Biologics in the treatment of pustular psoriasis

ABSTRACT

Introduction

Pustular psoriasis is a group of skin diseases characterized by neutrophil infiltration in the epidermis and formation of sterile pustules. Conventional treatments, such as retinoids and immunosuppressive drugs, have improved the clinical manifestations; however, many patients suffer from drug-related toxicity or are resistant to therapy.

Areas covered

In this review, the authors focus on the efficacy and safety of these biologics, including anti-IL‐1β (gevokizumab and canakinumab), anti-IL‐1 R (anakinra), anti-IL-36 R (BI 655130), anti-tumor necrosis factor-α (etanercept, infliximab, and adalimumab), anti-IL-12/23 (ustekinumab), anti-IL-17A (secukinumab and ixekizumab), anti-IL-17RA (brodalumab), anti-IL-2 R (basiliximab), anti-IL-6 R (tocilizumab), and anti-IL-23 (risankizumab and guselkumab), for treating pustular psoriasis.

Expert opinion

Patients with pustular psoriasis treated with biologics demonstrated positive responses. Anti-TNF-α is the most available biologics for the treatment of pustular psoriasis, and anti-IL-12/23 and anti-IL-17A might be considered as the first- or second-line therapy for moderate-to-severe and refractory pustular psoriasis. Anti-IL-17A can be used in the pustular psoriasis patients who failed to respond to anti-TNF agents and anti-IL-12/23. Therapeutic efficacy of biologics in pustular psoriasis might have no association with IL-36 RN mutation status.

KEYWORDS:

• Biologics
• pustular psoriasis
• acrodermatitis continua of Hallopeau
• IL-36RN

1. Introduction

Pustular psoriasis is an uncommon subtype of psoriasis, characterized by multiple sterile pustules on an erythematous base. Pustular psoriasis can be classified as either generalized pustular psoriasis (GPP) or localized pustular psoriasis. Localized pustular psoriasis includes acrodermatitis continua of Hallopeau (ACH) and palmoplantar pustular psoriasis (PPPP) [1]. GPP is an uncommon and life-threatening skin disease characterized by a widespread eruption of pustules overlying erythematous plaques and usually accompanied by fever and malaise [2,4]. The lethal complications of GPP include sepsis, acute respiratory distress syndrome and renal dysfunction [3,5,6]. Conventional treatments, including retinoids, cyclosporine, and methotrexate, have shown efficacy in GPP patients; however, the use of these drugs presents a risk of toxicity [7,8]. PPPP and palmoplantar pustulosis (PPP) are characterized by sterile pustules and erythema localized to the palms and/or soles and are often not well distinguished [9–11]. PPP can present as a separate condition, or in association with PPPP [12]. PPPP and PPP are not well distinguished in the literature [10]. Some authors propose PPP is referred as to PPPP [13]. Therefore, palmoplantar pustulosis was included in this review [14,15]. Several clinical trials have studied the efficacy and safety of biologics for treating psoriasis vulgaris (PV), but few have reported the efficacy and safety of biologics for treating pustular psoriasis. Despite the benefits of biologics, multiple potential adverse effects have been reported, particularly infections (especially reactivation of hepatitis B and C virus [16], latent tuberculosis [17], herpes zoster [18]) and malignancy [19]. Recent progress in studying the pustular psoriasis pathogenesis has led to novel therapies for this disease. In this review, we focus on the available evidence that has tested biological drugs for pustular psoriasis. This report provides an overview of pustular psoriasis, including not only GPP but also ACH, PPPP, PPP, and a discussion of the current options of biologics for GPP treatment and their limitations.

1. Pathogenesis

The exact pathogenesis of GPP remains unclear, But both environmental and genetic factors are involved. GPP may present with or without previous PV [7,20]. Triggering factors include withdrawal of systemic therapy (especially corticosteroids), stress, infection, pregnancy, and drugs (e.g., antibiotics, terbinafine, ustekinumab, and TNF-α inhibitors) [3,21]. A history of prior PV may help in diagnosing drug-induced GPP. IL-36 RN gene mutations may lead to deficiency of interleukin-36 (IL-36) receptor antagonist (DITRA), DITRA patients may present as early onset and high risk of systemic inflammation [22,23]. One study found that most patients (9/11) who had GPP without prior PV had IL-36 RN gene mutations (homozygous or heterozygous), and 2 of 20 who had GPP with prior PV had heterozygous IL-36 RN gene mutations [24]. However, another study revealed that only 1 of 6 patients who had GPP with PV had IL-36 RN mutations, and 6 of 13 who had GPP without PV had IL-36 RN gene mutations [25]. These studies indicated that the rate of IL-36 RN mutations in patients of GPP without PV was higher than patients of GPP with PV. One study found no difference in disease severity among patients with IL-36 RN single heterozygous mutation compared with the patients with homozygous and compound heterozygous mutations [26]. Consistent with this, a study of 61 GPP patients (25 with homozygous IL-36 RN mutations,7 with heterozygous IL-36RN mutations and 29 patients with no IL-36RN mutations) found no difference of in disease severity among patients in these groups [27]. In contrast, another study showed that GPP patients with IL-36RN mutations showed an earlier age of onset and higher risk of systemic inflammation [23]. IL-36RN mutations are correlated with upregulated level of IL-8 [28]. Other genes that considered to be related to GPP are CARD14 gain-of-function variants and AP1S3 [7,29,30].

