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Inhibition: A New Approach in the Treatment of Early Rheumatoid Arthritis
CME Authors & Financial Disclosures:Joan Bathon, MD, Ted R.
Mikuls, MD, Larry W.Moreland, MD
Rheumatoid arthritis (RA) is a systemic, inflammatory disorder characterized by a symmetrical polyarticular synovitis. Affecting approximately 1% of the US population, RA leads to increased mortality and significant functional decline, and represents one of the most common causes of treatable disability in the Western world. In addition to its health-related implications, the economic burden of RA is enormous. Annual per patient medical care costs are estimated to exceed $4000, and the total cost of RA, encompassing direct and indirect costs, has been estimated to be $14 billion per year.
Methotrexate (MTX), FDA-approved for RA treatment in the mid 1980s, has become the cornerstone of therapy and is now the most commonly prescribed first-line, disease-modifying antirheumatic drug (DMARD) by US rheumatologists. In comparison to other DMARDs (gold salts, hydroxychloroquine, sulfasalazine, D-penicillamine, azathioprine, and cyclosporine), MTX has a favorable efficacy-toxicity ratio and a substantially higher rate of continued use.[3,4] The relative long-term efficacy of MTX has been well documented in several studies. However, MTX monotherapy is rarely associated with sustained disease remissions.
The shortcomings of available treatments, along with a growing appreciation for the deleterious effects of the disease, have spawned intensive investigation into the pathogenesis of RA and new treatment approaches. In the past 10 years, it has become clear that early intervention with disease-modifying agents is critical and that DMARDs, when given in combination with MTX, are more effective than MTX alone.[5,6] In addition, there is growing acceptance of low-dose glucocorticoid therapy, since recent data suggest they may offer a potent disease-modifying effect.
An important advance in treatment is the availability of several new agents, including the first biological agents available for use in RA. Etanercept, a tumor necrosis factor-alpha (TNF), was the first biological agent approved for the treatment of RA. Infliximab, an anti-TNF monoclonal antibody (mAb), has also demonstrated efficacy and good tolerability in clinical trials[8-12] and represents another potentially important DMARD. Infliximab was FDA-approved for use in the treatment of RA in November 1999.
Anti-TNF therapies were the subject of several presentations at the 1999 American College of Rheumatology (ACR) Meeting in Boston, November 12-17. Most experience with TNF antagonists has been limited to adult RA patients with long-standing, DMARD-refractory disease, but new evidence supports the use of TNF-antagonists earlier in the disease course and in the treatment of polyarticular juvenile rheumatoid arthritis (JRA), psoriasis, and psoriatic arthritis.[15,16]
TNF in Rheumatoid Arthritis
The TNF precursor, a 26 kDa transmembrane protein, is found in a variety of cells throughout the body. Macrophages appear to be the primary site of TNF production in RA with the active form of TNF, a 17 kDa soluble protein fragment formed via TNF-alpha converting enzyme (TACE)-mediated cleavage of the precursor molecule. After being shed from the cell surface, these soluble TNF molecules aggregate into trimolecular complexes that subsequently bind receptors found on a variety of cells, including fibroblasts, leukocytes, and endothelial cells. Two TNF receptors have been described, the p55 (also called p60) receptor and the p75 (also called p80) receptor.
TACE acts not only on the TNF precursor molecule, but also cleaves the extracellular domain of its complementary ligand, forming soluble TNF receptors (sTNFRs). These circulating sTNFRs are then free to bind the trimolecular TNF complexes, rendering them biologically inactive; thus, the sTNFRs function as natural inhibitors of TNF-mediated inflammation.
A variety of physiologic functions have been ascribed to TNF-TNF receptor interactions. Also called cachexin, TNF blocks the action of lipoprotein lipase, causing severe cachexia in experimental models of
chronic infection. Additionally, TNF induces programmed cell death (apoptosis) and stimulates the release of several pro-inflammatory cytokines, including interleukin (IL)-6, IL-8, and IL-1. TNF also induces the release of matrix metalloproteinases (MMPs) from fibroblasts, chondrocytes, and neutrophils, and up-regulates the expression of endothelial adhesion molecules, leading to the migration of leukocytes into extravascular tissues.
