Selective Costimulation Modulators: Addressing Unmet Needs in Rheumatoid Arthritis Management

Abstract

Data from recent clinical trials of targeted biological therapies for the treatment of rheumatoid arthritis (RA) were presented last June at the 2004 European League Against Rheumatism (EULAR) meeting, held in Berlin, Germany. The clinical results presented for a novel agent that targets costimulatory activation of T cells, a central step in the immunologic response that eventually leads to joint destruction in RA, are discussed. Given the expanding number of biological targeted therapies available for treating RA, a working knowledge of the immune mechanisms underlying the disease has become a requirement for evaluating these new treatment options. This information should also help clinicians recognize the advantages and limitations of the available therapies and assist in the consideration of alternatives. This article first briefly reviews our current knowledge of the immunologic basis of RA. The next 2 sections examine how this knowledge has led to the development of novel, targeted biological agents. These agents have the potential not only to slow the progression of RA, but also to reverse the course of the disease, bringing the ultimate goal of a permanent remission closer.

Unmet Needs in the Treatment of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that causes progressive joint destruction, pain, and significant physical limitation. The course of RA is characterized by alternating remissions and exacerbations, and long-term treatment is usually required to prevent disease flares.[1]

Studies that have examined the prevalence of RA among twin pairs have consistently found that the concordance rate of RA is approximately 12% to 15% among monozygotic twins and approximately 3.5% among dizygotic twins.[2,3] This suggests that both genetic and environmental factors are important in the pathogenesis of RA.

It is estimated that more than 2 million people in the United States have RA. Epidemiologic studies conducted in Europe and the United States have generally reported prevalence estimates of .5% to 1% among adults, although the prevalence of RA is considerably higher than this in some populations (eg, as high as 5% to 8% among Chippewa and Pima American Indian tribes).[1] The age of onset is variable, but the mean age at first symptoms of RA is typically between 50 and 60 years. The disease results in an average decrease in life expectancy of approximately 5-10 years.[4,5] RA is more common in women than in men.[6,7]

Synthetic disease-modifying antirheumatic drugs (DMARDs) have long been used to slow the progression of joint destruction in patients with RA. However, these agents fail to significantly improve the course of RA in a substantial number of patients, and they are associated with considerable toxicity. During the last decade, a number of biological DMARDs, specifically agents that target inflammatory cytokines, have entered clinical practice. These agents are effective for the treatment of RA and are generally well tolerated. However, many patients still do not respond adequately to treatment with these available medications, even when they are used in combination with synthetic DMARDs.[8] Stopping treatment with these drugs generally leads to disease flares.[9] Thus, there remains a significant unmet need for new, clinically efficacious therapies for RA.

Underlying Immune Mechanisms in the Pathogenesis of RA

The underlying causes of the disorder are not completely understood. However, it is well established that the progressive joint destruction that occurs during RA is the result of inappropriate activation of cells of the immune system, specifically through antigen presentation to T cells by antigen-presenting cells (APCs), in which the major histocompatibility complex (MHC) plays an important role.

Genetics and RA

As suggested by RA concordance in twins in the previously described studies, the likelihood of developing RA is influenced to a significant degree by genetic factors. Polymorphisms of several genes that are important in the regulation of immune responses have been linked to an increased risk of developing RA. Many high-risk alleles have been identified in MHC class II genes, including HLA-DQB1, HLA-DQA1, and especially HLA-DRB1.[10] The HLA-DR4 region of the HLA-DRB1 gene cluster is strongly associated with an increased risk of severe and persistent RA.[10] The risk of RA associated with all of the high-risk HLA-DR4 alleles has been attributed to the presence of 1 of 3 specific amino acid sequences, comprising amino acids 70-74. These shared epitopes consist of various sequences of the amino acids glutamine (Q), leucine (K), arginine (R), and alanine (A): QKRAA, QRRAA, or RRRAA.[11] In monozygotic twins, the homozygous presence of either the QKRAA or QRRAA epitope in HLA-DR4 confers a 5-fold increase in the risk of developing RA.[12] Thus, it has been hypothesized that RA may be initiated when RA-associated MHC molecules present self-antigens to autoreactive T cells, although the antigens involved in this process have not been definitively identified.[10]

