Showing papers in "Therapeutic Advances in Musculoskeletal Disease in 2013"

Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations

Abstract: Osteoarthritis (OA) has traditionally been classified as a noninflammatory arthritis; however, the dichotomy between inflammatory and degenerative arthritis is becoming less clear with the recognition of a plethora of ongoing immune processes within the OA joint and synovium. Synovitis is defined as inflammation of the synovial membrane and is characteristic of classical inflammatory arthritidies. Increasingly recognized is the presence of synovitis in a significant proportion of patients with primary OA, and based on this observation, further studies have gone on to implicate joint inflammation and synovitis in the pathogenesis of OA. However, clinical OA is not one disease but a final common pathway secondary to many predisposing factors, most notably age, joint trauma, altered biomechanics, and obesity. How such biochemical and mechanical processes contribute to the progressive joint failure characteristic of OA is tightly linked to the interplay of joint damage, the immune response to perceived damage, and the subsequent state of chronic inflammation resulting in propagation and progression toward the phenotype recognized as clinical OA. This review will discuss a wide range of evolving data leading to our current hypotheses regarding the role of immune activation and inflammation in OA onset and progression. Although OA can affect any joint, most commonly the knee, hip, spine, and hands, this review will focus primarily on OA of the knee as this is the joint most well characterized by epidemiologic, imaging, and translational studies investigating the association of inflammation with OA.

Wnt signaling in bone formation and its therapeutic potential for bone diseases

Abstract: The Wnt signaling pathway plays an important role not only in embryonic development but also in the maintenance and differentiation of the stem cells in adulthood. In particular, Wnt signaling has been shown as an important regulatory pathway in the osteogenic differentiation of mesenchymal stem cells. Induction of the Wnt signaling pathway promotes bone formation while inactivation of the pathway leads to osteopenic states. Our current understanding of Wnt signaling in osteogenesis elucidates the molecular mechanisms of classic osteogenic pathologies. Activating and inactivating aberrations of the canonical Wnt signaling pathway in osteogenesis results in sclerosteosis and osteoporosis respectively. Recent studies have sought to target the Wnt signaling pathway to treat osteogenic disorders. Potential therapeutic approaches attempt to stimulate the Wnt signaling pathway by upregulating the intracellular mediators of the Wnt signaling cascade and inhibiting the endogenous antagonists of the pathway. Antibodies against endogenous antagonists, such as sclerostin and dickkopf-1, have demonstrated promising results in promoting bone formation and fracture healing. Lithium, an inhibitor of glycogen synthase kinase 3β, has also been reported to stimulate osteogenesis by stabilizing β catenin. Although manipulating the Wnt signaling pathway has abundant therapeutic potential, it requires cautious approach due to risks of tumorigenesis. The present review discusses the role of the Wnt signaling pathway in osteogenesis and examines its targeted therapeutic potential.

Targeting interleukin-17 in patients with active rheumatoid arthritis: rationale and clinical potential:

Abstract: Clinical and experimental evidence suggest that interleukin-17A (IL-17A; also known as IL-17) is an attractive therapeutic target in rheumatoid arthritis (RA). Rheumatoid synovial tissue produces I...

Biomarkers in systemic lupus erythematosus: challenges and prospects for the future

Abstract: The search for lupus biomarkers to diagnose, monitor, stratify, and predict individual response to therapy is currently more intense than ever before. This effort is essential for several reasons. First, epidemic overdiagnosis and underdiagnosis of lupus, even by certified rheumatologists, leads to errors in therapy with concomitant side effects which may be more serious than the disease itself. Second, identification of lupus flares remains as much an art as it is a science. Third, the capacity to stratify patients so as to predict those who will develop specific patterns of organ involvement is not currently possible but would potentially lead to preventive therapeutic strategies. Fourth, only one new drug for the treatment of lupus has been approved by the US Food and Drug Administration in over 50 years. A major obstacle in this pipeline is the dearth of biomarkers available to prove a patient has responded to an experimental therapeutic intervention. This review will summarize the challenges faced in the discovery and validation of lupus biomarkers, the most promising lupus biomarkers identified to date, and the promise of future directions.

