1,721,104 research outputs found
Comparing Originator Biologics and Biosimilars: A Review of the Relevant Issues
No full textPurpose: 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
New strategies to address the pharmacodynamics and pharmacokinetics of tumor necrosis factor (TNF) inhibitors: A systematic analysis
No full textAIM:
To assess the putative link between antibody formation to adalimumab, infliximab and etanercept, circulating drug levels and clinical outcomes.
METHODS:
A literature search was conducted using Pubmed from inception to 5th March 2013 of original research articles relating to adalimumab, etanercept and infliximab that investigated the immunogenicity of each drug. Data were extracted to document the disease, anti-TNF-α agent, regimen, study design, use of concomitant immunosuppressive therapy, the relationship between drug administration and antibody assessment, the type of immunoassay and cut-off, plasma drug concentration, frequency of antibody and clinical assessments, antibody positivity rate and relationship between antibody positivity and clinical outcome. Studies were stratified by drug, disease area and whether or not concomitant immunosuppressive therapy had been given. All data were tabulated by publication and analyzed descriptively.
RESULTS:
A total of 57 original research articles were included in the analysis (infliximab n=34; adalimumab n=18; etanercept n=5). There was considerable heterogeneity in study design, methodology for anti-drug antibody detection and drug bioavailability evaluation. Consequently, it was difficult to compare the immunogenic potential of infliximab, adalimumab and etanercept, particularly because different assays with variable sensitivity and specificity were used. The timing of occurrence and the persistence of anti-drug antibodies appeared to be influenced by administration schedules and concomitant immunosuppressive therapy. Monitoring of circulating drug levels and anti-drug antibodies appears to be an emerging and cost-effective strategy for the management of the individual patient.
CONCLUSIONS:
Monitoring drug and anti-drug antibody levels appears to be a putative strategy for optimal and cost-effective intervention. However studies of consistent and homogeneous design, methodology and duration are warranted to assess the true incidence and consequences of immunogenicity
Automated tests of ANA immunofluorescence as throughput autoantibody detection technology: strengths and limitations
Full text linkAnti-nuclear antibody (ANA) assay is a screening test used for almost all autoimmune rheumatic diseases, and in a number of these cases, it is a diagnostic/classification parameter. In addition, ANA is also a useful test for additional autoimmune disorders. The indirect immunofluorescence technique on monolayers of cultured epithelial cells is the current recommended method because it has higher sensitivity than solid phase assays. However, the technique is time-consuming and requires skilled operators. Automated ANA reading systems have recently been developed, which offer the advantage of faster and much easier performance as well as better harmonization in the interpretation of the results. Preliminary validation studies of these systems have given promising results in terms of analytical specificity and reproducibility. However, these techniques require further validation in clinical studies and need improvement in their recognition of mixed or less common staining patterns
Technology Innovation for Discovering Renal Autoantibodies in Autoimmune Conditions
No full textAutoimmune glomerulonephritis is a homogeneous area of renal pathology with clinical relevance in terms of its numerical impact and difficulties in its treatment. Systemic lupus erythematosus/lupus nephritis and membranous nephropathy are the two most frequent autoimmune conditions with clinical relevance. They are characterized by glomerular deposition of circulating autoantibodies that recognize glomerular antigens. Technologies for studying renal tissue and circulating antibodies have evolved over the years and have culminated with the direct analysis of antigen–antibody complexes in renal bioptic fragments. Initial studies utilized renal microdissection to obtain glomerular tissue. Obtaining immunoprecipitates after partial proteolysis of renal tissue is a recent evolution that eliminates the need for tissue microdissection. New technologies based on ‘super-resolution microscopy’ have added the possibility of a direct analysis of the interaction between circulating autoantibodies and their target antigens in glomeruli. Peptide and protein arrays represent the new frontier for identifying new autoantibodies in circulation. Peptide arrays consist of 7.5 million aligned peptides with 16 amino acids each, which cover the whole human proteome; protein arrays utilize, instead, a chip containing structured proteins, with 26.000 overall. An example of the application of the peptide array is the discovery in membranous nephropathy of many new circulating autoantibodies including formin-like-1, a protein of podosomes that is implicated in macrophage movements. Studies that utilize protein arrays are now in progress and will soon be published. The contribution of new technologies is expected to be relevant for extending our knowledge of the mechanisms involved in the pathogenesis of several autoimmune conditions. They may also add significant tools in clinical settings and modify the therapeutic handling of conditions that are not considered to be autoimmune
