Lai-Shan Tam

Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity.

IL-23-dependent IL-17-producing T helper (Th) lymphocytes are associated with autoimmunity. We investigated the immunopathological mechanisms for activation of Th17 cells of patients with systemic lupus erythematosus (SLE). Concentration of cytokines/chemokine in plasma and culture supernatant from SLE patients and healthy controls were measured by ELISA or flow cytometry. Plasma IL-12, IL-17, IL-23 and CXCL10 concentrations and the number of Th17 cells were significantly elevated in SLE patients than control subjects (both p<0.05). Elevated IL-12, IL-17 and CXCL10 concentrations correlated positively and significantly with SLEDAI (all p<0.05). Plasma IL-12 and IL-17 showed significant and positive correlation with plasma Th1 chemokine CXCL10 concentration in SLE patients (all p<0.05). Ex vivo inductions of IL-17 by IL-23 or IL-18 from co-stimulated lymphocytes were significantly higher in SLE patients than controls (all p<0.05). The activated IL-23/IL-17 axis is important for the inflammatory immunity in SLE.

Serum and Urinary Cell–free MiR-146a and MiR-155 in Patients with Systemic Lupus Erythematosus

Objective. Recent studies showed that micro-RNA play important roles in the pathogenesis of autoimmune diseases. We studied the levels of miR-146a and miR-155 in the serum and urinary supernatant of patients with systemic lupus erythematosus (SLE). Methods. The serum and urinary supernatant levels of miR-146a and miR-155 were determined by real-time quantitative polymerase chain reaction in 40 patients with SLE and 30 healthy controls. Results. Compared to controls, serum miR-146a and miR-155 levels were lower, and the urinary level of miR-146a was higher, in SLE. Estimated glomerular filtration rate (eGFR) correlated with both serum miR-146a (r = 0.519, p = 0.001) and miR-155 (r = 0.384, p = 0.014). Serum miR-146a inversely correlated with proteinuria (r = −0.341, p = 0.031) and the SLE Disease Activity Index (r = −0.465, p = 0.003). Serum miR-146a and miR-155 levels also correlated with red blood cell count, platelet count, and lymphocyte count. After treatment with calcitriol for 6 months, serum miR-146a level of SLE patients increased significantly (p < 0.001), and its change inversely correlated with the level of calcium-phosphate product (r = −0.466, p = 0.003). Conclusion. The results suggested that serum miR-146a and miR-155 participate in the pathophysiology of SLE and might be used as biomarkers of SLE.

Pathogenesis of ankylosing spondylitis

Ankylosing spondylitis (AS) is a potentially disabling form of seronegative spondyloarthritis. The main symptom of AS is inflammatory spinal pain; with time, some patients develop ankylosis and spinal immobility. The pathology mainly affects the entheses, where ligaments, tendons and capsules are attached to the bone. Three processes are observed at the entheses: inflammation, bone erosion and syndesmophyte (spur) formation. Tumor necrosis factor is an important mediator of the inflammatory processes, but this proinflammatory cytokine is not closely involved in bone erosion or syndesmophyte formation. The major causative factors of AS are genetic, with the gene encoding HLA-B27 being the most important genetic factor. Several other susceptibility genes have also been identified. An enormous number of papers have been published and many diverse hypotheses have been generated regarding the pathogenesis of AS. This Review outlines the key areas of current research in this field, describes several hypotheses regarding the pathogenesis of AS, which are under intense investigation, and concludes with a dissection of the processes involved in bone erosion and syndesmophyte formation.

ABCG2 Polymorphism Is Associated With the Low‐Density Lipoprotein Cholesterol Response to Rosuvastatin

The ATP‐binding cassette G2 (ABCG2) c.421C>A (rs2231142) polymorphism influences the pharmacokinetics of rosuvastatin. We examined whether this polymorphism influences the low‐density lipoprotein cholesterol (LDL‐C)‐lowering efficacy of the drug. In 305 Chinese patients with hypercholesterolemia who were treated with rosuvastatin at a dosage of 10 mg daily, the c.421A variant was found to be significantly associated with greater reduction in LDL‐C level, in a gene‐dose‐dependent manner. As compared with subjects with the c.421CC genotype, those with the c.421AA genotype showed a 6.9% greater reduction in LDL‐C level, which would be equivalent to the effect obtained by doubling the dose of rosuvastatin.

