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1.  Rituximab and its therapeutic potential in catastrophic antiphospolipid syndrome 
The catastrophic antiphospholipid syndrome (CAPS) is characterized by thrombosis in more than three organs or systems developing over a short period of time. Despite conventional treatment with a combination of anticoagulation plus corticosteroids plus plasma exchange, and/or intravenous immunoglobulin, mortality remains high and some patients suffer from recurrent CAPS episodes. In selected patients, new therapies such as rituximab may be a treatment option. In this review, the rationale for using rituximab in CAPS is discussed.
PMCID: PMC4314298  PMID: 25649844
anti-CD20; catastrophic antiphospholipid syndrome; refractory; rituximab
2.  The effects of neuromuscular taping on gait walking strategy in a patient with joint hypermobility syndrome/Ehlers–Danlos syndrome hypermobility type 
In this case study, biomechanical alterations induced by neuromuscular taping (NMT) were quantified, during walking, in a patient with joint hypermobility syndrome/Ehlers–Danlos syndrome hypermobility type (JHS/EDS-HT).
A female JHS/EDS-HT patient underwent NMT applications over the low back spine and bilaterally to the knee. Quantitative gait analyses were collected before the NMT application and at the end of the treatment (2 weeks after the first application of NMT).
At the end of treatment following the NMT application, left step length showed improvements in cadence and velocity, the left knee showed a reduction in its flexed position at initial contact, and the right ankle joint improved its position at initial contact and in the swing phase. Improvements were also found in kinetics, in terms of the ankle moment and power.
Results show that NMT seems to be a promising low-cost intervention for improving gait strategy in patients with JHS/EDS-HT. Further investigations are needed to assess the effects of this treatment intervention on pathological symptoms.
PMCID: PMC4314299  PMID: 25649985
Ehlers–Danlos syndrome; gait analysis; neuromuscular taping; rehabilitation
3.  Fragility fracture: recent developments in risk assessment 
More than half of older women who sustain a fragility fracture do not have osteoporosis by World Health Organization (WHO) bone mineral density (BMD) criteria; and, while BMD has been used to assess fracture risk for over 30 years, a range of other skeletal and nonskeletal clinical risk factors (CRFs) for fracture have been recognized. More than 30 assessment tools using CRFs have been developed, some predicting fracture risk and others low BMD alone. Recent systematic reviews have reported that many tools have not been validated against fracture incidence, and that the complexity of tools and the number of CRFs included do not ensure best performance with poor assessment of (internal or comparative) validity. Internationally, FRAX® is the most commonly recommended tool, in addition to QFracture in the UK, The Canadian Association of Radiologists and Osteoporosis Canada (CAROC) tool in Canada and Garvan in Australia. All tools estimate standard 10-year risk of major osteoporotic and 10-year risk of hip fracture: FRAX® is able to estimate fracture risk either with or without BMD, but CAROC and Garvan both require BMD and QFracture does not. The best evidence for the utility of these tools is in case finding but there may be future prospects for the use of 10-year fracture risk as a common currency with reference to the benefits of treatment, whether pharmacological or lifestyle. The use of this metric is important in supporting health economic analyses. However, further calibration studies will be needed to prove that the tools are robust and that their estimates can be used in supporting treatment decisions, independent of BMD.
PMCID: PMC4314300  PMID: 25650086
fracture risk assessment; FRAX®; Garvan; osteoporosis; postmenopausal women; QFracture
4.  Inflammatory eye reactions with bisphosphonates and other osteoporosis medications: what are the risks? 
Inflammatory eye reactions (IERs) are rare but have been associated with medications to treat osteoporosis. The aim of this review is to summarize the current literature on the association between IERs and specific medications to treat osteoporosis (bisphosphonates, selective estrogen receptor modulators, strontium, denosumab and teriparatide). We cover the known epidemiology, potential pathogenic mechanisms and a resume of unanswered questions. Briefly, this review highlights that none of the existing randomized clinical trials were powered to identify these rare adverse events, and the majority of the information available is from spontaneous case reports and case series reporting associations between bisphosphonates and IERs. No case reports describe IERs after other anti-osteoporosis medications. Importantly, some case reports describe recurrence of the IER after affected patients were rechallenged with the same or another bisphosphonate, and that no reported cases resolved without discontinuation of the bisphosphonate. However, three large population-based cohort studies have shown conflicting results between osteoporosis treatments and IERs, but overall these studies suggest that IERs may actually be part of underlying inflammatory disease processes that also cause osteoporosis, rather than due to the medications used to treat osteoporosis themselves. There are no clear pathogenic mechanisms for how bisphosphonates could potentially cause IERs. However, the drug is secreted into the tears by the lacrimal gland and could cause irritation to the mucous membranes with subsequent release of inflammatory mediators, similar to the systemic response typically seen after infusion of bisphosphonates. However, in summary it is still not known whether there is a true causal association between bisphosphonates or other anti-osteoporosis medications and IERs, or whether it is confounding by indication and is actually due to underlying inflammatory diseases that cause both osteoporosis and IERs.