Because of its array of proinflammatory effects, TNF has been implicated as playing a major role in several chronic inflammatory disorders, including RA, multiple sclerosis, Crohn's disease, systemic vasculitis, allograft rejection, and graft-versus-host disease. Certainly, there is accumulating evidence that TNF is indeed a key element in RA pathogenesis. Transgenic mice that overexpress TNF develop a chronic inflammatory arthritis. Treatment of the arthritic mice with an anti-TNF mAb ameliorates the arthritis. Anti-TNF therapies have also been shown to be effective in delaying the onset of collagen-induced
arthritis. In RA patients, synovial fluid levels of TNF are 4 to 5 times higher than peripheral blood levels, a discrepancy not seen in normal controls. Advances in recombinant DNA technology have allowed investigators to specifically target TNF, not only in arthritic animal models, but also in patients with active RA. The success of these agents in humans has provided unequivocal support for the role of TNF-mediated inflammation in RA.
Etanercept in long-standing RA. Etanercept is a recombinant, soluble TNF receptor (p75) fused to the Fc portion of a human IgG1 molecule. Fusion to an Fc fragment gives the agent several advantages over unconjugated soluble receptors. The dimeric construct results in a significantly longer serum half-life (3-4 days in the case of etanercept), increases the binding affinity for the trimolecular TNF aggregate. Etanercept's mode of action relies on its ability to bind TNF in serum, rendering the cytokine biologically inactive. The serum half-life of etanercept is 3-4 days. With clearance of etanercept from circulation, TNF is again available and biologically active - which is important in the event that TNF is needed for an intercurrent problem such as infection.
Etanercept has proven to be a potent DMARD with a favorable toxicity profile. In the initial phase I, dose-finding study, 16 patients with advanced RA were given twice-weekly etanercept injections, subsequent to a single intravenous bolus, for a total of 4 weeks of treatment. Patients receiving etanercept experienced 45% mean improvement in total pain and joint mobility (swelling and tenderness) scores, compared with 22% of those receiving placebo. Importantly, no patients experienced serious adverse events or developed antibodies to the drug.
A phase II, double-blind, placebo-controlled, 3-month trial randomized 180 patients with active, long-standing RA to 1 of 3 doses of etanercept (0.25, 2, or 16 mg/m2) or placebo, all given by subcutaneous (sc) injection twice weekly. High-dose (16 mg/m2) etanercept proved to be superior to both the low doses and placebo. Using standard ACR criteria  to evaluate the treatment response, 75% of patients
receiving etanercept 16mg/m2 experienced 20% improvement at trial end, the majority showing substantial benefit as early as 1 month into the study. Meeting these criteria requires 20% improvement in swollen and tender joints and at least 20% improvement in 3 of the 5 remaining core
set measures: patient and physician global assessments, pain, disability, and an acute-phase reactant. Etanercept injections were associated with minimal toxicity; minor injection site reactions were the only observed adverse effect seen more commonly in the etanercept groups versus placebo. No patients had evidence of anti-drug antibody formation.
The phase III trial differed from the phase II trial both in terms of dosing and duration of the investigation. In this 6-month, double-blind, placebo-controlled trial, investigators compared fixed doses (10 mg and 25 mg sc twice a week) with placebo. Again, the high-dose regimen resulted in substantial clinical benefit with little associated toxicity. Patients receiving etanercept experienced sustained and rapid benefit, often within the first month of therapy. Fifty-nine percent of patients met ACR criteria for 20% improvement (ACR 20).
Forty percent met similar criteria for 50% improvement. Functional activity, measured by the Health Assessment Questionnaire (HAQ), showed significant improvement over the course of the study. In terms of the disability index, patients receiving placebo had a mean change from baseline of 2, compared with 39 for those in the etanercept 25-mg group. Again, transient injection-site reactions remained the most commonly observed adverse event in the etanercept groups compared with placebo. In all of the controlled trials, injection-site reactions were seen in 37% of those receiving etanercept versus 10% of those receiving placebo (P < .05).
