Plasma Sclerostin Levels in Rheumatoid Arthritis Women on TNF-α Inhibitor Therapy.

Rheumatoid arthritis (RA) is associated with significant systemic and local bone loss. The aim of this study was to assess whether or not 15-month tumor necrosis factor α inhibitor (TNFαI) therapy in combination with methotrexate (MTX) affects circulating levels of sclerostin (SOST) in female RA patients. Plasma levels of SOST were measured using immunoassays kits. Baseline SOST levels showed no significant differences between RA patients and control participants. Postmenopausal women with RA tended to have higher sclerostin levels than premenopausal woman with RA. After 15 months of treatment with TNFαI, plasma levels of SOST were decreased. Before starting biological therapy, circulating levels of SOST significantly correlated with the patient's age (p < 0.05) and the marker of inflammation, such as ESR (p < 0.05). Multivariate regression analysis showed that age was the only significant predictor for baseline SOST levels in women with RA (ß = 0.008, p = 0.028, R2 model = 0.293). Moreover, a positive correlation between SOST levels and the 28 joint disease activity score value based on the erythrocyte sedimentation rate (DAS28-ESR) was found at baseline (p < 0.05), as well as after 15 months of biological therapy (p < 0.05). Thus, plasma SOST levels may be helpful for monitoring the efficacy of TNFαI treatment in RA patients. According to our results, TNFαI, in combination with MTX, has a beneficial effect on bone turnover with a significant reduction in bone metabolism marker SOST.

Effects of Etanercept and Adalimumab on Serum Levels of Cartilage Remodeling Markers in Women with Rheumatoid Arthritis.

Tumor necrosis factor α inhibitor (TNFαI) therapy is associated with a significant inhibition of radiographic progression, resulting in improved physical function and quality of life among patients with rheumatoid arthritis (RA). The mechanism by which TNFαI prevent joint destruction is still unknown. In this study, the effect of 15-month anti-TNF-α therapy in combination with methotrexate on circulating levels of biochemical markers of cartilage turnover in female RA patients was assessed. Serum levels of collagen type II C-terminal cleavage neoepitope (C2C), C-terminal propeptide of type II collagen (PIICP), cartilage oligomeric matrix protein (COMP), and matrix metalloproteinase-3 (MMP-3) were evaluated using immunoassays at baseline and 15 months after the start of TNFαI treatment. Baseline COMP, C2C, and MMP-3 levels and C2C/PIICP ratios were significantly higher in women with RA compared with those observed in the healthy subjects. No differences in PIICP levels between the controls and the women with RA were observed. After 15 months of TNFαI treatment, serum levels of C2C, COMP, and MMP-3 decreased, whereas the levels of PIICP increased but were still not different from those of the controls. These changes were accompanied by significantly reduced C2C/PIICP ratios. Before the start of TNFαI therapy, serum levels of COMP significantly correlated with the patients' ages (p < 0.05) and their 28-joint disease activity score values based on their erythrocyte sedimentation rates (DAS28-ESR; p < 0.05). Moreover, multiple linear regression analysis showed that baseline COMP levels retained a significant association with DAS28-ESR value (ß = 287.74, p = 0.022, R2 model = 0.25) after model adjustments. The largest area under the ROC curve was obtained for C2C/PIICP ratios (AUC: 0.830, 95% CI: 0.727-0.932, p < 0.001). Our results suggest that long-term anti-TNF-α therapy combined with MTX has a beneficial effect on cartilage remodeling that is associated with clinical improvement among RA patients. Serum C2C/PIICP ratios may help to monitor the effectiveness of anti-TNF-α treatment among RA patients.

TNF-α Inhibitors in Combination with MTX Reduce Circulating Levels of Heparan Sulfate/Heparin and Endothelial Dysfunction Biomarkers (sVCAM-1, MCP-1, MMP-9 and ADMA) in Women with Rheumatoid Arthritis.

