Rong Mu

Therapeutic potential of human umbilical cord mesenchymal stem cells in the treatment of rheumatoid arthritis.

IntroductionRheumatoid arthritis (RA) is a T-cell-mediated systemic autoimmune disease, characterized by synovium inflammation and articular destruction. Bone marrow mesenchymal stem cells (MSCs) could be effective in the treatment of several autoimmune diseases. However, there has been thus far no report on umbilical cord (UC)-MSCs in the treatment of RA. Here, potential immunosuppressive effects of human UC-MSCs in RA were evaluated.MethodsThe effects of UC-MSCs on the responses of fibroblast-like synoviocytes (FLSs) and T cells in RA patients were explored. The possible molecular mechanism mediating this immunosuppressive effect of UC-MSCs was explored by addition of inhibitors to indoleamine 2,3-dioxygenase (IDO), Nitric oxide (NO), prostaglandin E2 (PGE2), transforming growth factor β1 (TGF-β1) and interleukin 10 (IL-10). The therapeutic effects of systemic infusion of human UC-MSCs on collagen-induced arthritis (CIA) in a mouse model were explored.ResultsIn vitro, UC-MSCs were capable of inhibiting proliferation of FLSs from RA patients, via IL-10, IDO and TGF-β1. Furthermore, the invasive behavior and IL-6 secretion of FLSs were also significantly suppressed. On the other hand, UC-MSCs induced hyporesponsiveness of T cells mediated by PGE2, TGF-β1 and NO and UC-MSCs could promote the expansion of CD4+ Foxp3+ regulatory T cells from RA patients. More importantly, systemic infusion of human UC-MSCs reduced the severity of CIA in a mouse model. Consistently, there were reduced levels of proinflammatory cytokines and chemokines (TNF-α, IL-6 and monocyte chemoattractant protein-1) and increased levels of the anti-inflammatory/regulatory cytokine (IL-10) in sera of UC-MSCs treated mice. Moreover, such treatment shifted Th1/Th2 type responses and induced Tregs in CIA.ConclusionsIn conclusion, human UC-MSCs suppressed the various inflammatory effects of FLSs and T cells of RA in vitro, and attenuated the development of CIA in vivo, strongly suggesting that UC-MSCs might be a therapeutic strategy in RA. In addition, the immunosuppressive activitiy of UC-MSCs could be prolonged by the participation of Tregs.

Hypoxia and hypoxia-inducible factor-1α provoke toll-like receptor signalling-induced inflammation in rheumatoid arthritis

Objectives Hyperplasia of synovial fibroblasts, infiltration with lymphocytes and tissue hypoxia are major characteristics of rheumatoid arthritis (RA). Extensive data support a key role for toll-like receptors (TLRs) in RA. Little is known regarding the impact of hypoxia on TLR-induced inflammation in RA. The aim of this study was to reveal the effects of hypoxia and its regulator, hypoxia-inducible factor-1α (HIF-1α), on the inflammatory response of RA synovial fibroblasts (RASF) to TLR ligands. Methods Hypoxia was induced in RASF by incubation with Na2S2O4. TLR3 ligand polyIC, TLR2 ligand peptidoglycan, TLR4 ligand LPS and TLR9 ligand CpG were used to stimulate the cells. Effects of hypoxia on TLR-induced inflammatory mediators were determined by RT-PCR, qPCR and ELISA. Overexpression of HIF-1α as well as knocking-down its expression was used to reveal its fundamental role. RASF-induced inflammatory T cell expansion was determined by flow cytometry analysis of T helper (Th)1/Th17 cells, and IFN-γ/IL-17 production by ELISA after RASF/T cell coculture. Results Hypoxia potentiated the expression of inflammatory cytokines, metalloproteinases and VEGF in RASF stimulated by different TLR ligands, especially polyIC, a synthetic mimic of dsRNA from viruses or apoptotic cells. HIF-1α played a fundamental role in this synergy. Moreover, HIF-1α overexpression enhanced RASF-mediated expansion of inflammatory Th1 and Th17 cells, leading to proinflammatory IFN-γ and IL-17 production. Conclusions Our findings suggest that hypoxia and HIF-1α may function in conjunction with TLR-stimulated innate immune responses to drive inflammation in RA. This pathway may serve as a therapeutic target for the disease.

Hypoxia-Inducible Factor-1α and Interleukin 33 Form a Regulatory Circuit to Perpetuate the Inflammation in Rheumatoid Arthritis

Hyperplasia of synovial fibroblasts, infiltration with inflammatory cytokines, and tissue hypoxia are the major characteristics of rheumatoid arthritis (RA). Interleukin 33 (IL-33) is a newly identified inflammatory cytokine exacerbating the disease severity of RA. Hypoxia-inducible factor-1α (HIF-1α) showed increased expression in RA synovium and could regulate a number of inflammatory cytokine productions. Nevertheless, its correlation with IL-33 remains largely unknown. Here, we showed that elevated levels of IL-33 were demonstrated in RA patient synovial fluids, with upregulated expression of HIF-1α and IL-33 in the synovial fibroblasts. Knocking down HIF-1α compromised IL-33 expression in rheumatoid arthritis synovial fibroblasts (RASF), while enforcing HIF-1α expression in RASF substantially upregulated IL-33 levels. HIF-1α promoted the activation of the signalling pathways controlling IL-33 production, particularly the p38 and ERK pathways. Moreover, we showed for the first time that IL-33 in turn could induce more HIF-1α expression in RASF, thus forming a HIF-1α/IL-33 regulatory circuit that would perpetuate the inflammatory process in RA. Targeting this pathological pathway and HIF-1α may provide new therapeutic strategies for overcoming the persistent and chronic inflammatory disease.