Antibodies Against Anti-Oxidant Enzymes in Autoimmune Glomerulonephritis and in Antibody-Mediated Graft Rejection
No full textHistorically, oxidants have been considered mechanisms of glomerulonephritis, but a direct cause–effect correlation has never been demonstrated. Several findings in the experimental model of autoimmune conditions with renal manifestations point to the up-regulation of an oxidant/anti-oxidant system after the initial deposition of autoantibodies in glomeruli. Traces of oxidants in glomeruli cannot be directly measured for their rapid metabolism, while indirect proof of their implications is derived from the observation that Superoxide Oxidase 2 (SOD2) is generated by podocytes after autoimmune stress. The up-regulation of other anti-oxidant systems takes place as well. Here, we discuss the concept that a second wave of antibodies targeting SOD2 is generated in autoimmune glomerulonephritis and may negatively influence the clinical outcome. Circulating and renal deposits of anti-SOD2 antibodies have been detected in patients with membranous nephropathy and lupus nephritis, two main examples of autoimmune disease of the kidney, which correlate with the clinical outcome. The presence of anti-SOD2 antibodies in circulation and in the kidney has been interpreted as a mechanism which modifies the normal tissue response to oxidative stress. Overall, these findings repropose the role of the oxidant/anti-oxidant balance in autoimmune glomerulonephritis. The same conclusion on the oxidant/anti-oxidant balance may be proposed in renal transplant. Patients receiving a renal graft may develop antibodies specific for Glutathione Synthetase (GST), which modulates the amount of GST disposable for rapid scavenging of reactive oxygen species (ROS). The presence of anti-GST antibodies in serum is a major cause of rejection. The perspective is to utilize molecules with known anti-oxidant effects to modulate the anti-oxidative response in autoimmune pathology of the kidney. A lot of molecules with known anti-oxidant effects can be utilized, many of which have already been proven effective in animal models of autoimmune glomerulonephritis. Many molecules with anti-oxidant activity are natural products; in some cases, they are constituents of diets. Owing to the simplicity of these drugs and the absence of important adverse effects, many anti-oxidants could be directly utilized in human beings
Are IF-ANA the guiding light for SLE classification in the real-world setting?
No full textsponsorship: This work was funded by Ministero della Salute, Italy, Ricerca corrente 2020 to RG and PLM. (Ministero della Salute, Italy)status: Publishe
The challenges of lupus anticoagulants
No full textThe term "lupus anticoagulant" (LA) refers to a heterogeneous group of immunoglobulins behaving as acquired in vitro inhibitors of coagulation. These antibodies, namely anti-β2GPI and anti-prothrombin antibodies, induce the in vitro elongation of clotting time interfering with phospholipid-dependent coagulation cofactors. Positive LA is associated with thrombosis and pregnancy complications, providing one of the three laboratory criteria for the classification of the anti-phospholipid syndrome. LA is the strongest predictor of clinical events, especially when associated with other anti-phospholipid antibodies. Much more controversial is the risk conveyed by isolated and weak LA. LA detection is technically laborious, envisaging screening, mixing and confirming tests. Hopefully critical issues in LA detection, such as the interference of anticoagulants, will be overcome, in the next future
IMPROVEMENT OF CELL CHOLESTEROL TRAFFICKING-RELATED LIPOPROTEIN FUNCTIONS IN RHEUMATOID ARTHRITIS PATIENTS TREATED WITH ADALIMUMAB
No full textThe SPROUT study: A survey on current management practice of reproductive aspects in women of childbearing age with systemic autoimmune rheumatic diseases
No full textThe SPROUT (Survey on reproduction in RheUmaTology) study explored current practice in women of childbearing age with systemic autoimmune rheumatic diseases, investigating the counselling on contraception, the prescription of low dose acetylsalicylic acid (LDASA) to pregnant patients and the management of disease activity in the post-partum period. The SPROUT questionnaire was designed ad hoc and promoted in the three months before the "11th International Conference on Reproduction, Pregnancy and Rheumatic Disease". Between June and August 2021, 121 physicians responded to the survey. Even though 66.8% of the participants declared themselves to be confident in counselling surrounding birth control, only 62.8% of physicians always discuss contraception and family planning with women of childbearing age. Approximately 20% of respondents do not prescribe LDASA to pregnant women with rheumatic diseases, and wide heterogeneity exists in the dose and timing of LDASA prescription. Most respondents (43.8%) restart treatment with biological agents soon after delivery to prevent disease flares, opting for a drug compatible with breastfeeding while 41.3% of physicians continue biologics throughout pregnancy and post-partum. The SPROUT study highlighted the necessity to further foster physicians' education and identified the management of disease activity after delivery as a matter for discussion between all the clinicians involved in the care of pregnant women with rheumatic conditions
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