Adalimumab: 8 Years of Experience in Rheumatoid Arthritis
Adalimumab: 8 Years of Experience in Rheumatoid Arthritis
In this section, we summarize the evidence on clinical effectiveness on the basis of the continuation of adalimumab therapy beyond RCTs, or in registry studies.
During the open-label extension of the clinical trials, the effectiveness of adalimumab in achieving an ACR50 was better when combined with methotrexate. At 2 and 5 years, inhibition of structural damage was also maintained for responders, showing less or no radiographic progression in 54 and 50% of the patients, respectively. Similarly, more than 80% of the patients maintained an improvement in the disability score (HAQ <0.5) through 5 years of follow-up. Regarding patients with prior treatment using other TNF-α inhibitors, the ReAct open-label trial found that adalimumab 40 mg every other week had a significant clinical benefit at 12 weeks among the 899 patients previously treated with etanercept or infliximab (33% ACR50 response; 23% good European League Against Rheumatism response; 12% achieved a DAS <2.6; and 13% achieved a HAQ disability index score <0.5). Another comparative controlled study also found adalimumab to be effective for RA patients after 12 months when switching from infliximab with similar ACR20 and DAS28 RRs compared with patients on adalimumab as first TNF-α inhibitor therapy. These results, along with other similar findings from certain registries (Stockholm TNF-α inhibitors follow-up registry and the Finnish Register of Biological Treatment), suggest that adalimumab is also effective when given to patients with prior TNF-α inhibitors treatment.
Several studies on data from national registries found that the effectiveness of adalimumab was better when combined with methotrexate (or other DMARDs such as leflunomide), and no significant differences were found when comparing the first three approved TNF-α inhibitors (infliximab, etanercept and adalimumab). The Danish Registry for Biologic Therapies in Rheumatology (DANBIO) registry on the other hand reported better odds ratios (ORs) for achieving an ACR70 response at 6 months for adalimumab compared with infliximab (OR: 2.1; 95% CI: 1.5–2.8), and similar results when compared with etanercept (OR: 1.2; 95% CI: 0.82–1.6). The DANBIO findings were echoed by data from the Dutch RA Monitoring registry where at 12 months, the mean scores on the DAS28 and Short Form 36 items physical component scale showed greater benefit for adalimumab and etanercept compared with infliximab (p < 0.001). In addition, adalimumab showed a significant reduction in the DAS28 at 12 months compared with etanercept (p = 0.031). One study reporting radiographic changes (DANBIO registry) found that patients with RA had a significant reduction in radiographic progression while on TNF-α inhibitors (adalimumab, etanercept or infliximab) compared with the prior traditional DMARD treatment period (median radiographic progression rate decreased from 0.7 to 0 total Sharp score units/year when started TNF-α inhibitors p < 0.0001).
Finally, indirect comparisons among different BRMs in several meta-analysis show that adalimumab and other biologics, when combined with methotrexate, are more efficacious than placebo or controls. Some reviews did not find significant differences among biologics, while others reported potential benefit of one biologic over the others. A large network meta-analysis including six Cochrane reviews reported a significantly greater ACR50 response comparing adalimumab with anakinra. In one review, tocilizumab had better ACR70 RRs compared with TNF-α inhibitors (relative risk: 1.8; 95% CI: 1.2–2.6) and etanercept had lower ACR20, 50 and 70 responses compared with adalimumab (relative risk: 0.46, 95% CI: 0.34–0.61; 0.37, 95% CI: 0.22–0.60; 0.44, 95% CI: 0.21–0.93, respectively). One meta-analysis of 29 RCTs showed that adalimumab and etanercept monotherapy when given to methotrexate-naive patients with short disease duration (<3 years) were more effective than methotrexate alone in slowing radiographic joint damage.
The available data appear to support that adalimumab is most effective when given in combination with methotrexate. It has been recommended that infliximab should be administered in conjunction with methotrexate because it is a chimeric monoclonal antibody that can elicit humoral immune responses (neutralizing antibodies) in the recipient. Adalimumab is a fully human-derived antibody, so it is less likely to elicit an immune response. However, studies have shown that up to 44% of patients treated with adalimumab have circulating antibodies against this agent, and that the presence of such autoantibodies was associated with low functional drug levels and decreased clinical response. Therefore, the addition of methotrexate, as is the case for infliximab, could result in better efficacy. Furthermore, combination therapies in RA are usually more effective than monotherapy, thus adding methotrexate to a biologic agent could also enhance its efficacy by targeting additional pathogenic pathways.
