Search Results (102)

Lymphotoxin-alpha (LTα3) is a soluble cytokine of the TNF superfamily. Its role in inflammation and arthritis is not well known. Macrophages are important in K/BxN Serum-Transfer Arthritis (STA) and rheumatoid arthritis (RA). Anti-TNF monoclonal antibodies as well as etanercept (ETA), a soluble TNF receptor II that also neutralizes LTα3, are efficient in the treatment of RA. Objectives: To evaluate the role of LTα3 in macrophage phenotypes and in arthritis. Methods: Macrophages were cultured in the presence of recombinant LTα3, and their phenotypes were studied. The clinical effect of blocking LTα3 in STA was evaluated, as well as the effect of switching from anti-TNF monoclonal antibodies to etanercept in the “ROC” register of RA patients. Results: We showed that recombinant LTα3 was capable of directing mouse and human macrophages towards a pro-inflammatory “M1” phenotype. In K/BxN STA, ETA decreased clinical score and joint swelling. Anti-LTα3 reduced arthritis only in TNF-KO mice, indicating that the effect of LTα3 was visible in the absence of TNF. The “ROC” register indicated that switching anti-TNF mAb to ETA did not induce clinical and biological improvement in RA. Conclusion: We show a pro-inflammatory role for LTα3 in murine and human macrophages. The neutralization of both TNF and LTα3 is not beneficial in the treatment of RA. Full article

(1) Background: TNF inhibitors (TNFis) have revolutionized the treatment of rheumatoid arthritis (RA). However, 30–40% of RA patients do not respond adequately to those biologics. In addition to neutralizing soluble TNF, TNFis have the ability to bind the transmembrane form of TNF, tmTNF. Importantly, tmTNF can act itself as a receptor that induces “Reverse Signaling” (RS) in cells. We previously showed that certolizumab, a Fab’ TNFi, activates RS in human primary monocytes, at least in part through the transcription factor Nrf2 that is known to regulate the expression of genes involved in anti-inflammatory response and oxidative stress. (2) Methods: Here, we have developed an assay for the prediction of clinical response of RA patients to TNF inhibitors. This assay is based on mRNA quantitation of CD36 activation and of six genes induced by Nrf2 following tmTNF RS in fresh monocytes. (3) Results: We could predict the response to anti-TNF monoclonal antibodies (mAbs) with 93.3% accuracy. However, our method was not suitable for the prediction of the response to TNF soluble receptor etanercept. (4) Conclusions: We have developed a rather simple, short-term test that can be standardized. Predicting the response to TNF mAbs will help physicians offer the best available treatment and provide patients with personalized medicine. Full article

Psoriasis is a chronic inflammatory skin disease marked by abnormal keratinocyte proliferation and immune dysregulation. The vitamin D receptor (VDR) plays a crucial role in regulating skin cell growth and immune responses, but its expression in psoriatic skin and modulation by treatment remain unclear. This study aimed to analyze VDR mRNA expression in psoriatic skin tissue before and after etanercept therapy using RNAscope, an RNA in situ hybridization technique that, to the best of our knowledge, has not previously been applied in psoriasis research. Two bio-naïve adult patients with moderate to severe plaque psoriasis received etanercept (50 mg weekly) for 12 weeks. Skin biopsies from lesional and perilesional areas were collected at baseline and post-treatment. VDR expression was assessed in different epidermal layers and the dermis using a semi-quantitative scoring system. In one patient, a statistically significant decrease in VDR expression was observed in the perilesional dermis after treatment (p < 0.001), though this preliminary finding warrants careful interpretation given the very limited cohort size. Both patients exhibited a non-significant trend toward increased VDR expression in the lesional epidermis post-treatment. These preliminary findings suggest that etanercept may modulate VDR expression in psoriatic skin, but individual variability and the small sample size preclude definitive conclusions. The study primarily demonstrates the feasibility of using RNAscope for VDR analysis in patients with psoriasis, an approach that may be novel in this context, and underscores the need for larger investigations to confirm these preliminary findings and further clarify the role of VDR in disease pathogenesis and treatment response. Full article

