Current Rheumatology Reviews - Volume 6, Issue 4, 2010

Sir William Osler stated that in its more aggravated forms diffuse scleroderma is one of the most terrible of human ills. Like Tithonus to “wither slowly”and like him to be “beaten down and marred and wasted”, until one is literally a mummy, encased in an evershrinking, slowly contracting “skin of steel” is a fate not pictured in any tragedy ancient or modern [1]. While we have come a truly long way in our understanding of this complex disease and its pathophysiology, and indeed we might pat ourselves on the back for improving outcomes in this condition since the advent of ACE inhibitors; far too much work needs to be completed in adding new medications to our armamentarium. The mini review of scleroderma by Dr. Sakkas and colleagues summarizes the current understanding of the pathophysiology and clinical manifestations and also highlights potential new treatments for this vexing condition. In this edition of the Journal we also present a review of biomarkers for osteoarthritis. In simple terms, a biomarker is a measure that would predict a disease state or a treatment response. The articles in the section on osteoarthritis concisely summarize technological advances in our ability to diagnose osteoarthritis in a more precise and timely manner than has been previously possible. These articles should be recommended reading for rheumatologists who wish to familiarize themselves with these technological advances. We have had a wonderful year bringing you fresh and invigorating review topics in 2010. We look forward to the continuing contributions of our talented editorial board and contributors in 2011.

Osteoarthritis (OA) is the most common form of arthritis and results in substantial morbidity and disability in the elderly and imposes a great economic burden on society. While there are drugs available on the market that mitigate pain and improve function, there are no drugs that can cure, reverse or halt disease progression, partly because there is no reliable method that we can use to identify early OA changes. There is a pressing need to develop reliable biomarkers that can inform about the process of joint destruction in OA. Such biomarkers could aid in drug development by identifying fast progressors and detecting early response to therapy and so reducing patient numbers and time required for clinical trials. Over the last several years, dramatic advances in our understanding of the biochemistry of cartilage and of the ability to image biochemical and structural changes within cartilage using MRI techniques have led to a cascade of studies testing proteins and imaging findings as biomarkers of OA. Gene assay signatures and other signals of molecular changes within the joint promise other exciting future opportunities to characterize dynamic processes with the joint. This issue of Current Rheumatology Reviews features a selection of special review articles, which focus on the current state of biomarkers of OA. Dr. Livshits et al. summarize the data on the efficacy of the relevant biochemical factors affecting all the components of the joint that could be therefore useful targets in the treatment of OA. Dr. Cicuttini et al. review the research progress of three dimensional image technique - MRI in early diagnosis of OA. Dr. Valdes provides an overview of genetic factors of OA, particularly the recent findings from genome-wide association studies. And Dr. Williams et al. summarize the state of play of imaging biomarkers in the spine with emphasis on degenerative disc disease. These articles are important reading for rheumatologists as they give us a sense of the current state of the biomarkers of OA.

Osteoarthritis (OA) is a complex, age dependent disease in which various factors, including metabolic changes, are all major contributors to its onset and progression. Anatomically, OA embraces the whole joint, i.e. articular cartilage, subchondral bone alterations and joint-lining synovial membrane. Correspondingly, OA development involves elaborate interactions of cartilaginous tissue metabolism and maintenance, osteogenesis, mineralization and inflammation of the synovial membrane. Identification of the molecular pathways and individual factors involved in OA etiology, understanding of mechanisms of their action and interaction are necessary conditions for developing the accurate diagnostic and prognostic tools and for providing OA patients effective treatment. There is a major progress in understanding of the molecular mechanisms of OA appearance and progression, which are pointing out to the network of biochemical factors important for normal functioning of the joints and changes leading to OA. The present review summarizes the data on the efficacy of the relevant biochemical factors affecting all the components of the joint and that could be therefore useful targets in treatment of OA. However, despite the dramatic growth of the knowledge concerning the biochemistry of OA and discovery of a number of useful biomarkers the real breakthrough in this area is still not achieved.

Knee osteoarthritis (OA) is a common and significant cause of disability. Until recently, the major investigation to help establish a diagnosis of knee OA was the joint radiograph. This imaging modality offers only a two-dimensional image of a three-dimensional structure, and can only crudely identify major joint abnormalities at the later stage of disease. Moreover, joint radiographs cannot fully characterise subtle changes in intra and extraarticular structures, such as cartilage and bone marrow abnormalities that are now considered to be part of a whole-organ disease process. The recent advent of Magnetic Resonance Imaging (MRI) has enabled a three-dimensional assessment of the entire joint, thus providing new insights into the natural history of joint arthropathies. It is likely that morphological changes in articular structures caused by the OA process have their origins in the apparently healthy asymptomatic knee joint. MRI has therefore enabled the opportunity to better examine and understand pre-clinical and very subtle early aberrations in joint morphology, prior to the onset of radiographic disease. This discussion seeks to explore knee OA as a disease entity that can be recognised before any radiographic change. This may pose new, yet exciting challenges for the identification and classification of disease, and provide a better understand of the pathogenesis of knee OA.

Osteoarthritis (OA) is a chronic arthropathy, in which cartilage loss, osteophyte formation, and subchondral bone sclerosis lead to pain, disability, and a reduction in quality of life. OA is a multifactorial disease and OA cases are affected by both genetics and environment to varying degrees. Strong familial aggregation and heritabilities have been reported for OA at the hip, knee, hand and spine. Candidate gene studies and genome-wide linkage studies have identified genes in the bone morphogenetic pathway (e.g. GDF5), the thyroid regulation pathway (DIO2), apoptotic pathways as involved in genetic risk of large joint OA. Genome wide association studies have reported structural genes (COL6A4/DVWA), inflammation related genes (PTGS2/PLA2G4A) and a locus on chr 7q22 associated with knee OA and a gene involved transcriptional regulation (A2BP1) to be associated with hand OA. During the coming years, as additional genetic and functional studies further define the genetic architecture of OA and the underlying molecular mechanisms, additional targets for novel therapies and improved diagnostic and prognostic tests will be identified.

