The cortisol burden in elderly subjects with metabolic syndrome and its association with low-grade inflammation.

BACKGROUND: Elderly people are exposed to an increased load of stressful events and neuro-hormonal stimulation is a key finding in metabolic syndrome and its related disorders. AIMS: To determine the role of cortisol in elderly subjects, with or without metabolic syndrome (MetS), by means of a national multicentre observational study, AGICO (AGIng and Cortisol). METHODS: From 2012 to 2017, the AGICO study enrolled n.339 subjects (aged > 65), after obtaining their informed consent. The investigators assessed a cardio-metabolic panel (including electrocardiogram, carotid ultrasonography and echocardiography), the presence of MetS (on Adult Treatment Panel III criteria), a neurological examination (including brain imaging), and cortisol activity (using a consecutive collection of diurnal and nocturnal urine). RESULTS: In the patients presenting with MetS, the standardized diurnal and nocturnal cortisol excretion rates were 210.7 ± 145.5 and 173.7 ± 118.1 (mean ± standard deviation) µg/g creatinine/12 h; in those without MetS, the standardized diurnal and nocturnal cortisol excretion rates were 188.7 ± 92.7 and 144.1 ± 82.3 µg/g creatinine/12 h, respectively (nocturnal urinary cortisol in patients with MetS versus those without MetS p = 0.05, female patients with MetS vs female patients without MetS, p < 0.025). A significant positive correlation was found between the CRP levels and both the diurnal and nocturnal urinary cortisol levels with r = 0.187 (p < 0.025) and r = 0.411 (p < 0.00000001), respectively. DISCUSSION: The elderly patients with MetS showed a trend towards increased standardized nocturnal cortisol excretions, with particular regard to the female subjects. CONCLUSION: The positive correlation between cortisol excretion and low-grade inflammation suggests a common mechanism driving both hormonal and inflammatory changes.

One-year follow-up showing effects of single intra-articular injection of hyaluronic acid (1,500-2,000 kDa) in symptomatic knee osteoarthritis.

Clinical evidence on knee osteoarthritis suggests that intra-articular administration of hyaluronic acid may be useful in the management of patients with persistent pain. This study assesses the duration of effectiveness of a single intra-articular hyaluronic acid injection in a large population of patients with knee osteoarthritis. This retrospective post-marketing cohort study collected data from the ANTIAGE Registry (http://www.antiagefbf.it/registro), selecting patients of age ≥ 40 years, with symptomatic knee osteoarthritis (Kellgren-Lawrence grade I-III) of ≥ 12 months duration, and ≥12 months of follow-up. Patients had received a single intra-articular injection of high molecular weight hyaluronic acid (1,500-2,000 kDa) at baseline. WOMAC Osteoarthritis Index total scores measured using the LK 3.1 scale and 10 cm VAS pain scores were evaluated before IA Injection and at 6, 9, 10, 11 and 12 months. Blood cell counts, uricemia, erythrocyte sedimentation rates and levels of C-reactive protein were measured at baseline and 12 months. Time from initial treatment to second injection up to 12 months was recorded to assess event-free survival. Included patients (n=187) were 53.5% female and had a mean (±SD) age at baseline of 62 (±16.6) years and mean (±SD) body mass index of 26.2 (±2.5) kg/m2. Mean (±SD) WOMAC index total score and VAS pain scores were 60.9 (±7.1) and 5.9 cm (±1.8), respectively. There were statistically significant reductions compared to baseline in mean WOMAC index total score and VAS pain score at all time points (p less than0.01 at 6 and 9 months; p less than 0.05 at 10, 11 and 12 months for both parameters). These results support the clinical effectiveness and safety of hyaluronic acid for up to 12 months for pain relief and function improvement in patients with knee osteoarthritis, confirming previous data on intra-articular administration of hyaluronic acid as chronic therapy in the management of knee osteoarthritis.

Duration of symptom relief after intra-articular injection of hyaluronic acid combined with sorbitol (anti-ox-vs) in symptomatic hip osteoarthritis.

