Tofacitinib improves atherosclerosis despite up-regulating serum cholesterol in patients with active rheumatoid arthritis: a cohort study.

Patients with rheumatoid arthritis (RA) have an increased cardiovascular (CV) risk. This study aimed to analyze the effects of Tofacitinib treatment, a Janus kinase inhibitor, on atherosclerosis in patients with RA. Patients with an active RA (28-joint disease activity score-erythrocyte sedimentation rate > 3.2) despite methotrexate (MTX) treatment 12 mg/week were included in this open-label prospective study and started on Tofacitinib (10 mg/day, 5 mg twice/day). Japanese guideline does not allow high dose of MTX. All patients used a stable dosage of MTX, steroids, and statins or lipid-lowering drugs. The primary endpoint was the comparison of the carotid intima-media thickness (CIMT) at the baseline and 54 weeks after Tofa treatment. Clinical data were collected at regular visits. Forty-six patients completed this study. CIMT did not significantly change from baseline to 54 weeks (1.09 ± 0.69 and 1.08 ± 0.78 mm, p = 0.82). In 12 patients who had atherosclerosis at baseline (carotid intima-media thickness > 1.10 mm), there was a significant decrease in CIMT (0.05± 0.026 mm; p < 0.05). However, the decrease in CIMT was of limited clinical significance. Tofacitinib increased fasting total cholesterol levels from baseline to 54 weeks (216 ± 25.3 and 234 ± 28.8 mg/dL, p < 0.01). Tofacitinib affects atherosclerosis in patients with active RA The CIMT in RA patients was stable. Tofacitinib decreased the CIMT of patients who had increased CIMT at baseline. Tofacitinib reduced RA disease activity and limited vascular damage despite up-regulating cholesterol in patients with an active RA.

The effect of tocilizumab on bone mineral density in patients with methotrexate-resistant active rheumatoid arthritis.

OBJECTIVE: The aim of this study was to analyse the effects of therapy with tocilizumab (TCZ), an anti-IL-6 receptor antibody, on BMD of the lumbar spine and femoral neck in patients with RA. METHODS: Eighty-six patients with active RA (indicated by a 28-joint DAS ESR >3.2) despite treatment with MTX 12 mg/week were included in this open-label prospective study and started on TCZ (8 mg/kg every 4 weeks). All patients used a stable dosage of MTX and were not allowed to use steroids or bisphosphonates during the study period. BMD of the lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry at baseline and 52 weeks after initiating TCZ. RESULTS: Seventy-eight patients completed this study. BMD of the lumbar spine and femoral neck remained stable after 1 year of TCZ treatment. In 33 patients who had osteopenia at baseline, there was a significant increase in BMD of the lumbar spine [mean 0.022 (s.d.) 0.042, P < 0.05] and femoral neck [0.024 (0.0245), P < 0.05]. CONCLUSION: TCZ affects BMD in patients who had active RA despite treatment with MTX. BMD of the lumbar spine and femoral neck in patients with normal BMD at baseline was stable. TCZ increased the BMD of patients who had osteopenia at baseline.

Tocilizumab monotherapy reduces arterial stiffness as effectively as etanercept or adalimumab monotherapy in rheumatoid arthritis: an open-label randomized controlled trial.

OBJECTIVE: To compare the respective effects of tocilizumab (TCZ) monotherapy, etanercept (ETN) monotherapy, and adalimumab (ADA) monotherapy on arterial stiffness in patients with rheumatoid arthritis (RA) in an open-label, randomized controlled trial. METHODS: Patients with RA were eligible if they had active disease (28-joint Disease Activity Score > 3.2) and no prior treatment with methotrexate or biologics. All 64 patients had no history of cardiovascular disease or steroid treatment. Patients were randomly assigned to receive TCZ alone (n = 22), ETN alone (n = 21), or ADA alone (n = 21). Arterial stiffness was assessed with cardio-ankle vascular index (CAVI) and aortic augmentation index normalized to a fixed heart rate of 75 bpm (AIx@75) at baseline and 24 weeks' followup. Clinical data were collected at regular visits. RESULTS: The characteristics of each group at baseline were not significantly different. In all groups there was significant attenuation from baseline to 24 weeks in CAVI (Week 0-Week 24, TCZ: 0.85 ± 0.15 m/s, p = 0.02; ETN: 0.81 ± 0.18 m/s, p = 0.03; ADA: 0.90 ± 0.21 m/s, p = 0.02) and in AIx@75. There were no significant differences among the groups in measures of CAVI or AIx@75. The 3 therapies made no difference to carotid intima-media thickness and carotid artery plaque. Only TCZ increased fasting serum total cholesterol from baseline to 24 weeks. CONCLUSION: The 3 types of monotherapy limited arterial stiffness in patients with RA to a similar extent.

