- Email: [email protected]
Cytokines in rheumatoid arthritis: trials and tribulations
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Cytokines in rheumatoid arthritis: trials and tribulations Nancy L. Carteron
Biological agents that inhibit the activity of proinflammatory cytokines are being investigated for use in the treatment of rheumatoid arthritis. Thus far, two of these agents, both of which neutralize tumor necrosis factor a (TNF-a), have received US Food and Drug Administration approval for the treatment of the disease. Etanercept is a bioengineered fusion protein of the p75 soluble TNF receptor, and infliximab is a chimeric monoclonal antibody to TNF-a. Other agents that target proinflammatory cytokines are also being developed. By allowing earlier treatment and better-tolerated long-term therapy, biologics might help slow or prevent disease progression and joint destruction. bone and cartilage destruction1. Despite these similarities, in vitro studies indicate that TNF-a plays a primary role in the cytokine cascade in RA, controlling the production of IL-1 and other proinflammatory cytokines including IL-6 and IL-8 (Refs 2,3). By contrast, IL-1 does not induce the expression of TNF-a, although it does affect the release of IL-6 and IL-8 (Ref. 3). TNF-a and IL-1 mediate joint inflammation and destruction by inducing the synthesis and release of inflammatory metalloproteinases, prostaglandins and nitric oxide in a variety of cell types, and by inhibiting the production of matrix components1.
AFTER a decade of few notable advances in rheumatoid arthritis (RA) therapy, several biological response modifiers that target the pathophysiological processes of RA are on the horizon. Two such agents that inhibit tumor necrosis factor a (TNF-a) activity, etanercept and infliximab, have been approved by the United States Food and Drug Administration (FDA) for the treatment of RA. Other agents are in earlier stages of evaluation; some are no longer being studied owing to a lack of efficacy or unexpected toxicities. Although much is still to be learned about these biological response modifiers, they hold the promise of fundamentally changing treatment options for RA. The available data suggest that some of these agents provide rapid symptomatic relief in the absence of significant adverse effects. Of even more importance, some biological agents slow disease progression and allow patients to enjoy a healthier and more fulfilling life. This review focuses on agents aimed at modulating the activity of proinflammatory cytokines, particularly TNF-a and interleukin 1 (IL-1).
The targeting of proinflammatory cytokines, especially TNF-a and IL-1, has become a strategic basis for developing therapies to treat RA. Approaches that have been investigated include soluble TNF receptors, soluble IL-1 receptors, IL-1 receptor antagonists and monoclonal antibodies to TNF-a.
Cytokines and rheumatoid arthritis
Soluble receptors
Although the initiating event in RA has not yet been defined, a growing body of evidence indicates that cytokines help perpetuate the chronic inflammatory state associated with RA. One logical therapeutic approach, therefore, is to neutralize proinflammatory cytokines. TNF-a and IL-1 are believed to play key roles in the inflammation and joint damage that occur in RA (Fig. 1). Both cytokines are found at high levels in the synovial fluids of patients with RA, and both mediate
Cytokine receptors bind their ligands with high affinity and specificity. Soluble versions of these receptors retain the binding specificity of membrane-bound forms and can efficiently neutralize cytokine bioactivity. The binding of soluble receptors to their natural ligands prevents the ligands from participating in cell-surface receptor-mediated signal transduction. Soluble receptors are thus likely to play a physiological role in regulating cytokine activity.
Cytokine-targeted strategies for the treatment of RA
Soluble TNF receptors Nancy L. Carteron MD, FACR Rheumatology Consultant California Pacific Medical Center, 2100 Webster Street, Suite 200, San Francisco, CA 94115-2374, USA. Tel: 11 415 923 6534 Fax: 11 415 563 1521 e-mail: [email protected]
Two distinct TNF receptors, p55 and p75 (Fig. 1), are found on the surface of a wide variety of cells, including synovial fibroblasts4. These receptors bind to TNF-a and to a related molecule, lymphotoxin a (LT-a, previously referred to as TNF-b). Multimeric TNF-a and LT-a are postulated to initiate cellular signaling by cross-linking two or more receptors of the same type4. Both the p55 and p75 TNF receptors participate in signal transduction but appear to use different pathways and, in some cases, mediate different effects. Both receptors are involved in TNF-a-stimulated DNA synthesis and the release of IL-6, IL-8 and
1357-4310/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S1357-4310(00)01757-3
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longer half-life to the construct compared with monomeric sTNFRs. The p75-based molecule, etanercept, consists of two soluble p75 TNFRs joined to the Fc portion of a huTNF-a man immunoglobulin G1 (IgG1) molecule8. Analogously, the p55-based molecule, lenerIL-1 cept, is composed of two p55 sTNFRs linked anti TNF-a sTNFR mAb to a human IgG1-Fc (Ref. 9). A different sIL-1R version of p55 sTNFR, termed TNFbp, consists of two p55 sTNFRs covalently linked TNF-a through a polyethylene glycol (PEG) linker10. IL-1 On the basis of extensive data from clinical IL-1 trials (Table 1)11,12, etanercept became the first p55 IL-1 receptor biological agent approved by the US Food and TNF receptor receptor type II IL-1 receptor Drug Administration (FDA) for the treatment type I antagonist p75 of RA. In a pivotal Phase II study, patients reTNF receptor ceiving etanercept by subcutaneous administration experienced significant improvement in all measures of disease activity, including swollen joints, tender joints, pain, C-reactive No signaling protein levels and erythrocyte sedimentation rate compared with patients receiving IL-1 No TNF placebo11. At the highest dosage level, 75% signaling signaling signaling of patients experienced a 20% improvement Signal cascade according to American College of Rheumatology (ACR) response criteria. Improvement with etanercept was extremely rapid, with dePromotes Increases Inhibits Stimulates production and creases in measures of disease activity noted bone production of production of release of metalloproteinases within two weeks of initiation of therapy. resorption proinflammatory matrix (e.g., collagenase, stromelysin), Symptoms returned after therapy discontinucytokines components prostaglandin E2 and nitric oxide ation. The most common adverse events were mild injection site reactions and transient, mild, upper-respiratory-tract symptoms, which did Degradation of cartilage and tissue matrix Recruitment of inflammatory cells not necessitate treatment discontinuation. No blood abnormalities or anti-etanercept antibodies were detected11. Similar improvements Inflammation were observed in etanercept-treated patients in Joint destruction a Phase III trial, although non-neutralizing anti-etanercept antibodies were detected in one Molecular Medicine Today patient12. In addition, patients receiving the highest etanercept dose experienced significant Figure 1. Tumor necrosis factor a (TNF-a) and interleukin 1 (IL-1) bind to their receptors and initiate a signal transduction cascade that can result in the destruction of bone and cartilage. These effects might be antagimprovements in health-related quality of life. onized by specific inhibitors. Therapeutic approaches to blocking cytokine–receptor interactions include Additional studies have indicated that agents derived from soluble forms of the TNF (sTNFR) or IL-1 (sIL-1R) receptors, monoclonal antibodies etanercept is efficacious in combination with (mAbs) to TNF-a, and the IL-1 receptor antagonist. By preventing cytokine–receptor binding, these agents act methotrexate and in the treatment of polyupstream of drugs such as NSAIDs, which inhibit downstream mediators such as prostaglandins. articular-course juvenile RA (JRA). In patients with active disease despite methotrexate prostaglandin E2 in synovial fibroblasts4. However, the proliferation of treatment, the addition of etanercept resulted in significant clinical thymocytes in response to mitogen stimulation is mediated by the p75 benefit beyond that achieved with methotrexate alone (Fig. 2)13. receptor, but not by the p55 receptor5. Patients with active JRA, despite treatment with disease-modifying anSoluble versions of both the p55 and p75 receptors have been iden- tirheumatic drugs (DMARDs), experienced impressive decreases in tified in vivo6. These soluble receptors reach particularly high levels in disease activity in response to etanercept14. synovial fluid from patients with RA, suggesting that soluble TNF reA key question is whether etanercept and other biological response ceptor (sTNFR) molecules might play a regulatory role in normal modifiers act as true DMARDs, slowing joint erosion and long-term physiological responses by binding excess extracellular TNF-a (Ref. 7). disability. Several studies suggest that radiographic progression might Bioengineered versions of the p55 and p75 sTNFRs have been developed be the most relevant assessment with respect to long-term patient outand studied for therapeutic use. comes because many patients experience progressive joint damage deTo create these agents, the extracellular domain of the human TNF spite improvement in clinical and laboratory parameters (reviewed in receptor is fused with an immunoglobulin Fc domain, which imparts a Ref. 15). To address whether etanercept could modify radiographic TNF-a
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Table 1. Clinical studies of etanercept in patients with rheumatoid arthritisa Treatment regimen
Efficacyb
Adverse effects
Placebo-controlled, randomized, 180 Failed 1–4 double-blind, multicenter (3 mo)11 DMARDs
0.25–16 mg m22 SC 2 wk21
At highest dose, 61% reduction in SJC vs 25% for placebo
Mild injection site reactions FDA approved 11/98 and upper respiratory for moderate to tract symptoms severe RA failing at least 1 DMARD
Placebo-controlled, randomized, 234 DMARD-failing double-blind, multicenter (6 mo)12 with active RA
10 or 25 mg SC 2 wk21
At highest dose, 47% reduction in SJC vs 7% worsening for placebo
One patient with nonneutralizing antietanercept antibodies
Randomized, double-blind, placebo-controlled; in combination with MTX (6 mo)13
89 Active RA despite MTX treatment
25 mg SC 2 wk21 1 MTX (12.5–25 mg wk21)
78% reduction in SJC with etanercept/MTX vs 33% for placebo/MTX
Randomized, multicenter, double-blind etanercept vs MTX (ERA trial) (12 mo)16
632 Early active RA; Etanercept 25 mg disease or 10 mg SC 2 wk21; duration #3 yr MTX rapidly escalated to 20 mg wk21
Randomized, double-blind, placebo-controlled (3 mo on etanercept, then randomized to drug or placebo for 4 mo)14
69 Active JRA despite treatment; mean age 10.5 y
Study description (duration)
N
RA patient population
75% of etanercept patients Injection site reactions with no new erosions at greater with etanercept; 1 yr vs 57% for MTX; least all other AEs # to MTX, change in joint damage including infections with etanercept 25 mg
0.4 mg kg21 SC 2 wk21 Time to disease flare $116 days for etanercept vs 28 days for placebo
No different from placebo
Comments on agent
Demonstrated to be a DMARD
FDA approved 5/99 for moderately to severely active polyarticular-course JRA failing at least 1 DMARD
a
Abbreviations: RA, rheumatoid arthritis; TNF, tumor necrosis factor; DMARD, disease-modifying antirheumatic drug; SC, subcutaneous; FDA, Food and Drug Administration; SJC, swollen joint count; MTX, methotrexate; JRA, juvenile rheumatoid arthritis; AE, adverse event; IV, intravenous. b This efficacy summary focuses on reduction in swollen joint count; this parameter is the primary measure of efficacy in most of the studies.
