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The Leeds Behçet's disease quality-of-life (BD-QoL) questionnaire is a specific and valid measure which is applied in English-speaking patients. We conducted Persian adaptation of BD-QoL questionnaire. Between June and December 2012, 220 Iranian patients fulfilling International Study Group criteria for the diagnosis of BD attending the rheumatology clinics at Tehran University of Medical Sciences were enrolled. Bilingual translators undertook the forward translation and cross-cultural adaptation of the BD-QoL questionnaire. Back-translation was conducted, and this version was sent to the designer of the questionnaire and revised accordingly. SF-36 health survey, Iranian Behçet's disease dynamic activity measure (IBDDAM), and Behçet's Disease Current Activity Form (BDCAF) were other administered measures. The Varimax rotation method with Kaiser normalization defined 5 factors with eigenvalues greater than 1.0. Studied cases were comprised of 118 males (53.6 %) and 102 females (46.4 %). Mean age of the patients was 38.3 ± 11.3 years (range 16-73). The mean BD-QoL score was 10.3 ± 8.8. Test-retest reliability was high, and two time points were significantly correlated (Spearman's correlation coefficient of 0.75-0.84). Cronbach's α coefficient of 0.949 demonstrated the excellent internal consistency. These factors cumulatively explained 58.74 % of total variance. The ratio of first to second eigenvalue was 7.08, which underlined the undimensionality. The results revealed adapted BD-QoL scores had significant correlation with IBDDAM (correlation coefficient = 0.19, P value = 0.005) and BDCAF (correlation coefficient = 0.21, P value = 0.002). Conversely, no significant correlation between BD-QoL and SF-36 results was detected ( P value = 0.078). The Persian version of BD-QoL was shown to be unidimensional, highly reliable, and adequate construct validity. [ABSTRACT FROM AUTHOR]

• A 2A AR agonist decreases TNF-α secretion by macrophages of AS patients. • A 2A AR activation increases IL23A mRNA expression by macrophages of AS patients. • A 2A AR activation did not have any influence on macrophages of healthy individuals. Ankylosing spondylitis (AS) is an auto-inflammatory debilitating disorder with a complex pathogenesis. The adenosinergic pathway is an immunologic regulating pathway with a potential role in AS pathophysiology. In the present study, we have aimed to investigate the influence of A 2A adenosine receptor (A 2A AR) activation on tumor necrosis factor-α (TNF-α) and interleukin-23 (IL-23) expression and secretion by monocyte-generated macrophages of AS patients. Whole-blood separated monocytes were extracted from 14 AS patients and 14 healthy controls. Macrophages were differentiated by macrophage colony-stimulating factor (M-CSF), and surface markers were confirmed by flow cytometer. Cells were treated with CGS-21680 as a known agonist of A 2A AR. Analysis of ADORA2A , TNFA , and IL23A gene expression was performed by SYBR green real-time PCR. The concentration of secreted cytokines was also measured by ELISA kits. Based on our analysis, CGS-21680 significantly decreased TNF-α secretion by monocyte-derived macrophages of AS patients. Moreover, A 2A AR agonist increased the IL23A mRNA expression level in monocyte-derived macrophages of AS patients considerably. Whereas, CGS-21680 did not have any influence on macrophages of healthy individuals. According to our results, it appears that A 2A AR activation can increase IL-23 secretion by monocyte-derived macrophages of AS patients. Although the TNF-α reducing effect of A 2A AR agonists can be a potential target in AS treatment, robust increasing of IL-23 should be considered as the undesirable effect of these agents. [ABSTRACT FROM AUTHOR]

