Tofacitinib Decreases Autophagy of Fibroblast-Like Synoviocytes From Rheumatoid Arthritis Patients.

The pathway of Janus tyrosine kinases (JAKs) has a central role in the pathogenesis of Rheumatoid Arthritis (RA) by regulating multiple immune functions and cytokine production. The JAK inhibitor tofacitinib is effective in RA patients not responding to methotrexate or TNF-inhibitors. Since hyperactive autophagy has been associated with impaired apoptosis of RA fibroblast-like synoviocytes (FLS), we aimed to investigate the role of tofacitinib in modulating autophagy and apoptosis in these cells. FLS isolated from RA biopsies were cultured with tofacitinib in presence of autophagy inducer rapamycin and in serum deprivation condition. Levels of autophagy, apoptosis, and citrullinated proteins were analyzed by western blot, flow cytometry, immunocytofluorescence, and Real-Time PCR. Rapamycin induced an increase in RA-FLS autophagy while the levels of autophagy marker LC3-II were reduced after in vitro treatment with tofacitinib. The analysis of autophagic flux by specific fluorescence dye confirmed the reduction of autophagy in RA FLS. The treatment with tofacitinib did not influence apoptosis of RA FLS. Modulation of the autophagic process by tofacitinib did not significantly change citrullination. The results of this study demonstrate that tofacitinib is able to modulate autophagy of FLS contributing to its effectiveness in RA patients.

Nitric oxide proxies and ocular perfusion pressure in primary open angle glaucoma.

BACKGROUND: To investigate the levels of nitric oxide (NO) markers in plasma and aqueous humour of patients with primary open angle glaucoma (POAG) and their relation to ocular perfusion pressure. METHODS: Cyclic guanosine monophosphate (cGMP) and nitrite (NO(2)(-)) were determined in plasma and aqueous humour of 38 patients with POAG and 46 controls. Blood pressure and IOP were measured to calculate ocular perfusion pressure (PP). RESULTS: cGMP and NO(2)(-) plasma levels were significantly decreased in glaucoma patients compared with controls (p = 0.001 v p = 0.004). In the aqueous humour of subjects with POAG, cGMP and NO(2)(-) concentrations were also lower than in normal eyes (p = 0.0001 v p = 0.001). There was a linear association between cGMP in plasma and aqueous humour in glaucomas and controls (r = 0.514, p = 0.029 and r = 0.558, p = 0.004) and this relation differed in the two groups (p = 0.003). Considering glaucoma patients with controls, a positive correlation was found between cGMP and PP (r = 0.379, p = 0.01) and between NO(2)(-) and PP (r = 0.339, p = 0.040). The cGMP/PP correlation was of borderline statistical significance in controls (p = 0.050), whereas it did not attain statistical significance in POAG, as well as the association between NO(2)(-) and PP when glaucomas and controls were considered separately. CONCLUSIONS: The authors found alterations of NO markers in the plasma and aqueous humour of glaucoma patients. Primary or secondary impaired NO balance could alter ocular perfusion pressure.

Ocular haemodynamics and nitric oxide in normal pressure glaucoma.

The authors studied the ocular haemodynamics by means of the Color Doppler Imaging (CDI) technique and the levels of cyclic guanosine monophosphate (cGMP), the intracellular mediator of NO action in plasma and the aqueous humour in a Normal Pressure Glaucoma group and in a normal group. They found significant alterations of both the velocities, systolic and diastolic, in the Ophthalmic Artery and lower cGMP levels in NPGs than in the controls. These data suggest that a disorder of NO regulation processes might be involved in blood supply to the optic nerve and in aqueous humour outflow.

Ocular haemodynamics in glaucoma associated with high myopia.

The ocular blood flow of a group of high myopic and glaucomatous eyes has been investigated by means of the Color Doppler Imaging (CDI) technique, comparing the results with those of some very myopic eyes without glaucoma, some non-myopic glaucomatous eyes and with a control group. The Ophthalmic Artery (OA), the Short Posterior Ciliary Arteries (SPCAs) and the Central Retinal Artery (CRA) were considered. For every vessel, peak systolic velocity (SV), end-diastolic velocity (DV) and the Pourcelot Resistivity Index were studied. The statistical analysis was performed by means of t-test according to Bonferroni procedure for multiple comparisons. The authors registered in the group of eyes with glaucoma associated with very severe myopia some abnormalities of the OA blood flow systolic velocity which might be interpreted as a vascular risk factor for the pathogenesis of the glaucomatous optic neuropathy; these abnormalities are more severe in glaucoma patients with high myopia than in an age-matched group of glaucoma patients without myopia.

Ocular haemodynamics in some subgroups of normal pressure glaucoma.

The authors studied, by means of Color Doppler Imaging, a group of Normal Pressure Glaucoma subjects They found some haemodynamic abnormalities in them which differed in the various subgroups. It would seem that, for each NPG subgroup, there are specific physiopathological and clinical features.