progression, 632 patients with early active RA were enrolled in a randomized, double-blind study of etanercept versus methotrexate. Over the course of one year, significantly fewer patients receiving 25 mg etanercept twice weekly developed new erosions compared with patients receiving methotrexate, a known DMARD (Refs. 16,17). Etanercept remains effective and generally well-tolerated during long-term administration18. No serious adverse events were noted in patients receiving etanercept for up to 33 months: there were no increases in infection rate or malignancies and no development of new autoimmune disease. Children should also be observed for potential long-term effects on growth and fertility. Routine blood monitoring is not recommended for juvenile or adult RA patients receiving etanercept alone. By contrast with etanercept, clinical results with a p55-based TNFneutralizing agent, lenercept, were less encouraging (Table 2)9,19,20. Lenercept trials were hampered by high dropout rates, mostly owing to insufficient efficacy, and anti-lenercept antibodies were detected in a significant proportion of patients9,19,20. The clinical development of lenercept is no longer being pursued for RA. A third sTNFR-based agent, TNFbp, a p55 sTNFR–PEG fusion protein, has also been assessed (Table 2). Although TNFbp appeared efficacious in one trial, an overwhelming antibody response affected the half-life and clearance of the compound, raising doubts about its long-term efficacy10. A less antigenic monomeric version, PEG sTNFRI, is currently under study. In a Phase I trial with RA patients, the average number of tender/painful joints was decreased, and only four out
of 66 patients demonstrated seroreactivity to PEG sTNF-RI (Ref. 21). Large-scale clinical studies have yet to be completed with this agent.
Soluble IL-1 receptors Two types of IL-1 receptors have been detected on the cell surface (Fig. 1). Only the type I receptor appears to mediate signal transduction; the type II receptor appears to act as a decoy. Soluble forms of the IL-1 receptor have been identified in plasma22. A soluble form of the type I IL-1 receptor, recombinant human IL-1R1 (rHuIL-1R1), has been tested in Phase I trials of patients with active RA (Table 2), but the efficacy of this agent has not proven particularly promising23. In patients receiving rHuIL-1R1 by subcutaneous administration, only one of 23 patients demonstrated clinical improvement, and dose-limiting skin rashes were observed in two patients23. Intra-articular administration of rHuIL-1R1 into a joint with active rheumatoid synovitis resulted in somewhat better results24. The lack of efficacy of rHuIL-1R1 might be the result of complex interactions occurring within the IL-1 signal transduction system. In addition to binding IL-1, soluble IL-1 receptors (sIL-1Rs) also bind the IL-1 receptor antagonist (IL-1Ra)25. This interaction might complicate the therapeutic use of sIL-1Rs, particularly the type I sIL-1R, because the affinity of this molecule for IL-1Ra is higher than its affinity for IL-1a or IL-1b (Ref. 25). In vitro, type I sIL-1R causes a decrease in the natural anti-inflammatory inhibitory effects of the IL-1Ra26. If this also occurs in vivo, then the type I sIL-1R might not 317
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Placebo/MTX Etanercept/MTX P<0.001 vs placebo/MTX
100
% Patients
80 60 40 20 0 ACR 50
ACR 20
(b)
Placebo/MTX Etanercept/MTX P<0.001 vs placebo/MTX P<0.01 vs placebo/MTX
100
Monoclonal antibodies
80 % Improvement
a biological response can occur when only 2–3% of IL-1Rs are occupied22. Thus, up to 98% of all IL-1Rs might need to be occupied by IL-1Ra before an antagonistic effect is observed. A recombinant version of human IL-1Ra (rHuIL-1Ra), administered subcutaneously daily, has been tested in patients with RA (Table 3). The potential efficacy of such an agent was suggested in a dose-ranging study27, and further supported by a larger double-blind study28. Clinical improvement was observed as early as two weeks after treatment initiation, and disease progression was slowed28. The overall clinical improvement mediated by this agent was modest, with an approximate 10% reduction in swollen joint counts. In patients with active RA despite methotrexate treatment, the addition of rHuIL-1Ra resulted in an increased ACR 20 (20% improvement according to ACR criteria) response rate at 24 weeks29. The lack of an impressive clinical response to rHuIL-1Ra, despite effects on disease progression, suggests that there might be a difference between cytokines involved in pain and inflammation and cytokines involved in joint destruction.
60 40 20 0 Tender Swollen Morning joints stiffness joints
CRP
Pain Disability (VAS) index (HAQ) Molecular Medicine Today
Figure 2. Response to treatment with etanercept/methotrexate (n559) or placebo/methotrexate (n530) at 24 weeks in a randomized, double-blind clinical trial. (a) Percentage of patients with ACR response. ACR 20 indicates 20% improvement according to American College of Rheumatology criteria; ACR 50, 50% improvement according to American College of Rheumatology criteria. (b) Percentage improvement in disease activity from baseline. Abbreviations: VAS, visual analogue scale; HAQ, health-assessment questionnaire; CRP, C-reactive protein; MTX, methotrexate13.
mediate the desired decrease in IL-1 activity. The type II sIL-1R, on the other hand, binds to IL-1b more tightly than to the IL-1Ra25. This molecule might therefore have more therapeutic potential as an IL-1 neutralizer than does type I sIL-1R.
Another strategy for inhibiting cytokines is to neutralize cytokines with specific monoclonal antibodies. Possible drawbacks to the therapeutic use of antibodies include their potential to cause cell lysis through complement fixation, and loss of efficacy owing to neutralizing antibody formation. In an effort to avoid immunogenicity, monoclonal antibodies might be modified so that murine regions are replaced by their human counterparts. In ‘chimeric’ monoclonal antibodies, the Fc portion of the molecule is replaced by human sequences, whereas in ‘humanized’ monoclonal antibodies, both the Fc and non-antigen-binding regions of the Fab segment are replaced. Although these modifications help re duce antigenicity, the antibodies retain murine sequences in the variable region and thus still possess the potential to induce an immune response against the monoclonal antibody. Accordingly, most therapeutically useful monoclonal antibodies have been developed for short-term applications (for example, transplant rejection prevention and diagnosis). Recently, a strategy for developing nonimmunogenic monoclonal antibodies was devised: using a murine monoclonal antibody as a template, the murine heavy and light chains are replaced with human counterparts. The end result is a monoclonal antibody with a fully humanized primary sequence. Three monoclonal antibodies directed against TNF-a have been developed for clinical use: a chimeric monoclonal antibody (infliximab)30, a humanized monoclonal antibody (CDP571)31 and a fully human monoclonal antibody (D2E7)32.
Chimeric monoclonal antibody Receptor antagonists As with soluble receptors, receptor antagonists have the potential to block receptor–ligand interactions and consequent signaling. For a receptor antagonist to work, it must bind all cell-surface receptors and keep them continuously occupied; this might be difficult to achieve in clinical practice. Furthermore, constant receptor occupancy might be undesirable: a balance between bound and free receptors might be necessary to regulate cytokine activity.
