Selective Co-stimulation Modulator Research Articles

AB1000 Assessing the Impact of Subcutaneous Abatacept in Inhibiting Structural Damage in Rheumatoid Arthritis by Low Field Magnetic Resonance Imaging and X-Ray

BackgroundRheumatoid arthritis (RA) treatment has shifted from reducing symptoms to earlier inhibition of disease progression, thus preventing irreversible structural damage and disability. Detection of synovitis (SYN), osteitis (OST), and erosions...

SAT0243 Impact of Concomitant Methotrexate on the Enhanced Clinical Efficacy of Abatacept after 24 Weeks in Rheumatoid Arthritis Patients

BackgroundAbatacept (ABT), a selective co-stimulation modulator, is the first in a new class of biologic agents for the treatment of rheumatoid arthritis (RA) that inhibits T cell activation by binding...

Abatacept therapy for Rheumatoid Arthritis in patients with Hepatitis C Virus infection comorbidity: A Series of Four Patients

Patients with rheumatoid arthritis (RA) and hepatitis C present a diagnostic dilemma due to the viral induced immunogenistic response with subsequent biomarkers and an associated arthropathy that is difficult to distinguish from RA. They also present as a treatment dilemma due to restrictions in the use of disease modifying anti-rheumatic drugs that are standards of care such as methotrexate and leflunomide. Unfortunately they are often excluded from clinical trials in our newer RA therapeutics. In terms of biologics, beyond the American College of Rheumatology recommendations for tumor necrosis factor inhibitors, there are only case reports in alternate classes of biologic therapies. In this case report, four patients with hepatitis C are followed in terms of safety and efficacy while on abatacept (a soluble fusion protein that works as selective costimulation modulator inhibiting the activation of T cells) to treat their rheumatoid arthritis. Although each patient had varying benefit to the abatacept therapy, no patient had adverse reaction to infusion, or intolerance, and it did suggest the potential use of abatacept in this patient population.

Mesangial immunoglobulin (Ig)A glomerulonephritis in a patient with rheumatoid arthritis treated with abatacept

We report observations of a 47-year-old seropositive woman with rheumatoid arthritis (RA) suffering from mesangial immunoglobulin (Ig)A glomerulonephritis (GN) after initiation of abatacept, a selective T-cell co-stimulation modulator cytotoxic T-lymphocyte antigen 4 (CTLA4)-Ig. She was initially treated by corticosteroids, followed by methotrexate associated with a TNF inhibitor (adalimumab then switched to etanercept), finally switched to abatacept monotherapy, after secondary failure of these two forms of TNF inhibitors. Due to a progressively increased hematuria and proteinuria after abatacept therapy initiation, a renal biopsy was performed highlighting GN with mesangial IgA deposits, with necrosis and extracapillary crescent formations. IgA GN as a possible adverse event to abatacept was considered. Abatacept was stopped and a treatment by corticosteroids was initiated. Proteinuria decreased a couple of months after abatacept interruption. The short term between abatacept induction and IgA GN onset, as well as GN improvement since abatacept discontinuation, lend weight to the argument that CTLA4-Ig may play a crucial role in IgA GN pathogenesis. The possibility of a drug postponed adverse event justifies a long-term renal surveillance in RA patients treated by abatacept.

AB0563 Impact of the history and the type of previous biologic treatment on abatacept efficacy in rheumatoid arthritis patients

BackgroundAbatacept (ABT), a selective co-stimulation modulator, is the first in a new class of biologic agents for the treatment of rheumatoid arthritis (RA). Since ABT is often used as second...

THU0117 Abatacept can demonstrate maximum efficacy without background methotrexate treatment in rheumatoid arthritis

BackgroundAbatacept (ABT), a selective co-stimulation modulator, is the first in a new class of biologic agents for the treatment of rheumatoid arthritis (RA) that inhibits T cell activation by binding...

