Circulating miR-145 as a marker of therapeutic response to anti-TNF therapy in patients with ankylosing spondylitis.

Circulating miRNAs appear promising therapeutic and prognostic biomarkers. We aimed to investigate the predictive value of circulating miRNAs on the disease outcome following anti-TNF therapy in patients with ankylosing spondylitis (AS). Our study included 19 AS patients assessed at baseline (M0), after three (M3) and twelve months (M12) of therapy. Total RNA was isolated from plasma. A comprehensive analysis of 380 miRNAs using TaqMan Low Density Array (TLDA) was followed by a single assay validation of selected miRNAs. All AS patients had high baseline disease activity and an excellent response to anti-TNF therapy at M3 and M12. TLDA analysis revealed the dysregulation of 17 circulating miRNAs, including miR-145. Single assay validation confirmed that miR-145 is significantly downregulated at M3 compared to baseline. The decrease in the levels of miR-145 from M0 to M3 negatively correlated with the change in BASDAI from M0 to M3; and positively correlated with disease activity improvement from M3 to M12 as per BASDAI and ASDAS. The predictive value of the early change in miR-145 and levels of miR-145 at M3 were further validated by Receiver operating curves analysis. We show thatthe early change in circulating miR-145 may be a predictor for the future outcome ofAS patients treated with TNF inhibitors. Patients with a more significant decrease in miR-145 levels may show further significant improvement of disease activity after 12 months. Monitoring the expression of miR-145 in plasma in AS patients may, therefore, influence our therapeutic decision-making.

Elevated Tenascin-C Serum Levels in Patients With Axial Spondyloarthritis.

This study aimed to examine serum tenascin C (TNC) in different subsets of axial spondyloarthritis (axSpA) patients. Sixty-one patients fulfilling the Assessment of SpondyloArthritis international Society classification criteria for axSpA and 20 healthy subjects (HS) were included in study. Based on imaging, patients were classified as non-radiographic (n=16) and radiographic (n=45) axSpA. TNC serum levels were determined by ELISA. Disease-related factors including the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and C-reactive protein (CRP) levels, were determined. TNC levels were elevated in axSpA patients [535.3 (457.7-677.2) ng/ml] compared to HS [432.1 (329.1-565.9) ng/ml, p=0.007]. Dividing axSpA into radiographic and non-radiographic subsets, the difference in TNC was observed between the radiographic subset and HS [535.3 (434.5-677.2) vs. 432.1 (329.1-565.9) ng/ml, p=0.022]. TNC levels did not correlate with disease activity measures (serum CRP or BASDAI). Nevertheless, the weak correlation of TNC levels with different disease stages (r=0.25, p=0.025) was found, with the highest levels in patients with syndesmophytes. TNC levels are elevated across various subsets of axSpA, and although not related to systemic disease activity, TNC levels might reflect chronic structural spinal changes in axSpA patients. However, its specific role in bone metabolism should be elucidated in further studies.

Decrease in serum interleukin-21 levels is associated with disease activity improvement in patients with recent-onset rheumatoid arthritis.

Interleukin-21 (IL-21) plays an important role in the pathogenesis of rheumatoid arthritis (RA). The aim of our study was to assess serum levels of IL-21 in patients with recent-onset RA in relation to disease activity and response to treatment. We analyzed serum levels of IL-21 in 51 RA patients, both before and 12 weeks after the initiation of treatment and in 36 healthy individuals. Disease activity was assessed at baseline and at weeks 12 and 24 using the Disease Activity Score for 28 joints, serum levels of C-reactive protein, and the total swollen joint count. We found that IL-21 levels were not increased in patients with recent-onset RA compared with healthy controls, but they had significantly decreased from baseline to week 12 during treatment. Baseline levels of IL-21 significantly correlated with measures of disease activity (p<0.02 for all). Although IL-21 levels did not predict achievement of remission, decrease in IL-21 levels correlated with improvement in disease activity after 12 weeks (p<0.02) and also after 24 weeks (p<0.04) of treatment. Our data suggest that circulating IL-21 levels may serve as a biomarker of disease activity and better outcome in early phase of RA.

Low circulating Dickkopf-1 and its link with severity of spinal involvement in diffuse idiopathic skeletal hyperostosis.

