1SKiN Centre for Dermatology, Peterborough, ON, Canada
2Queen’s University, Kingston, ON, Canada
3Probity Medical Research, Waterloo, ON, Canada
4K Papp Clinical Research, Waterloo, ON, Canada
Conflict of interest:
Fabian Rodriguez-Bolanos has no conflicts of interest. Melinda Gooderham and Kim Papp have been an investigator, speaker, advisory board member and consultant for Valeant Pharmaceuticals.
The ili (IL)-17 inhibitors have proven to be highly effective in the treatment of psoriasis. The most recently approved agent, brodalumab, had few cases of suicidal behavior, including completed suicide, in the phase 3 clinical program leading both the US FDA and Health Canada to add a boxed warning to its label. This raises the importance of identifying the psychiatric comorbidities associated with psoriasis. It is also necessary to critically examine the data from the brodalumab clinical trial program to determine whether there is enough information to establish causality and whether other factors, other than the drug, could be playing a role.
biologics, brodalumab, IL-17, plaque psoriasis, Siliq, suicidal ideation and behavior
Psoriasis is a prevalent skin condition.1 Plaque psoriasis is the most common type of psoriasis in all populations.2 The impact of psoriasis is magnified by its nature and chronicity, which can lead to important psychological morbidity. It can significantly affect quality of life, even when the disease is not extensive.3
We are starting to understand the complexity of this disease, in which different genetic, immunologic and environmental factors all play a part.4 Psoriasis is considered a multisystem, immunemediated inflammatory disease.5 It has been observed epidemiologically that the frequency of some noncutaneous disorders and conditions is significantly higher in the psoriatic population, including rheumatologic, inflammatory bowel, cardiovascular, metabolic, and psychiatric/psychological diseases.6
By further elucidating the immune mechanisms involved, research has allowed for the development of targeted therapies. Brodalumab, a human monoclonal immunoglobulin G2 (IgG2) antibody directed at the interleukin (IL)-17 receptor A, is one of the latest medications to be approved for the treatment of moderate to severe plaque psoriasis. With data from research trials demonstrating impressive efficacy in clinical score improvement in psoriatic patients, brodalumab is proving to be a useful addition to our therapeutic arsenal.7-8
There have been some concerns regarding suicidal ideation and behavior (SIB) in patients treated with brodalumab, as four cases of suicide were documented during clinical trials. Because of these reports, a boxed warning was added to the monograph of the drug. The importance of this issue has prompted the authors to take a careful look through these cases in order to gain better insight into patient-specific contributing factors. The authors examined salient features of each incident, compared reports of SIB with other biologics and explored the complex relationship between inflammatory diseases, such as psoriasis, depression and suicidal ideation.
Mental Health and Psoriasis
It is not an understatement to say that the disease carries a burden which is not only physical but also psychological. Although the mechanisms of the relationship are not well understood and underestimated in its affects, psoriasis has long been recognized to be associated with adverse impacts on mental health. In the 1960s a popular ad campaign labeled the emotional burden of this skin disease as the “heartbreak of psoriasis”.9 Studies have reported that up to half of patients with psoriasis experience, at some point during their disease, helplessness and isolation that can lead to functional limitations, impacting them socially and psychologically.10-11
In general, SIB is not uncommon. According to the World Health Organization (WHO), about 804,000 suicide deaths occurred in 2012 worldwide.12 It is an important public health problem with complex and multiple risk factors, including a combination of demographic, social and cultural influences. A study by Vilhjalmsson et al. found that adults are more likely to contemplate suicide under certain conditions, such as highly stressful domestic, financial, and particularly legal circumstances; SIB is also more pervasive in individuals who experience extensive physical health problems and perceive their lives as stressful.13 A cross-national study reported an estimated lifetime prevalence of suicidal ideati on, plan, and attempt in the overall sample of 9.2%, 3.1%, and 2.7%, respectively.14
Suicidal behavior includes both attempted suicide and completed suicide. A systematic review with meta-analysis by Singh et al. reported that psoriasis patients were more than twice as likely to have suicidal ideation than those without psoriasis (odds ratio [OR], 2.05; 95% confidence interval [CI], 1.54–2.74).15 This same study also documented that patients with psoriasis have a higher likelihood of suicide attempts (OR, 1.32; 95% CI,1.14–1.54) and completed suicide (OR, 1.20; 95% CI, 1.04–1.39) compared to patients without psoriasis.15 Furthermore, younger patients and those with severe disease seem more likely to contemplate and attempt suicide.15 These results should be interpreted in the context of limited available studies and possible sources of heterogeneity and bias.
