Sarcoidosis is known as a T helper 1 lymphocyte (Th1-Ly) mediated disease which can imitate or sometimes accompany many primary rheumatic diseases. The purpose of this study is to share the clinical, demographic and laboratory data of patients presenting with rheumatologic manifestations and diagnosed with sarcoidosis.
A total of 42 patients (10 men) were included in the study. The patients were admitted to the rheumatology outpatient clinic for the first time with different rheumatic complaints between November 2011 and May 2013 and were diagnosed with sarcoidosis after relevant tests. Clinical, demographic, laboratory, radiological and histological data of these patients were collected during the 18-month follow-up period and then analyzed.
Mean patient age was 45.2 years (20–70 years) and mean duration of disease was 3.5 years (1 month–25 years). Evaluation of system and organ involvement revealed that 20 (47.6%) patients had erythema nodosum, 3 (7.1%) had uveitis, 1 (2.3%) had myositis, 1 (2.3%) had neurosarcoidosis, 32 (76.2%) had arthritis and 40 (95.2%) had arthralgia. Of the 32 patients with arthritis, 28 (87.5%) had involvement of the ankle, 3 (9.4%) had involvement of the knee and 1 (3.2%) had involvement of the wrist. No patient had cardiac involvement. Thoracic computed tomography scan showed stage 1, 2, 3 and 4 sarcoidosis in 12 (28.5%), 22 (52.4%), 4 (9.5%) and 4 (9.5%) patients, respectively. Histopathology of sarcoidosis was verified by endobronchial ultrasound, mediastinoscopy and skin and axillary biopsy of lymphadenopathies, which revealed noncaseating granulomas. Laboratory tests showed elevated serum angiotensin-converting enzyme in 15 (35.7%) patients, elevated serum calcium level in 6 (14.2%) patients and elevated serum 1,25-dihydroxyvitamin D concentrations in 2 (4.7%) patients. Serological tests showed antinuclear antibody positivity in 12 (28.5%) patients, rheumatoid factor positivity in 7 (16.6%) patients and anticyclic citrullinated antibody positivity in 2 (4.8%) patients.
Sarcoidosis can imitate or accompany many primary rheumatic diseases. Sarcoidosis should be considered not simply as an imitator but as a primary rheumatic pathology mediated by Th1-Ly. New studies are warranted on this subject.
primary rheumatic disease; rheumatologic manifestations; sarcoidosis
Polymyalgia rheumatica (PMR) is a common inflammatory condition that often affects people over the age of 50 years. Characteristic symptoms are shoulder and hip girdle pain and prolonged morning stiffness. Markers of inflammation are often elevated. Clinicians are often faced with the challenge of distinguishing PMR from other conditions, particularly rheumatoid arthritis and spondyloarthropathy that can mimic symptoms of PMR in older people. Additionally, there is an association between PMR and giant cell arteritis, a common large-vessel vasculitis which also affects people over the age of 50 years. Imaging of the large vessels in asymptomatic patients with PMR often reveals findings of subclinical vasculitis.
Presently, there are no tests that are specific for the diagnosis of PMR and clinicians rely on a combination of history, physical examination, laboratory tests and imaging studies to make a diagnosis. A recent undertaking by the European League Against Rheumatism/American College of Rheumatology has led to the publication of provisional classification criteria of PMR. Ultrasonography, which is being increasingly used by rheumatologists, can greatly aid in the diagnosis of PMR and often shows changes of synovitis and tenosynovitis.
Treatment consists of low doses of glucocorticoids which are associated with morbidity. Evaluation of newer biologic therapies targeting inflammatory cytokines is underway. Despite treatment, relapses are common.
classification; diagnosis; polymyalgia rheumatica; treatment; ultrasonography
Synovitis is a key feature in osteoarthritis and is associated with symptom severity. Synovial membrane inflammation is secondary to cartilage degradation which occurs in the early stage and is located adjacent to cartilage damage. This inflammation is characterized by the invasion and activation of macrophages and lymphocytes, the release in the joint cavity of large amounts of pro-inflammatory and procatabolic mediators, and by a local increase of synovial membrane vascularity. This latter process plays an important role in the chronicity of the inflammatory reaction by facilitating the invasion of the synovium by immune cells. Therefore, synovial membrane angiogenesis represents a key target for the treatment of osteoarthritis. This paper is a narrative review of the literature referenced in PubMed during the past 5 years. It addresses in particular three questions. What are the mechanisms involved in synovium blood vessels invasion? Are current medications effective in controlling blood vessels formation and invasion? What are the perspectives of research in this area?
angiogenesis; arthritis; synovium; vascularization
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.
