Best Practice & Research Clinical Rheumatology RSS feed: Current Issue. Evidence-based updates of best clinical practice across the spectrum of musculoskeletal conditions Best Practice and Research Clinical Rheumatology keeps the clinician or trainee informed of the latest developments and current recommended practice in the rapidly advancing fields of musculoskeletal conditions and science. The series provides a continuous update of current clinical practice. It is a topical serial publication that covers the spectrum of musculoskeletal conditions in a 4-year cycle. Each topic-based issue contains around 200 pages of practical, evidence-based review articles, which integrate the results from the latest original research with current clinical practice and thinking to provide a continuous update. Each issue follows a problem-orientated approach that focuses on the key questions to be addressed, clearly defining what is known and not known. The review articles seek to address the clinical issues of diagnosis, treatment and patient management. Management is described in practical terms so that it can be applied to the individual patient. The serial is aimed at the physician in both practice and training. The Best Practice and Research Clinical Rheumatology series provides up-to-date and expert information and opinion by drawing on Guest Editors and authors renowned for their expertise. This ongoing review of topics makes the serial ideally suited to supporting everyday clinical practice, for training needs as well as for maintaining knowledge and competency. Volume 22 (Volume 2008) 1. Connective tissue diseases M. Matucci-Cerinic & D. Furst 2. Musculoskeletal science T. Pap & U. Muller-Ladner 3. How to manage chronic musculoskeletal conditions - the principles P. Brooks & P. Conaghan 4. Miscellanous inflammatory musculoskeletal conditions J. Sibilia & H. Zeidler 5. Musculoskeletal conditions in the developing world G. Mody & R. Handa 6. Imaging in musculoskeletal conditions M. Cimmino and W. Grassi Volume 23 (2009) 1. Early rheumatoid arthritis 2. Vasculitis 3. How to do - practical procedures 4. Back pain 5. Systemic lupus erythematosus 6. Osteoporosis Volume 24 (2010) 1. Osteoarthritis 2. Paediatric rheumatology 3. How to manage chronic musculoskeletal conditions - a systematic approach to specific problems 4. Pharmacotherapy 5. Spondylo-arthropathies 6. Prevention / epidemiology This free sample chapter is being provided to demonstrate the Journal's approach to topics across the spectrum of musculoskeletal conditions.http://www.bprclinrheum.com/?rss=yesElsevier Inc.en © 2010 Published by Elsevier Inc. All rights reserved. Best Practice & Research Clinical Rheumatology1521-6942244August 2010 © 2010 Published by Elsevier Inc. All rights reserved. healthpermissions@elsevier.comhttp://www.bprclinrheum.com/article/PIIS1521694210000616/abstract?rss=yesEditorial Board/Aims and Scope10.1016/S1521-6942(10)00061-6Best Practice & Research Clinical Rheumatology 24, 4 (2010)2010-08-01Best Practice & Research Clinical Rheumatology2010-08-01244S1521-6942(10)X0004-3iiiiiihttp://www.bprclinrheum.com/article/PIIS152169421000029X/abstract?rss=yesThese are the most exciting times to be a rheumatologist! The therapeutics of rheumatoid arthritis (RA) have changed dramatically in the last decade with the arrival of novel biologic-based medicines. However, an even more significant impact on outcomes has arisen from the radical change in approach to the treatment of the disease embodied in ‘treatment to target’, specifically the relentless pursuit of a low disease-activity state in clinical practice. In one sense, we have learned much about how to optimally utilise our existing conventional disease-modifying anti-rheumatic drugs (DMARDs). Thus, a formal strategic approach to care, combined with regular assessment of the actual level of disease activity, however measured, has resulted in a significant proportion of patients achieving substantial improvements in their overall quality of life. Critically, however, few patients are yet reaching sustained remission as assessed by metrics of clinical disease activity – even fewer are in remission if more stringent