Genetic variant in IL33 is associated with susceptibility to rheumatoid arthritis.

IntroductionInterleukin (IL)-33 is a proinflammatory cytokine contributing to the pathogenesis of rheumatoid arthritis (RA). The gene encoding IL-33 may serve as a genetic factor and be associated with the risk of RA. To investigate the potential association between IL33 and RA, we performed a case–control study based on Chinese Han population.MethodsA three-stage case–control study was performed. Two tag single-nucleotide polymorphisms (SNPs) (rs7044343 and rs10975514), mapping to the IL33 gene, were first genotyped in the discovery population. We further genotyped rs7044343 and rs10975514 in the validation and replication population. The associations between the two tag SNPs and phenotypic subgroups of RA and levels of serum IL-33 were assessed with a logistic regression model.ResultsIn the discovery population, the CC genotype of rs7044343 was associated with RA patients (odds ratio (OR) = 0.777, 95% confidence interval (CI), 0.611 to 0.988; P = 0.040). After anti-citrullinated peptide antibody (ACPA) stratification, the CC genotype of rs7044343 was also shown to be a protective genotype in RA without ACPA (OR = 0.610; 95% CI, 0.379 to 0.982; P = 0.042). In the validation population and replication population, the association between rs7044343 and RA, especially ACPA-negative RA, was still significant. A meta-analysis of discovery, validation, and replication panels confirmed the association between CC genotype of rs7044343 and RA (Pcombined = 0.0004; ORcombined = 0.77; 95% CI, 0.67 to 0.89). No evidence was found for heterogeneity between three sample sets (Phet = 0.99; I2 = 0%). Similar results were also obtained in ACPA-negative RA (Pcombined = 0.0002; ORcombined = 0.57; 95% CI, 0.43 to 0.77). No association was detected between rs10975514 polymorphism and RA susceptibility in the discovery and validation population. The serum levels of IL-33 were significantly lower in the patients with the rs7044343 CC genotype.ConclusionThe CC genotype of rs7044343 in IL33 is associated with RA patients and downregulates IL-33 expression in RA.

Increased IL-33 in Synovial Fluid and Paired Serum Is Associated with Disease Activity and Autoantibodies in Rheumatoid Arthritis

Objectives. IL-33, a newly found cytokine which is involved in joint inflammation, could be blocked by a decoy receptor—sST2. The expression and correlation of IL-33 and sST2 in rheumatoid arthritis (RA) are of great interest. Methods. Synovial fluid (SF) was obtained from 120 RA and 30 osteoarthritis (OA) patients, and paired sera were collected from 54 of these RA patients. The levels of IL-33 and sST2 were measured by ELISA. Results. SF IL-33 was significantly higher in RA than in OA, which was correlated with disease activity score 28, erythrocyte sedimentation rate, rheumatoid factor (RF)-IgM, RF-IgG, glucose phosphate isomerase (GPI), and immunoglobulin. Serum IL-33 was correlated positively with SF IL-33 in RA. Furthermore, it was correlated with RF-IgM and GPI. sST2 was partly detectable in RA (13 out of 54, 24.1%), while not in OA. Serum sST2 in RA had no significant correlation with serum IL-33 or SF IL-33. However, SFs from both RA and OA patients did not express sST2. Conclusions. This study supported that IL-33 played an important role in the local pathogenesis of RA. Considering the tight correlation between IL-33 and clinical features, it may become a new target of local treatment.

Societal Costs of Rheumatoid Arthritis in China: A Hospital-Based Cross-Sectional Study

To estimate the annual direct and indirect costs of rheumatoid arthritis (RA) in China and identify the predictors for cost of illness.

Subclinical hypothyroidism and its association with lupus nephritis: a case control study in a large cohort of Chinese systemic lupus erythematosus patients:

The aim of this study was to evaluate the prevalence of thyroid diseases in Chinese systemic lupus erythematosus (SLE) patients and the relevance of subclinical hypothyroidism (SCH) with lupus nephritis (LN). A large cohort of 1006 SLE patients was retrospectively analyzed. The prevalence of autoimmune thyroid disease was 2.78%, clinical hypothyroidism 1.69%, subclinical hypothyroidism 10.04%, central hypothyroidism 1.29%, hyperthyroidism 1.19%, euthyroid sick syndrome (ESS) 9.54%, and nodules 1.09%, respectively. Compared with the prevalence of thyroid abnormalities in the general Chinese population (0.91–6.05%), SCH was much higher (10.04%) in this study. In addition, SCH was more frequent in patients with LN (13.4%) than those without LN (7.3%, p = 0.001). Case control study was performed to explore the relative risk factors of SCH. In multiple logistic regression models, 24 h urine protein and estimated glomerular filtration rate (eGFR) were retained as independent correlates of SCH after adjusting for demographic variables, risk factors, and other potential confounders. The results of the present study suggest that SCH is a common complication in SLE patients, and closely related with LN.

