T-cell Co-stimulation Modulator Research Articles

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.

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.

Abatacept: a T-cell co-stimulation modulator for the treatment of rheumatoid arthritis

Abatacept: a T-cell co-stimulation modulator for the treatment of rheumatoid arthritis

Abatacept: a T-cell co-stimulation modulator for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a debilitating autoimmune disease that has traditionally been treated with disease-modifying anti-rheumatic drugs (DMARDs). In the European Union (EU), patients who fail to respond to traditional DMARDs may receive tumor necrosis factor-alpha (TNF-alpha) antagonists. However, approximately one-third of patients fail TNF-alpha antagonists due to adverse effects or lack of efficacy, and there are limited treatment options available to these patients. As knowledge of the underlying immunopathology of RA evolves, new strategies for inhibiting the inflammatory process have emerged. It is well known that activated T cells play a key role in orchestrating the immunopathological mechanisms of RA. Inhibiting the full activation of T cells is a rational strategy in the treatment of RA and represents a novel method of inhibiting disease activity, distinct from inflammatory cytokine blockade. Here, the safety and efficacy of abatacept, a selective T-cell co-stimulation modulator recently approved in the EU, is reviewed in patients with RA who have shown an inadequate response to TNF-alpha antagonists. In a randomized, placebo-controlled, double-blind, phase III trial of patients with an inadequate response to TNF-alpha antagonism, abatacept was effective in improving the signs and symptoms of RA, as well as patient-centered outcomes, such as fatigue, disability, and other mental and physical aspects of health-related quality of life. These improvements were sustained through 2 years during the open-label, long-term extension period. In this trial, abatacept demonstrated a safety and tolerability profile similar to placebo. Taken together, these data suggest that selective co-stimulation modulation with abatacept may be a viable option for patients who are refractory to both traditional therapies and TNF-alpha antagonists.

Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial

Some children with juvenile idiopathic arthritis either do not respond, or are intolerant to, treatment with disease-modifying antirheumatic drugs, including anti-tumour necrosis factor (TNF) drugs. We aimed to assess the safety and efficacy of abatacept, a selective T-cell costimulation modulator, in children with juvenile idiopathic arthritis who had failed previous treatments. We did a double-blind, randomised controlled withdrawal trial between February, 2004, and June, 2006. We enrolled 190 patients aged 6-17 years, from 45 centres, who had a history of active juvenile idiopathic arthritis; at least five active joints; and an inadequate response to, or intolerance to, at least one disease-modifying antirheumatic drug. All 190 patients were given 10 mg/kg of abatacept intravenously in the open-label period of 4 months. Of the 170 patients who completed this lead-in course, 47 did not respond to the treatment according to predefined American College of Rheumatology (ACR) paediatric criteria and were excluded. Of the patients who did respond to abatacept, 60 were randomly assigned to receive 10 mg/kg of abatacept at 28-day intervals for 6 months, or until a flare of the arthritis, and 62 were randomly assigned to receive placebo at the same dose and timing. The primary endpoint was time to flare of arthritis. Flare was defined as worsening of 30% or more in at least three of six core variables, with at least 30% improvement in no more than one variable. We analysed all patients who were treated as per protocol. This trial is registered, number NCT00095173. Flares of arthritis occurred in 33 of 62 (53%) patients who were given placebo and 12 of 60 (20%) abatacept patients during the double-blind treatment (p=0.0003). Median time to flare of arthritis was 6 months for patients given placebo (insufficient events to calculate IQR); insufficient events had occurred in the abatacept group for median time to flare to be assessed (p=0.0002). The risk of flare in patients who continued abatacept was less than a third of that for controls during that double-blind period (hazard ratio 0.31, 95% CI 0.16-0.95). During the double-blind period, the frequency of adverse events did not differ in the two treatment groups. Adverse events were recorded in 37 abatacept recipients (62%) and 34 (55%) placebo recipients (p=0.47); only two serious adverse events were reported, both in controls (p=0.50). Selective modulation of T-cell costimulation with abatacept is a rational alternative treatment for children with juvenile idiopathic arthritis. Bristol-Myers Squibb.

