Anti-tumor necrosis factor α: originators versus biosimilars, comparison in clinical response assessment in a multicenter cohort of patients with inflammatory arthropathies.

OBJECTIVE: To compare etanercept and adalimumab biosimilars (SB4 and ABP501) and respective bioriginators in terms of safety and efficacy in a real-life contest. METHODS: We consequently enrolled patients affected by rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, treated with SB4, and ABP501, or with corresponding originators, belonging to the main biological prescribing centers in the Lazio region (Italy), from 2017 to 2020. Data were collected at recruitment and after 4, 8, 12, and 24 months of therapy. RESULTS: The multicenter cohort was composed by 455 patients treated with biosimilars [SB4/ABP501 276/179; female/male 307/146; biologic disease-modifying anti-rheumatic drug (b-DMARD) naïve 56%, median age/ interquartile range 55/46-65 years] and 436 treated with originators (etanercept/adalimumab 186/259, female/ male 279/157, b-DMARD naïve 67,2%, median age/interquartile range 53/43-62 years). No differences were found about safety, but the biosimilar group presented more discontinuations due to inefficacy (p<0.001). Female gender, being a smoker, and being b-DMARD naïve were predictive factors of reduced drug survival (p=0.05, p=0.046, p=0.001 respectively). The retention rate at 24 months was 81.1% for bioriginators and 76.5% for biosimilars (median retention time of 20.7 and 18.9 months, respectively) (p=0.002). Patients with remission/low disease activity achievement at 4 months showed a cumulative survival of 90% to biosimilar therapy until 24 months (p=0.001); early adverse reactions instead represented a cause of subsequent drug discontinuation (p=0.001). CONCLUSIONS: Real-life data demonstrated a similar safety profile between biosimilars and originators, but a reduced biosimilar retention rate at 24 months. Biosimilars could be considered a valid, safe, and less expensive alternative to originators, allowing access to treatments for a wider patient population.

Polypharmacy is a determinant of hospitalization in Parkinson's disease.

OBJECTIVE: Patients with Parkinson's disease (PD) are at a higher risk of hospitalization and recurrent hospitalizations, with consequent complications. Polypharmacy is associated with several adverse outcomes, including hospitalization, increased length of hospital stay, and mortality. The aim of this study was to evaluate among patients with PD the association between the number of medications and incident hospitalizations. PATIENTS AND METHODS: We analysed the data of 165 patients with Parkinson's disease attending a geriatric Day Hospital who were enrolled in a cohort study and followed for a median of two years. RESULTS: Over the follow-up, 46 participants (46%) were hospitalized at least one time; multiple admissions were observed in 12 subjects (7%). The median number of agents was 5 (4-7). In Cox regression, the number of drugs was associated with increased hospitalization rates (HR=1.23; 95% CI=1.06-1.43), also after excluding non-neurological medications (HR=1.18; 95% CI=1.01-1.38). Using Poisson regression, polypharmacy (i.e., use of >5 drugs) predicted the number of repeated hospitalizations (IRR=2.62; 95% CI=1.28-5.36; p=.008). CONCLUSIONS: Among patients with PD, the number of daily medications is associated with increased risk of hospitalization; an increasing number of drugs is associated with increasing number of hospitalizations.

Endothelial-to-mesenchymal transition in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by significant vascular alterations and multi-organ fibrosis. Microvascular alterations are the first event of SSc and injured endothelial cells (ECs) may transdifferentiate towards myofibroblasts, the cells responsible for fibrosis and collagen deposition. This process is identified as endothelial-to-mesenchymal transition (EndMT), and understanding of its development is pivotal to identify early pathogenetic events and new therapeutic targets for SSc. In this review, we have highlighted the molecular mechanisms of EndMT and summarize the evidence of the role played by EndMT during the development of progressive fibrosis in SSc, also exploring the possible therapeutic role of its inhibition.

Evaluation of the influence of social, demographic, environmental, work-related factors and/or lifestyle habits on Raynaud's phenomenon: a case-control study.

Raynaud's phenomenon (RP) is a clinical disorder characterized by recurrent, reversible episodes of digital vasospasm. RP can be classified as primary (pRP) or secondary, depending on whether it occurs as a benign condition (not disease-associated) or is associated with other diseases, mainly of the connective tissues. In both cases, it can be triggered by environmental factors, as indicated by the increased incidence of pRP episodes following exposure to cold, vibration injury or chemicals. The purpose of this prospective case-control study was to assess, in an Italian cohort of 132 pRP patients, the association of the phenomenon with demographic, lifestyle habits, environmental and work-related factors. Compared to healthy controls, pRP was found to be inversely associated with the use of contact lenses (OR = 0.4; p = 0.004) and of chlorous-based disinfectants (OR = 0.3; p < 0.001) and directly associated with the presence of prosthesis implants (OR = 5.3; p = 0.001) and the use of hydrogen peroxide-based compounds (OR = 2.6; p = 0.002), suggesting that the latter should be avoided in RP affected patients. Multivariate and multivariable analysis confirmed the associations. Further investigations are needed to understand the mechanism(s) underlying these findings.

