Additionally, she had experienced severe injection site reactions to ixelizumab. This is consistent with the adverse events reported in the plaque psoriasis pivotal clinical trials through week 12. According to the ixekizumab prescribing information,8 injection site reactions occurred in 17% of patients and were the most frequently reported adverse event. The worsening symptoms our patient experienced while on ixekizumab could have been due to immunogenicity. Data from clinical studies showed that 22% of subjects, treated at the recommended dosing regimen developed antibodies to ixekizumab during a 60-week treatment period, which was associated with reduced clinical response and 10% of these were classified as neutralizing antibodies which was associated with loss of efficacy.8
Could immunogenicity have been the problem with other agents and could immunotolerance to brodalumab be the reason why is she responding to one biologic when so many others failed? We may never know with absolute certainty, but in the meantime, we speculate that it could also be due to differences in the mechanism of action of these agents.
In psoriatic skin, immune triggers activate a signaling cascade. At the beginning of the cascade, dendritic cells create the inflammatory cytokines IL-12and IL-23. IL-12 activates Th1 cells, while IL-23 activates Th17 cells. Th1 has long been linked with immunological conditions, but the Th17 pathway has only recently been identified as one of the key culprits in psoriasis; since it’s a source of IL-17 cytokines, including IL-17A. Further downstream, on the surface of the keratinocyte, these cytokines bind to, and activate, signaling through the IL-17 receptor. IL-17 receptor activation results in the release of pro-inflammatory factors and additional IL-17 cytokines driving further inflammatory processes in the skin.
Several of the biologics approved for plaque psoriasis inhibit upstream cytokines such as TNF-α, IL-12, and IL-23, which can reduce production of IL-17 cytokines. Other biologics inhibit IL-17 downstream, by essentially gathering up cytokines and slowing the process before they bind with the receptor, whereas brodalumab is the only biologic that blocks the signaling of the IL-17 Receptor A (IL-17RA), thus inhibiting further downstream proinflammatory effects. Doing so affects several IL-17 cytokines including IL17A, IL-17F, IL-17C, IL-17A/F, and IL-25, interfering with transmission of the pro-inflammatory signs that lead to psoriasis.
Studies have shown that IL-17F contributes to skin manifestations and comorbidities of psoriasis in a tissue-specific fashion and is increased in both psoriatic lesional skin and the sera of psoriatic patients.9-11 IL-17C has been linked to skin inflammation and is also over-expressed in lesional skin of psoriatic patients.12-13 In murine models, IL-17C injections leads to epidermal thickening and psoriasiform dermatitis.
The results observed in this single patient need to be confirmed in larger Phase 4 studies of recalcitrant patients.
DISCLOSURES
Dr. Cooke has no relevant disclosures or conflicts of interest.
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