Background: Ankylosing spondylitis (AS) is a multifactorial rheumatic disease which mainly involves the axial skeleton. Macrophages and extracellular nucleotides have been shown to contribute to the inflammation process in autoimmune diseases. Membrane‐bound purinergic P2 receptors might be involved in the modulation of immune cells in AS. Therefore, we aimed to analyze the messenger RNA (mRNA) expression of P2 receptors in the macrophages of AS patients and healthy controls. Methods: Twenty‐three AS patients and 23 age‐ and sex‐matched healthy individuals were included in our study. Whole blood‐separated monocytes of study participants were stimulated by macrophage colony‐stimulating factor for 7 days and differentiated to macrophages. Monocyte and macrophage markers were analyzed by flow cytometry. SYBR green real‐time polymerase chain reaction was used to measure the relative expression levels of P2RX1, P2RX2, P2RX3, P2RX4, P2RX5, P2RX6, P2RX7, P2RY1, P2RY2, P2RY4, P2RY6, P2RY11, P2RY12, P2RY13, P2RY14, and PANX1 genes. Results: P2RY13 and P2RY6 genes had the highest expression levels in macrophages among P2RY genes. P2RY1 mRNA expression was significantly down‐regulated (−1.75 fold) and P2RY14 was up‐regulated (2.6 fold) in macrophages of AS patients compared to healthy individuals. P2RX4 gene had the highest expression in monocyte‐derived macrophages, followed by P2RX7 and P2RX1 genes. There was no significant difference in P2X receptor mRNA expression level between macrophages of AS patients and healthy individuals. Conclusions: Our results indicate that AS patients show altered expression levels of P2 receptor genes. Moreover, these changes might be associated with disease activity and patients' status. [ABSTRACT FROM AUTHOR]

Aim: Impaired regulation of immune tolerance results in autoimmune diseases, such as rheumatoid arthritis (RA). Survivin is an anti‐apoptotic protein and can induce cellular mitosis. In the current study, we assessed the transcript level of total survivin (survivin‐TS) and its three major variants and evaluated the expression level of important micro RNAs (miRNAs) involved in survivin expression regulation in RA patients. Method: Peripheral blood mononuclear cells (PBMCs) were isolated from 50 healthy controls and 50 RA‐active patients. RNA extraction was performed and then single‐strand complementary DNA was synthesized. Quantitative real‐time polymerase chain reaction was used to assess the expression level of survivin‐TS and its variants with effective miRNAs in PBMCs. Results: Overexpression of survivin‐2B (fold change = 1.57, P = 0.005), survivn‐ΔEx3 (fold change = 1.93, P = 0.009) and downregulation of survivin‐WT (fold change = 0.64, P = 0.0002) were found in PBMCs of patients, while messenger RNA (mRNA) expression of survivin‐TS had no significant difference between RA patients and controls. Expression levels of miR‐335‐5p, miR‐485‐5p, miR‐16‐5p, miR‐150‐5p, miR‐34a‐5p, and miR‐203a‐3p were significantly increased in PBMCs from patients compared with healthy controls. In a correlation study, dysregulation of these miRNAs were not correlated with mRNA expression level of survivin. Conclusion: While survivin‐TS was not differently expressed in RA patients, its variants had altered expression. Although miRNAs were aberrantly expressed in PBMCs from RA subjects, they did not regulate survivin‐TS. miRNAs might be involved in RA pathogenesis, but not through controlling survivin. [ABSTRACT FROM AUTHOR]

Takayasu arteritis (TA) is a chronic inflammatory disorder characterized by vascular damage and fibrosis in the intima that commonly occurs in the aorta. In many damaged sites in TA patients, natural killer (NK) cells have been shown to be hyperactivated and produce inflammatory cytokines and toxic components. Killer cell immunoglobulin-like receptors (KIRs) are found on NK cells and interact with human leukocyte antigen (HLA) class I ligands to activate or suppress NK cells. The present study assessed the possible role of KIR and their HLA ligand genes in susceptibility to TA in Iranian patients. This case-control study included 50 TA patients and 50 healthy subjects. DNA was extracted from whole peripheral blood samples, and polymerase chain reaction with sequence-specific primers (PCR-SSP) was performed to recognize the presence or absence of polymorphism in 17 KIR genes and 5 HLA class I ligands in each participant. Among the KIR and HLA genes, a significant decrease was detected in the frequency of 2DS4 (full allele) in TA patients (38%) compared with healthy controls (82%) (OR=0.13, 95 CI=0.05–0.34). However, none of the KIR and HLA genotypes or the interactions between these genes were associated with susceptibility to TA. The KIR2DS4 gene might be involved in the regulation of activation as well as the production of cytotoxic mediators of NK cells in patients with TA. [ABSTRACT FROM AUTHOR]