Background: Alopecia areata (AA) is an autoimmune disease affecting 2% of the global population, often causing localized scalp hair loss that can progress to alopecia totalis or universalis. While corticosteroids and JAK inhibitors are effective, their significant side effects highlight the need for safer, more targeted treatments. Recently, biologics have gained attention as potential treatments for AA. Methods: A review of clinical trials, case series, and case reports published on PubMed was conducted to assess the efficacy of cytokine-targeting biologics for the treatment of AA. Data on the mechanism of action, treatment outcomes, and safety were extracted and analyzed. Results: Cytokine-targeting biologics identified included Dupilumab, Secukinumab, Tralokinumab, Etanercept, Ustekinumab, Infliximab, Adalimumab, and Tildrakizumab. Dupilumab and ustekinumab demonstrated strong efficacy, with dupilumab showing significant regrowth in 89% of cases and ustekinumab in all patients. Tralokinumab demonstrated a 33.75% improvement, with no patients achieving SALT₅₀. Limited efficacy was observed with secukinumab, tildrakizumab, and adalimumab, with 71.4%, 77.8%, and 50% of patients, respectively, showing no response. Disease worsening was observed in patients who received etanercept (29%) and infliximab (50%). Conclusions: Further research is necessary to optimize treatment protocols, identify predictive biomarkers, and, crucially, discover novel and more effective cytokine targets to advance biologics as a cornerstone therapy for AA. Full article

Background/Objectives: This study aimed to investigate the effectiveness of etanercept biosimilar 1 under real-world clinical conditions in patients with rheumatoid arthritis (RA), using not only clinical evaluation but also musculoskeletal ultrasound (MSUS). Methods: This multicenter, interventional, open-label, single-arm clinical trial conducted a 24-week follow-up. Patients with RA with moderate to high disease activity received weekly subcutaneous injections of etanercept biosimilar 1 at 50 mg/dose for 24 weeks. The effectiveness was evaluated with clinical indices and MSUS. Results: Twenty-three patients were evaluated during the study period. The primary endpoint involves a change in the Global OMERACT-EULAR Synovitis Score by MSUS in bilateral second–fifth metacarpophalangeal joints from baseline, demonstrating median (IQR) values of 0 (−4, 1), including 4 (1, 9.8) and 2 (0, 5) at baseline and 24 weeks, respectively. The clinical endpoints exhibited a good treatment response, with 15 (68%) and 18 (86%) patients achieving low disease activity or remission at 12 weeks and 24 weeks, respectively. Additionally, MSUS scores improved at both 12 and 24 weeks compared to baseline. The patients who achieved power doppler remission (total power doppler score = 0) at 24 weeks demonstrated a shorter disease duration and no previous use of biological disease-modifying antirheumatic drugs compared to those with no power doppler remission. Conclusions: Etanercept biosimilar 1 exhibited significant improvements not only in clinical indices but also in MSUS assessment, indicating its effectiveness at the structural level. Full article

Background: The advent of biosimilars has revolutionized the management of conditions like rheumatoid arthritis by offering cost-effective alternatives to expensive biologics. Objectives: This study aims to compare the post-marketing safety profiles of biosimilars used in rheumatology with their respective reference products (RPs). Methods: Data were retrieved from EudraVigilance for biosimilars of adalimumab, etanercept, infliximab, and rituximab, and compared with their RPs. Our analysis focused on biosimilars authorized before 2021, using data from January 2021 to December 2023. We conducted a descriptive analysis of suspected adverse events, categorized using the Medical Dictionary for Regulatory Activities, and performed a comparative analysis using the reporting odds ratio to identify potential safety signals of disproportionate reporting. Results: We analyzed 75,327 reports, identifying 566,249 drug–event pairs. The results indicate that biosimilars have safety profiles largely comparable to their RPs. Female patients predominated in the reports, representing 69.4% of RPs and 56.9% of biosimilars. Notably, biosimilars demonstrated higher reporting rates for non-serious suspected adverse drug events (AEs), such as injection site pain, arthralgia, and fatigue. Specific AEs, including drug ineffectiveness and off-label use, were more frequent for infliximab and etanercept biosimilars, possibly reflecting real-world usage patterns and nocebo effects. Serious AEs, including malignancies and immunological reactions, were also noted, underscoring the necessity for ongoing monitoring. Conclusions: Our findings suggest that biosimilars are safe alternatives to RPs, contributing to significant healthcare cost savings in the EU. This study underscores the need for ongoing pharmacovigilance and long-term safety research to validate the clinical use of biosimilars in rheumatology. Full article

