Tofacitinib and metformin reduce the dermal thickness and fibrosis in mouse model of systemic sclerosis.

Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is important in the process of inflammation and fibrosis. The adenosine 5'-monophosphate-activated protein kinase (AMPK) enzyme can affect JAK/STAT pathway. Tofacitinib is a pan-JAK inhibitör. Metformin activates AMPK enzyme. We aimed to investigate the therapeutic efficacy of tofacitinib and metformin on IL-17 and TGF-ß cytokines, skin fibrosis and inflammation in mouse model of systemic sclerosis (SSc). 40 Balb/c female mice were divided into 4 groups: (control, sham (BLM), tofacitinib and metformin). The mice in the tofacitinib group received oral tofacitinib (20 mg/kg/daily) and mice in the metformin group received oral metformin (50 mg/kg/day) for 28 days. At the end of 4th week, all groups of mice were decapitated and tissue samples were taken for analysis. Histopathological analysis of skin tissue was performed, and mRNA expressions of collagen 3A, IL-17 and TGF-ß were assessed by real-time PCR and ELISA. Repeated BLM injections had induced dermal fibrosis. Moreover, the tissue levels of collagen 3A, IL-17 and TGF-ß were elevated in the BLM group. Tofacitinib and metformin mitigated dermal fibrosis. They reduced dermal thickness and tissue collagen 3A, IL-17 and TGF-ß levels. Tofacitinib and metformin demonstrated anti-inflammatory and anti-fibrotic effects in the mouse model of SSc.

Complementary alternative medicine in rheumatic diseases: Causes, choices, and outcomes according to patients.

OBJECTIVE: The knowledge of physicians about complementary and alternative medicine (CAM) applications is limited. However, especially in chronic diseases, patients and their relatives can often refer to CAM applications. Rheumatic diseases are chronic in nature presenting with a wide clinical spectrum. Despite developing treatment options, achieving treatment goals may not always be possible. For this reason, patients seek different treatment and use traditional and complementary medicine. The aim of this study was to investigate causes, consequences, and the frequency of applying to CAM in rheumatic diseases. METHODS: Ninety-five patients admitted to the rheumatology outpatient clinic were enrolled in the study. Health assessment questionnaire and short-form-36 were used to determine the quality of life of patients. Anxiety and depression symptoms were screened by the Hospital Anxiety and Depression scale, a questionnaire that was filled-in by the patients themselves. Also, patients were questioned about their place of residence, level of education, diagnosis, CAM modality types, application reasons, and outcomes. Chi-square test was used to analyze categorical data. Parametric data were analyzed using Student t-test, and nonparametric data were analyzed using Mann-Whitney U test. RESULTS: Thirty-two of our patients had applied to CAM modalities (phytotherapy [34.45%], cupping therapy [21.8%], acupuncture [12.5%], hirudotherapy [12.5%], food supplement [12.5%], and ozone treatment [6.25%]). Only 31.3% of the patients informed their doctors about CAM applications. 47.8% of fibromyalgia patients and 29.2% of patients with inflammatory rheumatic diseases had applied to CAM. Gender, working status, income level, smoking, and alcohol habits were not associated with the application to CAM. However, none of the residents of the village, 14.3% of the residents of the district center, and 41.1% of the residents of the city center had applied to CAM modality. The rate of applying to CAM was 18.2% for those who cannot read and write. The application ratio of CAM is over 40% among secondary school, high school, and university graduates. CONCLUSION: Among patients with rheumatic diseases, application to CAM is quite common. Very few patients inform their physicians about applying to CAM. Contrary to what is presumed, the rate of applying CAM applications is lower among those living in rural areas and with low education levels.

Wnt signaling pathway activities may be altered in primary Sjogren's syndrome

Background/aim: Sjögren's syndrome (SS) is an autoimmune disease and its pathogenesis is still not completely clear. The wingless (Wnt)/ß-catenin pathway has recently been shown to play an important role in inflammation. This study aims to determine the serum and saliva levels of Dickkopf (DKK)1 and sclerostin and to evaluate Wnt-1 and Wnt-3a expression in the salivary gland in patients with primary SS. Materials and methods: This study included 30 patients diagnosed with SS, 30 patients diagnosed with systemic lupus erythematosus (SLE), and 29 healthy controls. Serum and saliva levels of DKK1 and sclerostin were measured and the expressions of Wnt1 and Wnt3a in the salivary gland were measured immunohistochemically. Results: Serum DKK1 and sclerostin levels were lower in the SS and SLE groups compared to the control group (both p < 0.001). Saliva DKK1 levels were higher in the SS group compared to the control and SLE groups (p = 0.004 and p = 0.009, respectively). Wnt1 and Wnt3a expression were found in salivary gland tissue samples in 71.4% of primary SS patients and relatively frequent than control group. Conclusions: Serum DKK1 and sclerostin levels in primary SS and SLE were decreased. Moreover, levels of Wnt1 and Wnt3a expression in the salivary gland were also elevated in primary SS. Therefore, it can be concluded that the Wnt/ß-catenin pathway activities may be altered in case of glandular inflammation.

