Isolation and expression profiling of genes upregulated in the peripheral blood cells of systemic lupus erythematosus patients.

We have identified the genes whose expressions are augmented in the blood cells of the patients with systemic lupus erythematosus (SLE) using the 'stepwise subtraction' technique along with microarray analysis. The expression levels of these genes were assessed by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) in 31 SLE patients and 30 healthy controls. We found that the transcription levels of following eight genes were significantly increased in SLE patients; interferon (IFN)-alpha-inducible protein 27 (IFI27), IFN-alpha-inducible protein IFI-15K (G1P2), IFN stimulated gene 20 kDa (ISG20), epithelial stromal interaction 1 (EPSTI1), defensin-alpha (DEFA3), amphiregulin (AREG) and two genes of unknown function (BLAST accession nos AL050290 and AY358224 = SLED1). In comparison with idiopathic thrombocytopenic purpura (ITP), an organ-specific autoimmune disease, IFI27, G1P2 and SLED1 were preferentially upregulated in SLE. In contrast, AREG and AL050290 were more highly expressed in ITP than in SLE. We correlated changes in gene expression and clinical/laboratory features of SLE and found that expression of ISG20, EPSTI1 and SLED1 are significantly correlated with lymphocyte counts. Genes linked to IFN are well known to influence SLE, but several other novel genes unrelated to IFN signaling we report here would be useful to understand the pathophysiology of SLE.

Toxicity, pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-interleukin 6 receptor antibody MRA in rheumatoid arthritis. Phase I/II clinical study.

OBJECTIVE: To evaluate the safety and pharmacokinetics of multiple infusions of a humanized anti-interleukin-6 (IL-6) receptor antibody, MRA, in patients with rheumatoid arthritis (RA). METHODS: In an open label trial, 15 patients with active RA were intravenously administered 3 doses (2, 4, or 8 mg/kg) of MRA biweekly for 6 weeks, and pharmacokinetics were assessed. Patients continued on MRA treatment for 24 weeks, and were then assessed for safety and efficacy. RESULTS: The treatment was well tolerated at all doses with no severe adverse event. Increased total serum cholesterol was detected as an MRA related reaction in 10/15 (66%) patients. There was no statistically significant difference in the frequency of adverse events among the 3 dose groups. There were no new observations of antinuclear antibody or anti-DNA antibody, and no anti-MRA antibody was detected. The T1/2 increased with repeated doses and as the dose increased. T1/2 after the 3rd dose of 8 mg/kg reached 241.8 +/- 71.4 h. In 12/15 (80%) patients whose serum MRA was detectable during the treatment period, objective inflammatory indicators such as C-reactive protein, erythrocyte sedimentation rate, and serum amyloid A were completely normalized at 6 weeks, although there was no statistically significant difference in efficacy among the 3 dose groups. Nine of 15 patients achieved ACR 20 at 6 weeks. At 24 weeks, 13 patients achieved ACR 20 and 5 achieved ACR 50. CONCLUSION: Repetitive treatment with MRA was safe and normalized acute phase response in patients with RA. Optimal dosing schedule was not defined in this small study, but maintenance of serum MRA concentration seemed important to achieve efficacy.