Scleroderma is a disorder involving oral and facial tissues, with skin hardening, thin lips, deep wrinkles, xerostomia, tongue rigidity, and microstomia. The aim of this study was to investigate the ...prevalence of oral manifestations and temporomandibular disorders (TMD) in Systemic Sclerosis (SSc) patients compared with healthy people. Eighty patients (6 men, 74 women) fulfilling ACR/EULAR SSc Criteria were enrolled. A randomly selected group of 80 patients, matched by sex and age served as control group. The examination for TMD signs and symptoms was based on the standardized Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) through a questionnaire and clinical examination. SSc patients complained more frequently (78.8%) of oral symptoms (Xerostomia, dysgeusia, dysphagia and stomatodynia) than controls (28.7%) (χ² = 40.23 p = 0.001). TMD symptoms (muscle pain on chewing, difficulty in mouth opening, headaches) were complained by 92.5% of SSc patients and by 76.2% of controls (χ² = 8.012 p = 0.005). At the clinical examination, 85% of SSc patients showed restricted opening versus 20.0% of controls (χ² = 67.77 p = 0.001), 81.2% of SSc showed reduced right lateral excursion versus 50% of controls (χ² = 17.316 p = 0.001); 73.8% of SSc showed limited left lateral excursion versus 53.8% of controls (χ² = 6.924 p = 0.009); and 73.8% of SSc had narrow protrusion versus 56.2% of controls (χ² = 5.385 p = 0.02).
A complex web of dynamic relationships between innate and adaptive immunity is now evident for many autoinflammatory and autoimmune disorders, the first deriving from abnormal activation of innate ...immune system without any conventional danger triggers and the latter from self-/non-self-discrimination loss of tolerance, and systemic inflammation. Due to clinical and pathophysiologic similarities giving a crucial role to the multifunctional cytokine interleukin-1, the concept of autoinflammation has been expanded to include nonhereditary collagen-like diseases, idiopathic inflammatory diseases, and metabolic diseases. As more patients are reported to have clinical features of autoinflammation and autoimmunity, the boundary between these two pathologic ends is becoming blurred. An overview of monogenic autoinflammatory disorders, PFAPA syndrome, rheumatoid arthritis, type 2 diabetes mellitus, uveitis, pericarditis, Behçet’s disease, gout, Sjögren’s syndrome, interstitial lung diseases, and Still’s disease is presented to highlight the fundamental points that interleukin-1 displays in the cryptic interplay between innate and adaptive immune systems.
Abstract Purpose We provide a review of current knowledge on comparability between biosimilars and originator biologics in view of the continuous evolution occurring in this highly dynamic area. ...Methods English-language literature indexed in MEDLINE was explored, without time limits, to July 31, 2016, using the terms biosimilar , biotechnologic drug , biologic drug , monoclonal antibody , fusion protein , and anti–tumor necrosis factor . The reference lists of identified articles were examined carefully for additional pertinent publications. Findings Biological medicines are much more structurally complex and extremely sensitive to manufacturing conditions and therefore more difficult to characterize and produce than small molecule drugs. Even minor changes in manufacturing may lead to significant variations of the cellular systems used for biological production, as well as to differences in the structure, stability, or other quality aspects of the end product, all of which have the potential to affect tolerability and/or efficacy and increase the risk of immune responses. Owing to these issues, specific regulatory guidance on biosimilars is continuously evolving, and there is some disagreement on which studies need to be implemented to approve a biosimilar. According to current literature, the following points on biosimilars deserve consideration: biosimilar development is characterized by global harmonization, although several not fully answered questions remain regarding extrapolation of indications, switching or interchangeability, and tolerability; in patients with rheumatic diseases, the tolerability and efficacy of biosimilars in clinical practice remain to be established; several medical and patient associations have published position papers on biosimilars requesting that safety, efficacy, and traceability be carefully considered; long-term postmarketing studies should be implemented to allow physicians to gain confidence in biosimilars. Implications On the basis of current knowledge, and taking into consideration both regulatory rules and medical society positions, it can be concluded that, although cost savings are highly desirable, the approval process for biosimilars needs to place tolerability and efficacy, supported by scientifically sound evidence, as the highest priority. Moreover, physicians must retain full authority regarding the decision about which biopharmaceutical to use for treating patients.
