CTLA4-Ig Abatacept Research Articles

Urinary prostanoids are elevated by anti-TNF and anti-IL6 receptor disease-modifying antirheumatic drugs but are not predictive of response to treatment in early rheumatoid arthritis

BackgroundDisease-modifying antirheumatic drugs (DMARDs) are widely used for treating rheumatoid arthritis (RA). However, there are no established biomarkers to predict a patient’s response to these therapies. Prostanoids, encompassing prostaglandins, prostacyclins, and thromboxanes, are potent lipid mediators implicated in RA progression. Nevertheless, the influence of DMARDs on prostanoid biosynthesis in RA patients remains poorly understood. This study aims to assess the impact of various DMARDs on urinary prostanoids levels and to explore whether urinary prostanoid profiles correlate with disease activity or response to therapy.MethodsThis study included 152 Swedish female patients with early RA, all rheumatoid factor (RF) positive, enrolled in the NORD-STAR trial (registration number: NCT01491815). Participants were randomized into four therapeutic regimes: methotrexate (MTX) combined with (i) prednisolone (arm ACT), (ii) TNF-α blocker certolizumab pegol (arm CZP), (iii) CTLA-4Ig abatacept (arm ABA), or (iv) IL-6R blocker tocilizumab (arm TCZ). Urine samples, collected before start of treatment and at 24 weeks post-treatment, were analyzed for tetranor-prostaglandin E metabolite (tPGEM), tetranor-prostaglandin D metabolite (tPGDM), 2,3-dinor thromboxane B2 (TXBM), 2,3-dinor-6-keto prostaglandin F1a (PGIM), leukotriene E4 (LTE4) and 12-hydroxyeicosatetraenoic acid (12-HETE) using liquid chromatography–mass spectrometry (LC–MS). Generalized estimating equation (GEE) models were used to analyze the change in urinary eicosanoids and their correlations to clinical outcomes.ResultsPatients receiving MTX combined with CZP or TCZ exhibited significant elevations in urinary tPGEM and TXBM levels after 24 weeks of treatment. Other eicosanoids did not show significant alterations in response to any treatment. Baseline urinary eicosanoid levels did not correlate with baseline clinical disease activity index (CDAI) levels, nor with changes in CDAI from baseline to week 24. Their levels were also similar between patients who achieved CDAI remission and those with active disease at week 24.ConclusionsTreatment with anti-TNF or anti-IL6R agents in early RA patients leads to an increased systemic production of proinflammatory and prothrombotic prostanoids. However, urinary eicosanoid levels do not appear to be predictive of the response to DMARDs therapy.

CTLA4-Ig Abatacept Ameliorates Proteinuria by Regulating Circulating Treg/IL-17 in Adriamycin-Induced Nephropathy Rats

Objective This study is aimed at investigating the efficacy of CTLA4-Ig abatacept in normalizing proteinuria and its possible mechanism in adriamycin-induced nephropathy (AIN) rats. Methods A total of 32 healthy male Sprague-Dawley rats were randomly divided into a normal group, an AIN group, an abatacept group, and a prednisone group. Adriamycin (6.5 mg/kg) was injected once via the tail vein of rats to induce nephrotic syndrome. After adriamycin treatment, the abatacept group rats were given abatacept (0.5 mg/kg) once by intraperitoneal injection on day 14. In addition, the prednisone group rats were given prednisone (12.5 mg/kg) daily consecutively by gavage from day 14 to day 21. Blood, urine, and kidney tissue specimens were collected when sacrificed on day 21. The 24-hour urinary protein, serum albumin, cholesterol, creatinine, and urea nitrogen were then detected. An enzyme-linked immunosorbent assay was used to determine the level of urine CD80 and serum IL-17. Flow cytometry was used to investigate the prevalence of circulating Treg. Hematoxylin-eosin staining and electron microscopy were used for a renal histological study. Immunofluorescence staining was performed to confirm the CD80 expression of renal tissue. Results The 24-hour urinary protein of the abatacept group was significantly lower than that of the prednisone group and the AIN group. The level of urine CD80 of the abatacept group was significantly lower than that of the AIN group. Compared with the AIN group and the prednisone group, the circulating Treg prevalence of the abatacept group was significantly higher, while the level of serum IL-17 was lower. A negative kidney staining of CD80 expression was demonstrated in each group in this study. The 24-hour urinary protein had a negative correlation with the circulating Treg prevalence and Treg/IL-17 and a positive correlation with the urine CD80 and serum IL-17. Urinary CD80 had a positive correlation with serum IL-17 and no correlation with the circulating Treg prevalence. Conclusions CTLA4-Ig abatacept can reduce proteinuria of adriamycin-induced nephropathy rats, possibly at least partially as a result of regulating circulating Treg/IL-17. CTLA4-Ig abatacept could be a promising regimen for idiopathic nephrotic syndrome.

