The synovial grade corresponding to clinically involved joints and a feasible ultrasound-adjusted simple disease activity index for monitoring rheumatoid arthritis.

OBJECTIVES: To determine which grade of ultrasound (US) synovitis corresponds to clinically involved joints in rheumatoid arthritis (RA) and develops a new US-adjusted composite measure. METHODS: Clinical and US examinations were performed on 137 patients with RA (28 joints). Synovial effusion, hypertrophy, and blood flow were semiquantitatively graded from 0 to 3 using gray scale (GS) and power Doppler (PD) modes. We calculated US-adjusted simple disease activity index (SDAI) and assessed feasibility, and external validity by comparing with erythrocyte sedimentation rate (ESR), and modified health assessment questionnaires (MHAQ). RESULTS: GS ≥2 and PD ≥0 corresponds to clinically swollen joints, and GS ≥2 and PD ≥1 corresponds to tender joints. The US-adjusted SDAI showed the highest correlation when US-determined swollen joints were defined as PD ≥2 with ESR, and GS ≥3 and PD ≥2 with MHAQ. A feasible US-adjusted SDAI examining only clinically involved joints still showed a higher correlation with ESR and MHAQ than SDAI. CONCLUSION: Our composite measure complemented by US only for clinically involved joints is feasible and reliable for monitoring disease activity.

Immunoregulatory role of IL-35 in T cells of patients with rheumatoid arthritis.

OBJECTIVE: IL-35 is the most recently identified member of the IL-12 family. It consists of EBV-induced gene 3 (EBI3) and IL-12α chain p35. We investigated whether IL-35 enhances the in vitro immunosuppressive function of peripheral blood isolated from patients with RA. METHODS: Peripheral blood was harvested from 17 active and 10 inactive RA patients and IL-35 concentrations were quantified using an ELISA. An expression vector containing IL-35 with a FLAG tag at the carboxyl-terminus was constructed by covalently linking EBI3 and IL-12α (p35). The function of IL-35 was then evaluated in a suppression assay using T cells isolated from human RA patients with CD2, CD3 and CD28 antibodies. RESULTS: Serum IL-35 levels and the number of Treg were decreased significantly in patients with active RA. There was a significant correlation between serum IL-35 and the 28-joint DAS with ESR (DAS28-ESR) in patients with active RA. IL-35 treatment enhanced the regulatory function, suppressing the levels of inflammatory cytokines such as IL-17 and IFN-γ and the cellular growth of effector T cells stimulated by conjugation with CD2, CD3 and CD28. CONCLUSION: These data revealed that IL-35 might suppress T cell activation during the peripheral immune responses of RA. Therefore our data suggest that IL-35 might have multiple therapeutic targets.

Up-regulation of the endoplasmic reticulum transmembrane protein UNC93B in the B cells of patients with active systemic lupus erythematosus.

OBJECTIVES: The transmembrane endoplasmic reticulum (ER) protein UNC93B plays an essential role in the normal response to signalling through intracellular Toll-like receptor (TLR)3, TLR7, TLR8 and TLR9. In the current study, we examined the level of UNC93B expression on peripheral B cells from patients with active SLE, and investigated any correlation with SLE pathogenesis. METHODS: Peripheral blood mononuclear cells (PBMCs) and B cells from 43 active SLE patients were analysed by quantitative RT-PCR to determine the precise levels of UNC93B mRNA. We also analysed UNC93B protein expression on B cells from SLE patients using immunoblotting. RESULTS: The expression of UNC93B mRNA on PBMCs from active SLE patients was significantly higher than that of controls (P < 0.05). The intracellular expression level of UNC93B protein on CD20(+) B cells from active SLE patients was also higher than in the controls. Moreover, the expression of UNC93B on B cells from lupus patients correlated significantly with high titres of anti-dsDNA antibody (P < 0.05). CONCLUSIONS: Up-regulation of the ER membrane protein UNC93B on human lupus B cells suggests that TLR9 and UNC93B play a partial role in the pathogenesis of SLE by inducing defective peripheral B-cell tolerance.