imaging criteria are applied. Thus, RA remains a chronic disease with attendant co-morbidity and a requirement a priori for long-term continuous administration of pharmaceutical agents.Novel therapeutics – exciting gifts but how best to use them?I.B. McInnes, J.R. O’Dell10.1016/j.berh.2010.03.002Best Practice & Research Clinical Rheumatology 24, 4 (2010)2010-08-01Best Practice & Research Clinical Rheumatology2010-08-01244S1521-6942(10)X0004-3441442http://www.bprclinrheum.com/article/PIIS1521694209001454/abstract?rss=yesIn rheumatoid arthritis (RA), early use of disease-modifying anti-rheumatic drugs (DMARDs), intensive follow-up and ‘treating to target’ to achieve low disease activity produce significant improvements in measures of disease activity, functional impairment and retard erosive radiographic progression. Step-up, parallel and step-down regimens are all significantly more effective than sequential monotherapy; although the most effective regimen has not been established. Minimising the period of exposure to synovitis, by including a rapidly acting agent (e.g., corticosteroids or tumour necrosis factor α (TNFα) inhibitor), may slow radiographic progression further. Biologic therapies, especially TNFα inhibitors, are effective in early RA; however, their exact role is unclear. Current measures may overestimate the number of patients in clinical remission; therefore, musculoskeletal ultrasound and/or novel biomarkers may also have a role. Pre-clinical immunological markers could possibly be used to trigger pre-emptive treatment in asymptomatic, ‘at risk’ individuals. Potential treatment developments include combining biologic agents or targeting alternative immunological pathways.Optimising the strategy of care in early rheumatoid arthritisJames Dale, Duncan Porter10.1016/j.berh.2009.11.009Best Practice & Research Clinical Rheumatology 24, 4 (2010)2010-08-01Best Practice & Research Clinical Rheumatology2010-08-01244S1521-6942(10)X0004-3443455http://www.bprclinrheum.com/article/PIIS1521694209001442/abstract?rss=yesThe prognosis for patients with rheumatoid arthritis has improved dramatically, thanks in large part to many new therapies and therapeutic approaches. Paradoxically, this has created problems for rheumatologists since clinically useful information from appropriate clinical trials has not kept pace with all the new therapeutic options. Essentially, rheumatologists now have many more therapeutic options than they know what to do with. This article discusses why we are in this situation and suggests opportunities to move forward.Challenges in clinical trial design in inflammatory arthritisJames R. O'Dell10.1016/j.berh.2009.11.008Best Practice & Research Clinical Rheumatology 24, 4 (2010)2010-08-01Best Practice & Research Clinical Rheumatology2010-08-01244S1521-6942(10)X0004-3457461http://www.bprclinrheum.com/article/PIIS1521694209001600/abstract?rss=yesFull activation and differentiation of resting T cells into effector T cells requires at least two signals, the first through engagement of the T cell antigen receptor (TCR) by the antigen-major histocompatibility complex (MHC) on antigen-presenting cells (APCs), and the second by engagement of co-stimulatory molecules such as CD28, on T cells by ligands such as CD80/86 on APCs. Effector T cell differentiation is associated with proliferation, secretion of cytokines and expression of additional surface molecules. These inducible structures may have stimulatory (ICOS, OX40 and 4-1BB) or inhibitory (cytotoxic T-lymphocyte antigen (CTLA)-4) potential. To the extent that T cells have a role in particular immune-mediated diseases, interruption of T cell co-stimulation is a potentially worthwhile approach to the treatment of those conditions. This article summarises the experience in treating rheumatological disease by perturbation of T cell co-stimulation, and also describes structures that could be future targets for this type of therapeutic approach.Co-stimulation and T cells as therapeutic targetsAlison M. Gizinski, David A. Fox, Sujata Sarkar10.1016/j.berh.2009.12.015Best Practice & Research Clinical Rheumatology 24, 4 (2010)2010-08-01Best Practice & Research Clinical