LC-HRMS analysis of 13 classes of pharmaceutical substances in food supplements.

Food supplements should not contain substances considered unsafe or pose a health risk to consumers. In recent years illegal adulterants have been found in various functional foods without notification of their presence or amount in the labelling. In this study, a validated method was developed and applied as a screening method to detect 124 forbidden substances belonging to 13 classes of compounds in food supplements. Liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) and a simple and rapid extraction protocol was applied to 110 food supplements collected from the internet market or during official controls in Italy. The percentage of non-compliant samples was 4.5%, relatively high compared with the official control results for these substances usually obtained on other food matrices. The results suggested the need to strengthen controls in this field to detect food supplement adulteration, which represents a potential health risk for the consumer.

Preliminary Data on Post Market Safety Profiles of COVID 19 Vaccines in Rheumatic Diseases: Assessments on Various Vaccines in Use, Different Rheumatic Disease Subtypes, and Immunosuppressive Therapies: A Two-Centers Study.

An increased risk of developing severe infections has been evidenced in rheumatic disease (RD) patients, and anti-COVID-19 vaccination is strictly recommended for RD patients. However, up to now, no data are available on safety, immunogenicity and efficacy of COVID-19 vaccinations in RD patients. The possible development of adverse events (AEs), including the flare-up of underlying RD, represents a matter of growing importance. The aim of our study is to assess, in RD patients, the safety profile of different types of approved vaccines and the possible influence of immunosuppressive therapies and clinical or demographic characteristics of RD patients on development of AEs. Participants (n = 185; 30.7%) received anti-COVID-19 vaccinations, 137 with autoimmune/chronic inflammatory RD (Au/cIn-RD) and 48 with nonautoimmune/chronic inflammatory RD (no-Au/cIn-RD). AEs were recorded in 42% of patients after the first dose of vaccine, and in 26% of patients after the second dose. The most common reported AEs after anti-COVID 19 vaccines were site injection pain (17%), headache (12%), fever (12%), myalgia (10%) and fatigue (10%). Relapses of the underlying Au/c-In-RD were recorded in 2.2% of patients after the first dose of vaccine. In Au/c-In-RD the risk of developing AEs after the first dose of vaccine was lower in older patients (OR = 0.95; p = 0.001), and in the group of patients with complete control of RD (OR: 0.2; p = 0.010). A lower percentage of AEs was observed in patients with complete control of their Au/cIn-RD (29%) compared to those with low (57%) or moderate-high disease activity (63%) (p = 0.002 and p = 0.006 respectively). In this study all types of COVID-19 vaccines in use in Italy seemed safe in RD patients. The results of this study might provide reassuring information for Au/cIn RD patients and clinicians and could strengthen the data on vaccine safety to guide the use of COVID-19 vaccines in Au/cIn-RD on immunosuppressive agents.

Retrospective evaluation of patient profiling and effectiveness of apremilast in an Italian multicentric cohort of psoriatic arthritis patients.

OBJECTIVES: We aimed to evaluate the baseline characteristics, the reasons for prescription, and the effectiveness/safety profile of real-life apremilast for the treatment of psoriatic arthritis (PsA). METHODS: PsA patients treated with apremilast were retrospectively extracted from an Italian multicentric cohort. Baseline population characteristics and reasons for apremilast prescription were analysed. Clinical response was defined as the proportion of patients achieving Disease Activity in PSoriatic Arthritis (DAPSA) remission/low disease activity (LDA), minimal disease activity (MDA), and very low disease activity (VLDA). Six-month retention rate was computed by the Kaplan-Meier method, with a detailed analysis of reasons for discontinuation. Univariate and multivariate models were developed to examine predictors of clinical response and persistence. RESULTS: The study population included 131 patients mainly with oligoarticular PsA (58%), carrying at least one comorbidity (64.1%, in particular history of malignancies [25.9%] and latent tuberculosis [16.3%]) treated with apremilast as first-line targeted therapy (47.7%) or in biologics failures (52.3%). Contraindication to biologics (60.3%) and lack of poor prognostic factors (27.5%) were the most frequent reason for apremilast prescription. The 6-month retention rate was 72.1%. Inefficacy (n=7), diarrhoea (n=10), nausea (n=3), and headache (n=7) were the most frequent reasons for discontinuation. At 3 months DAPSA LDA/remission, MDA, and VLDA were observed in 40.3, 6.7, and 5.6% of patients, respectively. Female sex was a negative predictor of both retention rate and clinical response. CONCLUSIONS: In our real-life analysis apremilast was mainly used in oligoarticular PsA carrying comorbidities leading to contraindications to biologics. Effectiveness and safety profiles were consistent with clinical trials.

