Rheumatoid Arthritis: Ding C

Ding C. · University of Tasmania, Menzies Research Institute, Private Bag 23, Hobart, Tasmania 7000, Australia. · Expert Opin Biol Ther. · Pubmed #18847314 No free full text.

Abstract: BACKGROUND: B lymphocyte stimulator (BLyS) is a factor determining the survival of B cells, and elevated levels in serum or locally have been observed in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) patients. Belimumab (LymphoStat-B), a human monoclonal antibody that inhibits BlyS, was developed for the treatment of these diseases. OBJECTIVE: To summarize preclinical development, efficacy and safety of belimumab in treatment of RA and SLE. METHODS: Articles found in a PubMed search and data presented in abstract form at international conferences up to August 2008 are described. RESULTS/CONCLUSIONS: Belimumab was well tolerated in treatment of RA over 24 weeks and SLE over 3 years. It significantly decreased rheumatoid factor (RF) levels, and modestly reduced symptoms of RA, especially in some subgroups such as patients with high disease activity, positive RF and no anti-TNF treatment experience. It also significantly reduced symptoms of SLE, and decreased anti-double-stranded DNA autoantibodies among patients with positive baseline anti-double-stranded DNA or antinuclear antibodies during a long-period treatment. These results suggest that careful patient selection is necessary to achieve optimal outcomes.

Ding C, Jones G. · Menzies Research Institute, Hobart, Tasmania, Australia. · Rev Recent Clin Trials. · Pubmed #18473972 No free full text.

Abstract: Tocilizumab (namely MRA), a humanized anti-interleukin (IL)-6 receptor monoclonal antibody, is under development by Roche for the treatment of inflammatory autoimmune diseases such as rheumatoid arthritis (RA), systemic onset juvenile idiopathic arthritis (JIA), adult-onset Still's disease, Castleman's disease and Crohn's disease. Tocilizumab has a long plasma half-life, so it can be administered intravenously biweekly or monthly. Phase I and II clinical trials showed that tocilizumab (2, 4, 5, 8 or 10 mg/kg) reduced disease activity significantly in a dose-dependent manner. Tocilizumab not only improved signs and symptoms, but also normalized inflammatory markers such as C-reactive protein, erythrocyte sedimentation rate (ESR), fibrinogen and serum amyloid A, and reversed joint damage of RA. The efficacy of tocilizumab in the treatment of RA was at least as good as methotrexate. Tocilizumab was generally safe and well tolerated. Some adverse events such as significant rises in total cholesterol and triglyceride levels, liver function disorders, decreases in white blood cell counts, diarrhoea and infection were observed. In summary, preliminary clinical results suggest that tocilizumab is effective and generally well tolerated in the treatment of IL-6-related inflammatory autoimmune diseases. Like other anti-cytokine immunotherapies, caution and close monitoring for the adverse events, especially infection, are necessary in subsequent clinical trials.

Bao C, Chen S, Gu Y, Lao Z, Ni L, Yu Q, Xu J, Li X, Liu J, Sun L, He P, Ma J, Xu S, Ding C. · Department of Clinical Immunology, Shanghai Renji Hospital, Shanghai Second Medical University, Shanghai 200001, China. · Chin Med J (Engl). · Pubmed #12935395 links to  free full text

Abstract: OBJECTIVE: To evaluate the efficacy and safety of leflunomide in comparison with methotrexate (MTX) on patients with rheumatoid arthritis (RA) in China. METHODS: Five hundred and sixty-six patients with active rheumatoid arthritis were randomly assigned to receive leflunomide at 20 mg once daily or MTX at 15 mg once weekly in a controlled trial. Five hundred and four patients completed the 12-week treatment and some patients continued the treatment for 24 weeks. RESULTS: Both leflunomide and MTX could improve the symptoms, signs, and joint function, but there were no changes in X-ray observations of patients with rheumatoid arthritis. In the leflunomide group, the overall rates of effectiveness at 12 weeks and 24 weeks were 86.94% and 92.31% respectively; the rates of remarkable improvement were 64.95% and 79.81% respectively. In the MTX group, the overall rates of effectiveness at 12 weeks and 24 weeks were 84.04% and 83.15% respectively; the rates of remarkable improvement were 56.81% and 75.28% respectively. According to intent-to-treat analysis, the ACR 20% response rates at 12 weeks and 24 weeks in the leflunomide group were 62.54% and 67.18% respectively, compared with 60.08% and 61.32% respectively in MTX group. No statistical differences were shown in the efficacy between the two groups (P > 0.05). The adverse events in the leflunomide group were gastrointestinal symptoms, skin rash, alopecia, nervous system symptoms, decreased leukocyte count, and elevation of alanine aminotransferase (ALT). Most of these side effects were mild and transient. The incidence of adverse events in the leflunomide group was 16.84%, significantly lower than that in MTX group (28.17%, P = 0.002). CONCLUSIONS: Leflunomide is effective in the treatment of RA with less adverse events than MTX. Its efficacy is similar to MTX, but the incidence of adverse events and the rate of withdrawal due to adverse events were lower in the leflunomide group than in MTX group.

Ding C. · Menzies Research Institute, University of Tasmania, Hobart, Tasmania 7000, Australia. · Curr Opin Investig Drugs. · Pubmed #17117592 No free full text.

