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Selective Costimulation Modulators: Addressing Unmet Needs in Rheumatoid Arthritis Management: TNF-alpha Inhibitors


TNF-alpha Inhibitors

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


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

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

Figure 5. (click image to zoom) Efficacy results from the phase 3 Anti-TNF Therapy in RA with Concomitant Therapy (ATTRACT) trial of infliximab plus methotrexate (MTX) in active RA (data from Lipsky et al.[34] and Maini et al.[35]). For American College of Rheumatology (ACR) improvement criteria responses: *P < .001 vs placebo. For total Sharp score: *P < .001 vs placebo; MTX + placebo: n = 50, MTX + infliximab 3 mg/kg every 8 weeks: n = 58, MTX + infliximab 3 mg/kg q4w: n = 66, MTX + infliximab 10 mg/kg q8w: n = 69, MTX + infliximab 10 mg/kg q4w: n = 66.


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

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

Figure 6. (click image to zoom) Efficacy results from the phase 3 Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) in active RA (adapted with permission from Klareskog et al. (The Lancet, 2004;363:675-681).[40] For ACR responses: *P < .01 vs MTX; P < .05 vs etanercept; P < .0001 vs both MTX group and etanercept group. For total Sharp score: *P = .0112 etanercept vs MTX; P < .0001 combination vs MTX, P = .0722 combination vs etanercept; P = .0469 etanercept vs MTX; § P < .0001 combination vs MTX, P = .0006 combination vs etanercept, ||MTX: n = 212, etanercept: n = 212, combination: n = 218.


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

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

Figure 7. (click image to zoom) Efficacy results from a randomized, placebo-controlled phase 3 trial of adalimumab plus MTX in active RA (Adapted with permission from Keystone et al.[46]). For ACR responses: * P ≤ .001 vs placebo. For total Sharp score: *P ≤ .01 vs placebo; P ≤ .001 vs placebo; MTX + placebo: n = 161, MTX + adalimumab 20 mg every week: n = 183, MTX + adalimumab 40 mg every 2 weeks: n = 165.

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