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of adalimumab (equaling 0.4 events per 100 patient years).30 The patient was in the open-label treatment phase and had withdrawn consent due to lack of efficacy.IL-17 and the Pathophysiology of DepressionInvestigation has increasingly focused on the role of the immune system and systemic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.

CONCLUSION

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.

REFERENCES

  1. IM, Loring B, John SM. A systematic review of worldwide epidemiology of psoriasis. J Eur Acad Dermatol Venereol. 2017;31(2):205-12.
  2. Parisi R, Symmons DP, Griffiths CE, Ashcroft DM. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol. 2013;133(2):377-85.
  3. Yeung H, Takeshita J, Mehta NN, Kimmel SE, Ogdie A, Margolis DJ, et al. Psoriasis severity and the prevalence of major medical comorbidity: a population-based study. JAMA Dermatol. 2013;149(10):1173-9.
  4. Rapp SR, Exum ML, Reboussin DM, Feldman SR, Fleischer A, Clark A. The physical, psychological and social impact of psoriasis. J Health Psychol. 1997;2(4):525-37.
  5. Cohen BE, Martires KJ, Ho RS. Psoriasis and the Risk of Depression in the US Population: National Health and Nutrition Examination Survey 2009-2012. JAMA Dermatol. 2016;152(1):73-9.
  6. Dalgard FJ, Gieler U, Tomas-Aragones L, Lien L, Poot F, Jemec GBE, et al. The psychological burden of skin diseases: a cross-sectional multicenter study among dermatological out-patients in 13 European countries. J Invest Dermatol. 2015;135(4):984-91.
  7. Kurd SK, Troxel AB, Crits-Christoph P, Gelfand JM. The risk of depression, anxiety, and suicidality in patients with psoriasis: a population-based cohort study. Arch Dermatol. 2010;146(8):891-5.
  8. Koo J, Marangell LB, Nakamura M, Armstrong A, Jeon C, Bhutani T, et al. Depression and suicidality in psoriasis: review of the literature including the cytokine theory of depression. J Eur Acad Dermatol Venereol. 2017;31(12):1999-2009.
  9. Arican O, Aral M, Sasmaz S, Ciragil P. Serum levels of TNF-alpha, IFN-gamma, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psoriasis and correlation with disease severity. Mediators Inflamm. 2005;2005(5):273-9.
  10. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67(5):446-57.
  11. Nast A, Gisondi P, Ormerod AD, Saiag P, Smith C, Spuls PI, et al. European S3-Guidelines on the systemic treatment of psoriasis vulgaris--Update 2015--Short version--EDF in cooperation with EADV and IPC. J Eur Acad Dermatol Venereol. 2015;29(12):2277-94.
  12. Lebwohl M, Strober B, Menter A, Gordon K, Weglowska J, Puig L, et al. Phase 3 Studies Comparing Brodalumab with Ustekinumab in psoriasis. N Engl J Med. 2015;373(14):1318-28.
  13. Dowlatshahi EA, Wakkee M, Arends LR, Nijsten T. The prevalence and odds of depressive symptoms and clinical depression in psoriasis patients: a systematic review and meta-analysis. J Invest Dermatol. 2014;134(6):1542-51.
  14. Dommasch ED, Li T, Okereke OI, Li Y, Qureshi AA, Cho E. Risk of depression in women with psoriasis: a cohort study. Br J Dermatol. 2015;173(4):975-80.
  15. Lamb RC, Matcham F, Turner MA, Rayner L, Simpson A, Hotopf M, et al. Screening for anxiety and depression in people with psoriasis: a cross-sectional study in a tertiary referral setting. Br J Dermatol. 2017;176(4):1028-34.
  16. U.S. Food and Drug Administration [FDA]. Office Director Memo [brodalumab] [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761032Orig1s000ODMemo.pdf. Accessed April 19, 2018].
  17. U.S. Food and Drug Administration [FDA]. Medical Review [brodalumab] [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761032Orig1s000MedR.pdf. Accessed April 19, 2018].