AB0553 Switching from SC to IV abatacept: Pharmacokinetic simulations to support dose regimen

BackgroundAbatacept (ABA) is a selective T-cell co-stimulation modulator approved in the US for RA, available in both IV and SC formulations. There is a need to establish a safe and...

OP0112 Abatacept Treatment Reduces Disease Activity in Early Primary Sjögren’s Syndrome (Phase II Open Label Asap Study)

BackgroundAbatacept, a selective co-stimulation modulator of T lymphocytes, could be a new treatment option for primary Sjögren’s syndrome (pSS).ObjectivesTo assess short-term efficacy and safety of abatacept treatment in early pSS...

AB0515 Predictors of clinical remission (DAS28CRP

BackgroundThe first goal of treatment of rheumatoid arthritis (RA) is clinical remission. However, few studies have explored predictors of the remission with Abatacept (ABT) based on clinical data.ObjectivesThis study examined...

Abatacept for Crohn's Disease and Ulcerative Colitis

The efficacy of abatacept, a selective costimulation modulator, in Crohn's disease (CD) and ulcerative colitis (UC) is unknown. Four placebo-controlled trials evaluated the efficacy and safety of abatacept as induction (IP) and maintenance (MP) therapy in adults with active, moderate-to-severe CD (CD-IP; CD-MP) and UC (UC-IP1; UC-MP). In CD-IP and UC-IP1, 451 patients with CD and 490 patients with UC were randomized to abatacept 30, 10, or 3 mg/kg (according to body weight) or placebo, and dosed at weeks 0, 2, 4, and 8. In MP, 90 patients with CD and 131 patients with UC who responded to abatacept at week 12 in the induction trials were randomized to abatacept 10 mg/kg or placebo every 4 weeks through week 52. In CD-IP, 17.2%, 10.2%, and 15.5% of patients receiving abatacept 30, 10, and 3 mg/kg achieved a clinical response at weeks 8 and 12, vs 14.4% receiving placebo (P = .611, P = .311, and P = .812, respectively). In UC-IP1, 21.4%, 19.0%, and 20.3% of patients receiving abatacept 30, 10, and 3 mg/kg achieved a clinical response at week 12, vs 29.5% receiving placebo (P = .124, P = .043, and P = .158, respectively). In CD-MP, 23.8% vs 11.1% of abatacept vs placebo patients were in remission at week 52. In UC-MP, 12.5% vs 14.1% of patients receiving abatacept vs placebo were in remission at week 52. Safety generally was comparable between groups. The studies showed that abatacept is not efficacious for the treatment of moderate-to-severe CD or UC.

Abatacept for severe anti-TNF-alfa refractory JIA-associated uveitis: one year follow-up

Uveitis in JIA can be severe and immunosoppressive therapies may not be sufficient. Anti-TNF-alfa agents (Infliximab, Adalimumab) have been proposed. The percentage of success is different among series and no controlled trials have been published yet. Abatacept, a selective T-cell co-stimulation modulator, has been shown to be a valid alternative to anti-TNF-alfa agents in patients with refractory uveitis (Angels-Han S.2008; Zulian 2010).

Juvenile idiopathic arthritis: management and therapeutic options

THE GOALS OF TREATMENT FOR JUVENILE IDIOPATHIC ARTHRITIS (JIA) INCLUDE: suppression of inflammation, achievement of remission, relief of pain, maintenance of function and doing so with minimal toxicity. Important discoveries over the past 10-15 years have led to more targeted treatments for children with JIA. The International League of Associations for Rheumatology (ILAR) classification system for childhood arthritides, better assessment tools for clinical response, improved definitions of remission, new imaging techniques and evidence in gene expression profiling have all contributed to the development of more targeted treatments. Nonsteroidal anti-inflammatory agents still have a role in mild disease and intra-articular steroid injections continue to be used most commonly in patients with oligoarticular JIA. Disease-modifying agents such as methotrexate have demonstrated efficacy and safety; however, in many patients, the disease remains active despite this treatment. These children now receive more targeted treatment including the tumor necrosis factor alpha (TNFα) inhibitors, interleukin-1 blockade, interleukin-6 blockade, selective costimulation modulators and selective B-cell blockade. The biologic targeted therapies have changed the strategy in which we treat our children with JIA; however, there remains much to be learned about the long-term effects and safety of these medicines.