While there is an acknowledged need for biomarkers to progress arthritis research, imaging biomarkers for the spine have lagged behind those for peripheral joint osteoarthritis. Progress has been slow for a number of reasons. First and perhaps most importantly, there is currently no international agreement on definition of spine osteoarthritis (OA), either histologically or on imaging. Secondly, spine OA comprises two main pathologies, and debate continues as to whether they are separate entities or linked: degenerative disc disease and facet joint arthritis. Imaging those neighbouring joints is not straightforward and usually requires separate imaging investigations. Thirdly, it is only just becoming clear to what extent changes on imaging are associated with the main clinical problem - back pain. To compound the problem, the organisation of clinical services usually means that different specialties tend to focus on different anatomical areas, so a combined approach is not commonly adopted. Systematic evaluation of facet joints in epidemiological study is still in its infancy. Regardless of these hurdles, we have attempted in this review to summarise the state of play of imaging biomarkers in the spine with the emphasis on degenerative disc disease. MR imaging clearly leads the way and there exists a variety of specialist techniques such as T1rho and which may offer spine research imaging biomarkers in the future.

Systemic sclerosis (SSc) is a chronic, multisystemic disease of unknown etiology. Twin studies and the presence of geographical clusters of the SSc suggest that environmental factors play a major role in the development of this disease. The main characteristics of SSc are extensive deposition of extracellular matrix in skin and internal organs, microvasculopathy, and immune activation. These changes may cause devastating complications, which made rheumatologists feel uncomfortable before patients with SSc, as they could offer no help. However, in recent years there have been important advances in the understanding of the pathogenesis of SSc that reflected in the improvement in health care delivery for patients. Understandably, there was a great interest in SSc, and topics on SSc in Congresses attracted huge audiences. Fibroblasts are cells that produce extracellular matrix, and activation of fibroblasts can be intrinsic or caused by signals derived from other cells. In this issue we are happy to have eminent authors reviewing important aspects of SSc. Professor Jimenez and colleagues review recent advances in fibroblast activation and signal transduction. Professor Sakkas and colleagues review the immunological aspects of SSc and how these translate into management of SSc patients. Professor Matucci-Cerinic and colleagues review the clinical manifestations of SSc and their management. Professor Distler and colleagues review promising future treatments for SSc. We are grateful to our authors and we hope that readers will have useful information and will enjoy reading. We hope that this issue of the journal will help practicing clinicians in their care for SSc patients.

Systemic sclerosis (SSc) is characterized by activation of fibroblasts with extensive deposition of collagen, by small vessel vasculopathy with fibrointimal proliferation, and activation of the immune system, with hyper-γ- globulinaemia and autoantibodies. Twin studies have shown that genetic factors play a minor role in SSc development. Serum autoantibodies and skin lymphocytic infiltrates and small vessel damage occur very early before the appearance of skin fibrosis. T cells can cause fibrosis and vasculopathy through cell-cell contact and cytokines. They produce TH2 cytokines (IL-4, IL13) and TH17 cytokines (IL-17), which are profibrotic. TH2 cells in experimental models also induce pulmonary arterial hypertension. Genetically engineered TGFβ expression in pig arteries causes fibrointimal proliferation. T cells in skin lesions exhibit oligoclonality that persists over time, which indicates an antigen-driven T cell activation, but the antigen(s) responsible are not known. There are known environmental factors that can elicit an immune response and cause a SSc-like disease. T cells also provide help for B cells. B cells can contribute to fibrosis and vasculopathy through cytokines and autoantibodies. Autoantibodies can activate endothelial cells and fibroblasts to a profibrotic phenotype. Finally, treatments directed against T cells and B cells show promising effects in SSc.

The most severe clinical and pathologic manifestations of systemic sclerosis (SSc) are the result of a fibrotic process characterized by the excessive and often progressive deposition of collagen and other connective tissue macromolecules in skin and numerous internal organs. The mechanisms involved in the initiation and progression of the remarkable fibrotic process in SSc remain largely unknown. Extensive recent studies have indicated that a variety of polypeptide growth factors play a crucial role in this process. The most commonly implicated growth factors include transforming growth factor beta (TGF-β), connective tissue growth factor (CTGF), platelet derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Here, the experimental evidence supporting the participation of various growth factors in the pathogenesis of the fibrotic process in SSc and the molecular mechanisms involved will be reviewed.

Systemic sclerosis (SSc) is a severe autoimmune disease that involves skin and internal organs. Clinical manifestations of SSc are very heterogeneous and derive from microvascular, inflammatory and fibrotic tissue changes. Besides the skin, lung, gastrointestinal tract, heart and kidneys are mainly affected. Over the last years, a progress in the treatment was made, especially in the field of renal involvement and pulmonary hypertension, but prognosis of the disease remains still bad. More efforts are needed to improve the management of organ impairment by early detection and prompt treatment, in order to prevent the development of severe complications.

In the last years, several key-pathways for the aberrant activation of fibroblasts in SSc have been identified in pre-clinical studies. This review summarizes recently identified molecular targets for novel anti-fibrotic approaches in systemic sclerosis (SSc) and other fibrotic disorders. We will focus on pathways that can be targeted by drugs that are either already approved for other indications or that are currently evaluated in clinical trials.