Interestingly, another recent systematic review with metaanalysis by Chi et al. did not support an association between psoriasis and suicide.16 No increase in the risk of suicide (relative risk [RR] 1.13; 95% CI 0.87–1.46), suicide attempt (RR 1.25; 95% CI 0.89–1.75), or suicidality (RR 1.26; 95% CI 0.97–1.64) among people with psoriasis was found,16 therefore not substantiating the results reported by Singh. They also comment on the limited and very low-quality of the available evidence.
There has been interest in trying to elucidate possible neurophysiological impacts, such as mood and depression, from psoriasis linked to proinflammatory cytokines. Different studies have reported an association between IL-1, IL-6, IL-17, tumor necrosis factor-alpha (TNF-α), and depression;17-22 however, it has yet to be determined how these immunomodulatory changes could alter neurotransmitters and other neurological mechanisms. According to these observations, the implication could be made that reducing disease severity could potentially improve the proinflammatory state, including depression.
Brodalumab: Mechanism of Action
Brodalumab is one of the available therapies that target the IL-17A pathway of psoriasis. This pathway is also targeted by secukinumab and ixekizumab which specifically bind to IL-17A, and bimekizumab which targets both IL-17A and IL-17F. Brodalumab differs from these by its mechanism of action, because instead of blocking IL-17A or IL-17F directly, it blocks the IL-17 receptor A (IL-17RA). More specifically, brodalumab is a monoclonal antibody that selectively binds to the IL-17RA, thereby inhibiting its interactions with cytokines IL-17A, IL-17C, IL-17F, IL17A/F heterodimer, and IL-25. Significant gene expression changes and almost complete reversal of the psoriatic phenotype have occurred as a result of IL-17RA antagonism.23 It was approved by the US FDA in 2017 and by Health Canada in 2018 for the treatment of moderate to severe plaque psoriasis.24-25 Three different phase 3 studies have confirmed the efficacy of this medication in psoriasis: AMAGINE-1, AMAGINE-2, and AMAGINE-3.7-8 Data suggests that prior use of biologics does not affect the efficacy of brodalumab.26
Brodalumab and Reported SIB
During phase 3 clinical studies, concerns about brodalumab possibly causing suicidal ideation emerged with 4 completed suicides, which led to the early termination of all studies at that time.27 Most of these events occurred during the long-term, open-label phase. One case of completed suicide was later adjudicated as indeterminate according to the Columbia Classification Algorithm of Suicide Assessment (C-CASA). Even when there was lack of definitive causation, concerns regarding the association of brodalumab with SIB events remained.
Table 1 summarizes completed suicides and the clinical characteristics of these patients who received brodalumab for plaque psoriasis. The details of these deaths revealed pre-existing psychiatric and vulnerable social circumstances. One death, an overdose, was considered an indeterminate suicide.
Table 1: Completed suicides during clinical trials in patients treated with brodalumab for plaque psoriasis.
