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Objective To study the symptoms, clinical manifestations, laboratory tests, imaging, treatment and prognosis of neuromyelitis optica (NMOSD) with or without combined connective tissue disease (CTD). Methods The 226 NMOSD patients diagnosed at Ningxia Medical University General Hospital were divided into two groups according to the presence or absence of concurrent CTD. The clinical data and prognosis of NMOSD patients with combined CTD were analyzed and followed up. At the same time, NMOSD patients with combined CTD were compared with NMOSD patients without the presence of CTD in terms of laboratory tests, imaging tests, and the similarities and differences between the two groups were analyzed. Results CTD combined with NMOSD mostly occurred in females, and the most prevalent form of CTD is systemic lupus erythematosus (SLE) or primary Sjögren's syndrome (pSS). It has a variety of symptoms, the majority of which are visual loss or limb weakness and numbness, and the majority of patients are positive for AQP4-IgG. The symptoms resolve significantly after sequential hormonal shock therapy in the acute phase, but the relapse rate is high. Meanwhile, it was revealed that when compared between NMOSD patients with combined CTD and NMOSD patients without combined CTD, there was a significant difference between the recurrent events (including recurrence rate and number of recurrences) and degree of remission (pConclusions The high incidence of CTD combined with NMOSD in women and the high recurrence rate suggest that adjuvant immunosuppression should be given to further reduce recurrence.

Objective Interstitial lung disease (ILD) is a common extramuscular manifestation of the anti-synthetase syndrome (ASS). Patients with ASS-ILD are at risk in developing a progressive fibrosing phenotype despite appropriate treatments. This study investigated the risk factors and the predictive value of multiple risk factors for progressive pulmonary fibrosis (PPF) in patients with ASS-ILD. Methods Ninety patients with a diagnosis of ASS and evidence of ILD on high-resolution computed tomography (HRCT) were recruited. Among them, 72 participants completed follow-up for more than 12 months. These patients were further divided into a PPF-ASS group (n = 18) and a non-PPF-ASS group (n = 54). Logistic regression analysis was performed to investigate the risk factors for PPF. The predictive value of the combined risk factors for predicting PPF were analyzed by a ROC curve. Results The PPF-ASS group had a higher rate of positive non-Jo-1 antibodies, a significantly higher neutrophil-to-lymphocyte ratio (NLR) and serum lactate dehydrogenase (LDH), and a significantly lower PaO2/FiO2 ratio and diffusing capacity for carbon monoxide (DLCO%pred) than the non-PPF-ASS group. In addition, elevated serum Krebs von den Lungen-6 (KL-6) level and reticular opacities were significantly more common, and corticosteroid monotherapy at onset was administered more frequently in the PPF-ASS group. The median duration of follow-up was 37.4 months, survival was poorer in the PPF-ASS group, and the overall survival was 88.9%. Multivariate regression analysis further revealed that positive non-Jo-1 antibodies, NLR, and KL-6 were independent risk factors for PPF. These combined indexes had good accuracy (area under the curve = 0.874) in predicting PPF in patients with ASS-ILD. Conclusion Positive non-Jo-1 antibodies, NLR, and serum KL-6 are independent risk factors for PPF in patients with ASS-ILD. Monitoring these markers can potentially predict PPF in this group of patients. Key Points • Positive non-Jo-1 antibodies, NLR, and serum KL-6 are independent risk factors associated with PPF in patients with ASS-ILD. • Monitoring non-Jo-1 antibodies, NLR, and serum KL-6 can potentially predict PPF in patients with ASS-ILD.

Before and after the treatment of RA patients with DMARDs, how the interaction between abnormal intestinal flora and immune cells and cytokines is involved in the pathogenesis of RA remains unclear. Our study found that the α and β diversity of the gut microbiota did not change significantly in the untreated, csDMARDs and csDMARDs + bDMARD-treated RA patients. At the genus level, the relative abundance of Ruminococcaceae_Ruminococcus was decreased in the csDMARDs and csDMARDs + bDMARDs group, while the relative abundance of Faecalibacterium was reduced in the csDMARDs group compared to the untreated group. Ruminococcaceae_Ruminococcus was negatively correlated with Treg and pre-switched memory B cells, while positively correlated with effector memory Tfh and switched memory B cells in RA patients treated with DMARDs. Ruminococcaceae_Ruminococcus was positively interrelated with inflammatory cytokines such as IL-17A, IFN-γ, and TNF-α in RA patients receiving DMARDs. The disturbance of intestinal flora leads to the imbalance of immune cells and cytokines that are involved in the development of RA. Some intestinal flora might be used as novel biomarkers to evaluate the therapeutic effects of different DMARDs. These results provide theoretical support and experimental data for revealing the pathogenesis of RA and finding new targets for RA diagnosis and treatment.

