered that parasite-derived molecular secretions contribute to the anti-inflammatory phenotype and we have thus investigated the properties of a filarial nematode glycoprotein secreted in some abundance, ES-62. This molecule shows a plethora of immunomodulatory activities that can be classified as anti-inflammatory. It has been observed in a number of studies that several autoimmune disorders including rheumatoid arthritis (RA) exhibit reduced incidence and severity in geographic regions in which filarial nematodes are transmitted to humans. Furthermore, it has been speculated that these two observations are linked although molecular explanations for such an association have not been forthcoming. Although the aetiology of RA remains unknown a majority of data are consistent with it being mediated via excess pro-inflammatory cytokine production. Given that ES-62 is anti-inflammatory, we hypothesised that it might be able to counter the pathology associated with diseases like RA. Indeed, we found that exposure to ES-62 prevented initiation of collagen-induced arthritis (CIA) in a murine model and also suppressed progression of established disease. Ex vivo analyses demonstrated that these effects correlated with inhibition of TNF-alpha production and inhibition of collagen-specific TH-1 responses. The nematode product was also able to suppress pro-inflammatory cytokine release in vitro in synovial cells derived from RA patients. ES-62 thus constitutes a pathogen-derived immunomodulator with significant therapeutic potential.

Harnett W, Harnett MM, Leung BP, Gracie JA, McInnes IB. · Department of Immunology, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, UK. · Curr Top Med Chem. · Pubmed #14965306 No free full text.

Abstract: Filarial nematodes achieve long-term infection via modulation of the host immune system. Although human infection can result in severe pathology, the majority of infected individuals exhibit little evidence of this. Analysis of the immune response during infection indicates that the apparently healthy majority have an anti-inflammatory phenotype and it has been speculated that this may contribute to maintenance of host health. Recent data suggest that parasite-derived molecular secretions contribute to the anti-inflammatory phenotype and we have thus characterised a major filarial nematode secreted glycoprotein, ES-62. This molecule has been found to possess broad immunomodulatory activities that are in general, anti-inflammatory. It has long been recognised that several autoimmune disorders including rheumatoid arthritis (RA) exhibit reduced incidence and severity in geographic regions in which filarial nematodes are endemic. Furthermore, it has been speculated that these two observations are causally linked. However, molecular explanations for such an association have not been forthcoming. Although the aetiology of RA is unknown most data suggest that it is mediated via a pro-inflammatory immune response associated with excess cytokine production. Given that ES-62 is anti-inflammatory, we hypothesised that it might possess activity against diseases like RA. Indeed we found that subcutaneous injection of ES-62 prevented initiation of collagen-induced arthritis (CIA) and also suppressed progression of established disease. Ex vivo analyses demonstrated that these effects were due to inhibition of TNF-alpha production and reversal of collagen specific TH-1 responses. The nematode product was also found to inhibit pro-inflammatory cytokine release in vitro in synovial cells derived from RA patients. ES-62 thus represents a parasite-derived immunomodulator with significant therapeutic potential.

McInnes IB. · Centre for Rheumatic Diseases, University of Glasgow, Scotland, UK. · Arthritis Res Ther. · Pubmed #14680504 links to  free full text

This publication has no abstract.

Sattar N, McCarey DW, Capell H, McInnes IB. · Department of Pathological Biochemistry and Centre for Rheumatic Diseases, North Glasgow Hospitals University NHS Trust, Glasgow Royal Infirmary, Glasgow, Scotland, UK. · Circulation. · Pubmed #14676136 links to  free full text

Abstract: There is intense interest in mechanisms whereby low-grade inflammation could interact with conventional and novel vascular risk factors to promote the atheromatous lesion. Patients with rheumatoid arthritis (RA), who by definition manifest persistent high levels of inflammation, are at greater risk of developing cardiovascular disease. Mechanisms mediating this enhanced risk are ill defined. On the basis of available evidence, we argue here that the systemic inflammatory response in RA is critical to accelerated atherogenesis operating via accentuation of established and novel risk factor pathways. By implication, long-term suppression of the systemic inflammatory response in RA should be effective in reducing risk of coronary heart disease. Early epidemiological observational and clinical studies are commensurate with this hypothesis. By contrast, risk factor modulation with conventional agents, such as statins, may provide unpredictable clinical benefit in the context of uncontrolled systemic inflammatory parameters. Unraveling such complex relationships in which exaggerated inflammation-risk factor interactions are prevalent may elicit novel insights to effector mechanisms in vascular disease generally.

McInnes IB, Gracie JA, Harnett M, Harnett W, Liew FY. · Centre for Rheumatic Diseases, Division of Immunology, Infection and Inflammation, Department of Medicine, University of Glasgow, UK. · Ann Rheum Dis. · Pubmed #14532150 links to  free full text

This publication has no abstract.

Liew FY, Wei XQ, McInnes IB. · Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow G11 6NT, Scotland, UK. · Ann Rheum Dis. · Pubmed #14532149 links to  free full text

This publication has no abstract.

Liew FY, McInnes IB. · Department of Immunology and Bacteriology, University of Glasgow, Glasgow G11 6NT, UK. · Ann Rheum Dis. · Pubmed #12379638 links to  free full text

Abstract: Interleukin 15 (IL15) and interleukin 18 (IL18) are cytokines produced principally by macrophages during innate immune response and subsequently profoundly influence adaptive immunity. Recent studies have shown that IL15 and IL18 play an influential part in inflammatory response. Here we present recent data mainly from our own laboratories illustrating the importance of IL15 and IL18 in the induction and perpetuation of chronic inflammation during experimental and clinical rheumatoid synovitis.

Liew FY, McInnes IB. · Department of Immunology and Bacteriology, University of Glasgow, G11 6NT, UK. · Mol Immunol. · Pubmed #12009565 No free full text.

Abstract: Cytokines produced by innate immune response can profoundly influence the subsequent adaptive immunity. IL-15 and -18 are two of several mediators produced by macrophages that perform such a function. Here we present recent data mainly from our own laboratory illustrating the important role of IL-15 and -18 in the induction and perpetuation of chronic inflammation during experimental and clinical rheumatoid synovitis.

Gracie JA, Leung BP, McInnes IB. · Center for Rheumatic Diseases and Department of Immunology, University of Glasgow, Glasgow, UK. · Curr Opin Rheumatol. · Pubmed #11981325 No free full text.

Abstract: Clinical intervention studies have clearly shown the benefit in suppressing tumor necrosis factor-alpha (TNF-alpha) rheumatoid arthritis (RA). In consequence, considerable interest has arisen in those pathways that in turn regulate TNF-alpha production, because they may offer further possible therapeutic targets. Several candidate pathways are currently being investigated. They include T cell/macrophage interactions mediated primarily through cell-cell membrane contact; novel cytokine activities; microbial-derived products, in particular bacterial deoxyribonucleic acid sequences; autoreactive T cells, and immunoglobulins. At the subcellular level, there is further interest in targeting signaling and mRNA processing and cytokine cleavage pathways required for optimal TNF-alpha production. The key recent observations in these areas, particularly in the extracellular compartment, are reviewed.