Interleukin (IL)-10, IL-1ra and IL-12 profiles in active and quiescent systemic lupus erythematosus: could longitudinal studies reveal patient subgroups of differing pathology?

Several cytokines have been implicated individually in the pathogenesis of systemic lupus erythematosus (SLE) and some, including interleukin (IL)-10, IL-12 and IL-1ra are raised during flares of disease activity. Few studies have been directed at examining the interactions between these cytokines and how their combined profile relates to disease activity. We have examined serum levels of IL-10, IL-12 and IL-1ra in a cohort of SLE patients obtained from the Queen Elizabeth Hospital, Birmingham in cross-sectional and, in a smaller group, longitudinal analyses. In the cross-sectional study, there were significant correlations between levels of the three cytokines. There were also significant correlations between levels of each cytokine and measures of disease activity. IL-10 levels correlated with ESR, anti-dsDNA antibody titres and C3D, IL-12 levels with anti-dsDNA antibody titres and IL-1ra levels with ESR, anti-dsDNA antibody titres and C3D. IL-1ra levels also correlated with CRP. Circulating IL-10 and IL-1ra levels were higher in patients with SLE than in normal controls, although in this study group they did not reach significance. Circulating IL-12 levels were, however, significantly higher in SLE compared to controls. This was true both in patients with active disease and those sampled during a quiescent phase. These data add to the evidence that cytokines such as IL-10, IL-12 and IL-1ra are important in SLE pathogenesis. In a retrospective study of serial serum samples from seven patients, we found two patients whose cytokine profile was very different from the rest of the group. In most patients normalized IL-10, IL-12 and IL-1ra levels mirrored BILAG scores closely, but in these two patients, IL-10, IL-12 and IL-1ra levels did not fluctuate with disease activity. It is possible that there is a subgroup of SLE patients whose cytokine profile could be an important indicator of their pathology. In order to confirm this and determine the frequency of such patients this study needs to be repeated with a much larger subject group. The coexistence of patient groups with different patterns of cytokine activity might explain conflicting reports of associations of levels of particular cytokines with SLE. As the observed differences could reflect different aetiologies of SLE, this information could reveal valuable endophenotypes for genetic and functional studies of SLE and might, ultimately, inform therapeutic management.

Stability of serum interleukin-10 levels during the menstrual cycle.

PROBLEM: Menstrual cycle-associated variability in the circulating levels of several cytokines can be a confounding factor in measurements of in vivo cytokine levels in clinical studies. Since pregnancy-associated increases in interleukin-10 (IL-10) levels are well documented, we have investigated the variability in serum levels of IL-10 in healthy women at different stages of the menstrual cycle to ascertain whether this is a problem in comparative studies of circulating IL-10 levels. METHOD OF STUDY: We obtained fifty-four successive serum samples at points in the menstrual cycles of 12 healthy fertile women, precisely timed by measurement of the luteinizing hormone surge, and measured the interleukin-10 levels. RESULTS: Levels of IL-10 in successive serum samples from each woman taken on days LH - 7 (that is seven days prior to LH surge), LH - 4, LH + 1, LH + 7, and LH + 10 showed that IL-10 does not vary in a systematic way during the menstrual cycle. CONCLUSION: These results validate the sampling of women in studies of IL-10 levels in various clinical situations and establish that these levels are not dependent on menstrual cycle dates. They also suggest that menstrual cycle-related changes in IL-1 are not mediated by IL-10. The rise in progesterone in the luteal phase of the menstrual cycle is not mirrored by a rise in the circulating IL-10 level, which implies either that the pregnancy-associated rise is not related to progesterone or that it is only observed at the higher progesterone levels in pregnancy.