Cost-utility analysis of abatacept in rheumatoid arthritis in Italy

Objective: a substantial number of patients with rheumatoid arthritis (RA) have an insufficient or unsustained response to Tumor Necrosis Factor-α antagonists (anti-TNFs). The aim of the present study was to estimate the cost-utility of abatacept, a new selective T-cell co-stimulation modulator, in patients with moderately to severely active RA and an insufficient response or intolerance to anti-TNFs in the Italian setting. Methods: a probabilistic patient level simulation model was developed to estimate long-term costs and health outcomes of abatacept versus anti-TNFs (etanercept, adalimumab, infliximab) in RA patients. The model predicted patients’ HAQ (Health Assessment Questionnaire) scores over time based on the initial response to treatment (% change in HAQ score at six months). Responding patients continued treatment with a reduced rate of HAQ progression until long-term treatment failure. Health-state utilities and use of health care resources (excluding RA therapies) were assumed to depend on HAQ scores. The model used data from a Phase III clinical trial of abatacept in patients with inadequate response to anti-TNFs (Abatacept Trial in Treatment of anti-TNF Inadequate Responders [ATTAIN]) and various secondary data sources. The study was performed using the National Health Service (NHS) perspective. Cost-utility of abatacept vs other anti-TNFs was derived in terms of incremental cost per quality-adjusted life-year (QALY) gained based on a lifetime horizon with costs expressed in Euros. Single-way sensitivity analyses were performed on key parameters. Costs and health effects were discounted at 3% annually. Results: abatacept therapy was estimated to yield 1.18 additional QALYs per patient (5.02 abatacept vs 3.84 anti-TNFs) at an incremental cost of € 21,996.41 based on a 20 years time horizon. Cost per QALY gained was € 18,567.24. These results were robust to variation of key model parameters and are well within the usual cost-utility acceptance ranges. Conclusions: This study shows that in Italy, compared to anti-TNFs, abatacept therapy is cost-effective in patients with moderately to severely active RA and with an insufficient response or intolerance to anti-TNFs.

Vaccination response to tetanus toxoid and 23-valent pneumococcal vaccines following administration of a single dose of abatacept: a randomized, open-label, parallel group study in healthy subjects

The effect of abatacept, a selective T-cell co-stimulation modulator, on vaccination has not been previously investigated. In this open-label, single-dose, randomized, parallel-group, controlled study, the effect of a single 750 mg infusion of abatacept on the antibody response to the intramuscular tetanus toxoid vaccine (primarily a memory response to a T-cell-dependent peptide antigen) and the intramuscular 23-valent pneumococcal vaccine (a less T-cell-dependent response to a polysaccharide antigen) was measured in 80 normal healthy volunteers. Subjects were uniformly randomized to receive one of four treatments: Group A (control group), subjects received vaccines on day 1 only; Group B, subjects received vaccines 2 weeks before abatacept; Group C, subjects received vaccines 2 weeks after abatacept; and Group D, subjects received vaccines 8 weeks after abatacept. Anti-tetanus and anti-pneumococcal (Danish serotypes 2, 6B, 8, 9V, 14, 19F and 23F) antibody titers were measured 14 and 28 days after vaccination. While there were no statistically significant differences between the dosing groups, geometric mean titers following tetanus or pneumococcal vaccination were generally lower in subjects who were vaccinated 2 weeks after receiving abatacept, compared with control subjects. A positive response (defined as a twofold increase in antibody titer from baseline) to tetanus vaccination at 28 days was seen, however, in ≥ 60% of subjects across all treatment groups versus 75% of control subjects. Similarly, over 70% of abatacept-treated subjects versus all control subjects (100%) responded to at least three pneumococcal serotypes, and approximately 25–30% of abatacept-treated subjects versus 45% of control subjects responded to at least six serotypes.

Treatment of Immune-Mediated Extraintestinal Manifestations of Inflammatory Bowel Disease with Infliximab

The introduction of infliximab into clinical practice is one of the most significant advances in the care of patients who have IBD. Infliximab has become an important part of the medical armamentarium to treat extraintestinal manifestations that often are refractory to other medications and are a significant cause of morbidity in these patients. Two other TNF inhibitors recently have demonstrated efficacy in CD: certolizumab pegol and adalimumab. The Food and Drug Administration has approved adalimumab for use in RA. One predicts that these agents also may have activity in the extraintestinal manifestation for IBD. To determine whether future biologics are effective in the EIM of IBD, one may need to look no further than the vast clinical trial experience in primary chronic inflammatory diseases of the joints and skin: RA and psoriasis. For example, the Food and DRug Administration recently has approved an anti-B-cell therapy, rituximab, and a T-cell costimulation modulator, abatacept, for use in RA. It certainly will be of interest to determine whether these biologic agents demonstrate efficacy in the intestinal and EIM of IBD.