The pathogenic mechanisms of GPP and PV differ. Although the percentages of IL-17A+ CD4 + T cells did not differ among GPP patients, PV patients and healthy controls, PMA and ionomycin can induce higher IL-17A expression in CD4 + T cells in GPP patients compared with that in PV patients and healthy controls. Furthermore, in GPP, unopposed IL-36 signaling can promote TCR-driven proliferation of CD4 + T cells and cause higher IL-17A production [31]. Another study that includes GPP (n = 28) and PV (n = 12) patients and healthy controls (n = 20) showed that GPP and PV lesions had 479 and 854 differentially expressed genes, respectively, compared with healthy controls. The expression of CXCL1, CXCL2, CXCL8, IL-1, and IL-36 in GPP lesions was higher than those in PV lesions. However, IL-17A and interferon-γ (IFN-γ) expressions were lower than those in the PV lesions. These findings suggest that both IL-36 and neutrophil activation play crucial roles in GPP [32]. Whole-blood RNA sequencing revealed that the IFN scores (i.e. aggregate expressions of IFI6, IFIT3, IFITM3, OASL, and PLSCR1) were upregulated in GPP and associated with upregulation of IL-36-related genes. Additionally, IL-36 promotes IFN-I production through Toll-like receptor-9 [33].

ACH is a rare form of pustular psoriasis that usually begins at the tips of fingers and toes [34]. PPPP is another form of pustular psoriasis that presents as repeated eruptions of sterile pustules on the palms and soles [35]. The pathogenesis of ACH and PPPP is unclear. Previous studies demonstrated that IL-36RN, CARD14, and AP1S3 mutations were related to ACH and PPPP [28,36–39]. The rate of IL36RN mutation for all the GPP patients is 75%. The rate for GPP patients with ACH features and without ACH features is 93.8% and 56.3%, respectively [40]. Overall, little is known about the pathogenesis of pustular psoriasis; further studies on pustular psoriasis will be beneficial in treating it.

2. Literature search

We performed a literature search of Pubmed published from inception to 31 May 2020. The following terms were used for the search: ‘biologics,’ ‘generalized pustular psoriasis,’ ‘acrodermatitis continua of Hallopeau,’ ‘palmoplantar pustular psoriasis,’ ‘palmoplantar pustulosis,’ and ‘pustular psoriasis.’ Clinical trials, open label studies, retrospective studies, case reports concerning the use of biologics in pustular psoriasis were included. The use of biologics in annular pustular psoriasis and impetigo herpetiformis were not included in this review.

3. Anti-IL-1 and anti-IL −36 receptor (IL-36R)

Gevokizumab and canakinumab are monoclonal antibodies that bind to IL‐1β. An open‐label, expanded‐access study was performed with GPP patients to clarify the efficacy and safety of gevokizumab. These patients achieved 79% and 65% reductions in GPP area and severity index scores, respectively, at weeks 4. However, one patient discontinued the study due to a flank abscess [41]. Another study found that canakinumab therapy attenuated the lesions of a patient, who had failed to response to anakinra [42].

Anakinra is an IL‐1 R antagonist and potentially effective GPP treatment. Anakinra therapy decreased the skin severity score [43] of a 45-year-old GPP patient from 8 to 1 on day 2, which then stabilized at 2 on day 10. Another patient experienced clinical remission but developed bacteremia secondary to skin colonization with Staphylococcus aureus [44]. A patient who had compound heterozygous IL-36RN c.142 C > T and c.338 C > T mutations also improved significantly after anakinra therapy [45]. An infant with GPP also responded to anakinra therapy [46]. Only partial and transient clinical remission were observed in two PPP patients; one discontinued anakinra because of palmar pustular lesion relapse, and another stopped anakinra therapy because of fever [47]. Anakinra therapy completely stopped pustulation for one patient with ACH, the lesions dried out rapidly, but their erythematosquamous lesions were not alleviated [48]. These cases show that anakinra may be an efficacious therapy for GPP and ACH (Table 1). However, further randomized control trials are needed to evaluate the efficacy and safety of anakinra.

Table 1. Overview of anti-IL-1 and anti- IL-36R for pustular psoriasis.