Sulfated glycosaminoglycans (sGAGs) are likely to play an important role in the development and progression of rheumatoid arthritis (RA)-associated atherosclerosis. The present study investigated the effect of anti-tumor necrosis factor-α (anti-TNF-α) therapy in combination with methotrexate on plasma sGAG levels and serum markers of endothelial dysfunction. Among sGAG types, plasma chondroitin/dermatan sulfate (CS/DS) and heparan sulfate/heparin (HS/H) were characterized using electrophoretic fractionation. Serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9) and asymmetric dimethylarginine (ADMA) were measured by immunoassays. The measurements were carried out four times: at baseline and after 3, 9 and 15 months of anti-TNF-α therapy. All analyzed parameters, excluding ADMA, were significantly elevated in patients with RA before the implementation of biological therapy compared to healthy subjects. Performed anti-TNF-α treatment led to a successive decrease in HS/H levels toward normal values, without any effect on CS/DS levels in female RA patients. The treatment was also effective at lowering the serum levels of sVCAM-1, MCP-1, MMP-9 and ADMA. Moreover, a significant positive correlation was found between the circulating HS/H and the 28 joint disease activity score based on the erythrocyte sedimentation rate (DAS28-ESR, r = 0.408; p <0.05), MCP-1 (r = 0.398; p <0.05) and ADMA (r = 0.396; p <0.05) in patients before the first dose of TNF-α inhibitor. In conclusion, a beneficial effect of anti-TNF-α therapy on cell-surface heparan sulfate proteoglycans (HSPGs)/HS turnover and endothelial dysfunction was observed in this study. This was manifested by a decrease in blood HS/H levels and markers of endothelial activation, respectively. Moreover, the decrease in the concentration of HS/H in the blood of patients during treatment, progressing with the decline in disease activity, indicates that the plasma HS/H profile may be useful for monitoring the efficacy of anti-TNF-α treatment in patients with RA.

Bone Metabolism and RANKL/OPG Ratio in Rheumatoid Arthritis Women Treated with TNF-α Inhibitors.

The aim of this study was to evaluate the effect of anti-tumor necrosis factor α (anti-TNF-α) therapy in combination with methotrexate on bone remodeling and osteoclastogenesis in female patients with RA. Serum levels of bone turnover markers (i.e., C- and N-terminal propeptides of type I procollagen (PICP and PINP), C- and N-terminal cross-linking telopeptides of type I collagen (CTX-I and NTX-I), and soluble receptor activator of nuclear factor κB ligand (sRANKL) and osteoprotegerin (OPG)) were determined by immunoassay at baseline and 15 months after initiation of treatment. Bone mineral density was measured by dual-energy x-ray absorptiometry. We found a significant decrease in serum PINP levels, a biomarker of bone formation, and higher levels of CTX-I and sRANKL indicative of increased bone resorption in RA patients prior to TNFαI treatment compared to the controls. Anti-TNF-α therapy was effective in improving bone metabolism in RA patients as reflected in a decrease in CTX-I (at least partially due to the RANKL/OPG reduction) and a concomitant increase in PINP levels. The bone metabolism changes were independent of the type of TNFαI used. PINP and CTX-I were found to be useful markers of bone metabolism, which may prove the effectiveness of TNF-α therapy earlier than the bone density assessment.

Aggrecan Turnover in Women with Rheumatoid Arthritis Treated with TNF-α Inhibitors.

This study was performed to evaluate the effects of 15-month anti-tumor necrosis factor α (anti-TNF-α) therapy on the aggrecan turnover of female rheumatoid arthritis (RA) patients. Serum was obtained from healthy subjects and female RA patients treated with TNF-α inhibitors (TNFαI) in combination with methotrexate. We measured serum levels of aggrecan chondroitin sulfate 846 epitope (CS846), aggrecan fragments (AGC), disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and 5 (ADAMTS-5), as well as their natural inhibitor, known as tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), using immunoassay methods. Serum levels of CS846, AGC, ADAMTS-4, ADAMTS-5 and TIMP-3 were higher in female patients with RA before the treatment in comparison to healthy subjects. Ratio of ADAMTS-5 to TIMP-3 was significantly higher in RA women than in controls, whereas ADAMTS-4/TIMP-3 ratio did not differ from that in controls. During the anti-TNF-α therapy, the serum levels of 846 epitope increased, whereas levels of AGC decreased in female RA patients. Furthermore, 15 months of treatment with TNFαI downregulated serum levels of both ADAMTS, without any effect on TIMP-3 levels. These changes were accompanied by significantly reduced ratios of ADAMTS to TIMP-3. According to our results, anti-TNF-α therapy has a beneficial impact on aggrecan remodeling during RA.

