Arthritis Research & Therapy - Most accessed articles

Is there any scientific evidence for the use of glucosamine in the management of human osteoarthritis?

Yves Henrotin — 2012-01-30T00:00:00Z

Glucosamine in its acetylated form is a natural constituent of some glycosaminoglycans (for example, hyaluronic acid and keratan sulfate) in the proteoglycans found in articular cartilage, intervertebral disc and synovial fluid. Glucosamine can be extracted and stabilized by chemical modification and used as a drug or a nutraceutical. It has been approved for the treatment of osteoarthritis (OA) in Europe to promote cartilage and joint health and is sold over the counter as a dietary supplement in the United States. Various formulations of glucosamine have been tested, including glucosamine sulfate and glucosamine hydrochloride. In vitro and in vivo studies have uncovered glucosamine's mechanisms of action on articular tissues (cartilage, synovial membrane and subchondral bone) and justified its efficacy by demonstrating structure-modifying and anti-inflammatory effects at high concentrations. However, results from clinical trials have raised many concerns. Pharmacokinetic studies have shown that glucosamine is easily absorbed, but the current treatment doses (for example, 1,500 mg/day) barely reach the required therapeutic concentration in plasma and tissue. The symptomatic effect size of glucosamine varies greatly depending on the formulation used and the quality of clinical trials. Importantly, the effect size reduces when evidence is accumulated chronologically and evidence for the structure-modifying effects of glucosamine are sparse. Hence, glucosamine was at first recommended by EULAR and OARSI for the management of knee pain and structure improvement in OA patients, but not in the most recent NICE guidelines. Consequently, the published recommendations for the management of OA require revision. Glucosamine is generally safe and although there are concerns about potential allergic and salt-related side effects of some formulations, no major adverse events have been reported so far. This paper examines all the in vitro and in vivo evidence for the mechanism of action of glucosamine as well as reviews the results of clinical trials. The pharmacokinetics, side effects and differences observed with different formulations of glucosamine and combination therapies are also considered. Finally, the importance of study design and criteria of evaluation are highlighted as new compounds represent new interesting options for the management of OA.

The distribution pattern of critically short telomeres in human osteoarthritic knees

Maria Harbo — 2012-01-18T00:00:00Z

IntroductionTelomere shortening is associated with a number of common age-related diseases. A role of telomere shortening in osteoarthritis (OA) has been suggested, mainly based on the assessment of mean telomere length in ex vivo expanded chondrocytes. Here, we addressed this role directly in vivo by using a newly developed assay, which measures specifically the load of ultra-short single telomeres (below 1500 base pairs), i.e. the telomere subpopulation believed to promote cellular senescence. Methods: Samples were obtained from human OA knees at two distances from the central lesion site. Each sample was split into three: one was used for quantification of ultra-short single telomeres through the Universal single telomere length assay (STELA), one for histological Mankin grading of OA, and one for mean telomere length measurement through quantitative fluorescence in situ hybridization (Q-FISH) as well as for assessment of senescence through quantification of senescence-associated heterochromatin foci (SAHF). Results: The load of ultra-short telomeres as well as mean telomere length was significantly associated with proximity to lesions, OA severity, and senescence level. The degree of significance was higher when assessed through load of ultra-short telomeres per cell compared with mean telomere length. Conclusions: These in vivo data, especially the quantification of ultra-short telomeres, stress a role of telomere shortening in human OA.