Rheumatology2010-08-01244S1521-6942(10)X0004-3463477http://www.bprclinrheum.com/article/PIIS1521694210000057/abstract?rss=yesCurrent therapeutics for the treatment of rheumatoid arthritis (RA) offer limited efficacy in a restricted number of patients. There is, therefore, an unmet clinical need for the development of more efficacious therapeutics for the treatment of disease. Anti-TNFα therapy has provided proof of principle that cytokine blockade is an appropriate strategy by which to inhibit disease progression. In this review, we describe the basic biology of potential novel cytokine targets and the results of recent clinical trials, with particular focus on the cytokines related to Th17 biology, namely interleukin (IL)-12, IL-23 and IL-17, in addition to the TNF superfamily and the adipocytokines.Embracing novel cytokines in RA – complexity grows as does opportunity!Axel J. Hueber, Darren L. Asquith, Iain B. McInnes, Ashley M. Miller10.1016/j.berh.2010.01.004Best Practice & Research Clinical Rheumatology 24, 4 (2010)2010-08-01Best Practice & Research Clinical Rheumatology2010-08-01244S1521-6942(10)X0004-3479487http://www.bprclinrheum.com/article/PIIS1521694210000288/abstract?rss=yesThe spectrum of arthritis ranges from erosive (e.g., rheumatoid arthritis) to ossifying disease with formation of new bone (e.g., ankylosing spondylitis and osteoarthritis). The molecular basis for these different patterns of arthritis had long been unclear. In the last few years, however, characterisation of catabolic and anabolic molecular pathways in different forms of arthritis led to a better understanding of joint remodelling and revealed novel therapeutic targets.Recent findings show that catabolic and anabolic molecular pathways govern bone and cartilage remodelling in healthy and arthritic joints. The predominance of catabolic molecular pathways (e.g., receptor activator of nuclear factor-κB ligand (RANKL)/RANK and cathepsin K) causes erosive disease whereas anabolic signalling (e.g., Wnt and fibroblast growth factor (FGF)18) favours the formation of new bone including bony spurs and subchondral sclerosis. Other pathways may have a dual function in arthritis (e.g., hedgehog) leading to either catabolic or anabolic joint remodelling dependent on other factors. Key mediators within these signalling pathways may serve as novel targets for treating pathological remodelling of bone and cartilage in arthritis.Molecular pathways govern remodelling processes of bone and cartilage in arthritic joints. Future therapies will likely target the pathologic activity of these molecular pathways to specifically block either catabolic or anabolic joint remodelling in arthritis.Novel targets in bone and cartilageChristian Beyer, Georg Schett10.1016/j.berh.2010.03.001Best Practice & Research Clinical Rheumatology 24, 4 (2010)2010-08-01Best Practice & Research Clinical Rheumatology2010-08-01244S1521-6942(10)X0004-3489496http://www.bprclinrheum.com/article/PIIS1521694210000082/abstract?rss=yesTherapeutic tolerance embraces the concept of ‘switching off’ immunopathology by specifically targeting elements of the immune system. It has been achievable in preclinical models of transplantation and auto-immunity for more than two decades; however, previous attempts to translate to the clinic have been unsuccessful. Nonetheless, an improved understanding of tolerance mechanisms, along with novel therapeutic agents and strategies, are starting to bear fruit in a number of disease areas. True tolerance is achievable in transplantation settings, and long-term remissions can be induced in various auto-immune and atopic conditions. Equivalent outcomes should be achievable in inflammatory arthritis, although this may require an improved understanding of the immune dysregulation that is intrinsic to rheumatoid arthritis (RA), and better definitions of RA autoantigens. Biomarkers of tolerance induction would rapidly advance the field in all therapeutic areas. This article summarises the advances made in other therapeutic areas, and the lessons learned that we can now apply to RA.Treating to re-establish tolerance in inflammatory arthritis – lessons from other diseasesFaye