The Immune Complex Theory

The conventional view concerning the pathogenic mechanisms of RA has been that autoantibodies -- particularly rheumatoid factor (RF) and anticyclic citrullinated peptide (CCP) antibody -- appear to be of particular importance.[11] Nielen and colleagues[13] examined the relationship between these autoantibodies and the eventual diagnosis of RA symptoms by determining antibody concentrations in serial blood samples obtained for several years before the onset of RA symptoms. The proportion of patients with a positive test result for either antibody increased steadily in the years preceding the onset of symptoms. RF and anti-CCP antibody were not present in every patient, although they were more likely to appear in patients with more severe symptoms. These findings, and others,[14,15] suggest that an unidentified trigger stimulates the production of autoantibodies by B lymphocytes several years before the eventual onset of clinically evident RA. RF (or other autoantibody) immune complex deposition in the joint will eventually lead to joint destruction. Neutrophils and macrophages infiltrating the joint via chemotactic gradients bind to the immune complexes and/or to a fixed complement and are induced to degranulate, releasing destructive enzymes that damage the articular structures.[11]

T Cells and RA

Although there is little doubt that immune complex formation can account for some of the hallmarks of the disease, it has become increasingly clear that T lymphocytes are central to the pathogenesis of RA.[11,16,17] The importance of T cells in RA is supported by the observations that a large number of these cells accumulate in the joints of patients with RA[18]; that T cells from the synovium of patients with RA are able to transfer disease to immunodeficient mice[19]; and that the depletion of pathogenic T cells prevents collagen-induced arthritis in mice.[20]

In response to activation by antigen presentation, CD4⁺ T cells initiate and regulate several cell-mediated immune processes that cause the synovial inflammation and joint destruction of RA (Figure 1). Activated CD4⁺ T cells release chemical mediators, such as interferon (IFN)-? and interleukin (IL)-17, which stimulate the activity of other immune cells (such as B cells, monocytes, macrophages, and fibroblasts). These stimulated immune cells then release a second set of chemical mediators that induce inflammation and joint damage, including inflammatory cytokines IL-1 and IL-6, tumor necrosis factor (TNF)-alpha, as well as matrix metalloproteinases and other substances, such as prostaglandins and nitric oxide, which destroy connective tissue.[11] Two of these inflammatory cytokines, TNF-alpha and IL-1, appear to be of particular importance in the development of joint injury in RA. TNF-alpha is released primarily by monocytes and macrophages, although it is also released by B cells, T cells, and fibroblasts. TNF-alpha produces direct inflammatory effects by increasing the expression of cell-surface adhesion molecules that are used by leukocytes to migrate into inflammatory tissues,[16] and indirectly promotes inflammation by stimulating the release of a number of other proinflammatory cytokines, including IL-1, IL-6, and IL-8. IL-1 is also released by monocytes, macrophages, endothelial cells, B cells, and activated T cells. Both TNF-alpha and IL-1 stimulate the release of matrix metalloproteinases from fibroblasts and chondrocytes.[16]

Figure 1.

Antigen-bearing dendritic cells (DC) in the lymph node activate T cells (T) to proliferate and differentiate. Activated T cells are essential for the initiation of the immunologic cascade underlying rheumatoid arthritis (RA) pathogenesis, including subsequent activation of B cells (B), macrophages (M-phi), and fibroblast-like synoviocytes (FLS) (anti-CCP Abs = anticyclic citrullinated peptide antibodies; TNF-alpha = tumor necrosis factor-alpha; IL-1 = interleukin-1; MMPs = matrix metalloproteinases).

CD4+ T cells also activate macrophages and chondrocytes in the synovium by direct cell-to-cell interactions that are mediated by cell-surface receptor molecules (Figure 2). In addition, CD4+ T cells stimulate the production of antibodies, including RF, by B cells and promote the proliferation of bone-resorbing osteoclasts, which contribute to further bone injury (Figure 2).[16] As T cells infiltrate the joint, their activity may be maintained by local joint antigens that are unrelated to the autoantigens that initiated the disease process.[11]

Figure 2.

Cytokines secreted by activated T cells and direct cell-to-cell interactions activate the key cells involved in RA pathology (OC = osteoclast; C = chondrocyte; PMN = polymorphonuclear leukocyte [neutrophil]).

Under normal circumstances, T cells do not produce immune responses to self-antigens, as cells that react to self-peptides complexed with MHC are eliminated during T-cell development in the thymus. This is the main mechanism, known as central tolerance, by which the immune system establishes and maintains nonresponsiveness or tolerance to self. In general, it is thought that T cells in patients with RA may escape tolerance to joint-specific antigens (eg, type II collagen, proteoglycans, aggrecan, and cartilage link protein) or systemic antigens (eg, immunoglobulin [Ig]G Fc, citrullinated proteins, heat shock proteins, and glucose-6-phosphate isomerase) by 2 different means.[11] The cells may escape tolerance to the self-antigen directly. Alternatively, the cells may escape tolerance to the self-antigen indirectly by a process known as molecular mimicry, in which T cells generated in response to an exogenous antigen (eg, a viral peptide) cross-react with a self-antigen.

