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Long-term safety – part 1/2

Table 3: Documented long-term exposure of patients with psoriasis to different biologics64–69 Adalimumab

Exposure duration

3 years 4 years 5 years


565 127 86


0.5% 2.4% 3.5%

Infliximab N

83 51


3.6% 5.9% N/A

Etanercept N

1890 108


0.2% 2.8% N/A

1569 1482 838

Ustekinumab N


0.2% 0.2% 0.4%

N = number of patients; R = the maximal risk of the occurence of unexpected AE for the given exposure duration calculated from the formula R=3/N (Machin et al. Sample Size Tables For Clinical Studies. Wiley-Blackwell, Chichester (UK), 2009, pp. 142–152)

Databases and registries

the safety of biologics in patients with plaque psoriasis has recently been performed by Langley.3

It included 1403

patients who received adalimumab (1286 patient-years, 11 months exposure/ patient), etanercept (50mg or 100mg weekly, 4410 patients, 4090 patient/ years, 11.1 months of exposure/patient) and infliximab 3–5mg/kg (1564 patients, 1013 patient years, 7.8 months of exposure/patient). The rate of severe AEs was very low and the differences in the frequency between the active treatment and the placebo groups were below 1%. For many AEs, such as solid tumour malignancies, tuberculosis, opportunistic infections or demyelinating disorders, the risk difference was zero. The only consistent safety signal for all drugs was serious infection and NMSC (risk difference 0.2–1%). Ustekinumab has an even more favourable safety profile.14

In the controlled

period of clinical trials comprising 1582 patients (406 patient/years), there were no obvious differences in the frequency of severe AEs with the placebo group. The emerging picture is that all anti-TNF drugs and ustekinumab have a favourable benefit-to-risk profile in psoriasis. Assuming no cumulative toxicity of the biologics (the same risk of an AE over time during long-term treatment), it can be calculated that the patients may safely be treated for a lifetime without any significant risk. The shortest duration of drug exposure necessary to detect one serious AE ranged from 56 years (infliximab) to 73 years (etanercept), long enough to safely treat most patients.3

Professor Naldi will go on

to discuss the specific differences in long-safety data between these drugs in more detail, in part 2 of this chapter.


Lessons from open-label extension trials A great deal of safety data has been generated from the open-label extension (OLE) trials that often follow the double-blind phase. OLE trials cover longer drug exposure times (typically one

to four years) and are therefore more likely to capture rare AEs and the signs of cumulative toxicity. The disadvantage of OLE data, however, is the lack of comparator. The observed incidence of AEs in OLE trials is therefore compared to either historical data or general population data, which creates bias to the disadvantage of the drug.

The data gathered from OLE did not reveal any unexpected AEs in patients with psoriasis. A recent review by Rustin15 summarised the data from randomised clinical trials, OLE and meta-analyses of >one year duration and found an advantageous safety profile for anti-TNFs similar to what may be inferred from Tables 1 and 2. The safety of ustekinumab seems even more advantageous. Data from the five-year follow-up of 1569 patients did not reveal any evidence of increased rate of serious infections, malignancies (including NMSC and lymphoma) or major adverse cardiovascular events (MACEs).14


in the clinical trials with another anti-p40 antibody, briakinumab, a numerical imbalance in the frequency of MACEs to the disadvantage of the drug was observed within the first few months of treatment.16 Whether ustekinumab is able to induce MACEs in the initial phase of the treatment remains a matter of intense debate. It has, however, been established that no increase in MACEs occurs during long-term treatments, neither for anti-TNFs nor for ustekinumab.16,17

An important question to ask is the validity of the OLE data. How robust are the available data and what is the minimum number of patients who need to be followed over time in order to obtain clinically significant results? There is a helpful statistical rule, which enables us to assess this number. In a population of size N observed over time, the upper 95% confidence limit for the risk (R) is approximately R=3/N. For example, the follow-up of 600 individuals allows the detection of the AEs of the ≥ or greater than 0.5% (that is, 3/600).18

Table 3 summarises the known number

Databases are an excellent source of safety information and have been developed extensively in rheumatology.20,21


experience with the dermatological databases is more limited. One can distinguish between national and regional clinical registries (CR) (which in Europe comprise the Psonet network www.psonet. eu) and the drug-specific post-marketing surveillance databases (PMSD), which are often established and sponsored by the pharmaceutical companies (for example, PSOLAR registry owned by Janssen22


ESPRIT registry sponsored by AbbVie). There are important differences between these two types of registry. CR are likely to cover most patients in the given area, whereas PMSD usually involve selected sites, thus giving a possibility of a sampling error. On the other hand, the quality of the data in PMSD is often superior to CR and the number of registered patients tends to be higher.

Data from CR confirmed a low level of

known AEs, without any novel, unexpected events.23,24

Preliminary analyses of the

PSOLAR registry, which at the time of writing this paper comprised >2300 patients treated with ustekinumab, >1100 patients treated with infliximab or golimumab, >4000 patients on other biologic and >2000 patients on conventional therapy, are equally reassuring. There was a trend towards a slight increase in the incidence of severe infections in patients treated with anti-TNF agents, but not in those treated with ustekinumab.a

The rate of

malignancies was very low and comparable across the different treatments.b

The risk

of MACEs was actually lower for the patients treated with biologics compared to those who received conventional drugs,c which is similar to the findings from the Danish Dermbio database.25

a Leonardi et al. Poster P977, EADV Annual Meeting 2012

b Langley et al. Poster P973, EADV Annual Meeting 2012

c Naldi et al. Presentation at EADV Annual Meeting 2012

of patients treated continuously with different biologics for periods of three years and longer. With the exception of infliximab (for which the long-term follow up has not been documented sufficiently), the maximum risk of unexpected AEs is below 0.16%/year, a number that compares favourably with conventional treatments, such as methotrexate.19

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