A review on strontium ranelate long-term antifracture efficacy in the treatment of postmenopausal osteoporosis

Abstract: Osteoporotic fractures are one of the major causes of increased morbidity and mortality in postmenopausal women and the overall aging population. One of the major issues in the management of postmenopausal osteoporosis is to find a safe and effective treatment in the long term (>3 years) to achieve and maintain a reduction in the risk of fracture. Strontium ranelate (PROTELOS®) is a relatively novel drug, currently approved in Europe for the treatment of postmenopausal osteoporosis. Strontium ranelate is the first agent of a new therapeutic class in osteoporosis, capable of both promoting bone formation and, to a lesser extent, inhibiting bone resorption. This uncoupling in bone turnover results in a net gain in bone mineral density (BMD), bone quality improvement and reduction in risk of vertebral and nonvertebral fractures, as initially demonstrated in the preplanned long-term registrative trials SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (Treatment of Peripheral Osteoporosis) at 5 years. Recently, open-label extensions of the SOTI and TROPOS trials up to 8 and, recently, 10 years have confirmed the sustained efficacy of strontium ranelate in increasing BMD, the long-term safety profile and the high compliance to treatment, independently from baseline BMD or other risk factors for osteoporotic fractures. Recent economic impact analyses have proved that long-term treatment with strontium ranelate is highly cost effective, especially in women older than 70 years of age. Histomorphometric analyses in animals and humans participating in the phase III trials have proved that the quality of mineralization is preserved in the long term and bone microarchitecture is ameliorated, with increased bone strength. Thus, strontium ranelate has been confirmed to be an effective compound for the long-term, chronic treatment of postmenopausal osteoporosis.

Bisphosphonate drug holiday: who, when and how long:

Abstract: Bisphosphonates have been widely used in the treatment of osteoporosis with robust data from numerous placebo-controlled trials demonstrating efficacy in fracture risk reduction over 3–5 years of treatment. Although bisphosphonates are generally safe and well tolerated, concerns have emerged about adverse effects related to long-term use. For most patients with osteoporosis, the benefits of treatment outweigh the risks. Because these agents accumulate in bone with some persistent antifracture efficacy after therapy is stopped, it is reasonable to consider a ‘drug holiday.’ There is considerable controversy regarding the optimal duration of therapy and the length of the holiday, both of which should be based on individual assessments of risk and benefit.

Catastrophic antiphospholipid syndrome: how to diagnose a rare but highly fatal disease.

Abstract: Antiphospholipid syndrome (APS) is a multisystem autoimmune condition characterized by vascular thromboses and/or pregnancy loss associated with persistently positive antiphospholipid antibodies (aPL). Catastrophic APS (CAPS) is the most severe form of APS with multiple organ involvement developing over a short period of time, usually associated with microthrombosis. ‘Definite’ and ‘probable’ CAPS have been defined based on the preliminary classification criteria; however, in a real-world setting, aPL-positive patients with multiple organ thromboses and/or thrombotic microangiopathies exist who do not fulfill these criteria. Previous APS diagnosis and/or persistent clinically significant aPL positivity is of great importance for the CAPS diagnosis; however, almost half of the patients who develop CAPS do not have a history of aPL positivity. The purpose of this paper is to summarize the diagnostic challenges and the recently updated diagnostic algorithms for CAPS providing a ‘step-by-step’ approach for clinicians (and researchers) in the assessment of patients with multiple organ thromboses.

Management of cardiovascular risk in patients with rheumatoid arthritis: evidence and expert opinion.