The association between duration of remission, fatigue, depression and health-related quality of life in Italian patients with systemic lupus erythematosus.

OBJECTIVE: To evaluate the impact of duration of remission on the health-related quality of life (HRQoL) of patients with systemic lupus erythematosus (SLE). METHODS: We conducted a 5-year retrospective study on two Italian cohorts. Remission was defined as a continuative period of no clinical disease activity, according to the Systemic Lupus Erythematosus Disease Activity Index 2 K, and a permitted maximum prednisone dose of 5 mg/day. HRQoL was measured using the 36-Item Short-Form Health Survey (SF36) during the last visit. RESULTS: We enrolled 136 female SLE patients. During observation, 15 (11%) patients had been in remission for ≥1 and <2 years, 15 (11%) for ≥2 and <3 years, 19 (14%) for ≥3 and <4 years, 9 (7%) for ≥4 and <5 years, and 53 (39%) had been in prolonged remission for ≥5 years. In the multivariate model, considering depression and fatigue as covariates, patients in prolonged remission showed significantly better scores in the physical functioning (p = 0.039), role physical (p = 0.029), bodily pain (p = 0.0057), general health (p = 0.0033) and social functioning (p = 0.0085) components of the SF36, compared with those in remission <5 years or unremitted. Subsequent mediation analyses found that these effects were partly influenced by depression. CONCLUSION: Lupus remission could improve the HRQoL of SLE patients, particularly when associated with appropriate management of depression and fatigue.

Inflammation as a mediator of the association between osteoporosis and hearing loss in older subjects: a population-based study.

OBJECTIVE: Due to the aging of populations, the prevalence of hearing loss and osteoporosis is increasing. Previous studies have found an association between these conditions. Nevertheless, the pathophysiologic pathway of such an association has not yet been established. The present study aimed at evaluating the association, if any, of hearing loss with osteoporosis in an older unselected population, and whether this association varied according to inflammatory status. PATIENTS AND METHODS: We assessed the association of osteoporosis with a self-reported hearing loss in all 310 subjects aged 75+ living in Tuscania (Italy), without exclusion criteria. Bone density was assessed by calcaneal quantitative ultrasound; osteoporosis was defined as a T-score ≤ -2.5 Standard Deviation. RESULTS: Hearing loss was associated with osteoporosis (OR = 1.84, 95% CI = 1.03-3.28; p = 0.40) in multivariable logistic regression analysis, after adjusting for potential confounders. Analysis of the interaction term indicated that this association varied according to the erythrocyte sedimentation rate, ERS (p = 0.030), and high-sensitivity C reactive protein, hs-CRP (p = 0.017) but not sex (p = 0.832). Of notice, this association was significant only for higher levels of inflammatory parameters (OR = 2.82; 95% CI = 1.15-6.90; p = 0.023 for the higher ERS tertile; and OR = 3.81; 95% CI = 1.36-10.63; p = 0.011 for the higher hs-CRP tertile vs. lower tertiles). CONCLUSIONS: Hearing loss is associated with osteoporosis in community dwelling elderly. Such an association seems to depend upon higher inflammation levels.

Primary prevention of cardiovascular disease in patients with systemic lupus erythematosus: case series and literature review.

Background Systemic lupus erythematosus is associated with an increased risk of cardiovascular disease. Low-dose aspirin, hydroxychloroquine and statins have been suggested to play a prophylactic role of cardiovascular events. This study is devoted to reviewing the literature on the topic and assessing the effects of these drugs in preventing a first cardiovascular event in a two-centre Italian series. Methods A PubMed search on cardiovascular prevention in systemic lupus erythematosus was performed. Moreover, systemic lupus erythematosus patients admitted to two centres from 2000-2015, who at admission had not experienced any cardiovascular event, were investigated. Aspirin, hydroxychloroquine and statin use, and the occurrence of any cardiovascular event, were recorded at each visit. Kaplan-Meier and Cox regression analyses were performed to evaluate the role of traditional, disease-related cardiovascular risk factors and of each of the three drugs in the occurrence of new cardiovascular events. Results The literature search produced conflicting results. Two hundred and ninety-one systemic lupus erythematosus patients were included in the study and followed for a median of eight years. During follow-up, 16 cardiovascular events occurred. At multivariate analysis, taking aspirin (hazard ratio: 0.24) and hydroxychloroquine for more than five years (hazard ratio: 0.27) reduced, while antiphospholipid antibody positivity (hazard ratio: 4.32) increased, the risk of a first cardiovascular event. No effect of statins emerged. Conclusion Our study confirms an additive role of aspirin and hydroxychloroquine in the primary prophylaxis of cardiovascular events in Italian patients with systemic lupus erythematosus. The lack of any detected effect in previous reports may depend on the design of studies and their short follow-up period.