Objectives: There are many explanations for increased levels of serum uric acid (SUA) in patients with psoriatic arthritis (PsA), but correlation with different treatment options in PsA is not well elucidated. Our aim was to determine the effects of biological disease-modifying antirheumatic drugs (bDMARDs) on SUA levels in patients with PsA. Materials and methods: We analyzed the data of PsA patients treated with different bDMARDs from January 2007 to June 2021. Patients treated with interleukin-17 (IL-17) inhibitors (secukinumab and ixekizumab) and tumor necrosis factor α (TNFα) inhibitors (golimumab, infliximab, adalimumab, certolizumab pegol, and etanercept) were included. Results: A total of 87 patients were included. The SUA levels decreased in 60 (69%) patients after a 3–6-month-long follow-up, and in 25 (28.7%), we noticed an increase. The average decrease in SUA levels was 9.4 ± 49.5 µmol/L (p = 0.039); for TNFα patients, it was 7.3 ± 59.8 µmol/L (p = 0.386), and for IL-17 patients, it was 12.6 ± 28.4 µmol/L (p = 0.013). The levels of SUA decreased in 81.8% of patients treated with infliximab, as well as in 76% of those treated with secukinumab and in 72.7% of those treated with etanercept. The largest average decrease in SUA levels was recorded in the group treated with golimumab (23 µmol/L). Conclusions: A significant decrease in SUA levels was noticed, especially in patients treated with IL-17 inhibitors. Further studies should identify which bDMARD is the most potent in the lowering of SUA levels. bDMARDs were efficient in PsA disease activity. Full article

Background: The most effective treatment approach for sacroiliac joint (SIJ) pain in spondyloarthropathy (SpA) patients remains unclear. This systematic review and meta-analysis aimed to assess the safety and effectiveness of different injective therapies for SIJ pain in SpA patients. Methods: A comprehensive literature search was conducted up to January 2024. The inclusion criteria encompassed studies in English, including comparative and non-comparative studies, and case series. A meta-analysis was performed on the available data. The “Checklist for Measuring Quality” by Downs and Black was used to evaluate the quality of included papers. Results: A total of 17 studies involving 494 patients were included: 12 prospective case series, 1 retrospective comparative study, 2 prospective comparative studies, and 2 randomized controlled trials. Steroid injections were analyzed in 15 studies, etanercept in 1, and infliximab in 1. A meta-analysis of 375 patients receiving steroid injections showed a significant reduction in visual analog scale (VAS) scores from 8.2 pre-treatment to 3.2 (p < 0.001) at short-term follow-up, with stability at mid-term follow-up (VAS 3.3, p < 0.001) and worsening at the last follow-up (VAS 5.1, p < 0.001). The failure rate was 13% (p = 0.019), and one study reported a 12.5% complication rate. Biologic therapies showed no complications or failures, with improvements in both VAS and BASDAI scores. Conclusions: Intra-articular steroid injections are effective and safe for SIJ pain in SpA patients, although their efficacy diminishes over time, and not all patients respond to treatment. Biologic therapies have shown promising results, but further research is needed to confirm their long-term efficacy. Full article