Protéine de fusion ou anticorps monoclonal

Therapeutics options for inflammatory diseases, such as rheumatoid arthritis (RA), have increased tremendously in the past decade with the introduction of biologic therapies, such as monoclonal antibodies or recombinant fusion proteins. These have proven to be highly successful in treating inflammatory or autoimmune diseases, by blocking certain key molecules involved in the pathogenesis of the illness, cytokines (TNF) or immune coactivators (CTLA-4). Thus in rheumatoid arthritis, TNF can be neutralized both by monoclonal antibodies (adalimumab, infliximab) or recombinant inhibitors such as etanercept or CTLA-4 Ig abatacept. All have been marketed and proven to be highly effective in the treatment of RA, and we will discuss parameters which are taken into account to select monoclonal antibody or recombinant inhibitors. These include drug-related (target affinity, pharmacokinetics, mechanisms of action, etc.) and patient - (efficacy and side effects) or disease-related characteristics. Their impact on current clinical practice and future trends are discussed.

Efficacy of Biologicals in the Treatment of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic multisystem disease. A characteristic feature of RA is persistent inflammatory synovitis, usually involving the peripheral joints in a symmetric distribution. The prevalence of RA is approximately 0.8% of the population (range: 0.3–2.1%); women are affected approximately 3 times more often than men. The current therapeutic approach is to start a disease-modifying agent early in the illness to prevent eventual joint damage. Older disease-modifying anti-rheumatic drugs include methotrexate, sulphasalazine and hydroxychloroquine. Newer ones such as leflunomide and cyclosporin are also used. A recent advance in the management of rheumatoid arthritis is the use of biological agents, which block certain key molecules involved in the pathogenesis of the illness. They include tumour-necrosis-factor-α-blocking agents such as infliximab, etanercept and adalimumab, the anti-CD-20 agent, rituximab, and CTLA-4 Ig abatacept. The present study was planned with the aim of evaluating the efficacy of such newer biological therapies in refractory RA at various time points. Databases including Medline, Embase and the Cochrane Library were searched for all relevant studies up to January 2007. A total of 26 studies were included in present meta-analysis. The method of DerSimonian and Laird [Control Clin Trials 1986;7:177–188] was used to calculated a pooled odds ratio (OR) for the American College of Rheumatology (ACR) criteria 20, 50 and 70, at 24, 54 and 96 weeks. The overall pooled OR were found to be significantly more than the placebo at all 3 time points for all 3 criteria (ACR 20, 50 70). In conclusion, biologicals as a group are highly effective in the treatment of RA. Biologicals were efficacious both in treatment naïve and methotrexate-refractory patients.

The Use of Biological Agents in the Treatment of Rheumatoid Arthritis

Rheumatoid arthritis is a common and potentially devastating condition which did not have good treatment options until recently. Pharmacological treatment should not just comprise antiinflammatory agents and corticosteroids. The current therapeutic approach is to start a disease modifying agent early in the illness to prevent eventual joint damage. Older disease modifying anti-rheumatic drugs (DMARDs) include methotrexate, sulphasalazine and hydroxychloroquine. Newer ones such as leflunomide and cyclosporine are also used. A recent advance in the management of rheumatoid arthritis is the use of biological agents which block certain key molecules involved in the pathogenesis of the illness. They include tumour necrosis factor (TNF)- blocking agents such as infliximab, etanercept and adalimumab, the anti-CD 20 agent rituximab and CTLA-4 Ig abatacept. Other agents which are in development include anti-IL6 tocilizumab, anti-CD22 and anti-lymphostat B. In this review, the efficacy and side effects of these agents, their impact on current clinical practice and future trends are discussed.