Arthritis Research & Therapy - Most accessed articles

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.

Mitochondrial dysfunction and mitophagy activation in blood mononuclear cells of fibromyalgia patients: implication in the pathogenesis of the disease

Mario Cordero — 2010-01-28T00:00:00Z

IntroductionFibromyalgia is a chronic pain syndrome with unknown etiology. Recent studies have shown some evidence demonstrating that oxidative stress may have a role in the pathophysiology of fibromyalgia. However, it is still not clear whether oxidative stress is the cause or the effect of the abnormalities documented in fibromyalgia. Furthermore, the role of mitochondria in the redox imbalance reported in fibromyalgia is also controversial. We undertook this study to investigate the role of mitochondrial dysfunction, oxidative stress and mitophagy in fibromyalgia. Methods: We studied 20 patients (2 males and 18 females) recruited from the database of the Sevillian Fibromyalgia Association and 10 healthy controls. We evaluated mitochondrial function in blood mononuclear cells from fibromyalgia patients measuring coenzyme Q10 levels by high performance liquid chromatography (HPLC), and mitochondrial membrane potential by flow cytometry. Oxidative stress was determined by measuring mitochondrial superoxide production by MitoSOXTM, and lipid peroxidation in blood mononuclear cells and plasma from fibromyalgia patients. Autophagy activation was evaluated by quantifying the fluorescence intensity of LysoTrackerTM Red staining of blood mononuclear cells. Mitophagy was confirmed by measuring citrate synthase activity and electron microscopy examination of blood mononuclear cells. Results: We found reduced levels of coenzyme Q10, decreased mitochondrial membrane potential, increased level of mitochondrial superoxide in blood mononuclear cells, and increased levels of lipid peroxidation in both blood mononuclear cells and plasma from fibromyalgia patients. Mitochondrial dysfunction was also associated with increased expression of autophagic genes and the elimination of dysfunctional mitochondria by mitophagy. Conclusions: These findings may support the role of oxidative stress and mitophagy in the pathophysiology of fibromyalgia.

New insights in understanding the pathogenesis of spondyloarthropathies

Irene van der Horst-Bruinsma — 2010-01-18T00:00:00Z

Spondyloarthropathies (SpA) are characterised by dysregulation of the inflammatory processes and bone metabolism which may be clarified by gene expression profiles. Sharma and colleagues showed associations of axial SpA with the innate immune system, inflammation markers and markers of bone remodeling. Drawbacks of this study are the patient selection based on uveitis, which limits the extrapolation of these data, and the racial difference between index cases and controls, which contributes to differences in gene expression. Nevertheless, this study provides a direction for unraveling the intriguing balance between inflammation and ossification in ankylosing spondylitis.

Regulation of interferon response gene activity during infliximab treatment in rheumatoid arthritis is associated with clinical response to treatment

Lisa van Baarsen — 2010-01-22T00:00:00Z

IntroductionCross-regulation between tumor necrosis factor (TNF) and type I interferon (IFN) has been postulated to play an important role in autoimmune diseases. Therefore we determined the effect of TNF-blockade in rheumatoid arthritis (RA) on the type I IFN-response gene activity in relation to clinical response. Methods: Peripheral blood from 33 RA patients was collected in PAXgene tubes before and after the start of infliximab treatment. In a first group of 15 patients the baseline expression of type I IFN-regulated genes was determined using cDNA-microarrays and compared to levels one month after treatment. The remaining 18 patients were studied as an independent group for validation using quantitative (q)PCR. Results: Gene expression analysis revealed that anti-TNF antibody treatment induced a significant increase in type I IFN-response activity in a subset of RA patients, whereas expression levels remained similar or were slightly decreased in others. The findings appear clinically relevant since patients with an increased IFN-response gene activity after anti-TNF therapy had a poor clinical outcome. This association was confirmed and extended for an IFN-response gene set consisting of OAS1, LGALS3BP, Mx2, OAS2 and SERPING1 in five EULAR good and five EULAR poor responders, by qPCR. Conclusions: Regulation of IFN-response gene activity upon TNF-blockade in RA is not as consistent as previously described, but varies between patients. The differential changes in IFN-response gene activity appear relevant to the clinical outcome of TNF-blockade in RA.

