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Juvenile idiopathic arthritis (JIA) is a systemic inflammatory disease of childhood onset. The purpose of this study was to clarify the frequency of adverse events caused by drugs used in JIA treatment and characterize their safety profiles using a spontaneous reporting system database. We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports on drugs used for the treatment of JIA and which were submitted to the Pharmaceuticals and Medical Devices Agency were analyzed, and the reporting odds ratio (ROR) and 95% confidence interval (CI) for reports on each adverse event were calculated. A total of 5,748 reports were identified in the treatment of JIA, in which 35 different drugs were involved. Adverse events by drugs in JIA were frequently reported in females (64.3%) and in those younger than 10 (61.2%). Among the most frequently reported drugs, prednisolone (36.8%) and tocilizumab (36.0%) were predominant. Prednisolone was significantly correlated with hematophagic histiocytosis (ROR, 1.37; 95% CI, 1.18 - 1.61). Tocilizumab was associated with a high ROR for pneumonia (ROR, 8.61: 95% CI, 5.81 - 12.7), a decreased neutrophil count (ROR, 6.1; 95% CI, 4.07 - 9.16), and lymphadenitis (ROR, 8.34; 95% CI, 4.2 - 16.6). Our results revealed the safety profile of drugs for the treatment of JIA patients. It was suggested that there is a diversity in drugs and their strength of association with adverse events in JIA patients. Our results may provide useful information for the treatment of JIA patients, although further research with more data is needed.

Promoters of Drosophila melanogaster genes related to DNA replication, such as those for the 180-kDa catalytic subunit of DNA polymerase α and proliferating cell nuclear antigen (PCNA), contain a common 8-bp palindromic sequence (5′-TATCGATA-3′), named the DNA replication-related element (DRE) (12). These DREs are required for promoter activities both in cultured cells and in flies in vivo (41). We have purified the DRE-binding factor (DREF) from cultured Drosophila cells, consisting of an 86-kDa polypeptide homodimer specifically binding to DRE, and isolated a cDNA (12, 13). The importance of Drosophila DREF in development has been demonstrated from studies using transgenic flies (11, 14, 44). For example, ectopic expression of Drosophila DREF in eye imaginal disc cells behind the morphogenetic furrow, which are normally postmitotic, induced ectopic DNA synthesis and apoptosis and abolished photoreceptor specifications (11). More recently, we and Hyun et al. have succeeded in knocking down Drosophila DREF expression in various tissues (16, 45). Decreased levels of DREF in developing wing and eye imaginal discs were associated with reduction in wing size with smaller cells and drastically aberrant small and rough eyes, respectively. These lines of evidence indicate that the Drosophila DRE/DREF system performs important roles in regulation of cell growth as well as cell proliferation during development. How many and what kind of genes other than those described above are under control of the Drosophila DRE/DREF system? Immunostaining of polytene chromosomes of salivary glands revealed that Drosophila DREF binds to hundreds of loci (8, 10), and recent computational analysis of core promoters in the Drosophila genome showed DRE to be the second most frequent motif apparent in core promoter sequences from −60 to +40, with a frequency higher than those for the TATA box and initiator sequences (4, 24). Already, we and others have demonstrated that the Drosophila DRE/DREF system regulates a number of Drosophila genes involved in DNA replication as well as those involved in cell cycle progression through S (dE2F1) (33) and G2/M (D-raf, D-myb, and cyclin A) phases (25, 29, 34). Despite much progress in understanding the Drosophila DRE/DREF system, little is known about the corresponding mammalian DRE/DREF system. We have identified a human homologue of DREF (hDREF) and a binding consensus sequence [hDRE; 5′-TGTCG(C/T)GA(C/T)A-3′] (26). Our previous study showed that the expression level of hDREF is elevated during the G1-to-S transition and reaches a maximum at S phase in normal human fibroblasts. Moreover, RNA interference experiments targeting hDREF pointed to an important role in cell cycle progression. We also demonstrated that the histone H1 gene carrying an hDRE is regulated by hDREF (26). However, other functions and target genes of hDREF remain to be clarified. The ribosome is a vital organelle which is responsible for protein synthesis in all living organisms. Production of mature ribosomes consisting of rRNAs and ribosomal proteins (RPs) requires a highly coordinated multistep process, and many reports have shown that the initiation of rRNA transcription is tightly linked to cell cycle progression, with synthesis of rRNA increasing during G1 phase, becoming maximal in S and G2 phases, and being repressed during mitosis (7, 20, 22). Similarly, coordinated synthesis of all RP genes during the cell cycle, leading to the precise and equimolar production of the 79 RPs necessary for ribosome biogenesis and translation control, is required to support adequate protein synthesis (37). Despite the obvious importance of RP gene expression for cell proliferation, only a limited number of experimental studies of mammalian RP gene promoter structures and transcriptional regulation have been performed so far. Recent determination of a complete map and nucleotide sequences now allows searches for regulatory elements common to a number of human RP genes, and Perry has identified “box A” [5′-TCTCGCGA(G/T)-3′] as one of the most conserved sequences in RP gene promoters (28). In this report, we document evidence that hDREF is a transcription factor essential for cell proliferation which binds to box A and positively regulates a set of human RP genes. We also show that mammalian RP gene expression is induced during late G1 and S phases and that fluctuation of hDREF expression during the cell cycle is in line with cell cycle-dependent expression of RP genes.