Other biologic agents are effective in the treatment of RA.
However, to our knowledge, no adequately controlled trials or postmarketing studies have investigated the use of these agents in the older RA patients. The following is a summary of what fragmentary data are available.
Abatacept
Abatacept is the first in a new class of BRMs known as selec- tive co-stimulation modulators.
Abatacept is a soluble fusion protein that consists of the extracellular domain of human cytotoxic T-lymphocyte- associated antigen 4 linked to the modified Fc portion of
human IgG1. Abatacept binds to CD80 and CD86 thereby blocking the interaction of CD28–CD80/86 and inhibiting the activation of T-cells [161]. Abatacept’s dosage is based on patient’s weight: patients weighing less than 60 kg receive 500 mg/month, those weighing between 60 and 100 kg receive 750 mg/month, and those patients >100 kg receive 1,000 mg/month [161].
Clinical Pharmacology
Abatacept has a terminal half-life of 13.1 days in RA patients.
Its systemic clearance is 0.22 ml/h/kg. According to the package insert for abatacept, the clearance is unaffected by age [162]. No peer-reviewed data are available regarding its clinical pharmacology in the older RA patient.
Efficacy
Several randomized controlled trials (RCTs) have demon- strated the safety and efficacy of abatacept in the treatment of RA patients [163, 164]. In addition, abatacept is effective in the treatment of nonresponders to methotrexate and anti- TNF agents [165, 166]. In clinical studies, a total of 323 patients over the age of 65 (53 patients >75 years) received abatacept. The overall efficacy was similar between older and younger patients treated with abatacept [162]. No peer- reviewed data are available.
Safety
The package insert for abatacept reports a higher frequency of serious infection and malignancy among the older RA patients [162]. No peer-reviewed data are available.
In summary, no peer-reviewed data are available regard- ing the use of abatacept in the older RA patients, leaving the package insert as the only source of information regarding this aspect of using abatacept.
Anakinra
IL-1 was one of the first cytokines described to regulate cell- mediated and humoral immunity. It is produced by mac- rophages, monocytes, and dendritic cells. As TNF, IL-1 is considered a key proinflammatory cytokine in the develop- ment of RA [166].
Anakinra is an anti-IL-1 antibody that competitively inhibits the binding of IL-1 to the IL-1 type 1 receptor.
167 17 Disease-Modifying Antirheumatic Drug Use in Older Rheumatoid Arthritis Patients
The recommended dose of anakinra for the treatment of RA is 100 mg/day subcutaneously.
Clinical Pharmacology
Anakinra has a terminal half-life of 4–6 h [167]. However, the terminal half-life is significantly longer in patients with severe renal impairment than those with normal renal function (p-value < 0.05) [168]. Age does not appear to be a significant factor for the mean plasma clearance of anakinra [167].
Efficacy
According to the package insert for anakinra, no overall dif- ferences in efficacy were observed between older and younger patients (N = 635 patients ³65 years; 135 patients ³75 years) [167]. No published, peer-reviewed data are available.
Safety
In a study investigating the use of anakinra in 755 RA patients with approximately 68% of patients having one or more comorbidities (high risk), Schiff et al. reported a similar inci- dence of infections in high-risk patients treated with anak- inra (2.5%) when compared with serious infections observed in anakinra-treated patients in the entire population (2.1% as reported in literature [169, 170]. The authors of this and other studies suggested that the use of anakinra is reasonably safe and well tolerated in a diverse population of patients with RA, including those with comorbid conditions and those using multiple combinations of concomitant therapies. By implication, this should apply to older RA patients, but spe- cific data are not available.
In summary, there are no data available in the peer- reviewed literature specifically examining efficacy in older versus younger RA patients given anakinra, leaving only the package insert as a source of guidance.
This also applies to safety. We have extrapolated from published data by implication, indicating that older patients are probably not at significantly greater risk than younger RA patients. Here, as elsewhere, data are missing for specific comparisons.
Rituximab
Rituximab is a chimeric monoclonal antibody against CD20 B-cell antigen. It was first used to treat large B-cell lymphoma, and it has recently been approved for the treatment of RA.
Clinical Pharmacology
It has a terminal half-life of 19–22 days [170]. Rituximab is given intravenously and patients are given an infusion of Rituximab 1 g every 2 weeks for a total of two infusions, and this can be repeated in 6 months or with a flare of disease.
The Image study showed no clinical difference between 1,000 and 500 mg (both given twice), although there was a difference in radiographic outcome [171].
Efficacy
Use of rituximab is reserved for patients with inadequate response to at least one anti-TNF agent [139]. In a thorough review of the medical literature, it was found that rituximab was effective in the treatment of moderate-to-severe RA [172]. According to this review, rituximab can be used as a monotherapy; however, combination with methotrexate may have better clinical outcomes.
Safety
Among some adverse effects seen with the use of rituximab are infusion hypersensitivity reactions, infections, and car- diovascular events. The effect of prolonged B-cell depletion on IgG/IgM levels and the subsequent risk of infection is unclear [173].
Overall, no studies have specifically evaluated the use of rituximab in the treatment of older RA patients.
However, many studies have been published evaluating rituximab use (in addition to chemotherapy) in diffuse, large B-cell lymphoma patients [174]. Some of these stud- ies suggest that cardiac events (mainly supraventricular arrhythmias) and pulmonary events such as pneumonia and pneumonitis were more likely to occur in older lymphoma patients [174].
Summary
Overall, this chapter points to those areas where there is knowledge regarding the effect of age on the clinical pharma- cology of aging. It also reviews the knowledge about the use of DMARDs (both non-biologic and biologic) in the older RA patient. What is clear is that there is a great scarcity of appro- priate peer-reviewed data regarding how to use the biologic DMARDs in the older RA patient, a situation requiring sig- nificant research for the best patient care.
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