Levels of anti-citrullinated protein antibodies and IgM rheumatoid factor are not associated with outcome in early arthritis patients: a cohort study

Jennie Ursum — 2010-01-12T00:00:00Z

IntroductionTo investigate whether baseline levels of anti-citrullinated protein antibody (ACPA) or IgM rheumatoid factor (IgM-RF) and changes in the year thereafter are associated with disease activity, functional and radiographic outcome in early arthritis patients, and provide additional information over baseline autoantibody status. Methods: In 545 early arthritis patients ACPA and IgM-RF levels, disease activity (DAS28), the Health Assessment Questionnaire (HAQ) and Sharp/Van der Heijde Score (SHS) were assessed annually. Baseline status, levels and first-year changes of the autoantibodies were associated with these measures at the two-year follow-up and sub-analysed according to autoantibody status. Results: The mean age was 52.7 years, 69% was female, at baseline 56% was ACPA positive, 47% IgM-RF positive. At the two-year follow-up the mean DAS28 was 2.88, and the median HAQ and SHS were 0.38 and 1, respectively. At one year, ACPA and IgM-RF levels had decreased by 31% and 56%, respectively. A switch from negative to positive occurred in 2% for ACPA and 3% for IgM-RF. Positive ACPA and RF status were both associated with SHS at two years (P<0.001), but baseline levels only showed a minor correlation of ACPA with DAS28 and HAQ at two years. Level changes were not associated with the outcome parameters. Conclusions: Baseline levels and first-year changes of ACPA and IgM-RF are hardly associated with outcome after two years. Seroconversion seldom occurs. Therefore, it does not appear useful to repeat ACPA or IgM-RF measurements.

Risk of incident or recurrent malignancies among patients with rheumatoid arthritis exposed to biologic therapy in the German biologics register RABBIT

Anja Strangfeld — 2010-01-08T00:00:00Z

IntroductionWe used the data of the German biologics register RABBIT, a nationwide prospective cohort study, to investigate the risk of new or recurrent malignancy in patients with rheumatoid arthritis (RA) receiving biologics compared to conventional disease modifying anti-rheumatic drugs (DMARDs). Methods: The analysis was based on patients with RA enrolled in RABBIT at start of a biologic or conventional DMARD therapy between 01 May 2001 and 31 December 2006. Incidences of first or recurrent malignancies were analysed separately. A nested case-control design was used to investigate the risk of developing a first malignancy. Matching criteria were: age, gender, follow-up time, DAS28 at study entry, smoking status, and selected chronic co-morbid conditions (obstructive or other lung disease, kidney, liver or gastrointestinal disease, psoriasis). Results: A prior malignancy was reported in 122 out of 5,120 patients. 58 of these patients had received anti-TNFalpha agents, 9 anakinra, and 55 conventional DMARDs at study entry. In 14 patients (ever exposed to anti-TNFalpha: eight, to anakinra: one) 15 recurrent cancers were observed. The average time period since the onset of the 1st malignancy was 9 years. Crude recurrence rates per 1,000 patient-years (pyrs) were 45.5 for patients exposed to anti-TNFalpha agents, 32.3 for anakinra patients and 31.4 for patients exposed to DMARDs only (Incidence rate ratio anti-TNFalpha vs. DMARD = 1.4, p=0.6.).In patients without prior cancer, 74 patients (70% female, mean age: 61.3) developed a first malignancy during the observation. This corresponds to an incidence rate (IR) of 6.0 /1,000 pyrs. 44 of these patients were ever exposed to anti-TNFalpha treatment (IR= 5.1/1,000 pyrs). In a nested case-control study comparing cancer patients to cancer-free controls, 44 of the cancer patients and 44 of the cancer-free controls were ever exposed to anti-TNFalpha agents (P=1.0). Conclusion: No significant differences in the overall incidence of malignancies in patients exposed or unexposed to anti-TNFalpha or anakinra treatment were found. The same applied to the risk of recurrent malignancies. However, in particular this last finding needs further validation in larger data sets.