A.H. Cooles, John D. Isaacs10.1016/j.berh.2010.01.007Best Practice & Research Clinical Rheumatology 24, 4 (2010)2010-08-01Best Practice & Research Clinical Rheumatology2010-08-01244S1521-6942(10)X0004-3497511http://www.bprclinrheum.com/article/PIIS1521694210000276/abstract?rss=yesCP-690,550 is an orally active and selective inhibitor of the janus kinase (JAK) molecules. The molecular pathways through which the JAK moieties function are described along with the clinical mechanisms associated with their inhibition. Animal models of JAK inhibition are reviewed as a background for the possible inhibition of JAK in humans. The pharmacokinetics of CP-690,550 in humans is described, and the Phase IIA and IIB trials are reviewed in some detail. These trials were dose-ranging and showed a general dose response with relatively robust American College of Rheumatology 20 (ACR20) responses. A proof-of-concept 6-week trial in which CP-690,550 was given as monotherapy was associated with highly efficacious responses at the mid and higher twice-daily dose ranges employed. A subsequent 24 week dose-ranging trial in which CP-690,550 was administered in combination with methotrexate showed ACR20 responses, which were also statistically significant versus placebo interventions.CP-690,550 treatment was associated with side effects, which included headache and nausea. Infections were more common versus placebo as were elevations in transaminase enzymes when administered in combination with methotrexate, and increases in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol. Decreases in haemoglobin and white blood cell (WBC) counts were also observed along with small increases in serum creatinine. Occasional significant decreases of haemoglobin (>2gdl−1) were observed, although decreases of WBC to less than 1000 per mm3 were not seen. Plans for long-term follow-up of the described trials are described along with the features of five presently ongoing Phase III trials of the CP-690,550 janus kinase (JAK) inhibitor. Future directions include completion and publication of these trials along with study of JAK inhibition for other indications.Inhibition of JAK kinases in patients with rheumatoid arthritis: scientific rationale and clinical outcomesRichard J. Riese, Sriram Krishnaswami, Joel Kremer10.1016/j.berh.2010.02.003Best Practice & Research Clinical Rheumatology 24, 4 (2010)2010-08-01Best Practice & Research Clinical Rheumatology2010-08-01244S1521-6942(10)X0004-3513526http://www.bprclinrheum.com/article/PIIS1521694210000264/abstract?rss=yesThe Identification of key players of inflammation and pathologic immune response in rheumatoid arthritis (RA) has resulted in the development of novel therapeutic strategies revolutionising the treatment of disease. However, these new therapeutics only indirectly affect the mesenchymal compartment of the inflamed synovium and, in particular, the specific phenotype of activated fibroblast-like cells. These cells have been demonstrated to trigger not only the progressive destruction of articular cartilage and bone but also the switch from acute to chronic inflammation. Therefore, targeting of this population of fibroblast-like cells may provide interesting opportunities to go beyond the mere inhibition of inflammation and to interfere with key disease processes in RA. This review summarises our current knowledge on the role of fibroblast-like cells in RA and points to potentials ways of modulating their disease-specific activation.Therapeutic opportunities in fibroblasts in inflammatory arthritisMarianne Niedermeier, Thomas Pap, Adelheid Korb10.1016/j.berh.2010.02.002Best Practice & Research Clinical Rheumatology 24, 4 (2010)2010-08-01Best Practice & Research Clinical Rheumatology2010-08-01244S1521-6942(10)X0004-3527540http://www.bprclinrheum.com/article/PIIS1521694210000112/abstract?rss=yesGene therapy holds great promise for the treatment of rheumatoid arthritis (RA). In this article, we focus on innovation in vector, promoter or target genes. Gene therapy is defined as an introduction of nucleic acids into a host cell for therapeutic purposes; the option may be the overexpression of therapeutic gene or an