Correction to: Drug survival and effectiveness of ustekinumab in patients with psoriatic arthritis. Real-life data from the biologic Apulian registry (BIOPURE).

In Fig. 1 - paned D, incorrect image was published. This is now presented correctly in this article.

Drug survival and effectiveness of ustekinumab in patients with psoriatic arthritis. Real-life data from the biologic Apulian registry (BIOPURE).

This study aims to evaluate the drug survival and effectiveness of ustekinumab in psoriatic arthritis (PsA) patients naïve to biologics or inadequate responders to tumor necrosis factor (TNF-IR) inhibitors in real life. PsA patients starting ustekinumab were enrolled from 2014 to 2016. Joint involvement, peripheral or axial, Psoriatic Area Severity Index, Disease Activity Psoriatic Arthritis (DAPSA), Lee Enthesitis Index, Health Assessment Questionnaire, body mass index, comorbidities, co-therapies, mechanism of action, and causes of discontinuation of prior TNFi were collected at baseline, and 6 and 12 months. Twelve-month drug survival was evaluated by Kaplan-Meier curves. Hazard ratios (HRs) of drug discontinuation adjusted for baseline factors were estimated by multiple Cox regression analysis. Percentages of DAPSA-based remission, as crude value and adjusted for drug retention (LUNDEX index), were compared by χ2 test. Mean differences of DAPSA from baseline to 6 and 12 months were compared between naïve and TNF-IR patients by ANOVA. Of 160 PsA patients starting ustekinumab, 54 were naïve and 106 were TNF-IR. Twelve-month drug survival was significantly higher in naïve (87%) than in TNF-IR (68%, p = 0.01). Baseline co-therapy with methotrexate did not increase the persistence on ustekinumab. Naïve patients had the lowest risk of ustekinumab discontinuation (HR 0.27, p = 0.01), and the highest DAPSA-based remission (34%, LUNDEX 26%). Mean differences from baseline of DAPSA was significantly greater in naïve than in TNF-IR patients at 12 months (- 14.4 ± 10 vs. - 4.1 ± 17, p = 0.01). Our data showed that ustekinumab has a good effectiveness in real life and the best outcomes are achieved in biologic-naïve PsA patients.

Subclinical atherosclerosis and history of cardiovascular events in Italian patients with rheumatoid arthritis: Results from a cross-sectional, multicenter GIRRCS (Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale) study.

Several studies have pointed out a significant association between rheumatoid arthritis (RA) and accelerated atherosclerosis. At the best of our knowledge, no such study has been carried out in a large Italian series and, in this study, we aimed to investigate the prevalence of both subclinical atherosclerosis and history of cardiovascular events (CVEs), in patients consecutively admitted from January 1, 2015 to December 31, 2015 to Rheumatology Units throughout the whole Italy.Centers members of GIRRCS (Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale) were invited to enrol patients consecutively admitted from January 1, 2015 to December 31, 2015 and satisfying American College of Rheumatology/ European League Against Rheumatism criteria for RA and to investigate each of them for: traditional cardiovascular risk factors: sex, age, smoking habit, total cholesterol, triglycerides, glycaemia, high blood pressure, metabolic syndrome (MS), type 2 diabetes (T2D); RA features: disease duration as assessed from the first symptom, disease activity as evaluated by DAS28, radiographic damage as assessed by hands and feet x-ray, and previous joint surgery; prevalence of both subclinical atherosclerosis and history of CVEs.Eight centers participated to the study. From January 1, 2015 to December 31, 2015, the 1176 patients, who had been investigated for all the items, were enrolled in the study. They were mostly women (80.52%), with a median age of 60 years (range, 18-91 years), a median disease duration of 12 years (range, 0.8-25 years), seropositive in 69.21%. Nineteen percent were in remission; 17.51% presented low disease activity; 39.45% moderate disease activity; 22.61% high disease activity.Eighty-two patients (6.9%) had a history for CVEs (58 myocardial infarction, 38 heart failure, 10 ischemic transitory attack, and 7 stroke). This figure appears to be lower than that reported worldwide (8.5%). After excluding the 82 patients with a history of CV events, subclinical atherosclerosis was detected in 16% of our patients, (176 patients), a figure lower than that reported worldwide (32.7%) and in previous Italian studies.This is the first Italian multicenter study on subclinical and clinical atherosclerosis in patients with RA. We pointed out a low prevalence of both subclinical atherosclerosis and history of CV events.