Costimulatory Activation of T Cells

Regardless of the origin of the stimulating antigen, the T cell requires at least 2 signals for full activation (Figure 3). One signal is delivered by the binding of the antigen/MHC complex on the APC to an antigen-specific receptor on the T-cell surface. The best characterized second, or costimulation, signal is delivered by the interaction between a cell-surface receptor on the T cell (CD28) with its ligands CD80 (B7-1) and CD86 (B7-2) on the APC.[21] When T cells are stimulated by the antigen but do not receive the appropriate costimulation signal, they may enter a quiescent state known as anergy.[22] Anergic cells may fail to proliferate, or they may proliferate but fail to mount an immune response upon subsequent exposure to the antigen. Costimulatory activation initiates the induction of the IL-2 cytokine, stimulates cell proliferation, activates T-cell effector functions, and triggers cell-signaling pathways that promote cell survival.

Figure 3.

Two signals are required for optimal activation of CD4+ T cells by an antigen-presenting cell (APC). The first signal is generated when the T cell receptor (TCR) binds to its cognate antigen presented in the context of major histocompatibility complex (MHC) class II molecules present on the surface of the APC. Costimulation provided by the binding of the CD28 molecule on the T cell with CD80/86 on the APC generates signal 2.

Multiple costimulation pathways both positively (eg, CD40/CD40L and ICOS/ICOS-L) and negatively (eg, PD-1/PD-1L) regulate T-cell function.[21,23] Among these, the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) cell-surface molecule expressed by activated T cells shares about 30% of the amino acid sequence that makes up CD28 and binds to the same APC ligands, CD80 and CD86, that bind to CD28 (Figure 4).[21,24] CD28 and CTLA4 appear to act as part of a T-cell regulatory system in which activation by CD28 receptors stimulates the production of IL-2 and induces the expression of CTLA4. CTLA4, responding to the same APC ligands, signals a decrease in T-cell activity (Figure 4).[25] The central role of CTLA4 in immune regulation is illustrated by findings from in vitro model systems, in which signaling through CTLA4 suppresses T-cell proliferation and cytokine production, and from animal studies, in which mice lacking this receptor develop aggressive lymphoproliferative disorders and premature mortality.[26-28] CTLA4 is expressed by T cells within 24 hours after activation, reaching a peak after approximately 48-96 hours and then decreasing.[25] In vitro studies have found that CTLA4 binds to CD80 and CD86 with much greater affinity than does CD28 by a factor of approximately 2500 for CD80 and approximately 570 for CD86.[29] Thus, the negative effects of CTLA4 on T cells may occur as a result of 2 independent variables; engagement of CD80/86 by CTLA4 directly activates negative signaling pathways within the T cell, but also blocks the positive signaling pathways induced when CD28 binds to CD80/86, as CTLA4 would naturally outcompete CD28 for these ligands.[30,31] Both of these mechanisms that are used by CTLA4 to control T-cell activation could form the basis of potential new therapeutics for RA. Because physiological emulation of intracellular signaling pathways is an often difficult and impractical endeavor, modulation of T-cell activation through a blockade of CD28 costimulation may be the most attractive approach.

Figure 4.

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) outcompetes CD28 for binding of CD80/86 on the APC and provides a negative feedback control, thus attenuating activated T cells.

Targeted Biological Therapies for RA

The current treatment options in RA include nonsteroidal anti-inflammatory drugs; corticosteroids; synthetic DMARDs, such as methotrexate (MTX), hydroxychloroquine, sulfasalazine, leflunomide, and others; and more recently developed biological DMARDs, which target the specific downstream inflammatory mediators TNF-alpha (infliximab, etanercept, and adalimumab) or IL-1 (anakinra).[8] MTX remains the most widely used agent for initial therapy, although combination therapy has become increasingly common during the last decade, as several clinical trials have demonstrated that combination treatment is superior to monotherapy with DMARDs.[8] At present, none of the available treatments are a cure for RA, and joint damage is largely irreversible. Therefore, the goals of treatment are to produce a remission of symptoms and a full restoration of function with long-term therapy.

TNF-alpha Inhibitors

The inflammatory cytokine TNF-alpha is found in high concentration in inflamed joints in patients with RA.[11,16] As described previously, TNF-alpha produces several proinflammatory effects that contribute to joint destruction. It stimulates the release of other proinflammatory cytokines, promotes leukocyte migration, activates neutrophil and eosinophil functional activity, and induces tissue-degrading enzymes produced by synoviocytes or chondrocytes.