Repression of anti-proliferative factor Tob1in osteoarthritic cartilage

Mathias Gebauer — 2005-01-11T00:00:00Z

Osteoarthritis is the most common degenerative disorder of the modern world. However, many basic cellular features and molecular processes of the disease are poorly understood. In the present study we used oligonucleotide-based microarray analysis of genes of known or assumed relevance to the cellular phenotype to screen for relevant differences in gene expression between normal and osteoarthritic chondrocytes. Custom made oligonucleotide DNA arrays were used to screen for differentially expressed genes in normal (n = 9) and osteoarthritic (n = 10) cartilage samples. Real-time polymerase chain reaction (PCR) with gene-specific primers was used for quantification. Primary human adult articular chondrocytes and chondrosarcoma cell line HCS-2/8 were used to study changes in gene expression levels after stimulation with interleukin-1β and bone morphogenetic protein, as well as the dependence on cell differentiation. In situ hybridization with a gene-specific probe was applied to detect mRNA expression levels in fetal growth plate cartilage. Overall, more than 200 significantly regulated genes were detected between normal and osteoarthritic cartilage (P < 0.01). One of the significantly repressed genes, Tob1, encodes a protein belonging to a family involved in silencing cells in terms of proliferation and functional activity. The repression of Tob1 was confirmed by quantitative PCR and correlated to markers of chondrocyte activity and proliferation in vivo. Tob1 expression was also detected at a decreased level in isolated chondrocytes and in the chondrosarcoma cell line HCS-2/8. Again, in these cells it was negatively correlated with proliferative activity and positively with cellular differentiation. Altogether, the downregulation of the expression of Tob1 in osteoarthritic chondrocytes might be an important aspect of the cellular processes taking place during osteoarthritic cartilage degeneration. Activation, the reinitiation of proliferative activity and the loss of a stable phenotype are three major changes in osteoarthritic chondrocytes that are highly significantly correlated with the repression of Tob1 expression.

Autoimmunity induced by human cytomegalovirus in patients with systemic lupus erythematosus

Cecilia Soderberg-Naucler — 2012-01-23T00:00:00Z

Human cytomegalovirus is a common herpesvirus that is linked to autoimmunity, especially in genetically predisposed persons. The article by Hsieh and colleagues in a previous issue of Arthritis Research & Therapy suggests that a C-terminal peptide of the human cytomegalovirus protein pp65 is highly immunogenic in patients with systemic lupus erythematosus and that antibodies against this peptide cross-react with nuclear proteins and double-stranded DNA, which are highly frequent autoantibodies in systemic lupus erythematosus patients. These observations highlight the fact that immunization with one small cytomegalovirus-specific peptide results in multiple autoreactive antibodies, probably through molecular mimicry and epitope spreading, in genetically predisposed persons.

Local administration of glucocorticoids decrease synovial citrullination in rheumatoid arthritis

Dimtrios Makrygiannakis — 2012-01-27T00:00:00Z

IntroductionProtein citrullination is present in the rheumatoid synovium, presumably contributing to the perpetuation of chronic inflammation in the presence of specific autoimmunity. As a result, the present study examines the possibility that effective anti rheumatic treatment will decrease the level of synovial citrullination. Methods: Synovial biopsies were obtained from 11 rheumatoid arthritis (RA) patients before and after 8 weeks of treatment with 20 mg methotrexate weekly, 15 RA patients before and 2 weeks after an intra-articular glucocorticoid injection, 8 healthy individuals and 5 patients with osteoarthritis. Synovial inflammation was assessed by double blind semi quantitative analysis of lining thickness, cell infiltration and vascularity using a 4 points scale. Expression of citrullinated proteins (CP) with the monoclonal antibody F95 and peptidylarginine deiminase (PAD) 2 and 4 was assessed immunohistochemically by double blind semi-quantitative analysis. In vitro synovial fluid (SF), peripheral blood (PB) mononuclear cells (MC) and synovial explants obtained from RA patients were incubated with dexamethasone and analyzed by immunhistochemistry for expression of CP as well as PAD2 and PAD4 enzymes. Results: Presence of synovial CP was almost exclusive in RA compared to healthy synovium and correlated with the degree of local inflammation. Treatment with glucocorticoids but not methotrexate alters expression of synovial CP and PAD enzymes, in parallel with a decrease of synovial inflammation. Ex vivo and in vitro studies suggest also a direct effect of glucocorticoids on citrullination as demonstrated by the decrease in the level of citrullination and PAD expression following incubation of SFMC and synovial explants with dexamethasone. Conclusion: Synovial citrullination and PAD expression is depended on local inflammation and targeted by glucocorticoids.

Plasma proteins present in osteoarthritic synovial fluid can stimulate cytokine production via Toll-like receptor 4