The IL33/ST2 axis in Sjogren syndrome in relation to disease activity.

OBJECTIVE: Primary Sjogren's Syndrome (pSS) is a systemic autoimmune disorder characterized by infiltration of the exocrine glands leading to secretory insufficiency. Despite the progress made in understanding the pathogenesis of the SS, many aspects remain to be clarified. Interleukin-33 (IL33) is a recently discovered cytokine, belonging to IL-1 superfamily. IL33 and its soluble receptor ST2 were implied in a number of immune and in autoimmune diseases pathogenesis. In this work ,we analyzed expression of IL33 and ST2 in Sjogren's syndrome. PATIENTS AND METHODS: Serum IL-33 and soluble ST2 were analyzed using commercial ELISA kit in 15 pSS, 9 patients with Systemic Lupus Erythematosus and 9 controls. RESULTS: We found significant hyperexpression of sST2 in sera of SS patients and SLE patients compared to healthy subjects (p = 0.04 and p = 0.07, respectively). In pSS, sST2 levels in pSS positively correlated with activity index SSDAI (r = 0.662, p = 0.007). In SLE, we found positive correlation between ST2 and SLEDAI 2K (r = 0.685, p = 0.04). Circulating levels of IL-33 were detectable in 2 of 15 SS patients, in 2 SLE patients and in 1 of control subjects. CONCLUSIONS: We found an hyperexpression of sST2 in pSS and SLE patients with a possible immune modulatory role, because of a substantial suppression of circulating IL33. In our pSS and SLE cohort, sST2 levels were in correlation with disease activity indices.

Relationship between leptin and regulatory T cells in systemic lupus erythematosus: preliminary results.

OBJECTIVE: Crescent literature data demonstrated a role of adipokines in immune responses, particularly leptin is involved in wide spectrum of pro-inflammatory functions. Several evidences suggested that leptin is able to inhibit T regulatory cells proliferation and function in vitro models. In the present study, we investigate the relationship between leptin and circulating T regulatory cells (Tregs) in patients affected by systemic lupus erythematosus (SLE). PATIENTS AND METHODS: 13 SLE patients and 11 healthy controls were enrolled. Metabolic syndrome and cardiovascular parameters were evaluated. Serum leptin levels were detected by commercial ELISA kit and circulating regulatory T cells were determined by FACS analysis as CD4+CD25highFOP3+ lymphocytes. RESULTS: Metabolic syndrome, defined by ATPIII criteria, was more prevalent in SLE compared to controls (38.4% vs. 0%, p = 0.04), as well as arterial hypertension (38.4% vs. 0%, p = 0.04). We did not find significant differences in mean leptin levels among SLE and controls (13.13 ± 1.51 ng/ml vs. 9.48 ± 8.67 ng/ml, p = 0.6). Mean Tregs percentage of total CD4 were 1.27 ± 0.9 in SLE vs. 2.8 ± 1.2 in healthy controls (p = 0.001). We found a negative correlation between leptin levels and Tregs percentage of total CD4 in SLE patients (r = 0.4, p = 0.01). CONCLUSIONS: Our results suggest a role of leptin in the regulation of circulating T regulatory cells amount in human SLE.

Hepatic PPARs: their role in liver physiology, fibrosis and treatment.

Complex molecular and cellular mechanisms are involved in the pathway of liver fibrosis. Activation and transformation of hepatic stellate cells (HSCs) are considered the two main reasons for the cause and development of liver fibrosis. The peroxisome proliferator-activated receptors (PPARs) belonging to the family of ligand-activated transcription factors play a key role in liver homeostasis, regulating adipogenesis and inhibiting fibrogenesis in HSCs. Normal transcriptional function of PPARs contributes to maintain HSCs in quiescent phase. A reduced expression of PPARs in HSCs greatly induces a progression of liver fibrosis and an increased production of collagen. Here, we discuss role and function of PPARs and we take into consideration molecular factors able to reduce PPARs activity in HSCs. Finally, although further validations are needed, we illustrate novel strategies available from in vitro and animal studies on how some PPARs-agonists have been proved effective as antifibrotic substances in liver disease.

