Tocilizumab for the Treatment of Rheumatoid Arthritis and Other Systemic Autoimmune Diseases: Current Perspectives and Future Directions

Interleukin (IL)-6 is a cytokine featuring redundancy and pleiotropic activity. While IL-6, when transiently produced, contributes to host defense against acute environmental stress, continuous dysregulated IL-6 production plays a significant pathological role in several systemic autoimmune diseases. In response to the expectation that IL-6 blockade would constitute a novel therapeutic strategy for the treatment of these diseases, tocilizumab, a humanized anti-IL-6 receptor antibody, was developed. Clinical trials have verified the efficacy and the safety of tocilizumab for patients with rheumatoid arthritis, resulting in approval of this innovative biologic for the treatment of rheumatoid arthritis in more than 90 countries worldwide. Pathological analyses of the effect of IL-6 on the development of autoimmune diseases and a considerable number of case reports and pilot studies have also indicated the beneficial effects of this antibody on other systemic autoimmune diseases, including systemic lupus erythematosus, systemic sclerosis, polymyositis, and large-vessel vasculitis

Crystal structure of 7-methoxy-1-{[(E)-2,6-dimethylphenylimino] (phenyl)methyl}-2-naphthol: Clarification of non-covalent bonding interactions on the basis of spatial organization of single molecular structure and the molecular alignments

Crystal structure of the title compound, 7-methoxy-1-{[(E)-2,6-dimethylphenylimino] (phenyl)methyl}-2-naphthol, which has N-aryl group instead of ketonic carbonyl group has been comparatively analysed with the precursor compound of 1-benzoyl-2-hydroxy-7-methoxynaphthalene. The distinct features in the molecular accumulation structures of title triarylimine compound and the precursor diaryl ketone demonstrate that the spatial organization of the former is mainly determined π-π stacking interaction and for the latter the non-classical hydrogen bondings govern the spatial organization. Besides both of the compounds show non-coplanaryl accumulation of aromatic rings molecular structure, the title compound has molecular core of imino group which attaches three aromatic rings of C-1-naphthyl, C-phenyl, and N-phenyl stems of nearly perpendicular alignment of each aryl groups to residual two aryl ones respectively, giving highly congested circumstance at the inner site of molecules. On the other hand, the precursor aromatic ketone molecule has relatively large space compared to title compound, enabling conformational flexibility to some extent within restriction of maintaining non-coplanar organization. The molecules of the precursor compound in crystal are stabilized by a number of non-covalent bonding interactions, mainly by non-classical hydrogen bondings. The achievement stabilization contributed a number of non-classical hydrogen bonding is considered to be due to the inner-molecular motility of single molecular structure. Contrarily, the congested inner-molecular situation of title compound makes largely rigid molecular conformation, which affords at the same time exposure of three aromatic planes outside the molecular core. The single molecular organization permits π-π stacking interaction stabilization instead of formation of a number of weak interactions. Thus, the governing factors for the distinct feature of the single molecular and the accumulation structures of title compound and the precursor are interpreted from the viewpoint of predominantly effective intermolecular interaction, a strong π-π stacking interaction or sum of weak non-classical hydrogen bondings, determined by the inner-molecular congestive conditions directly affects the inner-molecular motility

Safety and Efficacy of Tocilizumab for the Treatment of Rheumatoid Arthritis

Because of the pathological role of IL-6 in rheumatoid arthritis (RA), tocilizumab (TCZ), a humanized anti-IL-6 receptor monoclonal antibody, was expected to improve inflammation and joint destruction of RA. Indeed, randomized clinical trials demonstrated the clinical efficacy of TCZ as monotherapy or combined with methotrexate (MTX) for RA patients with inadequate responses to disease-modifying antirheumatic drugs, MTX or tumor necrosis factor (TNF) inhibitors. Although long-term tolerability for TCZ is superior to that for TNF inhibitors, information regarding the potency of drug free remission of TCZ is limited at present. In terms of its safety profile, the general risk of infection when using TCZ is comparable to that of TNF inhibitors. TCZ has some advantage in RA patients who can not use MTX and are non-responders to TNF inhibitors. In conclusion, TCZ is one of the most prospective next generation biologics for the treatment of RA

DNA Damage in Rheumatoid Arthritis: An Age-Dependent Increase in the Lipid Peroxidation-Derived DNA Adduct, Heptanone-Etheno-2′-Deoxycytidine

Objective. To evaluate what types of DNA damages are detected in rheumatoid arthritis (RA). Methods. The DNA adducts such as 8-oxo-hydroxy-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG), 1,N6-etheno-2′-deoxyadenosine (εdA), and heptanone-etheno-2′-deoxycytidine (HεdC) in genomic DNAs, derived from whole blood cells from 46 RA patients and 31 healthy controls, were analyzed by high-performance liquid chromatography tandem mass spectrometry, and their levels in RA patients and controls were compared. In addition, correlation between DNA adducts and clinical parameters of RA was analyzed. Results. Compared with controls, the levels of HεdC in RA were significantly higher (P<0.0001) and age dependent (r = 0.43, P < 0.01), while there was no significant difference in 8-oxo-dG and εdA accumulation between RA patients and controls. HεdC levels correlated well with the number of swollen joints (r = 0.57, P < 0.0001) and weakly with the number of tender joints (r = 0.26, P = 0.08) of RA patients, while they did not show a significant association with serological markers such as C-reactive protein and matrix metalloproteinase 3. Conclusion. These findings indicate that HεdC may have some influence on the development of RA and/or its complications

Comparative genomics of Glandirana rugosa using unsupervised AI reveals a high CG frequency

The Japanese wrinkled frog (Glandirana rugosa) is unique in having both XX-XY and ZZ-ZW types of sex chromosomes within the species. The genome sequencing and comparative genomics with other frogs should be important to understand mechanisms of turnover of sex chromosomes within one species or during a short period. In this study, we analyzed the newly sequenced genome of G. rugosa using a batch-learning self-organizing map which is unsupervised artificial intelligence for oligonucleotide compositions. To clarify genome characteristics of G. rugosa, we compared its short oligonucleotide compositions in all 1-Mb genomic fragments with those of other six frog species (Pyxicephalus adspersus, Rhinella marina, Spea multiplicata, Leptobrachium leishanense, Xenopus laevis, and Xenopus tropicalis). In G. rugosa, we found an Mb-level large size of repeat sequences having a high identity with the W chromosome of the African bullfrog (P. adspersus). Our study concluded that G. rugosa has unique genome characteristics with a high CG frequency, and its genome is assumed to heterochromatinize a large size of genome via methylataion of CG