Background: Ankylosing spondylitis (AS) is an inflammatory autoimmune disease that mostly affects different joints of the body. Macrophages are the predominant cells that mediate disease progression by secreting several pro-inflammatory mediators. Different receptors are involved in macrophages' function including the adenosine receptors (AR). Our main objective in this study was to assess the effect of applying A2A adenosine receptor agonist (CGS-21,680) on the gene expression of inflammatory mediators including bone morphogenetic proteins (BMP)-2, 4 and matrix metalloproteinases (MMP)-3, 8, 9, and 13 on the macrophages from AS patients compared to healthy macrophages.Methods: Monocytes were isolated from the whole blood of 28 individuals (AS patients and healthy controls in a 1:1 ratio). Macrophages were differentiated using macrophage colony-stimulating factor (M-CSF), and flow cytometry was performed to confirm surface markers. CGS-21,680 was used to treat cells that had been differentiated. Using SYBR green real-time PCR, relative gene expression was determined.Results: Activating A2AAR diminished MMP8 expression in healthy macrophages while it cannot reduce MMP8 expression in patients' macrophages. The effect of A2AAR activation on the expression of BMP2 and MMP9 reached statistical significance neither in healthy macrophages nor in the patients' group. We also discovered a significant positive connection between MMP8 expression and patient scores on the Bath ankylosing spondylitis functional index (BASFI).Conclusion: Due to the disability of A2AAR activation in the reduction of MMP8 expression in patients' macrophages and the correlation of MMP8 expression with BASFI index in patients, these results represent defects and dysregulations in the related signaling pathway in patients' macrophages. [ABSTRACT FROM AUTHOR]

The inflammatory interleukin (IL)-23/IL-17 axis plays an important role in the pathogenesis of ankylosing spondylitis (AS), but with an unknown regulatory mechanism. This study aimed to investigate the role of endoplasmic reticulum (ER) stress and autophagy pathway in the expression of IL-23 in peripheral blood–derived macrophages in AS patients. Peripheral blood samples were obtained from 15 AS and 15 healthy control subjects. MACS was used to isolate monocytes from PBMCs. Then, M-CSF was used to differentiate monocytes to M2 macrophages. IFN-γ and/or LPS were used to activate macrophages and M2 polarization towards M1 macrophages. Thapsigargin was used to induce ER stress and 3-MA to inhibit autophagy. The purity of extracted monocytes and macrophage markers was evaluated by flow cytometry. mRNA expression of HLA-B and-B27, ER stress–related genes, autophagy-related genes, and IL-23p19 was performed using RT-qPCR. Soluble levels of IL-23p19 were measured using ELISA. Significant increase in mRNA expression of HLA-B, HLA-B27, BiP, XBP1, CHOP, and PERK mRNAs was observed in macrophages of AS patients before and after stimulation with IFN-γ and LPS. No significant change in autophagy gene expression was detected. mRNA and soluble levels of IL-23p19 demonstrated a significant increase in macrophages of AS patients compared to healthy subjects. ER stress induction led to a significant increase in IL-23p19 in macrophages. Inhibition of autophagy did not affect IL-23 expression. ER stress, unlike autophagy, is associated with increased IL-23 levels in macrophages of AS patients. Key Messages ER stress in macrophages from AS patients plays a role in the increased production of IL-23. The autophagy pathway is not involved in the modulation of IL-23 production by AS macrophages. [ABSTRACT FROM AUTHOR]

Purinergic receptors stimulation by adenosine triphosphate (ATP) contributes significantly to macrophage activation, and also macrophage cell death. Upon the macrophage activation, the protein load of the endoplasmic reticulum is increased which is resulted in the activation of unfolded protein response (UPR). In the current study, we aimed to evaluate the connection between prototypic P2X7 receptor agonist, extracellular 2'(3')-O-(4-Benzoylbenzoyl)-ATP (BzATP), and the UPR pathway in macrophages. The monocyte-derived macrophages from blood samples of 14 healthy volunteers were skewed toward M1 macrophages after incubation with LPS and IFN-γ. M1 macrophages were treated with 200 µM BzATP. The expression levels of UPR genes, including CHOP, HERP, GADD34, XBP1, and ATF6 in macrophages before and after treatment were measured using real-time polymerase chain reaction. The results demonstrated that the expression of CHOP, HERP, and ATF6 is significantly decreased and the expression level of GADD34 and XBP1 is significantly increased after M1 polarization. BzATP not only significantly increased the expression levels of CHOP, GADD34, ATF6, and HERP but also significantly decreases the XBP1 expression level in M1 macrophages. The present study showed that BzATP induces cellular stress in M1 macrophages by elevating the expression levels of UPR genes including CHOP, GADD34, ATF6, and reducing cell viability. [ABSTRACT FROM AUTHOR]