Molecular heterogeneity of arabinogalactan-protein from Coffea arabica instant coffee.

Arabinogalactan-protein complex (AGP), isolated from freeze-dried instant coffee powder of Coffea arabica beans, was subjected to ion-exchange chromatography. Stepwise elution with water and solutions of sodium chloride with increasing ionic strength afforded eight fractions (F1-F8). Chemical analyses have shown that compositions of individual conjugates varied in carbohydrate and protein contents, molecular mass and slightly in monosaccharide composition. Protein content was increasing by increasing ionic strength of the eluent and it was confirmed also by FT-IR spectra. NMR study has shown that carbohydrate moieties in individual ion exchange fractions differed in the degree of backbone and side chains branching. Performed study has confirmed a molecular heterogeneity of arabinogalactan-protein complex present in a commercial instant coffee.

Effect of sugars on liquid-vapour partition of volatile compounds in ready-to-drink coffee beverages.

The effect of sugars (sucrose, lactose, glucose, fructose, 10%w/v) on the liquid-vapour partition of selected volatile compounds of coffee beverages has been investigated in espresso coffee and ready-to-drink (RTD) canned coffee prepared and obtained by using the same Arabica roasted coffee beans blend. Aroma composition of coffee beverages has been preliminary investigated by headspace-gas chromatography (HS-GC) and solid phase microextraction-HS-GC-mass spectrometry to characterize the volatile pattern of the systems and to evaluate the effects of sugars on the aroma release/retention. Then, the liquid-vapour partition coefficient (k) of 4 selected key aroma compounds (diacetyl, 2,3-pentanedione, ethylpyrazine, hexanal) was determined in water, sugars solutions as well as RTD coffee brews added with the same sugars (10%w/v). Sugars added in coffee beverages affected the release of the volatiles and thus its aroma profile with differences due to the type of added sugar and coffee brew type. The k values of the selected volatile compounds resulted different depending on the model system composition (water, coffee brew) and sugar type added. In particular, melanoidins as well as other non-volatile components (lipids, acids, carbohydrates) in the RTD coffee brews could be implied in the change of k of the volatile compounds in respect to that observed in water. The effects of the sugar type on the release/retention of the four key coffee aroma compounds were partly explained in terms of 'salting out' especially for the more polar volatile compounds and in the sucrose-added model systems. The change of chemical and physico-chemical properties of the water and brews induced by the sugars as well as the occurrence of interactions between volatile compounds and non-volatile components may be implied in the reduction of the vapour partition of the aroma compounds.

Systemic lupus erythematosus patients with and without neuropsychiatric manifestations: a neck and transcranial duplex sonography study.

Neuropsychiatric manifestations are not rarely associated with systemic lupus erythematosus (SLE). Magnetic resonance angiography and positron emission tomography can provide excellent images of cerebral perfusion and metabolism whereas information is still lacking on a possible diagnostic role of ultrasound. In this study we aim to assess whether duplex sonography of neck and intracranial vessels may be useful in distinguishing patients with and without neuropsychiatric SLE (NPSLE). Neck and transcranial duplex sonography was performed by a single operator on 33 women affected by SLE (mean age +/- SD: 47.69+/-8.17 years) and on 15 healthy control subjects. Nineteen patients presented NPSLE. Pulsatility and resistivity indices (PI and RI) were automatically calculated by the ultrasound instrument in internal carotid (ICA) and middle cerebral artery (MCA), on both sides, according to standard methods. No significant haemodynamic differences were found in mean and median PI and RI values of ICA and MCA comparing SLE with NPSLE patients and with healthy control subjects. No correlation was found between MCA and ICA parameters in the same group of patients. Duplex sonography of cerebral vessels is unable to distinguish SLE and NPSLE patients. Heterogeneity of causes in the pathogenesis of NPSLE and the different vascular adaptation of cerebral macrocirculation as opposed to cerebral microcirculation may represent possible reasons that explain the inability of ultrasound to differentiate SLE patients from NPSLE patients.

Antitussive and immunomodulating activities of instant coffee arabinogalactan-protein.