Objective: We aimed to investigate the changes of gut microbiota and analyze the correlation of gut microbiota with lymphocyte subsets, cytokines and clinical indicators in RA patients with active and remission stage, and to find new makers to evaluate disease activity of RA. Method: The intestinal flora of subjects was collected for 16SrRNA gene sequencing. Flow cytometry to detect the number of lymphocyte subsets and their ability to secrete cytokines. ELISA was used to test the serum levels of cytokines. Result: The richness and diversity of gut microbiota were significantly decreased in active and remission stages of RA patients compared to HCs. Most importantly, at the phylum level, the relative abundance of Bacteroidetes and Actinobacteria was decreased in RA patients with remission stage, while the relative abundance of Fusobacteria was increased in RA patients with active compared to HCs. At the genus level, the relative abundance of Ruminococcaceae_Ruminococcus and Bacteroides was decreased, while the abundance of Megamonas was increased in RA patients with active and remission stage compared to HCs. Intestinal flora was directly correlated with lymphocytes, cytokines and clinical indicators in active and remission stages of RA patients. Conclusion: These results suggest that the changes of gut microbiota can lead to imbalances of CD4+T, CD8+T, memory B-cell subsets and cytokines that influence disease activity of RA patients. Interestingly, some intestinal flora may be used as markers to evaluate disease activity in RA patients.

Anti-melanoma differentiation-associated gene 5 (anti-MDA5) and anti-threonyl-tRNA synthetase (anti-PL-7) are myositis-specific autoantibodies, associated with rapidly progressive interstitial lung disease (RP-ILD). A 41-year-old woman presented productive cough, dyspnea, and muscle pain. Anti-MDA5 and anti-PL-7 were double-positive. The patient was diagnosed with dermatomyositis-associated ILD, and responded successfully to glucocorticoids and immunosuppressants.

No effective treatment is currently available for neurodegenerative diseases, and existing pharmacotherapy is inconsistent with severe side effects. Cell replacement therapy is promising for neurodegenerative disease treatment, and the induction of neurons is an unmet need for such therapy. The present study investigated the potential of a combined medium composed of conditioned medium and eight small molecular compounds in reprogramming human foreskin fibroblasts (HFFs) into neurons. HFFs were cultured from foreskin and then induced by small molecules to generate neurons. The results demonstrated that the conditioned medium containing forskolin, RepSox, SP600125, CHIR99021, Go6983, Y‑27632, IXS9 and I‑BET151 effectively induced human fibroblasts to change into neurons in vitro. Following a 30‑day induction, the cells exhibited neuronal properties as determined by morphological and phenotypical alterations. The induced cells exhibited expression of neuronal markers, including class III β‑tubulin, microtubule‑associated protein 2, vesicular glutamate transporter 1 and γ‑aminobutyric acid, accompanied by increased expression of neuronal transcription factors, including neuronal differentiation 1 and achaete‑scute family bHLH transcription factor 1, and decreased expression levels of fibroblast‑specific genes. Furthermore, these cells also exhibited electrophysiological properties of neurons. Notably, the course of cell morphological alterations demonstrated the differentiation of fibroblasts into neurons. The present study provided a novel combination of existing small molecular compounds that efficiently reprogramed human fibroblasts into neurons.