Abstract: Vertex Pharmaceuticals Inc, in collaboration with Kissei Pharmaceutical Co Ltd, is developing VX-702, one of a series of second-generation, orally active p38 MAP kinase inhibitors, for the potential treatment of inflammation, rheumatoid arthritis and cardiovascular diseases. In June 2005, a phase II clinical trial of VX-702 was initiated in rheumatoid arthritis. In July 2006, Vertex was planning to file an IND in the second half of 2006.

Ding C, Jones G. · Menzies Research Institute, University of Tasmania, Hobart 7000, Tasmania, Australia. · Curr Opin Investig Drugs. · Pubmed #16729724 No free full text.

Abstract: Belimumab, the lead in a series of human monoclonal antibodies against the human protein B-lymphocyte stimulator (BLyS), is under development by Human Genome Sciences, Cambridge Antibody Technology and GlaxoSmithKline for the potential treatment of autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). By January 2006, belimumab had completed phase II clinical trials in SLE and RA; a phase III clinical SLE trial is scheduled to begin later this year.

Ding C, MacVeigh M, Pidgeon M, da Costa SR, Wu K, Hamm-Alvarez SF, Schechter JE. · Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089-9112, USA. · Curr Eye Res. · Pubmed #16421015 No free full text.

Abstract: Lacrimal glands of male NOD and BALB/c mice have very small, pleomorphic acinar lumens. Acini contain isolated zones of highly complex cell surface interdigitations at the basal surface, sometimes occurring between acinar and myoepithelial cells. In NOD mice, cytological abnormalities, including mitochondrial deterioration, pleomorphic and heterogeneous cytoplasmic vacuoles, and lipid accumulation are evident within acinar cells at 1 month. Accumulation of lipid is further increased as the animal ages, accompanied by lymphocytic infiltration and destruction of acini. These results demonstrate alterations from normal cytology as early as 1 month in NOD mice, well before detection of clinical signs of Sjögren syndrome.

da Costa SR, Wu K, Veigh MM, Pidgeon M, Ding C, Schechter JE, Hamm-Alvarez SF. · Departments of Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA. · Exp Eye Res. · Pubmed #16005870 links to  free full text

Abstract: The lacrimal glands of male NOD mice exhibit many of the features of the human lacrimal gland in patients afflicted with the autoimmune disease, Sjögren's syndrome, including loss of secretory functions and lymphocytic infiltration into the lacrimal gland. To elucidate the early changes in the secretory pathway associated with development of Sjögren's syndrome, we investigated the organization of the exocytotic pathway in lacrimal glands of age-matched male BALB/c and NOD mice. Cryosections from lacrimal glands from 1 and 4 month male BALB/c and NOD mice were processed for confocal fluorescence and electron microscopic evaluation of different participants in exocytosis. No changes in apical actin filaments were noted in glands from NOD mice, but these glands exhibited thickening of basolateral actin relative to that seen in the BALB/c mice. Rab3D immunofluorescence associated with mature secretory vesicles was distributed abundantly in a continuous vesicular network concentrated beneath the apical plasma membrane in glands from 1 and 4 month BALB/c mice. In glands from 1 month NOD mice, rab3D immunofluorescence exhibited marked discontinuity and irregularity in the vesicular labeling pattern. While this change was also detected in glands from 4 month NOD mice, many of these glands exhibited an additional extension of rab3D labeling through the cell to the basolateral membrane. Electron microscopic analysis confirmed the formation of irregularly shaped, unusually large secretory vesicles in lacrimal glands from NOD mice. Quantitation of multiple secretory vesicles from electron micrographs revealed a significant (p< or =0.05) increase in the percentage of secretory vesicles incorporated into multivesicular aggregates in lacrimal glands from 1 and 4 month NOD mice compared to BALB/c mice. The M3 muscarinic receptor, a key signaling effector of exocytosis, was redistributed away from its normally basolateral locale in glands from BALB/c mice, with concomitant enrichment in intracellular aggregates in glands from NOD mice. These findings show that lacrimal glands in NOD mice as young as 1 month contain aberrant secretory vesicles with altered effector composition that undergo premature cytoplasmic fusion, and that changes in the distribution of the M3 muscarinic receptor occur within the same time frame.

Ding C, Jones G. · Menzies Centre for Population Health Research, University of Tasmania, 17 Liverpool Street, Hobart 7000, Tasmania, Australia. · IDrugs. · Pubmed #12800058 No free full text.

Abstract: Lumiracoxib, an inhibitor of cyclooxygenase 2 (COX-2), is under development by Novartis for the potential treatment of osteoarthritis, rheumatoid arthritis and pain. By late December 2000, phase III trials had been initiated and were ongoing in December 2001.

Ding C, Jones G. · Menzies Centre for Population Health Research, University of Tasmania, 17 Liverpool Street, Hobart, 7000 TAS, Australia. · Curr Opin Mol Ther. · Pubmed #12669473 No free full text.

Abstract: Chugai, the Japanese subsidiary of Roche, is developing a humanized anti-interleukin (IL)-6 receptor monoclonal antibody MRA for the potential treatment of multiple myeloma, rheumatoid arthritis, Crohn's disease and other IL-6-related disorders. MRA is currently undergoing phase II clinical trials for these indications.