Very early improvements in the wrist and hand assessed by power Doppler sonography predicting later favorable responses in tocilizumab-treated patients with rheumatoid arthritis.

OBJECTIVE: To investigate the response of tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) by ultrasonographic evaluation of changes in the wrist and hand, and to determine whether such assessments during early TCZ treatment predict later clinical outcome. METHODS: Thirty-two RA patients about to receive TCZ treatment were examined by ultrasound at baseline and after 2 weeks using the Outcome Measures in Rheumatology Clinical Trials semiquantitative scoring of 22 joints (both wrists, proximal interphalangeal joints 1-5, and metacarpophalangeal joints 1-5) as well as clinical and laboratory variables, leading to a calculation of composite indexes. The aim was to determine whether methotrexate treatment and clinical, laboratory, and ultrasonographic evaluation after 2 weeks of TCZ treatment predict treatment outcome at 24 weeks, as assessed by the Disease Activity Score in 28 joints (DAS28). RESULTS: Changes of ultrasound scores after 2 weeks were found to be correlated with changes in DAS28 at 24 weeks (r = 0.545-0.622, P < 0.05). The change of sum power Doppler scores after 2 weeks of treatment was identified as the variable most closely correlated with the change in DAS28 at 24 weeks (r = 0.622, P < 0.05). CONCLUSION: The best predictors after 2 weeks of favorable treatment outcome at 24 weeks were improved power Doppler scores. Methotrexate treatment and composite indexes did not predict favorable treatment outcome in this study.

Role of the JNK pathway in thrombin-induced ICAM-1 expression in endothelial cells.

OBJECTIVE: Thrombin induces leukocyte adherence to endothelial cells via increased expression of intercellular adhesion molecule-1 (ICAM-1). Although ICAM-1 expression is regulated by NF-kappaB, recent studies have suggested that additional signaling mechanisms may also be involved. The goal of this study was to determine whether mitogen-activated protein (MAP) kinases, including extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 MAP kinase (p38), mediate thrombin-induced ICAM-1 expression in endothelial cells. METHODS: Western blot analysis using anti-ICAM-1 antibody and luciferase assays were performed in cultured endothelial cells after addition of signal transduction inhibitors or transfection of various gene constructs. JNK kinase activity was determined by a kinase assay using c-Jun as a substrate or by Western blot analysis with anti-phospho-JNK antibody. RESULTS: Treatment of endothelial cells with the JNK-specific inhibitors, SP600125 or JNK inhibitory peptide 1 (JNKI1), resulted in a significant decrease in thrombin-induced ICAM-1 expression as demonstrated by Western blot analysis (67 +/- 3% and 72 +/- 7%, respectively). In contrast, inhibitors of MEK and p38 had only minimal effect. The combination of SP600125 and the NF-kappaB inhibitor, BAY11-7082, resulted in complete inhibition of thrombin-induced ICAM-1 expression. The Galpha(q) inhibitor, YM-254890, inhibited thrombin-induced JNK activation and ICAM-1 expression. Dominant-negative Ras and Rac1, but not Rho, inhibited thrombin-induced JNK activation and ICAM-1 promoter activity. Finally, thrombin-induced JNK activation and ICAM-1 promoter activity were inhibited by betaARK1ct (a Gbetagamma subunit scavenger) and Csk. CONCLUSIONS: These data suggest that, in concert with NF-kappaB, JNK regulates thrombin-induced ICAM-1 expression by a mechanism that is dependent on Galpha(q), Gbetagamma, Ras, Rac1 and the Src kinase family.