Dr. Larry Moreland presented data regarding the open-label, long-term use of etanercept at the national ACR meeting. A large cohort of patients (N = 713) receiving etanercept with a cumulative exposure to drug of 1152 patient-years was followed longitudinally. The clinical benefit seen in previous short-term clinical trials was maintained in long-term follow-up. Rates for continued use and ACR-response curves are shown in Figure 1. In addition, there was no increase in serious toxicity over the course of the study. Minor injection-site reactions, resulting in study withdrawal by less than 0.5% of patients, were the most common adverse event.
Data from this study begins to address some of the concerns about the general effects of blocking TNF activity. Specifically, there was no increase in infections requiring intravenous antibiotics. Long term follow-up revealed no increase in the incidence of any infection compared with placebo-controlled studies. There were 9 reported cases of incident neoplasia, less than the expected number (10.7) calculated from the NCI SEER (National Cancer Institute Surveillance, Epidemiology and End Results) database. No patients have developed drug-induced lupus or anti-cardiolipin antibody syndrome while receiving etanercept.
Etanercept in combination with MTX. Earlier this year, Weinblatt and colleagues reported on the use of etanercept in combination with MTX for the treatment of long-standing, refractory RA. Patients with active disease receiving an average 18.3 mg/wk of MTX were randomized to receive either etanercept (25 mg sc twice a week) or placebo. The addition of etanercept to MTX resulted in substantial benefit. At the end of the 24-week trial, 71% of those receiving combination therapy met ACR 20 criteria, compared with 27% of those receiving placebo-MTX. The combination resulted in significantly greater improvement in all individual measures of disease activity used to define improvement by the ACR method. The frequency of serious adverse events did not differ between the 2 groups. Minor injection-site reactions were the only adverse event reported more often in the MTX-etanercept group. In a follow-up, open-label study of 18 months' duration, the etanercept-MTX combination maintained its efficacy and remained well tolerated, allowing for dose reductions of concurrent glucocorticoids and MTX in a subset of patients.
Etanercept in early RA. Currently, etanercept is approved for use in RA patients who have not improved with 1 or more DMARDs. While the majority of studies have been in patients with long-standing, DMARD-refractory disease, there is accumulating evidence that etanercept will slow disease progression when given earlier in the disease course. Dr.
Barbara Finck presented results from the ERA (The Use of Etanercept in Early RA) trial at the ACR meeting.
The ERA trial included 632 patients with early RA (disease duration of less than 3 years) assigned to 1 of 3 treatment arms: (1)etanercept 25 mg and placebo oral tablets, (2) etanercept 10 mg and placebo tablets, or (3) MTX 7.5 to 20 mg and placebo injections. All patients received 1 mg folic acid daily, to reduce the dose-limiting toxicity of MTX. The trial duration was 1 year, and the data were assessed using intent-to-treat analysis. The MTX dose was rapidly escalated in the first 8 weeks of the trial in order to optimize its effect, and an average dose of 18.3 mg/wk was achieved. Baseline characteristics of the study groups, including measures of disease activity, were similar.
Radiographic evidence of joint damage was measured by the total Sharp score, including components for both joint space narrowing and erosions. At the end of the trial, there were no statistically significant differences in radiographic progression between etanercept and methotrexate, as measured by the total Sharp score. However, when examining the results by individual component scores, etanercept (25 mg) proved to be more effective than either low-dose etanercept or MTX at reducing the progression of joint erosions. This difference was
statistically significant. There was no statistical difference in the reduction of joint space narrowing among the treatment groups. Mean changes in radiographic progression are shown in Figure 2. Investigatorsalso evaluated the percentage of patients in the MTX and etanercept 25-mg groups who had no new radiographic erosions at the end of 12 months. Seventy-five (75%) of the patients in the etanercept 25-mg group had no erosions, versus 57% of the MTX group. This difference was statistically significant (P < .001).
Clinical efficacy was assessed in the study by the area under the curve (AUC) calculated from a numeric ACR (ACR-N) response. The ACR-N represents the actual percentage of improvement in ACR criteria for an individual patient. The AUC for etanercept was significantly superior to that for MTX at both 6 months and 12 months (P = .002 and P = .009, respectively). Standard ACR response curves are shown in Figure 3. At early time points (from 2 weeks to 4 months), there was a significantly higher response rate in those receiving etanercept (25 mg) versus methotrexate. At subsequent time points, there was a trend, although not statistically significant, in ACR responses favoring etanercept.
