E. K. Li

Cardiovascular risk profile of patients with psoriatic arthritis compared to controls—the role of inflammation

OBJECTIVE To examine the distribution of traditional and novel risk factors of cardiovascular disease (CVD) in patients with PsA compared with healthy controls. METHODS We compared risk factors for CVD between 102 consecutive PsA patients and 82 controls, adjusting for BMI. We also assessed the role of inflammation on the CVD risk factor by using a BMI and high-sensitivity CRP (hsCRP)-adjusted model. RESULTS The BMI of PsA patients were significantly higher than healthy controls. After adjusting for the BMI, PsA patients still have a higher prevalence of diabetes mellitus (DM) [odds ratio (OR) 9.27, 95% CI 2.09, 41.09) and hypertension (OR 3.37, 95% CI 1.68, 6.72), but a lower prevalence of low high density lipoprotein (HDL) cholesterol (OR 0.16, 95% CI 0.07, 0.41). PsA patients have significantly increased systolic and diastolic blood pressures, insulin resistance and inflammatory markers (hsCRP and white cell count) compared to controls. PsA patients have higher HDL cholesterol and apolipoprotein (Apo) A1 levels; and lower total cholesterol (TC) and low density lipoprotein cholesterol levels; and a lower TC/HDL ratio. However, the Apo B level (P < 0.05), and the Apo B/Apo A1 ratio (P = 0.07) were higher in PsA patients. Further adjustment for hsCRP level rendered the differences in the prevalence of hypertension and DM; the TC, and sugar levels; and white cell count non-significant between the two groups; while the differences in other parameters remained significant. CONCLUSION These data support the hypothesis that PsA may be associated with obesity, hypertension, dyslipidaemia and insulin resistance because of the shared inflammatory pathway.

Raised plasma concentration and ex vivo production of inflammatory chemokines in patients with systemic lupus erythematosus

Background: Chemokines are involved in leucocyte chemotaxis. Infiltrating leucocytes play an important role of tissue injury in systemic lupus erythematosus (SLE). Objective: To investigate the role of inflammatory chemokines and their association with interleukin 18 (IL18) in SLE pathogenesis and disease activity. Methods: Plasma concentrations and ex vivo peripheral blood mononuclear cell production of inflammatory chemokines IP-10, RANTES, MIG, MCP-1, TARC, IL8, and GROα, and proinflammatory cytokines IL18, IFNγ, IL2, IL4, and IL10 were assayed in 80 SLE patients with or without renal disease and 40 healthy controls by immunofluorescence flow cytometry and enzyme linked immunosorbent assay. Results: Plasma IP10, RANTES, MIG, MCP-1, GROα, and IL18 concentrations in all SLE patients were higher than in controls, and correlated significantly with SLEDAI score (all p<0.05). In SLE patients without renal disease, IP10, RANTES, MIG, MCP-1, IL8, and IL18 correlated positively with SLEDAI score, while in those with renal derangement, IP10, IL8, IL10, and IL18 correlated with disease activity (all p<0.05). Plasma IL18 concentration correlated positively with IP10, MIG, GROα, and IL8 in all SLE patients (all p<0.005). Mitogen induced increases in ex vivo production of IP10, MCP-1, TARC, IFNγ, IL4, and IL10 were higher in all SLE patients regardless of their difference in disease activity (all p<0.05). Patients with renal disease had an augmented ex vivo release of RANTES. Conclusions: The correlation of raised plasma concentration and ex vivo production of inflammatory chemokines with disease activity, and their association with IL18, supports the view that chemotaxis of Th1/Th2 lymphocytes and neutrophils is important in SLE pathogenesis.

Serum and urinary free microRNA level in patients with systemic lupus erythematosus

