Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade.

Systemic onset juvenile idiopathic arthritis (SoJIA) encompasses approximately 10% of cases of arthritis that begin in childhood. The disease is unique in terms of clinical manifestations, severity of joint involvement, and lack of response to tumor necrosis factor blockade. Here, we show that serum from SoJIA patients induces the transcription of innate immunity genes, including interleukin (IL)-1 in healthy peripheral blood mononuclear cells (PBMCs). Upon activation, SoJIA PBMCs release large amounts of IL-1beta. We administered recombinant IL-1 receptor antagonist to nine SoJIA patients who were refractory to other therapies. Complete remission was obtained in seven out of nine patients and a partial response was obtained in the other two patients. We conclude that IL-1 is a major mediator of the inflammatory cascade that underlies SoJIA and that this cytokine represents a target for therapy in this disease.

Update on pediatric systemic lupus erythematosus.

PURPOSE OF REVIEW: The purpose of this review is to provide an update on the clinical manifestations of SLE in children. Emerging clues on the pathogenesis of the disease based on recent human studies conducted both in children and adults, will also be summarized. RECENT FINDINGS: Pediatric Rheumatologists caring for children with SLE face many challenges. As the life expectancy of these patients improves, new recognized complications such as accelerated atherosclerosis and hypertension emerge as major causes of morbidity. However, few longitudinal studies describing the long term outcome of these children, including the impact of disease and treatment on their physical and psychological development are available. Few prospective interventional studies have been carried out to assess the efficacy of established and novel treatments in the pediatric population. Recently, basic studies aimed at understanding the immune alterations underlying this disease have been performed in children. These studies indicate an important role for interferon-alpha (IFN-alpha) in the pathogenesis of this disease and reveal an overall striking homogeneity of leukocyte gene expression profiles in children and adults with SLE. The contribution of novel gene polymorphisms to disease susceptibility and the sequential breakdown of tolerance to nuclear antigens that precedes clinical manifestations in patients with SLE are among the recent studies that are helping us understand the complex SLE puzzle. SUMMARY: SLE continues to cause significant morbidity in the pediatric age group. A better recognition of the age-specific manifestations and long-term complications of this disease is required to improve its outcome. Understanding its unique pathogenesis will hopefully lead to the development of better, more targeted and less toxic therapies.

Interferon and granulopoiesis signatures in systemic lupus erythematosus blood.

Systemic lupus erythematosus (SLE) is a prototype systemic autoimmune disease characterized by flares of high morbidity. Using oligonucleotide microarrays, we now show that active SLE can be distinguished by a remarkably homogeneous gene expression pattern with overexpression of granulopoiesis-related and interferon (IFN)-induced genes. Using the most stringent statistical analysis (Bonferroni correction), 15 genes were found highly up-regulated in SLE patients, 14 of which are targets of IFN and one, defensin DEFA-3, a major product of immature granulocytes. A more liberal correction (Benjamini and Hochberg correction) yielded 18 additional genes, 12 of which are IFN-regulated and 4 granulocyte-specific. Indeed immature neutrophils were identified in a large fraction of SLE patients white blood cells. High dose glucocorticoids, a standard treatment of disease flares, shuts down the interferon signature, further supporting the role of this cytokine in SLE. The expression of 10 genes correlated with disease activity according to the SLEDAI. The most striking correlation (P < 0.001, r = 0.55) was found with the formyl peptide receptor-like 1 protein that mediates chemotactic activities of defensins. Therefore, while the IFN signature confirms the central role of this cytokine in SLE, microarray analysis of blood cells reveals that immature granulocytes may be involved in SLE pathogenesis.

Blood dendritic cells and DC-poietins in systemic lupus erythematosus.

Dendritic cells (DCs) control immunity and tolerance. Hence, we surmised that systemic lupus erythematosus (SLE), a systemic autoimmune disease with autoreactive T and B cells, might be due to alterations in DC homeostasis. Taken together, our results demonstrate profound alterations of DCs and DC-poietins homeostasis in SLE. Elevated levels of interferon-alpha (IFN) in serum of SLE patients coexist with decreased numbers of cells producing IFN-alpha, i.e., plasmacytoid dendritic cells (PDCs). Decreased numbers of circulating DCs correlate with increased levels of soluble tumor necrosis factor (TNF) receptors, thus suggesting the potential role of TNF pathway in the observed DC alterations. Finally, increased FMS-like tyrosine kinase 3-ligand (FLT3-L) and its correlation with soluble TNF receptors suggest a physiologic response to compensate low DC numbers. Although IFN-alpha remains at the center of immunologic aberrations in SLE, it remains to be determined whether increased shedding of soluble TNF receptors could also be ascribed to IFN-alpha.