Background Follicular helper T (Tfh) cells are a subgroup of activated CD4+ T cells which can assist the formation and maintenance of germinal centers. Follicular regulatory T (Tfr) cells are a new class of regulatory T cells which play a major role in suppressing cells in humoral immunity. In contrast to the role of Tfh cells, Tfr cells can inhibit the function of Tfh cells and B cells. Imbalance of blood Tfr/Tfh ratio resulted in the expansion of auto-reactive B cells and auto-antibody production (). However, the effect of Tfr cells and Tfh cells in the pathogenesis of RA (rheumatoid arthritis) is unclear. The purpose of this study was to investigate the function of Tfr cells and Tfh cells in the pathogenesis of RA. Methods We recruited 20 patients fulfilled the the American College of Rheumatology diagnosis criteria and 20 healthy controls (HCs). The number of CD4+CXCR5+Foxp3+ Tfr cells and CD4+CXCR5+ Tfh cells in 20 RA patients were measured by flow cytometry analysis. Furthermore, the correlations between the Tfr/Tfh ratio and the characteristic clinical parameters were assessed. The serum levels of IL-21(interleukin-21), CXCL13 (chemokine (C-X-C motif) ligand 13) and TGF-β (Transforming growth factor-β) were measured by ELISA. The formation of ectopic germinal center (GC) of synovial membrane was examined by H&E staining. The transcriptional levels of CXCR5 (C-X-C chemokine receptor type 5), CXCL13, ICOS (inducible co-stimulater) and TGF-β mRNA were also analyzed. In addition, the expression of Bcl-6 (B-cell lymphoma 6), CXCR5, CXCL13 and ICOS in synovial membrane were examined by immunohistochemistry. Results RA patients had more Tfh cells in peripheral blood, conversely, the frequency of blood Tfr cells (p Conclusions The decreased blood CD4+CXCR5+Foxp3+ Tfr cells/CD4+CXCR5+ Tfh cells may be responsible for the immunopathogenesis of RA.

The present study aimed to examine the effects of FcγRIIB on systemic lupus erythematosus (SLE) and to investigate the underlying mechanisms. For this purpose, lentiviral vector carrying the membrane-bound type FcγRIIB gene (mFcγRIIB lentivirus) and soluble FcγRIIB (sFcγRIIB) protein were used to treat B cells from patients with SLE. The B cells were treated with calf thymus DNA (ctDNA) and anti-calf thymus DNA-immune complexes (anti-ctDNA-IC). mFcγRIIB lentivirus and sFcγRIIB protein were also injected into MRL/lpr SLE mice. The results revealed that anti-ctDNA-IC treatment significantly downregulated the IgG antibody secretion of B cells treated with mFcγRIIB lentivirus. mFcγRIIB and sFcγRIIB decreased the phosphorylation level of Bruton's tyrosine kinase (BTK) in B cells, and increased the phosphorylation level of Lyn proto-oncogene (Lyn), docking protein 1 (DOK1) and inositol polyphosphate-5-phospha-tase D (SHIP). mFcγRIIB promoted the apoptosis of B cells. Following the treatment of MRL/lpr SLE mice with mFcγRIIB lentivirus, the levels of urinary protein, serum anti-nuclear and anti-dsDNA antibodies were decreased, while the levels of mFcγRIIB in B cells were increased. mFcγRIIB ameliorated the pathologies of the kidneys, liver and lymph node tissues of the MRL/lpr SLE mice. Following treatment of the MRL/lpr SLE mice with sFcγRIIB, the levels of urinary protein, serum anti-dsDNA antibody and BTK and SHIP phosphorylation levels in B cells were decreased, while the serum sFcγRIIB and sFcγRIIB-IgG levels were increased. On the whole, the findings of the present study demonstrate that recombinant FcγRIIB inhibits the secretion of IgG antibody by B cells from patients with SLE, ameliorates the symptoms of SLE in mice, and alters the phosphorylation levels of downstream proteins of the FcγRIIB signaling pathway in B cells. These results suggest that FcγRIIB may play preventive and therapeutic roles in SLE by inhibiting B cell activation via the FcγRIIB signaling pathway, which provides a novel theory and strategy for the prevention and treatment of SLE.