Etanercept was better tolerated than MTX. Study withdrawals related to toxicity were significantly higher among those receiving MTX, while infection rates were significantly lower in those receiving etanercept. Of patients receiving MTX (n=217), 10 withdrew secondary to adverse events, compared with 5 of 207 receiving etanercept 25 mg. Study withdrawals related to efficacy failures were similar in both groups. Laboratory abnormalities were similar among the 3 cohorts, with the exception of elevated liver function tests and lymphopenia, which were significantly more frequent in the MTX group. Approximately twice as many patients taking MTX as patients taking etanercept (both dose groups had elevations of SGOT (32% vs 16%) or SGPT (44% vs 23%) These returned to baseline with cessation of the offending agent. Minor injection-site reactions were the most commonly observed adverse event for patients receiving etanercept (37% of those receiving 25 mg of etanercept experienced these reactions, vs 7% of those receiving MTX), necessitating withdrawal of 1 patient from the study protocol.
Etanercept in juvenile rheumatoid arthritis.
In addition to its use in adult patients, etanercept recently gained FDA approval for the treatment of polyarticular JRA. Dr. Daniel J. Lovell presented data from a study involving 69 JRA patients with MTX-refractory disease at the 1999 ACR meeting. The study involved an initial 3-month open-label period in which all patients received etanercept (0.04mg/kg/dose up to a maximum of 25 mg sc twice a week), followed by a 4-month double-blind component in which approximately one half of the patients crossed over into a placebo-controlled group. Prior to study enrollment, patients underwent a 2- to 4-week DMARD washout period, but were allowed to continue stable doses of corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs)
Improvement was assessed using the 6 JRA core criteria, which include:
number of active joints, number of joints with loss of motion, physician global assessment, patient/parent global assessment, childhood HAQ, and erythrocyte sedimentation rate (ESR). The definition of response (JRA30) requires 30% improvement in at least 3 of the 6 criteria. Additionally, in the double-blind portion of the study, the occurrence of flare and time to flare were used as primary outcome measures.
Of the 64 patients completing the first segment of the study, 51 (74%) met the criteria for response. Eighteen patients did not continue on to part 2 of the study protocol, the majority (12 patients) because of a lack of significant clinical response to etanercept. In the 4-month, double-blind portion of the study, improvement (JRA30) was maintained by a clear majority (80%) of those taking etanercept. Compared with
patients who were crossed over to placebo, those continuing on etanercept were much less likely to experience a flare (81% for placebo vs 28% for etanercept, P = .003). The median time to flare for control patients was 28 days, versus more than 116 days for those in the etanercept cohort (Figure 4). A specific median time to flare for the etanercept group was impossible to calculate, as less than 50% of those receiving etanercept had flared by the end of the study. In an ongoing open-label extension of the study, etanercept has been well tolerated with no new adverse events reported with long-term etanercept use. Additonally, etanercept has continued to maintain its efficacy, with 70% demonstrating at least 50% improvement in the JRA core set. Fifty-eight patients initially enrolled into the open-label follow-up study, and 50 remained enrolled after 1 year. A majority of withdrawals (n=5) have been due to a lack of efficacy.
Infliximab is a chimeric anti-TNF mAb composed of a constant region from human immunoglobulin and a variable region from murine (mouse) immunoglobulin. Previously approved for the treatment of Crohn's disease, infliximab recently received FDA approval for the treatment of RA. Clinical trials summarized below have confirmed both the efficacy and tolerability of the agent when used in patients with DMARD-refractory RA, both alone and in combination with MTX [8-12].