Abstract There is raising interest in the scientific community about the impact of body mass on different rheumatologic diseases. A growing body of evidence suggests that the effect of obesity on ...joint structure goes beyond the simply overload but is based on a complex interwinding of cytokines, hormones, growth factors, and intracellular regulators that at different stages can modify the course of a rheumatologic disease and the clinical response to biotherapies. In these settings, psoriatic arthritis (PsA) and rheumatoid arthritis (RA) have been the more extensively studied. Intriguing is the finding that the interaction between obesity and diseases seems different for PsA or RA. Concerning PsA, epidemiologic studies have provided robust data about the association between obesity and prevalence of psoriasis or PsA. Yet obesity is associated with an increase in degree of disability and poor clinical outcome on treatment with anti-tumor necrosis factor (TNF) drugs. Nevertheless, there are clues suggesting that weight reduction above 5% from baseline increases the probability of achieving a good clinical response in PsA patients on anti-TNF drugs. On the contrary, the epidemiological association between obesity and RA seems to be restricted to some categories of patients with peculiar demographic and autoimmune status. Furthermore, obesity definitely impairs the clinical response of RA patients to anti-TNF treatment, and this might be an effect limited to TNF-blocking agents, as preliminary studies are not confirming these findings for abatacept or tocilizumab. However, the most puzzling aspect of the impact of obesity on RA is that obese patients tend to have a more clinical active disease, an impaired response to biotherapies, and a less radiographically evident joint damage over time. The latter is a very stimulating issue and the knowledge of the underlying mechanisms should be an auspicious challenge for the researchers, which will provide further insights on the overall management of RA.
Abstract Behçet's disease (BD) is a multi-systemic disorder of unknown etiology characterized by relapsing oral–genital ulcers, uveitis, and involvement of the articular, gastrointestinal, ...neurologic, and vascular systems. Although the primum movens of this condition remains unknown, a tangled plot combining autoimmune and autoinflammatory pathways has been hypothesized to explain its start and recurrence. In-depth analysis of BD pathogenetic mechanisms, involving dysfunction of multiple proinflammatory molecules, has opened new modalities of treatment: different agents targeting interleukin-1 have been studied in recent years to manage the most difficult and multi-resistant cases of BD. Growing experience with anakinra, canakinumab and gevokizumab is discussed in this review, highlighting the relative efficacy of each drug upon the protean BD clinical manifestations. Safety and tolerability of interleukin-1 antagonists in different doses have been confirmed by numerous observational studies on both large and small cohorts of patients with BD. In particular, the potential for Mycobacterium tuberculosis reactivation and tuberculosis development appears to be significantly lower with interleukin-1 blockers compared to tumor necrosis factor-α inhibitors, thus increasing the beneficial profile of this approach.
Rheumatoid arthritis (RA) patients are at high risk of cardiovascular (CV) events, and the chronic inflammatory state may generate quantitative and qualitative changes in lipoprotein fractions. The ...anti-IL-6 receptor tocilizumab (TCZ), even if effective in inflammation and joint damage prevention, determined significant alterations to RA patients’ lipid levels in randomized controlled trials, but real-world data are lacking. We evaluated the changes in lipid fraction levels and disease activity in a longitudinal cohort of RA patients on long-term treatment with tocilizumab (TCZ) in a community setting. We retrospectively selected 40 naïve-biologic RA patients on treatment with intravenous TCZ compared to 20 RA patients on methotrexate treatment as the control group. Total cholesterol (Tot-Chol), low-density lipoproteins (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels were measured at the baseline and at 12, 24, and 52 weeks thereafter. At the same points, 28-joint disease activity score (DAS28), clinical disease activity index (CDAI), and EULAR clinical responses were also assessed. During the first 24 weeks, we observed in TCZ-treated patients a progressive statistically significant (p<0.001) increase in Tot-Chol, LDL, HDL, and TG, which returned close to the baseline at 52 weeks. But no changes in the lipid-related CV risk indices Tot-Chol/HDL and LDL/HDL ratios and the atherogenic index (log10 TG/HDL) were detectable. Notably, we observed a statistically significant negative correlation between changes in lipid fractions and DAS28 or CDAI. The prolonged treatment with TCZ was associated to a transient increase in cholesterol’s fractions during the first 6 months of treatment, with inverse correlation to disease activity, but with no impact on surrogate lipid indices of atherogenic risk. These findings may aid clinicians in interpreting the RA patient’s lipid profile in daily clinical practice.
Abstract 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 analysed 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 gender female (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 (HR 0.93), while golimumab monotherapy positively (HR 2.21) associated to drug interruption. 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.
