Edmund K. Li

Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial

BACKGROUND Systemic lupus erythematosus is a heterogeneous autoimmune disease that is associated with B-cell hyperactivity, autoantibodies, and increased concentrations of B-lymphocyte stimulator (BLyS). The efficacy and safety of the fully human monoclonal antibody belimumab (BLyS-specific inhibitor) was assessed in patients with active systemic lupus erythematosus. METHODS Patients (aged ≥18 years) who were seropositive with scores of at least 6 on the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) were enrolled in a multicentre phase 3 study, which was done in Latin America, Asia-Pacific, and eastern Europe. Patients were randomly assigned by use of a central interactive voice response system in a 1:1:1 ratio to belimumab 1 mg/kg or 10 mg/kg, or placebo by intravenous infusion in 1 h on days 0, 14, and 28, and then every 28 days until 48 weeks, with standard of care. Patients, investigators, study coordinators, and sponsors were masked to treatment assignment. Primary efficacy endpoint was improvement in the Systemic Lupus Erythematosus Responder Index (SRI) at week 52 (reduction ≥4 points in SELENA-SLEDAI score; no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new B organ domain score; and no worsening [<0·3 increase] in Physicians Global Assessment [PGA] score) versus baseline. Method of analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00424476. FINDINGS 867 patients were randomly assigned to belimumab 1 mg/kg (n=289) or 10 mg/kg (n=290), or placebo (n=288). 865 were treated and analysed in the belimumab (1 mg/kg, n=288; 10 mg/kg, n=290) and placebo groups (n=287). Significantly higher SRI rates were noted with belimumab 1 mg/kg (148 [51%], odds ratio 1·55 [95% CI 1·10-2·19]; p=0·0129) and 10 mg/kg (167 [58%], 1·83 [1·30-2·59]; p=0·0006) than with placebo (125 [44%]) at week 52. More patients had their SELENA-SLEDAI score reduced by at least 4 points during 52 weeks with belimumab 1 mg/kg (153 [53%], 1·51 [1·07-2·14]; p=0·0189) and 10 mg/kg (169 [58%], 1·71 [1·21-2·41]; p=0·0024) than with placebo (132 [46%]). More patients given belimumab 1 mg/kg (226 [78%], 1·38 [0·93-2·04]; p=0·1064) and 10 mg/kg (236 [81%], 1·62 [1·09-2·42]; p=0·0181) had no new BILAG A or no more than 1 new B flare than did those in the placebo group (210 [73%]). No worsening in PGA score was noted in more patients with belimumab 1 mg/kg (227 [79%], 1·68 [1·15-2·47]; p=0·0078) and 10 mg/kg (231 [80%], 1·74 [1·18-2·55]; p=0·0048) than with placebo (199 [69%]). Rates of adverse events were similar in the groups given belimumab 1 mg/kg and 10 mg/kg, and placebo: serious infection was reported in 22 (8%), 13 (4%), and 17 (6%) patients, respectively, and severe or serious hypersensitivity reactions on an infusion day were reported in two (<1%), two (<1%), and no patients, respectively. No malignant diseases were reported. INTERPRETATION Belimumab has the potential to be the first targeted biological treatment that is approved specifically for systemic lupus erythematosus, providing a new option for the management of this important prototypic autoimmune disease. FUNDING Human Genome Sciences and GlaxoSmithKline.

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.

Randomised trial of eradication of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers

