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Long-term safety – part 2/2

Long-term safety of biologics: Part 2 – Mechanistic and safety considerations when choosing a biologic

Luigi Naldi Department of Dermatology, Azienda Ospedaliera papa Giovanni XXIII, and Centro Studi GISED, Presidio Ospedaliero Matteo Rota, Bergamo, Italy

Professor Naldi examines the safety profiles of anti-TNFs and IL-12/23 inhibitors in psoriasis, and the relationship between safety concerns and the immunomodulatory effects of these drugs.

Safety profile of biologics: mechanistic considerations Biologic drugs, or biologics, are a relatively new class of treatment for psoriasis and psoriatic arthritis. They are large proteins, derived from living cells. Different from traditional small molecules, which can penetrate the cell membrane and which have a broad spectrum of activities, biologics remain outside the cell, and modulate (from the outside) specific functions of the immune system that are deemed to be relevant for psoriasis triggering and maintenance. The biologics currently used to treat psoriasis belong to two major groups: antagonists of TNF (formerly TNFa) and antagonists of the p40 subunit of IL-12/23. New biologics are being developed for treating psoriasis, including, in particular, antagonists of IL-17.

TNF is a member of a group of cytokines that stimulate the acute phase reaction of inflammation. It is produced chiefly by activated macrophages, although many other cell types could synthesise it. TNF is able to induce fever and apoptotic cell death, and to inhibit tumourigenesis and viral replication, responding to sepsis via IL-1 and IL-6 production. The myriad and often- conflicting effects mediated by TNF indicate the existence of extensive cross-talk. Inhibition of TNF can be achieved with a monoclonal antibody such as infliximab, adalimumab or certolizumab pegol, or with a circulating receptor fusion protein such as etanercept. All the above-mentioned molecules but certolizumab are registered for the treatment of moderate-to-severe plaque psoriasis. The only antagonist of the p40 subunit of IL-12 and IL-23 currently available is ustekinumab. The clinical development in psoriasis of

Safety issues: general considerations

“Safety concerns are directly related to the many potential

influences of blocking cytokines on defense mechanisms against infections”

another IL-12/23 antagonist,

briakinumab, was discontinued in 2011 in the US and Europe, due to safety concerns. IL-12 and IL-23 play key roles in the development of the immune response by inducing naïve CD4+ T lymphocytes to differentiate. While IL-12 causes CD4+ T lymphocytes differentiation to Th1 cells, IL-23 promotes the expansion of the Th17 population, which produce, among the other cytokines, IL-17A, IL-17F, IL-22 and IL-26. Functional studies of Th17 cytokines have revealed an important and unique role for these cytokines in host protection against infections with extracellular pathogens such as Gram negative bacteria and Candida albicans. In addition, preliminary evidence suggests that IL-12 is proatherogenic and that its inhibition should confer cardioprotection. In the phase 2 study of ustekinumab, serum levels of the p40 subunit of IL-12 were shown paradoxically to increase 13-fold in the first 12 weeks of treatment, with a gradual decrease to above-baseline levels at week 32.26 Contrary to traditional understanding of antibody–cytokine interactions, the binding of the antibody may produce agonistic rather than antagonistic activity.26

Biologics are prescribed for individuals with moderate-to-severe plaque psoriasis and psoriatic arthritis. They are a viable option for those who have not responded to or have experienced harmful side effects from other treatments. Safety concerns are directly related to the many potential influences of blocking cytokines on defence mechanisms against infections, on cancer immune surveillance, and on organ systems, particularly the cardiovascular system and central nervous system (Table 4). Safety data are derived from different sources, including systematic reviews of randomised clinical trials or their extension, and registry data. The latter ones offer information on treatments as employed in everyday practice (real-world conditions). It should be noted that, in current practice, patients on different treatments may differ remarkably at baseline for demographic characteristics and comorbidities which may per se influence outcome. Hence, methods of analysis that take into account these baseline differences, such as propensity score, should be adopted in adjusting comparisons of outcome data from ‘real-world’ data sets. Psoriasis is a chronic long-lasting disorder. In the context of our discussion, ‘long-term’ will refer to safety data beyond one year. While anti-TNF molecules are used in a wide range of conditions, allowing the gaining of evidence of safety across several disease areas, antagonists of IL-12/23 have indications restricted to chronic plaque psoriasis and psoriatic arthritis.

Evidence from randomised clinical trials and systematic reviews As previously discussed by Professor Gniadecki, data from randomised trials, non-randomised, open-label extension studies of randomised trials and systematic reviews which combine individual trials are available for all the biologics used in psoriasis. Systematic reviews pooling safety data across different indications offer the most comprehensive evidence, but may dilute specific effects restricted to individual indications. Studies that group biologics may fail to appreciate differences between individual drugs. A Cochrane systematic review of


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