Target	Drug	Improvement	Publication	Trial/Phase	Study population	Disease	Dosage
IL-1β	Gevokizumab [41]	2/2	Mansouri B et al.	Case report	2	GPP	60 mg at week 1, 4, 8.
	Canakinumab [42]	1/1	Skendros P et al.	Case report	1	GPP	150 mg monthly
IL-1 R	Anakinra [44]	1/1	Viguier. et al.	Case report	2	GPP	100 mg daily
	Anakinra [45]	1/1	Huffmeier U et al.	Case report	1	GPP	100 mg daily
	Anakinra [46]	1/1	Rossi-Semerano L et al.	Case report	1	GPP	2 mg/kg/day for 7 days and then 4 mg/kg/day
	Anakinra [47]	2/2	Tauber M et al.	Case report	2	PPPP	100 mg daily
	Anakinra [48]	1/1	Lutz V et al.	Case report	1	ACH	100 mg daily
	Anakinra [58]	0/1	Saunier J et al.	Case report	1	ACH	100 mg daily
IL-36R	Spesilumab [49]	7/7	Bachelez H et al.	Phase I	7	GPP	10 mg per kilogram of body weight
	ANB019	NA	NA	Phase II ongoing	NA	GPP	Identifier: NCT03619902

Spesilumab is a monoclonal antibody targeting IL-36R. A phase I study of GPP used GPPGA scores and Generalized Pustular Psoriasis Area and Severity Index (GPPASI) to evaluate GPP severity. A single dose of 10 mg/kg body weight was given to seven patients with moderate GPP (the average GPPGA score was 3). Three patients had homozygous IL-36RN mutations, one had a heterozygous CARD14 mutation. By week 4, all patients had achieved clear or almost clear skin regardless of the IL-36RN mutation presence. The mean percent improvement in the GPPASI score from baseline was 79.8% at week 4. The maintenance time of spesilumab may over 20 weeks. All patients experienced mild or moderate adverse events without serious adverse events [49]. This study showed the potential for using anti- IL-36R in treating GPP. A study, with an estimated 10 patients, is ongoing to assess the efficacy and safety of ANB019 in GPP patients (Table 1). However, further phase II and III randomized controlled trials are needed to evaluate the efficacy and safety of anti- IL-36R for treating GPP patients.

4. Anti-IL-12/23

Ustekinumab is a monoclonal antibody that binds to IL‐12/23 p40. A 90‐year‐old patient with GPP achieved rapid lesion clearance after being treated with ustekinumab [50]. Another case reported that a 45‐year‐old man with GPP achieved nearly complete lesion clearance after ustekinumab treatment [51]. All patients achieved clinical remission in a case series report that included four GPP patients (one had a homozygous IL-36RN mutation) [52]. However, another study showed that a 70‐year‐old patient with GPP, who experienced secondary failure of infliximab therapy, also failed to respond to ustekinumab [53]. A study that aimed to test drug survival of biologic agents for psoriasis patients included two GPP patients who were treated with ustekinumab, but this study did not include the efficacy of ustekinumab for GPP. The study revealed that ustekinumab had a higher drug survival than did adalimumab, infliximab, secukinumab, brodalumab, and ixekizumab [54]. In summary, ustekinumab may be a choice for GPP patients (Table 2), but more clinical trials are needed to clarify its efficacy and safety for treating GPP.

Table 2. Overview of anti- IL-12/23 for pustular psoriasis.

Target	Drug	Improvement	Publication	Trial/Phase	Study population	Disease	Dosage
IL-12/23	Ustekinumab [50]	1/1	Storan ER et al.	Case report	1	GPP	45 mg at month 0, 1, and then every 12 weeks.
	Ustekinumab [52]	4/4	Arakawa A et al.	Case report	4	GPP	One patient: 45 mg at weeks 0 and 4, and then 90 mg every 12 weeks. The other 3 patients: started at the dosage of 90 mg.
	Ustekinumab [51]	1/1	Dauden E et al.	Case report	1	GPP	45 mg at weeks 0 and 4, and then every 12 weeks.
	Ustekinumab [53]	0/1	Matsumoto A et al.	Case report	1	GPP	Started at the doseage of 45 mg.
	Ustekinumab [12]	5/5	Morales-Munera C et al.	Case report	5	PPPP	45 mg at weeks 0, 4, and then every 12 weeks.
	Ustekinumab [56]	7/20	Au SC et al.	open-label trial	20	Palmoplantar psoriasis	45 mg or 90 mg at weeks 0, 4, 12.
	Ustekinumab [55]	2/2	Bulai Livideanu C et al.	Case report	2	Palmoplantar psoriasis	45 mg or 90 mg, not regularly
	Ustekinumab [57]	NA	Bissonnette R et al.	RCT	10	PPPP	45 mg or placebo at week 0 and week 4.
	Ustekinumab [59]	1/1	Adisen E et al.	Case report	1	ACH	90 mg at weeks 0, then 45 mg at weeks 4, and then every 12 weeks.
	Ustekinumab [60]	1/1	Palacios-Alvarez I et al.	Case report	1	ACH	45 mg at weeks 0, 4, and then every 12 weeks.
	Ustekinumab [58]	1/1	Saunier J et al.	Case report	1	ACH	45 mg at weeks 0, 4, and then every 12 weeks.
	Ustekinumab [61]	1/1	Cymerman RM et al.	Case report	1	ACH	45 mg at months 0, 1, and then every 3 months.
	Ustekinumab [62]	1/1	Adas A et al.	Case report	1	ACH	45 mg at weeks 0, 4, and then 90 mg every 8 weeks.
	Ustekinumab [63]	4/4	Husson B et al.	Retrospective descriptive study	4	ACH	NA
	Ustekinumab [63]	21/30	Husson B et al.	Retrospective descriptive study	30	PPP	NA

Several studies examined the efficacy and safety of ustekinumab in PPPP patients and found that 20 weeks of ustekinumab could completely resolve in PPPP patients [12]. In another study, 7 out of 20 palmoplantar psoriasis patients achieved clinical clearance and the 90 mg dose was more effective than the 45 mg dose [56].