Anti-TNF-α effects on anemia in rheumatoid and psoriatic arthritis.

A key role in the pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) is played by inflammatory cytokines, including tumor necrosis factor-α (TNF-α), which are also involved in inducing inflammatory anemia. We have followed 67 RA patients and 64 PsA patients for 1 year to evaluate the effects of TNF-α inhibitors on disease activity and on inflammatory anemia. Patients were divided into three different treatment groups, according to a randomized assignment to receive therapy with etanercept, adalimumab, or infliximab. Treatment with anti-TNF-α resulted in a significant reduction in disease activity score-28 (DAS28) values both in RA and PsA patients, already from the third month of treatment ( P = 0.01). In both populations, there was an increase in hemoglobin (HB) levels already after 3 months of treatment ( P = 0.001), and HB levels were inversely proportional to the disease activity, regardless of the type of medication used. The increased HB values and the reduction of DAS28 values during the observation period suggest the existence of a negative correlation between them both in RA and PsA, regardless of the type of anti-TNF-α used. Our data suggest a pleiotropic action of anti-TNF-α, such as the well-known action on the activity of the disease, and the improvement in inflammatory anemia.

Golimumab in real-life settings: 2 Years drug survival and predictors of clinical outcomes in rheumatoid arthritis, spondyloarthritis, and psoriatic arthritis.

OBJECTIVES: To assess the drug survival of golimumab, and predictors thereof, in patients affected with rheumatoid arthritis (RA), spondyloarthritis (SpA), and psoriatic arthritis (PsA) in a prospective observational cohort. METHODS: This is a non-interventional, longitudinal study on RA, SpA, and PsA patients starting treatment with golimumab. Endpoints were the 2 years persistence rate of golimumab and predictors of therapy discontinuation. Drug retention was analyzed using Kaplan-Meier and Cox models. Hazard ratios (HR) of golimumab discontinuation were estimated by Cox-regression hazard models. RESULTS: Of 416 patients starting golimumab, 171 biologic-naïve and 245 inadequate responders to prior biologic drugs, 88 had RA, 147 SpA, and 181 PsA. Global 2 years drug retention was 70.2%, with no different hazard of discontinuation among diseases or line of biologic treatment. The strongest predictor of golimumab discontinuation was female gender (HR = 1.95). Golimumab monotherapy was associated with higher risk drug interruption (HR = 1.67). Within SpA, predictors of golimumab discontinuation were female sex (HR = 4.19), and absence of extra-articular manifestations (HR = 4.60). In PsA, duration of disease was negatively associated to drug interruption (HR = 0.93), whereas golimumab monotherapy was positively (HR = 2.21) associated. Interestingly, failing to achieve a good EULAR response at 3 months was the only predictor of golimumab discontinuation for RA patients (HR = 3.03). CONCLUSIONS: This study provided evidence that golimumab has high retention rate in real-life settings. SpA male patients with extra-articular manifestations, PsA patients on co-therapy with DMARDs, and RA patients attaining an early clinical response had the highest probability to continue golimumab over 2 years.

Biologic therapies and infections in the daily practice of three Italian rheumatologic units: a prospective, observational study.