Infliximab

Infliximab is an anti- TNF-alpha chimeric antibody that inhibits binding of TNF-alpha to its receptors, with a half-life of 8-10 days.[32] It is indicated for the treatment of moderate-to-severe RA as an infusion of 3-10 mg/kg over 2 hours, once every 4-8 weeks, in combination with MTX.[32]

The Anti-TNF Therapy in RA With Concomitant Therapy (ATTRACT) trial[33] examined the efficacy and safety of infliximab in 428 patients with active RA who were randomized to 1 of 5 treatment groups: MTX plus placebo (n = 88) or MTX plus 1 of 4 infliximab regimens (3 or 10 mg/kg, administered every 4 or 8 weeks; n = 81-86 per group) for 1 year,[34] with an additional year of posttreatment follow-up.[35] Patients were required to have received MTX treatment for ≥ 3 months (with no break in treatment lasting longer than 2 weeks), with a stable MTX dose of ≥ 12.5 mg/week for at least 4 weeks. No other DMARDs were allowed during the study. At the end of the first year, 51.8% of patients who received MTX plus infliximab had attained the American College of Rheumatology 20% improvement criteria (ACR 20), compared with 17.0% of patients who received MTX alone (P < .001).[34] Combination treatment was also associated with significantly less radiographic disease progression in all 4 combination treatment groups than in the MTX group. Compared with MTX plus placebo, all of the MTX plus infliximab groups, with the exception of the 3-mg/kg-every-8-weeks dosage group, exhibited significantly better quality-of-life scores at weeks 30 and 54 (P ≤ .001 for each comparison with MTX plus placebo).[34] In a recently reported follow-up study in which 259 of the patients continued treatment for a second year, the patient outcomes after a total of 102 weeks were generally similar to the outcomes during the first year (Figure 5).[34,35] The combination of infliximab and MTX was still associated with significant improvements in physical function, quality of life, and radiographic evidence of joint damage.[35]

Figure 5.

Efficacy results from the phase 3 Anti-TNF Therapy in RA with Concomitant Therapy (ATTRACT) trial of infliximab plus methotrexate (MTX) in active RA (data from Lipsky et al.[34] and Maini et al.[35]). For American College of Rheumatology (ACR) improvement criteria responses: *P < .001 vs placebo. For total Sharp score: *P < .001 vs placebo; ^†MTX + placebo: n = 50, MTX + infliximab 3 mg/kg every 8 weeks: n = 58, MTX + infliximab 3 mg/kg q4w: n = 66, MTX + infliximab 10 mg/kg q8w: n = 69, MTX + infliximab 10 mg/kg q4w: n = 66.

Etanercept

Etanercept is a fusion protein consisting of the ligand-binding region of the human TNF-alpha receptor linked to the Fc portion of human IgG1. Etanercept has a half-life of approximately 3-5.5 days.[36,37] It is indicated for the treatment of moderate-to-severe RA, alone or in combination with MTX, at a dose of 50 mg once weekly or 25 mg twice per week by subcutaneous injection.[38]

The efficacy of etanercept has been demonstrated in patients with early and chronic RA.[39,40] The Trial of Etanercept and Methotrexate With Radiographic Patient Outcomes (TEMPO)[40] was a double-blind study of 682 patients with active RA who were randomized to receive etanercept (25 mg subcutaneously twice weekly; n = 223), MTX (up to 20 mg once weekly; n = 228), or a combination of etanercept and MTX (n = 231). Patients who had previously received MTX were eligible to participate, provided that they had not exhibited clinically important toxic reactions to MTX treatment and that no MTX had been administered during the 6 months prior to the beginning of the study. All other DMARDs were discontinued 4 weeks prior to study initiation. The combination of etanercept and MTX provided significantly better reduction in RA disease activity than monotherapy with either MTX or etanercept, measured with the numeric index of the ACR response area under the curve (AUC) over the first 24 weeks of treatment. The proportion of patients who achieved ACR 20 at the end of 52 weeks was significantly greater with combination treatment (85%) than with MTX alone (P < .01; 75%) or etanercept monotherapy (P < .05; 76%). Similar findings were obtained for the proportion of patients who attained improvements in ACR 50 and ACR 70 responses (Figure 6).[40] Combination therapy was also associated with greater radiographic improvement from baseline in total joint damage after 52 weeks (Figure 6).[40] Combination treatment also significantly improved functional disability associated with RA (measured with the Health Assessment Questionnaire [HAQ] rating scale; P ≤ .001 for the comparison of combination treatment vs both etanercept and MTX monotherapy). The 3 treatment groups did not differ significantly in the number of adverse events reported, discontinuations due to adverse events, or the number of patients with infection.

