Hua Ye

Circulating Dickkopf-1 Is Correlated with Bone Erosion and Inflammation in Rheumatoid Arthritis

Objective. To explore the potential role of Dickkopf-1 (DKK-1) in rheumatoid arthritis (RA) and to evaluate the effect of a tumor necrosis factor-α (TNF-α) inhibitor (infliximab) and an interleukin 1 receptor antagonist (IL-1Ra; anakinra) on DKK-1 secretion in patients with RA. Methods. Serum samples were collected from 100 patients with RA, 100 patients with other rheumatic diseases (e.g., osteoarthritis and ankylosing spondylitis), and 40 healthy controls. DKK-1 and osteoprotegerin (OPG) levels in serum were detected by ELISA. Serum C-reactive protein (CRP) levels, erythrocyte sedimentation rates (ESR), rheumatoid factor (RF) titers, and anti-cyclic citrullinated peptide antibody were also measured in patients with RA. Results. The serum level of DKK-1 was significantly higher in patients with RA than in healthy controls and those with other rheumatic diseases (p < 0.01); the serum DKK-1 level was correlated with levels of CRP (r = 0.488, p = 0.003) and ESR (r = 0.458, p = 2.4 x 10−4) and the Sharp score of radiologic change (r = 0.449, p = 0.001) in RA. In contrast to the increasing level of OPG, DKK-1 was significantly decreased in RA patients treated with TNF-α inhibitor (p < 0.01). DKK-1 was significantly decreased in RA patients treated with IL-1Ra (p < 0.01). Conclusion. DKK-1, as an important mediator, was correlated with bone erosion and inflammation in RA. The change of DKK-1 level may serve as a biomarker of disease activity and bone erosion.

Low-dose interleukin-2 treatment selectively modulates CD4 + T cell subsets in patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a potentially life-threatening autoimmune disease characterized by altered balance of activity between effector and regulatory CD4+ T cells. The homeostasis of CD4+ T cell subsets is regulated by interleukin (IL)-2, and reduced production of IL-2 by T cells is observed in individuals with SLE. Here we report that treatment with low-dose recombinant human IL-2 selectively modulated the abundance of regulatory T (Treg) cells, follicular helper T (TFH) cells and IL-17-producing helper T (TH17) cells, but not TH1 or TH2 cells, accompanied by marked reductions of disease activity in patients with SLE.

Elevated Serum Interleukin 33 Is Associated with Autoantibody Production in Patients with Rheumatoid Arthritis

Objective. Interleukin 33 (IL-33) is a novel cytokine involved in joint inflammation in animal models. We analyzed the expression of IL-33 in the serum and synovial fluid of patients with rheumatoid arthritis (RA) and investigated its possible pathophysiological importance. Methods. The concentration of IL-33 was measured by ELISA in the serum of 223 patients with RA and 159 controls. Anticyclic citrullinated peptide, rheumatoid factor (RF)-IgA, and RF-IgG were tested by ELISA. Antikeratin antibody and antiperinuclear factor were tested by indirect immunofluorescence assay. Erythrocyte sedimentation rate, C-reactive protein, and immunoglobulins were measured by standard laboratory techniques. The association of IL-33 level with clinical and serologic features of RA was analyzed. We tested the change of IL-33 level following tumor necrosis factor (TNF-α) blockade therapy in 40 patients with RA. Results. In contrast to almost no detectable IL-33 in osteoarthritis and healthy serum, IL-33 could be detected in 94 out of the 223 RA cases (42.2%). Serum IL-33 concentration was significantly higher in patients with RA than in control groups. The level of serum IL-33 decreased after anti-TNF treatment. The level of serum IL-33 was correlated with the production of IgM and RA-related autoantibodies including RF and anticitrullinated protein antibodies. However, no correlation was found between IL-33 concentration and acute-phase inflammation reactant or the score of the Disease Activity Index, suggesting a complex or indirect character of the link between IL-33 and the inflammation in RA. Conclusion. The level of IL-33 is abnormally elevated in RA serum. The elevation of serum IL-33 was at least partly attributed to excessive TNF-α in RA. IL-33 might be involved in the regulation of autoantibody production in RA.