The clinical features of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (RA-ILD) usually manifest to an advanced stage of lung disease, which leads the challenge of early diagnosis and the difficulty in guiding treatments for patients with RA-ILD in clinical settings. The aim of this study was to construct a nomogram for identifying ILD in RA patients. Through the incorporation of the level of matrix metalloproteinase-3 (MMP-3) in plasma, demographics, clinical feature, and laboratory parameters of 223 RA patients (85 RA-ILD) which were grouped as training cohorts and validation cohorts, an identifying nomogram of RA-ILD was built. Candidate variables for the nomogram were screened using univariable analysis and multivariable logistic regression analysis. The accuracy of the diagnostic nomogram was measured via concordance index (C-index), calibration plots, and decision curve analysis (DCA). Results showed that plasma MMP-3 protein was elevated in RA-ILD patients compared with non-ILD RA patients in both training cohorts (p = 0.0475) and validation cohorts (p = 0.0006). Following a final regression analysis, the gender of male, current smoking state, levels of circulating rheumatoid factor (RF), C-reactive protein (CRP), and MMP-3 were identified as risk factors for the construction of the nomogram. The calibration plots further showed a favorable consistency between the identifying nomogram and actual clinical findings. In consistence, the C-index (0.826 for both training cohorts and validation cohorts) indicated the satisfactory discriminative ability of the nomogram. Although the incorporation of MMP-3 failed to significantly improve identified outcomes of the nomogram as determined by DCA, including the level of circulating MMP-3 increased the diagnostic accuracy of the nomogram for ILD in RA patients. Thus, our proposed model can serve as a non-invasive tool to identify ILD in RA patients, which may assist physicians to make treatment decisions for RA patients.

An early diagnosis of interstitial lung disease (ILD) is important for guiding treatments of rheumatoid arthritis (RA)-associated ILD (RA-ILD) in clinical settings. The non-canonical Wnt signaling representative ligand Wnt5a was recently found to involve in idiopathic pulmonary fibrosis (IPF) and pathogenesis of RA. The goal of this study was to examine the clinical relevance of Wnt5a in RA-ILD. In this report, the clinical relevance of plasma Wnt5a protein was evaluated in 40 RA-ILD patients and 41 non-ILD RA cohorts. The results showed an elevated Wnt5a protein in plasmas of RA-ILD patients compared with non-ILD RA patients (p 0.01), which was positively correlated with the plasma level of rheumatoid factor (RF). Of note, more abundant Wnt5a was also found in patients with usual interstitial pneumonia (UIP) than those with nonspecific interstitial pneumonia (NSIP) and other ILD patterns. More importantly, the disease severity was correlated with the circulating Wnt5a as ascertained by high-resolution computed tomography (HRCT)-UIP scores. The multiple-factor non-conditional logistic regression analysis further revealed that the age, RA duration, smoking and plasma Wnt5a were risk factors with clinical significance for RA-ILD. Interestingly, more Wnt5a-positive patients were identified in RA-ILD smokers relative to RA-ILD never-smokers, and longer smoking duration was strongly correlated with Wnt5a in RA-ILD patients. In consistence, ROC curve also suggested that the Wnt5a was a potential candidate biomarker for identifying patients with RA-UIP. These results demonstrate that the circulating Wnt5a may be a risk factor and potential biomarker for identifying UIP and accessing the severity and progression of ILD in RA patients.

BACKGROUND T follicular helper (Tfh) cells are a subgroup of activated CD4+ T cells in the germinal centers of secondary lymphoid organs, they play critical roles in the development of many chronic autoimmune inflammatory diseases. The aim of this study was to investigate whether circulating Tfh cells contribute to the development of rheumatoid arthritis (RA). MATERIAL AND METHODS Thirty patients fulfilled the diagnosis criteria that was established by the American College of Rheumatology and 30 healthy controls were recruited. The frequency of Tfh cells in patients and collagen-induced arthritis (CIA) in DBA/1J mice were analyzed by flow cytometry. The serum IL-21 level was examined by enzyme-linked immunosorbent assay (ELISA). The mRNA expression of Blimp-1 and Bcl-6 were detected by qRT-PCR. RESULTS RA patients had more CD4⁺PD-1⁺CXCR5⁺ Tfh cells in peripheral blood compared with healthy controls, and CIA in DBA/1J mice showed similar results. Higher mRNA expression of Bcl-6 and lower Blimp-1 mRNA expression were observed in patients with RA compared to healthy controls, and the expression level of IL-21 was higher in RA patients, which was also seen in CIA mice. Furthermore, the spleen CD4⁺ICOS⁺CXCR5⁺ Tfh cells in CIA mice show significantly higher frequency than that in the control mice. The percentage of CD4⁺PD-1⁺CXCR5⁺ Tfh cells was correlated positively with the values of erythrocyte sedimentation rate (ESR) (r=0.968, P