Abstract: The risk of cardiovascular morbidity and mortality is increased in rheumatoid arthritis. The classical cardiovascular risk factors, including smoking, hypertension, dyslipidaemia, insulin resistance and diabetes mellitus, obesity and physical inactivity do not appear to explain the excess cardiovascular risk in rheumatoid arthritis, although they do contribute, albeit in a different way or to a lesser extent, to rheumatoid arthritis in comparison with the general population. A very important link between rheumatoid arthritis and cardiovascular disease is inflammation as it plays a key role in all stages of atherosclerosis: from endothelial dysfunction to plaque rupture and thrombosis. It also has an influence on and accentuates some traditional cardiovascular risk factors, such as dyslipidaemia, obesity and insulin resistance. To date, the exact pathophysiologic mechanism by which this relation between cardiovascular disease and rheumatoid arthritis can be explained is not completely clear. Cardiovascular risk management in rheumatoid arthritis is mandatory. Unfortunately, the way this should be done remains a point of discussion. In this review issues regarding cardiovascular risk in rheumatoid arthritis and its management will be addressed, according to evidence presented in the latest studies and our own experience-based opinion.

Clinical experience with duloxetine in the management of chronic musculoskeletal pain. A focus on osteoarthritis of the knee

Abstract: Duloxetine is a serotonin and norepinephrine reuptake inhibitor (SNRI) with central nervous system activity. Its analgesic efficacy in central pain is putatively related to its influence on descending inhibitory pain pathways. The analgesic efficacy of duloxetine has been demonstrated in four distinct chronic pain conditions. These include neuropathic pain associated with diabetic peripheral neuropathy, fibromyalgia, chronic low back pain, and osteoarthritis knee pain (OAKP). The purpose of this review is to examine the clinical efficacy and safety of duloxetine in the management of chronic OAKP. Three separate randomized, double-blind placebo-controlled trials have demonstrated that (1) a clinically meaningful decrease in pain severity occurs at about 4 weeks relative to placebo, (2) patients receiving duloxetine report better improvements in physical functioning relative to placebo, (3) duloxetine is safe and effective when used adjunctively with nonsteroidal anti-inflammatory drugs, and (4) that there are no new safety signals beyond what has been observed in other indications.

Canakinumab in patients with cryopyrin-associated periodic syndrome: an update for clinicians.

Abstract: The cryopyrin-associated periodic syndrome (CAPS) is a very rare disease. It is estimated that there are 1-2 cases for every 1 million people in the US and 1 in every 360,000 in France. However, many patients are diagnosed very late or not at all, meaning the real prevalence is likely to be higher. CAPS encompasses the three entities of familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous and articular (CINCA) syndrome. They have in common a causative mutation in the NLRP3 gene. The altered gene product cryopyrin leads to activation of the inflammasome which in turn is responsible for excessive production of interleukin (IL)-1β. IL-1β causes the inflammatory manifestations in CAPS. These appear as systemic inflammation including fever, headache or fatigue, rash, eye disease, progressive sensorineural hearing loss, musculoskeletal manifestations and central nervous system (CNS) symptoms (NOMID/CINCA only). With the advent of IL-1 Inhibitors, safe and effective therapeutic options became available for this devastating disease. To prevent severe and possible life-threatening disease sequelae, early and correct diagnosis and immediate initiation of therapy are mandatory in most patients. Canakinumab is a fully human monoclonal IgG1 anti-IL-1β antibody. It provides selective and prolonged IL-1β blockade and has demonstrated a rapid (within hours), complete and sustained response in most CAPS patients without any consistent pattern of side effects. Long-term follow-up trials have demonstrated sustained efficacy, safety and tolerability. Canakinumab is approved by the US Food and Drug Administration for FCAS and MWS and by European Medicines Agency for treatment of all three phenotypes of CAPS.

Axial spondyloarthritis: is there a treatment of choice?

