Dendritic Nanotheranostic for the Delivery of Infliximab: A Potential Carrier in Rheumatoid Arthritis Therapy

Antibodies are macromolecules that specifically recognize their target, making them good candidates to be employed in various therapies. The possibility of attaching a drug to an immunoglobulin makes it possible to release it specifically into the affected tissue as long as it overexpresses the target. However, chemical coupling could affect the functionality (specificity and affinity) of the antibody. It has been observed that the use of intermediaries, such as dendrimers, could resolve this issue. Because carbosilane dendrimers have aroused great interest in the field of biomedicine, this report describes the synthesis of an anionic carbosilane dendrimer with a fluorochrome on its surface that then forms a conjugate with an antibody. It has been used as immunoglobulin and infliximab, whose target is TNF-α, which is a cytokine that is overexpressed in the inflamed area or even in the blood of patients with autoimmune diseases, such as rheumatoid arthritis. In addition, the integrity and functionality of the antibody has been studied to see if they have been affected after the chemical coupling process.

Download Full-text

Exploring pharmacogenetic variants for predicting response to anti-TNF therapy in autoimmune diseases: a meta-analysis

Pharmacogenomics ◽

10.2217/pgs-2021-0019 ◽

2021 ◽

Author(s):

Charalabos Antonatos ◽

Eleana F Stavrou ◽

Evangelos Evangelou ◽

Yiannis Vasilopoulos

Keyword(s):

Rheumatoid Arthritis ◽

Autoimmune Diseases ◽

Inflammatory Bowel Diseases ◽

Meta Analysis ◽

European Descent ◽

Systematic Overview ◽

Tnf Α ◽

Subgroup Analyses ◽

Bowel Diseases ◽

Inflammatory Bowel

Aim: The aim of this study is to explore how SNPs may affect the response to anti-TNF-α therapy in the major autoimmune diseases, such as psoriasis, rheumatoid arthritis, inflammatory bowel diseases and Spondyloarthritis. Methodology: We conducted a systematic overview on the field, by assessing all studies that examined the association between polymorphisms and response to anti-TNF-α therapy in participants of European descent. Results: In total, six independent SNPs located in FCGR2A, FCGR3A, TNF-α and TNFRSF1B genes were significantly associated with response to TNF-α blockers, found mainly in disease-subgroup analyses. Conclusion: No common pharmacogenetic variant was identified for all autoimmune diseases under study, suggesting the requirement of more studies in the field in order to capture such predictive variants that will aid treatment selection.

Download Full-text

Biological therapy of arthritis and systemic autoimmune diseases

Orvosi Hetilap ◽

10.1556/oh.2007.28038 ◽

2007 ◽

Vol 148 (Supplement-1) ◽

pp. 63-70 ◽

Cited By ~ 4

Author(s):

László Tamási ◽

Zoltán Szekanecz

Keyword(s):