MicroRNAs circulating in body fluid have been suggested as biomarkers of various diseases. We studied the serum and urinary level of several miRNA species (miR-200 family, miR-205 and miR-192) in patients with systemic lupus erythematosus (SLE). We studied 40 SLE patients. Serum and urinary miRNA levels were determined and compared with that of healthy controls. The serum levels of miR-200a, miR-200b, miR-200c, miR-429, miR-205 and miR-192, and urinary miR-200a, miR-200c, miR-141, miR-429 and miR-192 of SLE patients were lower than those of controls. Glomerular filtration rate (GFR) correlated with serum miR-200b (r = 0.411, p = 0.008), miR-200c (r = 0.343, p = 0.030), miR-429 (r = 0.347, p = 0.028), miR-205 (r = 0.429, p = 0.006) and miR-192 (r = 0.479, p = 0.002); proteinuria inversely correlated with serum miR-200a (r = −0.375, p = 0.017) and miR-200c (r = −0.347, p = 0.029). SLE disease activity index (SLEDAI) inversely correlated with serum miR-200a (r = −0.376, p = 0.017). Serum miR-200b (r = 0.455, p = 0.003) and miR-192 (r = 0.589, p < 0.001) correlated with platelet count, while serum miR-205 correlated with red cell count (r = 0.432, p = 0.005) and hematocrit (r = 0.370, p = 0.019). These pilot results suggested that miRNA may take part in the pathogenesis of SLE. Further studies are needed to validate the role of serum miRNA as a biomarker of SLE.

Tacrolimus for the treatment of systemic lupus erythematosus with pure class V nephritis

OBJECTIVES The treatment of pure membranous (class V) lupus nephropathy remains unsatisfactory. We studied the efficacy and safety of tacrolimus in the treatment of membranous nephritis secondary to SLE. METHODS We recruited 18 consecutive SLE patients (tacrolimus group) with recently confirmed biopsy-proven class V lupus nephritis. They were treated with a tailing dose of oral prednisolone and tacrolimus 0.1-0.2 mg/kg/day for 6 months, followed by maintenance prednisolone and AZA. The rate of resolution of proteinuria and SLEDAI were compared with 19 historical controls treated with oral cyclophosphamide or AZA (control group). All patients were followed for 12 months. RESULTS Baseline clinical characteristics were comparable between the groups. For the tacrolimus group, the complete and partial remission rates were 27.8 and 50.0%, respectively at 12 weeks; for the control group, they were 15.8 and 47.4%, respectively (overall chi-square test, P = 0.5). However, tacrolimus group had faster resolution of proteinuria than the control group by the general linear model with repeated measures (P = 0.032). At 12 weeks, proteinuria was reduced by 76.2 +/- 17.0% for the tacrolimus group and 47.1 +/- 51.1% for the control group (P = 0.028). Serial change in renal function and SLEDAI score did not differ between the groups. During the study period, four patients of the tacrolimus group, and 11 of the control group, developed lupus flare (P = 0.027). There was no serious adverse effect in the tacrolimus group. CONCLUSIONS A 6-month course of tacrolimus is a safe and effective treatment of pure class V (membranous) lupus nephritis. As compared with conventional cytotoxic treatment, tacrolimus possibly results in a faster resolution of proteinuria, and a lower risk of lupus flare within 1 yr. The long-term effect and optimal regimen of tacrolimus require further study.

Double-blind, randomized, placebo-controlled pilot study of leflunomide in systemic lupus erythematosus

Twelve systemic lupus erythematosus (SLE) patients with mild to moderate disease activity (SLEDAI of ≥6 and on prednisolone, 0.5 mg/kg/day) were included in a prospective, randomized, double-blind, placebo-controlled pilot study for 24 weeks. Six were randomized to receive oral leflunomide and six received placebo. Primary outcome of this study included the mean change of SLEDAI at 24 weeks. Secondary outcomes included the changes in proteinuria, complement levels, anti ds-DNA binding, and prednisolone dosage. The mean age of the 12 patients was 41 + 9 years, and the mean disease duration was 8.5 + 5.8 years. All were female except one patient. The disease activity of both groups of patients decreased significantly after six months of treatment (14.7 + 6.0 to 3.7 + 2.3 in leflunomide group, P 1/4 0.028, and 9.7 + 3.4 to 5.2 + 4.1 in placebo group, P 1/4 0.027). Reduction in the SLEDAI from baseline to 24 weeks was significantly greater in the leflunomide group than the placebo group (11.0 + 6.1 in the leflunomide group and 4.5 + 2.4 in the placebo group respectively, P 1/4 0.026). Minor adverse events included transient elevation in ALT, hypertension and transient leucopenia. In summary, leflunomide was more effective than placebo in treating SLE patients with mild to moderate disease activity and was safe and well-tolerated.