PMCID: PMC4314301  PMID: 25650170
adverse events; anti-osteoporosis medications; bisphosphonates; inflammatory eye reactions; osteoporosis; pathogenesis
5.  New strategies for osteoporosis patients previously managed with strontium ranelate 
The aim of this article is to describe potential alternatives to patients no longer eligible for management with strontium ranelate for osteoporosis according to the recommendations by the European Medicines Agency. A systematic search of Pubmed was done for papers on fracture efficacy of various treatments for osteoporosis, and potential harms especially in terms of cardiovascular events and stroke. The results showed that drugs more efficacious in terms of relative risk reduction of fractures than strontium ranelate were alendronate, risedronate, zoledronate, and denosumab. Raloxifene, as for strontium, may be associated with an increased risk of deep venous thromboembolism and fatal stroke. In terms of cardiovascular events special attention may be given to calcium supplements. Thus, patients at risk of stroke and ischemic cardiac events such as acute myocardial infarction should not use strontium ranelate. Ideally more efficacious drugs in terms of fracture reduction should be used such as alendronate, risedronate, zoledronate or denosumab. Raloxifene may pose a special problem as this too may be associated with an increased risk of fatal strokes. Other less-potent drugs in terms of fracture reduction should only be used if no alternatives are available (ibandronate, pamidronate, clodronate). Parathyroid hormone or analogs may be used for a limited time interval in specially selected patients and needs to be followed up with antiresorptive treatment to prevent loss of the bone gained. However, it should be remembered that no head-to-head comparison studies exist.
PMCID: PMC4239150  PMID: 25435924
alendronate; bisphosphonate; cardiovascular; denosumab; raloxifene; stroke; strontium ranelate; teriparatide
6.  Biological drugs for the treatment of rheumatoid arthritis by the subcutaneous route: interpreting efficacy data to assess statistical equivalence 
No equivalence analysis has yet been conducted on the effectiveness of biologics in rheumatoid arthritis. Equivalence testing has a specific scientific interest, but can also be useful for deciding whether acquisition tenders are feasible for the pharmacological agents being compared.
Our search covered the literature up to August 2014. Our methodology was a combination of standard pairwise meta-analysis, Bayesian network meta-analysis and equivalence testing. The agents examined for their potential equivalence were etanercept, adalimumab, golimumab, certolizumab, and tocilizumab, each in combination with methotrexate (MTX). The reference treatment was MTX monotherapy. The endpoint was ACR50 achievement at 12 months. Odds ratio was the outcome measure. The equivalence margins were established by analyzing the statistical power data of the trials.
Our search identified seven randomized controlled trials (2846 patients). No study was retrieved for tocilizumab, and so only four biologics were evaluable. The equivalence range was set at odds ratio from 0.56 to 1.78. There were 10 head-to-head comparisons (4 direct, 6 indirect). Bayesian network meta-analysis estimated the odds ratio (with 90% credible intervals) for each of these comparisons. Between-trial heterogeneity was marked. According to our results, all credible intervals of the 10 comparisons were wide and none of them satisfied the equivalence criterion. A superiority finding was confirmed for the treatment with MTX plus adalimumab or certolizumab in comparison with MTX monotherapy, but not for the other two biologics.
Our results indicate that these four biologics improved the rates of ACR50 achievement, but there was an evident between-study heterogeneity. The head-to-head indirect comparisons between individual biologics showed no significant difference, but failed to demonstrate the proof of no difference (i.e. equivalence). This body of evidence presently precludes any option of undertaking competitive tenderings for the procurement of these agents.