OBJECTIVE: Dickkopf-1 (DKK-1) is an inhibitor of osteoblastogenesis, and its lower levels are linked to new bone formation. The aim of this study was therefore to explore serum levels of DKK-1 and to evaluate DKK-1's association with the severity of spinal involvement in diffuse idiopathic skeletal hyperostosis (DISH). METHODS: Serum levels of total and functional DKK-1 and C-reactive protein (CRP) were measured in 37 patients with DISH and 22 healthy age and sex-matched controls. Plain radiographs of the cervical and thoracic spine were performed, and the diagnosis of DISH was defined using the Resnick criteria. Patients were divided into three groups based on spinal involvement. Bone mineral density (BMD) and bone turnover markers were evaluated in patients with DISH. RESULTS: The levels of total serum DKK-1 were significantly lower in patients with DISH than in healthy controls (p<0.0001). Importantly, low serum levels of DKK-1 were associated with more severe spinal involvement in DISH, independent of age, sex, disease duration, CRP, bone turnover markers or BMD. However, these findings were less significant for functional DKK-1. CONCLUSION: These observations indicate that DKK-1 may play a significant role in bone formation during DISH.

Anti-TNF therapy of ankylosing spondylitis in clinical practice. Results from the Czech national registry ATTRA.

OBJECTIVES: To estimate efficacy, safety and adherence to therapy of ankylosing spondlitis (AS) patients included in the Czech National Registry ATTRA, and to look for predictive factors for therapy discontinuation. METHODS: Patients were included according to the guidelines of the Czech Society for Rheumatology, which involve failure of previous therapy, BASDAI >4, and CRP >10 mg/l. Only patients with anti-TNF administered for the first time were analysed. Adherence to therapy was evaluated using Kaplan-Meier analysis and results were presented as cumulative survival. Comparison with data on patients with rheumatoid arthritis (RA) followed in the same registry was made. RESULTS: 310 of AS patients who had reached at least 1 year as well as those who discontinued the treatment before this time point were analysed. Drug survival was longer in patients with AS than in those with RA: 84% vs. 78% and 72% vs. 49% after 1 and 3 years of treatment. Significant risk factors for treatment discontinuation were female gender (RR 2.22, p=0.001) and CRP (RR 1.33, p=0.025). The proportion of patients with BASDAI <4 during the treatment period was higher in the etanercept group than in the infliximab group (p<0.001). The number of patients fully employed increased in the whole group from 48% to 63% after 1 year of treatment. CONCLUSION: Follow-up of patients with AS in the national registry shows that it is an effective and safe way of treatment with longer adherence to anti-TNF therapy in comparison with RA patients.

Factors influencing health status and disability of patients with ankylosing spondylitis in the Czech Republic.

The aim of the study was to evaluate factors that influence health status and work disability in patients with ankylosing spondylitis (AS) in the Czech Republic. Data were collected in a retrospective fashion directly from patients with AS using mailed questionnaires containing questions regarding sociodemographic characteristics of patients, the course of their disease, therapy, rehabilitation, quality of life, and ability to work. HAQ-DI (Health Assessment Questionnaire-Disability Index) and BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) were also included in the questionnaires; 1,008 questionnaires were suitable for further statistical analysis. The average age +/- SD of patients was 50.2 +/- 10.7 years, the average symptom duration was 23.0 +/- 11.6 years. Mean time from first symptoms to diagnosis was 9.1 years. Full disability had been awarded to 303 patients (30%) at some point of their disease. Twenty seven percent of patients reported receiving full disability pension for 10 or more years. Four hundred fifty six subjects (45%) were currently or had been previously receiving partial disability pension. Receiving disability pension was more frequent among men (64%) compared to women (56%) (P = 0.012), despite the fact that women had higher BASDAI (P < 0.001) and HAQ-DI (P = 0.004) scores. Patients with a family history of AS had higher BASDAI and HAQ-DI scores (P = 0.001 and P = 0.008, respectively) compared to patients without a family history of AS. BASDAI and HAQ-DI scores correlated with age and duration of illness, younger patients and those with shorter disease duration had lower values. Fifty eight percent of patients reported a BASDAI score > or =4 (current cutoff value for initiation of biological therapy), but only 1% of patients were treated by anti TNF alpha agents within the last year. Seven hundred ninety one patients underwent spa treatment in the previous year; 96% of them experienced improvement of their health condition.