Abstract: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease predominantly affecting the axial skeleton (sacroiliac joints and spine). Nonradiographic axSpA (axSpA without radiographic sacroiliitis) and ankylosing spondylitis (AS; radiographic form of axSpA) are considered nowadays as two consecutive stages of one disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) are highly effective against the major symptoms of axSpA (pain and stiffness) and may have disease-modifying properties including retarding progression of structural damage in the spine. Therefore, NSAIDs, unless contraindicated, are the treatment of choice for the majority of patients with axSpA. Beyond NSAIDs, only tumour necrosis factor (TNF) α blockers are effective and approved for the treatment of active axSpA. Several novel drugs (i.e. monoclonal antibodies targeting interleukin-17, interleukin-12/23, inhibitors of phosphodiesterase-4 and kinases), which might be effective in axSpA, are currently under investigation. Pharmacological therapy of axSpA should always be combined with nonpharmacological treatment including education and regular exercise/physiotherapy.

Ustekinumab in the treatment of psoriatic arthritis: latest findings and clinical potential:

Abstract: Ustekinumab (UST) is a fully human immunoglobulin G1κ (IgG1κ) monoclonal antibody against common sub-unit p40 of interleukin-12 (IL-12) and interleukin-23 (IL-23). IL-12 and IL-23 are essential com...

Clinical experience with intravenous zoledronic acid in the treatment of male osteoporosis: Evidence and opinions

Abstract: Osteoporosis frequently remains underrecognized and undertreated in men. Most osteoporosis-related fractures could be prevented if men at risk would be diagnosed, treated, and remained compliant with therapy. Bisphosphonates, the mainstay of osteoporosis treatment, are potent antiresorptive agents that inhibit osteoclast activity, suppress in vivo markers of bone turnover, increase bone mineral density, decrease fractures, and likely improve survival in men with osteoporosis. The focus of the article is on intravenous zoledronic acid, which may be a preferable alternative to oral bisphosphonate therapy in patients with cognitive dysfunction, the inability to sit upright, polypharmacy, significant gastrointestinal pathology or suspected medication noncompliance. Zoledronic acid is approved in the United States (US) and European Union (EU) as an annual 5 mg intravenous infusion to treat osteoporosis in men. The zoledronic acid 4 mg intravenous dose has been studied in the prevention of bone loss associated with androgen deprivation therapy. This article reviews the evidence for zoledronic acid, currently the most potent bisphosphonate available for clinical use, and its therapeutic effects in the treatment of men with osteoporosis.

The kinase inhibitor tofacitinib in patients with rheumatoid arthritis: latest findings and clinical potential:

Abstract: Macrophages, T and B cells, and neutrophils concentrate mainly into the synovial tissue of rheumatoid arthritis (RA) patients and produce several inflammatory mediators including cytokines. More recently, small molecule inhibitors of signalling mediators which have intracellular targets (mainly in T and B cells) such as the Janus kinase (JAK) family of tyrosine kinases have been introduced in RA treatment. The JAK family consist of four types: JAK1, JAK2, JAK3 and TyK2. In particular, JAK3 is the only JAK family member that associates with just one cytokine receptor, the common gamma chain, which is exclusively used by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 critically involved in T and natural killer (NK)-cell development, and B-cell function and proliferation. Tofacitinib is one of the first JAK inhibitors tested and mainly interacts with JAK1 and JAK3. Four phase II (one A and three B dose-ranging) trials in RA patients, lasting from 6 to 24 weeks, achieved significant improvements of American College of Rheumatology 20% improvement criteria (ACR20) and Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) or erythrocyte sedimentation rate (DAS-ESR; in one study that analysed this), as early as week 2 and sustained at week 24 in two studies. Doses ranged from 1, 3, 5, 10, 15, 20 up to 30 mg and were administered orally twice a day. ACR20 response rates for dosages ≥3 mg were found to be significantly (p ≤ 0.05) greater than those for placebo in all phase II studies. In general, the major adverse effects included liver test elevation, neutropenia, lipid and creatinine elevation and increased incidence of infections. More recently, RA patients randomly assigned to 5 or 10 mg of tofacitinib twice daily, in both 6- and 12-month phase III trials, achieved a significantly higher ACR20 than those receiving placebo. Adverse events occurred more frequently with tofacitinib than with placebo, and included pulmonary tuberculosis and other serious infections. The balance of efficacy and safety of tofacitinib compared with standard of care therapy is bringing this first orally available biological disease-modifying antirheumatic drug (DMARD) a step closer for RA patients.