Objective To investigate the potential mechanism of follicular regulatory T (Tfr) cells in the pathogenesis of rheumatoid arthritis (RA). Methods The percentage of CD4

The present study was designed to examine the relationship between gene polymorphisms of C1q, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), T cell immunoglobulin mucin (Tim-1), and systemic lupus erythematosus (SLE).A total of 245 SLE patients were selected from February 2012 to August 2016, along with 245 healthy donors as the control group. Genomic DNA was extracted from peripheral blood samples from all subjects followed by mutational analyses. Gene polymorphisms of the C1q gene (rs292001, rs631090, rs294223 loci); the TRAIL gene (1525A/G, 1588A/G, 1595T/C locus); and the Tim-1 gene were detected by sequencing after polymerase chain reaction amplification. The concentration of anti-C1q antibody and the protein levels of sTRAIL/Tim-1 in serum of all subjects were measured by enzyme-linked immunosorbent assay.As for the C1q gene, the frequency of the T allele at the rs631090 locus in the study group was lower than that in the controls, and the frequency of the C allele was higher in the study group than in the healthy donors. The frequency of the G allele at the 1525A/G locus of TRAIL gene in the study group was significantly higher than those in the control group. The frequency of the G allele at -1454G/A of Tim-1 was dramatically higher in the study group than in the control group. Anti-C1q antibody concentrations of subjects carrying CC and CT genotype at the rs631090 locus were statistically higher than TT genotype carriers. The sTRAIL protein level of the TRAIL 1525A/G GG genotype carriers was significantly higher than that of GA and AA genotype carriers, as well as CC genotype carriers at 1595T/C site compared with CT/TT genotype carriers. GG genotype carriers at -1454G/A had higher Tim-1 expression levels than GA/AA genotype carriers.The C allele at the rs631090 locus of C1q, the G allele at 1525A/G site of TRAIL, and the G allele of Tim-1 at -1454G/A site are susceptibility variants associated with SLE.

Follicular helper T (Tfh) cells are a subgroup of activated CD4We recruited 20 patients fulfilled the the American College of Rheumatology diagnosis criteria and 20 healthy controls (HCs). The number of CD4RA patients had more Tfh cells in peripheral blood, conversely, the frequency of blood Tfr cells (p0.05) and the ratio of Tfr/Tfh were significantly decreased compared to healthy controls (p0.05, p0.01). Furthermore, the ratio of Tfr/Tfh was negatively correlated with values of ESR (r=-0.57, p0.05), RF (r=-0.5275, p0.001), CRP (r=-0.4486, p0.001), IgG (r=-0.4631, p0.05), DAS28 scores (r=-0.5645, p0.01), as well as the levels of IL-21(r=-0.7398, p0.01), CXCL13 (r=-0.4832, p0.05). However, the ratio of Tfr/Tfh was positively with the serum level of TGF-β (r=0.5115, p0.05). Higher mRNA expression of CXCR5, CXCL13, ICOS and lower TGF-β mRNA expression were observed in RA patients. The serum expression level of IL-21, CXCL13 was significantly increased and expression of TGF-β was significantly decreased in RA patients. Furthermore, ectopic germinal center formation and higher expression of Bcl-6, CXCR5, ICOS, CXCL13 in the synovial membrane of the joints in RA patients were observed.The decreased blood CD4

Interstitial lung disease (ILD) is a common, devastating pulmonary complication. An increased number of reports suggesting that biological disease modifying antirheumatic drugs (DMARDs) induced or exacerbated ILDs in rheumatoid arthritis (RA) patients has garnered increased attention. Areas covered: This article discusses ILDs induced by or exacerbated during biological therapy in RA patients. The article summarizes the efficacy and safety of a variety of licensed and off-label biologics clinically used for rheumatic diseases, focusing on the onset or exacerbation of RA-associated ILDs (RA-ILDs) in RA patients treated with biologics targeting tumor necrosis factor, CD20, interleukin 1 (IL-1) and IL-6 receptors. Additionally, the pathogenesis of RA-ILDs is discussed. Expert opinion: To some extent, the possibility of biologic-induced RA-ILDs increases the difficulty in choosing an optimal regimen for RA treatment with biological agents, as the relationship between biological therapy safety and the induction or exacerbation of RA-ILDs has not been established. A framework to assess baseline disease severity, particularly standardizing the evaluation of the pulmonary condition stage in RA patients and monitoring the outcome during the biological therapy treatment, is highly needed and may substantially help guide treatment decisions and predict the treatment benefits.

