Apremilast: A Review in Oral Ulcers of Behçet's Disease.

The oral phosphodiesterase 4 inhibitor apremilast (Otezla®) is indicated for the treatment of oral ulcers associated with Behçet's disease in some countries, including the USA (where it is the first agent approved for the disease) and Japan. In phase 2 and 3 trials in adults with this chronic and debilitating disorder, 12 weeks of treatment with apremilast 30 mg twice daily reduced the number and pain of oral ulcers and disease activity relative to placebo, with these clinical benefits being accompanied by improvements in health-related quality of life (HR-QOL). Benefits of apremilast were seen regardless of baseline patient/disease characteristics and in Japanese patients, and were sustained over up to 64 weeks of treatment. Apremilast was generally well tolerated, with gastrointestinal adverse events being among the most common tolerability issues. Emerging real-world data also support the drug's use in this setting. Thus, for patients with oral ulcers associated with Behçet's disease, apremilast provides an effective and generally well tolerated approved treatment option.

Role of endothelin-1-dependent up-regulation of leptin in oral mucosal repair.

Leptin, a multifunctional hormone that regulates food intake and energy expenditure, has emerged recently as an important modulator of inflammatory cascades associated with wound healing. In this study, we applied the animal model of buccal mucosal ulcer to investigate the role of endothelin-1 (ET-1) and leptin in soft oral tissue repair. Using groups of rats with experimentally induced buccal mucosal ulcers we show that ulcer onset was characterized by a marked increase in the mucosal level of ET-1 and leptin. However, while the ET-1 level gradually declined with healing, the mucosal level of leptin increased reaching maximum expression on the 4th day of healing. Therapeutic administration of phosphoramidon, an inhibitor of ECE-1 activity, not only led to a 53.2% drop in the ET-1, but also produced a dose-dependent reduction (up to 50.9%) in the mucosal level of leptin and up to 42.3% decline in the rate of ulcer healing. A marked drop (54.2%) in the mucosal level of leptin and the reduction (46.8%) in the rate of ulcer healing was also attained in the presence of ETA receptor antagonist BQ610 administration, but not the ETB receptor antagonist BQ788. Moreover, administration of ERK inhibitor, PD98059 in the presence of ETB receptor antagonist, but not the ETA receptor antagonist, caused the reduction the mucosal leptin level as well as a decline in the rate of ulcer healing. Our findings are the first to implicate the requirement for both ET-1 and leptin in orderly progression of the events of soft oral tissue repair. We also show that ET-1 is a key factor in up-regulation of leptin production associated with oral mucosal ulcer healing , and that the effect of ET-1 on leptin production is a consequence of ETA receptor activation and subsequent signaling through MAPK/ERK.

Activity of matrix metalloproteinase-9 is elevated in sera of patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the increased production of autoantibodies and by systemic clinical manifestations and damage to multiple organs. The aim of the present study was to analyse matrix metalloproteinase (MMP)-9 activity in sera of patients with active and inactive SLE in order to evaluate its role in the pathogenesis and course of the disease, as well as its diagnostic value. We measured activity levels of MMP-9 and MMP-2, using both gel zymography and activity assay kits, in sera of 40 SLE patients and of 25 healthy controls. We found that MMP-9 activity, but not MMP-2 activity, is significantly elevated in the sera of SLE patients compared with sera samples of healthy controls. High activity levels of MMP-9 were determined in sera of 68% of the SLE patients. Elevated levels of MMP-9 were correlated with the presence of discoid rash, Raynaud phenomenon, pneumonitis, mucosal ulcers and anti-phospholipid antibodies. Changes in activity levels of MMP-9, but not of MMP-2, were observed in sera of the same patient at different periods of the disease course. High levels of MMP-9 did not correlate with disease activity index (SLEDAI, BILAG) in female patients, but correlated with SLE activity in the group of male patients. The results of the present study suggest that MMP-9 plays a role in the pathogenesis of SLE.

Delay in oral mucosal ulcer healing by aspirin is linked to the disturbances in p38 mitogen-activated protein kinase activation.

BACKGROUND: Among the early manifestations of oral mucosal impairment by nonsteroidal anti-inflammatory drugs is the delay in soft oral tissue repair brought about by the amplification of apoptotic events. In this study, we investigated the effect of a specific inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), SB 203580, on the rate of buccal mucosal ulcer healing and the apoptotic processes in rats subjected to intragastric administration of aspirin. METHODS: Groups of rats with experimentally induced buccal mucosal ulcers were administered twice daily for 10 days with SB 203580 (5, 10, and 20 mg/kg) or vehicle followed 30 min later by concomitant administration (twice daily for 10 days) of aspirin at 20 mg/kg. The animals were killed at different periods of treatment and their mucosal tissue subjected to macroscopic assessment of ulcer healing rate, measurement of soluble tumor necrosis factor-alpha (TNF-alpha), and the assay of epithelial cell apoptosis. RESULTS: In the control group the ulcer healed by the tenth day and the rate of healing was not affected by SB 203580 administration, whereas a 54.8% reduction in the ulcer area was attained in the presence of aspirin administration. Moreover, by the tenth day, the delay in ulcer healing caused by aspirin was manifested in a 5.6-fold higher rate of apoptosis and a 5.2-fold higher level of soluble TNF-alpha. Treatment with SB 203580 produced dose-dependent reduction (59.5-74.8%) in aspirin-induced increase in the mucosal level of soluble TNF-alpha, evoked 53.2-69.7% decrease in the rate of epithelial cell apoptosis, and led to a marked reversal (51.8-73.9%) in aspirin-induced delay in ulcer healing. CONCLUSIONS: The results of our findings link the delay in buccal mucosal ulcer healing caused by aspirin ingestion to the disturbances in the p38 MAPK activation.

Suppression of caspase-3 and nitric-oxide synthase-2 during buccal mucosal ulcer healing: effect of chronic alcohol ingestion.

In this study, we analyzed the effect of chronic alcohol ingestion on the expression of constitutive (cNOS) and inducible (NOS-2) nitric-oxide synthase and the activity of an apoptotic protease, caspase-3, during buccal mucosal ulcer healing in rats maintained for 5 weeks on alcohol-containing or control liquid diet. In comparison with the controls, the ulcer onset in the alcohol group was characterized by a 2.5-fold greater epithelial cells apoptosis, 2.1-fold greater expression of caspase-3 activity, and a 1.4-fold greater enhancement in NOS-2, but expression of cNOS showed a 1.3-fold decrease. In both groups the ulcer healing was accompanied by a gradual decline in apoptosis, caspase-3, and NOS-2 and a recovery in cNOS activity, but the changes were considerably slower in the alcohol diet group, as manifested by a 40%(4 days) delay in ulcer healing. These results suggest that chronic alcohol ingestion interferes with the suppression of NOS-2 and the apoptotic events propagated by caspase-3 and hence affects the efficiency of oral mucosal repair process.