Strontium ranelate in the treatment of knee osteoarthritis: new insights and emerging clinical evidence

Abstract: Osteoarthritis is a primary cause of disability and functional incapacity. Pharmacological treatment is currently limited to symptomatic management, and in advanced stages, surgery remains the only solution. The therapeutic armamentarium for osteoarthritis remains poor in treatments with an effect on joint structure, that is, disease-modifying osteoarthritis drugs (DMOADs). Glucosamine sulfate and chondroitin sulfate are the only medications for which some conclusive evidence for a disease-modifying effect is available. Strontium ranelate is currently indicated for the prevention of fracture in severe osteoporosis. Its efficacy and safety as a DMOAD in knee osteoarthritis has recently been explored in the SEKOIA trial, a 3-year randomized, double-blind, placebo-controlled trial. Outpatients with knee osteoarthritis, Kellgren and Lawrence grade 2 or 3, and joint space width (JSW) of 2.5-5 mm received strontium ranelate 1 g/day (n = 558) or 2 g/day (n = 566), or placebo (n = 559). This sizable population was aged 62.9 years and had a JSW of 3.50 ± 0.84 mm. Treatment with strontium ranelate led to significantly less progression of knee osteoarthritis: estimates for annual difference in joint space narrowing versus placebo were 0.14 mm [95% confidence interval (CI) 0.05-0.23 mm; p < 0.001] for 1 g/day and 0.10 mm (95% CI 0.02-0.19 mm; p = 0.018) for 2 g/day, with no difference between strontium ranelate groups. Radiological progression was less frequent with strontium ranelate (22% with 1 g/day and 26% with 2 g/day versus 33% with placebo, both p < 0.05), as was radioclinical progression (8% and 7% versus 12%, both p < 0.05). Symptoms also improved with strontium ranelate 2 g/day only in terms of total WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) score (p = 0.045), and its components for pain (p = 0.028) and physical function (p = 0.099). Responder analyses using a range of criteria for symptoms indicated that the effect of strontium ranelate 2 g/day on pain and physical function was clinically meaningful. Strontium ranelate was well tolerated. The observation of both structure and symptom modification with strontium ranelate 2 g/day makes SEKOIA a milestone in osteoarthritis research and treatment.

Odanacatib in postmenopausal women with low bone mineral density: a review of current clinical evidence.

Abstract: Human bones are in a continuous process of remodeling that ensures renovation and maintenance of the skeletal mass. Bone remodeling has two phases that are normally coupled and balanced: bone resorption mediated by osteoclasts and bone formation mediated by osteoblasts. An increase in bone resorption over bone formation results in a progressive loss of bone mass and impairment of bone microarchitecture leading to osteoporosis and its associated fractures. Recent advances in the understanding of the molecular and cellular mechanisms involved in the remodeling process have allowed the development of new targets for osteoporosis treatment. Cathepsin K, a cysteine protease, is found in osteoclasts along the bone resorption surfaces and very efficiently degrades type I collagen, the major component of the organic bone matrix. Inhibition of cathepsin K reduces bone resorption but does not impair bone formation particularly at cortical sites. Odanacatib, a potent and highly selective cathepsin K inhibitor, showed prevention of bone loss without reduction of bone formation in preclinical and clinical trials (phase I and II). Odanacatib is currently in a phase III fracture outcome international trial for the treatment of postmenopausal osteoporosis.

Milnacipran combined with pregabalin in fibromyalgia: a randomized, open-label study evaluating the safety and efficacy of adding milnacipran in patients with incomplete response to pregabalin

Abstract: Objective:To evaluate the safety, tolerability, and efficacy of adding milnacipran to pregabalin in patients with fibromyalgia who have experienced an incomplete response to pregabalin.Methods:In t...