A randomized controlled trial revealed that ustekinumab lacked statistically significant efficacy in PPPP and PPP patients. Furthermore, the study also demonstrated that IL-17A expression in the lesions of PPPP and PPP patients was significantly higher than that of the normal controls [57]. This study indicated that IL-17A may play a more crucial role than dose IL‐12/23 in PPPP and PPP patients. Several case reports revealed that ustekinumab can be used to treat ACH patients who failed to respond to anti-TNF agents [58–62]. Another study found no difference in clinical response to ustekinumab and anti-TNF agents in PPP or ACH patients [63]. (Table 2).

5. Anti-IL-17A and anti-IL-17RA

Secukinumab is a monoclonal antibody that targets IL‐17A. A phase III, multicenter, open‐label study of GPP used JDA severity index scores of 0–17 to determine the severity of GPP. At 16 weeks, 9 of 12 patients achieved clinical global impression (CGI) ratings of ‘very much improved,’ and 1 achieved ‘much improved.’ All patients had at least one adverse event, but no unexpected safety issues or deaths until the end of the 52‐week period [64]. A 6-year-old patient, with an IL-36RN c.115 + 6 T > C mutation and who had GPP from 40 days after birth, was successfully treated with 150 mg secukinumab (19.2 kg bodyweight) after failure of prior methotrexate, acitretin, cyclosporin A, and anti-TNF-α. Significant pain relief and reduced lesions were seen after the first dose; the skin was completely cleared after the second dose [65]. A 4-year-old GPP patient with an interleukin-36 antagonist deficiency was successfully treated with secukinumab at 75 mg/week [66]. An adolescent male with GPP, who had a homozygous mutation within the IL-36RN gene at position c.115 + 6 T > C, failed to respond to infliximab, adalimumab, ustekinumab, apremilast, and anakinra. Compared with the skin of healthy control, this patient had approximately 25-fold more IL-17A-producing CD4 + T cells. After secukinumab treatment, he achieved rapid and robust clinical and laboratory responses [67]. A study with 159 PPPP patients found that 21 of 79 (26.6%) who received 300 mg secukinumab achieved PPPASI75, 14 of 80 (17.5%) patients who received 150 mg secukinumab therapy achieved PPPASI75, and 11 of 78 (14.1%) patients who received a placebo achieved PPPASI75 at week 16 [68]. Other reports revealed that ACH patients showed significant clinical improvement after treatment with secukinumab [69–71]. (Table 3)

Table 3. Overview of anti- IL-17A and anti-IL-17RA for pustular psoriasis.

Target	Drug	Improvement	Publication	Trial/Phase	Study population	Disease	Dosage
IL-17A	Secukinumab [64]	10/12	Imafuku S et al.	III	12	GPP	150 mg at week 0, 1, 2, 3 and 4, and then every 4 weeks. Two non‐responders were up‐titrated to 300 mg.
	Secukinumab [67]	1/1	Cordoro KM et al.	Case report	1	GPP	150 mg at week 0, 1, 2, 3 and 4, and then every 4 weeks.
	Secukinumab [65]	1/1	Ho PH et al.	Case report	1	GPP	150 mg (19.2 kg bodyweight) at week 0, 1, and then every month.
	Secukinumab [66]	1/1	Kostner K et al.	Case report	1	GPP	75 mg every week
	Secukinumab [77]	5/6	Wilsmann-Theis D et al.	Case report	6	GPP	As the dosage of licensed for PV
	Secukinumab [68]	NA	Mrowietz U et al.	IIIb	159	PPPP	300 mg or 150 mg at week 0, 1, 2, 3 and 4, and then every 4 weeks.
	Secukinumab [69]	1/1	Baron JA et al.	Case report	1	ACH	300 mg at week 0, 1, 2, 3 and 4
	Secukinumab [71]	1/1	Galluzzo M et al.	Case report	1	ACH	300 mg at week 0, 1, 2, 3 and 4, and then every month.
	Secukinumab [70]	1/1	Smirnova LM et al.	Case report	1	ACH	300 mg at week 0, 1, 2, 3 and 4, and then every month.
	Ixekizumab [75]	5/5	Saeki H et al.	III	5	GPP	160 mg at week 0, 80 mg every 2 weeks from weeks 2 to 12, 80 mg every 4 weeks from weeks 16 to 52.
	Ixekizumab [77]	1/1	Wilsmann-Theis D et al.	Case report	1	ACH	as the dosage of licensed for PV.
	Ixekizumab [76]	1/1	Miller AC et al.	Case report	1	ACH	80 mg every 2 weeks.
IL-17RA	Brodalumab [72]	11/12	Yamasaki K et al.	III	12	GPP	140 mg at week 0, 1, 2, and then every 2 weeks.
	Brodalumab [73]	0/4	Pinter A et al.	Case report	4	PPPP	210 mg at week 0, 1 and then every 2 weeks.
	Brodalumab [74]	1/1	Milani-Nejad N et al.	Case report	1	ACH	210 mg at week 0, 1 and then every 2 weeks.