IL-1Ra The IL-1Ra binds to IL-1R, blocking its interaction with IL-1 and inhibiting IL-1-mediated signal transduction. In vitro data suggest that 318
Phase III clinical trials have been completed for a chimeric human IgG1 monoclonal anti-TNF-a antibody, infliximab (cA2), in patients with RA. This agent provides clinical improvement of RA symptoms (Table 4)33,34. Drawbacks include the development of anti-infliximab antibodies, and a possible decrease in efficacy over time34,35. In vitro data suggest that infliximab mediates complement-mediated cell lysis, a possible explanation for the marked and sustained decrease in total monocyte counts following infliximab treatment36. To overcome problems related to anti-infliximab antibodies, infliximab treatment was combined with methotrexate therapy, resulting in reduced development of anti-infliximab antibodies and improved duration of response compared with infliximab alone34. Although treatment
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Table 2. Clinical studies of lenercept, TNFbp, PEG sTNF-R1 and rHuIL-1R in patients with rheumatoid arthritisa Study drug
Study description (duration)
N
Lenercept (soluble TNF Placebo-controlled 118 p55 receptor fusion (3 mo)19 protein)
Double-blind, randomized, parallel group, multicenter (12 wk)20
RA Treatment patient regimen population
Efficacyb
Adverse effects
RA
At highest dose, 25% SJC reduction at 2 wk, worsening to 23% at 12 wk
Development of antiDevelopment discontinued lenercept antibodies in due to lack of superiority 14% to 59% of patients vs MTX and high prevalence of antilenercept antibodies Non-neutralizing antilenercept antibodies developed in most patients
247 RA
0.01 to 0.5 mg kg21 IV 1 mo21
5 to 50 mg At 5-mg dose, 54% SC 1 wk21; SJC reduction; also 12.5 mg adding MTX did not 1 MTX (7.5 improve responses to 15 mg wk21)
Comments on agent
TNFbp (soluble TNF p55 receptor-PEG fusion protein)
Placebo-controlled, 34 randomized, double-blind, multicenter (6 wk)10
RA
30 to 300 mg kg21 IV 1 3wk21
Unspecified ‘evidence of in vivo activity’
Overwhelming antibody response affecting half-life and clearance
Attempts in progress to develop a less immunogenic version
PEG sTNF-R1
Placebo-controlled, 81 double-blind, dose-escalation, multicenter (28 d)21
RA
Single injection of 100 to 1000 mg kg21, followed by injections of 100–600 mg kg21
Tender and swollen joint counts decreased by unspecified amounts in sTNF-R1-treated groups
Some headache, infrequent injectionsite reactions
Appears well tolerated and less immunogenic than other p55 derivatives
rHuIL-1R (soluble IL-1 type I receptor)
Placebo-controlled, 23 randomized, double-blind (28 d)23 Placebo-controlled, 16 randomized, double-blind (7 d)24
Failed at least 1 DMARD
125 to 1000 At highest dose, 1/8 Injection site reactions, mg m22 d21 SC patients >40% dose-limiting rashes improvement in SJC vs 0% for placebo Single dose of Dose-related reduction Injection site reactions, 25 to 500 mg/ in target knee dose-limiting rashes joint intracircumference articularly
RA
Limited efficacy, possibly owing to interactions with IL-1Ra
a
Abbreviations: RA indicates rheumatoid arthritis; TNF, tumor necrosis factor; DMARD, disease-modifying antirheumatic drug; SC, subcutaneous; FDA, Food and Drug Administration; SJC, swollen joint count; MTX, methotrexate; JRA, juvenile rheumatoid arthritis; AE, adverse event; IV, intravenous; IL-1, interleukin 1; IL-1Ra, interleukin 1 receptor antagonist. bThis efficacy summary focuses on reduction in swollen joint count; this parameter is the primary measure of efficacy in most of the studies.
with infliximab plus methotrexate was generally well tolerated, two serious infections occurred and one patient developed systemic lupus erythematosus (SLE). A Phase III trial of infliximab (the ATTRACT trial) further assessed the combination of infliximab plus methotrexate37,38. The addition of infliximab resulted in significant improvements in ACR 20 response rates compared with methotrexate plus placebo. Radiographic results indicated that infliximab appears to halt progression of joint damage. Based on these data, the FDA approved infliximab for use in conjunction with methotrexate for the treatment of RA. However, this agent is probably not appropriate for long-term use in patients who cannot tolerate methotrexate. The association of infliximab with immunological abnormalities, including autoantibodies, SLE and com-
plement-mediated cell lysis, requires further assessment in long-term clinical trials.
Humanized monoclonal antibody A humanized anti-TNF-a monoclonal antibody, CDP571, has been tested in a Phase I trial (Table 4)31. Treatment with CDP571 resulted in significant improvements in measures of disease activity, including pain, tender and swollen joint counts, and C-reactive protein levels at weeks 1 and 2. Improvements were generally maintained throughout the eight-week follow-up period. However, some parameters began to increase towards baseline levels at week 4 (Ref. 31). In an open-label continuation of this study, patients received a second infusion of CDP571. Rapid symptomatic relief was again observed, but by eight weeks most parameters had returned to preinfusion 319
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Table 3. Clinical studies of recombinant human IL-1 receptor antagonist in patients with rheumatoid arthritisa Study description (duration)
N
RA patient population
Treatment regimen
Efficacyb
Randomized, double-blind, dose- and regimen-ranging (3-wk treatment, 4-wk maintenance)27
175 Active RA
20–200 mg SC daily Highest dose 3 or 7 times weekly resulted in a 10% SJC reduction at 7 wk
Placebo-controlled, randomized, double-blind, multicenter (24 wk)28
472 Early active RA
30–150 mg SC daily 10% reduction in SJC; Larsen score indicated slower disease progression
Placebo-controlled, randomized, double-blind, multicenter (24 wk)29
419 Active RA 0.04–2 mg kg21 SC despite MTX daily 1 MTX
ACR 20 response at 24 wk 42% for 1 mg kg21 and 35% for 2 mg kg21 vs 23% for placebo
Adverse effects
Comments on agent
Generally mild injection site reactions; infectious events, including soft-tissue infections; low incidence of anti-rHuIL-1Ra antibodies
Requires frequent administration; extended-release formulation under development
Injection site reactions
Lack of dose– response relationship for ACR 20 at doses tested
a
Abbreviations: RA, rheumatoid arthritis; SC, subcutaneous; SJC, swollen joint count; MTX, methotrexate; ACR 20, 20% improvement as measured by American College of Rheumatology response criteria. bThis efficacy summary focuses on reduction in swollen joint count; this parameter is the primary measure of efficacy in most of the studies.
levels31. The data from this study suggest a shortened duration of response following repeated administration of CDP571, as was seen with infliximab. No obvious drug-related adverse effects were observed. However, the authors did not report whether assays to detect autoantibodies or anti-CDP571 antibodies were performed31.
Fully humanized antibody A fully humanized anti-TNF-a antibody, D2E7, has been assessed in clinical trials (Table 4). Administration of D2E7, intravenously or subcutaneously, resulted in 60% reductions in swollen and tender joint counts39–41. Radiographic measurements performed on 66 patients after
Glossary Acute-phase reactant – A protein induced by systemic inflammation, usually measured through C-reactive protein levels or erythrocyte sedimentation rates. American College of Rheumatology (ACR) response criteria – An improvement in RA symptoms is defined as 20% improvement from baseline in tender and swollen joint counts, and 20% improvement in three of the five remaining ACR core set of disease activity measures: patient and physician global assessments; pain; disability; and acute-phase reactant levels. Other levels of improvement (50% or 70%) may also be assessed in clinical trials. Biological agent – In the context of this review, a biological agent is a cellular product such as a cytokine or antibody used to treat a disease state. These agents might be less toxic than pharmacological agents because they are similar or identical to their natural counterparts. Biological response modifier – A biological agent that targets one specific molecule involved in modulating normal or abnormal biological function, thus resulting in an altered cellular or systemic response. C-reactive protein – A globulin that, in the presence of calcium ions, precipitates the C substance of pneumococcal cells. Presence of this protein correlates with radiographic disease progression in RA. Disease-modifying antirheumatic drug (DMARD) – A drug that can modify the course of RA by slowing or stopping disease progression, as assessed by radiographic analysis of involved joints (in contrast to providing only symptomatic relief with no effect on disease course). Erythrocyte sedimentation rate (ESR) – The rate at which erythrocytes settle in a test tube in one hour. ESR is a nonspecific indicator of disease, especially inflammatory conditions, and correlates with radiographic disease progression in RA. Juvenile rheumatoid arthritis (JRA) – A chronic inflammatory arthritis in children. There are three major onset types based on symptoms during the first 6 months: polyarticular (five or more joints involved); pauciarticular (fewer than five joints involved); and systemic (marked by body-wide symptoms such as fever and rash). Following the initial six-month period, the disease course can vary (for instance, a case of pauciarticular onset can change to a polyarticular course).
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Table 4. Clinical studies of monoclonal antibodies to cytokines in patients with rheumatoid arthritisa Study drug
Study description (duration)
N
RA patient population
Treatment regimen
Efficacyb
Adverse effects
Infliximab (chimeric monoclonal TNF antibody; cA2)
Placebo-controlled, randomized, double-blind, multicenter (single infusion, 4-wk follow-up)35 Repeated treatment of disease flares (2–4 cycles)35
73
Failed at least 1 DMARD
Single dose of 1 or 10 mg kg21 IV
At highest dose, 61% reduction in SJC vs 2% for placebo at 4 wk
Infections most common Approved by FDA for use adverse event with MTX; questions about immunogenicity and association with SLE persist
8
Previously enrolled in open-label infliximab trial Active RA, on MTX
20 mg kg21 IV Response duration 1st cycle; decreased from 10 mg kg21 IV 12 wk (cycle 1) to subsequent 7.7 wk (cycle 4) cycles 1 to 10 mg kg21 IV MTX increased 1 2wk21 with or duration of response without MTX (1 mg kg21) 3 or 10 mg kg21 Slowed progression of q 8 wk 1 MTX joint erosions and (15 mg wk21) reduced SJC vs q 4 wk or MTX 1 placebo q 8 wk
Development of antiinfliximab antibodies reduced by concomitant MTX Trend to increased infections at higher doses; rare cases of SLE, hypersensitivity reaction
Single dose of 0.1 to 10.0 mg kg21 IV
Some skin rashes and injection site reactions in both active and placebo groups
Placebo-controlled, 101 randomized, multicenter (26 wk)34 Double-blind, 428 randomized, placebo-controlled (ATTRACT trial) (54 wk)37,38
Active RA despite MTX
CDP571 (humanized Placebo-controlled, 36 monoclonal TNF randomized, antibody) double-blind (single infusion, 8-wk follow-up)31
Failed $1 $1 DMARD and disease duration of #10 yr
D2E7 (fully human monoclonal TNF antibody)
Active RA
Open-label (data up to 12 mo)39,40
120
Randomized, 283 placebo-controlled, double-blind (data up to 3 mo)41
Single IV dose of 0.5 to 10.0 mg kg21, then 0.5 to 1.0 mg kg21 1 2wk21 Patients with 20, 40, long80 mg SC standing active RA
At highest dose, 30% reduction in SJC at wk 1 and 2 vs 9% for placebo
Comments on agent
Development of antiinfliximab antibodies with repeated administration
Demonstrated to be a DMARD; best dose = 10 mg kg21 q 4 wk
Limited efficacy; may not be appropriate as longterm therapy
About 60% reduction in 1 case of pneumonia SJC (pooled data); no evidence of radiographic progression
Ongoing study; early data promising
About 60% reduction in SJC at 2 mo; no clear dose response over doses studied
Ongoing; no safety data reported yet
a
Abbreviations: RA, rheumatoid arthritis; IV, intravenous; SJC, swollen joint count; SLE, systemic lupus erythematosus; MTX, methotrexate; FDA, Food and Drug Administration; DMARD, disease-modifying antirheumatic drug; TNF, tumor necrosis factor; SC, subcutaneous. b This efficacy summary focuses on reduction in swollen joint count; this parameter is the primary measure of efficacy in most of the studies.
