Publications by authors named "Mahdi Vojdanian"

21 Publications

  • Page 1 of 1

Efficacy and safety of Romosozumab in treatment for low bone mineral density: a systematic review and meta-analysis.

Clin Rheumatol 2020 Nov 8;39(11):3261-3276. Epub 2020 May 8.

Health Management and Economics Research Center, Iran University of Medical Sciences, Tehran, Iran.

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.
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http://dx.doi.org/10.1007/s10067-020-04948-1DOI Listing
November 2020

Identification of RELN variant p.(Ser2486Gly) in an Iranian family with ankylosing spondylitis; the first association of RELN and AS.

Eur J Hum Genet 2020 06 30;28(6):754-762. Epub 2020 Jan 30.

Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Ankylosing spondylitis (AS) is a common complex inflammatory disease; however, up to now distinct genes with monogenic pattern have not been reported for this disease. In the present study, we report a large Iranian family with several affected members with AS. DNAs of the three affected and two healthy cases were chosen for performing whole-exome sequencing (WES). After several filtering steps, candidate variants in the following genes were detected: RELN, DNMT1, TAF4β, MUC16, DLG2, and FAM208. However, segregation analysis confirmed the association of only one variant, c.7456A>G; p.(Ser2486Gly) in the RELN gene with AS in this family. In addition, in silico predictions supported the probable pathogenicity of this variant. In this study, for the first time, we report a novel variant in the RELN gene, c.7456A>G; p.(Ser2486Gly), which completely co-segregates with AS. This association suggests potential insights into the pathophysiological bases of AS and it could broaden horizons toward new therapeutic strategies.
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http://dx.doi.org/10.1038/s41431-020-0573-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253431PMC
June 2020

Activation of adenosine A receptor induced interleukin-23 mRNA expression in macrophages of ankylosing spondylitis patients.

Cytokine 2020 04 21;128:154997. Epub 2020 Jan 21.

Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran; Inflammation Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Background: 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 adenosine receptor (AAR) activation on tumor necrosis factor-α (TNF-α) and interleukin-23 (IL-23) expression and secretion by monocyte-generated macrophages of AS patients.

Methods: 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 AAR. 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.

Results: Based on our analysis, CGS-21680 significantly decreased TNF-α secretion by monocyte-derived macrophages of AS patients. Moreover, AAR 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.

Conclusion: According to our results, it appears that AAR activation can increase IL-23 secretion by monocyte-derived macrophages of AS patients. Although the TNF-α reducing effect of AAR agonists can be a potential target in AS treatment, robust increasing of IL-23 should be considered as the undesirable effect of these agents.
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http://dx.doi.org/10.1016/j.cyto.2020.154997DOI Listing
April 2020

P2 receptors mRNA expression profiles in macrophages from ankylosing spondylitis patients and healthy individuals.

Int J Rheum Dis 2020 Mar 29;23(3):350-357. Epub 2019 Dec 29.

Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.

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 P2RX , P2RX , P2RX , P2RX , P2RX , P2RX , P2RX , P2RY , P2RY , P2RY , P2RY , P2RY , P2RY , P2RY , P2RY , and PANX1 genes.

Results: P2RY and P2RY genes had the highest expression levels in macrophages among P2RY genes. P2RY mRNA expression was significantly down-regulated (-1.75 fold) and P2RY was up-regulated (2.6 fold) in macrophages of AS patients compared to healthy individuals. P2RX gene had the highest expression in monocyte-derived macrophages, followed by P2RX and P2RX 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.
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http://dx.doi.org/10.1111/1756-185X.13783DOI Listing
March 2020

The safety and efficacy of Guluronic acid (G2013) in ankylosing spondylitis: A randomized controlled parallel clinical trial.

Pharmacol Rep 2019 Jun 10;71(3):393-398. Epub 2019 Feb 10.

Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Background: To assess the therapeutic efficacy, safety and tolerability of Guluronic acid (G2013) in patients with ankylosing spondylitis (AS) patients.

Methods: This investigation was a 12-week randomized, placebo-controlled, phase I/II clinical trial involving 75 AS patients that were randomly divided into 3 groups: 25 as placebo, 25 Guluronic acid and 25 naproxen groups. Patients who had AS with active disease at baseline according to the modified New York criteria were considered for this trial. The primary consequence measure was the Appraisement of Spondyloarthritis International Society (ASAS) 20 response-rate at week 12.