Brodalumab is monoclonal antibody that targets human IL‐17‐receptor A (IL‐17RA), which blocks the biological activities of IL‐17. A 52-week, phase III, multicenter, open‐label study in Japan found 9 of 12 (75.0%), 10 of 12 (83.3%) and 11 of 12 (91.7%) GPP patients presented CGI ratings of ‘improved’ or ‘remission’ at week 2, 12 and at 52, respectively. Eleven of 12 GPP patients had adverse events, with nasopharyngitis having the highest incidence [72]. A case series with four PPPP patients showed that PPPP did not respond well to brodalumab [73]. Conversely, another case report demonstrated that 210 mg brodalumab effectively controlled PPPP [74]. (Table 3)

A 52-week, open-label, multicenter, phase III study of ixekizumab (a humanized, anti-IL-17A monoclonal antibody) for treating GPP found that 2 of 5 (40%) and 3 of 5 (60%) patients achieved ‘resolved’ and ‘improved’ global improvement scores ratings, respectively, at week 52. All five patients had at least one adverse event with infection having the highest incidence [75]. An ACH patient treated with ixekizumab achieved a positive response [76]. A study with 7 GPP patients (6 treated with secukinumab, 1 treated with ixekizumab) showed that all patients achieved good or excellent clinical responses. Among six patients who were tested for IL-36RN mutation status, only one had a heterozygous IL-36RN mutation, indicating that IL‐17A antagonists can effectively treat GPP patients without IL-36RN mutations [77] (Table 3). These results suggest that further trials should be planned for patients with pustular psoriasis.

6. Anti-TNFα

Infliximab is chimeric mouse/humanized monoclonal anti-TNFα antibody; adalimumab is a fully human monoclonal antibody. Both can bind to monomeric and trimeric TNFα. Etanercept is a fusion protein that binds to trimeric TNFα and lymphotoxin [78]. The reasons for changing treatment mainly are unsatisfactory response, undesirable side effects and diminished effectiveness over time. Because pustular psoriasis is life-long, these patients may have used many drugs, both systemic and external drugs. For the patients who switched biologic treatment, the mainly failed pre-biologics were also exhibited in this review.

Case reports revealed that etanercept was effective in patients with GPP with or without DITRA and taking 50 mg of etanercept twice weekly was more effective with good efficacy and rapidity of effect [79–87]. Case reports also reported that etanercept can be used in the treatment of GPP induced by systemic glucocorticosteroids [88]. However, a retrospective study found that some patients did not respond to etanercept therapy [89]. A 61-year-old ACH patient achieved significant clinical remission after a 100 mg weekly etanercept therapy, but the lesions reappeared when the dosage was decreased to 50 mg weekly [62]. A 71-year-old ACH patient achieved clinical improvement after taking 50 mg of etanercept twice weekly, but the lesions reappeared after the dosage was decreased to 25 mg twice weekly [90]. Several cases indicated that ACH patients benefitted from etanercept therapy [91–95], While others showed that ACH patients did not respond to etanercept therapy [58,96]. Of 16 GPP patients and 9 ACH patients who received etanercept therapy, 15 and 6 achieved clinical remission, respectively. Thus, the response to etanercept therapy may be dose dependent in GPP and ACH patients. (Table 4)

Table 4. Overview of anti- TNFα for pustular psoriasis.