PMCID: PMC4239151  PMID: 25435923
adalimumab; biologics; certolizumab; equivalence; etanercept; golimumab; meta-analysis; rheumatoid arthritis; tocilizumab
7.  Therapy gloves for patients with rheumatoid arthritis: a review 
Rheumatoid arthritis is a chronic inflammatory disease that causes pain, joint stiffness and swelling leading to impaired hand function and difficulty with daily activities. Wearing therapy gloves has been recommended by occupational therapists as one of the alternative treatment methods for rheumatoid arthritis. This study aims to review the available literature on the effects of wearing therapy gloves on patients’ hand function and symptoms as well as to discuss the attributes of gloves that might influence the glove performance. An electronic databases search of MEDLINE, Physiotherapy Evidence Database, Occupational Therapy Systematic Evaluation of Evidence, Wiley Online Library, ScienceDirect and Cochrane Central Register of Controlled Trial was performed. Eight articles met the inclusion criteria, and covered seven clinical trials and one case study. Seven outcome measures were identified from the included studies and were then classified into two categories: hand function and hand symptoms. The hand symptoms such as pain, stiffness and swelling improve substantially when the therapy gloves are used. However, marginal or no improvement in hand function (with the exception of grip strength) linked to the use of therapy gloves is being reported. Further research is needed to quantify the effectiveness of therapy gloves, especially in improvement of hand function and in patients’ interest in wearing therapy gloves. Furthermore, future studies should include parameters which might influence therapy gloves’ performance, such as duration of trials, interface pressure generated by the gloves on the underlying skin and tissue, glove fit and construction, as well as thermophysiological comfort.
PMCID: PMC4239152  PMID: 25435925
gloves; hand functions; hand symptoms; rheumatoid arthritis; therapy
8.  Medication-induced osteoporosis: screening and treatment strategies 
Drug-induced osteoporosis is a significant health problem and many physicians are unaware that many commonly prescribed medications contribute to significant bone loss and fractures. In addition to glucocorticoids, proton pump inhibitors, selective serotonin receptor inhibitors, thiazolidinediones, anticonvulsants, medroxyprogesterone acetate, aromatase inhibitors, androgen deprivation therapy, heparin, calcineurin inhibitors, and some chemotherapies have deleterious effects on bone health. Furthermore, many patients are treated with combinations of these medications, possibly compounding the harmful effects of these drugs. Increasing physician awareness of these side effects will allow for monitoring of bone health and therapeutic interventions to prevent or treat drug-induced osteoporosis.
PMCID: PMC4206646  PMID: 25342997
anticonvulsants; aromatase; calcineurin; osteoporosis; glucocorticoids; medroxyprogesterone; proton pump; serotonin; thiazolidinediones
9.  Experience with subcutaneous abatacept for rheumatoid arthritis: an update for clinicians 
Abatacept is recommended by several expert consensus groups including the 2013 update of the EULAR recommendations for the pharmacologic management of rheumatoid arthritis (RA), as a potential choice for biologic therapy for patients with RA. Initially developed, studied, and approved as an intravenous (IV) formulation, abatacept is now also available as a subcutaneous (SC) injection. Having both options available makes abatacept a particularly versatile agent for the management of RA, greatly expanding the population of patients who could benefit from this treatment. This review provides a summary of the most important clinical trials that have investigated this molecule in both of its formulations, with a focus on the more recent trials evaluating the SC formulation, specifically the AMPLE study, the first major trial evaluating two biologic agents (abatacept and the tumor necrosis factor (TNF)-inhibitor adalimumab) in a head-to-head manner. In that study, SC abatacept was found to have an efficacy profile similar to that of SC adalimumab, both in combination with methotrexate.
PMCID: PMC4206647  PMID: 25342995
abatacept; biologic; costimulation modulator; rheumatoid arthritis; subcutaneous
10.  Use of DMARDs and biologics during pregnancy and lactation in rheumatoid arthritis: what the rheumatologist needs to know 
Rheumatoid arthritis (RA), a chronic autoimmune inflammatory disease of synovial joints, can lead to chronic pain and structural joint damage, as well as other organ involvement, especially if not adequately controlled. Because it can affect women in their reproductive years, care of pregnant women with RA requires a delicate balance of maintaining disease control while limiting potential toxicity to the fetus and neonate. While most women experience a substantial improvement in disease activity during pregnancy, for some women their RA remains active. It can even manifest itself for the first time during pregnancy or early in the post-partum period. Optimizing disease control prior to conception is key, but utilizing disease-modifying treatments effectively and safely throughout pregnancy and lactation requires open dialogue and shared decision making. This review provides evidence-based recommendations for use of disease-modifying antirheumatic drugs (DMARDs) and biologic response modifiers to guide rheumatologists in their care of pregnant and lactating women with RA and serves as a guide to counsel male patients with RA on family planning decisions.