Leflunomide in the treatment of rheumatoid arthritis

BACKGROUND Current drug therapies for rheumatoid arthritis (RA), including nonsteroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs, help control inflammation but can cause significant toxicity. Drugs are needed that are able to suppress inflammation and modify the underlying immune response with improved tolerability. Leflunomide is an agent that affects the inflammatory process, particularly in RA. OBJECTIVE This paper reviews the pharmacology of leflunomide, its approved use in RA, and the results of major clinical trials, including adverse events. METHODS Relevant trials were identified through a search of the English-language literature indexed on EMBASE, MEDLINE, Current Contents, and the Cochrane Controlled Trials Register from January 1980 to November 2003. Search terms were limited to leflunomide. RESULTS In 3 large Phase III clinical trials (US301, MN301, and MN302), leflunomide had equivalent clinical efficacy and tolerability to methotrexate and sulfasalazine and superior efficacy and tolerability compared with placebo. In US301 (N = 482), the ACR (American College of Rheumatology) 20 response rate (proportion of patients with > or =20% improvement from baseline in tender and swollen joint counts, patients assessment of pain, patients and physicians global assessment of disease activity, physical function, and acute-phase reactant value) at 1 year was similar with leflunomide and methotrexate and significantly greater with both active treatments than with placebo (52%, 46%, and 26%, respectively; both, P < 0.001). The efficacy of leflunomide was seen early (after 4 weeks of treatment) and was sustained throughout the study. There was less radiographic damage in both active-treatment groups compared with placebo (leflunomide, P < or = 0.001; methotrexate, P = 0.02). In MN301 (N = 358), the ACR20 response rate at 6 months was similar with leflunomide and sulfasalazine and significantly greater with both active treatments compared with placebo (55%, 56%, and 29%, respectively; both, P < 0.001). Radiographic progression was also similar with leflunomide and sulfasalazine, both of which were significantly superior to placebo (Larsen score, 0.42, 0.41, and 1.4; both, P < 0.001). An extension of this study revealed maintenance of efficacy at 12 and 24 months. In MN302 (intent-to-treat population, N = 999), 50.5% of patients in the leflunomide group were ACR20 responders at the end of 1 year, compared with 64.8% in the methotrexate group (P < 0.001 vs leflunomide). After 2 years, ACR20 response rates were similar with leflunomide and methotrexate (64.3% and 71.7%). The overall safety profile of leflunomide appears promising, although monitoring for elevations in liver enzymes and bone marrow suppression is recommended. The most common drug-related adverse events associated with leflunomide in these clinical trials were diarrhea, abnormalities in liver enzymes, rash, and hypertension.

The gene expression of type 17 T-helper cell-related cytokines in the urinary sediment of patients with systemic lupus erythematosus

OBJECTIVE We studied the role of type 17 Th cells (TH17) in the pathogenesis of SLE. METHODS We quantified the mRNA expression of IL-17, -23, -27 and retinoic-acid-related orphan receptor (ROR)-gamma, the regulator for the development and function of TH17, in the urinary sediment of 23 subjects with active lupus nephritis, 25 subjects with a history of lupus nephritis in remission, 30 SLE patients with no history of renal involvement and 8 healthy subjects. RESULTS All three groups of lupus patients had a higher urinary expression of TH17-related cytokines than the controls. However, urinary expression of IL-17 and -27 was found to be inversely correlated with the SLEDAI score (r = -0.252 and -0.258, respectively; P < 0.05 for both). For patients with active lupus nephritis, the histological activity index of kidney biopsy was also found to be inversely correlated with the urinary expression of ROR-gamma (r = -0.447; P = 0.032), IL-17 (r = -0.454; P = 0.029) and IL-23 (r = -0.455; P = 0.029). Urinary expression of IL-17, -23, -27 and ROR was also found to be inversely correlated with the urinary expression of IFN-gamma and T-bet, the key transcription factor of type 1 Th cells. After 6 months of treatment, urinary IL-27 expression rose significantly in patients with complete response (from 2.07 +/- 1.62 to 3.70 +/- 1.69; P = 0.028) but remained unchanged in those with partial or no response (from 2.60 +/- 1.87 to 2.52 +/- 1.94; P = 0.9). CONCLUSIONS The urinary expression of TH17-related genes is increased in SLE patients. The degree of up-regulation, however, is inversely related to systemic and renal lupus activity, as well as urinary expression of TH1-related genes. Urinary expression of TH17-related genes increased again after successful immunosuppressive treatment of active disease. Our findings suggest a regulatory role of TH17-related cytokines in pathogenesis of lupus nephritis.