Secukinumab and metformin ameliorate dermal fibrosis by decreasing tissue interleukin-17 levels in bleomycin-induced dermal fibrosis.

Although the pathogenesis of systemic sclerosis is not exactly known, it is thought that immune activation has prominent roles in pathogenesis. Secukinumab is a monoclonal antibody against interleukin (IL)-17A. Metformin, a widely used antidiabetic medication, has anti-proliferative, immunomodulating and anti-fibrotic activities. The purpose of our study is to determine the therapeutic efficacy of secukinumab and metformin on bleomycin (BLM) induced dermal fibrosis. Fifty Balb/c female mice were divided into 5 groups: (group 1 control, 2 sham, 3 secukinumab, 4 metformin and 5 secukinumab + metformin). The mice in the control group received 100 µL phosphate-buffered saline (PBS), while the mice in other groups received 100 µL (100 µg) BLM in PBS subcutaneously (sc) every day for 4 weeks. In addition, mice in groups 3 and 5 received secukinumab at a dose of 10 mg/kg/wk sc, and mice in the groups 4 and 5 received oral metformin 50 mg/kg/d for 28 days. All groups of mice were sacrificed at the end of the 4th week and tissue samples were taken for analysis. In addition to histopathological analysis, skin tissue messenger RNA (mRNA) expressions of IL-17 and collagen 3A were measured by real-time polymerase chain reaction. Repeated BLM injections had caused dermal fibrosis. In addition, the mRNA expressions of IL-17 and collagen 3A were increased in the BLM group. Secukinumab and metformin ameliorated dermal fibrosis. They decreased dermal thickness and tissue IL-17A and collagen 3A mRNA levels. Secukinumab and metformin exhibit anti-fibrotic effects in the BLM-induced dermal fibrosis.

Ginger extract suppresses the activations of NF-κB and Wnt pathways and protects inflammatory arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is a disabling inflammatory disorder. Ginger is used for food and medicine to treat arthralgia, sprains, and muscle aches. Anti-inflammatory effects of ginger have been observed. The aim of our study was to detect the effects of ginger on experimentally induced inflammatory arthritis. METHODS: Female Wistar albino rats (n = 21) were randomly separated into three groups (control, arthritis, and arthritis + ginger). Arthritis was generated by an appropriate method using type 2 collagen and Freund's adjuvant (collagen-induced arthritis model). The ginger group was treated starting at the first collagen injection with ginger root extract for 32 days by oral gavage (50 mg/kg/daily). Interleukin (IL)-6, IL-17, tumor necrosis factor-α (TNF-α), sclerostin, dickkopf-related protein-1 (DKK-1), and obestatin serum levels were studied by enzyme-linked immunosorbent assay method. Tissue TNF-α, IL-17, cyclooxygenase-2 (COX-2), and nuclear factor kappa B (NF-κB) levels were detected using the Western blot method. RESULTS: Mean arthritis score and serum levels of TNF-α, IL-6, and IL-17 were significantly decreased in ginger group than in the arthritis group. Increased sclerostin serum level and decreased DKK-1 serum levels were detected in ginger group compared with arthritis group. The decreases of IL-17, TNF-α, COX-2, and NF-κB tissue levels were statistically significant in the ginger group compared with arthritis group. Histopathological evaluation of the ginger group showed a decrease in the inflammation score compared to arthritis group. CONCLUSION: It can be concluded that ginger has protective properties in the development of inflammatory arthritis. The antiarthritic acts of ginger are related to NF-κB activity and Wnt pathway. Thus, it may be suggested that ginger is a candidate to research in human RA treatment.

The effect of secukinumab treatment on hematological parameters in ankylosing spondylitis and psoriatic arthritis.

OBJECTIVE: Secukinumab, a new treatment agent, selectively neutralizes interleukin (IL)-17A. It is used in the treatment of ankylosing spondylitis (AS), psoriatic arthritis (PsA), and psoriasis. It is known that the agents used in the treatment of rheumatic diseases have effects on hematological parameters. In this study, we aimed to determine whether hematological parameters are affected in secukinumab therapy in patients with AS and PsA. METHODS: Thirty-six patients on secukinumab treatment were included in the study by scanning the database of our hospital. Data on patients' age, gender, complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), uric acid, aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, creatinine values, and additional drug treatments were recorded from our database. The 0- and 6-month values of patients were analyzed. RESULTS: Sixteen males (44.4%) and 20 females (55.6%) were included in our study. The average age was calculated to be 39.8±8.9 years. Of these, 30 patients receiving secukinumab treatment were diagnosed with AS, and 6 patients were diagnosed with PsA. Twenty-three patients (63.9%) were continued with secukinumab treatment at the 6th month. When CBC, glucose, urea, creatine, AST, ALT, ESR, CRP, and uric acid values of the patients at 0 and 6 months were compared, there was no significant difference. CONCLUSION: In our study, no significant difference was found between 0 and 6 months in terms of CBC, AST, ALT, urea, creatinine, uric acid, glucose, CRP, and ESR levels in patients receiving secukinumab. However, an increase in hemoglobin values was observed in patients who continued the treatment. These results may suggest that secukinumab treatment has no negative effects on hematological parameters.