[Problems of cardiovascular toxicity of coxibs and non-selective NSA]. / Problematika kardiovaskulárni toxicity koxibu a neselektivních NSA.

Non-steroidal antirheumatics (NSA) belong to the most often prescribed drugs. Certain observation studies indicate that they are used by 20 to 30% of population of developed countries. The most common NSA's adverse effects are gastrointestinal complications. Coxibs have been developed as an alternative to conventional non-selective NSA; with similar efficacy, they should reduce the risk of development of gastrointestinal complications. In the few last years, possible toxicity of coxibs and other non-steroidal antirheumatics has been widely discussed. The VIGOR study, which was performed 6 years ago, showed five times higher incidence of nonfatal myocardial infarction in patients with rofecoxib therapy as compared with naproxen. Afterwards, there was much debate about rofecoxib, and coxibs in general, whose cardiotoxicity was supported and confuted at the same time. Possible cardioprotective effect of naproxen was discussed too. Later on, results of the APPROVE study (Adenoma Polyp Prevention on Vioxx) made Merck & Co., Inc. withdraw rofecoxib from all markets voluntarily. In the end of 2004, three controversial studies on celecoxib were published. Although the first study (Adenoma Prevention with Celecoxib study, APC) showed higher cardiovascular risk of celecoxib, the second study (Prevention of Adenomatosus Polyps, PreSAP) did not verify these results. Surprisingly, the third study (Alzheimer Disease and Prevention Trial, ADAPT) proved 50% increase of the risk of cardiovascular (CV) toxicity of naproxen. In the last year, researchers have tried to decide whether CV toxicity is a class effect of coxib group or a class effect of all NSA. Many observation studies proved higher CV risk both of coxibs (particularly rofecoxib) and non-selective NSA including naproxen. These new findings moved the American FDA (Food and Drug Administration) to publish guidance concerning higher CV risk of all coxibs and NSA. For the time being, the EMEA (European Agency for Evaluation of Medicinal Products) does not change its attitude to NSA; coxibs are contraindicated in patients with ischemic heart disease, cerebrovascular disease and peripheral artery disease; they should be used with caution in high-risk patients. Final assessment of the problems of CV toxicity of NSA and coxibs will be a case of a long-term randomized study focused on the incidence of cardiovascular adverse effects.

Correlation of some MR findings in ankylosing spondylitis.

Results of the spinal magnetic resonance (MR) in patients with ankylosing spondylitis (AS) were evaluated prospectively in correlation with age, symptoms duration and some inflammatory tests. 20 patients with AS were prospectively examined by complex clinical and laboratory tests. All were examined with X-ray and 1,5T magnetic resonance. The visibility, margination and extent of acute and chronic pathological vertebral lesions were qualitatively and quantitatively compared statistically. The axial form of AS strongly prevailed (70%). If acute AS vertebral changes are evaluated CRP did not correlated with local vertebral changes, erythrocyte sedimentation rate and functional tests BASDAI and BASFI correlated with vertebral changes on the various significance level due to the MR sequence used. Chronic spinal changes correlated with age of the patients and duration of the symptoms. BASFI test with chronic changes did not correlate. MR is the best method for evaluating changes in vertebrae and in the adjacent soft tissues. The excellent evaluation of acute and chronic local MR changes of vertebral marrow is provided by Braun's scoring system. In acute AS changes short T1 inversion recovery (STIR) sequence showed most vertebral marrow changes, while in the chronic AS changes T1 weighted images were the statistically significantly best sequence in depicting the marrow and ligamentous pathology.

Increased pentosidine, an advanced glycation end product, in serum and synovial fluid from patients with knee osteoarthritis and its relation with cartilage oligomeric matrix protein.

