1 1 American Journal of Clinical Dermatology 2 Review Article 3 4 Generalized pustular psoriasis: Clinical management and update on autoinflammatory 5 aspects 6 7 Takuya Takeichi, MD, PhD and Masashi Akiyama, MD, PhD 8 9 Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan 10 11 Corresponding Author: 12 Takuya Takeichi, MD, PhD 13 Department of Dermatology, Nagoya University Graduate School of Medicine 14 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan 15 Tel: +81-52-744-2314, Fax: +81-52-744-2318 16 E-mail: [email protected] 17 Masashi Akiyama, MD, PhD 18 E-mail: [email protected] 19 20 Running heading: Review of GPP as autoinflammatory disease 21 22 Compliance with Ethical Standards: 23 Author: Takuya Takeichi 24 Funding sources: JSID’s Fellowship Shiseido Research Grant 2019 to TT. 25 Conflicts of interest: None declared 1 2 26 27 Author: Masashi Akiyama 28 Funding sources: JSID’s Fellowship Shiseido Research Grant 2019 to TT. 29 Conflicts of interest: None declared 30 31 32 Word, table and figure counts: 3,371/6,000 words, 60 references, 4 tables, 1 figure 33 2 3 34 Abstract 35 Generalized pustular psoriasis (GPP) is a chronic, systemic inflammatory disease accompanied 36 by high fever and general malaise. Diffuse erythema and swelling of the extremities occur with 37 multiple sterile pustules all over the body in GPP patients. GPP often relapses over the lifetime 38 and can be life-threatening. Recent discoveries of the underlying molecular genetic basis of 39 many cases of this disorder have provided major advances to clinicians and researchers towards 40 an understanding of the pathomechanism of GPP. However, the therapeutic management of GPP 41 still faces many challenges and much uncertainty, and an evidence-based review summarizing 42 the available clinical data on the management of this heterogeneous disease is needed. The 43 present review addresses challenges regarding the precise clinical diagnosis and evaluation of 44 clinical symptoms in GPP. In addition, we update and briefly summarize the current 45 understanding of molecular pathomechanisms behind GPP as an autoinflammatory keratinization 46 disease. Recent publications have clarified the genetic backgrounds of patients with GPP and 47 ethnic differences in predisposing factors. Although there are ethnic differences in the 48 prevalences of these pathogenic alleles, from the recent reports, at most 60.5% (IL36RN), 5.9% 49 (CARD14) and 10.8% (AP1S3) of GPP patients have the mutations/variations of these genes. All 50 the reported biologics studied seemed effective and relatively safe. Although it is difficult to 51 evaluate therapeutic efficacy from studies on just a few cases, recent findings suggest that 52 biologics can be a useful, powerful tool for controlling skin and systemic inflammation in GPP 53 and for improving the quality of life of GPP patients. 54 55 Key points 56 Generalized pustular psoriasis patients frequently have IL36RN mutations and occasionally have 57 CARD14 or AP1S3 variants/mutations. 3 4 58 Generalized pustular psoriasis cases with IL36RN, CARD14 or AP1S3 mutations/variants are 59 included in autoinflammatory keratinization diseases (AiKD). 60 Biologics are promising treatments for generalized pustular psoriasis. 61 4 5 62 1. Introduction 63 1.1 Background 64 Generalized pustular psoriasis (GPP) is traditionally classified as the most severe form of pustular 65 psoriasis (Table 1), although some reports have proposed that GPP alone can be treated as a distinct 66 etiology because it differs strikingly from psoriasis vulgaris and pustular psoriasis in terms of its 67 clinical, histological and genetic backgrounds [1, 2]. Diffuse erythema and swelling of the 68 extremities occur with multiple sterile pustules all over the body in patients with GPP (Fig. 1a). 69 GPP is a chronic, systemic inflammatory disease accompanied by high fever and general malaise. 70 GPP often relapses over the lifetime, and fatal outcomes have been reported [3]. Various findings 71 indicate that the GPP pathogenesis involves a combination of autoinflammation and T-cell 72 mediated mechanisms, although these mechanisms would not normally seem related and might 73 even seem contradictory [4]. In 2011, IL36RN mutations were reported as causative genetic defects 74 in several GPP cases, suggesting deficiency of the IL-36 receptor antagonist [5, 6]. Moreover, we 75 and another group reported that CARD14 mutations/variants are associated with GPP [7-9]. 76 Proinflammatory genetic variants in CARD14 and APIS3 found in GPP promote NF-κB activation 77 [10]. Thus, discovering the underlying molecular genetic basis of many cases has given clinicians 78 and researchers major advances in their understanding of GPP pathomechanisms. 