Clinical Effectiveness
In this section, we summarize the evidence on clinical effectiveness on the basis of the continuation of adalimumab therapy beyond RCTs, or in registry studies.
During the open-label extension of the clinical trials, the effectiveness of adalimumab in achieving an ACR50 was better when combined with methotrexate. At 2 and 5 years, inhibition of structural damage was also maintained for responders, showing less or no radiographic progression in 54 and 50% of the patients, respectively. Similarly, more than 80% of the patients maintained an improvement in the disability score (HAQ <0.5) through 5 years of follow-up. Regarding patients with prior treatment using other TNF-α inhibitors, the ReAct open-label trial found that adalimumab 40 mg every other week had a significant clinical benefit at 12 weeks among the 899 patients previously treated with etanercept or infliximab (33% ACR50 response; 23% good European League Against Rheumatism response; 12% achieved a DAS <2.6; and 13% achieved a HAQ disability index score <0.5). Another comparative controlled study also found adalimumab to be effective for RA patients after 12 months when switching from infliximab with similar ACR20 and DAS28 RRs compared with patients on adalimumab as first TNF-α inhibitor therapy. These results, along with other similar findings from certain registries (Stockholm TNF-α inhibitors follow-up registry and the Finnish Register of Biological Treatment), suggest that adalimumab is also effective when given to patients with prior TNF-α inhibitors treatment.
Several studies on data from national registries found that the effectiveness of adalimumab was better when combined with methotrexate (or other DMARDs such as leflunomide), and no significant differences were found when comparing the first three approved TNF-α inhibitors (infliximab, etanercept and adalimumab). The Danish Registry for Biologic Therapies in Rheumatology (DANBIO) registry on the other hand reported better odds ratios (ORs) for achieving an ACR70 response at 6 months for adalimumab compared with infliximab (OR: 2.1; 95% CI: 1.5–2.8), and similar results when compared with etanercept (OR: 1.2; 95% CI: 0.82–1.6). The DANBIO findings were echoed by data from the Dutch RA Monitoring registry where at 12 months, the mean scores on the DAS28 and Short Form 36 items physical component scale showed greater benefit for adalimumab and etanercept compared with infliximab (p < 0.001). In addition, adalimumab showed a significant reduction in the DAS28 at 12 months compared with etanercept (p = 0.031). One study reporting radiographic changes (DANBIO registry) found that patients with RA had a significant reduction in radiographic progression while on TNF-α inhibitors (adalimumab, etanercept or infliximab) compared with the prior traditional DMARD treatment period (median radiographic progression rate decreased from 0.7 to 0 total Sharp score units/year when started TNF-α inhibitors p < 0.0001).
Finally, indirect comparisons among different BRMs in several meta-analysis show that adalimumab and other biologics, when combined with methotrexate, are more efficacious than placebo or controls. Some reviews did not find significant differences among biologics, while others reported potential benefit of one biologic over the others. A large network meta-analysis including six Cochrane reviews reported a significantly greater ACR50 response comparing adalimumab with anakinra. In one review, tocilizumab had better ACR70 RRs compared with TNF-α inhibitors (relative risk: 1.8; 95% CI: 1.2–2.6) and etanercept had lower ACR20, 50 and 70 responses compared with adalimumab (relative risk: 0.46, 95% CI: 0.34–0.61; 0.37, 95% CI: 0.22–0.60; 0.44, 95% CI: 0.21–0.93, respectively). One meta-analysis of 29 RCTs showed that adalimumab and etanercept monotherapy when given to methotrexate-naive patients with short disease duration (<3 years) were more effective than methotrexate alone in slowing radiographic joint damage.
The available data appear to support that adalimumab is most effective when given in combination with methotrexate. It has been recommended that infliximab should be administered in conjunction with methotrexate because it is a chimeric monoclonal antibody that can elicit humoral immune responses (neutralizing antibodies) in the recipient. Adalimumab is a fully human-derived antibody, so it is less likely to elicit an immune response. However, studies have shown that up to 44% of patients treated with adalimumab have circulating antibodies against this agent, and that the presence of such autoantibodies was associated with low functional drug levels and decreased clinical response. Therefore, the addition of methotrexate, as is the case for infliximab, could result in better efficacy. Furthermore, combination therapies in RA are usually more effective than monotherapy, thus adding methotrexate to a biologic agent could also enhance its efficacy by targeting additional pathogenic pathways.
Source...