Elevated production of interleukin-18 is associated with renal disease in patients with systemic lupus erythematosus

Summary To investigate the production mechanism and proinflammatory role of the cytokine interleukin (IL‐18) in lupus nephritis, we investigated the plasma concentrations of IL‐18 and nitric oxide (NO) and the release of IL‐18 and NO from mitogen‐activated peripheral blood monomuclear cells (PBMC), in 35 SLE patients with renal disease (RSLE), 37 patients without renal disease (SLE) and 28 sex‐ and age‐matched healthy control subjects (NC). IL‐18 and NO concentrations were measured by ELISA and colourimetric non‐enzymatic assay, respectively. Gene expressions of IL‐18 and IL‐18 receptor were analysed by RT‐PCR. Plasma IL‐18 and NO concentrations were significantly higher in RSLE than NC (both P < 0·01). Elevation of plasma IL‐18 in RSLE correlated positively and significantly with SLE disease activity index and plasma NO concentration (r = 0·623, P < 0·0001 and r = 0·455, P = 0·017, respectively), and the latter also showed a positive and significant correlation with plasma creatinine (r = 0·410, P = 0·034) and urea (r = 0·685, P < 0·0001). There was no significant difference in gene expressions of IL‐18 and IL‐18 receptor in PBMC among RSLE, SLE and NC. Percentage increase in culture supernatant IL‐18 concentration was significantly higher in RSLE than SLE and NC (both P < 0·05). The basal NO release was significantly higher in RSLE than that in SLE and NC (both P < 0·005). IL‐18 is therefore suggested to play a crucial role in the inflammatory processes of renal disease in SLE.

Predictors of maternal and fetal outcomes in pregnancies of patients with systemic lupus erythematosus.

Disease activity 6 months before pregnancy of patients with systemic lupus erythematosus (SLE) associated with adverse maternal and fetal outcomes is not well studied. The aim of the study was to identify predictors of adverse maternal and fetal outcomes in pregnant SLE patients, based on patients’ background characteristics, clinical and laboratory data 6 months before pregnancy. Of 103 pregnancies, 55 pregnancies in 39 SLE patients were investigated. Clinical and laboratory data were recorded at regular intervals from 6 months before conception to 1 year after delivery. Primary outcomes included the predictors of combined adverse maternal and fetal outcomes. Potential explanatory variables included demographic, clinical and laboratory data 6 months before conception. Using logistic regression, history of nephritis (p = 0.001, odds ratio [OR] 13.3, 95% confidence interval [CI] 2.7–65.1) and a high SLE Disease Activity Index (SLEDAI) score 6 months before pregnancy (p = 0.015, OR 1.7, 95% CI 1.1–2.7) were associated with combined adverse maternal outcome, whereas flare during pregnancy (p = 0.003, OR 29.3, 95% CI 3.1–273.1) predicted combined adverse fetal outcome. The area under the curve for SLEDAI score of combined maternal outcome was 0.73 (95% CI 0.58–0.87). The optimal cut-off point according to the receiver operating characteristic curve was 4, with a sensitivity of 64% and a specificity of 75%. In conclusion, a history of nephritis or a SLEDAI score of 4 or more in SLE patients 6 months before conception predicts adverse maternal outcomes, while disease flare during pregnancy predicts adverse fetal outcomes. Pregnancies should be delayed until the disease has been in remission for 6 months.

Activation profile of Toll-like receptors of peripheral blood lymphocytes in patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease associated with aberrant activation of T and B lymphocytes for the production of inflammatory cytokines and autoreactive antibodies. Animal studies of SLE have indicated that Toll‐like receptors (TLR) are important in the pathogenesis of murine lupus. In the present clinical study, differential protein expressions of TLR‐1–9 of monocytes and different lymphocyte subsets from patients with SLE and normal control subjects were determined by flow cytometry. Results showed that the expression of intracellular TLRs (TLR‐3, ‐8, ‐9) and extracellular TLRs (TLR‐1, ‐2, ‐4, ‐5, ‐6) were elevated in monocytes, CD4+ T lymphocytes, CD8+ T lymphocytes and B lymphocytes of SLE patients compared to control subjects (all P < 0·001). Moreover, cell surface expression of TLR‐4 on CD4+ T lymphocytes and CD8+ T lymphocytes, and TLR‐6 on B lymphocytes, were correlated positively with SLE disease activity index (SLEDAI) (TLR‐4 on CD4+ T lymphocytes and CD8+ T lymphocytes: r = 0·536, P = 0·04; r = 0·713, P = 0·003; TLR‐6 in B lymphocytes: r = 0·572, P = 0·026). In concordance with the above results, there is an observable increased relative induction (%) of inflammatory cytokine interleukin (IL)‐1β, IL‐6, IL‐10 and IL‐12, chemokines CCL2, CXCL8, CCL5 and CXCL10 from peripheral blood mononuclear cells (PBMC) upon differential stimulation by PolyIC (TLR‐3 ligand), lipopolysaccharide (TLR‐4 ligand), peptidoglycan (TLR‐2 ligand), flagellin (TLR‐5 ligand), R837 (TLR‐7 ligand) and CpG DNA (TLR‐9 ligand) in SLE patients compared to controls. These results suggest that the innate immune response for extracellular pathogens and self‐originated DNA plays immunopathological roles via TLR activation in SLE.