Anti-TNF therapy in patients with HBV infection—analysis of 87 patients with inflammatory arthritis

This study aims to investigate the incidence of hepatitis B virus (HBV) reactivation in inflammatory arthritis (IA) patients with HBV infection using anti-tumor necrosis factor (TNF) agents and evaluate the efficacy of antiviral therapy in reducing the risk of viral reactivation in chronic HBV infection. IA patients using anti-TNF agents from six centers were enrolled. Their HBV infection conditions and ALT and HBV-DNA levels were monitored periodically. Among the six chronic hepatitis B patients, HBV reactivation was found in two patients without antivirus prophylaxis and no viral replication was detected in the other four patients with antivirus prophylaxis. In the 31 inactive carriers, the increase of viral load was detected in 6 of 22 (27.3xa0%) patients without antiviral prophylaxis, and there was no viral reactivation in the other 9 patients with antiviral prophylaxis. HBV reactivation was not found in the 50 patients with resolved HBV infection. It is suggested that anti-TNF therapy might increase the risk of HBV reactivation in patients with chronic HBV infection, and antiviral prophylaxis could effectively decrease the risk. Anti-TNF agents seem to be safe in patients with resolved HBV infection.

CD4 T-cell transcriptome analysis reveals aberrant regulation of STAT3 and Wnt signaling pathways in rheumatoid arthritis: evidence from a case-control study.

IntroductionRheumatoid arthritis (RA) is a systemic autoimmune disease in which T cells play a pivotal role in the pathogenesis. Knowledge in terms of the CD4 T-cell transcriptome in RA is limited. The aim of this study was to examine the whole-genome transcription profile of CD4 T cells in RA by comparing patients with RA to healthy controls.MethodsPeripheral blood CD4 T cells were isolated from 53 RA patients with active disease and 45 healthy individuals; 13 cases and 10 controls were enrolled in microarray analysis. The remaining 40 cases and 35 controls were recruited as an independent cohort for the validation study. Bioinformatics was performed on Gene Ontology (GO), gene-gene interaction networks, and pathway analysis. The gene modules, by combining the results from GO, gene networks, and pathway analysis, were selected for further validation.ResultsThe CD4 T cells showed 1,496 differentially expressed (DE) genes in RA patients relative to healthy individuals. GO analysis revealed that the DE genes were enriched in immune response, T-cell response, apoptosis process, and Wnt receptor signaling. Pathway analysis also identified that ‘Wnt signaling pathway’ was differentially regulated between two groups (Pu2009=u20092.78u2009×u200910−10). By gene-gene network analysis, we found that the DE genes were enriched in T-cell receptor (TCR), JAK-STAT signaling, and Wnt signaling pathway. By gene module analysis, we found that a number of DE genes overlapped in the three different analyses. In total, 23 genes were selected for further validation, and nine genes were confirmed. Of these, four genes (SOCS3, CBL, IFNAR1, and PIK3CA) were involved in STAT3 (signal transducer and activator of transcription 3) signaling, and three genes (CBL, KLF9, and CSNK2A1) were involved in the Wnt signaling pathway. Additionally, several zinc finger transcription factors (ZEB1, ZNF292, and ZNF644) were confirmed.ConclusionsWe report here the first case–control study of the CD4 T-cell transcriptome profile in RA. Our data provide evidence that CD4 T cells from patients with RA have abnormal functional networks in STAT3 signaling and Wnt signaling. Our results also suggest that the aberrant expression of several zinc finger transcription factors (ZEB1, ZNF292, and ZNF644) may be potential pathogenic factors for RA.

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 (pu2009<u20090.05), 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.

