A Closer Look at the Data Regarding Suicidal Ideation and Behaviour in Psoriasis Patients: The Case of Brodalumab (Family Practice)

Fabian Rodriguez-Bolanos MD¹, Melinda Gooderham MD, MSc, FRCPC^1-3, Kim Papp MD, PhD, FRCPC^3,4

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 Leo Pharma, Kyowa Hakko Kirin, Valeant Pharmaceuticals and Bausch Health.

Introduction

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, thus leading 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 play a part.⁴ Psoriasis is considered a multisystem, immune-mediated inflammatory disease.⁵  It has been observed epidemiologically that the frequency of some noncutaneous diseases and conditions are significantly increased in psoriasis; including rheumatologic conditions, inflammatory bowel disease, cardiovascular disease, metabolic disease, and psychological disorders.⁶

Brodalumab, a human monoclonal IgG2 antibody directed at the IL-17 receptor A, is one of the latest medications to be approved for the treatment of moderate to severe plaque psoriasis. Data from clinical trials show brodalumab to be highly effective and is a useful tool to add to our therapeutic arsenal.^7-8 Attention to suicidal ideation and behaviour (SIB) in patients treated with brodalumab developed following four cases of suicide documented during the psoriasis clinical trial program. We consider it necessary to critically examine these cases in order to gain insight into why they might have happened and possible causal relationships.

Mental Health and Psoriasis

• Psoriasis has long been associated with an impact on mental health.⁹
• Studies have reported that up to half of patients with psoriasis experience helplessness and isolation that translate into functional limitations consequently impacting psoriasis patients socially and psychologically.^10-11
• According to the WHO, about 804 000 suicide deaths occurred in 2012 across the world.¹²
• SIB is an important public health problem that has been associated with an interaction between multiple factors, including: demographic, social, and cultural.
• Vilhjalmsson et al.¹³ found that adults are more likely to contemplate suicide under certain conditions, such as highly stressful domestic, financial, and particularly legal, circumstances.  As well, those who experience extensive physical health problems and who perceive their lives as stressful are also susceptible.¹³
• A cross-national study reported an estimated lifetime prevalence of suicidal ideation, plan, and attempt in the overall sample of 9.2%, 3.1%, and 2.7%, respectively.¹⁴
• Suicidal behaviour includes both attempted suicide and completed suicide.
• Singh et al.¹⁵ reported that psoriasis patients were more than twice as likely to have suicidal ideation than patients without psoriasis (odds ratio [OR], 2.05; 95% CI, 1.54-2.74).¹⁵  That 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
• Also, younger patients and patients with severe disease seemed more prone to suicidal ideation and attempted suicide.¹⁵ It was discussed that these results should be interpreted in the light of limited available studies and possible sources of heterogeneity and bias.
• Another recent systematic review with meta-analysis by Chi et al.¹⁶ 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 which does not support the results reported by Singh. They also comment on the limited and very low-quality of the available evidence.
• There are ongoing investigations into the possible neurophysiological impact of psoriasis in mood and depression with special emphasis on the relationship between proinflammatory cytokines and mood disorders.
• Different studies have reported an association between IL-1, IL-6, IL-17, TNF-α, and depression;^17-20 however, it is yet to be determined how these changes could alter neurotransmitters and other neurological mechanisms.

Brodalumab as Effective Therapeutic Option

• Brodalumab is one of the available therapies that target the interleukin-17A (IL-17A) pathway of psoriasis.
• Other antibody therapies, secukinumab and ixekizumab, specifically bind to IL-17A while bimekizumab binds to a common epitope of IL-17A and F.
• Brodalumab blocks the interleukin-17 receptor A (IL-17RA).  It is a monoclonal antibody that selectively binds to the IL-17RA, thereby inhibiting its interactions with the array of IL-17 homologues: IL-17A, IL-17C, IL-17F, IL17A/F heterodimer, and IL-25.
• Significant gene expression changes and near complete reversal of the psoriatic phenotype have occurred as a result of IL-17RA antagonism.²¹
• Brodalumab was approved by the FDA in 2017 and by Health Canada in 2018 for the treatment of moderate to severe plaque psoriasis.^22-23
• Three phase III studies have confirmed the efficacy of this medication in psoriasis: AMAGINE-1, AMAGINE-2, and AMAGINE-3.^7-8 Data suggests that prior use biologics does not affect the efficacy of brodalumab.²⁴

Brodalumab and Reported SIB

• Late in the clinical studies, a suicide signal emerged with 4 completed suicides occurring during the Phase 3 clinical trials. This led Amgen to terminate all, then current, clinical studies.²⁵
• Most of the suicides 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). Despite the lack of definitive causal association between SIB and brodalumab, concerns regarding a possible association remained. See Table 1.
• According to their analysis, brodalumab users with a history of suicidality had an approximate of 12 – 18 fold increase in SIB incidence rate than users without a history.²⁵ However, more detailed information regarding this analysis, including confidence intervals, are not provided in the document.
• It is logical to expect those with a prior history of suicidality are prone to develop 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, all cases could be explained by exogenous factors.
• As mentioned 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.²⁶
• Lebwohl et al.,²⁷ published a study in which psychiatric adverse effect data was gathered from 5 psoriasis clinical trials in the brodalumab development program.  According to their analysis, SIB events among patients with psoriasis in the brodalumab program did not demonstrate evidence of causality when compared with controls and timing of those events,²⁷ given that the incidence of suicides in the study population does 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 caused increased observations of SIB.²⁸

Table 1: Completed suicides during clinical trial in patients treated with brodalumab for plaque psoriasis.

SIB Observed During Treatment with Other Biologics

• Depression and suicidal ideation have been reported with other psoriasis therapies including monoclonal therapies.
• A review of the literature regarding SIB events with biologic agents and small molecules used to treat psoriasis has previously been published.²⁹Reports of SIB with monoclonal antibodies in clinical trials, case reports and post-marketing data include: anti TNF-α (infliximab, adalimumab), anti-IL12/23 (ustekinumab) and anti-IL-17A (ixekizumab) medications.^29-31 However, the quality of the case reports is weak, rates 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.³² also explored the association between monoclonal antibodies and depression and SIB. They reported that those monoclonal antibodies that suppress the immune system showed 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.³² Methodologically, however, the study has limitations including the source of data and lack of a control population.

Conclusions

Psychiatric pathology and SIB may be more common in psoriasis patients. Medical professionals should be aware of this association and also provide the necessary interventions when faced with a patient reporting significant depression or SIB. There is no clear evidence that monoclonal antibodies can influence neurological function and modulate behaviour in humans. More research in this area is necessary to begin to understand the effects of proinflammatory cytokines may have on 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 rates correspond to the prevalence in the background population. 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 research of newer drugs. Nevertheless, it is yet to be determined whether the screening tools used will translate into plausible changes. The regulatory agencies were concerned about the completed suicides that occurred with this medication and, therefore, the FDA included a black box warning. When prescribing brodalumab, or any other biologic agent, physicians should screen patients for psychiatric comorbidities. Assessment of risk versus benefit, and having an honest conversation with patients regarding the label, will help provide better patient care for both physical and mental health.