Infliximab in long-standing RA. In the initial phase I, open-label trial, Elliott and colleagues studied the use of infliximab in 20 patients with active, long-standing RA. Patients had a median disease duration of 10.5 years and had failed a median of 4 previous DMARDs. Patients received a total of 20 mg/kg of intravenous infliximab given in divided doses over the course of 12-14 days. Clinical response to the treatment was substantial. Morning stiffness decreased from a median of 180 minutes at study entry to a median of 5 minutes at week 6. Pain
scores decreased from 7.1 to 1.9 (range, 0-10) over the same time period, representing an improvement of 73%. Swollen joint count dropped from 18 to 5. while serum C-reactive protein (CRP) levels fell from a median of 39.5mg/dL at study entry to 8mg/dL at week 6. Functional capacity, as measured by HAQ score, improved significantly from a median of 2.0 at study entry to 1.1 by 6 weeks. Patients showed sustained benefit following the last dose of infliximab, with response duration ranging from 8 to 25 weeks (median of 14).
The phase II trial included 73 patients who, similar to those in the phase I trial, had long-standing, DMARD-refractory RA. Results in this trial were similar. Patients in the active treatment groups received only a single intravenous infusion of infliximab, either 1 mg/kg or 10 mg/kg. At the 4-week assessment, 79% of patients receiving 10 mg/kg reported at least 20% improvement in symptoms, and half had at least 50% improvement (measured by the Paulus criteria).
In both the phase I and phase II trials, infliximab was well tolerated without reports of any clinically significant adverse events. No patients had evidence of human anti-chimeric antibodies (HACAs) subsequent to infliximab administration when assessed at the 4-week examination .
In a continuation of this phase II trial, 8 of the original 20 patients from the phase I, open-label trial, returned after a 4-week interval and were re-treated with up to 3 additional doses of infliximab. The timing of the additional doses was determined by disease relapse. Repeat administration resulted in significant clinical improvement with minimal adverse effects. The interval between doses, however, became progressively shorter during the course of the study.
Additionally, 4 of the 8 patients developed HACAs; antibody development may well account for the decreasing response duration observed during the course of the study.
Infliximab in combination with MTX. In 1998, Maini and colleagues published data on the combination of infliximab and low-dose weekly MTX in the treatment of RA. In a double-blind, placebo-controlled trial, 101 patients were given intravenous infliximab (1, 3, or 10 mg/kg) with or without MTX (7.5 mg/week) or MTX plus intravenous placebo. Sixty percent of patients receiving infliximab, with or without MTX, experienced at least 20% improvement using the Paulus criteria. Importantly, co-administration of low-dose MTX significantly prolonged the duration of response seen with low-dose (1 mg/kg) infliximab. Co-administration of MTX with higher doses of infliximab (3 and 10 mg/kg) also prolonged response duration, although not in a statistically significant fashion. All treatment arms were associated with minimal toxicity; headache was the most commonly observed adverse effect in patients receiving combination therapy. The overall incidence of HACAs was 17% for patients receiving infliximab (with and without MTX), with the incidence inversely proportional to the dose of infliximab. Half of the patients receiving low-dose infliximab (1 mg/kg) without MTX developed HACAs, compared with 7% of those receiving 10 mg/kg. Concurrent administration of low-dose MTX greatly diminished development of HACAs (by approximately 3-fold), suggesting that MTX induces an immunologic tolerance to infliximab. Although there were no reports of drug-induced lupus, 8% of patients receiving infliximab developed antibodies to double-stranded DNA.
Results from a 54-week, double-blind, placebo-controlled trial of infliximab in combination with MTX were reported at the ACR meeting. Infliximab (3mg/kg or 10mg/kg intravenously) or placebo was given at 4- to 8-week intervals to patients with active RA who were also receiving MTX. Fifty-nine percent of patients receiving 10 mg/kg and 42% of those receiving 3 mg/kg at - to 8-week intervals experienced 20% improvement by ACR criteria. There were no statistically significant differences in percentage of responders among the infliximab groups. When compared to placebo, there was no increase in the incidence of adverse effects. The combination resulted in a statistically significant reduction in radiographic progression (as measured by Sharp score) when compared with MTX treatment alone.
Emerging Uses of TNF Antagonists
Although not FDA-approved for use in these conditions, TNF antagonists have shown promise as potential disease-modifiers in both psoriasis and psoriatic arthritis[15,16]. Both serum and synovial levels of TNF are increased in patients with active psoriatic arthritis. Additionally, TNF is present in psoriatic skin plaques, with a higher bioactivity noted in involved versus uninvolved skin. These findings underscore a potential pathogenic role for TNF in this disorder.