Background: Psoriasis is a skin disease characterized by the presence of erythematous, scaly plaques on the extensor surfaces of the body. Treatment varies according to the stage of the disease, with the most severe cases being treated with biologic treatments that differ in efficacy and persistence over time. This study aimed to evaluate the 10-year persistence of biologic drugs (adalimumab, etanercept, infliximab and ustekinumab) in the treatment of moderate-to-severe plaque psoriasis. Methods: A total of 143 patients (61 women and 82 men) were evaluated; data were collected from the electronic clinical history, and statistical analysis was performed using the SPSS program. In addition, 115 of them were genotyped in a previous study for 173 immune system genetic polymorphisms. Results: The persistence of biologic drugs at 10 years was 25.9% (95% CI: 17.2–34.5%). Adalimumab was the most persistent drug (41.5%), followed by ustekinumab (34.8%), infliximab (28%) and etanercept (9.3%). The main reason for discontinuation was insufficient efficacy (51%). Adalimumab allowed an increase in the dosing interval in 82.4% of patients who persisted and ustekinumab allowed an increase in 37.5%. The 10-year persistence was related to sex (higher in men, p < 0.001), biologic drug (p = 0.002) and polymorphisms in LMO4 (rs983332) (p = 0.014) and IL20RA (rs1167846) (p = 0.013). Conclusion: The results show that 25% of psoriasis patients treated with first-line biologics persisted at 10 years. Full article

Background/Objectives: Pulmonary fibrosis (PF) results in a progressive decline of lung function due to scarring. Drugs are among the most common causes of PF. The objective of our study was to reveal the structure of drugs involved in PF development. Methods: we performed a retrospective descriptive pharmacoepidemiologic study on spontaneous reports (SRs) with data on PF registered in the Russian National Pharmacovigilance database for the period from 4 January 2019 to 31 May 2024. Results: A total of 1308 SRs on PF were finally identified with patients mean age of 59.3 ± 23.4 years. Death was reported in 30.7% (n = 401) with mean age of 59.9 ± 13.8 years. In the structure of culprit drugs, the following groups were leaders: antineoplastic and immunomodulating agents (51.9%); systemic hormonal preparations, excluding sex hormones and insulins (7.4%); drugs affecting nervous system (7.1%); respiratory system (7.1%); alimentary tract and metabolism (6.5%); and cardiovascular system (5.5%). In the total sample, the top ten drugs were rituximab (5.5%), methotrexate (4.4%), etanercept (4.2%), leflunomide (4.0%), adalimumab (3.7%), tocilizumab (3.3%), abatacept (3.0%), alendronic acid (2.7%), secukinumab (2.6%), and infliximab (2.4%). The number of SRs per year nearly doubled from 2021 to 2022 and from 2022 to 2023 with a maximum peak expected for 2024. Conclusions: Our study demonstrated increased reporting on PF in the National Pharmacovigilance database from 2019 to 2024. We revealed outstanding results for the role of antineoplastic and immunomodulating agents in PF development. Full article

Background/Objectives: Neuropathic pain is challenging to treat, often resistant to current therapies, and associated with significant side effects. Pregabalin, an anticonvulsant that modulates calcium channels, is effective but can impair mental and motor functions, especially in older patients. To improve patient outcomes, reducing the doses of pregabalin and combining it with other drugs targeting different neuropathic pain mechanisms may be beneficial. TNF-α blockers such as etanercept have shown potential in addressing neuropathic pain by affecting sodium channels, synaptic transmission, and neuroinflammation. This study evaluates the efficacy and safety of combining low doses of etanercept and pregabalin in allodynia and nociceptive tests. Materials and Methods: Male C57/BL6 mice underwent chronic constriction injury (CCI) of the sciatic nerve to induce neuropathic pain. They were divided into seven groups: sham control, CCI control, low and high doses of pregabalin, low and high doses of etanercept, and a combination of low doses of both drugs. Behavioral tests, including von Frey, hot-plate, and rotarod tests, were used to assess pain responses and motor activity. Results: The results indicated that a high dose of pregabalin significantly reduced mechanical allodynia and thermal hyperalgesia but impaired motor function. Conversely, low doses of etanercept alone had no significant effect. However, the combination of low doses of etanercept (20 mg/kg) and pregabalin (5 mg/kg) effectively alleviated pain without compromising locomotor activity. Conclusions: These results suggest a novel therapeutic strategy for neuropathic pain, enhancing analgesic efficacy while minimizing adverse effects. Full article