Chronic pain management; drug interactions; duloxetine; osteoarthritis
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.
canakinumab; cryopyrin-associated periodic syndrome (CAPS); IL-1β-inhibition
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.
anti-β2-glycoprotein-1 antibody; antiphospholipid syndrome; anticardiolipin antibody; catastrophic antiphospholipid syndrome; lupus anticoagulant; thrombosis
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.
alendronate; bisphosphonates; hypogonadism; osteoporosis; risedronate; zoledronic acid
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.
joint space narrowing; osteoarthritis; strontium ranelate; symptoms; treatment
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 components of the Th1 and Th17 inflammatory pathways, respectively, and are the key mediators of psoriasis. Psoriatic arthritis (PsA), an important systemic inflammatory disorder, has similar pathogenesis to psoriasis. Many of PsA patients do not respond to tumor necrosis factor (TNF) inhibitor therapy, highlighting the need for additional treatment modalities with distinct mechanisms of action. Also, many patients stop responding to these agents after a certain period of use. A significant number of patients have a recurrent course or a persistent disease process. To meet these challenges a new agent working on different inflammatory aspect of PsA is needed. UST has been demonstrated to be effective, safe on short-term use and convenient in the treatment of plaque psoriasis and PsA. Long-term safety is still a concern. Until recently, the exact role of UST in the management of PsA had not been very clear. This article reviews the mechanism of action, pharmacokinetics, efficacy, safety profile and the clinical potential of UST in patients with PsA. We also discuss the three major trials conducted to show the efficacy and safety of UST in PsA.
Psoriatic arthritis; ustekinumab; psoriasis; PSUMMIT-I
The connective tissue disorders comprise a number of related conditions that include systemic lupus erythematosus (SLE) and the antiphospholipid (Hughes) syndrome, scleroderma, myositis and Sjögren’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 Sjögren’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.
new therapies in connective tissue disorders; Myositis specific antibodies; Systemic Lupus Erythematosus; antiphospholipid antibody syndrome; Myositis; scleroderma; Sjogren’s syndrome
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.
biomarker; lupus; systemic lupus erythematosus; SLE
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.
bisphosphonates; bone mineral density; fracture; men; osteoporosis; zoledronic acid
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.
animal models; bone demineralization; bone density conservation agents; bone remodeling; cathepsin K; osteoporosis postmenopausal; pathologic
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.
cardiovascular risk; cardiovascular risk management; inflammation; rheumatoid arthritis
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.
bisphosphonates; drug holidays; fractures; osteoporosis
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.
anabolic; antiresorptive; bone formation; bone mineral density; bone resorption; mineralization; safety; tolerability
To evaluate the safety, tolerability, and efficacy of adding milnacipran to pregabalin in patients with fibromyalgia who have experienced an incomplete response to pregabalin.
In this randomized, multicenter, open-label study, patients received pregabalin 300 or 450 mg/day during a 4- to 12-week run-in period. Patients with weekly recall visual analog scale (VAS) pain score of at least 40 and up to 90, Patient Global Impression of Severity score of at least 4, and Patient Global Impression of Change (PGIC) score of at least 3 were classified as incomplete responders and randomized to continue pregabalin alone (n = 180) or receive milnacipran 100 mg/day added to pregabalin (n = 184). The primary efficacy parameter was responder status based on PGIC score of up to 2. The secondary efficacy parameter was change from randomization in weekly recall VAS pain score. Safety parameters included adverse events (AEs), vital signs, and clinical laboratory tests.
The percentage of PGIC responders was significantly higher with milnacipran added to pregabalin (46.4%) than with pregabalin alone (20.8%; p < 0.001). Mean improvement from randomization in weekly recall VAS pain scores was greater in patients receiving milnacipran added to pregabalin (−20.77) than in patients receiving pregabalin alone (−6.43; p < 0.001). During the run-in period, the most common treatment-emergent AEs with pregabalin were dizziness (22.8%), somnolence (17.3%), and fatigue (9.1%). During the randomized period, the most common treatment-emergent AEs with milnacipran added to pregabalin were nausea (12.5%), fatigue (10.3%), and constipation (9.8%).