Rheumatoid Arthritis ◽

Autoimmune Diseases ◽

Lupus Erythematosus ◽

Biological Therapy ◽

Systemic Autoimmune Diseases ◽

Tnf Α ◽

Spondylitis Ankylopoetica

A biológiai terápia lényege, hogy a gyulladás egyetlen, jól meghatározott pontján (pl. egy adott citokin szintjén) hat. Ezáltal a sokszor igen bonyolult mechanizmusokból álló patogenetikai hálózatot egy adott ponton szakítja meg. Ma a rheumatoid arthritis a biológiai terápia szempontjából modellbetegség, mivel a legtöbb szerrel ebben a kórképben próbálkoztak. Ezt követően egyéb arthritisekben (pl. spondylitis ankylopoetica, psoriasisos arthropathia), majd egyes szisztémás autoimmun kórképekben (pl. szisztémás lupus erythematosus, scleroderma, myositisek, vasculitisek, Sjögren-szindróma stb.) kezdték el alkalmazni. A legtöbb kórkép esetében egy központi szereppel bíró citokin, a tumornekrózis faktor-α (TNF-α) gátlószerei állnak a terápia középpontjában. Azonban a biológiai terápia megtervezésekor az adott kórkép patogenezisét (pl. döntően Th1 vagy Th2 jellegét) figyelembe kell venni. Nem véletlen, hogy amíg egyes kórképekben (pl. rheumatoid arthritis, spondylitis ankylopoetica, psoriasis, polymyositis, polyarticularis juvenilis arthritis) döntően a TNF-blokkolók és a T-sejtek elleni gátlás vált be, addig másoknál (pl. lupus, Sjögren-szindróma, dermatomyositis) a B-sejt elleni terápia kecsegtet sikerrel. Ezen összefoglalóban a szerzők áttekintik az arthritisek és szisztémás autoimmun kórképek biológiai terápiájára vonatkozó legfontosabb adatokat. Kitérnek az alkalmazott szerek tulajdonságaira, a hatékonyság és biztonságosság kérdéseire egyaránt.

Download Full-text

The pulmonological manifestations of rheumatoid arthritis

Orvosi Hetilap ◽

10.1556/oh.2008.28385 ◽

2008 ◽

Vol 149 (29) ◽

pp. 1355-1361

Author(s):

György Bernscherer ◽

Csaba Karabélyos ◽

Zsolt Tarján

Keyword(s):

Rheumatoid Arthritis ◽

Hodgkin Lymphoma ◽

Non Hodgkin Lymphoma ◽

Tnf Α

A szerzők összefoglaló közleményükben az irodalmi adatok figyelembevételével áttekintik a rheumatoid arthritis primer és szekunder pulmonalis szövődményeit. A rheumatoid arthritis gyógyszeres terápiájának pulmonológiai szövődményei közül kiemelik a betegségmódosító antireumatikus szereket, amelyek közül kitérnek a methotrexat indukálta tüdőgyógyászati kórképekre. A methotrexat szinte majdnem minden additív hatású kettős és hármas – O’Dell-séma – kombinációs terápiában szerepel, ezért is fontos e gyógyszer okozta pulmonalis szövődmények időben történő felismerése. A reumatológusok számára egyre nagyobb kihívást jelent a methotrexattal szemben rezisztens rheumatoid arthritis kezelése. A biológiai terápiás szerek citokinantagonistaként, TNF-α-blokkolás révén fejtik ki hatásukat, és a betegségmódosító antireumatikus szerekhez képest hatásosabban tudják fékezni a betegség progresszióját. Ezek a biológiai válaszmódosító szerek. Főbb képviselőik az infliximab, az adalimumab és az etanercept. A szerzők végül foglalkoznak a biológiai válaszmódosító szerek okozta szekunder pulmonalis szövődményekkel: a pulmonalis tuberculosissal, a bakteriális tracheobronchitisszel, a bakteriális pneumoniával, bronchiectasiával és pulmonalis oedemával, a rapid progresszív fibrotizáló alveolitisszel, valamint a coccidiomycosissal. Az Arizona, Kalifornia, Nevada területén élő, biológiai válaszmódosító szerekkel végzett terápiában részesülő rheumatoid arthritises betegek mintegy 3%-ánál várható a 15%-os halálozással járó pulmonalis és szisztémás gombafertőzés – coccidiomycosis – kialakulása. A gyakori földrengések következtében a talajból a légtérbe kerülő spórák betegítik meg a gyógyszeres terápia miatt immunszupprimált egyéneket. A szerzők felhívják a figyelmet, hogy az előbb említett endémiás, valamint egyéb földrengésaktív területre utazó, biológiai terápiában részesülő betegek potenciális fertőzésveszélynek vannak kitéve, amely miatt a betegek ez irányú tájékoztatása a kezelőorvos részéről elengedhetetlen. A biológiai válaszmódosító szerek újabb és újabb csoportjainak kipróbálása és felhasználása a közeljövőben várható rheumatoid arthritisben. Jelenleg a TNF-α-gátló kezelésre nem reagáló betegeknél lehetőség van a non-Hodgkin-lymphoma terápiájában használatos B-lymphocyta-gátló rituximab alkalmazására. Ez utóbbi citokin rheumatoid arthritisben történő felhasználása során észlelt pulmonalis szövődményeiről még nem rendelkezünk elegendő ismerettel. Napjaink antireumatikus terápiái a betegek életminőségének jelentős javulását eredményezik, miközben az egyre korszerűbb kezelési módok a pulmonalis szövődmények körét gyarapítják.