Genetic predictors of efficacy and toxicity of iguratimod in patients with rheumatoid arthritis

Iguratimodxa0(IGU)xa0is a novel disease-modifying anti-rheumatic drugxa0(DMARD) in rheumatoid arthritis (RA).xa0Like other DMARDs, IGU exhibited significant differences in effectiveness and safety.nnnAIMnThe aim of this study was to identify genetic predictorsof efficacyand toxicity of IGU in patients with RA.nnnMATERIALS & METHODSnSeven SNPs from IGU-metabolizing genes were genotyped in 272 IGU-treated patients with RA.xa0Results:xa0ABCG2 rs2231142xa0A allele conferred a higher response to IGU, while NAT2xa0rs1495742 G carriersconferred a lower response to IGU. CYP2C19*2xa0rs4244285xa0A carriers had higher risk for IGU-induced toxicity compared to the GG carriers.nnnCONCLUSIONnOur study suggests that the polymorphisms of ABCG2xa0(rs2231142), NAT2 (rs1495741)and CYP2C19*2 (rs4244285) may help to predict thetherapeutic effectiveness and toxicity of IGU in patients with RA.

Magnetic resonance imaging in early rheumatoid arthritis: a multicenter, prospective study.

To identify the magnetic resonance imaging (MRI) features of hands and wrists in early rheumatoid arthritis (RA). A total of 129 early arthritis patients (≤1xa0year) were enrolled in the study. At presentation, MRI of the hands was performed, with clinical and laboratory analyses. After a 1-year follow-up, clinical diagnosis of early RA or non-RA was confirmed by two rheumatologists. The characteristics of MRI variables at baseline in RA patients not fulfilling ACR 1987 criteria [RA-87(−)] were compared with those fulfilling ACR1987 criteria [RA-87(+)] and non-RA. In the 129 early arthritis patients, 90 were diagnosed with RA in a 1-year follow-up. There were 47.8xa0% (43/90) of the RA patients not fulfilling ACR 1987 criteria [RA-87(−)]. The scores of synovitis in RA-87(−) patients were similar with those in RA-87(+) [Synovitis score, 14.0 (IQR, 4.0–25.0) vs. 14.0 (IQR, 10.0–25.0), pu2009>u20090.05]. Compared with those in non-RA, RA-87(−) patients had higher synovitis scores and occurrence of synovitis in proximal interphalangeal (PIP) joints [synovitis score, 14.0 (IQR, 4.0–25.0) vs. 6.0 (IQR, 2.0–14.5), pu2009=u20090.046; occurrence of PIP synovitis: 53.5 vs. 27.3xa0%, pu2009=u20090.02]. There was no significant difference of bone marrow edema, bone erosion, and tenosynovitis between RA-87(−) and non-RA. Synovitis in PIP joints was independent predictor for RA-87(−) [OR, 3.1 (95xa0%CI 1.2–8.1)]. High synovitis scores and synovitis in PIP joints on MRI were important in early RA, especially those not fulfilling ACR 1987 criteria.

Comparison of three classification criteria of rheumatoid arthritis in an inception early arthritis cohort

The aim of this study is to compare the three classification criteria for rheumatoid arthritis (RA) in a large cohort of early arthritis patients. Patients who had at least one clinically swollen joint with disease duration no more than 1xa0year and age more than 18xa0years were enrolled. The clinical and laboratory parameters were recorded. The patients were diagnosed by two experienced rheumatologists. Undiagnosed patients were followed up every 3xa0months until 1xa0year. The sensitivity, specificity, and predictive value were compared among the early RA (ERA) criteria, the 1987 ACR criteria, and the 2010 ACR/EULAR criteria in this inception cohort of early arthritis patients. A total of 417 patients with inflammatory arthritis were recruited. By the end of 1xa0year follow-up, there were 399 patients (95.7xa0%) with a definitive diagnosis and 18 (4.3xa0%) patients remained as undifferentiated arthritis. Among the patients with definitive diagnosis, 202 (50.6xa0%) patients were diagnosed with RA and 197 (49.4xa0%) with non-RA. The sensitivity of ERA criteria was equal to 2010 ACR/EULAR criteria (both were 72.3xa0%), but much higher than 1987 ACR criteria (72.3 vs. 39.1xa0%, Pu2009<u20090.001); the specificity of ERA criteria was comparable to 2010 ACR/EULAR criteria (87.8 vs. 83.2xa0%) and slightly lower than 1987 ACR criteria (87.8 vs. 92.4xa0%, Pu2009<u20090.001). Unlike the complicated scoring system of 2010 criteria, the ERA criteria were more feasible to use in practice with five criteria only. The ERA criteria have a high sensitivity and more clinically feasibility in daily practice for early RA diagnosis.