12 months of treatment showed no evidence of disease progression40. This agent thus appears promising, but larger studies will be required to fully assess its benefits and safety.
The future of biological response modifiers Biological response modifiers hold the promise of providing both significant clinical benefits and key insights into the pathophysiology of RA. Because biological response modifiers target one specific molecule, they might be less likely to cause the adverse effects associated with older DMARDs, which typically interact with multiple receptors and enzyme systems42.
Many of the most effective DMARDs, including methotrexate, leflunomide, gold, and penicillamine, can cause severe, sometimes irreversible, toxic effects43,44. Even most nonsteroidal anti-inflammatory drugs can result in significant gastrointestinal toxicity45. The adverse effects associated with DMARDs result in a high rate of treatment discontinuation, thus preventing optimal disease blockade43,44. The favorable safety profiles of some biological agents might make them well-suited for early RA therapy. Studies indicate that early, aggressive DMARD therapy improves patient outcome46,47. A therapeutic window of opportunity appears to exist in patients with early RA, suggesting that earlier disease might differ pathophysiologically from 321
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References
The outstanding questions
• • • • • •
Will inhibition of TNF-a and IL-1 be the next major advance in RA therapy? Will such combination therapy be able to prevent comorbid conditions, such as osteoporosis and congestive heart failure? Will chronic TNF-a blockade continue to effectively prevent cell trafficking to the synovium? Will other inflammatory processes like asthma or allergies decrease in patients receiving long-term anti-inflammatory therapy? Will autoimmune or malignant processes increase? Will these highly targeted therapies facilitate discovery of RA disease subsets and thus drive diagnosis and treatment/ cure discoveries? Will certain routes of administration improve efficacy or be more cost effective? Will the same biological agent given subcutaneously, intravenously or transdermally modulate different functions? How will reallocation of health-care dollars/resources occur to allow expensive, but more effective and safer, therapies to gain widespread application?
later disease. In particular, it might be easier to downregulate the inflammatory events of RA soon after disease onset, possibly preventing irreversible joint damage. Biological response modifiers might also provide important insights into the pathophysiology of RA. For instance, cytokine-targeted therapies might allow the identification of subsets of RA. A complete understanding of the pathophysiology of RA could fuel the search for more and better treatments or even, perhaps, a vaccine or other ‘cure.’ As with nonbiological agents, the road to clinical fruition can be rocky. Some of the biological response modifiers are likely to fall by the wayside. Nevertheless, biologics aimed at cytokines have the potential to revolutionize the treatment of RA. Results with etanercept, which has been shown to elicit rapid, significant, and sustained reductions in disease activity, show that such agents can immediately improve the quality of life of patients with RA. Of even more importance, etanercept and some other biological agents decrease radiographic joint damage, which might favorably impact long-term outcomes. Other treatment strategies beyond those discussed here are also being actively explored. Some of these involve alternate means of modulating the cytokine network, including administration of antiinflammatory cytokines, cytokine blockade by antisense technology, and localization of therapeutic molecules through gene therapy. Additional strategies are targeting other systems that might be involved in RA, such as activated T cells and fibroblastlike synoviocytes. Agents that block angiogenesis, intracellular adhesion molecules and matrix metalloproteinases are also being explored. Together with existing treatment modalities, biological response modifiers – those already developed as well as those still in experimental stages – are likely to expand both our knowledge of the pathophysiology of RA and our options for successfully treating the disease. Acknowledgment. We thank Sharon L. Cross PhD for her invaluable assistance during the preparation of this manuscript.
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1 Maini, R.N. (1996) The role of cytokines in rheumatoid arthritis. The Croonian Lecture 1995. J. R. Coll. Physicians Lond. 30, 344–351 2 Brennan, F.M. et al. (1989) Inhibitory effect of TNF-a antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 2, 244–247 3 Butler, D.M. et al. (1995) Modulation of proinflammatory cytokine release in rheumatoid synovial membrane cell cultures. Comparison of monoclonal anti TNF-a antibody with the interleukin-1 receptor antagonist. Eur. Cytokine Netw. 6, 225–230 4 Butler, D.M. et al. (1994) p55 and p75 tumor necrosis factor receptors are expressed and mediate common functions in synovial fibroblasts and other fibroblasts. Eur. Cytokine Netw. 5, 441–448 5 Tartaglia, L.A. et al. (1993) Stimulation of human T-cell proliferation by specific activation of the 75-kDa tumor necrosis factor receptor. J. Immunol. 151, 4637–4641 6 Engelmann, H. et al. (1990) Two tumor necrosis factor-binding proteins purified from human urine. Evidence for immunological cross-reactivity with cell surface tumor necrosis factor receptors. J. Biol. Chem. 265, 1531–1536 7 Brennan, F.M. et al. (1995) TNF inhibitors are produced spontaneously by rheumatoid and osteoarthritic synovial joint cell cultures: evidence of feedback control of TNF action. Scand. J. Immunol. 42, 158–165 8 Mohler, K.M. et al. (1993) Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. J. Immunol. 151, 1548–1561 9 Sander, O. et al. (1996) Neutralization of TNF by lenercept (TNFR55–IgG1, Ro 45) in patients with rheumatoid arthritis treated for 3 months: results of a European Phase II trial (Abstr.). Arthritis Rheum. 39 (suppl. 9), Abstr. 1288 10 McCabe, D. et al. (1998) A Phase I/II study to evaluate the safety, immunogenicity, pharmacokinetics and potential efficacy of IV rHuTNF binding protein pegylated dimer (TNFbp) in patients with active RA (Abstr.). Arthritis Rheum. 41 (suppl. 9), S58 11 Moreland, L.W. et al. (1997) Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)–Fc fusion protein. New Engl. J. Med. 337, 141–147 12 Moreland, L.W. et al. (1999) Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial. Ann. Intern. Med. 130, 478–486 13 Weinblatt, M.E. et al. (1999) A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. New Engl. J. Med. 340, 253–259 14 Lovell, D.J. et al. (2000) Etanercept in children with polyarticular juvenile rheumatoid arthritis. New Engl. J. Med. 342, 763–769 15 Pincus, T. et al. (1999) Does partial control of inflammation prevent long-term joint damage? Clinical rationale for combination therapy with multiple disease-modifying antirheumatic drugs. Clin. Exp. Rheumatol. 17 (suppl. 18), S2–S7 16 Finck, B. et al. (1999) A Phase III trial of etanercept vs methotrexate (MTX) in early rheumatoid arthritis (Enbrel® ERA trial) (Abstr.). Arthritis Rheum. 42 (suppl. 9), S117 17 Peterfy, C. et al. (1999) Comparison of etanercept vs methotrexate (MTX) in early rheumatoid arthritis using gadolinium-enhanced magnetic resonance imaging (Enbrel® ERA trial) (Abstr.). Arthritis Rheum. 42 (suppl. 9), S241 18 Moreland, L.W. et al. (1999) Long-term use of etanercept in patients with DMARD–refractory rheumatoid arthritis (Abstr.). Arthritis Rheum. 42 (suppl. 9), S401 19 Furst, D. et al. (1996) Neutralization of TNF by lenercept (TNFR55-IgG1, Ro 45–2081) in patients with rheumatoid arthritis treated for 3 months: results of a US Phase II trial (Abstr.). Arthritis Rheum. 39 (suppl. 9), Abstr. 1295 20 McKay, J. et al. (1998) A double-blind, randomized, 6 arm, parallel-group, dose finding, double-dummy, multi-center comparison of sTNFr55lgG [Ro 45-2081Lenercept (LEN)] subcutaneous (SC) to reference treatment with oral methotrexate (MTX) and their combination in patients with rheumatoid arthritis (RA) (12 week dose–finding efficacy/safety study) (Abstr.). Arthritis Rheum. 41 (suppl. 9), S132