Age (years): 58
Ethnicity: Caucasian; from Poland
- Comorbid psoriatic arthritis
- Patient completed suicide by hanging 329 days after beginning treatment with brodalumab and 58 days after his last dose
- No prior psychiatric history
- Patient stated to the investigator that he experienced ongoing financial distress and had debts
- No reported warning signs before the suicide
Ethnicity: Caucasian; from the US
- The method of suicide is unknown (it was reported by the patient’s mother)
- Patient completed suicide 140 days after first dose of brodalumab and 27 days after the last dose
- No prior psychiatric history
- Patient disclosed to the investigator that he had considerable legal problems and would likely be incarcerated soon
- No other psychiatric adverse events during the study
Ethnicity: Caucasian; from the US
- Patient completed suicide by jumping from the roof of his apartment building 845 days after his first dose of brodalumab and 19 days after the last dose
- Patient reported he recently moved to a new apartment and felt stressed and isolated
- History of depression and anxiety; treated with trazodone
- Patient reported one brief episode of mild depression
- Patient was screened with the PHQ-8 and eC-SSRS with negative results prior to completing suicide
Ethnicity: Asian American
- Later adjudication showed that this was an indeterminate suicide
- Patient’s wife stated that he had financial problems and had a drug addiction
- Patient was found dead in his vehicle 97 days after his first dose of brodalumab and 14 days after the last dose>
- Patient had a history of depression and anxiety, which was treated with citalopram and alprazolam
- Authorities concluded that the cause was an unintentional heroin and alcohol overdose
- Toxicology results indicated that the patient had ingested heroin; alcohol, alprazolam and citalopram were also present in his system
Following the initial concern regarding SIB reports, the electronic Columbia Suicide Severity Rating Scale (eC-SSRS) and Patient Health Questionnaire-8 (PHQ-8) were implemented for prospective evaluation of most patients in the long-term extension phase studies (after the double-blind phase had been completed). According to the FDA analysis, brodalumab users with a history of suicidality had approximately 12-18 fold increase in SIB incidence than users without a history.27 However, more detailed information regarding this analysis, including confidence intervals, are not provided in the FDA review. As the psychologic and psychiatric aspects of many skin disorders, including psoriasis, are known to coexist, it is not unreasonable to expect that individuals with a prior history of suicidality are prone to exhibit SIB in the future. The cross-national study referenced earlier in this paper,14 reported that among individuals with a lifetime history of suicidal ideation, the probability of ever planning a suicide is approximately 33% and the probability of ever making a suicide attempt is approximately 30%.
If we consider the clinical information from all of the patients who completed suicide, each case could be explained by exogenous factors. As reported by Hashim et al., there are several factors that may have created an exaggerated suicidality signal in the brodalumab trials. Unlike the clinical trials for other recently approved biologics, there was not a specific exclusion of subjects with a history of psychiatric events or prior suicide attempts.28
Lebwohl et al.29 published a study in which psychiatric adverse effect data was gathered from five psoriasis clinical trials in the brodalumab development program: a phase 2, randomized, double-blinded, placebo-controlled, dose-ranging study; an open-label, long-term extension of the phase 2 study; and three phase 3, randomized, double-blind, controlled trials (AMAGINE-1, AMAGINE-2, AMAGINE-3 and their open-label long-term extensions). According to the investigators’ analysis, SIB events among psoriatic patients in the brodalumab program did not demonstrate evidence of causality when compared with controls and timing of those events,29 given that the incidence of suicides in the study population did not differ significantly from that seen in a general background population. Danesh and Kimball commented that the timing of the clinical trial during an economic crisis in the United States, in combination with demographics of the patients recruited in the study, could have contributed to the increased incidence of SIB.30
SIB with Other Biologics
Depression and suicidal ideation have been reported with other psoriasis treatments including monoclonal therapies. A review of the literature focusing on SIB events linked with biologic agents and small molecules used to treat psoriasis has previously been published.29 More specifically, clinical trials, case reports and post-marketing data covering SIB with monoclonal antibodies, including anti-TNF-α (infliximab, adalimumab), anti-IL12/23 (ustekinumab) and anti-IL-17A (ixekizumab) medications.31-33 Although the quality of the case reports is weak, rates reported in the clinical trials are not different than rates in the general population and, therefore, no clear association can be established.
A study by Minnema et al. also explored the association with monoclonal antibodies, depression and SIB. The investigators collected data reported in VigiBase (the WHO’s global Individual Case Safety Report [ICSR] database) of adverse effects related to depression and SIB. The findings showed that monoclonal antibodies used to treat autoimmune diseases for immune system suppression had a higher reporting odds ratio (ROR), 1.9 (95% CI 1.8–2.0) for depression and 3.6 (95% CI 3.0–4.4) for SIB.34 Methodologically, however, the study suffers from many limitations, including the source of the data and the fact that there is no control population.