Diagnosis of giant cell arteritis by head-contrast three-dimensional computed tomography angiography: two case reports.

INTRODUCTION: Temporal artery biopsy is essential for the diagnosis of giant cell arteritis. It has been shown that 18F-fluorodeoxyglucose positron emission tomography-computed tomography, magnetic resonance angiography, and ultrasonography are useful for the diagnosis of giant cell arteritis. However, there are only a few reports on the usefulness of three-dimensional computed tomography angiography in the diagnosis of giant cell arteritis. We describe two cases in which giant cell arteritis was difficult to diagnose using positron emission tomography-computed tomography and magnetic resonance angiography but was diagnosed using three-dimensional computed tomography angiography, thus showing the importance of three-dimensional computed tomography angiography in the diagnosis of giant cell arteritis. CASE PRESENTATION: Case 1: An 81-year-old Japanese man. Laboratory investigations revealed normocytic anemia and raised inflammatory marker levels. Slight bleeding in the right posterior pole of his eyeball and leukoma of his left cornea were observed on fundus examination. Stenosis and stoppage of the temporal artery were detected on three-dimensional computed tomography angiography. A diagnosis of giant cell arteritis was made, and he was started on orally administered prednisolone. His headache and C-reactive protein levels improved. Four weeks after glucocorticoid steroid treatment, three-dimensional computed tomography angiography revealed improvement in stenosis and stoppage of temporal artery. Case 2: A 74-year-old Japanese woman. A dose of 20 mg of prednisolone was administered and her polymyalgia and polyarthritis improved; however, her headache and ear occlusion persisted. Although vasculitis was not detected on positron emission tomography-computed tomography, stenosis and stoppage of the temporal artery were detected on computed tomography angiography. She was diagnosed as having giant cell arteritis and started on orally administered prednisolone treatment (60 mg daily). Her headache and C-reactive protein levels improved. Four weeks after glucocorticoid treatment, three-dimensional computed tomography angiography showed improvement in stenosis and stoppage of temporal artery. CONCLUSIONS: In both patients with giant cell arteritis, three-dimensional computed tomography angiography revealed improvement in stenosis and stoppage of temporal artery after glucocorticoid treatment. We conclude that computed tomography angiography along with magnetic resonance angiography, positron emission tomography-computed tomography, and ultrasonography are important for the diagnosis of giant cell arteritis.

Down-regulation of CD72 and increased surface IgG on B cells in patients with lupus nephritis.

The significance of both the acceleratory and inhibitory functions of the CD72 molecule was investigated among patients with systemic lupus erythematosus (SLE) during modification of B cell differentiation. Expression of the CD72 molecule and mRNA on B cells was decreased in SLE with lupus nephritis, while CD100 expression on both CD4+ T cells and CD8+ T cells was not significant in comparison with the controls. When the relationship between CD72 expression and other B cell markers was examined, decreased expression of CD72 was associated with differences in the stage of differentiation. In patients with decreased expression of CD72, switching to IgG was evident, and the disease stage was started to severe. In patients with lupus nephritis, the decreased expression of CD72 was related to class switching on B cells, suggesting that CD72 is a useful marker for determining class switching of B cells in lupus nephritis.

Elevated serum level of circulating syndecan-1 (CD138) in active systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) is characterized by loss of B cell tolerance and by the presence of polyclonal B cell activation. Syndecan-1 (CD138) is expressed on plasma cells derived from B cells, and is suspected to play a role in SLE. We evaluated the level of soluble CD138 (sCD138) and cell surface expression of CD138 in patients with active SLE, and also examined correlations among the serum levels of BAFF, a proliferation-inducing ligand (APRIL), and CD138 in these patients. METHODS: Peripheral blood samples were obtained from 22 SLE patients in an active disease state and 14 normal controls. The levels of serum sCD138, sBAFF, and sAPRIL were measured using ELISA, and cell surface CD138 was analyzed by flow cytometry. The levels of CD138 mRNA were analyzed by RT-PCR. Blood samples were obtained longitudinally when the patients were in an inactive disease state. RESULTS: The levels of circulating CD138, CD138 mRNA in PBMC, and the numbers of CD20(- )CD38(+)CD138(+) plasma cells were increased in patients with active SLE in comparison with normal controls. Furthermore, the serum sCD138 level in SLE patients was found to correlate with the proportion of CD20(- )CD38(+)CD138(+) plasma cells. On the other hand, patients with active SLE showed a reduced level of sCD138, and this was inversely correlated with the serum level of sAPRIL. CONCLUSIONS: These results suggest that sCD138 may be applicable as a surrogate marker of disease activity, and that syndecan-1/APRIL signaling may be a potential therapeutic target for patients with active SLE.