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21 Caldwell, J.R. et al. (1999) A Phase 1 study of pegylated soluble tumor necrosis factor receptor type I (PEG sTNF–RI [55]) in subjects with rheumatoid arthritis (RA) (Abstr.). Arthritis Rheum. 42 (suppl. 9), S236 22 Dinarello, C.A. (1994) The interleukin-1 family: 10 years of discovery. FASEB J. 8, 1314–1325 23 Drevlow, B.E. et al. (1996) Recombinant human interleukin-1 receptor type I in the treatment of patients with active rheumatoid arthritis. Arthritis Rheum. 39, 257–265 24 Drevlow, B. et al. (1993) Phase I study of recombinant human interleukin-1 receptor (RHU IL-1R) administered intra-articularly in active rheumatoid arthritis. Arthritis Rheum. 36 (suppl. 9), S39 25 Arend, W.P. et al. (1994) Binding of IL-1a, IL-1b, and IL-1 receptor antagonist by soluble IL-1 receptors and levels of soluble IL-1 receptors in synovial fluids. J. Immunol. 153, 4766–4774 26 Burger, D. et al. (1995) The inhibitory activity of human interleukin-1 receptor antagonist is enhanced by type II interleukin-1 soluble receptor and hindered by type I interleukin-1 soluble receptor. J. Clin. Invest. 96, 38–41 27 Campion, G.V. et al. (1996) Dose-range and dose-frequency study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. Arthritis Rheum. 39, 1092–1101 28 Bresnihan, B. et al. (1998) Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum. 41, 2196–2204 29 Cohen, S. et al. (1999) Treatment of interleukin-1 receptor antagonist in combination with methotrexate (MTX) in rheumatoid arthritis (RA) patients (Abstr.). Arthritis Rheum. 42 (suppl. 9), S273 30 Elliott, M.J. et al. (1993) Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor a. Arthritis Rheum. 36, 1681–1690 31 Rankin, E.C.C. et al. (1995) The therapeutic effects of an engineered human antitumour necrosis factor alpha antibody (CDP571) in rheumatoid arthritis. Br. J. Rheumatol. 34, 334–342 32 Salfeld, J. et al. (1998) Generation of fully human anti-TNF antibody D2E7 (Abstr.). Arthritis Rheum. 41 (suppl. 9), S57 33 Elliott, M.J. et al. (1994) Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor a (cA2) versus placebo in rheumatoid arthritis. Lancet 344, 1105–1110 34 Maini, R.N. et al. (1998) Therapeutic efficacy of multiple intravenous infusions of
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anti-tumor necrosis factor a monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 41, 1552–1563 Elliott, M.J. et al. (1994) Repeated therapy with monoclonal antibody to tumour necrosis factor a (cA2) in patients with rheumatoid arthritis. Lancet 344, 1125–1127 Lorenz, H-M. et al. (1996) In vivo blockade of TNF-a by intravenous infusion of a chimeric monoclonal TNF-a antibody in patients with rheumatoid arthritis. Short term cellular and molecular effects. J. Immunol. 156, 1646–1653 Maini, R. et al. (1999) Infliximab (chimeric anti-tumour necrosis factor a monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised Phase III trial. Lancet 354, 1932–1939 Lipsky, P. et al. (1999) 54-week clinical and radiographic results from the ATTRACT trial: a Phase III study of infliximab (RemicadeÔ) in patients with active RA despite methotrexate (Abstr.). Arthritis Rheum. 42 (suppl. 9), S401 Rau, R. et al. (1998) Long-term efficacy and tolerability of multiple I.V. doses of the fully human anti-TNF antibody D2E7 in patients with rheumatoid arthritis (Abstr.). Arthritis Rheum. 41 (suppl. 9), S55 Rau, R. et al. (1999) Long-term treatment with the fully human anti-TNF antibody D2E7 slows radiographic disease progression in rheumatoid arthritis (Abstr.). Arthritis Rheum. 42 (suppl. 9), S400 van de Putte, L.B.A. et al. (1999) Efficacy of the fully human anti–TNF antibody D2E7 in rheumatoid arthritis (Abstr.). Arthritis Rheum. 42 (suppl. 9), S400 Bondeson, J. (1997) The mechanisms of action of disease-modifying antirheumatic drugs: a review with emphasis on macrophage signal transduction and the induction of proinflammatory cytokines. Gen. Pharmacol. 29, 127–150 Felson, D.T. et al. (1990) The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis: results of two metaanalyses. Arthritis Rheum. 33, 1449–1461 Wolfe, F. (1997) Adverse drug reactions of DMARDs and DC-ARTs in rheumatoid arthritis. Clin. Exp. Rheumatol. 15 (suppl. 17), S75–S81 García Rodríguez, L.A. (1997) Nonsteroidal antiinflammatory drugs, ulcers and risk: a collaborative meta-analysis. Semin. Arthritis Rheum. 26, 16–20 Egsmose, C. et al. (1995) Patients with rheumatoid arthritis benefit from early 2nd line therapy: 5 year followup of a prospective double blind placebo controlled study. J. Rheumatol. 22, 2208–2213 van der Heide, A. et al. (1996) The effectiveness of early treatment with ‘second-line’ antirheumatic drugs: a randomized, controlled trial. Ann. Intern. Med. 124, 699–707
What you missed last month… Here’s a taste of what you might have missed in the July issue of Molecular Medicine Today… • • • • • • • • • • •
Mass spectrometry for genotyping: an emerging tool for molecular medicine Lissencephaly and subcortical band heterotopia: molecular basis and diagnosis Gene therapy for peripheral arterial disease The role of nonhuman primate models in AIDS vaccine development Prions, peptides and protein misfolding Patent and be damned: the new slogan for human genetics? Bone-marrow analysis predicts breast-cancer recurrence Telomerase: the search for a universal cancer vaccine Structural genomics Plasma oxysterols: reliable indicators of heart disease? Home HIV testing – a possibility?
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Cytokines in rheumatoid arthritis: trials and tribulations Nancy L. Carteron
Biological agents that inhibit the activity of proinflammatory cytokines are being investigated for use in the treatment of rheumatoid arthritis. Thus far, two of these agents, both of which neutralize tumor necrosis factor a (TNF-a), have received US Food and Drug Administration approval for the treatment of the disease. Etanercept is a bioengineered fusion protein of the p75 soluble TNF receptor, and infliximab is a chimeric monoclonal antibody to TNF-a. Other agents that target proinflammatory cytokines are also being developed. By allowing earlier treatment and better-tolerated long-term therapy, biologics might help slow or prevent disease progression and joint destruction. bone and cartilage destruction1. Despite these similarities, in vitro studies indicate that TNF-a plays a primary role in the cytokine cascade in RA, controlling the production of IL-1 and other proinflammatory cytokines including IL-6 and IL-8 (Refs 2,3). By contrast, IL-1 does not induce the expression of TNF-a, although it does affect the release of IL-6 and IL-8 (Ref. 3). TNF-a and IL-1 mediate joint inflammation and destruction by inducing the synthesis and release of inflammatory metalloproteinases, prostaglandins and nitric oxide in a variety of cell types, and by inhibiting the production of matrix components1.
AFTER a decade of few notable advances in rheumatoid arthritis (RA) therapy, several biological response modifiers that target the pathophysiological processes of RA are on the horizon. Two such agents that inhibit tumor necrosis factor a (TNF-a) activity, etanercept and infliximab, have been approved by the United States Food and Drug Administration (FDA) for the treatment of RA. Other agents are in earlier stages of evaluation; some are no longer being studied owing to a lack of efficacy or unexpected toxicities. Although much is still to be learned about these biological response modifiers, they hold the promise of fundamentally changing treatment options for RA. The available data suggest that some of these agents provide rapid symptomatic relief in the absence of significant adverse effects. Of even more importance, some biological agents slow disease progression and allow patients to enjoy a healthier and more fulfilling life. This review focuses on agents aimed at modulating the activity of proinflammatory cytokines, particularly TNF-a and interleukin 1 (IL-1).
The targeting of proinflammatory cytokines, especially TNF-a and IL-1, has become a strategic basis for developing therapies to treat RA. Approaches that have been investigated include soluble TNF receptors, soluble IL-1 receptors, IL-1 receptor antagonists and monoclonal antibodies to TNF-a.
Cytokines and rheumatoid arthritis
Soluble receptors
Although the initiating event in RA has not yet been defined, a growing body of evidence indicates that cytokines help perpetuate the chronic inflammatory state associated with RA. One logical therapeutic approach, therefore, is to neutralize proinflammatory cytokines. TNF-a and IL-1 are believed to play key roles in the inflammation and joint damage that occur in RA (Fig. 1). Both cytokines are found at high levels in the synovial fluids of patients with RA, and both mediate
Cytokine receptors bind their ligands with high affinity and specificity. Soluble versions of these receptors retain the binding specificity of membrane-bound forms and can efficiently neutralize cytokine bioactivity. The binding of soluble receptors to their natural ligands prevents the ligands from participating in cell-surface receptor-mediated signal transduction. Soluble receptors are thus likely to play a physiological role in regulating cytokine activity.