Selektive Modulation der T-Zell-Kostimulation: Sicherheit und Verträglichkeit von Abatacept in der Langzeitanwendung

Biologika haben die Behandlungsmöglichkeiten bei rheumatoider Arthritis (RA) deutlich bereichert. Da diese Therapien potenziell über viele Jahre angewendet werden, sind Erfahrungen zu ihrer langfristigen Sicherheit und Verträglichkeit von besonderer Bedeutung. Für den selektiven T-Zell-Kostimulations-Modulator Abatacept liegen aus Extensionsstudien von randomisierten kontrollierten Studien der Phasen IIb und III Daten vor, welche die Sicherheit und Verträglichkeit der Substanz für einen Zeitraum von bis zu 7 Jahren dokumentieren. Diese Studien ergaben, dass in der Langzeitanwendung vs. einer 6- oder 12-monatigen Behandlung kein Anstieg der Inzidenzen von Infektionen, schwerwiegenden Infektionen und Malignitäten resultiert. Allgemein zeigten sich unter der Therapie eine gering erhöhte Rate schwerwiegender Infektionen im Vergleich zu Plazebo sowie eine geringere oder vergleichbare Häufigkeit schwerwiegender Infektionen im Vergleich zu anderen Biologika. Opportunistische Infektionen wurden im Zusammenhang mit der Gabe von Abatacept selten beobachtet. Das Malignomrisiko entsprach in den bisherigen Untersuchungen dem Risiko, das in einer alters- und geschlechtsangepassten Gruppe der RA-Patienten zu erwarten ist.

P13 Prevalence of rheumatic disorders in a rural population of South India, Kerala using the WHO-ILAR COPCORD Bhigwan model

Rheumatoid arthritis (RA) has been associated with significant morbidity and economic burden. Traditional pharmacotherapy (eg, NSAIDs, corticosteroids, disease-modifying antirheumatic drugs [DMARDs]) can be inadequate in controlling symptoms and disease progression. Abatacept is the first selective co-stimulation modulator approved by the US Food and Drug Administration for the management of RA. It is a fusion protein developed to modulate the T -cell co-stimulatory signal that is mediated through the CD28-CD80/86 pathway.The objective of this manuscript was to review the clinical pharmacology, pharmacokinetic and pharmacodynamic properties, tolerability, and clinical efficacy of abatacept.MEDLINE and International Pharmaceutical Abstracts were searched through June and May, respectively, of 2006 using the term abatacept or CTLA4-Ig. All prospective, randomized, Phase II and III trials, and their extension phases, were included.Phase II and III clinical trials found that abatacept, at a dose of 10 mg/kg administered as a short IV infusion in combination with DMARDs, was associated with significant clinical benefit in patients with active RA. After 6 months of treatment, the American College of Rheumatology (ACR) criteria for 20% clinical improvement (ACR20 response) was attained in 41.9% to 67.9% of patients who received abatacept compared with 19.5% to 39.7% of patients who received placebo (P < 0.001). The percentages of patients achieving the ACR criteria for 50% and 70% clinical improvement (ACR50 and ACR70) were 20.3% to 39.9% and 10.2% to 19.8%, respectively, in the groups that received abatacept compared with 3.8% to 16.8% and 1.5% to 6.5%, respectively, in the patients who received placebo (P = 0.03 and P < 0.001). Additionally, abatacept was found to improve disease activity, physical function, pain, and health-related quality of life (HRQOL). The most commonly reported adverse effects associated with abatacept treatment were headache (18.2%), upper respiratory tract infection (12.7%), nasopharyngitis (11.5%), and nausea (11.5%). The incidences of infections and serious infections were higher in the group that received abatacept compared with patients who received placebo (53.8% vs 48.3% and 3.0% vs 1.9%, respectively; P not reported). No significant between-group differences in mortality were found.Available evidence suggests that abatacept was effective in controlling symptoms and improving HRQOL in patients with active RA and an inadequate response to DMARD therapy. The most commonly reported adverse effects associated with abatacept treatment were headache, upper respiratory infection, nausea, and nasopharyngitis. Additional trials are needed to determine the long-term safety profile of this agent and whether the clinical benefits of abatacept found in the current clinical trials will be sustained over time.