Various studies suggest that ankylosing spondylitis (AS) as a chronic inflammatory disease with many disabilities can have impacts on different aspects of patients' life. Despite many quantitative studies, only few qualitative studies have thus far been published on this subject. For the first time, the present study aims at gaining insight into the life experience of Iranian AS patients. We performed a content analysis through semi-structured interviews with twenty-eight patients diagnosed with AS, including three females and twenty-five males with an average age of 38.5 years, to gain insight into their experiences. Whatever the patients expressed was written and transcribed verbatim. Then, we did analysis of the results after each interview. The detailed information completely extracted from the interviews was classified as sub-themes and main themes. Three main themes were identified by the analysis: (i) "Always with pain" describing the effects were found in regard to pain on patients' life, (ii) "The perceived limitation" describing many difficulties that people may face in the society as a result of their disease, and (iii) "Fearing the unknown future" which implies to both patients and their families have concerns about the future and what will happen. Our research findings in line with other qualitative studies showed that AS disease puts a heavy and intolerable burden on patients and their family. It seems that the experiences of people living with AS can be useful to meet challenges caused by the disease and it can enhance their coping with the disease. [ABSTRACT FROM AUTHOR]

Osteoporosis is a chronic skeletal disease with an increasing prevalence. Romosozumab, as a monoclonal anti-sclerostin antibody with a dual function, has been produced. In this meta-analysis, we aimed to examine the efficacy of Romosozumab in patients with low bone mineral density. A systematic search was conducted in the most important electronic search engines like Cochrane Library, PubMed, Web of Science, Scopus, Google Scholar, and ClinicalTrials.gov at the end of July 2019 to retrieve randomized controlled trials (RCTs), which evaluated the effect of Romosozumab in patients with osteoporosis and/or low bone mineral density. After evaluating the quality of articles with the Cochrane checklist, data related to the outcomes of bone mineral density (BMD) of lumbar spine, femoral neck, and total hip, risk of clinical, vertebral and non-vertebral fractures, and risk of adverse events were extracted. Quality of evidence was assessed according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Heterogeneity between studies was evaluated by I2 and Q statistics. The meta-analysis was performed using CMA v.2.0 software. Of all the 671 initially retrieved articles, seven articles were entered into the meta-analysis after removing duplicates and reviewing papers with inclusion and exclusion criteria. The results of the meta-analysis showed that Romosozumab 210, 140, and 70 mg compared with Alendronate, Teriparatide, and placebo can increase the bone mineral density in the lumbar spine, femoral neck, and total hip. The risk of adverse events like adjudicated cardiovascular serious adverse events and adjudicated cardiovascular death was more in Romosozumab 210 mg in comparison with placebo. However, this difference was not statistically significant. Treatment with anti-sclerostin antibodies can be a proper therapeutic option in patients with osteoporosis and low bone mineral density. Based on the results of this meta-analysis, it seems that Romosozumab, with its dual function, has a positive role in the treatment of osteoporosis and low bone mineral density. [ABSTRACT FROM AUTHOR]