Increased arterial stiffness correlated with disease activity in systemic lupus erythematosus

To evaluate the relationships between arterial stiffness, disease activity and end-organ damage in systemic lupus erythematosus (SLE), non-invasive vascular assessments were made on 32 female SLE patients and 32 female normal controls. The patients had significantly increased brachial-ankle pulse wave velocity (PWV) (13.06 ± 1.79 vs. 11.50 ± 1.00 m/s; P < 0.001), heart-ankle PWV (8.98 ± 1.16 vs. 7.88 ± 0.73 m/s; P < 0.001), carotid augmentation index (AI) (21.6 ± 17.2% vs. 5.4 ± 14.0%; P = 0.001) and carotid intima-medial thickness (IMT) (0.753 ± 0.132 vs. 0.644 ± 0.092 mm; P = 0.002) when compared with controls. The disease activity and organ damage were evaluated by SLE disease activity index (SLEDAI) and systemic lupus international collaborating clinics (SLICC) damage index. Patients with active disease (SLEDAI ≥ 3) had significantly higher carotid AI (34.4 ± 9.7% vs. 17.8 ± 17.3%, P < 0.05) than stable ones (SLEDAI < 3) and those with organ damage (SLICC ≥ 1) had significantly higher heart-ankle PWV (9.69 ± 1.13 vs. 8.61 ± 1.02 m/s, P < 0.05) than those with SLICC = 0. After making adjustments for age, body mass index (BMI) and blood pressure, carotid AI was found to show correlation with SLEDAI and haPWV with SLICC. A carotid AI value of 33.3% identified SLEDAI ≥ 3 with a sensitivity of 83% and a specificity of 80%, whereas a heart-ankle PWV value of 9.0 m/s identified SLICC ≥ 1 with a sensitivity of 91% and a specificity of 67%. In conclusion, SLE was an independent risk factor of sub-clinical atherosclerosis and arterial stiffness may identify the presence of active disease.

Short-term efficacy of combination methotrexate and infliximab in patients with ankylosing spondylitis: a clinical and magnetic resonance imaging correlation

OBJECTIVE To examine the short-term efficacy and safety of MTX in combination with infliximab compared with infliximab and placebo in the treatment of AS using MRI to monitor its effect. METHOD Thirty-eight subjects with active AS were randomized to receive MTX (MTX group) or placebo (placebo group) for 22 weeks. Both groups received infliximab for three infusions of 5 mg/kg at week 16, 18 and 22 and were followed up until week 30. MRI changes in the spine were assessed before and after infusion. RESULTS The Assessments in Ankylosing Spondylitis (ASAS) 20 response at week 16 was 5.4% in the MTX group vs 15.8% in the placebo group (P = 0.17). In the MTX group, 5.4, 31.6, 52.6 and 63.2% of patients vs 15.8, 21.1, 57.9 and 68.4% patients in the placebo group achieved ASAS20 at week 16, 18, 22, 30, respectively. There were no significant differences between the two groups at any time points. Likewise, the secondary outcome showed no significant differences between the two groups. MRI changes in 31 subjects showed an overall improvement of 36.4% but the changes were not significant between the two groups. CONCLUSIONS Combination MTX with infliximab is as safe and as effective as infliximab monotherapy in the treatment of AS with a significant improvement in ASAS20 and in the different core sets in assessment. MRI improvements were also seen. However, there was no additional clinical or MRI improvement with the addition of MTX to infliximab in AS.