Dong Hyun Sohn — 2012-01-08T00:00:00Z

IntroductionOsteoarthritis (OA) is a degenerative disease characterized by cartilage breakdown in the synovial joints. The presence of low-grade inflammation in OA joints is receiving increasing attention, with synovitis shown to be present even in the early stages of the disease. How the synovial inflammation arises is unclear, but proteins in the synovial fluid of affected joints could conceivably contribute. We therefore surveyed the proteins present in OA synovial fluid and assessed their immunostimulatory properties. Methods: We used mass spectrometry to survey the proteins present in the synovial fluid of patients with knee OA. We used a multiplex bead-based immunoassay to measure levels of inflammatory cytokines in serum and synovial fluid from patients with knee OA and patients with rheumatoid arthritis (RA), as well as in sera from healthy individuals. Significant differences in cytokine levels between groups were determined by Significance Analysis of Microarrays, and relationships were determined by unsupervised hierarchical clustering. To assess the immunostimulatory properties of a subset of the identified proteins, we tested their ability to induce the production of inflammatory cytokines by macrophages. For proteins found to be stimulatory, the macrophage stimulation assays were repeated using Toll-like receptor 4 (TLR4)-deficient macrophages. Results: We identified 108 proteins in OA synovial fluid, including plasma proteins, serine protease inhibitors, proteins indicative of cartilage turnover, and proteins involved in inflammation and immunity. Multiplex cytokine analysis revealed that levels of several inflammatory cytokines were significantly higher in OA sera than in normal sera, and levels of inflammatory cytokines in synovial fluid and serum were, as expected, higher in RA samples than in OA samples. As much as 36% of the proteins identified in OA synovial fluid were plasma proteins. Testing a subset of these plasma proteins in macrophage stimulation assays, we found that Gc-globulin, alpha1-microglobulin, and alpha2-macroglobulin can signal via TLR4 to induce macrophage production of inflammatory cytokines implicated in OA. Conclusion: Our findings suggest that plasma proteins present in OA synovial fluid, whether through exudation from plasma or production by synovial tissues, could contribute to low-grade inflammation in OA by functioning as so-called damage-associated molecular patterns in the synovial joint.

Cardiac autonomic impairment and chronotropic incompetence in fibromyalgia

Roberta Ribeiro — 2011-11-18T00:00:00Z

IntroductionWe aimed to gather knowledge on the cardiac autonomic modulation in patients with fibromyalgia (FM) in response to exercise and to investigate whether this population suffers from chronotropic incompetence (CI). Methods: Fourteen women with FM (age: 46 ± 3 years; body mass index (BMI): 26.6 ± 1.4 kg/m2) and 14 gender-, BMI- (25.4 ± 1.3 kg/m2), and age-matched (age: 41 ± 4 years) healthy individuals (CTRL) took part in this cross-sectional study. A treadmill cardiorespiratory test was performed and heart-rate (HR) response during exercise was evaluated by the chronotropic reserve. HR recovery (deltaHRR) was defined as the difference between HR at peak exercise and at both first (deltaHRR1) and second (deltaHRR2) minutes after the exercise test. Results: FM patients presented lower maximal oxygen consumption (VO2 max) when compared with healthy subjects (22 ± 1 versus CTRL: 32 ± 2 mL/kg/minute, respectively; P < 0.001). Additionally, FM patients presented lower chronotropic reserve (72.5 ± 5 versus CTRL: 106.1 ± 6, P < 0.001), deltaHRR1 (24.5 ± 3 versus CTRL: 32.6 ± 2, P = 0.059) and deltaHRR2 (34.3 ± 4 versus CTRL: 50.8 ± 3, P = 0.002) than their healthy peers. The prevalence of CI was 57.1% among patients with FM. Conclusions: Patients with FM who undertook a graded exercise test may present CI and delayed HR recovery, both being indicative of cardiac autonomic impairment and higher risk of cardiovascular events and mortality.

Anterior chest wall inflammation by whole body MRI in patients with spondyloarthritis: lack of association between clinical and imaging findings in a cross-sectional study