underexpression of a target gene highly expressed in disease (small interfering RNA (siRNA)). The proof of principle in animal models of arthritis has shown convincingly that gene therapy can be an advantageous strategy in the treatment of RA. A gene therapy approach is advantageous over biologics for joint-specific targeting and long-term expression of an anti-arthritic molecule, replacing the frequent administration of recombinant proteins. We also discuss the currently used gene therapy clinical trials and define optimal strategies for success.Prospects for gene therapy in inflammatory arthritisChristian Jorgensen, Florence Apparailly10.1016/j.berh.2010.02.001Best Practice & Research Clinical Rheumatology 24, 4 (2010)2010-08-01Best Practice & Research Clinical Rheumatology2010-08-01244S1521-6942(10)X0004-3541552http://www.bprclinrheum.com/article/PIIS1521694209001429/abstract?rss=yesThere has been renewed interest in the B cell as a target for the treatment of rheumatoid arthritis (RA) over the past decade. Efficacy with rituximab has been demonstrated in randomised clinical trials (RCTs) resulting in regulatory approval for patients failing tumour necrosis factor (TNF) inhibitors. Although the actual mechanism of action has not been clearly delineated, several molecules are under development to modify B cell number/function in hope of superior efficacy/safety or ease of administration. The safety of rituximab over the intermediate time point has been comparable to that seen with other biologic disease-modifying anti-rheumatic drugs (DMARDs). The recent report of cases of progressive multifocal leukoencephalopathy in three patients receiving rituximab for RA is a concern and, for now, limits rituximab to salvage therapy for the treatment-resistant patient. How this impacts on other B-cell inhibitors under development is not yet clear. Development of biomarkers that will assist our therapeutic decisions to enhance the benefit/risk ratio for our patients are needed as we move forward with further selective targeted therapies.Targeting the B Cell in Rheumatoid ArthritisStanley B. Cohen10.1016/j.berh.2009.11.006Best Practice & Research Clinical Rheumatology 24, 4 (2010)2010-08-01Best Practice & Research Clinical Rheumatology2010-08-01244S1521-6942(10)X0004-3553563http://www.bprclinrheum.com/article/PIIS1521694210000094/abstract?rss=yesAutologous haematopoietic stem cell transplantation in patients with rheumatoid arthritis (RA) resulted in a positive short-term outcome clinically with low treatment-related toxicity. However, early conditioning regimens were of low immunoablative intensity and most patients relapsed. Mechanistic studies suggest that residual lesional effector cells may have been responsible for the relapses. The introduction of biopharmaceuticals has, for the moment, reduced the need for further experimental studies.Juvenile idiopathic arthritis patients, mostly of the systemic subgroup, have shown nearly 33% durable drug-free remission, but with significant toxicity, including fatal macrophage-activation syndrome early in the programme. Later modifications to the protocol have reduced this toxicity.Mesenchymal stem cells (MSCs), derived from several sources including bone marrow and adipose tissue, are being tested as tissue-regenerative and immunomodulating agents in many autoimmune diseases and animal models of inflammatory arthritis have been positive. MSCs and other stromal cells derived from actively inflamed synovium and peripheral blood of RA patients do not always demonstrate a full range of differentiation potential compared with healthy MSCs, although their immunomodulalatory capacity is unimpaired.Stem cells in the treatment of inflammatory arthritisAlan Tyndall, Jacob M. van Laar10.1016/j.berh.2010.01.008Best Practice & Research Clinical Rheumatology 24, 4 (2010)2010-08-01Best Practice & Research Clinical Rheumatology2010-08-01244S1521-6942(10)X0004-3565574http://www.bprclinrheum.com/article/PIIS1521694210000689/abstract?rss=yesIndex10.1016/S1521-6942(10)00068-9Best Practice & Research Clinical Rheumatology 24, 4 (2010)2010-08-01Best Practice & Research Clinical Rheumatology2010-08-01244S1521-6942(10)X0004-3II