Arthritis Research & Therapy - Latest Articles

Serum levels of hyaluronic acid and chondroitin sulfate as a non-invasive method to evaluate healing after cartilage repair procedures

Andreas Gomoll — 2009-07-03T00:00:00Z

MRI remains the only non-invasive method to assess the quality of cartilage repair procedures, but ideally would be complemented by other modalities, particularly blood tests. Pruksakorn et al. investigated serum levels of hyaluronic acid (HA) and chondroitin sulfate (CS) for their correlation with tissue quality after cartilage repair with autologous chondrocytes versus subchondral drilling in a dog model. They reported better tissue quality in animals treated with chondrocyte implantation. Serum levels correlated with the histological score of biopsy samples: CS showed a negative (r= -0.69), and HA a positive correlation (r= +0.46). Many questions remain to be answered before serum markers can provide a reliable, non-invasive tool to assess tissue quality, but these data provide an important foundation for additional research.

Apoptotic cell-mediated suppression of streptococcal cell wall-induced arthritis is associated with alteration of macrophage function and local regulatory T cell increase: a potential cell-based therapy?

Sylvain Perruche — 2009-07-01T00:00:00Z

IntroductionExperimental streptococcal cell wall (SCW)-induced arthritis is characterized by two successive phases of the disease. The acute phase occurs early and is associated with an inflammatory process and neutrophil infiltration into the synovium. The second chronic phase is related to effector T cell activation and the dysregulation of macrophage function. Creation of an immunomodulatory environment has been attributed to apoptotic cells themselves, apoptotic cell uptake by phagocytes as well as a lesser sensitivity of phagocytes capturing apoptotic bodies to activation. Therefore we evaluated the potential of apoptotic cell injection to influence the course of inflammation in SCW-induced arthritis in rats. Methods: Rat apoptotic thymocytes were injected i.p. (2.10e8) in addition to an arthritogenic dose of systemic SCW in LEW female rats. Control rats received SCW immunization and PBS. Rats were then followed for arthritis occurrence and circulating cytokine detection. At sacrifice, regulatory T cells (Treg) and macrophages were analyzed. Results: Apoptotic cell injection profoundly suppressed joint swelling and destruction typically observed during the acute and chronic phases of SCW-induced arthritis. Synovial inflammatory cell infiltration and bone destruction were also markedly suppressed. Ex vivo experiments revealed reduced levels of tumor necrosis factor (TNF) in cultures of macrophages from rats challenged with SCW in the presence of apoptotic thymocytes as well as reduced macrophage response to lipo-polysaccharide (LPS). Moreover, apoptotic cell injection induced higher Foxp3+ Tregs in the lymphoid organs, especially in the draining lymph nodes. Conclusions: Our data indicate that apoptotic cells modulate macrophage function and result in Treg generation/increase. This may be involved in inhibition of inflammation and amelioration of arthritis. This highlights and confirms previous studies showing that in vivo generation of Tregs using apoptotic cell injection may be a useful tool to prevent and treat inflammatory autoimmune responses.

Antibodies to cyclic citrullinated protein and erythrocyte sedimentation rate predict hand bone loss in patients with rheumatoid arthritis of short duration: a longitudinal study

Pernille Boyesen — 2009-07-01T00:00:00Z

IntroductionRadiographic progression in rheumatoid arthritis (RA) has in several studies been shown to be predicted by serological markers widely used in daily clinical practice. The objective of this longitudinal study was to examine if these serological markers also predict hand bone mineral density (BMD) loss in patients with RA of short disease duration. Methods: 163 patients with RA of short disease duration (2.4 years) were included and followed longitudinally. Antibodies to cyclic citrullinated protein (anti-CCP), rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were analysed from baseline blood-samples. Hand BMD was measured by digital X-ray radiogrammetry (DXR) based on hand and wrist radiographs obtained at baseline and 1, 2 and 5-year follow-up. Results: During the study period, DXR-BMD decreased by median (inter quartile range) 1.7% (4.1 to 0.4), 2.8% (5.3 to 0.9) and 5.6% (11.7 to 2.3) after 1, 2 and 5 years, respectively. Elevated baseline anti-CCP, RF, ESR and CRP levels were in univariate linear regression analyses consistently associated with DXR-BMD change at all time-points. Anti-CCP and ESR were independently associated with hand DXR-BMD in multivariate linear regression analyses. Elevated anti-CCP levels were consistent and independent predictors of loss in cortical hand bone during the study period, with the odds ratios (95% confidence interval) 2.2 (1.0 to 4.5), 2.6 (1.1-6.2) and 4.9 (1.4-16.7) for the 1, 2, and 5-year follow-up periods, respectively. Conclusions: Anti-CCP and ESR were found to be independent predictors of early localised BMD loss. This finding adds to the understanding of anti-CCP and ESR as important predictors of bone involvement in RA.