Ulrich Weber — 2012-01-06T00:00:00Z

IntroductionInflammatory involvement of the anterior chest wall (ACW) impacts the quality of life in patients with spondyloarthritis (SpA) although involvement of the ACW is often neglected on clinical and imaging evaluation. Whole body (WB) MRI is an imaging method to assess the ACW in addition to the sacroiliac joints and spine without additional inconvenience for patients. The goals of this study were to describe the distribution of ACW inflammation by WB MRI in both early and established SpA and associations between clinical and imaging findings indicative of inflammation. Methods: The ACW of 122 consecutive SpA patients (95 with ankylosing spondylitis (AS) and 27 with non-radiographic SpA (nrSpA)) and 75 healthy controls was scanned by sagittal and coronal WB MRI. The MR images were scored independently in random order by 7 readers blinded to patient identifiers. Active and structural inflammatory lesions of the ACW were recorded on a web-based data entry form. ACW pain by patient self-report, ACW tenderness on physical examination according to the Maastricht ankylosing spondylitis enthesitis score (MASES) and MRI lesions were analyzed descriptively. Kappa statistics served to assess the agreement between clinical and imaging findings. Results: ACW pain or tenderness was present in 26% with little difference between AS and nrSpA patients. Bone marrow edema (BME), erosion and fat infiltration were recorded in 44.3%, 34.4% and 27.0% of SpA patients and in 9.3%, 12.0% and 5.3% of controls. MRI lesions occurred more frequently in AS patients (BME, erosion and fat infiltration in 49.5%, 36.8%, and 33.7%, respectively) compared with nrSpA patients (25.9%, 25.9%, and 3.7%, respectively). The most frequently affected joint by MRI lesions was the manubriosternal joint. The kappa values between clinical assessments and MRI inflammation ranged from -0.10 to only 0.33 for both AS and nrSpA patients. Conclusions: 26% of SpA patients showed clinical involvement of the ACW. WB MRI signs of ACW inflammation occurred in a substantial proportion of patients with AS (49.5%) and nrSpA (25.9%). There was no association between clinical assessments of ACW, including the MASES, and MRI features.

Advances in rheumatology: new targeted therapeutics

2011-05-25T00:00:00Z

Treatment of inflammatory arthritides - including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis - has seen much progress in recent years, partially due to increased understanding of the pathogenesis of these diseases at the cellular and molecular levels. These conditions share some common mechanisms. Biologic therapies have provided a clear advance in the treatment of rheumatological conditions. Currently available TNF-targeting biologic agents that are licensed for at east one of the above-named diseases are etanercept, infliximab, adalimumab, golimumab, and certolizumab. Biologic agents with a different mechanism of action have also been approved in rheumatoid arthritis (rituximab, abatacept, and tocilizumab). Although these biologic agents are highly effective, there is a need for improved management strategies. There is also a need for education of family physicians and other healthcare professionals in the identification of early symptoms of inflammatory arthritides and the importance of early referral to rheumatologists for diagnosis and treatment. Also, researchers are developing molecules - for example, the Janus kinase inhibitor CP-690550 (tofacitinib) and the spleen tyrosine kinase inhibitor R788 (fostamatinib) - to target other aspects of the inflammatory cascade. Initial trial results with new agents are promising, and, in time, head-to-head trials will establish the best treatment options for patients. The key challenge is identifying how best to integrate these new, advanced therapies into daily practice.

Safety, pharmacokinetics, and biologic activity of a novel monoclonal antibody targeting lymphotoxin-alpha: results of a phase I randomized, placebo-controlled trial

Brinda Emu — 2012-01-08T00:00:00Z

IntroductionMLTA3698A is a humanized monoclonal antibody against lymphotoxin-alpha (LTalpha), a transiently expressed cytokine on activated B and T cells (Th1, Th17) which are implicated in rheumatoid arthritis (RA) pathogenesis. This study was conducted to assess safety, tolerability, and biologic activity of single and multiple doses of intravenous (IV) or subcutaneous (SC) MLTA3698A in RA patients. Methods: The single ascending dose (SAD) phase in patients with stable RA consisted of 6 cohorts (4:1 active:placebo at 0.3 IV, 1.0 IV, 1.0 SC, 3.0 IV, 3.0 SC, and 5.0 mg/kg IV; n=5/cohort). In the multiple ascending dose (MAD) phase, patients with pre-specified RA disease activity received 3 doses of MLTA2698A or placebo (4:1) every 2 weeks (1.0 SC, n=10; 3.0 SC, n=20; or 5.0 IV mg/kg, n=5). Safety and tolerability were assessed throughout and clinical activity was determined after 3 doses (Week 6). Results: There were no serious adverse events (SAEs) or dose-limiting toxicities, and the majority of AEs were mild-to-moderate. Pharmacokinetic profiles were linear, and clearance was independent of dose. Reductions in levels of serum CXCL13 were observed, supporting the biologic activity of MLTA3698A on the LTalpha pathway. Patients receiving MLTA3698A in the 3.0 mg/kg MAD dose group (3.0 mg/kg SC) demonstrated ACR20/50/70 response rates at Week 6 of 75%, 56%, and 25%, respectively, versus 57%, 29%, and 0% in the placebo group. The median DAS28-CRP reduction was 28% for MLTA3698A versus 8.4% for placebo. Conclusion: MLTA3698A was generally well-tolerated in RA patients. Preliminary evidence of clinical activity was observed in active RA patients at the dose level targeted for clinical effect.