Our study further supports that secukinumab is an effective therapy in EP and suggests that the use of recreational and accepted drugs (alcohol, cannabis, and tobacco) is prevalent in EP patients.

Furthermore, in the literature, EP patients treated with secukinumab had 16 [4] or 24 [5] months of follow up, lacking an assessment of long-term DLQI. Thus we assessed DLQI at 8, 12, 16, 24, and 52 weeks and found that secukinumab contributed to the improvement, not only in skin disease, but also in the long-term quality of life of EP patients. In our cohort, EP patients that responded to secukinumab did not exhibit recurrences and maintained long-term responsiveness to the drug. This study further supports the results described in a retrospective 52-week, observational, multicenter study, evaluated by Galluzzo et al., which suggested long-term efficacy of secukinumab in plaque psoriasis [12].

Focusing on EP patients, we assessed for the first time in detail the timing related to clearance of erythroderma, and after that, how secukinumab managed to clear the residual plaque psoriasis during the 52-week follow-up period. These two parameters together, are of pivotal importance in the clinical setting to guide therapeutic decisions made by dermatologists. In addition, the 52-week follow-up data highlighted that the EP responders to secukinumab achieved at least PASI 90 after clearing EP.

Among the three patients who did not respond to secukinumab therapy, one patient developed generalized urticaria at week three, the second patient experienced recurrent oral candidiasis and stopped the drug at week 12, and the third patient lost response at week 16. Remarkably, the second non-responder also smoked cannabis. Non-responders have not previously been treated with ustekinumab, and in accord with the recent real-life data on secukinumab non-responders, they were switched to ustekinumab and achieved a complete remission [13]. Ustekinumab is an IL-12/IL-23 blocker that targets the p40 subunit shared by these two cytokines. Furthermore, IL-12 plays a pivotal role in T helper cell type 1 (Th-1) polarization, as does IL-23 in Th-17 polarization [14]. We interpret the non-responsiveness of our patients as potentially due to the development of anti-secukinumab antibodies or up-regulation of Th-1-related pro-inflammatory cytokines, as previously demonstrated by Zaba et al. [15].

Evaluation of clinical characteristics in secukinumab non-responders indicated that all three had a familial history of EP and had used more than one drug, including smoking, alcohol, and cannabis. However, none of them were treated with any drug known to trigger psoriasis.

In the literature, the prevalence of drug abuse in the rare subset of EP is not reported, conversely, in plaque psoriasis patients several authors addressed the problem of drug abuse prevalence (alcohol and tobacco smoking) and its impact on anti-psoriatic therapies [7,8,16,17].

Alcohol intake and, consequently, also the abuse, may favor psoriasis-related systemic inflammation by promoting lipopolysaccharide (LPS) translocation from intestine to blood flow, increasing the pro-inflammatory activation of several immune cells, including lymphocytes (producing TNF-α and IFN-γ) and monocytes/macrophages (producing TNF-α), and directly by triggering keratinocytes pro-inflammatory activation via keratinocyte growth factor receptor (KGFR) [9]. These observations are further supported by Brenaut and colleagues, who conducted a meta-analysis on the epidemiological link between psoriasis and alcohol intake, and found that alcohol is a risk factor in developing psoriasis [17]. Furthermore, Qureshi et al. described a correlation between heavy beer intake and psoriasis severity during exacerbation [8]. This concept is translatable to EP patients, where erythroderma is an acute and very severe exacerbation of pre-existent psoriasis. Thus, alcohol abuse seems to increase TNF-α levels and may theoretically explain a possible lack or loss of response to IL-17 blockers, as with secukinumab in our EP patients.

Tobacco smoking and its link with psoriasis was assessed by Armstrong and colleagues in a large meta-analysis, involving 28 studies. They found an odds-ratio (OR) of 1.78 (95% confidence interval = 1.52–2.06) and a higher PASI in psoriatic smokers compared to non-smokers [16]. Remarkably, psoriasis severity gradually increases with the number of cigarettes smoked per day [17], but may benefit from a stop in smoking [18,19]. The nicotine contained in cigarettes activates nicotinic acetylcholine receptors (nAChRs) on the surface of dendritic cells, macrophages, endotheliocytes and keratinocytes, leading to an increased Th-1/Th-17 polarization of naïve T cells and to an increased production of pro-inflammatory cytokines, such as TNF-α, IL-12, IL-17, IL-23, IL-1β and IFN-γ [20]. These are all capable of decreasing the therapeutic effects of both TNF-α [7] and IL-17 blockers.

Conversely, fragmentary data exist regarding the effects of cannabis on the immune system and skin [21,22], but no data have been published about cannabis smoking in psoriatic patients or in murine models of psoriasis. However, some purified extracts derived from cannabis may inhibit in vitro keratinocyte proliferation [21] and Th-17 cell-related cytokine production in a dose-dependent manner [22]. Cannabinoids mainly interact with two receptors, cannabinoid-1 receptor (CB1R) and (CB2R), and both inhibit adenylate cyclase and activate mitogen-activated protein kinase (MAPK) [11]. This theoretically contrasts the anti-psoriatic function of apremilast, with regard to the intracellular cyclic adenosine monophosphate (AMPc) increase due to phosphodiesterase-4 inhibition. CB1R is prevalently present in keratinocytes, whilst CB2R is prevalent in immune cells, such as T cells and monocytes/macrophages [11]. Upon stimulation in the presence of purified cannabis extracts, namely cannabidiol (CBD) and tetrahydrocannabinol (THC), Th-17 cells massively decrease both transcription and release of IL-17A [22], which may theoretically act synergistically with IL-17 blockers. This aspect may be also confirmed by reports that list candidiasis as a side effect of both IL-17 blockers and chronic cannabis use [23]. Consequently, patients under IL-17 blockers that use cannabis may be exposed to a higher risk of candidiasis. Remarkably, Russo and colleagues pointed out that, in order to evaluate the global effect of cannabis, it is necessary to take into consideration the synergism existing among different cannabis compounds that altogether determine the final so-called entourage effect, capable of enhancing or even obscuring the properties of single compound [24]. Furthermore, no studies evaluated how smoking cannabis can modify these compounds and their biological effect. Thus, this is the first report to evaluate this relevant use of such drugs in a cohort of patients affected by EP, a chronic systemic inflammatory disease.

Moreover, both smoking and alcohol consumption were found to increase IL-17 and TNF-α production [9,12,16], corroborating our hypothesis that drug use may promote systemic inflammation, contributing to less favorable results from anti-psoriatic therapies.

The main limitation of the present study remains the small sample of enrolled patients, which was due to EP rarity and due to the fact secukinumab is still off-label in treating EP. Therefore, we cannot conclude that drug use in the non-responding patient group was causal. Other plausible reasons for the failed response in the small number of patients with addiction problems in the present cohort might well be insufficient compliance, even though all of our patients regularly attended dermatological appointments and reported to have auto-injected secukinumab.