Cytokine-targeted strategies for the treatment of RA
Soluble TNF receptors Nancy L. Carteron MD, FACR Rheumatology Consultant California Pacific Medical Center, 2100 Webster Street, Suite 200, San Francisco, CA 94115-2374, USA. Tel: 11 415 923 6534 Fax: 11 415 563 1521 e-mail: [email protected]
Two distinct TNF receptors, p55 and p75 (Fig. 1), are found on the surface of a wide variety of cells, including synovial fibroblasts4. These receptors bind to TNF-a and to a related molecule, lymphotoxin a (LT-a, previously referred to as TNF-b). Multimeric TNF-a and LT-a are postulated to initiate cellular signaling by cross-linking two or more receptors of the same type4. Both the p55 and p75 TNF receptors participate in signal transduction but appear to use different pathways and, in some cases, mediate different effects. Both receptors are involved in TNF-a-stimulated DNA synthesis and the release of IL-6, IL-8 and
1357-4310/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S1357-4310(00)01757-3
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longer half-life to the construct compared with monomeric sTNFRs. The p75-based molecule, etanercept, consists of two soluble p75 TNFRs joined to the Fc portion of a huTNF-a man immunoglobulin G1 (IgG1) molecule8. Analogously, the p55-based molecule, lenerIL-1 cept, is composed of two p55 sTNFRs linked anti TNF-a sTNFR mAb to a human IgG1-Fc (Ref. 9). A different sIL-1R version of p55 sTNFR, termed TNFbp, consists of two p55 sTNFRs covalently linked TNF-a through a polyethylene glycol (PEG) linker10. IL-1 On the basis of extensive data from clinical IL-1 trials (Table 1)11,12, etanercept became the first p55 IL-1 receptor biological agent approved by the US Food and TNF receptor receptor type II IL-1 receptor Drug Administration (FDA) for the treatment type I antagonist p75 of RA. In a pivotal Phase II study, patients reTNF receptor ceiving etanercept by subcutaneous administration experienced significant improvement in all measures of disease activity, including swollen joints, tender joints, pain, C-reactive No signaling protein levels and erythrocyte sedimentation rate compared with patients receiving IL-1 No TNF placebo11. At the highest dosage level, 75% signaling signaling signaling of patients experienced a 20% improvement Signal cascade according to American College of Rheumatology (ACR) response criteria. Improvement with etanercept was extremely rapid, with dePromotes Increases Inhibits Stimulates production and creases in measures of disease activity noted bone production of production of release of metalloproteinases within two weeks of initiation of therapy. resorption proinflammatory matrix (e.g., collagenase, stromelysin), Symptoms returned after therapy discontinucytokines components prostaglandin E2 and nitric oxide ation. The most common adverse events were mild injection site reactions and transient, mild, upper-respiratory-tract symptoms, which did Degradation of cartilage and tissue matrix Recruitment of inflammatory cells not necessitate treatment discontinuation. No blood abnormalities or anti-etanercept antibodies were detected11. Similar improvements Inflammation were observed in etanercept-treated patients in Joint destruction a Phase III trial, although non-neutralizing anti-etanercept antibodies were detected in one Molecular Medicine Today patient12. In addition, patients receiving the highest etanercept dose experienced significant Figure 1. Tumor necrosis factor a (TNF-a) and interleukin 1 (IL-1) bind to their receptors and initiate a signal transduction cascade that can result in the destruction of bone and cartilage. These effects might be antagimprovements in health-related quality of life. onized by specific inhibitors. Therapeutic approaches to blocking cytokine–receptor interactions include Additional studies have indicated that agents derived from soluble forms of the TNF (sTNFR) or IL-1 (sIL-1R) receptors, monoclonal antibodies etanercept is efficacious in combination with (mAbs) to TNF-a, and the IL-1 receptor antagonist. By preventing cytokine–receptor binding, these agents act methotrexate and in the treatment of polyupstream of drugs such as NSAIDs, which inhibit downstream mediators such as prostaglandins. articular-course juvenile RA (JRA). In patients with active disease despite methotrexate prostaglandin E2 in synovial fibroblasts4. However, the proliferation of treatment, the addition of etanercept resulted in significant clinical thymocytes in response to mitogen stimulation is mediated by the p75 benefit beyond that achieved with methotrexate alone (Fig. 2)13. receptor, but not by the p55 receptor5. Patients with active JRA, despite treatment with disease-modifying anSoluble versions of both the p55 and p75 receptors have been iden- tirheumatic drugs (DMARDs), experienced impressive decreases in tified in vivo6. These soluble receptors reach particularly high levels in disease activity in response to etanercept14. synovial fluid from patients with RA, suggesting that soluble TNF reA key question is whether etanercept and other biological response ceptor (sTNFR) molecules might play a regulatory role in normal modifiers act as true DMARDs, slowing joint erosion and long-term physiological responses by binding excess extracellular TNF-a (Ref. 7). disability. Several studies suggest that radiographic progression might Bioengineered versions of the p55 and p75 sTNFRs have been developed be the most relevant assessment with respect to long-term patient outand studied for therapeutic use. comes because many patients experience progressive joint damage deTo create these agents, the extracellular domain of the human TNF spite improvement in clinical and laboratory parameters (reviewed in receptor is fused with an immunoglobulin Fc domain, which imparts a Ref. 15). To address whether etanercept could modify radiographic TNF-a
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Table 1. Clinical studies of etanercept in patients with rheumatoid arthritisa Treatment regimen
Efficacyb
Adverse effects
Placebo-controlled, randomized, 180 Failed 1–4 double-blind, multicenter (3 mo)11 DMARDs
0.25–16 mg m22 SC 2 wk21
At highest dose, 61% reduction in SJC vs 25% for placebo
Mild injection site reactions FDA approved 11/98 and upper respiratory for moderate to tract symptoms severe RA failing at least 1 DMARD
Placebo-controlled, randomized, 234 DMARD-failing double-blind, multicenter (6 mo)12 with active RA
10 or 25 mg SC 2 wk21
At highest dose, 47% reduction in SJC vs 7% worsening for placebo
One patient with nonneutralizing antietanercept antibodies
Randomized, double-blind, placebo-controlled; in combination with MTX (6 mo)13
89 Active RA despite MTX treatment
25 mg SC 2 wk21 1 MTX (12.5–25 mg wk21)
78% reduction in SJC with etanercept/MTX vs 33% for placebo/MTX
Randomized, multicenter, double-blind etanercept vs MTX (ERA trial) (12 mo)16
632 Early active RA; Etanercept 25 mg disease or 10 mg SC 2 wk21; duration #3 yr MTX rapidly escalated to 20 mg wk21
Randomized, double-blind, placebo-controlled (3 mo on etanercept, then randomized to drug or placebo for 4 mo)14
69 Active JRA despite treatment; mean age 10.5 y
Study description (duration)
N
RA patient population
75% of etanercept patients Injection site reactions with no new erosions at greater with etanercept; 1 yr vs 57% for MTX; least all other AEs # to MTX, change in joint damage including infections with etanercept 25 mg
0.4 mg kg21 SC 2 wk21 Time to disease flare $116 days for etanercept vs 28 days for placebo
No different from placebo
Comments on agent
Demonstrated to be a DMARD
FDA approved 5/99 for moderately to severely active polyarticular-course JRA failing at least 1 DMARD
a
Abbreviations: RA, rheumatoid arthritis; TNF, tumor necrosis factor; DMARD, disease-modifying antirheumatic drug; SC, subcutaneous; FDA, Food and Drug Administration; SJC, swollen joint count; MTX, methotrexate; JRA, juvenile rheumatoid arthritis; AE, adverse event; IV, intravenous. b This efficacy summary focuses on reduction in swollen joint count; this parameter is the primary measure of efficacy in most of the studies.
progression, 632 patients with early active RA were enrolled in a randomized, double-blind study of etanercept versus methotrexate. Over the course of one year, significantly fewer patients receiving 25 mg etanercept twice weekly developed new erosions compared with patients receiving methotrexate, a known DMARD (Refs. 16,17). Etanercept remains effective and generally well-tolerated during long-term administration18. No serious adverse events were noted in patients receiving etanercept for up to 33 months: there were no increases in infection rate or malignancies and no development of new autoimmune disease. Children should also be observed for potential long-term effects on growth and fertility. Routine blood monitoring is not recommended for juvenile or adult RA patients receiving etanercept alone. By contrast with etanercept, clinical results with a p55-based TNFneutralizing agent, lenercept, were less encouraging (Table 2)9,19,20. Lenercept trials were hampered by high dropout rates, mostly owing to insufficient efficacy, and anti-lenercept antibodies were detected in a significant proportion of patients9,19,20. The clinical development of lenercept is no longer being pursued for RA. A third sTNFR-based agent, TNFbp, a p55 sTNFR–PEG fusion protein, has also been assessed (Table 2). Although TNFbp appeared efficacious in one trial, an overwhelming antibody response affected the half-life and clearance of the compound, raising doubts about its long-term efficacy10. A less antigenic monomeric version, PEG sTNFRI, is currently under study. In a Phase I trial with RA patients, the average number of tender/painful joints was decreased, and only four out
of 66 patients demonstrated seroreactivity to PEG sTNF-RI (Ref. 21). Large-scale clinical studies have yet to be completed with this agent.
Soluble IL-1 receptors Two types of IL-1 receptors have been detected on the cell surface (Fig. 1). Only the type I receptor appears to mediate signal transduction; the type II receptor appears to act as a decoy. Soluble forms of the IL-1 receptor have been identified in plasma22. A soluble form of the type I IL-1 receptor, recombinant human IL-1R1 (rHuIL-1R1), has been tested in Phase I trials of patients with active RA (Table 2), but the efficacy of this agent has not proven particularly promising23. In patients receiving rHuIL-1R1 by subcutaneous administration, only one of 23 patients demonstrated clinical improvement, and dose-limiting skin rashes were observed in two patients23. Intra-articular administration of rHuIL-1R1 into a joint with active rheumatoid synovitis resulted in somewhat better results24. The lack of efficacy of rHuIL-1R1 might be the result of complex interactions occurring within the IL-1 signal transduction system. In addition to binding IL-1, soluble IL-1 receptors (sIL-1Rs) also bind the IL-1 receptor antagonist (IL-1Ra)25. This interaction might complicate the therapeutic use of sIL-1Rs, particularly the type I sIL-1R, because the affinity of this molecule for IL-1Ra is higher than its affinity for IL-1a or IL-1b (Ref. 25). In vitro, type I sIL-1R causes a decrease in the natural anti-inflammatory inhibitory effects of the IL-1Ra26. If this also occurs in vivo, then the type I sIL-1R might not 317
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Placebo/MTX Etanercept/MTX P<0.001 vs placebo/MTX
100
% Patients
80 60 40 20 0 ACR 50
ACR 20
(b)
Placebo/MTX Etanercept/MTX P<0.001 vs placebo/MTX P<0.01 vs placebo/MTX
100
Monoclonal antibodies
80 % Improvement
a biological response can occur when only 2–3% of IL-1Rs are occupied22. Thus, up to 98% of all IL-1Rs might need to be occupied by IL-1Ra before an antagonistic effect is observed. A recombinant version of human IL-1Ra (rHuIL-1Ra), administered subcutaneously daily, has been tested in patients with RA (Table 3). The potential efficacy of such an agent was suggested in a dose-ranging study27, and further supported by a larger double-blind study28. Clinical improvement was observed as early as two weeks after treatment initiation, and disease progression was slowed28. The overall clinical improvement mediated by this agent was modest, with an approximate 10% reduction in swollen joint counts. In patients with active RA despite methotrexate treatment, the addition of rHuIL-1Ra resulted in an increased ACR 20 (20% improvement according to ACR criteria) response rate at 24 weeks29. The lack of an impressive clinical response to rHuIL-1Ra, despite effects on disease progression, suggests that there might be a difference between cytokines involved in pain and inflammation and cytokines involved in joint destruction.