Factors associated with quality of life in systemic sclerosis: a cross-sectional study.

INTRODUCTION: Systemic sclerosis (SSc) is a connective tissue disease characterized by progressive fibrosis of the skin and internal organs, leading to their failure and disturbances in the morphology and function of blood vessels. The disease affects people in different ways, and identifying how the difficulties and limitations are related to quality of life may contribute to designing helpful interventions. The aim of this study was to identify factors associated with quality of life in people with SSc. METHODS: This was a cross-sectional study conducted in 11 rheumatic centres in Poland. Patients diagnosed with SSc were included. Quality of life was measured using the SSc Quality of Life Questionnaire (SScQoL). The following candidate factors were entered in preliminary multivariable analysis: age, place of residence, marital status, occupational status, disease type, disease duration, pain, fatigue, intestinal problems, breathing problems, Raynaud's symptoms, finger ulcerations, disease severity, functional disability, anxiety and depression. Factors that achieved statistical significance at the 10% level were then entered into a final multivariable model. Factors achieving statistical significance at the 5% level in the final model were considered to be associated with quality of life in SSc. RESULTS: In total, 231 participants were included. Mean age (SD) was 55.82 (12.55) years, disease duration 8.39 (8.18) years and 198 (85.7%) were women. Factors associated with quality of life in SSc were functional disability (ß = 2.854, p < 0.001) and anxiety (ß = 0.404, p < 0.001). This model with two factors (functional disability and anxiety) explained 56.7% of the variance in patients with diffuse SSc and 73.2% in those with localized SSc. CONCLUSIONS: Functional disability and anxiety are significantly associated with quality of life in SSc. Interventions aimed at improving either of these factors may contribute towards improving the quality of life of people with SSc.

The effect of LILRB1 but not LILRA3 gene polymorphism in immunopathology of ankylosing spondylitis-A parallel to KIR genes.

LILR and KIR receptors recognize HLA-B27 and may influence immune response in ankylosing spondylitis (AS) development. Purpose of the study was to analyse LILRB1/LILRA3 polymorphisms in AS. We observed a possible protective effect of the T allele of LILRB1 rs1061680:T>C and no association with insertion/deletion polymorphisms of LILRA3 with AS.

ERAP1-ERAP2 haplotypes are associated with ankylosing spondylitis in Polish patients.

The objective of this case-control study was to evaluate the role of four single-nucleotide polymorphisms in the ERAP1 (rs2287987, rs30187, rs27044) and ERAP2 (rs2248374) genes and their haplotypes in predicting the risk for ankylosing spondylitis (AS) on a well-defined Polish population. Our study confirmed the strong association between the HLA-B*27 allele and the disease. For all tested ERAP1 SNPs we found significant differences in the minor allele and genotype distribution between patients and controls. The strongest association with AS was observed for rs30187. The minor T allele and homozygous TT genotype of this SNP significantly increased disease risk (OR = 1.56, 95%CI = 1.22-1.99, p = 0.0004 and OR = 2.52, 95%CI = 1.50-4.25, p = 0.001, respectively). In the case of rs2287987, minor C allele exerted a protective effect (OR = 0.64, 95%CI = 0.46-0.88, p = 0.008). In contrast to ERAP1, we observed no effect of rs2248374 in ERAP2 on the disease. We also carried out ERAP1-ERAP2 haplotype analysis to demonstrate a possible association of both genes with AS. Results showed that the haplotype H4, containing ERAP1 SNPs associated with high enzymatic activity, together with the presence of ERAP2 expression, significantly increased the risk of AS (OR = 1.97, 95% CI = 1.21-3.21, pcorr = 0.048). By contrast, the haplotype H5 coding for low activity of ERAP1 and the lack of ERAP2 expression was strongly protective (OR = 0.41, 95% CI = 0.23-0.72, pcorr = 0.008).