The prevalence of sarcopenia in rheumatic diseases has been evaluated in single diseases using various diagnostic approaches, generating conflicting data on the pathogenetic mechanism(s). Herein, we ...evaluated both muscle mass index (MMI) and muscle strength to assess sarcopenia and presarcopenia in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). Moreover, we evaluated the possible impact of disease/patient-related characteristics, therapeutic regimens, and nutritional aspects on sarcopenia. The present study included 168 patients of both genders, aged 40⁻75 years. All patients underwent a nutritional evaluation, physical activity level assessment, rheumatologic evaluation, and an MMI and muscle strength assessment. The prevalence of sarcopenia was about 20% in all the three rheumatologic diseases, whereas presarcopenia was significantly different in RA, PsA and AS (
= 0.006). At multivariate analysis, only age ≥60 years and the presence of a disability were associated with a significantly increased risk of sarcopenia (
= 0.006 and
= 0.01, respectively), while a higher C-reactive protein did not reach statistical significance. Sarcopenia is similar in RA, PsA and AS, whereas presarcopenia significantly differs in these three diseases. Disease activity/inflammation and nutritional aspects do not influence sarcopenia, while age ≥60 years and the presence of a disability significantly increase the risk of sarcopenia.
Objectives
EULAR recommendations do not suggest which biologic disease-modifying anti-rheumatic drug (bDMARD) should be preferred after failure of a first bDMARD in the treatment of rheumatoid ...arthritis (RA). In particular, few data are available regarding the effectiveness of a second-line bDMARD after failure of abatacept (ABA), tocilizumab (TCZ), and rituximab (RTX). The aim of this study was to analyze the retention rate of a second line with tumor necrosis factor inhibitors (TNFi) or other mechanisms of action (MoAs), after the failure of either RTX, TCZ, or ABA.
Methods
Two hundred and seventy-eight RA patients from the Italian GISEA registry were included in the study. RTX was the first bDMARD in 18% of patients, ABA in 45.7%, and TCZ in 36.3%, while the second bDMARD was a TNFi (group 1) in 129 patients and an agent with a different MoA (group 2) in 149.
Results
During a median follow-up of 22 months (IQR 68), 129 patients discontinued their treatment; patients of group 1 discontinued the treatment more frequently than patients of group 2 (
p
<0.001) with retention rates of 33.6±5.7% and 63.6±4.6% after 104 weeks for group 1 and group 2, respectively (
p
<0.001). At multivariate analysis, the mechanism of action was the only predictor for the maintenance in therapy.
Conclusions
According to our data, ABA, RTX, and TCZ seem to maintain a good retention rate also when used as a second-line therapy, suggesting their use after the failure of a non-TNFi as first-line therapy. However, specifically designed studies are needed to evaluate the more appropriate therapeutic strategies in RA, according to the first-line drug, including new targeted synthetic DMARDs.
Key Points
• A large proportion of rheumatoid arthritis patients fail the first biologic DMARD.
• Few data are available about the efficacy of biologic DMARD after the failure of a non-TNF inhibitor.
• Abatacept, rituximab, or tocilizumab seem to maintain a good retention rate after the failure of a first-course therapy with a non-TNF inhibitor.
The pathophysiology of osteoarthritis Iannone, Florenzo; Lapadula, Giovanni
Aging clinical and experimental research,
10/2003, Volume:
15, Issue:
5
Journal Article
Peer reviewed
Osteoarthritis (OA) is a complex disease whose pathogenesis includes the contribution of biomechanical and metabolic factors which, altering the tissue homeostasis of articular cartilage and ...subchondral bone, determine the predominance of destructive over productive processes. A key role in the pathophysiology of articular cartilage is played by cell/extra-cellular matrix (ECM) interactions, which are mediated by cell surface integrins. In a physiologic setting, integrins modulate cell/ECM signaling, essential for regulating growth and differentiation and maintaining cartilage homeostasis. During OA, abnormal integrin expression alters cell/ECM signaling and modifies chondrocyte synthesis, with the following imbalance of destructive cytokines over regulatory factors. IL-1, TNF-alpha and other pro-catabolic cytokines activate the enzymatic degradation of cartilage matrix and are not counterbalanced by adequate synthesis of inhibitors. The main enzymes involved in ECM breakdown are metalloproteinases (MMPs), which are sequentially activated by an amplifying cascade. MMP activity is partially inhibited by the tissue inhibitors of MMPs (TIMPs), whose synthesis is low compared with MMP production in OA cartilage. Intriguing is the role of growth factors such as TGF-beta, IFG, BMP, NGF, and others, which do not simply repair the tissue damage induced by catabolic factors, but play an important role in OA pathogenesis.
PDF