60 40 20 0 Tender Swollen Morning joints stiffness joints
CRP
Pain Disability (VAS) index (HAQ) Molecular Medicine Today
Figure 2. Response to treatment with etanercept/methotrexate (n559) or placebo/methotrexate (n530) at 24 weeks in a randomized, double-blind clinical trial. (a) Percentage of patients with ACR response. ACR 20 indicates 20% improvement according to American College of Rheumatology criteria; ACR 50, 50% improvement according to American College of Rheumatology criteria. (b) Percentage improvement in disease activity from baseline. Abbreviations: VAS, visual analogue scale; HAQ, health-assessment questionnaire; CRP, C-reactive protein; MTX, methotrexate13.
mediate the desired decrease in IL-1 activity. The type II sIL-1R, on the other hand, binds to IL-1b more tightly than to the IL-1Ra25. This molecule might therefore have more therapeutic potential as an IL-1 neutralizer than does type I sIL-1R.
Another strategy for inhibiting cytokines is to neutralize cytokines with specific monoclonal antibodies. Possible drawbacks to the therapeutic use of antibodies include their potential to cause cell lysis through complement fixation, and loss of efficacy owing to neutralizing antibody formation. In an effort to avoid immunogenicity, monoclonal antibodies might be modified so that murine regions are replaced by their human counterparts. In ‘chimeric’ monoclonal antibodies, the Fc portion of the molecule is replaced by human sequences, whereas in ‘humanized’ monoclonal antibodies, both the Fc and non-antigen-binding regions of the Fab segment are replaced. Although these modifications help re duce antigenicity, the antibodies retain murine sequences in the variable region and thus still possess the potential to induce an immune response against the monoclonal antibody. Accordingly, most therapeutically useful monoclonal antibodies have been developed for short-term applications (for example, transplant rejection prevention and diagnosis). Recently, a strategy for developing nonimmunogenic monoclonal antibodies was devised: using a murine monoclonal antibody as a template, the murine heavy and light chains are replaced with human counterparts. The end result is a monoclonal antibody with a fully humanized primary sequence. Three monoclonal antibodies directed against TNF-a have been developed for clinical use: a chimeric monoclonal antibody (infliximab)30, a humanized monoclonal antibody (CDP571)31 and a fully human monoclonal antibody (D2E7)32.
Chimeric monoclonal antibody Receptor antagonists As with soluble receptors, receptor antagonists have the potential to block receptor–ligand interactions and consequent signaling. For a receptor antagonist to work, it must bind all cell-surface receptors and keep them continuously occupied; this might be difficult to achieve in clinical practice. Furthermore, constant receptor occupancy might be undesirable: a balance between bound and free receptors might be necessary to regulate cytokine activity.
IL-1Ra The IL-1Ra binds to IL-1R, blocking its interaction with IL-1 and inhibiting IL-1-mediated signal transduction. In vitro data suggest that 318
Phase III clinical trials have been completed for a chimeric human IgG1 monoclonal anti-TNF-a antibody, infliximab (cA2), in patients with RA. This agent provides clinical improvement of RA symptoms (Table 4)33,34. Drawbacks include the development of anti-infliximab antibodies, and a possible decrease in efficacy over time34,35. In vitro data suggest that infliximab mediates complement-mediated cell lysis, a possible explanation for the marked and sustained decrease in total monocyte counts following infliximab treatment36. To overcome problems related to anti-infliximab antibodies, infliximab treatment was combined with methotrexate therapy, resulting in reduced development of anti-infliximab antibodies and improved duration of response compared with infliximab alone34. Although treatment
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Table 2. Clinical studies of lenercept, TNFbp, PEG sTNF-R1 and rHuIL-1R in patients with rheumatoid arthritisa Study drug
Study description (duration)
N
Lenercept (soluble TNF Placebo-controlled 118 p55 receptor fusion (3 mo)19 protein)
Double-blind, randomized, parallel group, multicenter (12 wk)20
RA Treatment patient regimen population
Efficacyb
Adverse effects
RA
At highest dose, 25% SJC reduction at 2 wk, worsening to 23% at 12 wk
Development of antiDevelopment discontinued lenercept antibodies in due to lack of superiority 14% to 59% of patients vs MTX and high prevalence of antilenercept antibodies Non-neutralizing antilenercept antibodies developed in most patients
247 RA
0.01 to 0.5 mg kg21 IV 1 mo21
5 to 50 mg At 5-mg dose, 54% SC 1 wk21; SJC reduction; also 12.5 mg adding MTX did not 1 MTX (7.5 improve responses to 15 mg wk21)
Comments on agent
TNFbp (soluble TNF p55 receptor-PEG fusion protein)
Placebo-controlled, 34 randomized, double-blind, multicenter (6 wk)10
RA
30 to 300 mg kg21 IV 1 3wk21
Unspecified ‘evidence of in vivo activity’
Overwhelming antibody response affecting half-life and clearance
Attempts in progress to develop a less immunogenic version
PEG sTNF-R1
Placebo-controlled, 81 double-blind, dose-escalation, multicenter (28 d)21
RA
Single injection of 100 to 1000 mg kg21, followed by injections of 100–600 mg kg21
Tender and swollen joint counts decreased by unspecified amounts in sTNF-R1-treated groups
Some headache, infrequent injectionsite reactions
Appears well tolerated and less immunogenic than other p55 derivatives
rHuIL-1R (soluble IL-1 type I receptor)
Placebo-controlled, 23 randomized, double-blind (28 d)23 Placebo-controlled, 16 randomized, double-blind (7 d)24
Failed at least 1 DMARD
125 to 1000 At highest dose, 1/8 Injection site reactions, mg m22 d21 SC patients >40% dose-limiting rashes improvement in SJC vs 0% for placebo Single dose of Dose-related reduction Injection site reactions, 25 to 500 mg/ in target knee dose-limiting rashes joint intracircumference articularly
RA
Limited efficacy, possibly owing to interactions with IL-1Ra
a
Abbreviations: RA indicates rheumatoid arthritis; TNF, tumor necrosis factor; DMARD, disease-modifying antirheumatic drug; SC, subcutaneous; FDA, Food and Drug Administration; SJC, swollen joint count; MTX, methotrexate; JRA, juvenile rheumatoid arthritis; AE, adverse event; IV, intravenous; IL-1, interleukin 1; IL-1Ra, interleukin 1 receptor antagonist. bThis efficacy summary focuses on reduction in swollen joint count; this parameter is the primary measure of efficacy in most of the studies.
with infliximab plus methotrexate was generally well tolerated, two serious infections occurred and one patient developed systemic lupus erythematosus (SLE). A Phase III trial of infliximab (the ATTRACT trial) further assessed the combination of infliximab plus methotrexate37,38. The addition of infliximab resulted in significant improvements in ACR 20 response rates compared with methotrexate plus placebo. Radiographic results indicated that infliximab appears to halt progression of joint damage. Based on these data, the FDA approved infliximab for use in conjunction with methotrexate for the treatment of RA. However, this agent is probably not appropriate for long-term use in patients who cannot tolerate methotrexate. The association of infliximab with immunological abnormalities, including autoantibodies, SLE and com-
plement-mediated cell lysis, requires further assessment in long-term clinical trials.
Humanized monoclonal antibody A humanized anti-TNF-a monoclonal antibody, CDP571, has been tested in a Phase I trial (Table 4)31. Treatment with CDP571 resulted in significant improvements in measures of disease activity, including pain, tender and swollen joint counts, and C-reactive protein levels at weeks 1 and 2. Improvements were generally maintained throughout the eight-week follow-up period. However, some parameters began to increase towards baseline levels at week 4 (Ref. 31). In an open-label continuation of this study, patients received a second infusion of CDP571. Rapid symptomatic relief was again observed, but by eight weeks most parameters had returned to preinfusion 319
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Table 3. Clinical studies of recombinant human IL-1 receptor antagonist in patients with rheumatoid arthritisa Study description (duration)
N
RA patient population
Treatment regimen
Efficacyb
Randomized, double-blind, dose- and regimen-ranging (3-wk treatment, 4-wk maintenance)27
175 Active RA
20–200 mg SC daily Highest dose 3 or 7 times weekly resulted in a 10% SJC reduction at 7 wk
Placebo-controlled, randomized, double-blind, multicenter (24 wk)28
472 Early active RA
30–150 mg SC daily 10% reduction in SJC; Larsen score indicated slower disease progression
Placebo-controlled, randomized, double-blind, multicenter (24 wk)29
419 Active RA 0.04–2 mg kg21 SC despite MTX daily 1 MTX
ACR 20 response at 24 wk 42% for 1 mg kg21 and 35% for 2 mg kg21 vs 23% for placebo
Adverse effects
Comments on agent
Generally mild injection site reactions; infectious events, including soft-tissue infections; low incidence of anti-rHuIL-1Ra antibodies
Requires frequent administration; extended-release formulation under development
Injection site reactions
Lack of dose– response relationship for ACR 20 at doses tested
a
Abbreviations: RA, rheumatoid arthritis; SC, subcutaneous; SJC, swollen joint count; MTX, methotrexate; ACR 20, 20% improvement as measured by American College of Rheumatology response criteria. bThis efficacy summary focuses on reduction in swollen joint count; this parameter is the primary measure of efficacy in most of the studies.
levels31. The data from this study suggest a shortened duration of response following repeated administration of CDP571, as was seen with infliximab. No obvious drug-related adverse effects were observed. However, the authors did not report whether assays to detect autoantibodies or anti-CDP571 antibodies were performed31.