The intra-articular administration of hyaluronic acid (HA) in hip osteoarthritis (OA) has been recently increased following the use of ultrasound guidance to perform an accurate delivery of the injected product. Viscosupplementation in hip OA seems to show similar results to those obtained by viscosupplementation in knee OA. However, an unmet need is the duration of symptomatic relief, therefore several new products are proposed to prolong and increase symptomatic effects. Among these, an innovative viscosupplement has been produced from high a concentration of HA combined with a high concentration of sorbitol as a free radical scavenger. The aim of this study is to evaluate the mid-term pain-relief effect of an ultrasound-guided injection of SynolisV-A (ANTI-OX-VS) in patients suffering from symptomatic hip osteoarthritis. Lequesne index, Health Assessment Questionnaire (HAQ), pain reduction, Global Patient Assessment (GPA), Global Medical Assessment (GMA) and reduction in monthly analgesic consumption were assessed during the 12-month follow-up after the injection. A total of 20 patients were enrolled in the study and received one IA US-guided injection of two syringes of ANTI-OX-VS into the target hip. Eleven drop-out patients were registered, of whom 2 were for loss of efficacy at 6 months, 1 for loss of efficacy at 9 months and 8 patients for severe comorbilities. Mean scores of all clinical parameters evaluated at each control visit were significantly different when compared with baseline mean value. No systemic adverse events were observed. Even though the sample size of this study is limited, the results suggest a durable good efficacy of a 4-ml single injection of ANTI-OX-VS in hip OA, at least for the patients who completed the study. A larger number of patients and an RCT are needed to confirm these data, investigating also the predictive factors of clinical response to ANTI-OX-VS.

Ranking antireabsorptive agents to prevent vertebral fractures in postmenopausal osteoporosis by mixed treatment comparison meta-analysis.

INTRODUCTION: Bisphosphonates are considered as a first-line therapy for the prevention and treatment of osteoporosis, showing in double-blind, randomized, controlled trials a significant reduction of incidence of new vertebral fractures compared to placebo. Recently also, Denosumab has been shown to reduce the appearance of new vertebral fractures by blocking RANK. There are not head to head comparative studies between the above mentioned drugs. Mixed treatment comparison, an extension of traditional meta-analysis, is able to compare simultaneously several drugs across a range producing a synthetic evidence of efficacy and a range of probability as to the best treatment. OBJECTIVES: The aim of this study is to simultaneously compare alendronate, risedronate, ibandronate, zolendronate and denosumab in the prevention of OP vertebral fractures in a Bayesian meta-analysis for assessing indirect comparisons. MATERIALS AND METHODS: A search for randomized controlled trials involving alendronate, risedronate, ibandronate, zolendronate and denosumab was conducted using several databases. Randomized controlled trials (RCTs) with a double blind treatment period of at least 3 years were included. Men and Glucorticoid Induced osteoporosis, RCTs having as primary or secondary endpoints continuous values as body mineral density (BMD) and studies comparing different dosing regimens of the same agent, which are not used in clinical practice, were excluded. Only fully published reports were considered. RESULTS: A total of 9 RCTs were identified providing data on 31,393 participants. Zolendronate had the highest probability (52%) of being the most effective treatment towards placebo, followed by denosumab (46% probability), ibandronate and then alendronate and risedronate against placebo. CONCLUSIONS: Although the mixed treatment comparisons among alendronate, risedronate, ibandronate, zolendronate and denosumab did not show a statistically significant difference, this analysis suggests that zolendronate, compared to placebo, is expected to provide the highest rate of reduction in vertebral fractures affecting osteoporosis affected patients.

Biologics for psoriatic arthritis: network meta-analysis in review.

OBJECTIVE: A review of network meta-analysis to assess efficacy and safety of biologics for the treatment of psoriatic arthritis (PsA). MATERIALS AND METHODS: A systematic search was conducted on electronic databases to identify Bayesian meta-analysis reporting clinical parameters of efficacy, safety and cost-effectiveness of biologics that are approved for the treatment of PsA patients. RESULTS: We identified 19 studies and included them for review. There is insufficient statistical evidence to demonstrate clear differences in effectiveness between available biologic agents for PsA due to many differences in methods and clinical parameters reported in the studies. Old biologics are reported to be safe. CONCLUSIONS: New molecules approved for the treatment of PsA appear promising treatments but further comparative studies methodologically well-conducted are necessary. It is also necessary to follow strictly international recommendations to conduct NMA to better help physicians and decision-makers in making appropriate decisions.

HyalOne® in the treatment of symptomatic hip OA - data from the ANTIAGE register: seven years of observation.