Dual-energy X-ray absorptiometry versus quantitative ultrasonography in diagnosing osteoporosis in patients with refractory epilepsy and chronic antiepileptic drug use.

Abstract: Background: The aim of this study was to assess the feasibility of calcaneal quantitative ultrasonography (QUS) as a screening method for increased risk of osteoporosis in a unique population of people with chronic epilepsy, intellectual disability (ID), and chronic use of antiepileptic drugs.

Fibrates as therapy for osteoarthritis and rheumatoid arthritis? A systematic review.

Abstract: Fibrates are used as lipid-lowering drugs to prevent cardiovascular pathology. Fibrates are ligands of peroxisome proliferator-activated receptor α (PPARα). Besides altering lipid metabolism, PPARα ligands exert anti-inflammatory effects on various cell types. In this study, we hypothesized that PPARα agonists exert beneficial effects on osteoarthritis (OA) and rheumatoid arthritis (RA) by their local anti-inflammatory effects, but also by their systemic influences. A systematic literature search of Medline and EMBASE databases was performed up to August 2011. The main search items were osteoarthritis, rheumatoid arthritis, peroxisome proliferator-activated receptor alpha and fibrates. Inclusion criteria were in vivo or in vitro studies regarding humans or animals in which the effects of PPARα ligands were studied. Six in vivo human studies, four in vivo animal studies and seven in vitro studies were included. The in vivo human studies showed all beneficial clinical effects of PPARα ligands, but studies were small and only four were randomized. Ligands for PPARα significantly reduced pain, swelling of the joints and decreased systemic inflammatory markers. In vitro and in vivo animal studies indicate that PPARα agonists inhibit bone resorption, and reduce inflammatory and destructive responses in cartilage and synovium. PPARα agonists such as fibrates should be considered as potential therapeutic strategy for RA. There is no clinical evidence for their use in OA, although in vitro studies indicate that PPARα agonists demonstrate different joint-protective effects locally, and systemic effects on inflammation, serum lipid levels and vascular pathology. Animal studies should be performed and after confirmation of the protective effects of PPARα, large randomized controlled trials could investigate fibrates in OA and RA.

Treatment of osteoporosis in men with bisphosphonates: rationale and latest evidence:

Abstract: Osteoporosis in men contributes to significant morbidity and mortality. Hip fractures in men are associated with greater mortality compared with women, with a mortality rate of up to 37.5% within a year following the fracture. Its timely diagnosis and treatment are therefore essential. However, despite one-third of all hip fractures worldwide occurring in men, osteoporosis in men remains an immensely under-recognized and undertreated public health problem. Bisphosphonates are well studied first-line treatments for postmenopausal women with osteoporosis and have been shown to reduce fragility fractures at all clinically important sites (vertebral, nonvertebral, hip and wrist). However, the majority of studies of oral or intravenous bisphosphonate therapy in men with osteoporosis report effects on surrogate markers, including bone mineral density (BMD) and biochemical bone turnover markers, rather than on fragility fractures. Oral or intravenous bisphosphonate therapy increases spinal, total hip and femoral neck BMD compared with placebo in men with osteoporosis. Both bone resorption and bone formation markers are decreased following bisphosphonate therapy, with the onset of the decrease in bone formation markers being delayed. In a study of intravenous zoledronic acid given to older men and women following a hip fracture, any clinical vertebral and nonvertebral fractures were all reduced compared with placebo infusions. In addition, mortality was reduced in patients who received zoledronic acid. Recent studies in men with osteoporosis have increasingly reported reductions in incident vertebral fractures with oral or intravenous bisphosphonate therapy, although all studies have been underpowered to detect effects on nonvertebral and hip fracture outcomes. Bisphosphonates have a role as monotherapy, as consolidative therapy after a course of teriparatide therapy, or in combination with testosterone replacement in men with hypogonadism and osteoporosis. Bisphosphonate therapy is validated and important in the treatment of osteoporosis in men.