Satisfaction and discontent of Polish patients with biological therapy of rheumatic diseases: results of a multi-center questionnaire study.

OBJECTIVES: Biologics are medications widely applied in the management of inflammatory rheumatic diseases. The drugs were found to be effective but their application is associated with some disadvantages. Medication with biologics is relatively expensive, and in Poland, it is carried out in specialized centers. The study was designed to evaluate various aspects of satisfaction and dissatisfaction of Polish patients treated with biologics. MATERIAL AND METHODS: An anonymous questionnaire was distributed in 23 Polish rheumatological centers involved in the treatment; 1212 returned questionnaires were used for analysis. Responses were received from 606 patients with rheumatoid arthritis, 427 with ankylosing spondylitis, 117 psoriatic arthritis, and 62 adult patients with juvenile idiopathic arthritis (in whom administration of the drugs had been introduced before they were 18 years old). The investigated group constituted about one-fifth of all rheumatic patients on biologics in Poland. RESULTS: A beneficial or very beneficial influence of the medication on the state of physical health was found mostly in patients with rheumatoid arthritis (51.3 and 30.5%) and ankylosing spondylitis (51.0 and 36.8%). Family life was improved by the treatment especially in patients with ankylosing spondylitis (40.7 and 35.6% beneficial and very beneficial, respectively), sleep quality and sexual life mostly in those with ankylosing spondylitis (beneficial/very beneficial influence 41.5/38.4, and 38.7/23.9, respectively). There was a rather small influence of biological treatment on the financial situation of the patients. In general, satisfaction with the treatment was evaluated as positive or very positive in 88% of all investigated patients.In a significant part of the patients, transportation to the medical center was considered as a disadvantage of the treatment. About one-third of the patients considered laboratory and imaging tests to be done before initiation of the medication as a difficulty, and for about 40% waiting time for qualification for the medication was a significant disadvantage. The route of drug administration was without importance for 4/5 of the patients. CONCLUSIONS: Summing up, the results were similar in the patients suffering from various diseases although those with psoriatic arthritis felt the highest satisfaction (possibly due to the positive aesthetic effect), and those with ankylosing spondylitis had significant improvement in sexual life (probably due to younger age). Relatively low satisfaction was found in patients with juvenile idiopathic arthritis. There was a small influence of medication on financial status of the patients. Application of biologics has few disadvantages and most of them are associated with the organization of health services (waiting time for the tests, transportation to the medical centers).

Diagnostic delays in rheumatic diseases with associated arthritis.

OBJECTIVE: The objective of this study was to determine the length of delay in diagnosis of inflammatory rheumatic diseases, and to indicate the main factors responsible for such delays. MATERIAL AND METHODS: A retrospective multi-centre questionnaire survey carried out among 197 patients with diagnosed inflammatory rheumatic diseases or undergoing the diagnostic process. RESULTS: The most common early symptoms of inflammatory rheumatic disease included joint pain (94%), joint swelling (78%), morning joint stiffness (77%), fatigue (76%), and sleep disturbed by joint pain (74%). When asked about the reasons for seeking medical help, most patients indicated intensification of the symptoms (89%) and the fact that the symptoms made them unable to perform daily activities or work (86%). Limited access to specialists (70%) and the conviction that the symptoms will resolve spontaneously (57%) had the biggest impact on delaying a visit to a doctor. Before visiting a rheumatologist, the patients consulted their symptoms with their general practitioners (GPs, 95%), orthopaedicians (43%), and neurologists (29%). Almost half of the patients (48%) consulted their symptoms with at least 2 non-rheumatologists, whereas as many as 21% of patients visited 4 or more specialists. After the onset of symptoms of rheumatic disease, 28% of patients delayed seeing any doctor for 4 months or longer. 36% of patients waited 4 months or longer for a referral to a rheumatologist. The great majority of the patients (85%) made an appointment with a rheumatologist within a month of receiving a referral. 25% of patients waited 4 months or longer to see a rheumatologist. CONCLUSIONS: Diagnostic delays result from both the level of patients' awareness (ignoring early symptoms) and improper functioning of the health care system. In the case of the health care system, the source of delays is not only "queues to rheumatologists", but also referring patients to non-rheumatologists.