Target	Drug	Improvement	Publication	Trial/Phase	Study population	Disease	Dosage
TNFα	Etanercept [82]	1/1	Fialova J et al.	Case report	1	GPP	0.4 mg/kg twice weekly
	Etanercept [86]	1/1	Pereira TM et al.	Case report	1	GPP	0.4 mg/kg twice weekly
	Etanercept [87]	1/1	Mazzotta A et al.	Case report	1	GPP	0.4 mg/kg twice weekly
	Etanercept [88]	3/3	Brenner M et al.	Case report	3	GPP	50 mg twice weekly
	Etanercept [80]	6/6	Esposito M et al.	Case report	6	GPP	25 or 50 mg biweekly
	Etanercept [81]	1/1	Lo Schiavo A et al.	Case report	1	GPP	50 mg twice weekly for three months, then 50 mg weekly for three months
	Etanercept [79]	1/1	Kamarashev J et al.	Case report	1	GPP	25 mg twice weekly
	Etanercept [83]	1/1	Cuperus E et al.	Case report	1	GPP	12.5 mg weekly
	Etanercept [84]	1/1	Ricotti C et al.	Case report	1	GPP	50 mg twice weekly
	Etanercept [89]	3/4	Viguier M et al.	Retrospective study	4	GPP	NA
	Etanercept [85]	1/1	Rodriguez-Lomba E et al.	Case report	1	GPP	100 mg weekly
	Etanercept [62]	0/1	Adas A et al.	Case report	1	ACH	100 mg weekly for three months, then 50 mg weekly
	Etanercept [58]	0/1	Saunier J et al.	Case report	1	ACH	50 mg twice weekly
	Etanercept [90]	1/1	Puig L et al.	Case report	1	ACH	50 mg twice weekly, then 25 mg twice weekly
	Etanercept [91]	1/1	Thielen AM et al.	Case report	1	ACH	25 mg twice weekly
	Etanercept [96]	0/1	Adisen E et al.	Case report	1	ACH	25 mg twice weekly for 1 week, then 50 mg twice weekly for 11 weeks.
	Etanercept [92]	1/1	Weisshaar E et al.	Case report	1	ACH	25 mg twice weekly
	Etanercept [93]	1/1	Kazinski K et al.	Case report	1	ACH	NA
	Etanercept [94]	1/1	Bonish B et al.	Case report	1	ACH	NA
	Etanercept [95]	1/1	Silpa-archa N et al.	Case report	1	ACH	NA
	Etanercept [63]	16/31	Husson B et al.	Retrospective descriptive study	31	PPP	NA
	Infliximab [53]	4/4	Matsumoto A et al.	Case report	4	GPP	5–10 mg/kg
	Infliximab [113]	1/1	Pan J et al.	Case report	1	GPP	3.3 mg/kg
	Infliximab [97]	3/3	Routhouska SB et al.	Case report	3	GPP	5–10 mg/kg
	Infliximab [105]	0/1	Kawakami H et al.	Case report	1	GPP	NA
	Infliximab [117]	0/1	Furusawa K et al.	Case report	1	GPP	5 mg/kg
	Infliximab [98]	3/3	Poulalhon N et al.	Case report	3	GPP	5 mg/kg
	Infliximab [114]	1/1	Chen W et al.	Case report	1	GPP	5 mg/kg
	Infliximab [99]	1/1	Adachi A et al.	Case report	1	GPP	5 mg/kg
	Infliximab [100]	1/1	Sugiura K et al.	Case report	1	GPP	5 mg/kg
	Infliximab [115]	1/1	Skrabl-Baumgartner A et al.	Case report	1	GPP	5 mg/kg
	Infliximab [101]	4/4	Trent JT et al.	Case report	4	GPP	5 mg/kg
	Infliximab [102]	1/1	Tang MM et al.	Case report	1	GPP	5 mg/kg
	Infliximab [103]	2/2	Kim HS et al.	Case report	2	GPP	3 mg/kg
	Infliximab [104]	1/1	Smith N et al.	Case report	1	GPP	5 mg/kg
	Infliximab [105]	1/1	Kawakami H et al.	Case report	1	GPP	NA
	Infliximab [106]	1/1	Vieira Serrao V et al.	Case report	1	GPP	NA
	Infliximab [107]	1/1	Chandran NS et al.	Case report	1	GPP	5 mg/kg
	Infliximab [108]	2/2	Weishaupt C et al.	Case report	2	GPP	4–5 mg/kg
	Infliximab [89]	8/10	Viguier M et al.	Case report	10	GPP	NA
	Infliximab [109]	1/1	Sheth N et al.	Case report	1	GPP	5 mg/kg
	Infliximab [110]	1/1	Schmick K et al.	Case report	1	GPP	5 mg/kg
	Infliximab [111]	1/1	Puig L et al.	Case report	1	GPP	5 mg/kg
	Infliximab [116]	1/1	Tsang V et al.	Case report	1	GPP	5 mg/kg
	Infliximab [112]	2/2	Kawakami H et al.	Case report	2	GPP	NA
	Infliximab [118]	1/1	Mang R et al.	Case report	1	ACH	3–4 mg/kg
	Infliximab [119]	1/1	Rubio C et al.	Case report	1	ACH	5 mg/kg
	Infliximab [120]	1/1	Ahmad K et al.	Case report	1	ACH	5 mg/kg
	Infliximab [58]	0/1	Saunier J et al.	Case report	1	ACH	5 mg/kg
	Infliximab [91]	0/1	Thielen AM et al.	Case report	1	ACH	5 mg/Kg at week 0, 2, 6
	Infliximab [63]	17/22	Husson B et al.	Retrospective descriptive study	22	PPP	NA
	Adalimumab [121]	7/10	Morita A et al.	III	10	GPP	80 mg at week 0, and then 40–80 mg every 2 weeks
	Adalimumab [122]	1/1	Gallo E et al.	Case report	1	GPP	80 mg at week 0, 40 mg at week 1, and then 40 mg every 2 weeks
	Adalimumab [123]	1/1	Callen JP et al.	Case report	1	GPP	40 mg every 2 weeks
	Adalimumab [124]	1/1	Zangrilli A et al.	Case report	1	GPP	40 mg weekly
	Adalimumab [126]	1/1	Jordan J et al.	Case report	1	GPP	40 mg at week 0, 1, and then 40 mg every 2 weeks
	Adalimumab [127]	1/1	Gkalpakiotis S et al.	Case report	1	GPP	80 mg at week 0, 40 mg at week 1
	Adalimumab [65]	0/1	Ho PH et al.	Case report	1	GPP	20 mg every 2 weeks
	Adalimumab [53]	4/4	Matsumoto A et al.	Case report	4	GPP	40–80 mg every 2 weeks
	Adalimumab [112]	2/2	Kawakami H et al.	Case report	2	GPP	40–80 mg every 2 weeks
	Adalimumab [89]	3/3	Viguier M et al.	Retrospective study	3	GPP	NA
	Adalimumab [88]	1/1	Brenner M et al.	Case report	1	GPP	80 mg at week 0, and then 40 mg every week
	Adalimumab [125]	1/1	Kimura U et al.	Case report	1	GPP	80 mg at week 0, and then 40 mg every 2 weeks.
	Adalimumab [128]	1/1	Hansel K et al.	Case report	1	GPP	80 mg at week 0, 40 mg at week 1, and then 40 mg every 2 weeks
	Adalimumab [131]	1/1	Dini V et al.	Case report	1	ACH	80 mg at week 0, 40 mg at week 1, and then 40 mg every 2 weeks
	Adalimumab [129]	2/2	Di Costanzo L et al.	Case report	2	ACH	40 mg every 2 weeks
	Adalimumab [130]	1/1	Crowley EL et al.	Case report	1	ACH	80 mg at week 0, and then 40 mg every 2 weeks
	Adalimumab [132]	1/1	Sopkovich JA et al.	Case report	1	ACH	80 mg at week 0, 40 mg at week 1, and then 40 mg every 2 weeks
	Adalimumab [133]	3/3	Ryan C et al.	Case report	3	ACH	40 mg weekly, or 40 mg every 2 weeks
	Adalimumab [90]	1/1	Puig L et al.	Case report	1	ACH	80 mg at week 0, 40 mg at week 1, and then 40 mg every 2 weeks
	Adalimumab [63]	18/35	Husson B et al.	Retrospective descriptive study	35	PPP	NA