Broad-range PCR, cloning and sequencing of the full 16S rRNA gene for detection of bacterial DNA in synovial fluid samples of Tunisian patients with reactive and undifferentiated arthritis

Mariam Siala — 2009-07-01T00:00:00Z

IntroductionBroad-range rDNA polymerase chain reaction (PCR) provides an alternative, cultivation-independent approach for identifying bacterial DNA in reactive and other form of arthritis. The aim of this study was to use broad-range rDNA polymerase chain reaction targeting the 16S rRNA gene in patients with reactive and other forms of arthritis and to screen for the presence of DNA from any given bacterial species in synovial fluid (SF) samples. Methods: We examined the synovial fluid (SF) samples from a total of 27 patients consisting of patients with reactive arthritis (ReA) (n=5), undifferentiated arthritis (UA) (n=9), rheumatoid arthritis (n=7), and osteoarthritis (n=6) of which the latter two were used as controls. Using broad-range bacterial PCR amplifying a 1,400-base-pair fragment from the 16S rRNA gene, we identified and sequenced at least 24 clones from each synovial fluid sample. To identify the corresponding bacteria, DNA sequences were compared to the EMBL (European Molecular Biology Laboratory) database. Results: Bacterial DNA was identified in 20 of the 27 SF samples (74, 10 %). Analysis of a large number of sequences revealed the presence of DNA from more than one single bacterial species in the SF of all patients studied. The nearly complete sequences of the 1,400 bp were obtained for most of the detected species. DNA of bacterial species including Shigella sp, Escherichia sp, and other coli-form bacteria as well as opportunistic pathogens such as Stenotrophomonas maltophilia and Achromobacter xylosoxidans were shared in all arthritis patients. Among pathogens described to trigger ReA, DNA from Shigella sonnei was found in ReA and UA patients. We also detected DNA from rarely occurring human pathogens such as Aranicola sp and Pantoea ananatis. We also found DNA from bacteria so far not described in human infections such as Bacillus niacini, Paenibacillus humicus, Diaphorobacter sp and uncultured bacterium genera incertae sedis OP10. Conclusions: Broad-range PCR followed by cloning and sequencing the entire 16S rDNA, allowed the identification of the bacterial DNA environment in the SF samples of arthritic patients. We found a wide spectrum of bacteria including those known to be involved in ReA and others not previously associated with arthritis.

Increased production of soluble CTLA-4 in patients with spondylarthropathies correlates with disease activity

Eric Toussirot — 2009-07-01T00:00:00Z

IntroductionSpondylarthropathies (SpA) are characterized by abnormal immune responses including T cell activation. Cytotoxic T lymphocyte associated molecule-4 (CTLA-4) is involved in down-regulating immune responses. A soluble form of CTLA-4 (sCTLA-4), resulting from an alternative splicing, has been identified and was found increased in several autoimmune diseases. Here, we evaluated circulating levels of sCTLA-4 as a marker of immune dysregulation in SpA. Intracellular CTLA-4 and levels of CTLA-4 transcript expression in peripheral blood lymphocytes (PBL) were also studied. Methods: Sera from 165 patients with SpA were evaluated for sCTLA-4 measurements. Results were compared to those from 71 patients with rheumatoid arthritis (RA) and 88 healthy subjects. In 32 patients with SpA, 22 patients with RA and 15 healthy controls, we analyzed the intracellular CTLA-4 expression in CD4+ T cells, CD8+ T cells, activated (HLA-DR+Foxp3-) CD4+ T cells, CD4+ regulatory (CD25+Foxp3+) T cells and in CD3 negative cells by flow cytometry. Expression of the full length (coding for membrane CTLA-4) and spliced form (coding for sCTLA-4) of CTLA-4 transcripts in PBL were analyzed by quantitative real-time polymerase chain reaction (RT-PCR). Results: High levels of sCTLA-4 were found in the SpA group compared to the RA group and healthy controls (P< 0.0001). Soluble CTLA-4 serum levels strongly correlated with clinical index of disease activity BASDAI (r= 0.42, P< 0.0001) and C-reactive protein (CRP) levels (r= 0.17, P= 0.037). In contrast to RA patients, SpA patients did not exhibit changes in intracellular CTLA-4 expression in the different PBL subsets tested. Finally, the SpA group showed a preferential expression of the spliced CTLA-4 mRNA (P= 0.0014) in PBL. Conclusions: SpA patients exhibit high levels of circulating sCTLA-4 that may result from an alternative splicing of CTLA-4 transcripts. This may influence immune activation and regulation in SpA.

Pathogenesis of tendinopathies: inflammation or degeneration?

Michele Abate — 2009-06-30T00:00:00Z

The intrinsic mechanisms of tendinopathies are largely unknown and whether inflammation or degeneration have the prominent pathogenetic role is debated.Assuming that there is a continuum from physiology to pathology, overuse may be considered as the initial disease factor; microruptures of tendon fibers occur and several molecules are expressed: some of them promote the healing process, others, including inflammatory-cytokines can act as disease mediators. The neural ingrowth, accompanying the neovessels, explains the occurrence of pain and triggers a neurogenic mediated inflammation.It is conceivable that inflammation and degeneration are not mutually exclusive, but work together in the pathogenesis of tendinopathies.