Download Full-text

Genetic Variation in TNF-α, its Relation with Inflammatory Biomarkers and Susceptibility to Rheumatoid Arthritis

Annals of Immunology & Immunotherapy ◽

10.23880/aii-16000122 ◽

2020 ◽

Vol 2 (2) ◽

Author(s):

Khadiga Ahmed Ismail

Keyword(s):

Rheumatoid Arthritis ◽

Serum Level ◽

Functional Disability ◽

Serum Levels ◽

Amplification Refractory Mutation System ◽

Reactive Protein ◽

Tnf Α ◽

Mutation System ◽

Potential Factor ◽

Factor Α

Background: Tumor necrosis Factor-α (TNF-α) is encoded and controlled by TNF-α gene, which is involved in rheumatoid arthritis (RA) susceptibility. This research aimed to identify genetic variations of TNF-α (G308A) and to establish its association with inflammatory markers in Rheumatoid Arthritis predisposition. Methods: In the present study, fifty RA patients and fifty volunteers were involved and evaluated for the C-reactive protein, rheumatoid factor, and TNF-α were estimated by ELISA, Erythrocyte Sedimentation Rate (ESR) by Wintergreen method and for TNF-α-308 G>A polymorphism by polymerase chain reaction with amplification refractory mutation system (PCR-ARMS). Results: The CRP, RF, ESR and TNF-α were significantly elevated in RA patients relative to controls. The serum level TNF-α was also significantly elevated in female patients and in patients ≥50 years. Analysis of TNF-308 gene polymorphism revealed that GG genotypes were more prevalent in RA patients than in the healthy individuals and that GG genotype may be a potential factor to RA. The G allele was more common in RA than in the control. Elevated TNF-α serum levels were significantly associated the GG genotype and functional disability in RA patients. Conclusion: TNF-α promoter 308polymorphism GG genotype may be considered as a risk factor for RA and the TNF-α serum level was significantly related to the functional disability in the disease.

Download Full-text

Evaluating the efficacy of intra-articular injections of platelet rich plasma (PRP) in rheumatoid arthritis patients and its impact on inflammatory cytokines, disease activity and quality of life.

Current Rheumatology Reviews ◽

10.2174/1573397116666201113090629 ◽

2020 ◽

Vol 16 ◽

Author(s):

Dalia S. Saif ◽

Nagwa N. Hegazy ◽

Enas S. Zahran

Keyword(s):