Ustekinumab is a fully human IgG1k monoclonal antibody that binds with high affinity and specificity to the p40 subunit of interleukins (IL-) 12 and 23, inhibiting their activity by preventing binding to their receptors. The European extension of the patent (Supplementary Protection Certificate) of ustekinumab expired on 20 July 2024. Biosimilar alternatives to ustekinumab are now an additional option for treating patients. The efficacy data for this drug in moderate-to-severe psoriasis obtained both from clinical trials and indirect comparisons through meta-analyses, are superior to those of etanercept and adalimumab, and its safety profile is more favorable than that of tumor necrosis factor (TNF) inhibitors. Several ustekinumab biosimilars have already been approved by regulatory agencies: between October 2023 and October 2024, Wezlana^® (Amgen ABP 654), Uzpruvo^® (Alvotech AVT04) and Pyzchiva^® (Samsung/Bioepis SB17) have been approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). SteQeyma^® (Celltrion Healthcare CT-P43) was approved by the EMA in August 2024. Otulfi^® (Fresenius Kabi/Formycon) was approved by the FDA in October 2024. Several other potential biosimilar candidates are under development, including BAT2206 (Bio-Thera), DMB-3115 (Dong-A ST), QX001S (Qyuns Therapeutic), BFI-751 (BioFactura), NeuLara (Neuclone), ONS3040 (Oncobiologics), and BOW090 (Epirus Biopharmaceuticals). In most cases, these monoclonal antibodies are expressed in cell lines (e.g., Chinese Hamster Ovary, CHO) different from those used for the originator (Sp2/0 spleen cell murine myeloma); of note, the cell line of origin is not a requirement for biosimilarity in the totality-of-evidence comparison exercise and may facilitate the production and reduce the immunogenicity of biosimilars originated in CHO cultures. This narrative review summarizes the available data on characteristics of the full comparability exercises and comparative clinical trials of these drugs. Full article

This case report describes an uncommon overlap syndrome between ankylosing spondylitis (AS) and amyotrophic lateral sclerosis (ALS). Initially, the patient was diagnosed with AS, for which he received various specific treatments, including TNF-α inhibitors. After five years of treatment with TNF-α inhibitor etanercept, the patient was referred for a full neurological assessment after he reported balance disturbances, postural instability, muscle weakness, and other neurological symptoms that indicated the presence of a neurological disorder. After a thorough investigation, the patient was diagnosed with ALS. This case report aims to contribute to the limited literature by providing a detailed case study regarding the crosstalk between AS and ALS while also exploring the potential underlying mechanisms and the possible link between TNF-α inhibitors therapy and ALS. Full article

Background: The treatment of psoriasis has made considerable progress with biologicals, including tumor necrosis factor inhibitors, and recently, monoclonal antibodies inhibiting directly interleukin (IL) 17, IL-23, or both IL-12/23. Newer biologicals are directed to the interleukin pathway and appear to improve complete or near-complete clearance. The newer biologicals have also been shown to have an excellent safety profile. However, despite experience with patients having confirmed the results obtained in clinical trials, there are still few data on using the newer biologicals. Methods: The present active study aimed to prospectively evaluate safety profiles and persistence of some biologicals in a multicenter pharmacovigilance study, that enrolled 733 patients treated with a biologic drug in five Calabrian hospital units. Informative and treatment persistence evaluations with predictors for suspension and occurrence of adverse events (AEs) were executed. In particular, reasons for treatment discontinuation in our program take account of primary/secondary failure or development of an AE. Results: AEs occurred in 187/733 patients and serious AEs (SAEs) were identified in 5/733 patients. An number of 182/733 patients showed a primary/secondary inefficacy. The AEs and SAEs were described with adalimumab, infliximab, and etanercept but not with abatacept, brodalumab, tildrakizumab, golinumab, ixekizumab, guselkumab, risankizumab, secukinumab, and ustekinumab. Conclusions: Our analysis, although limited by a small sample size and a short-term follow-up period, offers suitable data on commonly used biological agents and their safety, interruption rate, and the attendance of SAEs. Real-world studies should be carried out to evaluate other safety interests. Full article