OBJECTIVE: Several studies on knee osteoarthritis suggest that the intra-articular administration of hyaluronic acid products may be a relevant option in the management of patients with persistent pain. The aim of this study is to report the data of efficacy of US-guided HyalOne®/Hyalubrix® 60 injections in a large population of patients with hip osteoarthritis, repeated at least 2 times per year for up to seven years. PATIENTS AND METHODS: This is a prospective, post-marketing, cohort study. Data were collected from the ANTIAGE registry. Values of Lequesne index, pain VAS, NSAIDs intake, global medical and patients assessments were evaluated every six months from the baseline to the end of the follow-up, seven years later. The inclusion criteria were: age ≥18 years, symptomatic hip osteoarthritis of at least 1-year duration, and up to 84 months of follow-up. All the patients received hyaluronic acid injections at least every six months, using ultrasound guidance to ensure accurate placement. RESULTS: 1022 patients were included in the study. The patients were categorized by age classes, gender, and body mass index (BMI). All the groups show a statistically significant reduction at all time points compared to baseline values of Lequesne index, pain VAS, NSAIDs intake, global medical and patients assessments. There are slight differences in the subgroups of overweighted, obese and over 70 years patients. CONCLUSIONS: Our study supports the clinical efficacy and safety of HyalOne®/Hyalubrix®60 in patients affected by osteoarthritis. This is the first study, reporting on a large cohort of patients in different categories with a long follow-up on seven years. The data confirm the proper use of ultrasound-guided viscosupplementation (VS) as background therapy in the management of hip osteoarthritis.

An open randomized active-controlled clinical trial with low-dose SKA cytokines versus DMARDs evaluating low disease activity maintenance in patients with rheumatoid arthritis.

BACKGROUND: Biologic agents are currently the strongest immunosuppressive drugs able to induce remission in rheumatoid arthritis (RA). One of the objectives of the medical scientific community now is how to maintain remission or low disease activity (LDA). The aim of this trial is to evaluate the contribution of low-dose sequential kinetic activation (SKA) IL-4, IL-10, and anti-IL-1 antibodies (10 fg/mL) in patients affected by RA in maintaining LDA or remission obtained after biological therapy. METHOD: This is a randomized, open, active-controlled, prospective, Phase IV trial. Disease activity score (DAS28), clinical disease activity index, simplified disease activity index, erythrocyte sedimentation rate and C-reactive protein levels, global health assessment, and pain visual analog scale were evaluated at baseline visit and then every 3 months together with an assessment of side effects till 12 months. Thirty-nine RA patients were enrolled and randomized to continue disease-modifying antirheumatic drugs (DMARDs) therapy or to receive a combination of SKA low-dose cytokines formulated in concentration of 10 fg/mL orally administered at a dose of 20 drops/d for 12 consecutive months. RESULTS: The rate of maintenance of LDA at 12 months was superior in the group treated with low-dose cytokines compared with patients treated with DMARDs, 66.7% and 42.1%, respectively; however, the difference between the groups was not statistically significant. No side effects were reported in both groups. CONCLUSION: This is the first study using a combination of three low-dose cytokines in RA, after data published on psoriasis. These data suggest that the use of a combination of low-dose SKA cytokines may be an opportunity to explore in the management of RA.

Inhibition of contact hypersensitivity reaction to picryl chloride: effect of small molecular weight peptidomimetic compounds possessing inhibitory activity against metalloproteinases.

We have studied the effect of small molecular weight inhibitors of snake venom metalloproteinases (SVMP) and matrix metalloproteinases (MMPs) on the induction and effector phase of the contact hypersensitivity reaction (CHR) in a mouse model. Identification of nonsteroid small molecules is very important for the development of new anti-inflammatory drugs. The compounds that we tested were synthetically modified tripeptides (peptidomimetic compounds) POL-257, POL-509, POL-443, POL-491, and POL-647, with structures based on natural occurring peptides in snake venom. A well-known hydroxamate-based inhibitor of the MMPs, Batimastat (BB-94), was also used. We have shown that these peptidomimetics possess in vitro inhibitory activity against the MMP-2 (gelatinase-A), MMP-9 (gelatinase-B), and MMP-3 (stromelysin). They also inhibit metalloproteinases purified from the venom of Crotalus adamanteus and C. atrox snakes, which are very similar to the so-called A Desintegrine, A Metalloproteinase (ADAMs) enzymes. When injected intraperitonealy before the topical application of the contact sensitizer (picryl chloride) or before the challenge, these compounds significantly inhibited the development of CHR. BB-94 at doses 0.4 and 4 mg/kg before the sensitization or before the challenge almost completely abrogated the reaction. POL-257 and POL-443 were among the most active peptidomimetics tested. They inhibited the inflammatory reaction up to 70-80%, when applied either immediately before sensitization or before challenge. POL-509, a methylated derivative of POL-257, inhibited the CHR to 40-50% when administered at either challenge or sensitization. However, when applied 24 h before the challenge, it completely abrogated the inflammatory reaction. The results show that these small molecular weight peptidomimetic compounds, as well as BB-94, are able to significantly inhibit the CHR. This finding opens possibilities for using metalloproteinase inhibitors in the treatment of allergic contact dermatitis and other inflammatory diseases.