An early diagnosis of lupus nephritis (LN) has an important clinical implication in guiding treatments of systemic lupus erythematosus (SLE) in clinical settings. In this study, the concentrations of Wnt-3A, Frizzled-8 (FZD-8), and Dickkopf-1 (DKK-1) of Wnt signaling, as well as their diagnostic values for accessing LN, were evaluated by ELISA in sera and urine of 111 SLE patients (31 with LN and 80 without LN) and 70 healthy cohorts. Significantly more abundances of DKK-1 protein were determined in both of sera and urine of SLE patients compared to healthy cohorts (p<0.0001); in particular the serum DKK-1 concentration was even higher in LN-SLE patients relative to non-LN SLE subjects (p<0.0001). Intriguingly, concentrations of above examined proteins in SLE patients showed no correlation between serum and urine. Moreover, a combination of DKK-1 with anti-dsDNA and/or levels of complement C3 and C4 could not increase the specificity and/or sensitivity for identification of patients with LN diseases, but both ROC curve and multiple-factor nonconditional logistic regression analysis showed that serum DKK-1 was considered better positive biomarker for identification of LN in SLE patients. These results imply that serum and/or urine DKK-1 may be a valuable and independent biomarker for identification of SLE patients with LN.

Background.Serum concentrations of soluble interleukin-7 receptor (sIL-7R) and anti-C1q antibody have recently been identified as unique serological markers for lupus nephritis (LN) in patients with systemic lupus erythematosus (SLE). In this study, we evaluated the correlation of serum sIL-7R and anti-C1q in SLE patients.Methods.Sera from 134 patients with SLE and 84 healthy cohorts were tested for levels of sIL-7R and anti-C1q antibodies in terms of ELISA. Correlations of the sIL-7R and anti-C1q autoantibodies were evaluated.Results.The serum concentrations of sIL-7R and anti-C1q antibodies were significantly higher in SLE patients and LN patients in comparison with healthy individuals/controls and SLE patients with non-LN, respectively. In addition, both sIL-7R and anti-C1q concentrations were found to significantly correlate with the SLE disease activity as evaluated by SLEDAI scores. Interestingly, the serum sIL-7R concentration was strongly correlated with the level of anti-C1q antibodies (r=0.2871,p=0.0008) but not statistically correlated with other serological markers, including the anti-dsDNA and complements C3 and C4 concentrations in SLE patients.Conclusion.Both serum sIL-7R and anti-C1q antibodies were strongly associated with disease activity and LN in SLE patients, suggesting that they may be reliable serological markers for identification of SLE patients with active diseases and LN.

Objective. An early diagnosis of lupus nephritis (LN) has an important clinical implication in guiding treatments of systemic lupus erythematosus (SLE) in clinical settings. In this study, the diagnostic values of circulating autoantibodies to C1q alone or in combination with other markers for accessing active SLE and LN were evaluated.Methods. The diagnostic value of anti-C1q autoantibodies for identification of patients with active SLE disease and LN was evaluated by analyzing the level of anti-C1q antibodies in sera from 95 SLE patients, 40 non-SLE patients, and 34 healthy cohorts.Results. The prevalence of anti-C1q antibodies was significantly higher in patients with SLE (50/95, 52.6%), active SLE (40/51, 78.4%), and LN (30/35, 85.7%) in comparison with non-SLE patient controls, patients with inactive SLE, and non-LN, respectively. A combination of anti-C1q with anti-dsDNA and/or levels of complements C3 and C4 exhibited an increased specificity but a decreased sensitivity for identification of patients with active SLE and LN diseases relative to each of these markers alone.Conclusion. Anti-C1q antibodies were strongly associated with disease activity and LN in SLE patients, suggesting that it may be a reliable serological marker for identification of SLE patients with active LN and active SLE disease.