Chronic arthritis leads to disturbances in the bone collagen network

Joana Caetano-Lopes — 2010-01-15T00:00:00Z

IntroductionIn this study we used a mice model of chronic arthritis to evaluate if bone fragility induced by chronic inflammation is associated with an imbalance in bone turnover and also a disorganization of the bone type I collagen network. Methods: Serum, vertebrae and femur bones were collected from eight months old polyarthritis SKG mice and controls. Strength of the femoral bones was evaluated using three-point bending tests and density was assessed with a pycnometer. Bone turnover markers carboxy-terminal collagen cross-linking telopeptides (CTX-I) and amino-terminal propeptide of type I procollagen (PINP) were measured in serum. The organization and density of bone collagen was analyzed in vertebrae using second-harmonic generation (SHG) imaging with a two-photon microscope and trabecular bone microstructure was assessed by scanning electron microscope (SEM). Results: Femoral bones of SKG mice revealed increased fragility expressed by deterioration of mechanical properties namely altered stiffness (P=0.007) and reduced strength (P=0.006), when compared to controls. In accordance intertrabecular distance and trabecular thickness as observed by SEM were reduced in SKG mice. PINP was significantly higher in arthritic mice (9.18+/-3.21ng/ml) when compared to controls (1.71+/-0.53ng/ml, P<0.001). Bone resorption marker CTX-I was 9.67+/-3.18ng/ml in arthritic SKG mice compared to 6.23+/-4.11ng/ml in controls (P=0.176). The forward-to-backward signal ratio measured by SHG was higher in SKG animals reflecting disorganized matrix and loose collagen structure compared to controls. Conclusions: We have shown for the first time that chronic arthritis by itself impairs bone matrix architecture, probably due to disturbed bone remodeling and increased collagen turnover. This effect might predispose to bone fragility fractures.

Correlation of pain relief with physical function in hand osteoarthritis: randomized controlled trial post-hoc analysis

H Richard Barthel — 2010-01-11T00:00:00Z

IntroductionNonsteroidal anti-inflammatory drugs are recommended for the relief of pain associated with hand osteoarthritis (OA) but do not alter the underlying structural changes that contribute to impaired physical function. The current analysis examined the relationship of pain relief with measures of function and global rating of disease in patients with hand OA. Methods: This was a combined analysis of 2 prospective, randomized, double-blind, 8-week, multicentre, parallel-group studies comparing diclofenac sodium 1 percent gel with placebo gel (vehicle) in patients with radiographically confirmed mild to moderate hand OA. Patients (n=783) aged [greater than or equal to] 40 years applied diclofenac sodium 1 percent gel (2 g) or vehicle to each hand 4 times daily for 8 weeks. Outcome measures included pain intensity assessed on a 100-mm Visual Analog Scale (VAS); the Australian/Canadian Osteoarthritis Hand Index (AUSCAN) subscales for pain, stiffness, and physical function (100-mm VAS); and a global rating of disease (100-mm VAS). Change in VAS pain intensity from baseline to week 8 was categorized (<0 percent, 0 percent - <15 percent, 15 percent - <30 percent, 30 percent - <50 percent, 50 percent - <70 percent, and [greater than or equal to] 70 percent) without regard to treatment and compared in each category with the mean change from baseline in each AUSCAN subindex and the global rating of disease. Pearson correlations between changes in outcome measures from baseline to week 8 were calculated. Results: Changes in VAS pain intensity were accompanied by similar changes in AUSCAN scores and global rating of disease. Pearson correlations confirmed significant associations (P<0.001) between change in VAS pain intensity and changes in AUSCAN pain (correlation coefficient [r]=0.81), AUSCAN function (r=0.75), AUSCAN stiffness (r=0.66), and global rating of disease (r=0.76). Conclusions: Pain relief correlated with improvements in physical function, stiffness, and global rating of disease in patients with hand OA, irrespective of treatment. This suggests that pain or anticipation of pain inhibits physical function and influences patient perception of disease severity in hand OA. These results also suggest that any intervention to relieve the pain of hand OA may improve function and patient perception of disease severity, despite the absence of a disease-modifying mechanism of action.Trial Registration: Clinicaltrials.gov NCT00171652, NCT00171665.

