What Lies Beneath the Face Value of a BOX WARNING: A Deeper Look at Brodalumab
August 2018 | Volume 17 | Issue 8 | Supplement Individual Articles | 29 | Copyright © August 2018
Peter W. Hashim MD MHS,a Tinley Chen BA,a Mark G. Lebwohl MD,a Lauren B. Marangell MD,d Leon H. Kircik MDa,b,c
aThe Icahn School of Medicine at Mount Sinai, Department of Dermatology, New York, NY bIndiana University School of Medicine, Indianapolis, IN cPhysicians Skin Care PLLC, Louisville, KY dBrain Health Consultants, Houston, TX
Data Warehouse), which found no safety signal between apremilast and SIB.28AdalimumabThere are rare reports of suicide while on adalimumab treatment.29 During clinical trial development of the drug, one patient with a known history of heavy alcohol use and anxiety disorder committed suicide 40 days after his last dose of adalimumab (equaling 0.4 events per 100 patient years).30 The patient was in the open-label treatment phase and had withdrawn consent due to lack of efficacy.IL-17 and the Pathophysiology of DepressionInvestigation has increasingly focused on the role of the immune system and systemic inflammation in the pathophysiology of depression. Studies have shown that serum levels of IL-6, TNF-α, and IL-1 are elevated in patients with depression.10,31,32At present, the exact role of IL-17 in depression remains unclear. One study in patients with rheumatoid arthritis examined the levels of IL-17 among those with or without comorbid depression or anxiety.33 Serum IL-17 levels were significantly higher in patients with both rheumatoid arthritis and anxiety relative to those without anxiety (P = 0.044), and levels of IL-17 positively correlated with the severity of anxiety, even after adjustment for pain and arthritis disease severity. In contrast, a study examining plasma levels of IL-17 and IL-23 in patients with major depressive disorder found no difference in these markers relative to healthy controls.34 There was also no significant correlation between changes in cytokine levels and changes in depression scores after 6-week treatment with an anti-depressant.A recent study using mouse models examined the effects of increasing Th17 cell counts on depressive symptoms.35 The administration of Th17 cells was associated with an elevation in depression-like behaviors, whereas the administration of undifferentiated CD4+ cells or vehicle was not. In addition, mice who were deficient in RORγt—the transcription factor necessary for Th17 cell development—were more resistant to the depression-like state. Further investigation is needed to evaluate the direct role IL-17 may play in pathologic conditions of the central nervous system.
It is difficult to accurately capture SIB data in clinical trials, and this challenge only increases in the post-market setting. Interpretation of SIB data is complex, especially in diseases such as psoriasis, where there exists a significant background signal of depression that itself is not well understood (and has been reported at a widely ranging prevalence). In addition, data from different development programs can be problematic to compare because of variations in patient characteristics, follow-up methods, and ascertainment of SIB.In the case of brodalumab, several factors should be considered by prescribing dermatologists in evaluating the merit of its boxed warning. These issues include a clinical trial design that did not exclude patients based on psychiatric history, the lack of increased SIB during periods when brodalumab was actively compared to placebo or ustekinumab, as well as the known risk of SIB in the psoriasis population. In addition, the labeling decision by the FDA was heavily influenced by the fact that SIB behavior in the brodalumab trial manifested as completed suicides, despite the presence of attempted suicides in other biologic trials.In summary, regardless of the treatment agent used, the concern over SIB in the psoriasis population remains a relevant issue. Continued research is needed to help identify vulnerable patients and to better assess risk versus benefit at the level of the individual. Importantly, the role of the physician in remaining vigilant of SIB in psoriasis patients should not be limited to solely biologic therapies or boxed warnings.
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Leon H. Kircik MD firstname.lastname@example.org