Since the introduction of biologics, many concerns about the increased risk of infections have been reported and, to date, the real impact of infections on the daily practice in the rheumatologic centers is still largely unknown. In this work, we evaluated the infection rates associated with the use of biologics in a large cohort of patients. A prospective study, between January 2010 and December 2013, enrolling 731 rheumatic patients, was performed. Demographic and disease characteristics, therapies, comorbidities, and infectious events were recorded and statistically analyzed by multivariate analysis. Two-hundred thirty-five infectious episodes were observed in 28.4 % of patients. About total infections, bacteria were identified in 70.6 % of total cases and viruses in 18.3 %. The most common site of not-serious infection was the urinary tract. Duration of disease, longer follow-up, concomitant steroid therapy, and comorbidities were significantly associated with not-serious infection. In our cohort, 17 episodes fulfilled the criteria of serious infection and occurred in 17 different patients (2.3 %), the majority involving the lower respiratory tract. Serious infections were associated with the beginning of biologics in older age. Our prospective, observational study showed that, in daily practice, a lesser rate of serious as well as not-serious infections may be observed in rheumatic patients treated with biologics than those reported in previous papers. The most common sites of not-serious infections are both the urinary and the respiratory tracts, and for serious infections, the respiratory tract. When pathogens were isolated, we did not find any multidrug-resistant organism.

Metabolic syndrome and chronic arthritis: effects of anti-TNF-α therapy.

TNF-α plays a key role in the inflammatory cytokine cascade involved in the pathogenesis of chronic arthritis, including rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Systemic inflammation and the increased production of pro-inflammatory cytokines in these patients may favor the onset of metabolic syndrome. In patients affected by chronic arthritis, TNF-α is considered as one of the factors responsible for favouring insulin resistance and dyslipidemia, which are important features of the metabolic syndrome. Even if TNF-α is a single player in the great molecular cauldron of inflammation, the use of TNF-α inhibitors may be an important approach for not only treating articular and cutaneous symptoms but also for ameliorating glucose and lipid metabolism. Nevertheless, further research and clinical trials are needed to better determine the effects of biologic therapies on metabolic components in chronic arthritis patients and to identify the most appropriate strategies on the basis of the comorbidities in these patients.

Why TNF-α inhibition is not sufficient to avoid juxta-articular erosions in chronic arthritis?

There is an emerging interest in the role of anti-TNF-α therapy in reducing bone damage in chronic arthritis with special regard to rheumatoid arthritis. Accumulation of osteoclasts in rheumatoid synovial tissues, and their activation due to osteoclastogenic cytokines and chemokines at cartilage erosion sites suggest that they may advantageously be considered as therapeutic targets. Given that the primary role of TNF-α in osteoclastogenesis, the inhibition of TNF-α represents an important strategy for reducing bone damage in rheumatoid arthritis. In point of fact, there is evidence that treatment with anti-TNF-α agents may avoid or reduce bone damage in rheumatoid arthritis, even if further studies are required to provide a biological explanation and a link for the observation of the advantageous effects of TNF-α inhibitors on the progression of bone damage in chronic arthritis. The existence of factors involved in osteoclast activation, including IL-1, IL-6, IL-7, IL-11, IL-17, M-CSF, TGF-ß, MIP-1α, MIP-1ß, IP-10, MIG, and OSCAR, indicates that TNF-α is only a single player in the great molecular cauldron of osteoclastogenesis. The presence of mediators behind the TNF-α and RANK-RANKL complex that may be independent in inducing osteoclastogenesis, such as NFATc1, suggests that the anti-TNF-α therapy will not provide a complete reduction of bone damage in chronic arthritis.

Osteoclastogenesis and arthritis.

There is emerging interest for osteoclasts as key players in the erosive and inflammatory events leading to joint destruction in chronic arthritis. In fact, chronic inflammatory joint diseases such as psoriatic arthritis and rheumatoid arthritis are often characterized by destruction of juxta-articular bone and erosions due to the elevated activity of osteoclasts, which are involved in bone resorption. The main step in inflammatory bone erosion is an imbalance between bone resorption and bone formation: osteoclast formation is enhanced by proinflammatory cytokines such as TNF-α, IL-1ß, and IL-17 and is not balanced by increased activity of bone-forming osteoblasts. T-cells, stromal cells, and synoviocytes enhance osteoclast formation via expression of RANKL and, under pathologic conditions, of proinflammatory cytokines. In rheumatoid arthritis, accumulation of osteoclasts in synovial tissues and their activation associated with osteoclastogenic cytokines and chemokines at cartilage erosion sites suggest that they could be usefully selected as therapeutic target. In particular, in consideration of the primary role of RANKL and TNF-α in osteoclastogenesis, the control of the production of RANKL and the inhibition of TNF-α represent important strategies for reducing bone damage in this disease.