BACKGROUND Helicobacter pylori infection is common in patients with peptic ulcers caused by the use of non-steroidal anti-inflammatory drugs (NSAIDs). But the pathogenic role of H pylori in this disease is controversial. We studied the efficacy of eradication of H pylori in the prevention of NSAID-induced peptic ulcers. METHODS We recruited patients with musculoskeletal pain who required NSAID treatment. None of the patients had previous exposure to NSAID therapy. Patients who had H pylori infection but no pre-existing ulcers on endoscopy were randomly allocated naproxen alone (750 mg daily) for 8 weeks or a 1-week course of triple therapy (bismuth subcitrate 120 mg, tetracycline 500 mg, metronidazole 400 mg, each given orally four times daily) before administration of naproxen (750 mg daily). Endoscopy was repeated after 8 weeks of naproxen treatment or when naproxen treatment was stopped early because of bleeding or intractable dyspepsia. All endoscopic examinations were done by one endoscopist who was unaware of treatment assignment. The primary endpoint was the cumulative rate of gastric and duodenal ulcers. FINDINGS 202 patients underwent endoscopic screening for enrolment in the trial, and 100 eligible patients were randomly assigned treatment. 92 patients completed the trial (47 in the naproxen group, 45 in the triple-therapy group). At 8 weeks, H pylori had been eradicated from no patients in the naproxen group and 40 (89%) in the triple-therapy group (p < 0.001). 12 (26%) naproxen-group patients developed ulcers: five had ulcer pain and one developed ulcer bleeding. Only three (7%) patients on triple therapy had ulcers, and two of these patients had failure of H pylori eradication (p = 0.01). Thus, 12 (26%) patients with persistent H pylori infection but only one (3%) with successful H pylori eradication developed ulcers with naproxen (p = 0.002). INTERPRETATION Eradication of H pylori before NSAID therapy reduces the occurrence of NSAID-induced peptic ulcers.

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.

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.

Cardiac involvement in systemic lupus erythematosus detected by echocardiography

Cardiac involvement in patients with systemic lupus erythematosus (SLE) was assessed by full echocardiography and continuous wave Doppler in 50 consecutive patients and 50 age- and sex-matched control subjects in a prospective, blinded study. The left ventricular ejection fraction was decreased in patients compared to control subjects (61 +/- 9 vs 68 +/- 7%, p less than 0.001), whereas interventricular septum (12 +/- 3 vs 9 +/- 1 mm, p less than 0.001), and posterior wall dimension (9 +/- 2 vs 8 +/- 1 mm, p less than 0.001), left ventricular mass (186 +/- 54 vs 130 +/- 32 g, p less than 0.001) and mitral valve Doppler A:E ratio (0.8 +/- 0.2 vs 0.7 +/- 0.1, p less than 0.01) were increased. Pericardial effusion was detected in 27 patients and 5 control subjects, and valvular regurgitation was more frequent in the patients (aortic 2 vs 0; mitral 23 vs 5, p less than 0.001; tricuspid 34 vs 22, p less than 0.01 and pulmonary 28 vs 17, p less than 0.05). Mitral or aortic regurgitation was more common in patients with active SLE (60 vs 40%, difference not significant) but was not related to the duration of SLE (r = 0.02), duration of prednisone therapy (r = -0.13) or current dosage of prednisone (r = 0.01). This study demonstrates that pericardial effusion, valvular regurgitation and myocardial abnormalities are frequently present in patients with SLE.

Elevated Production of B Cell Chemokine CXCL13 is Correlated with Systemic Lupus Erythematosus Disease Activity

IntroductionB lymphocyte chemoattractant (BLC/CXCL13), a CXC chemokine, is involved in B1 and B2 cell trafficking for the activation of autoreactive T helper (Th) cells and autoantibody production in target organs during the development of lupus. CXCL13 can induce the trafficking of CXCR5+ T lymphocyte subset designated as follicular helper T lymphocytes (TFH) which are specifically involved in autoantibody production.Materials and MethodsWe herein measured the plasma concentrations of CXCL13, B-cell-activating factor of the TNF family (BAFF), and TFH-cells-related cytokine IL-21 and cell surface expression of TFH-related receptor CXCR5 and IL-21R on CD4+Th and CD19+B cells in 35 systemic lupus erythematosus (SLE) patients and 23 sex- and age-matched control subjects (NC) using enzyme-linked immunosorbent assay and flow cytometry, respectively.Results and DiscussionPlasma CXCL13, BAFF, and IL-21 concentrations were significantly higher in SLE patients than NC group (all p < 0.0001). Increase in CXCL13 concentration correlated positively and significantly with SLEDAI score in SLE patients (r = 0.399, p = 0.032). Cell surface expression of CXCR5 on Th and B cells and IL-21R on B cells was however significantly lower in SLE patients than controls (both p < 0.01). It may indicate that most differentiated TFH cells migrate out from circulation into lymphoid organ upon activation during the disease development of SLE.ConclusionsThe above results suggest that the elevated production of CXCL13, BAFF, and IL-21 may be associated with the function of TFH for the immunopathogenesis in SLE, and CXCL13 may serve as a potential disease marker of SLE.

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.