Phytalgic(R), a food supplement, vs placebo in patients with osteoarthritis of the knee or hip: a randomised double-blind placebo-controlled clinical trial

Alain Jacquet — 2009-12-16T00:00:00Z

IntroductionThe medicinal treatment of osteoarthritis (OA) is mostly symptomatic to relieve pain and incapacity with analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), drugs with well-known risks. Complementary medicines might reduce the symptoms of OA and decrease the need for NSAIDs. This study tested the effects of a food supplement, Phytalgic®, on pain and function in patients with osteoarthritis and their use of analgesic and NSAIDs. Methods: A randomized double-blind parallel-groups clinical trial compared Phytalgic® (fish-oil, vitamin E, Urtica dioica) to a placebo for three months, in 81 patients with OA of the knee or hip using NSAIDs and/or analgesics regularly. The main outcome measures were use of NSAIDs (in Defined Daily Doses per day - DDD/day) or analgesics (in 500 mg paracetamol-equivalent tablets per week (PET/week) measured each month, and Western Ontario-McMaster University Osteo-Arthritis Index (WOMAC) function scales. Results: After three months of treatment, the mean use of analgesics in the active arm (6.5 PET/week) vs. the placebo arm (16.5) was significantly different (P < 0.001) with a group mean difference of -10.0 (95% CI: -4.9 to -15.1). That of NSAIDs in the active arm (0.4 DDD/day) vs the placebo arm (1.0 DDD/day) was significantly different (P = 0.02) with a group mean difference of - 0.7 DDD/day (95% CI: -0.2 to -1.2). Mean WOMAC scores for pain, stiffness and function in the active arm (respectively 86.5, 41.4 and 301.6) vs the placebo arm (resp. 235.3, 96.3 and 746.5) were significantly different (P < 0.001) with group mean differences respectively of -148.8 (95% CI: -97.7 to -199.9), -54.9 (95% CI: -27.9 to -81.9) and -444.8 (95% CI: -269.1 to -620.4). Conclusions: The food supplement tested appeared to decrease the need for analgesics and NSAIDs and improve the symptoms of osteoarthritis.Trial registrationClinicaltrials.gov NCT00666523.

Heterogeneity of human effector CD4+ T cells

Francesco Annunziato — 2009-12-09T00:00:00Z

For many years the heterogeneity of CD4+ T-helper (Th) cells has been limited to Th1 and Th2 cells, which have been considered not only to be responsible for different types of protective responses, but also for the pathogenesis of many disorders. Th1 cells are indeed protective against intracellular microbes and they are thought to play a pathogenic role in organ-specific autoimmune and other chronic inflammatory disorders. Th2 cells provide protection against helminths, but are also responsible for the pathogenesis of allergic diseases. The identification and cloning of new cytokines has allowed one to enlarge the series of functional subsets of CD4+ Th effector cells. In particular, CD4+ Th cells producing IL-17 and IL-22, named Th17, have been initially implicated in the pathogenesis of many chronic inflammatory disorders instead of Th1 cells. However, the more recent studies in both humans and mice suggest that Th17 cells exhibit a high plasticity toward Th1 cells and that both Th17 and Th1 cells may be pathogenic. More recently, another two subsets of effector CD4+ Th cells, named Th9 and Th22 cells, have been described, even if their pathophysiological meaning is still unclear. Despite the heterogeneity of CD4+ effector Th cells being higher than previously thought and some of their subsets exhibiting high plasticity, the Th1/Th2 paradigm still maintains a strong validity.