Psychiatric pathology and SIB may be more common in psoriasis patients. Medical professionals should be aware of this association and be poised to provide the necessary interventions when faced with a patient reporting significant depression or SIB. There is no clear evidence that monoclonal antibodies influence neurological function and modulate behavior in humans. More research in this area is necessary in order to begin to understand the potential effects of proinflammatory cytokines on inducing changes in the nervous system and mood. In the specific case of brodalumab, there is not enough evidence to establish causation of SIB in patients treated, as prevalence is comparable to the background population. Additionally, based on existing evidence, brodalumab exhibits a similar safety profile with other IL-17 cytokine inhibitors used to treat moderate to severe plaque psoriasis. We should take into consideration that the clinical trials for brodalumab did not exclude patients according to their psychiatric history, something that has become standard in the research of newer drugs. Nevertheless, it is yet to be determined whether the screening tools currently in use will translate into plausible changes. Based on observed risk of SIB attributable to the completed suicides, the FDA included a boxed label warning for this medication. When prescribing brodalumab, or any other biologic agent, physicians should screen patients for psychiatric comorbidities. Assessment of risk versus benefit and having ongoing honest conversations with patients are crucial and extend beyond the label warning in order to mitigate SIB risk. Thus, the optimal therapeutic approach in the psoriatic population addresses both the obvious physical symptoms as well as complex emotional aspects of psoriasis.
- Kaufman BP, Alexis AF. Psoriasis in skin of color: insights into the epidemiology, clinical presentation, genetics, quality-of-life impact, and treatment of psoriasis in non-white racial/ethnic groups. Am J Clin Dermatol. 2018 Jun;19(3):405-23.
- Parisi R, Symmons DP, Griffiths CE, et al. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol. 2013 Feb;133(2):377-85.
- Stern RS, Nijsten T, Feldman SR, et al. Psoriasis is common, carries a substantial burden even when not extensive, and is associated with widespread treatment dissatisfaction. J Investig Dermatol Symp Proc. 2004 Mar;9(2):136-9.
- Hawkes JE, Chan TC, Krueger JG. Psoriasis pathogenesis and the development of novel targeted immune therapies. J Allergy Clin Immunol. 2017 Sep;140(3): 645-53.
- Boehncke WH, Schon MP. Psoriasis. Lancet. 2015 Sep 5;386(9997):983-94.
- Grozdev I, Korman N, Tsankov N. Psoriasis as a systemic disease. Clin Dermatol. 2014 May-Jun;32(3):343-50.
- Papp KA, Reich K, Paul C, et al. A prospective phase III, randomized, doubleblind, placebo-controlled study of brodalumab in patients with moderate-tosevere plaque psoriasis. Br J Dermatol. 2016 Aug;175(2):273-86.
- Lebwohl M, Strober B, Menter A, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015 Oct;373(14):1318-28.
- Kurd SK, Troxel AB, Crits-Christoph P, et al. The risk of depression, anxiety, and suicidality in patients with psoriasis: a population-based cohort study. Arch Dermatol. 2010 Aug;146(8):891-5.
- Bewley A, Burrage DM, Ersser SJ, et al. Identifying individual psychosocial and adherence support needs in patients with psoriasis: a multinational two-stage qualitative and quantitative study. J Eur Acad Dermatol Venereol. 2014 Jun;28(6):763-70.
- Ring L, Kettis-Lindblad A, Kjellgren KI, et al. Living with skin diseases and topical treatment: patients’ and providers’ perspectives and priorities. J Dermatolog Treat. 2007 18(4):209-18.
- World Health Organization. Preventing suicide: a global imperative. 2014. Available at: http://www.who.int/mental_health/suicide-prevention/world_report_2014/en/. Accessed May 26, 2019.
- Vilhjalmsson R, Kristjansdottir G, Sveinbjarnardottir E. Factors associated with suicide ideation in adults. Soc Psychiatry Psychiatr Epidemiol. 1998 Mar;33(3):97-103.