GPP patients with or without DITRA can achieve rapid clinical remission after infliximab therapy [97–111], but secondary failure of infliximab therapy can occur during treatment and may be due to anti-infliximab antibody formation [53,112]. The clinical efficacy of infliximab improves as the dose increases [97]. Case reports also showed that infliximab can effectively treat juvenile GPP [113–116]. However, case reports also showed that infliximab was ineffective for treating GPP patients [105,117]. Some cases illustrated the efficacy and safety of infliximab for treating ACH [118–120], while others showed that ACH was refractory to infliximab [58,91]. Of 46 GPP patients and 5 ACH patients who received infliximab therapy, 42 and 3 achieved clinical remission, respectively. (Table 4)

After 16 weeks, 7 of 10 GPP patients who received adalimumab therapy achieved clinical response. Nine patients experienced at least one adverse event, and 2 discontinued the study because of adverse events [121]. A case series revealed that adalimumab can be used in the GPP patients, including those who experienced secondary failure of infliximab therapy and induced by systemic glucocorticosteroids [53,89,112,122–127] . Adalimumab might be used as first-line drug for childhood GPP [128]. However, adalimumab-resistant GPP patients have also been reported [65]. Case reports suggest that adalimumab is a therapeutic option for severe therapy-resistant ACH [58,90,129–133]. Of 23 GPP patients and 9 ACH patients who received infliximab, 19 and 9 achieved clinical remission, respectively. A retrospective descriptive study has demonstrated that clinical improvement was seen in 50% PPP patients who received etanercept, 77.3% PPP patients who received infliximab and 50% PPP patients who received adalimumab [63]. (Table 4)

In summary, anti-TNFα agents can successfully treat GPP, PPP, and ACH. Adalimumab can be used in patients who experienced secondary failure of infliximab or etanercept therapy, also offering the therapeutic option of dose tapering by dose reduction or increase of interval between doses to reduce the risk of drug-exposure and to increase cost-effectiveness [134]. Because most studies are case reports, further phase II and III trials are needed to assess the benefits and adverse effects of anti- TNFα agents.

7. Others

Basiliximab is a monoclonal antibody against IL-2 R. A GPP patient gained marked clinical improvement after basiliximab treatment [135]. Tocilizumab, a humanized monoclonal anti-IL‐6R antibody, was beneficial in the treating of plantar pustular psoriasis [136]. Guselkumab is a human monoclonal anti-IL‐23 antibody. A 52‐week, phase III, multicenter, open‐label study, which included 10 GPP patients, was performed to evaluate the efficacy and safety of guselkumab in treating GPP. Of the nine patients who completed the week‐16 visit, two were ‘very much improved,’ two were ‘much improved,’ and three ‘minimally improved’ according to clinical global impression ratings. Of the 10 patients enrolled, one who had received previous phototherapy developed skin squamous cell carcinoma and dropped out of the study on day 29. The other discontinued the study due to lack of efficacy. The adverse events included nasopharyngitis, nausea, and alopecia [137]. Previous studies have showed that guselkumab can be used in the treatment of PPP. A randomized clinical trial which included 49 patients randomized to receive guselkumab or placebo showed that the mean PPSI total scores were significantly decreased of guselkumab group compared to placebo group at week 16 [138]. Risankizumab is another monoclonal antibody targeting the p19 subunit of IL-23. A phase III trial is ongoing in Japan to evaluate the efficacy and safety of risankizumab in Japanese GPP patients with generalized pustular psoriasis [139]. (Table 5).