Does the KIR2DS5 gene protect from some human diseases?

BACKGROUND: KIR2DS5 gene encodes an activating natural killer cell receptor whose ligand is not known. It was recently reported to affect the outcome of hematopoietic stem cell transplantation. METHODOLOGY/PRINCIPAL FINDINGS: In our studies on KIR2DS5 gene associations with human diseases, we compared the frequencies of this gene in patients and relevant controls. Typing for KIR2DS5 gene was performed by either individual or multiplex polymerase chain reactions which, when compared in the same samples, gave concordant results. We noted an apparently protective effect of KIR2DS5 gene presence in several clinical conditions, but not in others. Namely, this effect was observed in ankylosing spondylitis (p=0.003, odds ratio [OR]=0.47, confidence interval [CI]=0.28-0.79), endometriosis (p=0.03, OR=0.25, CI = 0.07-0.82) and acute rejection of kidney graft (p=0.0056, OR=0.44, CI=0.24-0.80), but not in non-small-cell lung carcinoma, rheumatoid arthritis, spontaneous abortion, or leukemia (all p>0.05). In addition, the simultaneous presence of KIR2DS5 gene and HLA-C C1 allotype exhibited an even stronger protective effect on ankylosing spondylitis (p=0.0003, OR=0.35, CI=0.19-0.65), whereas a lack of KIR2DS5 and the presence of the HLA-C C2 allotype was associated with ankylosing spondylitis (p=0.0017, OR=1.92, CI=1.28-2.89), whereas a lack of KIR2DS5 and presence of C1 allotype was associated with rheumatoid arthritis (p=0.005, OR=1.47, CI=1.13-1.92). The presence of both KIR2DS5 and C1 seemed to protect from acute kidney graft rejection (p=0.017, OR=0.47, CI=0.25-0.89), whereas lack of KIR2DS5 and presence of C2 seemed to favor rejection (p=0.0015, OR=2.13, CI=1.34-3.37). CONCLUSIONS/SIGNIFICANCE: Our results suggest that KIR2DS5 may protect from endometriosis, ankylosing spondylitis, and acute rejection of kidney graft.

Seronegative arthritis in patient with solitary bone plasmacytoma.

We report a patient with localized focus of the bone destruction due to a rare disease, solitary bone plasmacytoma (SBP). The patient suffered from arthritis, mimicking seronegative rheumatoid arthritis. To our knowledge, it is the first description of coexistence of arthritis and SBP.

[Interleukin-1 receptor antagonists in the treatment rheumatoid arthritis]. / Antagonista receptora interleukiny-1 w leczeniu reumatoidalnego zapalenia stawów.

Interleukin-1 (IL-1) is one of the main inflammatory mediators associated with development of rheumatoid arthritis (RA). Deficiency in secretion of the natural IL-1 antagonist was found in RA patients, and enhanced joint inflammation. This finding was confirmed by numerous studies using the animal model of the disease. Two randomized, multicenter clinical trials with anakinra, a recombinant IL-1 receptor antagonist (rHHHuIL-1Ra), revealed that application of anakinra with or without methotrexate induces remission (ACR 20) in 38-71% of patients with RA. Induction of remission was dose and treatment-time-dependent. The present paper reviews theoretical application of rHuIL-1Ra in patients with RA and summarizes results of published clinical trials of the drug.