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Long-term safety – part 2/2


randomised controlled trials, and open-label extension studies of nine biologics (TNF antagonists, IL-1 or IL-6 antagonists, anti-CD28, and anti-B cell for use in any indication) included a total of 160 randomised trials with 48,676 participants and 46 extension studies with 11,954 participants.27


Among people


who took any biologic, 127 out of 1000 had serious side effects, compared with 118 people out of 1000 who took placebo (1% absolute harm) and 137 out of 1000 who dropped out of the study due to side effects, compared with 98 people out of 1000 who took placebo (4% absolute harm). There was a small increased risk of infection, with a total of 35 people out of 1000 experiencing serious infections in the group treated by biologics, compared with 26 people out of 1000 in the placebo-treated group (1% absolute harm). Among people who took any biologic, 20 out of 10,000 had tuberculosis compared with four people out of 10,000 who took placebo (0.16% absolute harm). Over the short time frame of the trials, there was little or no difference in the number of people who experienced cancer or congestive heart failure while taking any biologic, compared with people who took placebo. A systematic review limited to randomised trials in psoriasis and psoriatic arthritis, including twenty studies with a total of 6810 patients, documented a small increased risk of overall infection (but not of severe infections) in patients treated short term with TNF antagonists, and no evidence of a statistically significant increased risk in cancer.9


Table 4: Safety considerations with biologics70–73 Safety issue


Severe infections and opportunistic infections Malignancies


Deterioration of congestive cardiac failure Demyelinating disease


Formation of autoantibodies Formation of antibodies against the drug


Anti TNF x x x x x x


Anti IL-12/23 x x


x


“The binding of antibody may produce agonistic rather than antagonistic activity”


At variance with these results, an earlier systematic review documented an increased risk of serious infections and a dose-dependent increased risk of malignancies in patients with rheumatoid arthritis treated with anti-TNF antibody therapy (infliximab or adalimumab).28


In another analysis of


published randomised trials of antagonists of TNF in psoriasis, and their open label extension, safety data were expressed as Number Needed to Harm (NNH), that is, a measure indicating the number of patients to be treated over a specific period to cause harm in one patient who would not otherwise have been harmed.3


In the study, the NNH for 24


serious infections ranged from 99 for infliximab to -183 and -291 for etanercept and adalimumab, respectively (indicating a potential protective effect for these two drugs), while the NNH for NMSC ranged


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from 99 for infliximab to 324 and 470 for etanercept and adalimumab, respectively. Notably, the 95% confidence intervals for the NNHs overlapped for the three TNF antagonists, indicating that there were no significant differences in risks of these types of AE between active treatments. For ustekinumab, a combined analysis of safety data from placebo-controlled studies (Phase 2, PHOENIX 1, PHOENIX 2) and from a comparative trial against etanercept (ACCEPT) involving a total of 3117 ustekinumab-treated patients (48% treated for four or more years, and 27% treated for more than five years), rates of AEs were comparable among patients treated with ustekinumab 45mg (242.6/100 patient years) or with ustekinumab 90mg (225.3/100 patient years). When adjusted for duration of follow-up, overall rates of AE were comparable between patients treated with ustekinumab 45mg (516.2/100 patient years), ustekinumab 90mg (490.6/100 patient years) and placebo (412.1/100 patient years).14


During the controlled


period of the ACCEPT trial, AE rates were comparable for all arms of the study (etanercept: 70.0%; ustekinumab 45mg: 66.0%; and ustekinumab 90mg: 69.2%), and rates of serious AEs through the controlled periods were comparable among all groups (1.2% to 1.9%). No cases of demyelination or tuberculosis were reported in these trials and their extension period.14,29


A recent meta-analysis of randomised controlled trials of ustekinumab, briakinumab, adalimumab, etanercept and infliximab, involving over 10,000 patients with moderate-to-severe plaque psoriasis, concluded that there were no documented significant differences in the rate of MACEs between patients receiving anti-IL-12/23 antibodies, or anti-TNF


treatments, and patients receiving placebo. Only one in 3858 patients receiving anti-TNF agents experienced a MACE, compared with one in 1812 patients receiving placebo (p = 0.94), but ten in 3179 patients receiving antagonists of IL-12/23 experienced MACEs, compared with none in 1474 patients receiving placebo (p = 0.12).30


Another


meta-analysis of randomised controlled trials of anti-IL-12/23 biologic agents for chronic plaque psoriasis did find a significantly higher risk of MACEs in those patients treated with IL-12/23 antibodies than in placebo recipients (odds ratio = 4.23, 95% confidence interval, 1.07–16.75; p = 0.04).31 The rates of AE in patients treated with biologics can vary across therapeutic indications. Differences between populations (for example, disease- inherent risks, frequency of comorbidities and use of concomitant immunosuppressant drugs) may contribute to these differences. An analysis of safety data from 71 clinical trials, including long-term extension studies, of adalimumab for the treatment of six immune-mediated inflammatory diseases, showed individual differences in rates by disease populations, with infections having the greatest incidence in rheumatoid arthritis and Crohn’s disease trials, lymphoma having increased incidence in patients with rheumatoid arthritis, and NMSC rates being raised in rheumatoid arthritis, psoriasis and Crohn’s disease.32


When analysing individual trials, the profile of AEs may show some peculiarities for individual drugs. In particular, data from randomised trials of infliximab indicate that treatment may be associated with serious infusion reactions, and liver enzymes are significantly


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