79 However, the therapeutic management of GPP still faces many challenges and much uncertainty, 80 and an evidence-based review summarizing the available clinical data on the management of this 81 heterogeneous disease is warranted. This review addresses challenges regarding the precise 82 clinical diagnosis and presentation of GPP and the issues surrounding them. We focus on 83 evaluating the short-term and long-term safety, efficacy and tolerability of treatments available for 84 GPP. In addition, we briefly update the current understanding of molecular pathomechanisms 85 behind GPP as an autoinflammatory keratinization disease (AiKD). 86 5 6 87 1.2 Comorbidities of GPP 88 Choon et al. reported 102 Malaysian patients with adult-onset GPP [11]. In their paper, 89 comorbidities of adult-onset GPP included obesity (42.9%), hypertension (25.7%), hyperlipidemia 90 (25.7%) and diabetes mellitus (23.7%) [11]. Additionally, nine cases with ischemic heart disease 91 (8.8%, 9/102) and four with hepatitis B infection (3.9%, 4/102) were reported [11]. Borges-Costa 92 et al. noted that abnormalities in liver enzymes were present in 47% of patients [12]. In a 93 comparison between groups of patients with versus without liver abnormalities, a male 94 preponderance and higher leukocyte counts were found in the former, with a positive correlation 95 between the absolute neutrophil count and total bilirubin also being observed [12]. Although the 96 actual prevalence and long-term outcome of neutrophilic cholangitis is currently unknown in 97 patients with GPP, neutrophilic cholangitis is also known as a complication of GPP [13]. Moreover, 98 around 30% of patients are eventually affected with polyarthritis [14, 15]. In terms of oral lesions, 99 an association between GPP and geographic tongue was identified. A higher prevalence of 100 geographic tongue was reported in both a GPP cohort (83.9%, 47/56) and a family member cohort 101 (47.8%, 32/67), versus the control cohort (0/168) or previous reports (ranging from 0.2 to 14.29%) 102 [16, 17]. The lips may become red and scaly, and superficial ulceration may occur [15]. Although 103 the comprehensive frequencies have not been reported, other possible comorbidities are 104 hypoalbuminemia, hypocalcemia (a consequence of hypoalbuminemia), renal tubular necrosis (as 105 a result of hypovolemia) and secondary infectious diseases. Hypoparathyroidism has also been 106 reported in association with GPP [18, 19]. On other rare occasions, the disease is followed by 107 pulmonary capillary leakage, pulmonary emphysema, jaundice and renal failure [15]. 108 109 110 2. Diagnostic criteria and differential diagnosis 111 2.1 Diagnostic criteria for GPP 6 7 112 Fujita et al. summarized the primary parameters for the diagnosis of GPP in the Japanese 113 therapeutic guidelines for GPP [20]. The four primary features are (i) systemic symptoms (e.g., 114 high fever and fatigue), (ii) systemic or extensive flush accompanied by multiple sterile pustules 115 that sometimes merge to form lakes of pus, (iii) neutrophilic subcorneal pustules 116 histopathologically characterized by Kogoj’s spongiform pustules, and (iv) the repeated recurrence 117 of the above clinical and histological features [20]. They assessed the sensitivity of the four 118 primary features with reference to 41 patients with GPP, as summarized in Table 2. These four 119 primary parameters can be assessed in most dermatology clinics, because no special techniques 120 are required. The current clinical diagnostic parameters for patients with GPP may benefit 121 clinicians when they evaluate patients in the early stage, by enabling accurate diagnostic data that 122 can have immediate clinical relevance to patient diagnosis and management [20]. 123 124 2.2 Diagnostic methods 125 Skin biopsies may show hyperkeratosis with neutrophilic microabscesses in the epidermis (Fig. 126 1b). The formation of subcorneal pustules and spongiform pustules of Kogoj is characteristic of 127 GPP. In addition, neutrophilic and lymphocytic infiltration is often seen in the upper dermis. A 128 combination of the clinical features, histological observations and DNA sequencing of IL36RN, 129 CARD14 and AP1S3 is the best way to establish the diagnosis of GPP. Although there are ethnic 130 differences in the prevalences of these pathogenic alleles, from recent reports, at most 60.5% 131 (IL36RN) [21-25], 5.9% (CARD14) [21] and 10.8% (AP1S3) [21] of GPP patients have the 132 mutations/variations of these genes. 133 134 2.3 Differential diagnoses for GPP 135 Clinically, a number of inflammatory diseases should be excluded for the accurate diagnosis of 136 GPP, and these are described here. 7 8 137 138 2.3.1 Infectious diseases 139