A low molecular mass arabinogalactan-protein (AGP) composed of galactose and arabinose with a low protein content, isolated from the instant coffee powder of Coffea arabica beans, has been tested on antitussive (in vivo) and immunomodulating (ex vivo) activities. The results of antitussive tests revealed a significant dose dependant cough-suppressive effect of coffee AGP. It was observed 30 or 60 min after AGP administration and its efficacy lasted during the entire experiment course. Immunological tests showed that AGP affected some mediators of immunocompetent cells of immune system as TNF-α, IFN-γ and IL-2 cytokines. It seems that coffee AGP is a good inductor of both pro-inflammatory cytokines TNF-α and IFN-γ, however, less potent in TNF-α induction in comparison with that of ß-D-glucan. Evident induction of TNF-α, IL-2 and IFN-γ cytokines, pro-TH1 polarization supports our conclusion about bio-immunological efficacy of AGP with an emphasis on the cellular immunity.

Mechanism of chiral recognition in the enantioseparation of 2-aryloxypropionic acids on new brush-type chiral stationary phases.

New brush-type chiral stationary phases (CSP I-IV) comprising N-3,5,6-trichloro-2,4-dicyanophenyl-L-alpha-amino acids (1-4) were prepared by binding of chiral selectors 1-4 to gamma-aminopropyl silica gel. To check the role of excess free aminopropyl groups, CSP V was prepared by binding N-3,5,6-trichloro-2,4-dicyanophenyl-L-alanyl-(3-triethoxysilyl)propylamide to unmodified silica gel. The best separation of racemic 2-aryloxypropionic acids (TR-1-13) was obtained with CSP I; the -(-)-S enantiomer were regularly eluted first, as determined by a CD detector. The mechanism of chiral recognition implies a synergistic interaction of carboxylic acid analyte with the chiral selector and achiral free gamma-aminopropyl units on silica. In fact, CSP V, which is lacking an achiral aminopropyl spacer, shows a lower separation ability for 2-aryloxypropionic acids, but a similar enantioselective discrimination of esters TR-19-20, in comparison with CSP I. CSP I-IV retain unaltered separation ability after a few months of continuous work using a large number of various mobile phases.

Isolation and characterization of the exopolysaccharide produced by Streptococcus thermophilus SFi20.

This paper reports isolation, structural characterization and some physico-chemical properties in aqueous solution of the exopolysaccharide (EPS) produced by Streptococcus thermophilus strain SFi20. The yield of the purified EPS was found to be reproducible and close to the average value of 143 mg/l. The chemical structure, previously suggested, has been confirmed on the basis of NMR data. Viscometric, chiro-optical and rheological measurements have been carried out with the aim of characterizing the conformational state of the polysaccharide in aqueous solution. All the data reported indicate that the EPS does not undergo a cooperative conformational transition under the investigated experimental conditions. Furthermore, the viscosity data and the viscoelastic behaviour suggest that the polymer is rather flexible and adopts a random coil conformation in aqueous solution.

Exopolysaccharide-producing lactic acid bacteria strains from traditional Thai fermented foods: isolation, identification and exopolysaccharide characterization.

Lactic Acid Bacteria (LAB) isolated from various traditional Thai fermented foods were screened for exopolysaccharides (EPS) production. From 104 isolates, two rod-shaped and five coccal-shaped LAB were able to produce EPS from sucrose on solid media. However, only the cocci were capable of producing EPS in liquid media and these were identified as Pediococcus pentosaceus. Pediococcus pentosaceus strains AP-1 and AP-3 produced EPS in high yield. In liquid media containing sucrose as carbon source, the amount of EPS produced by AP-1 and AP-3 strains was 6.0 and 2.5 g/L, respectively. The isolated and purified EPSs were chemically characterized. On the basis of sugar composition, methylation analysis and nuclear magnetic resonance spectroscopy, both the EPSs were shown to belong to the same dextran class. In particular, both EPSs differed from linear dextran by branching through 3,6-di-Osubstituted alpha-D-glucopyranosyl residues. The EPS from P. pentosaceus AP-3 was characterized by a relatively higher degree of branching and by a higher molecular weight than that from P. pentosaceus AP-1.

Effect of monomer composition on proton dissociation of weak polyacids.

The study of the proton dissociation process of weak polyacids (eg a carboxylic poly(monoprotic)acid) is based on the knowledge of the change in electrostatic free energy, G(el), as a function of the variation of the number of charges on the polymer chain. The original treatment proposed by Manning can be used to describe the proton dissociation process of weak poly(monoprotic)acids, in the absence of pH-induced conformational transitions. In order to describe the alpha dependence of pKa of weak co-poly(monoprotic)acids containing two different acidic groups in different amounts along the polymer chain, a simple modification of the model is proposed.