Figure 6.

Efficacy results from the phase 3 Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) in active RA (adapted with permission from Klareskog et al. (The Lancet, 2004;363:675-681).[40] For ACR responses: *P < .01 vs MTX; ^†P < .05 vs etanercept; ^‡P < .0001 vs both MTX group and etanercept group. For total Sharp score: *P = .0112 etanercept vs MTX; ^†P < .0001 combination vs MTX, P = .0722 combination vs etanercept; ^‡P = .0469 etanercept vs MTX; ^§P < .0001 combination vs MTX, P = .0006 combination vs etanercept, ^║MTX: n = 212, etanercept: n = 212, combination: n = 218.

Adalimumab

Adalimumab, a recombinant human IgG1 monoclonal antibody specific for human TNF-alpha, inhibits binding of TNF-alpha to both of its receptors and lyses cells that bear TNF-alpha on their surfaces.[41,42] It does not bind or inactivate lymphotoxin (TNF-beta).[43] Adalimumab has a half-life of 10-20 days.[43] It is indicated for use alone or with other DMARDs in patients with moderate-to-severe RA and is administered at a dose of 40 mg every 2 weeks by subcutaneous injection.[43]

Clinical trials have demonstrated that adalimumab is effective for the treatment of RA either as monotherapy or in combination with MTX.[44-46] The efficacy and safety of adalimumab in combination with MTX therapy were examined in a recent phase 3, clinical trial involving patients with active RA.[46] In this double-blind, placebo-controlled study, 619 patients who had an inadequate response to MTX were randomized to receive MTX and weekly adalimumab (20 mg subcutaneously; n = 212), MTX and biweekly adalimumab (40 mg subcutaneously; n = 207), or MTX and placebo (n = 200). The combination of MTX and adalimumab treatment was associated with significant improvement in the signs and symptoms of RA, as measured by the ACR criteria. The proportion of patients who exhibited an improvement in ACR 20, 50, or 70 between baseline and 24 weeks, as well as 52 weeks, was significantly greater for each of the combination treatment groups than for MTX alone (Figure 7).[46] Both of the adalimumab and MTX combination treatment groups also exhibited significantly less radiographic progression of RA after 52 weeks of treatment than the MTX monotherapy group (Figure 7).[46] Physical function (measured with the disability index of the HAQ) after 52 weeks was also significantly better for patients who received either combination treatment than for those on MTX alone (P ≤ .001 for each comparison).

Figure 7.

Efficacy results from a randomized, placebo-controlled phase 3 trial of adalimumab plus MTX in active RA (Adapted with permission from Keystone et al.[46]). For ACR responses: *P ≤ .001 vs placebo. For total Sharp score: *P ≤ .01 vs placebo; ^†P ≤ .001 vs placebo; ^‡MTX + placebo: n = 161, MTX + adalimumab 20 mg every week: n = 183, MTX + adalimumab 40 mg every 2 weeks: n = 165.

The rates of most side effects were similar between the adalimumab and placebo groups.[46] Serious infections, however, were significantly more common with adalimumab than with placebo. The investigators calculated the rate of infections per year of treatment for the 3 groups. Serious infections occurred at a rate of .06 patients per year with weekly adalimumab, .03 patients per year with biweekly treatment, and .01 per year with placebo.

Other Considerations of TNF-alpha Inhibitors

TNF-alpha inhibitors are generally safe and well tolerated. The most common safety concerns with TNF-alpha inhibitors include infusion reactions (infliximab)[35,47,48] or injection-site reactions (etanercept and adalimumab).[49,50] There are reports of increased risk of infection with these agents, including upper respiratory tract infections, opportunistic infections, and reactivation of tuberculosis.[51,52] Other adverse effects of treatment include lupus-like syndrome,[34,45,49,53] demyelinating syndrome,[54] and the development of blocking antibodies.[39,47,55] An increased incidence of malignancies (lymphoma) has also been described with TNF-alpha inhibitors,[56] although it remains a matter of debate whether there is a causal relationship between malignancy and the use of TNF-alpha inhibitors.[42]

A study addressed the effects of ceasing and restarting the TNF-alpha inhibitor, infliximab.[9] Seventeen patients who received infliximab during the ATTRACT trial[33] continued to receive MTX alone in a 2-year extension phase. All 17 patients flared after stoppage of infliximab therapy with a mean time to flare ranging from 13.5 to 15 weeks for the 4 treatment groups. No adverse reactions were experienced by the 15 patients who were re-established on infliximab therapy, and the resulting ACR response was comparable to that established in the original trial in 12 of 14 patients (worse in 2). Thus, ongoing, long-term anti- TNF-alpha treatment is required to maintain responses in patients with established RA.