Quality Of Life ◽

Rheumatoid Arthritis ◽

Disease Activity ◽

Inflammatory Cytokines ◽

Platelet Rich Plasma ◽

Joint Inflammation ◽

Monthly Interval ◽

Post Injection ◽

Tnf Α

Background: Among rheumatoid arthritis patients (RA), general disease activity is well regulated by diseasemodifying anti-rheumatic medications (DMARDS), but sometimes local inflammation still persists among a few joints. Adjuvant modern molecular interventions as Platelet Rich Plasma (PRP) with a suggested down regulating effect on inflammatory mediators has a proven effect in management of RA. We aim to evaluate the therapeutic effect of intra-articular PRP versus steroid in RA patients and their impact on inflammatory cytokines IL1B , TNF α, local joint inflammation, disease activity and quality of life (QL). Methods: Open labeled parallel randomized control clinical trial was carried out on 60 RA patients randomly divided into 2 groups, Group 1: included 30 patients received 3 intra-articular injections of PRP at monthly interval, Group 2: included 30 patients received single intra-articular injection of steroid. They were subjected to clinical, laboratory, serum IL1B and TNF α assessment at baseline and at 3, 6 months post injection. Results: Patients of both groups showed improvements in their scores of evaluating tools at 3months post injection and this improvement was persistent in the PRP group up to 6 months post injection while it was continued only for 3 months in the steroid group. Conclusions: PRP is a safe, effective and useful therapy in treating RA patients who had insufficient response and persistent pain and inflammation in just one or two joints through its down regulating effect on inflammatory cytokines IL1B, TNF α with subsequent improvement of local joint inflammation, disease activity and QL.

Download Full-text

Can Cytokines be used as an Activation Marker in Rheumatoid Arthritis?

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666201019115030 ◽

2020 ◽

Vol 20 ◽

Author(s):

Fatih Öner Kaya ◽

Yeşim Ceylaner ◽

Belkız Öngen İpek ◽

Zeynep Güneş Özünal ◽

Gülbüz Sezgin ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Healthy Volunteers ◽

Venous Blood ◽

Cross Sectional Study ◽

Joint Disease ◽

Control Group ◽

Cross Sectional ◽

Positive Correlation ◽

Das 28 ◽

Tnf Α

Aims: The etiopathogenesis of Rheumatoid Arthritis (RA) is not clearly understood. However, the role of the cytokines takes an important part in this mechanism. We aimed to bring a new approach to the concept of 'remission' in patients with RA. Background: RA is a chronic, autoimmune, inflammatory disease that involves small joints in the form of symmetrical polyarthritis and progresses with exacerbations and remissions. Pain, swelling, tenderness and morning stiffness are typical of the joints involved. Although it is approached as a primary joint disease, a wide variety of extra-articular involvements may also occur. It is an interesting pathophysiological process, the exact cause of which is still unknown, with many environmental, genetic and potentially undiscovered possible factors in a chaotic manner. Objective: In this cross-sectional study, sedimentation rate (ESR), C- Reactive protein (CRP), Tumor necrosis factor (TNF)-α, soluble-TNF-α receptor (TNF-R), Interleukin (IL)-1B and IL-10 were measured in three groups which were healthy volunteers, patients with RA in the active period, and patients with RA in remission. Disease activity score-28 (DAS-28) was calculated in active RA and RA in remission. Methods: This study included 20 healthy volunteers, 20 remission patients with RA and 20 active RA patients. Venous blood samples were collected from patients in both healthy and RA groups. Results: RA group consisted 43 (71.6%) female and 17 (28.4%) male. Control group consisted 11 (55%) female and 9 (45%) male. TNF-R was significantly high only in the active group according to the healthy group (p=0.002). IL-10 was significantly high in active RA according to RA in remission (p=0.03). DAS-28 was significantly high in active RA according to RA in remission (p=0.001). In the active RA group, ESR and TNF-R had a positive correlation (r:0.442; p=0.048). In the active RA group, there was also a positive correlation between TNF-R and CRP (r:0.621; p=0,003). Both healthy and active RA group had significant positive correlation between ESR and CRP (r: 0.481; p=0.032 and r: 0,697; p=0,001 respectively). Conclusion: TNF-R can be the main pathophysiological factor and a marker showing activation. TNF-R can be very important in revealing the effect of TNF on the disease and the value of this effect in the treatment and ensuring the follow-up of the disease with CRP instead of ESR in activation.