- Nock MK, Borges G, Bromet EJ, et al. Cross-national prevalence and risk factors for suicidal ideation, plans and attempts. Br J Psychiatry. 2008 Feb;192(2):98-105.
- Singh S, Taylor C, Kornmehl H, et al. Psoriasis and suicidality: a systematic review and meta-analysis. J Am Acad Dermatol. 2017 Sep;77(3):425-40 e2.
- Chi CC, Chen TH, Wang SH, et al. Risk of suicidality in people with psoriasis: a systematic review and meta-analysis of cohort studies. Am J Clin Dermatol. 2017 Oct;18(5):621-7.
- Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med. 2009 Feb;71(2):171-86.
- Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010 Mar 1;67(5):446-57.
- Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006 Jan;27(1):24-31.
- Davami MH, Baharlou R, Ahmadi Vasmehjani A, et al. Elevated IL-17 and TGF-beta serum levels: a positive correlation between T-helper 17 cell-related pro-inflammatory responses with major depressive disorder. Basic Clin Neurosci. 2016 Apr;7(2):137-42.
- Tsuboi H, Sakakibara H, Minamida Y, et al. Elevated levels of serum IL-17A in community-dwelling women with higher depressive symptoms. Behav Sci (Basel). 2018 Nov 4;8(11).
- Nadeem A, Ahmad SF, Al-Harbi NO, et al. IL-17A causes depression-like symptoms via NFkappaB and p38MAPK signaling pathways in mice: Implications for psoriasis associated depression. Cytokine. 2017 Sep;97:14-24.
- Roman M, Chiu MW. Spotlight on brodalumab in the treatment of moderateto-severe plaque psoriasis: design, development, and potential place in therapy. Drug Des Devel Ther. 2017;11:2065-75.
- Siliq™ (brodalumab) [Prescribing information]. Revised February 2017. Valeant Pharmaceuticals, Bridgewater, NJ. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761032lbl.pdf. Accessed May 26, 2019.
- Siliq™ (brodalumab) [Product monograph]. Last revised March 1, 2018. Valeant Canada LP, Laval, QC. Available at: https://pdf.hres.ca/dpd_pm/00044076.PDF. Accessed May 26, 2019.
- Papp KA, Gordon KB, Langley RG, et al. Impact of previous biologic use on the efficacy and safety of brodalumab and ustekinumab in patients with moderateto-severe plaque psoriasis: integrated analysis of the randomized controlled trials AMAGINE-2 and AMAGINE-3. Br J Dermatol. 2018 Aug;179(2):320-8.
- Center for Drug Evaluation and Research. Clinical review: brodalumab (Siliq®). Review completed August 25, 2016. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761032Orig1s000MedR.pdf. Accessed May 26, 2019.
- Hashim PW, Chen T, Lebwohl MG, et al. What lies beneath the face value of a box warning: a deeper look at brodalumab. J Drugs Dermatol. 2018 Aug 1;17(8):s29-s34.
- Lebwohl MG, Papp KA, Marangell LB, et al. Psychiatric adverse events during treatment with brodalumab: analysis of psoriasis clinical trials. J Am Acad Dermatol. 2018 Jan;78(1):81-9 e5.
- 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 Jan;74(1):190-2.
- Gooderham M, Gavino-Velasco J, Clifford C, et al. A review of psoriasis, therapies, and suicide. J Cutan Med Surg. 2016 Jul;20(4):293-303.
- Eshuis EJ, Magnin KM, Stokkers PC, et al. Suicide attempt in ulcerative colitis patient after 4 months of infliximab therapy–a case report. J Crohns Colitis. 2010 Nov;4(5):591-3.
- Center for Drug Evaluation and Research. Clinical outcome assessment review: ixekizumab (Talz®). Review completed January 7, 2016. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125521Orig1s000MedR.pdf. Accessed May 26, 2019.
- Minnema LA, Giezen TJ, Souverein PC, et al. Exploring the association between monoclonal antibodies and depression and suicidal ideation and behavior: a VigiBase study. Drug Saf. 2019 Jan 8.