Summary of Clinical Data With TNF-alpha Inhibitors

The currently available biological DMARDs work by targeting downstream inflammatory cytokines, which are produced by a number of immune cells in response to stimulation by CD4+ T cells. Several large, randomized, controlled trials demonstrate that these agents have resulted in significant progress toward the alleviation of symptoms, the slowing of disease progression, and the restoration of function in many patients with RA. Evidence continues to suggest the long-term utility of these agents in both early and longstanding disease, particularly when used in combination with background DMARDs, such as MTX. They are not effective or well tolerated in all patients. Treatment strategies that target earlier steps in the inflammatory cascade may provide valuable alternatives to these therapies.

Targeting T-Cell Activation Through Selective Costimulation Modulation

As T cells activate and coordinate a number of biological pathways that cause synovial inflammation and joint destruction in patients with RA, therapeutic strategies that specifically modulate T-cell function may reduce the severity of symptoms or slow the progression of the disease more effectively than the currently available treatment options.[57]

A Novel Costimulation Modulator

Abatacept (CTLA4Ig), the first in a new class of agents known as costimulation modulators, is in development for the treatment of RA. Abatacept is a chimeric fusion protein that consists of the extracellular domain of the human CTLA4 molecule and the heavy-chain constant region of human IgG1 (Figure 8).[58,59] Abatacept binds to CD80 and CD86 on APCs, with its extracellular CTLA4 portion, preventing them from making contact with CD28 on T cells. By blocking engagement of CD28, abatacept, like CTLA4, prevents positive costimulation signals required for optimal T-cell activation (Figure 9). In RA, this may prevent the stimulation of T-cell effector functions in response to autoantigen exposure and may suppress the proliferation of autoreactive T cells, restoring the balance between self-tolerance and autoimmunity.

Figure 8.

Abatacept is a chimeric fusion protein that consists of the extracellular domain of the human CTLA4 molecule and the heavy-chain constant region of human IgG1.

Figure 9.

Abatacept selectively modulates T-cell activation by preventing the costimulation signal generated by binding of CD28 with CD80/86.

Abatacept Attenuates T-Cell-Mediated Immune Responses

The immunologic effects of abatacept offer a unique mechanism of action for the treatment of patients with RA. By preventing positive costimulation signals normally generated through engagement of CD28, abatacept can block the release of T-cell cytokines that stimulate other immune cells, while it simultaneously suppresses T-cell proliferation -- with cytokine release and T-cell proliferation being the hallmarks of optimal T-cell activation. This was demonstrated in an in vitro lymphocyte activation model in which human T cells were stimulated with APCs and antigen.[60] Abatacept exposure produced a clear, dose-related inhibition of T-cell proliferation, attaining approximately 80% suppression of proliferation at concentrations of 10 mcg/mL or higher. It also significantly reduced the release of IL-2, TNF-alpha, and IFN-gamma from the T cells during the 72 hours after antigen exposure. Thus, the results of this in vitro study confirmed that abatacept suppresses T-cell responses (both the release of inflammatory cytokines and proliferation) to stimulation by APCs and antigen and does so at concentrations that are similar to the serum concentration produced by abatacept doses evaluated in clinical trials of patients with RA (described below).

Abatacept has also been shown to reduce serum markers of joint inflammation in patients with RA after 6 months of treatment.[61] Blood samples obtained from patients treated with abatacept exhibited reductions from baseline levels of several inflammatory biomarkers, including C-reactive protein, E-selectin, soluble IL-2 receptor, and the macrophage-derived cytokine IL-6. Blood samples from patients treated with abatacept also demonstrated reductions from baseline levels of autoantibodies (RF) produced by B cells. Abatacept has also been shown to have a direct inhibitory effect on dendritic cells.[62] Taken together, these studies suggest that abatacept may act to decrease joint inflammation in RA.