Ankylosing spondylitis (AS) is a highly heritable immune-mediated arthritis common in Turkish and Iranian populations. Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease most common in people of Mediterranean origin. MEFV, an FMF-associated gene, is also a candidate gene for AS. We aimed to identify AS susceptibility loci and also examine the association between MEFV and AS in Turkish and Iranian cohorts. We performed genome-wide association studies in 1001 Turkish AS patients and 1011 Turkish controls, and 479 Iranian AS patients and 830 Iranian controls. Serum IL-1β, IL-17 and IL-23 cytokine levels were quantified in Turkish samples. An association of major effect was observed with a novel rare coding variant in MEFV in the Turkish cohort (rs61752717, M694V, OR = 5.3, P = 7.63×10−12), Iranian cohort (OR = 2.9, P = 0.042), and combined dataset (OR = 5.1, P = 1.65×10−13). 99.6% of Turkish AS cases, and 96% of those carrying MEFV rs61752717 variants, did not have FMF. In Turkish subjects, the association of rs61752717 was particularly strong in HLA-B27-negative cases (OR = 7.8, P = 8.93×10−15), but also positive in HLA-B27-positive cases (OR = 4.3, P = 7.69×10−8). Serum IL-1β, IL-17 and IL-23 levels were higher in AS cases than controls. Among AS cases, serum IL-1β and IL-23 levels were increased in MEFV 694V carriers compared with non-carriers. Our data suggest that FMF and AS have overlapping aetiopathogenic mechanisms. Functionally important MEFV mutations, such as M694V, lead to dysregulated inflammasome function and excessive IL-1β function. As IL-1 inhibition is effective in FMF, AS cases carrying FMF-associated MEFV variants may benefit from such therapy. [ABSTRACT FROM AUTHOR]

Background: Ankylosing spondylitis (AS) is a common debilitating rheumatic disease in which the innate immune components especially the Interleukin (IL)-23/IL-17 axis related genes play important role in its pathogenesis. Nucleotide binding oligomerization domain-containing protein (NOD)2, as an innate receptor, is critical for IL-23 production in cells. Therefore, we aimed to stimulate NOD2 signaling and study its effects on cytokine production in peripheral blood mononuclear cells (PBMC) of these patients. Methods: PBMCs from 18 patients with active AS and 18 healthy individuals were separated by Ficoll-Hypaque density gradient centrifugation and cultured in the presence of muramyl dipeptide (MDP), as NOD2 ligand. Quantitative expression analysis of NOD1, NOD2, RIPK2, SLC15A4, NLRP1, NLRP3, IL23A, IL17A, IL1B, and TNFA genes was performed using Real-time polymerase chain reaction (PCR). Finally, protein changes of IL23A and IL17A expression were validated using enzyme linked immunosorbent assay (ELISA). Results: Apart from NOD1 that tend to be downregulated in the controls, all the selected genes showed overexpression in response to MDP in cells from the studied groups. Except RIPK2, all the genes had higher expression changes upon MDP stimulation in the AS population. Overexpression of IL23A and IL17A were confirmed at protein levels using ELISA. The strong positive correlation between NLRP3 and NOD2 was decreased after stimulation but new correlations between NLRP3 and IL1B, RIPK2 and SLC15A4 were observed after treatment. Conclusions: This study indicated that AS PBMCs were hyper-responsive to MDP stimulation. This observation implies an important role of NOD2 in the pathogenesis of inflammatory diseases including AS. [ABSTRACT FROM AUTHOR]

Background: Ankylosing Spondylitis (AS) is a chronic autoinflammatory Spondyloarthropathy (SpA) which is characterized by sacroiliitis, which progresses to the axial skeleton. It seems that non-Human Leukocyte Antigen (HLA) and also HLA-B27 are associated with the susceptibility and pathogenesis of the disease. The recent Genome-Wide Association Studies (GWASs) have reported intergenic rs6759298 to be associated with AS etiology. The aim of this study was investigation of the rs6759298 polymorphism in Iranian AS patients. In addition, probable correlations with clinical indices and manifestations were considered. Methods: This study included 403 patients with AS. The control group consisted of 506 healthy individuals who were matched for sex, age, and ethnicity with AS group. Genotyping of rs6759298 was determined using the Amplification-Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR). Results: The GG genotype and G allele were found to be significantly more prevalent in the patient group in comparison to the control group [(p=2x10-6 and 7.44x10-9; OR (95% CI) =2.16 (1.56-2.98) and 1.73 (1.43-2.08)], respectively. Conclusion: No associations were found between patients with three genotypes and any disease manifestations or clinical indices. This investigation confirmed a highly significant association of rs6759298 with disease susceptibility, with no effect on disease progress or clinical presentations. Since rs6759298 belongs to the 2p15 gene desert, further studies would elucidate the exact role of this polymorphism in the pathogenesis of AS. [ABSTRACT FROM AUTHOR]