PMCID: PMC4206648  PMID: 25342996
biologics; DMARDs; lactation; pregnancy; rheumatoid arthritis
11.  The evolving role of biomarkers for osteoarthritis 
Osteoarthritis (OA) is an increasingly important public health concern as the prevalence of this disease becomes higher and higher due to the ageing population. However, in addition to the absence of disease-modifying treatments, there are no sensitive diagnostic techniques beyond classical radiography, and physicians cannot predict who will progress with the disease. As a result, disease progression cannot be prevented or halted. Therefore, there is an urgent need for more effective techniques than radiography. Reliable, quantitative and dynamic tests to detect early damage and measure the progress of treatments targeted against joint destruction are required. Biomarkers, in addition to magnetic resonance imaging, are tools that can address these therapeutic shortcomings. Structural molecules and fragments derived from bone, cartilage and the synovium, all of which are affected by OA, have been reported to be potential candidates for biomarkers of OA. As the identification of biomarkers that can be applied more broadly from the very early to the end stages of knee OA is required, advances in the OA biomarker field remain challenging, but steadily progressive. Such advances will come not only from basic, but also preclinical and clinical research. In this review, we highlight recent OA biomarker studies generally published between 2011 and 2012. We classified the studies in this review into the following three categories: unique characteristics of the urinary level of C-terminal telopeptide of type II collagen; insight into the pathophysiology of OA revealed by biochemical biomarkers; and candidates for novel biomarkers of OA revealed by proteomics.
PMCID: PMC4206655  PMID: 25342994
osteoarthritis; biomarkers; CTX-II
12.  Comparative evaluation of cardiovascular outcomes in patients with osteoarthritis and rheumatoid arthritis on recommended doses of nonsteroidal anti-inflammatory drugs 
Aims and objectives:
We conducted an analysis to explore whether the cardiovascular outcomes associated with nonsteroidal anti-inflammatory drugs (NSAIDs), when used in licensed doses by patients with osteoarthritis or rheumatoid arthritis, was class or compound dependent.
Using the Ovid technology search engine, we conducted a search of the literature for relevant studies published between 1995 and 2011. We also retrieved further studies following manual searches. The primary endpoint was major vascular events and the secondary endpoints were stroke, hypertension and congestive heart failure. A total of 19 studies were analysed. Studies conducted in the osteoarthritis and rheumatoid arthritis patients’ population that reported on cardiovascular events were included in the analysis. The analysis was conducted using the software Review Manager 5.1 and Cochrane methodology.
Using the primary endpoint of major vascular events (MVE) and a prespecified cutoff point of 1.30, diclofenac (versus 1 comparator) and rofecoxib (versus 2 comparators) had increased risk for MVE [odds ratio (OR) >1.30]. Using the same criteria, diclofenac (versus 1 comparator) had an increased risk of myocardial infarction (MI). Although celecoxib had a slightly increased risk for MI (OR 1.33, versus 1 comparator), the confidence interval included 1 and was not significant. For the secondary endpoints, etoricoxib and rofecoxib were significantly worse off for HT (versus 1 comparator each) and naproxen was significantly worse off for stroke (versus 1 comparator). Although ibuprofen was worse off for HT (versus 1 comparator) the increased risk was not significant.
From the analysis conducted, it appears that the risk for cardiovascular events in arthritis patients on licensed doses of NSAIDs varies considerably and is likely to depend on the individual compound.
PMCID: PMC4206656  PMID: 25342992
cardiovascular risk; nonsteroidal anti-inflammatory drugs; NSAIDs
13.  Imaging in gout: A review of the recent developments 
Gout is a common inflammatory arthritis and is caused by accumulation of monosodium urate crystals in joints and soft tissues. Apart from joint damage, untreated gout is associated with cardiovascular and renal morbidity. Gout, whilst in principle considered to be well understood and simple to treat, often presents diagnostic and management challenges, with evidence to suggest that it is often inadequately treated and poor compliance is a major issue. Imaging tools can aid clinicians in establishing the correct diagnosis, when histological crystal diagnosis is unable to be established, and also assess the burden of inflammatory and structural disease. Imaging can also be used to monitor treatment response. The imaging techniques that currently have a role in the imaging of gout include conventional radiography, ultrasound, computed tomography, dual energy computed tomography, magnetic resonance imaging and nuclear medicine. Despite the lack of major technological advances in imaging of gout in recent years, scientific studies of existing imaging modalities have improved our understanding of the disease, and how to best utilize imaging techniques in the clinical setting.