BACKGROUND: Pentosidine, an advanced glycation end product, increasingly accumulates in articular cartilage with age, and contributes to the pathogenesis of osteoarthritis (OA). Increased pentosidine concentrations are associated with inflammatory disorders-for example, rheumatoid arthritis. OBJECTIVE: To compare pentosidine serum concentrations in patients with knee OA and in healthy volunteers and to determine a relationship between pentosidine and cartilage oligomeric matrix protein (COMP)-a marker of articular cartilage destruction. METHODS: Paired serum and synovial fluid samples were obtained by arthrocentesis from 38 patients with knee OA and from 38 healthy volunteers. Pentosidine concentration was measured by reverse phase high performance liquid chromatography with fluorescent detection and COMP was determined by sandwich ELISA. RESULTS: Significantly increased serum pentosidine (p<0.01) and COMP (p<0.05) levels were detected in the patients with OA compared with the control group. Serum pentosidine correlated significantly with synovial fluid pentosidine (p<0.001). Pentosidine in synovial fluid (p<0.05) and in serum (p<0.05) correlated significantly with synovial fluid COMP. Pentosidine and COMP concentrations did not correlate significantly with the radiological stage of the disease. CONCLUSION: Increased pentosidine serum concentration in patients with OA and its correlation with the cartilage destruction marker COMP in synovial fluid suggests that pentosidine may be important in OA pathology and is a new potential OA marker.

Hyaluronic acid levels may have predictive value for the progression of knee osteoarthritis.

STUDY OBJECTIVES: To study prognostic value of different biochemical markers for morphological progression of early knee osteoarthritis. DESIGN: A total of 89 patients with knee osteoarthritis (OA) were enroled into the study. The follow-up period was 2 years. Radiological OA progression was evaluated by measuring joint space width. Pentosidine was detected using the HPLC method described earlier, cartilage oligomeric matrix protein (COMP) using the method published by our team. MMP-9, tissue inhibitors of metalloproteinases (TIMP), YKL-40 and hyaluronic acid were detected using commercially available kits. RESULTS: In the group of patients suffering from knee OA, higher serum levels of pentosidine (P=0.04), MMP-9 (P=0.02), TIMP (P=0.04) and COMP (P=0.05) were detected compared with healthy control subjects. Using a correlation analysis method, it has been found that the patients with higher basic serum levels of hyaluronic acid had a faster radiological progression (r=0.56, P<0.005), as well as the patients with higher basic serum pentosidine levels (r=0.30, P<0.005). Other biochemical markers had no statistically significant prognostic value. CONCLUSIONS: In our study, serum levels of hyaluronic acid and pentosidine had a predictive value for further development of knee OA in that further joint space narrowing was detected in the patients with knee OA in the next 2 years.

Analysis of the reasons for DMARD therapy discontinuation in patients with rheumatoid arthritis in the Czech and Slovak republics.

The aim of the study was to evaluate the efficacy and safety of disease-modifying drugs (DMARDs) in everyday clinical practice in Central European States (the Czech and Slovak republics). This was a retrospective, multicentre study. With the help of a special questionnaire, the medical files of 760 patients in 15 centres were analysed looking for reasons for DMARD discontinuation (e.g. insufficient efficacy, toxicity). The secondary endpoints were duration of therapy with individual DMARDs and the influence of other factors (demographic, disease specific, concomitant therapy) on duration of therapy. In 47.1 % of patients therapy was interrupted because of lack of efficacy, in 43.2 % because of adverse events, and in 9 % for undefined reasons. Toxic reactions leading to withdrawal were most common with gold (62.6 %) and methotrexate (62.5 %). Because of insufficient effect, treatment was most frequently interrupted with antimalarials (62.3 %) and penicillamine (53.2 %), but in only 22% treated with methotrexate. The mean duration of one treatment episode with DMARDs was 28.1 +/- 48.9 months. Surprisingly, it was longest for cyclophosphamide (53.5 + 55.1 months) and shortest for cyclosporin (7.0 +/- 6.7 months). The mean duration of treatment with methotrexate was only 14.9; +/- 16.2 months. The mean duration of treatment with one DMARD was statistically longer in patients with positive rheumatoid factor, extra-articular disease and age lower than 50 years. There was no impact of sex, concomitant steroid treatment and high or low sedimentation rate on treatment duration. Considerable differences in everyday clinical practice with DMARDs between Central European states and published data from the US and western Europe have been found. More education about modern strategies in the treatment of RA is probably necessary for practising rheumatologists.