Intrarenal cytokine gene expression in lupus nephritis

Background: Lupus nephritis is characterised by intrarenal inflammation and lymphocyte activation. Aim: To examine the profile of cytokine gene expression in glomerulus and tubulointerstitium in patients with lupus nephritis. Methods: 36 consecutive patients with systemic lupus erythematosus having active renal disease were recruited, and they were required to undergo kidney biopsy. Glomerular and tubulointestitial cytokine expression of interleukin (IL)2, 4, 10, 12, 18, interferon γ (IFN)γ, T-bet (the Th1 transcription factor), GATA-3 (the Th2 transcription factor), transforming growth factorβ and monocyte chemoattractant protein (MCP)1 were studied by laser microdissection of the renal biopsy specimen, followed by real-time quantitative PCR. Results: There were 13 patients with World Health Organization class III nephritis, 14 patients with class IV nephritis and 9 patients with class V nephritis. There was a significant correlation between serum C3, C4 and anti-double strand DNA antibody level with glomerular expression of T-bet, IFNγ and IL2. There was a significant correlation between histological activity index and glomerular expression of IL12, IL18, IL10 and MCP1. In addition, the degree of glomerular leucocyte infiltration significantly correlated with glomerular expression of IFNγ, IL10, IL12 and IL18. By contrast, histological chronicity index correlated with the tubulointerstitial expression of IL2, MCP1 and GATA-3. Conclusions: Intraglomerular expression of certain target genes correlate with the severity of systemic as well as histological activity, whereas the tubulointerstitial expression of other target genes correlate with the degree of chronic kidney scarring. This result may shed light on the immunopathogenesis of lupus nephritis.

Glomerular and tubulointerstitial miR-638, miR-198 and miR-146a expression in lupus nephritis.

Aim:  MicroRNAs (miRNAs) play important roles in the pathogenesis of autoimmune diseases. We studied the intra‐renal expression of miRNA targets that were reported to be differentially expressed in peripheral blood or urine between lupus nephritis (LN) patients and normal controls.

Cost‐of‐illness studies in systemic lupus erythematosus: A systematic review

To summarize the state of knowledge regarding the economic burden of systemic lupus erythematosus (SLE) and to evaluate the quality of cost‐of‐illness (COI) studies conducted to date.

The impact of flare on disease costs of patients with systemic lupus erythematosus

OBJECTIVE To evaluate both direct and indirect costs of systemic lupus erythematosus (SLE) patients with and without flares from a societal perspective, and to investigate the impact of the severity and clinical manifestations of flares on direct/indirect costs. METHODS A retrospective cost-of-illness study was performed on 306 SLE patients. Participants completed questionnaires on sociodemographics, employment status, and out-of-pocket expenses. Health resources consumption was recorded by chart review and patient self-reported questionnaire. The total number of flares and involved organs during the preceding 12 months were recorded. Multiple linear regression was performed to determine the cost predictors. RESULTS Patients with flares were younger, had shorter disease duration, and had higher disease activity at the time of the assessment. The overall incidence of lupus flares was 0.24 episodes per patient-year. Patients with flares used more health care resources and incurred significantly higher annual direct and indirect costs. The mean total costs per patient-year were 2-fold higher for patients with flares (