PMCID: PMC4206657  PMID: 25342993
asymptomatic hyperuricemia; computed tomography; conventional radiography; dual energy computed tomography; erosions; magnetic resonance imaging; nuclear medicine; plane X-ray; tophus; ultrasound
15.  The osteocyte as a therapeutic target in the treatment of osteoporosis 
Osteoporosis is characterized by a low bone-mineral density associated with skeletal fractures. The decrease in bone-mineral density is the consequence of an unbalanced bone-remodeling process, with higher bone resorption than bone formation. The orchestration of the bone-remodeling process is under the control of the most abundant cell in bone, the osteocyte. Functioning as an endocrine cell, osteocytes are also a source of soluble factors that not only target cells on the bone surface, but also target distant organs. Therefore, any drugs targeting the osteocyte functions and signaling pathways will have a major impact on the bone-remodeling process. This review discusses potential advances in drug therapy for osteoporosis, including novel osteocyte-related antiresorptive and anabolic agents that may become available in the coming years.
PMCID: PMC4040939  PMID: 24891879
drug therapy; osteocyte; osteoporosis
16.  Biological therapies for spondyloarthritis 
Biological therapies and new imaging techniques have changed the therapeutic and diagnostic approach to spondyloarthritis. In patients with axial spondyloarthritis, tumor necrosis factor α (TNFα) inhibitor treatment is currently the only effective therapy in patients for whom conventional therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) has failed. TNFα inhibitor treatment is more effective in preventing articular damage in peripheral joints than in axial ones. It is important to treat patients at an early stage of disease to reduce disease progression; moreover it is necessary to identify causes of therapy inefficacy in preventing joint damage in the axial subset.
PMCID: PMC4040940  PMID: 24891880
biological therapy; spondyloarthritis; tumor necrosis factor
17.  Role of sclerostin in bone and cartilage and its potential as a therapeutic target in bone diseases 
Sclerostin is a small protein expressed by the SOST gene in osteocytes, bone cells that respond to mechanical stress applied to the skeleton and appear to play an important role in the regulation of bone remodeling. When sclerostin binds to its receptors on the cell surface of osteoblasts, a downstream cascade of intracellular signaling is initiated, with the ultimate effect of inhibiting osteoblastic bone formation. Recent studies have shown that the SOST gene is also expressed by articular chondrocytes and that modulation of its activity may have effects on articular cartilage and subchondral bone. The role of sclerostin in the pathogenesis of osteoarthritis in humans has not yet been defined, and the potential utility of treating osteoarthritis with interventions that alter sclerostin is not known. Rare genetic skeletal disorders in humans with low sclerostin levels, such as sclerosteosis and van Buchem disease, have been associated with a high bone mineral density (BMD) phenotype and low risk of fractures. This has led to the concept that antisclerostin interventions might be useful in the treatment of patients with osteoporosis and skeletal disorders associated with low bone mass. Compounds that inhibit sclerostin have been shown to stimulate bone formation and reduce bone resorption, with a robust increase in BMD. Investigational monoclonal antibodies to sclerostin, including romosozumab, blosozumab, and BPS804, have advanced to phase II clinical trials or beyond. If antisclerostin therapy is found to have beneficial effects on clinical endpoints, such as reduction of fracture risk or improvement in quality of life in patients with osteoarthritis, with a favorable balance of benefit and risk, then this class of compounds may become a prominent addition to the options for therapy of osteoporosis and other skeletal disorders.
PMCID: PMC3956136  PMID: 24688605
anabolic; blosozumab; BPS804; osteoporosis; romosozumab; sclerostin
18.  Role of ultrasound in the understanding and management of vasculitis 
Vasculitis is characterized by a circumferential vessel-wall thickening (‘halo’), which can be visualized by modern imaging techniques. In particular, the resolution of ultrasound has increased to 0.1 mm. Ultrasound detects abnormalities that are pathognomonic even in arteries with a diameter below 1 mm. It is particularly helpful in the diagnosis of large-vessel vasculitides, such as classic temporal arteritis, large-vessel giant-cell arteritis (GCA), Takayasu arteritis and idiopathic aortitis. Echocardiography is important for determining cardiac involvement in Takayasu arteritis and also for examining the coronary arteries of children with suspected Kawasaki disease, which is a medium-vessel vasculitis. In small vessel vasculitides ultrasound has only a role for determining the distribution or organ involvement.