In a 3-month, randomized, double-blind trial, investigators examined the use of etanercept (25 mg sc twice a week) for the treatment of psoriasis with and without arthritis. The study design allowed for continued use of stable-dose NSAIDs, corticosteroids, and MTX. All other DMARDs and topical preparations were discontinued prior to enrollment. All patients receiving etanercept completed the study protocol, with active treatment displaying a safety profile similar to that seen in previous RA studies.
Clinical response was defined using the Psoriatic Arthritis Response Criteria (PsARC). Responders displayed significant improvement in at least 2 of 4 criteria, which included physician global assessment,
patient global assessment, and tender and swollen joint scores. Improvement in skin disease was defined using the Psoriasis Area and Severity Index (PASI). The PASI is a composite index reflecting overall severity of skin involvement. At the trial's conclusion, 87% of patients receiving etanercept met PsARC criteria for improvement versus 23% of those receiving placebo (P < .001). For patients with skin involvement, those receiving etanercept had a median improvement in their PASI score of 46% versus 9% for those receiving placebo (P = .003). Study results are shown in Figures 5A & B.
Infliximab has also shown activity in the treatment of psoriatic arthritis. In a preliminary, open-label trial of 6 patients with MTX-refractory disease, patients were given an intravenous infusion of infliximab at weeks 0, 2, and 6 in addition to stable-dose MTX and NSAIDs. All 6 patients displayed a rapid and sustained response through the short trial, with all patients meeting criteria for improvement as defined by the ACR50, and 5 of the 6 meeting the more stringent ACR70 threshold. PASI scores decreased from 5.3 to 2.6. Other disease parameters also showed substantial improvement. The median ESR improved by 77%, while the median CRP improved by 91%.
TNF Antagonists on the Horizon
Preliminary studies suggest that D2E7 (a fully human anti-TNF mAb) and a pegylated soluble TNF type I receptor (PEG sTNF-RI) may soon offer additional options to block TNF and treat RA.
PEG sTNF-RI was developed when investigators identified antigenic epitopes on the p55 (type I) TNF receptor. These epitopes were truncated, resulting in the formation of a novel monomeric soluble receptor, PEG sTNF-RI. In a phase I trial, PEG sTNF-RI did not appear to be immunogenic. In a phase II, double-blind, dose-escalating trial, D2E7 was efficacious and well tolerated when administered to patients with RA.
In a separate trial, D2E7 was associated with a significant reduction in radiographic disease progression. The toxicity and efficacy of both PEG sTNF-RI and D2E7 are being evaluated in placebo-controlled trials.
Anti-TNF therapies have provided patients and physicians with a new and exciting means of treating RA and other allied conditions. With continued advances in our understanding of cytokine biology, new ways of blocking TNF are likely to evolve. Selective TACE inhibition, by preventing release of its cell-surface subunit, may be a potential mechanism of TNF blockade. Gene-delivery systems may someday provide another effective way of modulating the action of TNF and TNF receptors.
There has been increased appreciation of the possibility that TNF production may be dependent on costimulatory pathways in T-cell activation, specifically CD40 (found on B cells and antigen-presenting cells) - CD40 ligand (on T cells) binding pathways. CD40 ligand is hyper-expressed in RA synovia, and ligation with CD40 has been shown to increase TNF production in a dose-dependent fashion. Blocking CD40-CD40 ligand interactions "upstream" (ie, with an anti-CD40 ligand mAb) may down-regulate TNF's pro-inflammatory effect. Similarly, agents targeting other cytokines, metalloproteinases, and adhesion molecules may effectively block "downstream" biologic actions of TNF.
Several important issues regarding TNF inhibition remain to be addressed. While long-term data have been encouraging, safety concerns associated with chronic TNF blockade mandate continued, close follow-up. Cost-effectiveness data for etanercept and infliximab are lacking. Furthermore, clinical response to these agents has not been universal, suggesting that the pathogenesis of these disorders is far more complex than simple "TNF excess." Given the considerable cost associated with these agents, it will be important to find ways to predict individual response to these agents as well as to other standard DMARDs and DMARD combinations. The precise role that TNF antagonists will play in the DMARD armamentarium remains to be defined.
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