Biologic Therapy for Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic, disabling disease of the synovial joints, thought to be autoimmune in origin. The emergence of biologic therapies has proven to be highly successful in effectively treating RA in the majority of cases. However, the cost of these agents is high and some patients do not respond to these drugs, or they suffer from adverse events. This article will review the currently available data on efficacy and the clinical, genetic, and biomarkers of response to these biologic therapies in RA. The anti-tumour necrosis factor-alpha (anti-TNFalpha) agents, adalimumab, etanercept and infliximab, act to neutralize the pro-inflammatory cytokine. Response to these agents is higher in patients receiving concurrent disease modifying anti-rheumatic drugs or non-steroidal anti-inflammatory drugs, in those with lesser disability, and in non-smokers. Many genetic predictors of response have been investigated, such as the shared epitope, the TNF gene and its receptors, but none have been absolutely confirmed. Synovial expression of TNFalpha has been suggested as a biomarker of response, while anti-cyclic citrullinated peptide antibody and rheumatoid factor (RF)-positivity predict poor response. Newer biologic agents include the interleukin (IL)-1 receptor antagonist anakinra, the B-cell depleting agent rituximab, the selective costimulation modulator abatacept, and the anti-IL-6 receptor monoclonal antibody tocilizumab. No genetic studies of response to these agents have been performed to date. However, it has been reported that low synovial infiltration of B cells and complete B-cell depletion after the first rituximab infusion are predictors of good response to this agent.

Costimulation blockade in rheumatic diseases: where we are?

To describe the mechanisms of action of abatacept (CTLA4-Ig) and summarize the evidence of its efficacy and safety in rheumatoid arthritis (RA) and other rheumatic diseases such as juvenile idiopathic arthritis (JIA). Several studies have demonstrated the clinical efficacy (disease activity, quality of life, prevention of structural damage) of abatacept in patients with RA who have failed to respond to standard disease-modifying antirheumatic drugs (DMARDs) and antitumour necrosis factor-alpha biologic agents. Selective modulation of T-cell costimulation may also be an alternative therapy for children with JIA who are resitant to conventional DMARDs or biologics. T-cell activation is critical to the onset and maintenance of RA. Abatacept (CTLA4-Ig), the first selective T-cell costimulation modulator has shown to be effective in RA and JIA. Recent 2-year data from the 'AIM' trial suggests an increased and sustained effect of blocking of T cell signalling on the inhibition of RA structural damage progression over time. Abatacept's safety profile in combination with DMARDs also seems to be favourable but should be avoided in combination with other biologics.

Safety and Efficacy of the Selective Costimulation Modulator Abatacept in Patients with Rheumatoid Arthritis Receiving Background Methotrexate: A 5-year Extended Phase IIB Study

