Rheumatoid arthritis secondary non-responders to TNF can attain an efficacious and safe response by switching to certolizumab pegol: a phase IV, randomised, multicentre, double-blind, 12-week study, followed by a 12-week open-label phase.

OBJECTIVE: To study the efficacy and safety of certolizumab pegol (CZP) in patients with active rheumatoid arthritis (RA) who had discontinued an initially effective TNF inhibitor (TNF-IR). METHODS: A randomised 12-week double-blind trial with CZP (n=27) or placebo (n=10) followed by an open-label 12 week extension period with CZP. RESULTS: Baseline characteristics of the 2 groups were similar. ACR20 response (primary end point) at week 12 was achieved in 61.5%, and none of CZP and placebo-treated patients, respectively. Weeks 12-24 showed a maximum effect for CZP at 12 weeks, and that placebo patients switched blindly to CZP attained similar results seen with CZP in weeks 0-12. Since this result was highly significant, study inclusion was terminated after entry of 33.6% of the originally planned 102 patients. Adverse events occurred in 16/27 (59.3%) CZP subjects and 4/10 (40%) placebo subjects. There were no serious adverse events, neoplasms, opportunistic, or serious infections. CONCLUSIONS: This first, prospective, blinded trial of CZP in secondary TNF-IR shows that the ACR20 response rate observed with CZP was higher than that reported in most previous studies of TNF-IR. Additionally, CZP demonstrated good safety and tolerability. This study supports the use of CZP in RA patients who are secondary non-responders to anti-TNF therapies.

Safety and tolerability of concurrent natalizumab treatment for patients with Crohn's disease not in remission while receiving infliximab.

BACKGROUND: Natalizumab, a humanized monoclonal IgG(4) antibody to alpha4 integrin, was investigated as a treatment of active Crohn's disease (CD). The safety of natalizumab given in combination with infliximab has not previously been studied. METHODS: Seventy-nine adult patients with active CD (Crohn's Disease Activity Index [CDAI] score > or = 150) despite ongoing infliximab treatment were randomized 2:1 to receive 3 intravenous infusions of natalizumab (300 mg; n = 52) or placebo (n = 27) every 4 weeks. Patients received infliximab (5 mg/kg) every 8 weeks for at least 10 weeks before randomization and throughout the study. The primary objective was to assess the short-term safety and tolerability of natalizumab in patients concurrently receiving infliximab. Secondary and tertiary objectives included measures of efficacy, health-related quality of life (HRQoL), and effects on inflammatory markers. A subset of patients also participated in a pharmacokinetic/pharmacodynamic (PK/PD) analysis of the effects of concurrent treatment. RESULTS: Incidence of adverse events (AEs) was similar in the treatment groups. AEs frequently reported in both groups were headache, CD exacerbation, nausea, and nasopharyngitis. No patient had a hypersensitivity-like reaction to natalizumab, whereas 4 patients (5%) experienced reactions to infliximab. Two patients (4%) developed anti-natalizumab antibodies; 10 patients (14%) developed anti-infliximab antibodies. The mean CDAI score decreased with natalizumab plus infliximab but was unchanged with infliximab alone (-37.7 versus +3.5; P = 0.084). Patients in both groups showed small increases in HRQoL (P = 0.811). No drug-drug interactions were noted. CONCLUSIONS: The combination of natalizumab plus infliximab was well tolerated. Several positive trends suggested that treating patients not in remission with infliximab plus natalizumab had greater efficacy than treatment with infliximab alone.

Natalizumab induction and maintenance therapy for Crohn's disease.

BACKGROUND: Natalizumab, a humanized monoclonal antibody against alpha4 integrin, inhibits leukocyte adhesion and migration into inflamed tissue. METHODS: We conducted two controlled trials to evaluate natalizumab as induction and maintenance therapy in patients with active Crohn's disease. In the first trial, 905 patients were randomly assigned to receive 300 mg of natalizumab or placebo at weeks 0, 4, and 8. The primary outcome was response, defined by a decrease in the Crohn's Disease Activity Index (CDAI) score of at least 70 points, at week 10. In the second trial, 339 patients who had a response to natalizumab in the first trial were randomly reassigned to receive 300 mg of natalizumab or placebo every four weeks through week 56. The primary outcome was a sustained response through week 36. A secondary outcome in both trials was disease remission (a CDAI score of less than 150). RESULTS: In the first trial, the natalizumab and placebo groups had similar rates of response (56 percent and 49 percent, respectively; P=0.05) and remission (37 percent and 30 percent, respectively; P=0.12) at 10 weeks. Continuing natalizumab in the second trial resulted in higher rates of sustained response (61 percent vs. 28 percent, P<0.001) and remission (44 percent vs. 26 percent, P=0.003) through week 36 than did switching to placebo. Serious adverse events occurred in 7 percent of each group in the first trial and in 10 percent of the placebo group and 8 percent of the natalizumab group in the second trial. In an open-label extension study, a patient treated with natalizumab died from progressive multifocal leukoencephalopathy, associated with the JC virus, a human polyomavirus. CONCLUSIONS: Induction therapy with natalizumab for Crohn's disease resulted in small, nonsignificant improvements in response and remission rates. Patients who had a response had significantly increased rates of sustained response and remission if natalizumab was continued every four weeks. The benefit of natalizumab will need to be weighed against the risk of serious adverse events, including progressive multifocal leukoencephalopathy. (ClinicalTrials.gov numbers, NCT00032786 and NCT00032799.)