Fast-track clinics for the diagnosis of GCA help to initiate treatment before complications such as blindness occur; patients receive appointments within 24 h in these clinics. Clinical examination and ultrasound of temporal and axillary arteries are performed by an experienced rheumatologist. In most cases this is able to determine if GCA is present. Temporal artery biopsy can be still carried out in ambivalent cases. The wall swelling of temporal arteries disappears after 2–3 weeks of glucocorticoid treatment. After 3 days of treatment, diagnosis becomes more difficult with ultrasound in some cases. In larger arteries, such as the axillary arteries, wall thickening disappears within months. It tends to be darker (more hypoechoic) in acute disease because of oedema.
PMCID: PMC3956137  PMID: 24688604
aortitis; giant-cell arteritis; Kawasaki disease; Takayasu arteritis; temporal arteritis; ultrasound; vasculitis
19.  Experience with rituximab in the treatment of antineutrophil cytoplasmic antibody associated vasculitis 
Prior to the 1970s, severe cases of antineutrophil cytoplasmic antibody associated vasculitis (AAV) were thought to be invariably fatal. However, the use of cyclophosphamide-based treatment regimens fundamentally altered disease outcomes, transforming AAV into a manageable, chronic illness. Despite the tremendous success of cyclophosphamide in the treatment of AAV, there remained a need for alternative therapies, due to high rates of treatment failures and significant toxicities. In recent years, with the introduction of targeted biologic response modifiers into clinical practice, many have hoped that the treatment options for AAV could be expanded. Rituximab, a chimeric monoclonal antibody directed against the B-lymphocyte protein CD20, has been the most successful biologic response modifier to be used in AAV. Following the first report of its use in AAV in 2001, experience with rituximab for treatment of AAV has rapidly expanded. Rituximab, in combination with glucocorticosteroids, is now well established as a safe and effective alternative to cyclophosphamide for remission induction for severe manifestations of granulomatosis with polyangiitis and microscopic polyangiitis. In addition, initial experiences with rituximab for remission maintenance in these diseases have been favorable, as have experiences for remission induction in eosinophilic granulomatosis with polyangiitis.
PMCID: PMC3956138  PMID: 24688606
antineutrophil cytoplasmic antibody; antineutrophil cytoplasmic antibody associated vasculitis; eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome); granulomatosis with polyangiitis (Wegener’s granulomatosis); microscopic polyangiitis; rituximab; vasculitis
20.  Sarcoidois: is it only a mimicker of primary rheumatic disease? A single center experience 
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.
PMCID: PMC3897166  PMID: 24489610
primary rheumatic disease; rheumatologic manifestations; sarcoidosis
21.  Advances and challenges in the diagnosis and treatment of polymyalgia rheumatica 
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.
PMCID: PMC3897167  PMID: 24489611
classification; diagnosis; polymyalgia rheumatica; treatment; ultrasonography
22.  Targeting the synovial angiogenesis as a novel treatment approach to osteoarthritis 
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?
PMCID: PMC3897168  PMID: 24489612
angiogenesis; arthritis; synovium; vascularization
23.  Clinical experience with duloxetine in the management of chronic musculoskeletal pain. A focus on osteoarthritis of the knee 
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.
PMCID: PMC3836379  PMID: 24294303
Chronic pain management; drug interactions; duloxetine; osteoarthritis
24.  Canakinumab in patients with cryopyrin-associated periodic syndrome: an update for clinicians 
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.
PMCID: PMC3836377  PMID: 24294305
canakinumab; cryopyrin-associated periodic syndrome (CAPS); IL-1β-inhibition
25.  Catastrophic antiphospholipid syndrome: how to diagnose a rare but highly fatal disease 
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.
PMCID: PMC3836378  PMID: 24294304
anti-β2-glycoprotein-1 antibody; antiphospholipid syndrome; anticardiolipin antibody; catastrophic antiphospholipid syndrome; lupus anticoagulant; thrombosis

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