Results: There were no statistically significant differences between groups at the entry. ASAS20 response at week 12 was achieved (60.8%) in patients receiving Guluronic acid compared with - (68.4% of) - patients in the naproxen group (p > 0.05) and (21.0%) of patients in the placebo group. In comparison with the placebo group from the baseline to week 12, patients who received Guluronic acid and naproxen showed significantly greater improvement in all secondary endpoints. Moreover, Guluronic acid decreased some inflammatory parameters more dramatically than naproxen and placebo group. Patients in the naproxen group had more incidence of gastrointestinal and others adverse events in comparison with Guluronic acid and placebo groups.

Conclusion: The present research indicated that Guluronic acid and naproxen are similar in terms of efficacy. However, Guluronic acid had more notable safety characteristics identifying information than naproxen. Accordingly, it is proposed that Guluronic acid could be appropriate for management of AS. Clinical trial identifier; IRCT2016091813739N4.
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http://dx.doi.org/10.1016/j.pharep.2019.02.002DOI Listing
June 2019

Genome-wide association study in Turkish and Iranian populations identify rare familial Mediterranean fever gene (MEFV) polymorphisms associated with ankylosing spondylitis.

PLoS Genet 2019 04 4;15(4):e1008038. Epub 2019 Apr 4.

Department of Internal Medicine, Division of Rheumatology, Celal Bayar University, Manisa, Turkey.

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.
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http://dx.doi.org/10.1371/journal.pgen.1008038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467421PMC
April 2019

microRNA involvement in the regulation of survivin in peripheral blood mononuclear cells from rheumatoid arthritis patients.

Int J Rheum Dis 2019 Jun 5;22(6):1107-1114. Epub 2019 Mar 5.

Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.

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.
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http://dx.doi.org/10.1111/1756-185X.13520DOI Listing
June 2019

Association study of copy number variation in BMP8A gene with the risk of ankylosing spondylitis in Iranian population.

J Cell Biochem 2018 Nov 28. Epub 2018 Nov 28.

Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Background: Copy number variation (CNV) of DNA segments has been considered as an important component of genetic variation, affecting the quality and quantity of gene expression. Bone morphogenic protein 8A (BMP8A) has been reported to function in bone formation. With respect to the bone and joint complications in ankylosing spondylitis (AS), this investigation aimed to study the role of BMP8A gene CNV in impressing the gene expression as well as the disease risk.

Methods: A total of 900 individuals, including 450 patients with AS and 450 healthy controls were enrolled. The copy numbers of BMP8A gene were detected by TaqMan real-time polymerase chain reaction (PCR) method. BMP8A messenger RNA (mRNA) transcript level in peripheral blood mononuclear cells (PBMCs) was also measured by SYBR Green real-time gene expression PCR method.

Results: No significant association of BMP8A copy number was detected with the risk of AS. BMP8A mRNA expression level was significantly downregulated in patients compared with controls. mRNA expression level of BMP8A in both AS patients with and without syndesmophyte was significantly lower than the healthy control group. There was no correlation between the mRNA expression level of BMP8A and both demographic and clinical data of the patients.

Conclusions: Although BMP8A gene expression was downregulated in patients with AS, its copy number could not affect the transcript level of BMP8A gene in PBMCs and was not associated with susceptibility to AS in Iranian population. BMP8a may take into account as an indicator of bone formation process in AS, but it seems that mechanisms other than CNV may regulate this protein.
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http://dx.doi.org/10.1002/jcb.28120DOI Listing
November 2018

Increased inflammatory responsiveness of peripheral blood mononuclear cells (PBMCs) to NOD2 ligand stimulation in patients with ankylosing spondylitis.

Immunopharmacol Immunotoxicol 2018 Oct 28;40(5):393-400. Epub 2018 Sep 28.

b Rheumatology Research Center, Tehran University of Medical Sciences , Tehran , Iran.

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. 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 , , , , , , , , and genes was performed using Real-time polymerase chain reaction (PCR). Finally, protein changes of and expression were validated using enzyme linked immunosorbent assay (ELISA). Apart from 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 , all the genes had higher expression changes upon MDP stimulation in the AS population. Overexpression of and were confirmed at protein levels using ELISA. The strong positive correlation between and was decreased after stimulation but new correlations between and , and were observed after treatment. 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.
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http://dx.doi.org/10.1080/08923973.2018.1510963DOI Listing
October 2018

Association between rs6759298 and Ankylosing Spondylitis in Iranian Population.

Avicenna J Med Biotechnol 2018 Jul-Sep;10(3):178-182

Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.

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 Ge-nome-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=2×10 and 7.44×10; 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 gene desert, further studies would elucidate the exact role of this polymorphism in the pathogenesis of AS.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6064007PMC
August 2018

A phase I/II randomized, controlled, clinical trial for assessment of the efficacy and safety of β-D-mannuronic acid in rheumatoid arthritis patients.

Inflammopharmacology 2018 Jun 25;26(3):737-745. Epub 2018 Apr 25.

Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Box: 14155-6446, Tehran, Iran.

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.
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http://dx.doi.org/10.1007/s10787-018-0475-zDOI Listing
June 2018

Ankylosing spondylitis monocyte-derived macrophages express increased level of A adenosine receptor and decreased level of ectonucleoside triphosphate diphosphohydrolase-1 (CD39), A and A adenosine receptors.

Clin Rheumatol 2018 Jun 9;37(6):1589-1595. Epub 2018 Mar 9.

Rheumatology Research Center, Shariati Hospital, Tehran University of Medical Sciences, Kargar Ave., P.O. Box: 1411713137, Tehran, Iran.

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 A, A, A, and A 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 AAR and reduced level of A, AAR, and CD39 mRNA compared to healthy controls. We found an inverse correlation between AAR 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.
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http://dx.doi.org/10.1007/s10067-018-4055-9DOI Listing
June 2018

Hematological Improvement of Patients with Active Rheumatoid Arthritis by β-D-Mannuronic Acid (M2000) as a Novel NSAID with Immunosuppressive Property.

Iran J Allergy Asthma Immunol 2017 Oct;16(5):433-442

Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.

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.
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October 2017

Evaluation of the efficacy and safety of β-d-mannuronic acid in patients with ankylosing spondylitis: A 12-week randomized, placebo-controlled, phase I/II clinical trial.

Int Immunopharmacol 2018 Jan 8;54:112-117. Epub 2017 Nov 8.

Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

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.
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http://dx.doi.org/10.1016/j.intimp.2017.11.003DOI Listing
January 2018

Targeting of circulating Th17 cells by β-D-mannuronic acid (M2000) as a novel medication in patients with rheumatoid arthritis.

Inflammopharmacology 2018 Feb 23;26(1):57-65. Epub 2017 Oct 23.

Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Box: 14155-6446, Tehran, Iran.

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.
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http://dx.doi.org/10.1007/s10787-017-0410-8DOI Listing
February 2018

The effects of β-D-mannuronic acid (M2000), as a novel NSAID, on COX1 and COX2 activities and gene expression in ankylosing spondylitis patients and the murine monocyte/macrophage, J774 cell line.

Inflammopharmacology 2018 Apr 17;26(2):375-384. Epub 2017 Aug 17.

Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Box: 14155-6446, Tehran, Iran.

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 .
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http://dx.doi.org/10.1007/s10787-017-0386-4DOI Listing
April 2018

A phase III, randomized, two-armed, double-blind, parallel, active controlled, and non-inferiority clinical trial to compare efficacy and safety of biosimilar adalimumab (CinnoRA®) to the reference product (Humira®) in patients with active rheumatoid arthritis.

Arthritis Res Ther 2017 07 20;19(1):168. Epub 2017 Jul 20.

Tehran University of Medical Sciences, Faculty of Pharmacy, Tehran, Iran.

Background: This study aimed to compare efficacy and safety of test-adalimumab (CinnoRA®, CinnaGen, Iran) to the innovator product (Humira®, AbbVie, USA) in adult patients with active rheumatoid arthritis (RA).

Methods: In this randomized, double-blind, active-controlled, non-inferiority trial, a total of 136 patients with active RA were randomized to receive 40 mg subcutaneous injections of either CinnoRA® or Humira® every other week, while receiving methotrexate (15 mg/week), folic acid (1 mg/day), and prednisolone (7.5 mg/day) over a period of 24 weeks. Physical examinations, vital sign evaluations, and laboratory tests were conducted in patients at baseline and at 12-week and 24-week visits. The primary endpoint in this study was the proportion of patients achieving moderate and good disease activity score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR)-based European League Against Rheumatism (EULAR) response. The secondary endpoints were the proportion of patients achieving American College of Rheumatology (ACR) criteria for 20% (ACR20), 50% (ACR50), and 70% (ACR70) responses along with the disability index of health assessment questionnaire (HAQ), and safety.

Results: Patients who were randomized to CinnoRA® or Humira® arms had comparable demographic information, laboratory results, and disease characteristics at baseline. The proportion of patients achieving good and moderate EULAR responses in the CinnoRA® group was non-inferior to the Humira® group at 12 and 24 weeks based on both intention-to-treat (ITT) and per-protocol (PP) populations (all p values >0.05). No significant difference was noted in the proportion of patients attaining ACR20, ACR50, and ACR70 responses in the CinnoRA® and Humira® groups (all p values >0.05). Further, the difference in HAQ scores and safety outcome measures between treatment arms was not statistically significant.

Conclusion: CinnoRA® was shown to be non-inferior to Humira® in terms of efficacy at week 24 with a comparable safety profile to the reference product.