To evaluate the safety and efficacy of abatacept plus methotrexate (MTX) over 5 years in patients with rheumatoid arthritis. Patients were randomized to abatacept 10 or 2 mg/kg or placebo, plus MTX. Patients completing the 1-year, double-blind period entered the longterm extension, where all patients received a fixed dose of abatacept ~10 mg/kg. We describe safety analyses for all patients who received at least 1 dose of abatacept and efficacy analyses for the original ~10 mg/kg abatacept-treated group, over 5 years. Of the 235 abatacept- or placebo-treated patients completing the double-blind period, 219 entered the longterm extension; 130 (59.4%) were continuing at Year 5. No unexpected safety events were observed during the longterm extension compared with the double-blind period. Incidence rates of adverse events (AE) and serious AE were 489.7 and 20.0/100 patient-years in Year 1 versus 374.9 and 18.9/100 patient-years in the cumulative period, respectively. Using exploratory analyses, improvements observed at Year 1 in the 10 mg/kg group were maintained at Year 5, as assessed by ACR responses (ACR20=77.1% vs 82.7%; ACR50=53.0% vs 65.4%; ACR70=28.9% vs 40.4% at Years 1 and 5, respectively) and disease activity (Low Disease Activity State=48.2% vs 58.5%; Disease Activity Score-28-defined remission=25.3% vs 45.3% at Years 1 and 5, respectively). Abatacept maintained the efficacy observed at Year 1 over 5 years of treatment, and demonstrated consistent safety and tolerability. These data, along with relatively high retention rates, support the longterm clinical benefit provided by selective T cell costimulation modulation. ClinicalTrials.gov; clinical trial registration number: NCT00254293.

Abatacept in difficult-to-treat juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children and an important cause of short-term and long-term disability. Gene changes in the immune system can predispose to JIA and regulation of the immune system is crucial in the pathogenesis. The goal of therapy is complete disease control using disease-modifying antirheumatic drugs (DMARDS). Activated T-cells may play a role in the immunopathology of JIA. Therefore, targeting T-cell activation is a rational approach for the treatment of JIA. Abatacept (ABA), a selective co-stimulation modulator, has been shown to be effective in treating all JIA subtypes and is generally safe and well tolerated in JIA. Neutralizing antibodies were found in 6/9 (67%) of seropositive patients, but anti-ABA antibodies did not appear to be associated with disease flare, serious adverse events, acute infusional adverse events, hypersensitivity, autoimmune disorders, or low ABA serum concentrations. Anti-ABA antibodies were more frequent when ABA concentrations were below therapeutic levels. Although information on ABA in JIA is still limited, available data suggest a potential role in difficult to treat JIA patients previously treated with other biologic agents and for non-responders to TNF-blockade.

KAWASAKI DISEASE ASSOCIATED WITH REACTIVE HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

We report a case of Kawasaki disease with significant coronary artery aneurysms subsequently associated with reactive hemophagocytic lymphohistiocytosis in a young child with low T-cell perforin expression and NK-cell dysfunction. The patient was treated with a selective T-cell costimulation modulator in an effort to regulate T-cells. This case is unique for several reasons: (1) the severe degree of coronary artery aneurysms; (2) low T-cell perforin and NK-cell values; and (3) treatment with a selective T-cell costimulation modulator, none of which has been described in prior cases.

Biologics in the treatment of rheumatoid arthritis: recent advances

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease with multiple joints involvement. The disease involves inflammation of the synovial membrane, which releases inflammatory cytokines that cause damage to joint components, cartilage and bone, and thus leads to progressive joint destruction. The traditional drugs used for treating RA are known as disease-modifying antirheumatic drugs (DMARDs). The limited efficacy and/or side effects of traditional DMARDs limit their use. Although the etiology of RA remains unknown, recent advances in molecular technology have made it possible to identify distinct cell subsets, cell surface markers, and cell products that contribute to the immune-mediated inflammatory responses associated with the disease. This enhanced understanding of the immunopathogenesis of RA provides opportunities to specifically target the immune response pathways using therapies that are more specific. Over the last decade, five novel biological agents for treatment of RA have already been used in practice or on the horizon: interleukin 1 receptor antagonist (anakinra), anti-TNF agents (infliximab, etanercept, adalimumab), anti-CD20 agent (rituximab), selective T-cell co-stimulation modulator (abatacept), and anti-interleukin 6 receptor (tocilizumab). Here, we briefly discuss the targets of these drugs and the roles of these targets in the pathogenesis of RA and review the efficacy of these drugs from the clinical trial data.