Download Full-text

Evaluation of Toll-like Receptor 2 Gene Expression in Rheumatoid Arthritis and Correlation with the Disease Activity

Current Chemical Biology ◽

10.2174/2212796813666181219124924 ◽

2019 ◽

Vol 13 (2) ◽

pp. 140-148

Author(s):

Mai Nasser ◽

Noha M. Hazem ◽

Amany Atwa ◽

Amina Baiomy

Keyword(s):

Rheumatoid Arthritis ◽

Gene Expression ◽

Autoimmune Diseases ◽

Disease Activity ◽

Mrna Expression ◽

Disease Activity Score ◽

Activity Score ◽

Tlr2 Expression ◽

Positive Correlation ◽

Tlr2 Mrna

Background: Rheumatoid Arthritis (RA) is an autoimmune, chronic, and systematic disease. It affects joints and bones. The exact etiology of RA is still unclear. Varied genetic and environmental factors have been associated with the increased risk for RA. Overactivation of Toll-Like Receptors (TLRs) could initiate the development of autoimmune diseases including RA. Objective: The aim of the study was to evaluate TLR2 gene expression in rheumatoid arthritis patients and investigate its correlation with the disease activity. Materials and Methods: This study included 60 patients and 20 healthy individuals. The patients were diagnosed with RA according to the 2010 American College of Rheumatology/ European League Against Rheumatism criteria (ACR/EULAR). All included subjects did not have any joint disorders and /or autoimmune diseases. RA disease activity was determined by the disease activity score of 28 joints. Whole blood was collected from all participants. Total RNA extraction was done. TLR2 mRNA expression was assessed by reverse transcription-PCR (RT-PCR). Results: TLR2 mRNA expression was found to be significantly higher in RA patients compared to healthy controls. Also, a strong positive correlation was found between TLR2 expression level and the disease activity score. A non significant positive correlation was found between TLR2 expression and serum Rheumatoid Factor (RF) level. Conclusion: TLR2 pathway may have an important role in RA pathogenesis and could be a new biomarker for diagnosis and monitoring disease activity.

Download Full-text

Serum IL-35 is decreased in overweight patients with rheumatoid arthritis: its correlation with Th1/Th2/Th17-related cytokines

BMC Immunology ◽

10.1186/s12865-021-00431-x ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yuxuan Li ◽

Yang Jie ◽

Xiaofei Wang ◽

Jing Lu

Keyword(s):

Rheumatoid Arthritis ◽

Medical Records ◽

Clinical Information ◽

Serum Cytokines ◽

Healthy Donors ◽

Potential Biomarker ◽

Tnf Α ◽

Ifn Γ ◽

Quantitative Changes ◽

Anti Inflammatory Cytokine

Abstract Background Obesity is correlated with worse drug responses and high disease activity in patients with rheumatoid arthritis (RA). Interleukin (IL)-35 is a novel anti-inflammatory cytokine that mainly produced by regulatory T (Treg). This study was performed to analyze whether IL-35 was correlated with obesity in RA and investigate the correlation between other Th1/Th2/Th17-related cytokines and obesity in RA. Results The serum IL-35 level was analyzed in RA (n = 81) and healthy donors (n = 53) by ELISA assay, and was compared between three groups (body mass index (BMI) < 18.5,≥18.5 to 25, > 25). Serum cytokines including IL-2, IL-4, IL-10, IL-17, INF-γ, TNF-α levels were measured using Flowcytometry assay. Clinical information was extracted from medical records. Serum IL-35 level in overweight patients were significantly decreased than those in lean patients. Furthermore, Th1/Th2/Th17-related cytokines from overweight patients with RA showed the characteristic immunological features. Serum IL-6, IL-17 and TNF-α levels were positively correlated with BMI. However, serum IL-2, IL-4, IL-10 and IFN-γ concentrations were not correlated with BMI. Conclusions Quantitative changes in serum IL-35 level were characteristic in overweight patients with RA. These findings indicate that IL-35 plays an important role in the development of RA and may prove to be a potential biomarker of active RA.