Fully humanized antibody A fully humanized anti-TNF-a antibody, D2E7, has been assessed in clinical trials (Table 4). Administration of D2E7, intravenously or subcutaneously, resulted in 60% reductions in swollen and tender joint counts39–41. Radiographic measurements performed on 66 patients after
Glossary Acute-phase reactant – A protein induced by systemic inflammation, usually measured through C-reactive protein levels or erythrocyte sedimentation rates. American College of Rheumatology (ACR) response criteria – An improvement in RA symptoms is defined as 20% improvement from baseline in tender and swollen joint counts, and 20% improvement in three of the five remaining ACR core set of disease activity measures: patient and physician global assessments; pain; disability; and acute-phase reactant levels. Other levels of improvement (50% or 70%) may also be assessed in clinical trials. Biological agent – In the context of this review, a biological agent is a cellular product such as a cytokine or antibody used to treat a disease state. These agents might be less toxic than pharmacological agents because they are similar or identical to their natural counterparts. Biological response modifier – A biological agent that targets one specific molecule involved in modulating normal or abnormal biological function, thus resulting in an altered cellular or systemic response. C-reactive protein – A globulin that, in the presence of calcium ions, precipitates the C substance of pneumococcal cells. Presence of this protein correlates with radiographic disease progression in RA. Disease-modifying antirheumatic drug (DMARD) – A drug that can modify the course of RA by slowing or stopping disease progression, as assessed by radiographic analysis of involved joints (in contrast to providing only symptomatic relief with no effect on disease course). Erythrocyte sedimentation rate (ESR) – The rate at which erythrocytes settle in a test tube in one hour. ESR is a nonspecific indicator of disease, especially inflammatory conditions, and correlates with radiographic disease progression in RA. Juvenile rheumatoid arthritis (JRA) – A chronic inflammatory arthritis in children. There are three major onset types based on symptoms during the first 6 months: polyarticular (five or more joints involved); pauciarticular (fewer than five joints involved); and systemic (marked by body-wide symptoms such as fever and rash). Following the initial six-month period, the disease course can vary (for instance, a case of pauciarticular onset can change to a polyarticular course).
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Table 4. Clinical studies of monoclonal antibodies to cytokines in patients with rheumatoid arthritisa Study drug
Study description (duration)
N
RA patient population
Treatment regimen
Efficacyb
Adverse effects
Infliximab (chimeric monoclonal TNF antibody; cA2)
Placebo-controlled, randomized, double-blind, multicenter (single infusion, 4-wk follow-up)35 Repeated treatment of disease flares (2–4 cycles)35
73
Failed at least 1 DMARD
Single dose of 1 or 10 mg kg21 IV
At highest dose, 61% reduction in SJC vs 2% for placebo at 4 wk
Infections most common Approved by FDA for use adverse event with MTX; questions about immunogenicity and association with SLE persist
8
Previously enrolled in open-label infliximab trial Active RA, on MTX
20 mg kg21 IV Response duration 1st cycle; decreased from 10 mg kg21 IV 12 wk (cycle 1) to subsequent 7.7 wk (cycle 4) cycles 1 to 10 mg kg21 IV MTX increased 1 2wk21 with or duration of response without MTX (1 mg kg21) 3 or 10 mg kg21 Slowed progression of q 8 wk 1 MTX joint erosions and (15 mg wk21) reduced SJC vs q 4 wk or MTX 1 placebo q 8 wk
Development of antiinfliximab antibodies reduced by concomitant MTX Trend to increased infections at higher doses; rare cases of SLE, hypersensitivity reaction
Single dose of 0.1 to 10.0 mg kg21 IV
Some skin rashes and injection site reactions in both active and placebo groups
Placebo-controlled, 101 randomized, multicenter (26 wk)34 Double-blind, 428 randomized, placebo-controlled (ATTRACT trial) (54 wk)37,38
Active RA despite MTX
CDP571 (humanized Placebo-controlled, 36 monoclonal TNF randomized, antibody) double-blind (single infusion, 8-wk follow-up)31
Failed $1 $1 DMARD and disease duration of #10 yr
D2E7 (fully human monoclonal TNF antibody)
Active RA
Open-label (data up to 12 mo)39,40
120
Randomized, 283 placebo-controlled, double-blind (data up to 3 mo)41
Single IV dose of 0.5 to 10.0 mg kg21, then 0.5 to 1.0 mg kg21 1 2wk21 Patients with 20, 40, long80 mg SC standing active RA
At highest dose, 30% reduction in SJC at wk 1 and 2 vs 9% for placebo
Comments on agent
Development of antiinfliximab antibodies with repeated administration
Demonstrated to be a DMARD; best dose = 10 mg kg21 q 4 wk
Limited efficacy; may not be appropriate as longterm therapy
About 60% reduction in 1 case of pneumonia SJC (pooled data); no evidence of radiographic progression
Ongoing study; early data promising
About 60% reduction in SJC at 2 mo; no clear dose response over doses studied
Ongoing; no safety data reported yet
a
Abbreviations: RA, rheumatoid arthritis; IV, intravenous; SJC, swollen joint count; SLE, systemic lupus erythematosus; MTX, methotrexate; FDA, Food and Drug Administration; DMARD, disease-modifying antirheumatic drug; TNF, tumor necrosis factor; SC, subcutaneous. b This efficacy summary focuses on reduction in swollen joint count; this parameter is the primary measure of efficacy in most of the studies.
12 months of treatment showed no evidence of disease progression40. This agent thus appears promising, but larger studies will be required to fully assess its benefits and safety.
The future of biological response modifiers Biological response modifiers hold the promise of providing both significant clinical benefits and key insights into the pathophysiology of RA. Because biological response modifiers target one specific molecule, they might be less likely to cause the adverse effects associated with older DMARDs, which typically interact with multiple receptors and enzyme systems42.
Many of the most effective DMARDs, including methotrexate, leflunomide, gold, and penicillamine, can cause severe, sometimes irreversible, toxic effects43,44. Even most nonsteroidal anti-inflammatory drugs can result in significant gastrointestinal toxicity45. The adverse effects associated with DMARDs result in a high rate of treatment discontinuation, thus preventing optimal disease blockade43,44. The favorable safety profiles of some biological agents might make them well-suited for early RA therapy. Studies indicate that early, aggressive DMARD therapy improves patient outcome46,47. A therapeutic window of opportunity appears to exist in patients with early RA, suggesting that earlier disease might differ pathophysiologically from 321
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References
The outstanding questions
• • • • • •
Will inhibition of TNF-a and IL-1 be the next major advance in RA therapy? Will such combination therapy be able to prevent comorbid conditions, such as osteoporosis and congestive heart failure? Will chronic TNF-a blockade continue to effectively prevent cell trafficking to the synovium? Will other inflammatory processes like asthma or allergies decrease in patients receiving long-term anti-inflammatory therapy? Will autoimmune or malignant processes increase? Will these highly targeted therapies facilitate discovery of RA disease subsets and thus drive diagnosis and treatment/ cure discoveries? Will certain routes of administration improve efficacy or be more cost effective? Will the same biological agent given subcutaneously, intravenously or transdermally modulate different functions? How will reallocation of health-care dollars/resources occur to allow expensive, but more effective and safer, therapies to gain widespread application?
later disease. In particular, it might be easier to downregulate the inflammatory events of RA soon after disease onset, possibly preventing irreversible joint damage. Biological response modifiers might also provide important insights into the pathophysiology of RA. For instance, cytokine-targeted therapies might allow the identification of subsets of RA. A complete understanding of the pathophysiology of RA could fuel the search for more and better treatments or even, perhaps, a vaccine or other ‘cure.’ As with nonbiological agents, the road to clinical fruition can be rocky. Some of the biological response modifiers are likely to fall by the wayside. Nevertheless, biologics aimed at cytokines have the potential to revolutionize the treatment of RA. Results with etanercept, which has been shown to elicit rapid, significant, and sustained reductions in disease activity, show that such agents can immediately improve the quality of life of patients with RA. Of even more importance, etanercept and some other biological agents decrease radiographic joint damage, which might favorably impact long-term outcomes. Other treatment strategies beyond those discussed here are also being actively explored. Some of these involve alternate means of modulating the cytokine network, including administration of antiinflammatory cytokines, cytokine blockade by antisense technology, and localization of therapeutic molecules through gene therapy. Additional strategies are targeting other systems that might be involved in RA, such as activated T cells and fibroblastlike synoviocytes. Agents that block angiogenesis, intracellular adhesion molecules and matrix metalloproteinases are also being explored. Together with existing treatment modalities, biological response modifiers – those already developed as well as those still in experimental stages – are likely to expand both our knowledge of the pathophysiology of RA and our options for successfully treating the disease. Acknowledgment. We thank Sharon L. Cross PhD for her invaluable assistance during the preparation of this manuscript.
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What you missed last month… Here’s a taste of what you might have missed in the July issue of Molecular Medicine Today… • • • • • • • • • • •
Mass spectrometry for genotyping: an emerging tool for molecular medicine Lissencephaly and subcortical band heterotopia: molecular basis and diagnosis Gene therapy for peripheral arterial disease The role of nonhuman primate models in AIDS vaccine development Prions, peptides and protein misfolding Patent and be damned: the new slogan for human genetics? Bone-marrow analysis predicts breast-cancer recurrence Telomerase: the search for a universal cancer vaccine Structural genomics Plasma oxysterols: reliable indicators of heart disease? Home HIV testing – a possibility?
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