Trial Registration: IRCT.ir, IRCT2015030321315N1 . Registered on 5 April 2015.
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http://dx.doi.org/10.1186/s13075-017-1371-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520357PMC
July 2017

The Anti-Migraine Effects of M2000 (β-D-Mannuronic Acid) on a Patient with Rheumatoid Arthritis: Case Report.

Curr Clin Pharmacol 2017 ;12(2):127-130

Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.

Background: Rheumatoid arthritis (RA) and migraine are both common disorders which are caused by a faulty immune system and autonomic nervous system dysfunction, respectively. Although current treatment outlook has shown a great improvement in these two diseases, however many side effects have been reported.

Case Report: We reported a case of 43-years-female that has suffered from rheumatoid arthritis for 3 years with a 6 years history of migraine. She had used different types of medication for both rheumatoid arthritis and migraine but during these 6 years no improvement had been observed and even migraine progression in this patient became worse. She was admitted to the hospital for 12 weeks follow-up to evaluate the effect of β-D-mannuronic acid (M2000) on her RA disease.

Materials And Methods: During 12 weeks of M2000 therapy, the signs and symptoms of migraine along with RA indices including Disease Activity Score (DAS28), simple disease activity index (SDAI) and C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), anti-cyclic citrullinated peptide antibodies (anti-CCP) and blood determinants were measured.

Results And Discussion: The patient achieved a strong clinical improvement after 12 weeks of M2000 therapy in DAS28, SDAI and laboratory parameters. Moreover, M2000 showed a significant effect on the severity and the duration of migraine pain as well as times of migraine attack. In the present case, both rheumatoid arthritis and migraine as two different inflammatory diseases were diagnosed. Therefore, reducing the inflammation could be a valuable target to decrease the signs and symptoms of migraine and rheumatoid arthritis and help to the treatment process.

Conclusion: M2000 as a novel designed non-steroidal anti-inflammatory drug (NSAID) with immunosuppressive property is able to treat migraine in addition to its potent efficacy on treatment of rheumatoid arthritis.
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http://dx.doi.org/10.2174/1574884712666170605101845DOI Listing
April 2019

Ankylosing spondylitis M-CSF-derived macrophages are undergoing unfolded protein response (UPR) and express higher levels of interleukin-23.

Mod Rheumatol 2017 Sep 15;27(5):862-867. Epub 2016 Dec 15.

a Department of Immunology, School of Medicine , Tehran University of Medical Sciences , Tehran , Iran.

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-B27 patients and five HLA-B27 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.
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http://dx.doi.org/10.1080/14397595.2016.1259716DOI Listing
September 2017

Effect of TNF-α Blockade in Gingival Crevicular Fluid on Periodontal Condition of Patients with Rheumatoid Arthritis.

Iran J Immunol 2016 Sep;13(3):197-203

Department of Periodontology, School of Dentistry, Tehran University of Medical Science, Tehran, Iran.

Background: Periodontitis and rheumatoid arthritis (RA) share a number of clinical and pathologic features, one of which is the presence of the tumor necrosis factor alpha (TNF-α)-induced bone resorption that is involved in the pathogenesis of both.

Objectives: To investigate the effect of TNF-α blockade on periodontal conditions in patients with active RA.

Method: The periodontal statuses of 36 patients (26 females, 10 males) diagnosed with active RA were evaluated both before and after anti-TNF-α therapy. Gingival index, bleeding on probing (BOP), probing pocket depth (PPD), oral hygiene index (OHI), and levels of TNF-α in gingival crevicular fluid (GCF) were measured at the baseline and 6 weeks after the treatment. Wilcoxon signed ranked test was used for statistical analyses.

Results: Based on OHI (p=0.860), the level of plaque control did not change during the study period, but there was a significant reduction in gingival inflammation based on the mean BOP (p=0.049) and GI (p=0.036) before and after 6 weeks of anti-TNF-α therapy. The mean PPD index did not significantly differ at the baseline and 6 weeks after treatment (p=0.126).

Conclusion: Anti-TNF-α therapy might have a desirable effect on periodontal conditions and might reduce TNF-α level in GCF of patients with RA.
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http://dx.doi.org/IJIv13i3A5DOI Listing
September 2016

Validity and reliability of the Persian version of Behçet's disease quality-of-life (BD-QoL) questionnaire: a cross-cultural adaptation.

Rheumatol Int 2015 Apr 13;35(4):677-84. Epub 2014 Sep 13.

Rheumatology Research Center, Shariati Hospital, Tehran University of Medical Sciences, North Kargar Avenue, Tehran, Iran.

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.
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http://dx.doi.org/10.1007/s00296-014-3128-6DOI Listing
April 2015