Latest advances in connective tissue disorders

Abstract: The connective tissue disorders comprise a number of related conditions that include systemic lupus erythematosus (SLE) and the antiphospholipid (Hughes) syndrome, scleroderma, myositis and Sjogren's syndrome. They are characterized by autoantibody production and other immune-mediated dysfunction. There are common clinical and serological features with some patients having multiple overlapping connective tissue disorders. The latest advances include new approaches to therapy, including more focused utilization of existing therapies and the introduction of biological therapies in SLE, more precise protocols for assessment of severe disease manifestations such as in interstitial lung disease and pulmonary artery hypertension in scleroderma, new antibodies for disease characterization in myositis and new approaches to patient assessment in Sjogren's syndrome. B cells have a critical role in most, if not all of these disorders such that B-cell depletion or suppression of B-cell activating cytokines improves disease in many patients. In particular, the introduction of rituximab, a monoclonal antibody targeting the CD20 molecule on B cells, into clinical practice for rheumatoid arthritis and B-cell lymphoma has been a key driver of experimental approaches to therapy in connective tissue disorders. Genetic studies also suggest a role for the innate immune system in disease pathogenesis, suggesting further future targets for biological therapies over the next few years.

Personalized medicine for osteoarthritis: where are we now?

Abstract: Personalized medicine is a much talked about subject that is a timely and important development to healthcare in general and also specifically for patients affected by osteoarthritis. This review uses biomarker examples pertinent to osteoarthritis to highlight the current status of the field, while also highlighting probable future developments. It is not meant to be an exhaustive account. The BIPED(s) [Burden of disease, Investigative, Prognosis, Efficacy, Diagnosis (safety)] classification system is used to organize the discussion of examples. Biomarkers pertaining to burden, investigation, prognosis, efficacy, diagnosis and safety are highlighted. The examples are followed by a discussion of issues related to interpretation and application of biomarker results and approaches to solve the challenges interpretation faces, including graphical, mathematical and synthetic representations. Through this review, it is hoped that a better appreciation can be gained of the potential and pitfalls of personal medicine in the care of patients with osteoarthritis.

Important issues at heart: cardiovascular risk management in rheumatoid arthritis

Abstract: Atherosclerosis remains the predominant cause of cardiovascular diseases (CVDs) and heart failure, which are the leading causes of death worldwide. It is now well established that patients with rheumatoid arthritis (RA) experience an accelerated atherosclerosis increasing their risk of CVD and related mortality compared with the general population [Nicola et al. 2005; Roubille and Tardif, 2013; Solomon et al. 2003]: a recent meta-analysis highlighted an increased risk of all CVDs of 48% in RA, as well as of myocardial infarction of 68% and of strokes of 41% [Avina-Zubieta et al. 2012]. Over the past decade, inflammation appeared to be the cornerstone of both atherosclerosis and RA. Indeed, atherosclerosis is no longer considered a condition in which lipids are being deposited passively in the arterial wall but rather fully recognized as an inflammatory, dynamic and complex disease involving multiple cell types, including inflammatory cells as well as endothelial and smooth muscle cells [Newby, 2010; Roubille et al. 2013c; Shah, 2009]. RA has long been recognized as a systemic inflammatory syndrome with several extra-articular manifestations such as interstitial lung disease and vasculitis. However, these features do not occur in all RA patients. In contrast, vascular inflammation and accelerated atherosclerosis may affect a larger RA population, probably all RA patients, especially in the early stage of the disease, as pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 and IL-6 as well as B cells contribute to the pathogenesis of both atherosclerosis and RA [Hansson, 2005]. Moreover, traditional cardiovascular risk factors should not be overlooked. Hence, assessment and management of cardiovascular risk factors is recommended for RA patients [Haraoui et al. 2012; Peters et al. 2010]. The treatment goal should be to achieve remission or at least low disease activity as early as possible [Smolen et al. 2010], not only to lead to better structural and functional outcomes, but also to reduce the cardiovascular risk [Peters et al. 2010].