Macrophages play an important role in the ankylosing spondylitis (AS) auto-inflammatory responses and fibrocartilage destruction. Adenosine is a key modulator of inflammatory conditions. The various effects of adenosine are mediated by its interaction with adenosine receptors (AR). In this study, we investigated the mRNA expression of A1, A2A, A2B, and A3 adenosine receptors, ectonucleoside triphosphate diphosphohydrolase-1 (CD39), and ecto-5′-nucleotidase (CD73) in the monocyte-derived macrophages from AS patients in comparison to healthy controls. We also explored the correlation between analyzed gene expression and patients’ clinical manifestations. Whole blood-separated monocytes from 23 healthy controls and 23 active AS patients were stimulated by macrophage colony-stimulating factor (M-CSF) for 7 days and differentiated to macrophages. Monocyte and macrophage markers were analyzed by flow cytometry. Analysis of adenosine receptors (ADORA1، ADORA2A، ADORA2B، ADORA3), CD39 and CD73 gene expression was performed by SYBR green real-time PCR. Our results demonstrated monocyte-derived macrophages from AS patients expressed increased level of A2AAR and reduced level of A1, A2BAR, and CD39 mRNA compared to healthy controls. We found an inverse correlation between A2AAR mRNA expression and Bath Ankylosing Spondylitis Functional Index (BASFI) score in AS patients. According to our results, altered expression level of adenosine-relying system would be involved in AS macrophage dysfunction and inflammation and correlated with functional status in AS patients. [ABSTRACT FROM AUTHOR]

Background: Following the potent efficacy of β-D-mannuronic acid (M2000) in phase I/II trial in ankylosing spondylitis patients, the present clinical trial was conducted to evaluate the efficacy, safety, and tolerability of this novel drug in rheumatoid arthritis (RA) patients who had inadequate response to conventional therapy.Method: The study was a 12-week randomized, controlled, phase I/II clinical trial with two treatment arms: M2000 and conventional treatment. Patients who had RA according to the modified American College of Rheumatology (ACR) criteria, with active disease at baseline also inadequate response to conventional therapy, were enrolled in this study. M2000 was administrated at a dose of two capsules (500 mg) per day orally during a period of 12 weeks. The primary endpoint was the proportion of patients fulfilling the ACR 20% improvement criteria after 12 weeks of M2000 therapy. Moreover, the patients were also followed up for safety.Results: There were no statistically significant differences between treatment and conventional groups at baseline characteristics. The ACR20 response rate was significantly higher among M2000-treated patients than conventional-treated control, so that 74% of patients in treatment group showed an ACR20 response after 12 weeks of M2000 therapy (74 versus 16%; P = 0.011). 10% of M2000-treated patients and 57.1% of conventional-treated patient’s adverse events occurred during this study.Conclusion: Treatment with M2000 in combination with conventional therapy showed a significantly superior efficacy along with a high safety profile compared to conventional-treated patients. Thereby, M2000 might be suggested as a suitable option in the treatment of RA. [ABSTRACT FROM AUTHOR]

Ankylosing spondylitis (AS) is a debilitating chronic inflammatory disease with genetic predisposition, which is characterized by the involvement of spine and sacroiliac joints. Due to the relatively unsuccessful treatments, we designed β-d-mannuronic (M2000) with the beneficial effects in various experimental models as a novel non-steroidal anti-inflammatory drug (NSAID). The aims of our present study were: first, to compare the therapeutic effects of M2000, as a novel designed NSAID, with naproxen and placebo in Iranian patients with AS during 12 weeks; second, to evaluate the effect of M2000 on gene expression of cyclooxygenase enzyme (COX-1/COX-2), a key enzyme in the initiation of inflammatory pathways in AS patients; and third, to assess the activity of COX-1 and COX-2 enzymes in the presence/absence of M2000 at the different doses in the murine macrophage, J774 cell line. This was a sub-study of phase II, randomized, placebo-controlled trial with three treatment arms: M2000, naproxen, and placebo. The outcome measures were the mean changes from baseline to week 12. The gene expression was assessed by real-time PCR. The COX-1 and COX-2 activities were evaluated by ELISA in J774 cell line induced by LPS and arachidonic acid (AA). Our findings demonstrated that M2000 had beneficial therapeutic effects on pain, stiffness, and inflammation, whereas no adverse effects were observed following the use of M2000 after 12 weeks. The analysis of gene expression showed that M2000 could effectively reduce the expression levels of COX-1 and COX-2 in comparison with untreated patients. In addition, the enzymatic activities in the presence of M2000 were significantly less than LPS- and AA-treated groups. Our results indicate that M2000, as a novel designed NSAID with immunosuppressive properties, can be considered as one of the therapeutic options for the treatment of inflammatory diseases without adverse events.Clinical trial identifier IRCT2013062213739N1/http://www.IRCT.ir. [ABSTRACT FROM AUTHOR]