Download Full-text

Anti-Rheumatic Effect of Antisense Oligonucleotide Cytos-11 Targeting TNF-α Expression

International Journal of Molecular Sciences ◽

10.3390/ijms22031022 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1022

Author(s):

Tatyana P. Makalish ◽

Ilya O. Golovkin ◽

Volodymyr V. Oberemok ◽

Kateryna V. Laikova ◽

Zenure Z. Temirova ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Gene Expression ◽

Rat Model ◽

Peripheral Blood ◽

Antisense Oligonucleotide ◽

Joint Inflammation ◽

Blood Concentrations ◽

Tnf Α ◽

Effective Drugs ◽

First Time

The urgency of the search for inexpensive and effective drugs with localized action for the treatment of rheumatoid arthritis continues unabated. In this study, for the first time we investigated the Cytos-11 antisense oligonucleotide suppression of TNF-α gene expression in a rat model of rheumatoid arthritis induced by complete Freund’s adjuvant. Cytos-11 has been shown to effectively reduce peripheral blood concentrations of TNF-α, reduce joint inflammation, and reduce pannus development. The results achieved following treatment with the antisense oligonucleotide Cytos-11 were similar to those of adalimumab (Humira®); they also compared favorably with those results, which provides evidence of the promise of drugs based on antisense technologies in the treatment of this disease.

Download Full-text

Association analysis of juvenile idiopathic arthritis genetic susceptibility factors in Estonian patients

Clinical Rheumatology ◽

10.1007/s10067-021-05756-x ◽

2021 ◽

Author(s):

Tiit Nikopensius ◽

Priit Niibo ◽

Toomas Haller ◽

Triin Jagomägi ◽

Ülle Voog-Oras ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Juvenile Idiopathic Arthritis ◽

Autoimmune Diseases ◽

Genetic Risk ◽

Association Studies ◽

Control Sample ◽

Case Control ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide

Abstract Background Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition of childhood. Genetic association studies have revealed several JIA susceptibility loci with the strongest effect size observed in the human leukocyte antigen (HLA) region. Genome-wide association studies have augmented the number of JIA-associated loci, particularly for non-HLA genes. The aim of this study was to identify new associations at non-HLA loci predisposing to the risk of JIA development in Estonian patients. Methods We performed genome-wide association analyses in an entire JIA case–control sample (All-JIA) and in a case–control sample for oligoarticular JIA, the most prevalent JIA subtype. The entire cohort was genotyped using the Illumina HumanOmniExpress BeadChip arrays. After imputation, 16,583,468 variants were analyzed in 263 cases and 6956 controls. Results We demonstrated nominal evidence of association for 12 novel non-HLA loci not previously implicated in JIA predisposition. We replicated known JIA associations in CLEC16A and VCTN1 regions in the oligoarticular JIA sample. The strongest associations in the All-JIA analysis were identified at PRKG1 (P = 2,54 × 10−6), LTBP1 (P = 9,45 × 10−6), and ELMO1 (P = 1,05 × 10−5). In the oligoarticular JIA analysis, the strongest associations were identified at NFIA (P = 5,05 × 10−6), LTBP1 (P = 9,95 × 10−6), MX1 (P = 1,65 × 10−5), and CD200R1 (P = 2,59 × 10−5). Conclusion This study increases the number of known JIA risk loci and provides additional evidence for the existence of overlapping genetic risk loci between JIA and other autoimmune diseases, particularly rheumatoid arthritis. The reported loci are involved in molecular pathways of immunological relevance and likely represent genomic regions that confer susceptibility to JIA in Estonian patients. Key Points• Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease with heterogeneous presentation and genetic predisposition.• Present genome-wide association study for Estonian JIA patients is first of its kind in Northern and Northeastern Europe.• The results of the present study increase the knowledge about JIA risk loci replicating some previously described associations, so adding weight to their relevance and describing novel loci.• The study provides additional evidence for the existence of overlapping genetic risk loci between JIA and other autoimmune diseases, particularly rheumatoid arthritis.

Download Full-text