In this exploratory, open-label study, adding milnacipran to pregabalin improved global status, pain, and other symptoms in patients with fibromyalgia with an incomplete response to pregabalin treatment.
clinical trials; fibromyalgia; milnacipran; pain; pregabalin
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 IL-17A, which causes cartilage and bone degradation in synovial and bone explants. Overexpression of IL-17A induces synovial inflammation and joint destruction in animal RA models. These effects are attenuated in IL-17A-deficient animals and by agents that block IL-17A. Serum IL-17A levels and, to a greater extent, synovial fluid IL-17A levels are elevated in many patients with RA. In some RA cohorts, higher IL-17A levels have been associated with a more severe clinical course. Several IL-17A blockers, including the anti-IL-17A monoclonal antibodies secukinumab and ixekizumab, and the anti-IL-17 receptor subunit A monoclonal antibody brodalumab have been evaluated in phase II clinical trials. Of these, secukinumab is the most advanced with respect to clinical evaluation in RA, with phase III trials ongoing in patients on background methotrexate who had inadequate responses to previous tumor necrosis factor blocker therapy.
interleukin-17A; methotrexate; rheumatoid arthritis; secukinumab
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.
Wnt signaling; bone formation; osteoporosis; fracture healing; bone tumors
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.
ankylosing spondylitis; axial spondyloarthritis; nonsteroidal anti-inflammatory drugs; treatment; tumour necrosis factor α blocker
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.
fibrates; osteoarthritis; peroxisome proliferator activated receptor α; rheumatoid arthritis
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.
biological disease-modifying antirheumatic drug (DMARD); Janus kinase inhibitors; kinases; rheumatoid arthritis; therapy for rheumatoid arthritis
Spondyloarthritis (SpA) is a chronic inflammatory disease with either predominantly axial symptoms of the spine and sacroiliac joints (axial SpA, including ankylosing spondylitis) or predominantly arthritis (peripheral SpA). Next to these spinal and articular symptoms, many patients with SpA also have extra-articular manifestations (EAMs). EAMs associated with SpA include anterior uveitis (25–30%), psoriasis (10–25%) or inflammatory bowel disease (IBD) (5–10%) and cardiovascular manifestations. Peripheral arthritis occurs in approximately 30% of patients, especially in large joints, and shows an asymmetrical, oligoarticular pattern. Other common joint complaints are due to enthesitis, which manifest as extra-articular bony tenderness in areas such as the Achilles tendon. Acute anterior uveitis presents with acute pain, loss of vision and redness in one eye that usually subsides spontaneously after several weeks. Rapid treatment by an ophthalmologist is required to prevent synechiae formation which could ultimately result in glaucoma and blindness. Although less common, organ involvement in SpA can also be located in the heart, lungs or kidneys. The risk of cardiovascular events is increased in SpA. Cardiac manifestations can involve the aortic valve (1–10%) or the atrioventricular node and the risk of atherosclerotic events is increased in this group. Treatment of SpA includes physical exercise and nonsteroidal anti-inflammatory drugs (NSAIDs), and in case of peripheral arthritis, sulphasalazine can be added. When there is insufficient response to NSAIDs, tumor necrosis factor blockers, especially infliximab, etanercept, adalimumab and golimumab, are very effective in treating axial manifestations, arthritis, enthesitis and psoriasis. Anterior uveitis in SpA can be treated adequately by the ophthalmologist and in the case of refractory uveitis, treatment with adalimumab and infliximab seems to be more effective compared with etanercept. When IBD occurs with SpA, the use of NSAIDs should be minimized, except for celecoxib, and infliximab or adalimumab are preferred to etanercept. The incidence of atherosclerotic events or SpA-specific cardiac manifestations may be decreased by cardiovascular risk management or effective antirheumatic treatment. Overall it is important to realize that extra-articular manifestations frequently occur in patients with SpA and should be taken into account in the choice of treatment.
Ankylosing spondylitis; anterior uveitis; arthritis; cardiac manifestations; enthesitis; IBD; psoriasis; spondyloarthritis