Objective: This study aimed at investigating the inhibitory effect of β-D-mannuronic acid (M2000) on the Th17 circulating levels and IL-17 a related cytokine in rheumatoid arthritis (RA) patients. Methods: The study included 27 patients with RA who had failed response to treatment. All patients were treated orally by M2000 at a dose of 500 mg twice daily for 12 weeks (Clinical trial identifier: IRCT2014011213739N2). The patients based on anti-tumor necrosis factor alpha (TNFα) blocker treatment were classified into two groups (conventional group and etanercept group). They were then allowed to continue their treatment excluding non-steroidal anti-inflammatory drugs (NSAIDs). The frequency of circulating Th17 cells and IL-17 serum level were determined before and 12 weeks after M2000 therapy and were compared to the healthy controls by using flow cytometry analysis and ELISA method, respectively. Results: At baseline, higher circulating Th17 and IL-17 serum levels were significantly observed in both groups of RA patients than in the healthy controls (all P < 0.001). The frequency of Th17 cells significantly decreased in the conventional group as well as in the etanercept group after M2000 therapy but the level of reduction was higher in the conventional group compared to the etanercept group ( P < 0.03 and P < 0.04, respectively). The IL-17 serum level significantly decreased in both groups after M2000 therapy ( P < 0.01 and P < 0.02, respectively). Furthermore, the frequency of Th17 cells was positively correlated with Disease Activity Score (DAS28) ( r = 0.34, P = 0.02). Conclusion: M2000 shows the inhibitory effect on the frequency of circulating Th17 cells as well as in the production of IL-17 in RA patients. [ABSTRACT FROM AUTHOR]

Objective To evaluate the efficacy, safety and tolerability of β- d -mannuronic acid (M2000) in the treatment of ankylosing spondylitis (AS). Methods The study was a 12-week randomized, double-blind, placebo-controlled, phase I/II clinical trial with 3 treatment arms: placebo, β- d -mannuronic acid and naproxen. Patients who had AS according to the modified New York criteria, with active disease at baseline were eligible for study. Primary outcome measure was the Assessment of SpondyloArthritis international Society (ASAS) 20 response rate at week 12. Results Of the 85 randomized patients, 27 were allocated to receive placebo, 28 naproxen, and 30 β- d -mannuronic acid. There were no statistically significant differences between treatment groups at baseline. Of the patients receiving β- d -mannuronic acid, 57.7% achieved an ASAS20 response at week 12, compared with 59% of the patients in the naproxen group (P > 0.05) and 19% of the patients in the placebo group (P = 0.007). In comparison with patients receiving placebo over the 12-week treatment period, those receiving β- d -mannuronic acid and naproxen demonstrated statistically significantly greater improvement in all secondary endpoints. Interestingly, β- d -mannuronic acid reduced some parameters associated with inflammation more effectively than naproxen and placebo. The incidence of gastrointestinal and other adverse events were higher on naproxen than on β- d -mannuronic acid and placebo. Conclusion The present study demonstrated similar efficacy, but with a more favorable safety profile for β- d -mannuronic acid than naproxen and, therefore, suggest that β- d -mannuronic acid is suitable for the management of AS. Trial registration Iranian registry of clinical trials; www.irct.ir ; IRCT2013062213739N1. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effect of β-D-mannuronic acid (M2000) on hematological parameters in patients with active rheumatoid arthritis. This study was conducted on 25 patients with active rheumatoid arthritis (RA) (identifier: IRCT2014011213739N2). M2000 was administered orally for anemic and non-anemic RA patients at a dose of 500 mg twice daily for 12 weeks. The patients were permitted to continue the conventional treatments excluding NSAIDs. Blood samples were collected at baseline, 4 and 12 weeks after drug administration and were tested for hematological parameters. Moreover, serum levels of TNF-α and IL-6 were analysed before and after M2000 therapy compared to healthy controls using enzyme linked immunosorbent assay method. We found a significant increase in the count of red blood cells and also hemoglobin (Hb) concentration (0.9 g/dL) in anemic patients after 12 weeks of M2000 therapy (p<0.02 and p<0.01, respectively). Furthermore, our results showed an improvement in Hb level (0.45 g/dL) even in non-anemic patients who were treated by M2000 (p<0.04). The leukocytosis in RA patients, significantly decreased in both anemic and non-anemic patients after 12 weeks of M2000 therapy (p<0.02 and p<0.03, respectively). The percent of neutrophils significantly increased in anemic patients (p<0.01) while in non-anemic patients it significantly decreased after 12 weeks of M2000 therapy (p<0.01). The serum levels of IL-6 and TNF-α significantly decreased after 12 weeks of M2000 therapy (p<0.01 and p<0.04, respectively). M2000 improves hematological parameters in RA patients by its potent inhibitory effect on serum levels of TNF-α and IL-6. [ABSTRACT FROM AUTHOR]