  18. Reeves A, Stuckler D, McKee M, Gunnell D, Chang SS, Basu S. Increase in state suicide rates in the USA during economic recession. Lancet. 2012;380(9856):1813-4.
  19. Danesh MJ, Kimball AB. Brodalumab and suicidal ideation in the context of a recent economic crisis in the United States. J Am Acad Dermatol. 2016;74(1):190-2.
  20. Lebwohl MG, Papp KA, Marangell LB, Koo J, Blauvelt A, Gooderham M, et al. Psychiatric adverse events during treatment with brodalumab: Analysis of psoriasis clinical trials. J Am Acad Dermatol. 2018;78(1):81-9 e5.
  21. Umezawa Y, Nakagawa H, Niiro H, Ootaki K, Japanese Brodalumab Study G. Long-term clinical safety and efficacy of brodalumab in the treatment of Japanese patients with moderate-to-severe plaque psoriasis. J Eur Acad Dermatol Venereol. 2016;30(11):1957-60.
  22. U.S. Food and Drug Administration [FDA]. Medical Review [Ixekizumab] [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125521Orig1s000MedR.pdf. Accessed April 19, 2018].
  23. Griffiths CEM, Fava M, Miller AH, Russell J, Ball SG, Xu W, et al. Impact of Ixekizumab treatment on depressive symptoms and systemici nflammation in patients with moderate-to-severe psoriasis: An integrated analysis of three Phase 3 clinical studies. Psychother Psychosom. 2017;86(5):260-7.
  24. Secukinumab Advisory Committee Briefing Book, 2014 [Available from: https://www.pharmamedtechbi.com/~/media/Supporting%20Documents/The%20Pink%20Sheet%20DAILY/2014/October/101614%20Novartis%20briefing%20docs.pdf. Accessed April 19, 2018].
  25. Apremilast Medical Review, Psoriasis, 2014 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206088Orig1s000MedR.pdf. Accessed April 19, 2018].
  26. Crowley J, Thaci D, Joly P, Peris K, Papp KA, Goncalves J, et al. Long-term safety and tolerability of apremilast in patients with psoriasis: Pooled safety analysis for >/=156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2). J Am Acad Dermatol. 2017;77(2):310-7 e1.
  27. Otezla (apremilast): New important advice regarding suicidal ideation and behaviour [Available from: https://www.hpra.ie/docs/default-source/default-document-library/important-safety-information---otezla-(apremilast).pdf?sfvrsn=0. Accessed May 30, 2018].
  28. Vakharia PP, Orrell KA, Lee D, Rangel SM, Lund E, Laumann AE, et al. Apremilast and suicidality - a retrospective analysis of three large databases: the FAERS, EudraVigilance and a large single-centre US patient population. J Eur Acad Dermatol Venereol. 2017;31(10):e463-e4.
  29. Ellard R, Ahmed A, Shah R, Bewley A. Suicide and depression in a patient with psoriasis receiving adalimumab: the role of the dermatologist. Clin Exp Dermatol. 2014;39(5):624-7.
  30. FDA Briefing Document Arthritis Advisory Committee Meeting [Available from: https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM361564.pdf. Accessed May 30, 2018].
  31. Diniz BS, Teixeira AL, Talib L, Gattaz WF, Forlenza OV. Interleukin-1beta serum levels is increased in antidepressant-free elderly depressed patients. Am J Geriatr Psychiatry. 2010;18(2):172-6.
  32. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27(1):24-31.
  33. Liu Y, Ho RC, Mak A. The role of interleukin (IL)-17 in anxiety and depression of patients with rheumatoid arthritis. Int J Rheum Dis. 2012;15(2):183-7.
  34. Kim JW, Kim YK, Hwang JA, Yoon HK, Ko YH, Han C, et al. Plasma levels of IL-23 and IL-17 before and after antidepressant treatment in patients with Major Depressive Disorder. Psychiatry Investig. 2013;10(3):294-9.
  35. Beurel E, Harrington LE, Jope RS. Inflammatory T helper 17 cells promote depression-like behavior in mice. Biol Psychiatry. 2013;73(7):622-30

AUTHOR CORRESPONDENCE

Leon H. Kircik MD wedoderm@yahoo.com