Molecular therapies for systemic lupus erythematosus: clinical trials and future prospects

Fanny Monneaux — 2009-06-30T00:00:00Z

The prognosis of patients with systemic lupus erythematosus has greatly improved since treatment regimens combining corticosteroids and immunosuppressive medications have been widely adopted in therapeutic strategies given to these patients. Immune suppression is evidently efficient but also leads to higher susceptibility to infectious and malignant diseases. Toxic effects and sometimes unexpectedly dramatic complications of current therapies have been progressively reported. Identifying novel molecular targets therefore remains an important issue in the treatment of lupus. The aim of this review article is to highlight emerging pharmacological options and new therapeutic avenues for lupus with a particular focus on non-antibody molecular strategies.

Epidemiology, costs, and the economic burden of fibromyalgia

Michael Spaeth — 2009-06-30T00:00:00Z

The assumption, that fibromyalgia is associated with a maior impact on the utilization of both healthcare and non-healthcare resources has not been thoroughly supported by many evidence-based data. Despite the differences between health care and sociopolitical systems in various countries, more recent results from epidemiological research now clearly demonstrate the socioeconomic burden of fibromyalgia and its comorbidities. The costs of the disease, calculated in single studies and countries, allow estimates for populations in other countries. The alarming results highlight the urgent need both for more research (including pathophysiology and epidemiology) and for the acceptance of emerging treatment challenges.

Myeloid dendritic cells correlate with clinical response whereas plasmacytoid dendritic cells impact autoantibody development in rheumatoid arthritis patients treated with infliximab

Christophe Richez — 2009-06-29T00:00:00Z

IntroductionThe objective of our study was to identify the significance of the sub-types of dendritic cell (DC), specifically myeloid DC (mDC) and plasmacytoid DC (pDC), in rheumatoid arthritis (RA) pathogenesis through their longitudinal follow-up in patients receiving infliximab. Methods: Circulating mDC and pDC levels were evaluated by flow cytometry in RA patients (n = 61) and healthy volunteers (n = 30). In RA patients, these levels were measured before and during infliximab therapy. Their counts were correlated to RA disease activity markers and anti-nuclear antibodies occurrence. Interferon-a production was measured by ELISA in serum of RA patients and, in vitro, in supernatant of peripheral blood mononuclear cells stimulated by influenza virus in presence or absence of infliximab. Statistical evaluations were based on Mann-Whitney tests or Wilcoxon's signed rank tests. Results: RA patients with active disease were characterized by a baseline decrease in both circulating pDCs and mDCs. Disease activity markers inversely correlated only with mDC level. This level increased in RA patients responsive to infliximab therapy, to reach the level observed in controls. Conversely, anti-nuclear antibodies appearance during infliximab therapy correlated inversely with pDCs level and was associated with increased serum interferon-a level and circulating plasma cells number. In vitro studies revealed that infliximab kept pDCs in an interferon-a secreting state upon viral stimulation allowing differentiation of B cells into anti-nuclear antibody-secreting plasma cells. Conclusions: This study reveals two distinct roles for pDC and mDC in RA. Circulating mDCs mainly contribute to RA activity, whereas pDCs seem to be involved in appearance of anti-nuclear antibodies under infliximab therapy through the ability of this drug to keep pDCs in an interferon-a secreting state.

Early and long-standing rheumatoid arthritis: distinct molecular signatures identified by gene-expression profiling in synovia

Thierry Lequerre — 2009-06-29T00:00:00Z

IntroductionRheumatoid arthritis (RA) is a heterogeneous disease and its underlying molecular mechanisms are still poorly understood. Because previous microarray studies have only focused on long-standing (LS) RA compared to osteoarthritis, we aimed to compare the molecular profiles of early and LS RA versus control synovia. Methods: Synovial biopsies were obtained by arthroscopy from 15 patients (4 early untreated RA, 4 treated LS RA and 7 controls, who had traumatic or mechanical lesions). Extracted mRNAs were used for large-scale gene-expression profiling. The different gene-expression combinations identified by comparison of profiles of early, LS RA and normal synovia were linked to the biological processes involved in each situation. Results: Three combinations of 719, 116 and 52 transcripts discriminated, respectively, early from LS RA, and early or LS RA from normal synovia. We identified several gene clusters and distinct molecular signatures specifically expressed during early or LS RA, thereby suggesting the involvement of different pathophysiological mechanisms during the course of RA. Conclusions: Early and LS RA have distinct molecular signatures with different biological processes participating at different times during the course of the disease. These results suggest that better knowledge of the main biological processes involved at a given RA stage might help to choose the most appropriate treatment.