Serum Cortistatin Levels in Patients with Ocular Active and Ocular Inactive Behçet Disease.

PURPOSE: To evaluate serum cortistatin (CST) levels in patients with ocular active and ocular inactive Behçet disease (BD) and its relationship with disease activity. METHODS: 24 BD patients with ocular active, 24 BD patients with ocular inactive patients and 24 healthy control subjects were included in the study. RESULTS: In ocular active and ocular inactive BD patients and healthy control subjects, the mean serum CST levels were 4.38 ± 1.63ng/ml, 5.46 ± 1.81ng/ml and 7.56 ± 1.73ng/ml, respectively. ESR, serum CRP, CST levels and NLR were significantly different between the groups (p < 0.001 for all). The CST levels were similar between ocular active and inactive BD patient groups (p = 0.197). ESR, CRP and NLR were significantly higher in ocular active BD patients compared to ocular inactive BD patients and healthy control subjects (p < 0.05 for all). CONCLUSION: Serum CST level was significantly lower in BD patients. CST may be a neuropeptide that plays a role in the pathogenesis of BD.

Imaging of sacroiliac joints in patients with acromegaly.

Acromegaly can lead to structural alterations of joints and bones. Patients with acromegaly may, therefore, have musculoskeletal complaints. In this study, sacroiliac joints are investigated in patients with acromegaly. 33 patients with acromegaly were enrolled. Sacroiliac joints were examined by X-ray and magnetic resonance imaging (MRI). In acromegaly, sacroiliac joints were abnormal in 36% of the patients by X-ray and 12.1% by MRI. When current axial spondylarthritis (SpA) classification criteria were taken into account, 6.1% of acromegaly patients could be classified as non-radiographic axial SpA and 2% as radiographic axial SpA. Sacroiliac joints are frequently affected in acromegaly and thus this disorder mimics the features of AS and SpA. Acromegaly should be kept in mind in the differential diagnosis of AS and SpA.

Resveratrol inhibits Src tyrosine kinase, STAT3, and Wnt signaling pathway in collagen induced arthritis model.

Resveratrol, a phytochemical, acts several cellular signaling pathways and has anti-inflammatory potentials. The purpose of this study is to research the therapeutic effect of resveratrol in collagen-induced arthritis (CIA) model in rats and whether resveratrol affects the activities of signaling pathways those are potent pathogenic actors of rheumatoid arthritis. Arthritis was induced by intradermal injection of chicken type II collagen combined with incomplete Freund's adjuvant in Wistar albino rats. One day after the onset of arthritis (day 14), resveratrol (20 mg/kg/day) was given via oral gavage, until day 29. The paws of the rats were obtained for further analysis. Tissue Wnt5a, mitogen-activated protein kinase (MAPK), Src tyrosine kinase and signal transducer, and activator of transcription-3 (STAT3) mRNA expressions were determined by real-time polymerase chain reaction. Resveratrol ameliorated the clinical and histopathological (perisynovial inflammation and cartilage-bone destruction) findings of inflammatory arthritis. The tissue mRNA expressions of Wnt5a, MAPK3, Src kinase, and STAT3 were increased in the sham group compared to the control group. Resveratrol supplement decreased their expressions. The present study shows that Src kinase, STAT3, and Wnt signaling pathway are active in the CIA model. Resveratrol inhibits these signaling pathways and ameliorates inflammatory arthritis. © 2018 BioFactors, 45(1):69-74, 2019.

Plasma urotensin II levels in primary Raynaud's phenomenon and systemic sclerosis

Background/aim: The pathogenesis of Raynaud's phenomenon (RP) has not yet been fully elucidated. RP is characterized by exaggerated cold-induced vasoconstriction. Urotensin II (UII) is a potent vasoconstrictor. The aim of the present study was to evaluate plasma UII levels in both primary RP and secondary RP associated with systemic sclerosis (SSc).Materials and methods: Fifteen patients with primary RP, 30 patients with RP secondary to SSc, and 30 healthy controls (HC) were included in the study. Raynaud condition scores (RCS) were determined in the primary RP and SSc groups. Modified Rodnan skin score (MRSS) was determined for the SSc patients. Plasma UII level was analyzed by the ELISA method. Results: When compared to the HC group, plasma UII level was lower in the secondary RP group, but not in the primary RP group. Plasma UII level was not directly related to RCS in either the primary or secondary RP group. Moreover, it was not correlated with MRSS in the secondary RP group.Conclusion: The results of the present study suggest that UII is not associated with primary RP. Its level was lower in the secondary RP (SSc) patients. Therefore, it can be concluded that decreased UII level is related to SSc instead of RP.