Induction and membrane expression of heat shock proteins in heat-treated HPC-4 cells is correlated with increased resistance to LAK-mediated lysis.

In human pancreatic carcinoma cells (HPC-4), a hyperthermic treatment at 43 degrees C for 30 min resulted in the vigorous induction of Hsp72, along with a less pronounced increase in the rate of synthesis of Hsp90, Hsp60 and Hsp 27. Biotinylation of surface-exposed proteins, followed by isolation of biotin-tagged proteins by affinity chromatography, demonstrated that both Hsp72 and Hsp60 are expressed on plasma membrane. Membrane expression of these two Hsps was confirmed by immunoprecipitation of surface biotinylated proteins with anti-Hsp72 and anti-Hsp60 specific antibodies. Cytotoxic assays showed that untreated HPC-4 cells are intrinsically resistant to NK-mediated lysis, while they were efficiently killed by LAK lymphocytes, as well as by exposure to TNFalpha. Following heat-treatment, cells became much more resistant to LAK-mediated lysis, while their sensitivity to NK-mediated lysis and to TNFalpha cytotoxicity remained unmodified.

Effective anti-tumor immunity induced in mice by a two-step vaccination protocol.

BACKGROUND: TS/A cells (a Balb/c-derived tumor cell line), when injected into syngenic mice, give rise to rapidly growing tumors. In this study, a vaccination protocol was established which was able to elicit an immune response effective in controlling tumor growth. MATERIALS AND METHODS: T19.2.1, a TS/A clone enginereed to stably express the mycobacterial cell wall-associated 19-kDa lipoprotein, was used as cell vaccine to immunize Mycobacterium Bovis-BCG pre-immunized Balb/c mice. RESULTS: Mice receiving the two-step vaccination protocol were able to develop a strong anti-TS/A DTH reaction. Moreover, following a challenge with wild-type TS/A cells, some vaccinated animals rejected the tumor and the remaining animals showed a significantly increased survival in respect to controls. CONCLUSION: The expression on TS/A cells of the mycobacterial 19-kDa antigen, recognised in the context of a pre-existing memory immune response, promotes the immunological recognition of the otherwise non-immunogenic wild-type TS/A cells.

Radiological outcomes in randomized controlled trials on biologic therapies for rheumatoid arthritis: a narrative review.

Several scores are currently used to estimate the radiologic progression of patients affected by rheumatoid arthritis. Modified Sharp score, Genant-modified Sharp score and van der Heijde-modified Sharp score are actually the most commonly used scores in randomized controlled trials on biologic drugs actually available in scientific literature. An intensive literature search (EMBASE, PubMed, MEDLINE) was performed in order to identify randomized controlled studies reporting on the efficacy of biologic drugs on radiologic progression in rheumatoid arthritis by means of approved scoring methods such as Sharp score variants. All studies were evaluated for their approach to radiologic outcome, and a global evaluation of trends towards radiologic evaluation was performed. Eighteen studies were identified and analyzed, and data from such randomized controlled trials (RCTs) were reported and described regarding their approach to radiologic outcomes. The use of three different scoring methodologies generated similar but non-comparable data; although a big part of the studies reported good efficacy profiles of several biologic drugs on radiologic progression, data from such studies are not comparable as the three different scoring methods are not convertible from one to another. At present, there is no standardization for the evaluation of radiologic outcomes, thus preventing comparison of results obtained by different drugs. The use of a single, standardized and widely approved scoring method would grant the possibility of comparing such data.