Table 5. Overview of other biologics for pustular psoriasis.

Target	Drug	Improvement	Publication	Trial/Phase	Study population	Disease	Dosage
IL-2 R	Basiliximab [135]	1/1	Salim A et al.	Case report	1	GPP	40 mg at day 1 and 4.
IL-6R	Tocilizumab [136]	1/1	Jayasekera P et al.	Case report	1	PPPP	NA
IL-23	Guselkumab [137]	7/9	Sano S et al.	III	9	GPP	50 mg at weeks 0, 4 and then every 8 weeks
	Guselkumab [138]	15/25	Terui T et al.	RCT	25	PPP	200 mg at weeks 0, 4
	Risankizumab [139]	NA	NA	Phase III ongoing	NA	GPP	Identifier: NCT0322045

8. Conclusion

In conclusion, biologics offer excellent clinical effects for refractory pustular psoriasis and long-term response. Despite the encouraging results for pustular psoriasis therapy shown in case reports on the safety and efficacy of biologics, further trials and development of basic studies are needed to guarantee long-term control of pustular psoriasis. As pustular psoriasis presents clinical heterogeneity that is unpredictable and life-long, recruiting a homogeneous subpopulation of patients is difficult. Because pustular psoriasis is life-long, these patients may have used many drugs, both systemic and external drugs; thus, background therapies must be controlled in future clinical trials of biologics for pustular psoriasis.

In addition, there is a publication bias because articles mainly reported positive results of their studies. Studies that focus on the differences in efficacy and safety among biologics are also needed. Serious adverse events have also been reported in previous studies and case reports; therefore, dermatologists should be careful of adverse events during biologic therapy. More long-term studies are needed to clarify the biologic-induced adverse events.

9. Expert opinion

Pustular psoriasis can be classified as either generalized pustular psoriasis (GPP) or localized pustular psoriasis. As a life-threatening disease, GPP patients can present many systemic symptoms such as fever, pain, arthralgia, and fatigue. The therapeutic goals of GPP are to improve skin manifestations and to alleviate systemic symptoms. Localized pustular psoriasis affect mostly hands and feet, and the therapeutic goal is to reducing the disabling symptoms. In localized pustular psoriasis patients, systemic therapies are given to patients who fail to respond to local treatment.

The mutation of IL-36RN in GPP patients has been attracting considering attention.

IL-36RN gene mutations can be found in GPP patients with or without prior PV. Studies have showed that the mutation of IL-36RN is related to GPP, but the results about the relationship between the mutation of IL-36RN and disease severity of GPP were inconsistent.

The biologics, which have used in the treatment of pustular psoriasis, include anti-TNF-α, anti-IL-12/23, anti-IL-17A, anti-IL-17RA, anti-IL-2R, anti-IL-6R, and anti-IL-23. The results of the studies conducted so far with biologics in pustular psoriasis are encouraging. Although many biologics are used for the treatment of pustular psoriasis, certain biological therapy may be better for pustular psoriasis patients. Anti-TNF-α agents are the most available biologics for the treatment of pustular psoriasis. The efficacy of anti-TNF-α agents was dose-dependent and the lesions may reappear after the dosage was decreased. Adalimumab can be used in patients who experienced secondary failure of infliximab or etanercept therapy. Anti-IL-17A agents have proved to be very effective and well tolerated, and infection is the highest incidence. It also has been proved that anti-IL-17A agents can be used in the treatment in children patients with GPP. Anti-IL-12/23 and anti-IL-17A might be considered as the first- or second-line therapy for moderate-to-severe and refractory pustular psoriasis. Anti-IL-17A can be used in the pustular psoriasis patients who failed to respond to anti-TNF-α and anti-IL-12/23 agents. Therapeutic efficacy of biologics in pustular psoriasis might has no association to IL-36RN mutation status.

Although many new biologics have been used in the treatment of pustular psoriasis, there is a lack of large sample, prospective, randomized controlled trials and head-to-head comparison between different biologics. The studies include in our review are mainly limited to uncontrolled studies, retrospective studies, case reports, and case series. Hence, it is different to recommend any of the biologics as the best one for the treatment of pustular psoriasis. Furthermore, patient’s disease feature, previous therapies, comorbidities, and the expectations of treatment should also be taken into consideration.

Article highlights

• Many biologics have been used for the treatment of pustular psoriasis in recent years and the results are encouraging, but long-term safety data are limited.

• IL-36RN gene mutations can be found in GPP patients with or without prior PV. Therapeutic efficacy of biologics in pustular psoriasis might have no association with IL-36RN mutation status.

• Anti-TNF-α agents are the most available biologics for the treatment of pustular psoriasis. The efficacy of anti-TNF-α agents was dose-dependent.

• Switching from one biologic to another has also been shown to be effective.

• More studies are needed to demonstrate the long-term safety and efficacy of biologics in the treatment of pustular psoriasis.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was supported by the National Natural Science Foundation of China (81773331), CAMS Initiative for Innovative Medicine (2017-12M-3-020) and The National Key Research and Development Program of China (2016YFC0901500).