Preclinical Studies With Abatacept

Preclinical studies provided the proof of concept for abatacept in RA. Data from several animal model studies of T-cell-mediated disease have demonstrated that targeting T cells may decrease the severity of autoimmune diseases, including RA. In systemic lupus erythematosus-prone mice (NZBxW strain), abatacept blocked the production of autoantibodies, inhibited T-cell-dependent B-cell maturation, and increased life span.[63,64] Webb and colleagues[65] examined the effects of CTLA4Ig in a mouse model of collagen-induced arthritis, in which exposure of genetically susceptible mice to type II collagen results in cell-mediated and humoral immune responses, synovial inflammation, infiltration of immune cells into the joint, and destruction of bone and cartilage. In 2 experiments, pretreatment with CTLA4Ig markedly reduced the number of mice that developed arthritis following collagen exposure. In the first study, 9 of 10 control mice and 1 of 10 mice treated with CTLA4Ig developed arthritis; in the second study, 9 of 10 control mice and 0 of 10 CTLA4Ig mice developed arthritis (P < .001 for both comparisons). When administered after arthritis was already established, CTLA4Ig significantly reduced the number of arthritic joints and improved other clinical signs of arthritis over 10 days following treatment. CTLA4Ig also significantly reduced lymphocyte proliferation in the lymph nodes.

Pilot and Clinical Studies With Abatacept

Abatacept has recently been evaluated in a series of clinical trials in patients with autoimmune T-cell-mediated diseases. The first study to examine abatacept in humans was a phase 1 clinical trial of 43 patients with psoriasis.[66] Patients received abatacept at doses of .5, 1, 2, 4, 8, 16, 25, and 50 mg/kg, administered at study days 1, 3, 16, and 29, with 4-6 patients enrolled at each dose. Abatacept treatment produced clinically significant improvement in psoriasis symptoms (defined as a decrease of at least 50% in disease activity) in 46% of patients, with a clear relationship between improvement and abatacept dose. All doses studied were well tolerated by the patients.

In a clinical trial that was primarily intended to evaluate safety and tolerability, patients with RA were treated with abatacept at doses of .5, 2, or 10 mg/kg.[67] Abatacept appeared to be safe and well tolerated, with no change in abatacept antibody levels from baseline. Serious adverse events (in most cases, worsening of RA requiring hospitalization) occurred in 4 of 32 patients who received placebo and 4 of 90 patients who received abatacept. The 10-mg/kg dose provided optimal efficacy compared with placebo, in the proportion of patients who attained ACR 20, 50, or 70 responses. This study provided the initial confirmation that monotherapy with abatacept is safe and effective for the treatment of RA.

Phase 2, Efficacy and Safety Clinical Trial of Abatacept

Combination treatment with abatacept and MTX was recently evaluated in a phase 2, randomized, double-blind, placebo-controlled efficacy and safety study.[68] A total of 339 patients with active RA and an inadequate response to MTX were randomized to treatment with MTX in combination with 1 of 2 abatacept dosages (2.0 mg/kg or 10 mg/kg administered as a 30-minute infusion every 2 weeks for the first month, and every month thereafter, for a total of 6 months) or MTX and placebo. All other DMARDs were discontinued at least 28 days before randomization. The patients had a mean duration of disease activity of 8.9-9.7 years, and more than 96% of the patients had no prior biological therapy.

The effects of abatacept on the study primary end point (the proportion of patients with ACR 20 response after 6 months of treatment) were analyzed for the 3 treatment groups. Beginning at day 60, patients who received high-dose abatacept and MTX (n = 115) were significantly more likely to have an ACR 20 response than patients who received placebo and MTX (n = 119; P < .001).[68] This improvement was sustained throughout the 6-month study. Patients who received low-dose abatacept (n = 105) tended to have an increased likelihood of an ACR 20 response, although the difference between the low-dose and placebo groups was not statistically significant. Both abatacept treatments were associated with significant increases in the number of patients who attained ACR 50 or ACR 70 responses, compared with placebo, as well as significantly improved patient quality-of-life ratings, which were measured with the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36).

Additional 1-year follow-up results from this study showed a sustained increase in the ACR 20 score in the abatacept 10-mg/kg group compared with placebo (Figure 10).[69] Clinical outcomes after 12 months reported at the recent European League Against Rheumatism (EULAR) 2004 annual meeting were similar to the results observed after 6 months, with significantly more patients in the abatacept 10-mg/kg group attaining ACR 20, 50, and 70 responses (Figure 11).[70] Adverse events were reported by 16.0% of patients in the placebo group and 12.2% of those who received abatacept. Reports of serious adverse events, or of the most common adverse events (nasopharyngitis, headache, nausea, cough, diarrhea, and upper respiratory tract infection), were similar for the MTX-plus-placebo and MTX-plus-abatacept treatment groups. The treatment response was sustained after 1 year in patients with early ( ≤ 3 years) and established (> 3 years) RA, although treatment with abatacept produced a trend toward a greater improvement in ACR response rates in patients with a shorter disease duration.[70] One year of treatment with abatacept was also associated with significant improvements in physical function and patient-reported pain, with improvements occurring before clinically evident improvement in ACR scores.[71,72] Finally, abatacept significantly increased the number of patients who exhibited disease remission (measured with the Disease Activity Score-28 [DAS28] rating scale, with remission defined as a DAS28 score < 2.6) compared with placebo (Figure 12).[73]

Figure 10.