Chemoattractant mechanism of Th1 cells in class III and IV lupus nephritis.

Proliferative lupus nephritis (PLN) is the common, severe, and important form of lupus nephritis. Recent report showed that T cells producing Interferon (IFN)gamma (Th1 cells) increased in patients with World Health Organization class IV. However, the relation between the increase of Th1 cells and the pathogenesis has been made unclear. The aim of this study was to examine the chemoattractant mechanism of Th1-producing cells and whether in vitro IFNgamma secretion from Th1-producing cells in PLN. The Th1:Th2 ratio in peripheral blood was measured by flow cytometry. The serum levels of IL-2, IFNgamma, IL-13, monocyte chemoattractant protein-1 (MCP-1) and IP-10 were determined by using enzyme-linked immunosorbent assay. In in vitro IFNgamma production assay, CD4(+)T cells co-cultured with IL-12 and/or IL-18. Th1:Th2 ratio in PLN was high and not correlated with the serum Th1 cytokine level. This Th1-producing cell tended to go toward the inflammatory lesion by low CD62L expression and chemokines. The level of MCP-1 and IP-10 in patients with PLN significantly increased. Lastly, in vitro IFNgamma production assay, patients with PLN CD4(+)T cells produced IFNgamma by the addition of IL-12 and IL-18, while CD4(+)T cells in normal controls did not produce. These findings suggest that combination of Th1 inducers and chemokine inhibition might be powerful threrapeutic approach in PLN.

Decrease in CD4+CD25+ and CD8+CD28+ T cells in interstitial pneumonitis associated with rheumatic disease.

The expression of CD25 or CD28 on T cells was examined in patients with rheumatic diseases associated with interstitial pneumonitis (IP), in order to investigate the conditions of CD4+CD25+ regulatory T cells and CD8+CD28- suppressor T cells. Fifty-five patients with various rheumatic diseases and 23 normal controls were enrolled. CD4+CD25+ T cells of patients with IP were significantly decreased in comparison with non-IP patients, and the ratio of CD8+CD28- T cells in patients with IP was significantly higher than that in non-IP patients or normal controls. These results for CD8+CD28- T cells were in accord with the decrease in CD8+CD28+ T cells, and may be related to activation-induced CD8+CD28+ T-cell death. Thus, the abnormality of CD4+CD25+ regulatory T cells may be related to the pathogenesis of IP, and the survival and activation of CD8+ T cells.

CD19/22 balance relates to improvement of disease activity in systemic lupus erythematosus.

B cells in patients with systemic lupus erythematosus (SLE) are hyperactivated and B-cell receptor signal transduction may be affected by various response regulators. CD19 and CD22 play a major role as regulators of B-cell response. Therefore, we examined CD19 and CD22 expressions on B cells of patients with SLE, and how they were related to disease activity. Thirty-one patients with active SLE were selected and enrolled in this study. Evaluation of CD19 and CD22 expressions on B cells was performed prior to and after treatments with flow cytometry analysis. Disease activity was determined according to the SLE disease activity index score. CD19 and CD22 expressions on B cells in SLE patients revealed no significant differences when compared with the controls. However, improvement of SLE was recognized among patients with an increased ratio of CD22-positive cells. Our results suggest that this balance is a useful marker for determining improvement of SLE disease activity, although the CD19/22 balance does not contribute to the pathogenesis of SLE.