Objective: Interleukin (IL)-23/IL-17 pathway involves in the pathogenesis of ankylosing spondylitis (AS). The exact mechanism implicated in overexpression of IL-23 and activation of the IL-23/IL-17 axis is not clear. The aim of the study was to clarify whether macrophages of AS patients undergo unfolded protein response (UPR) and secret increased IL-23. Methods: Peripheral blood monocyte isolated from 10 HLA-B27þ patients and five HLA-B27þ normal subjects were differentiated to macrophages by macrophage-colony stimulating factor (M-CSF) for seven days. Flow cytometry was used to detect monocyte purity and expression of macrophage markers. Analysis of mRNA expression for HLA-B and B27, UPR-associated proteins (BiP, CHOP, MDG1, and XBP1) and IL-23 was performed by RT-qPCR. Results: RT-qPCR data showed a significant overexpression of HLA-B27, UPR genes (BiP, CHOP, and XBP1), and IL-23 in M-CSF-derived macrophages from AS patients compared to healthy controls. Increased expression of MDG1 was not significant. Conclusions: Our data suggest that UPR activation occurs in M-CSF-derived macrophages of AS patients and is accompanied by overexpression of HLA-B27. UPR appears to be associated with overproduction of IL-23 in AS macrophages. [ABSTRACT FROM AUTHOR]

Background: The hepatoprotective effects of silymarin have been confirmed by various researchers worldwide; however few studies are available about the therapeutic impact of silymarin on the level of aminotransferases in patients nonalcoholic steatohepatitis (NASH). Our purpose is to determine whether silymarin improves the serum level aminotransferases in patients with NASH. Materials and Methods: This was a double blind, randomized, placebo-controlled trial performed on 100 patients with NASH. Subjects were randomized to receive silymarin (140 mg/ql2h) for three months or placebo, given in the same manner. A blood sample was drawn at baseline (before treatment) and after completion of the treatment schedule to assess serum aminotransferase levels. We measured body mass index (BMI) before and after administration of the treatments for both groups of patients. Results: There were insignificant changes in BMI for both groups. The mean serum alanine aminotransferase (ALT) level in the case group significantly changed from 84.06 to 68.54 IU/mL following treatment with silymarin (p<0.001) however this change was not significant in the control group. The mean serum aspartate aminotransferase (AST) level in the case group significantly decreased from 71.94 to 54.70 1U/mL after treatment with silymarin. This change in the placebo group was not significant (from 62.94 to 61.56 IU/mL). Conclusion: Administration of silymarin can effectively reduce liver aminotransferases without any changes in BMI in patients with NASH disease. [ABSTRACT FROM AUTHOR]