The combination of abatacept with MTX promotes a sustained increase in the ACR 20 response rate in patients with RA who have inadequate responses to MTX (reprinted with permission from Westhovens et al.[69]). *P < .001 vs placebo + MTX. Placebo + MTX: n = 119; abatacept 10 mg/kg + MTX: n = 115.

Figure 11.

At 12 months, the combination of abatacept with MTX significantly increases the ACR 20, 50, and 70 response rates in patients with RA who have inadequate responses to MTX (data from Keystone et al.[70]). *P < .001; ^†P < .05 vs placebo + MTX. Placebo + MTX: n = 119; abatacept 10 mg/kg + MTX: n = 115.

Figure 12.

The combination of abatacept with MTX significantly increases the remission rate, defined as a DAS28 < 2.6, in patients with RA who have inadequate responses to MTX (reprinted with permission from Dougados et al.[73]). *P < .05 vs placebo + MTX. Placebo + MTX: n = 119; abatacept 10 mg/kg + MTX: n = 115.

Phase 3 Clinical Trials of Abatacept

Several ongoing phase 3 trials are currently examining the efficacy and safety of abatacept, including the effects of abatacept treatment on radiographic measures of disease progression. The Abatacept in Inadequate Responders to Methotrexate (AIM) clinical trial is evaluating abatacept safety and efficacy in patients who have exhibited incomplete responses to 12 months of MTX treatment. The Abatacept Trial in Treatment of Anti-TNF Inadequate Responders (ATTAIN) is evaluating the safety and efficacy of abatacept treatment in patients for whom 6 months of treatment with TNF-alpha inhibitors has failed. The Abatacept Study of Safety in Use With Other RA Therapies (ASSURE) is a large clinical trial that is evaluating the safety of abatacept after 12 months.

Targeting Costimulation and Normal Immune Function

One of the concerns associated with the use of biological DMARDs in the treatment of RA is that normal immune responses against infectious agents, for instance, may be compromised. In the case of costimulation modulators, such as abatacept, this may be less of a worry, because the selective targeting of only 1 costimulation pathway most likely leaves the multiple other pathways involved in T-cell activation intact. This hypothesis of selectivity is supported by animal model studies, in which CD28-deficient mice display normal infectious immunity both before and after treatment with abatacept.[74] In this study, abatacept did not block cytokine production or proliferation of lymph node T cells in response to challenge with the infectious antigen.[74]

Further, abatacept specifically targets a T-cell signaling pathway that has recently been associated with autoimmunity.[75] An autoimmune disease-susceptible haplotype of CTLA4, which most likely results in reduced blocking of CD80/86, has been identified. It is interesting to hypothesize that abatacept could potentially compensate for this reduction in CD80/86 binding in patients who carry the CTLA4 risk haplotype.

Also, it is likely that abatacept primarily prevents the activation of naive T cells, with less effect on the reactivation of memory T cells, as memory T cells are thought to be less dependent on CD28 costimulation.[23]

Conclusion

Considerable advances in our understanding of the immunologic mechanisms underlying the pathophysiology of RA have led to the recent development of new, targeted biological therapies. The recognition that T cells orchestrate the immune response in RA has prompted the search for therapies that depress activation of T cells. Selective targeting of the CD80/86:CD28 costimulation pathway with agents, such as abatacept, appears to be a particularly attractive approach. Targeting one costimulation pathway, while leaving other pathways controlling T-cell activation largely unaltered, may be the ideal strategy for treating RA and other autoimmune diseases. The clinical trial experience with abatacept suggests that agents that modulate T-cell costimulation pathways provide an effective, safe, and well-tolerated alternative to RA treatments that are currently available. In clinical trials of up to 1 year in duration, abatacept has been shown to significantly improve the clinical signs, functional impairment, and pain associated with RA. Abatacept reduces the severity of RA in patients with varying duration of the disorder and provides additional clinical benefit when used in combination with a synthetic DMARD, such as MTX. Abatacept also appears to be well tolerated, with an adverse event profile in clinical trials that is similar to that of placebo. The low risk of adverse events may make abatacept a good choice for patients with RA who have other comorbidities. Ongoing clinical trials continue to evaluate the role of costimulation blockade in patients for whom anticytokine therapy has failed; these trials will address the effect of costimulation blockade on joint damage.