Management of rheumatoid arthritis in People's Republic of China - focus on tocilizumab and patient considerations.

The prevalence of rheumatoid arthritis (RA) is 0.19%–0.41% in Chinese population. RA exerts profound influence on health-related quality of life (HRQoL), which imposed huge burdens on patients physically, mentally, and economically. As a developing country, People’s Republic of China faces enormous challenges in management of RA. Conventional-synthesized disease-modifying antirheumatic drugs (csDMARDs) remain the most selective therapeutic options for RA in People’s Republic of China owing to their affordable price and fair efficacy as well as tolerability. Unfortunately, there are substantial RA patients who are poor responders to csDMARDs, even to subsequently combined therapy with tumor necrosis factor antagonist (anti-TNF). Tocilizumab (TCZ) has been approved as a subsequent-line biological agent in patients with moderate-to-severe RA worldwide including People’s Republic of China. TCZ is the first biological agent approved for the treatment of RA inhibiting interlukin-6 (IL-6) by blocking both membrane-bound and soluble IL-6 receptors. Open-label studies in real-life practice and strictly controlled clinical trials demonstrated its high efficacy and safety profile in treatment of patients with RA who have inadequate responses to csDMARDs and anti-TNF. HRQoL of RA patients was improved in various measurements. TCZ was associated with 1.2 times the risk of adverse events, such as infections, dyslipidemia, and hepatic transaminases elevation, compared with pooled placebo. A relatively long half-life allowing for monthly intravenous administration and a newly developed subcutaneous injection make TCZ more acceptable. However, data are not enough so far comparing TCZ to anti-TNF. Lack of evidence in Chinese patients and high cost of TCZ limit its prescription in People’s Republic of China being a developing country. Further clinical trials and post-marketing surveillance may offer a comprehensive assessment of patient satisfaction and acceptability, which may help us define the optimal role for TCZ in therapeutic strategy.

Clinical and laboratory profiles of rhupus syndrome in a Chinese population: a single-centre study of 51 patients

Objective: The objective of this paper is to clarify the demographic, clinical and serologic characteristics of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) overlap syndrome, known as ‘rhupus syndrome’. Methods: Between 1995 and 2012, 51 patients were classified as having rhupus among 3733 consecutive SLE patients. Rhupus was defined as a condition involving an overlap of RA and SLE features meeting the respective criteria of the American College of Rheumatology. The clinical and laboratory parameters of patients with rhupus syndrome were compared with those of 230 RA patients and 120 unselected SLE patients. Results: The age at the onset of rhupus was significantly younger than that of RA (p < 0.05), but similar to that of SLE. The initial manifestation was arthritis in 84.3% (43/51) of rhupus patients. Symptoms of SLE manifested after an average of 9.2 years. SLE was the initial diagnosis in 7.8% (four of 51) of patients, whereas both diseases developed simultaneously in 7.8% of the patients. SLE-associated manifestations were mild in rhupus syndrome, particularly neurologic disorders. Haematopoietic involvement was the most prominent systemic manifestation in rhupus patients. Conclusion: Rhupus syndrome constitutes a subgroup of patients with distinct demographic, clinical and immunological characteristics. RA typically presents first, and less-severe SLE-associated damage is apparent.

Antilymphocyte antibodies in systemic lupus erythematosus: Association with disease activity and lymphopenia

Purpose. We analyzed the prevalence, clinical correlation, and the functional significance of ALA in patients with systemic lupus erythematosus (SLE). Methods. ALA IgG was detected by indirect immunofluorescence in the serum of 130 SLE patients, 75 patients with various rheumatic diseases, and 45 healthy controls (HC). Results. The sensitivity and specificity of ALA IgG in SLE were 42.3% and 96.7%, respectively. ALA was observed in 55.6% (50/90) of patients with lymphopenia, which was significantly higher than in patients with normal lymphocytes (5/40, 12.5%; P < 0.001). Patients with active SLE showed higher ALA positivity (60.9%) than those with inactive disease (24.2%; χ 2 = 17.925; P < 0.001). ALA correlated significantly with hypocomplementemia, anti-dsDNA antibodies, and higher SLEDAI scores. The incidences of ALA in SLE patients who were seronegative for anti-dsDNA, anti-Sm, or both antibodies were 32.9% (26/79), 41.0% (43/105), and 32.4% (22/68), respectively. The ALA-positive group also had higher incidences of neuropsychiatric SLE (NPSLE) and lupus nephritis (LN). In multivariate analyses, ALA was independently associated with lymphopenia, higher SLEDAI scores, and increased risk for LN. ALA titers significantly decreased as clinical disease was ameliorated following treatment. Conclusions. ALA occurred more frequently in patients with active SLE and was independently associated with lymphopenia, disease activity, and LN.