Clinical and genetic characteristics of generalized pustular psoriasis: A retrospective study based on a registry database

To the Editor: Generalized pustular psoriasis (GPP) is a rare, severe inflammatory dermatosis that exhibits significant clinical and genetic heterogeneity which characterized by primary acute widespread sterile pustules or subacute annular variant arising on erythematous skin background. Due to its rarity and complexity, the phenotype and genotype remain under-documented.[1,2] This study aimed to investigate the clinical and genetic profiles of GPP in a large single-center cohort based on flare frequency, IL36RN mutations, psoriasis vulgaris (PsV) history, and age of GPP onset. This study adhered to the Declaration of Helsinki and was approved by the Ethics Committee of Sichuan University West China Hospital (No. 2024-1473). Informed consent was obtained orally via telephone or in writing during face-to-face inquiries. We retrieved clinical data of hospitalized GPP patients from Sichuan University West China Hospital’s electronic medical records system (2008–2024). Two dermatologists reviewed the medical histories and conducted follow-ups to verify and complete the data. A total of 438 unrelated GPP cases met the International Psoriasis Council (IPC) 2024 criteria.[3] Additionally, 91 patients provided blood samples for whole-genome sequencing (WGS) to detect the IL36RN mutation, which encodes the interleukin-36 receptor antagonist protein.[4] Exclusion criteria included cases with pustules limited to acral regions or psoriatic plaques and those reclassified as other pustular dermatoses, such as acute generalized exanthematous pustulosis (AGEP) and subcorneal pustular dermatosis (SPD) [Supplementary Figure 1, https://links.lww.com/CM9/C521]. Categorical variables were described as numbers (%) and analyzed using the Chi-square or Fisher’s exact test. Continuous variables were expressed as mean ± standard deviation (t-test) or median (interquartile range) for non-normal data (Mann–Whitney U test). Analyses were conducted in Python 3.12 (Wilmington, DE, USA). This study included 438 GPP patients (male-to-female ratio, 1.34:1). Among them, 136 (31.1%) had a single flare, while 302 (68.9%) had ≥2 flares. GPP-only cases comprised 195/438 (44.5%), and GPP-PsV cases 243/438 (55.5%). Pediatric-onset GPP (PGPP, onset <18 years old) accounted for 118/438 (26.9%), with 320/438 (73.1%) being adult-onset (AGPP). WGS was performed in 91 (20.8%) patients, of whom 54 (59.3%) carried IL36RN mutations. Additionally, 27 (6.2%) had acrodermatitis continua of Hallopeau (ACH), 14 (3.2%) had palmoplantar pustulosis (PPP), and 64 (14.6%) developed post-GPP erythrodermic psoriasis (EP). Psoriatic arthritis (PsA) and nail involvement were observed in 66 (15.1%) and 170 (38.8%) cases, respectively. Fever was reported in 207 (47.3%) patients, and follow-up confirmed the death of 33 (7.5%) patients [Supplementary Table 1, https://links.lww.com/CM9/C521]. Based on the updated IPC criteria, patients with ≥2 flares had higher rates of GPP-only (57.6% vs. 15.4%, P <0.001), PGPP (34.4% vs. 10.3%, P <0.001), and IL36RN variants (70.1% vs. 29.2%, P = 0.001). They had an earlier onset (29.00 [12.00, 44.00] vs. 43.50 [26.00, 55.00] years, P <0.001) and were more prone to combine with ACH (7.9% vs. 2.2%, P = 0.036), fever (52.0% vs. 36.8%, P = 0.004), and higher armpit temperatures (39.00 [37.10, 39.50]°C vs. 37.80 [36.55, 39.00]°C, P <0.001). No significant differences were found in PsA, nail involvement, comorbidities, or lab tests [Supplementary Table 1, https://links.lww.com/CM9/C521]. Among 91 patients, 54 (59.3%) carried pathogenic IL36RN variants. Biallelic mutations were more common in GPP-only (51.9%) than in GPP-PsV (27.0%), while monoallelic rates were 20.4% and 13.5%, respectively. IL36RN mutations were more frequent in GPP-only than GPP-PsV (72.2% vs. 40.5%, P = 0.005). IL36RN-positive patients had higher rates of ≥2 flares (87% vs. 54.1%, P = 0.001), fissured/geographic tongue (78.8% vs. 19.0%, P <0.001), nail involvement (63% vs. 29.7%, P = 0.004), and earlier onset (22.06 ± 17.47 vs. 34.19 ± 21.71 years, P = 0.004). They also had lower white blood cell (WBC) counts (12.83 ± 4.35 × 109vs. 16.33 ± 7.06 × 109/L, P = 0.03) and antistreptolysin O (ASO) levels (68.98 ± 47.13 vs. 207.00 ± 45.25 IU/mL, P = 0.017). No significant differences were found in PsA, comorbidities, or other GPP-related factors [Supplementary Tables 2 and 3, https://links.lww.com/CM9/C521]. Compared to GPP-PsV, GPP-only had higher rates of ≥2 flares (89.2% vs. 52.7%) and PGPP (46.2% vs. 11.5%) (P <0.001), a higher IL36RN-positive rate (72.2% vs. 40.5%, P = 0.005), and increased incidences of fissured/geographic tongue (65.9% vs. 26.3%, P = 0.01), ACH (11.3% vs. 2.1%), and PPP (6.7% vs. 0.4%) (P <0.001). In contrast, GPP-only had lower rates of hypertension (11.8% vs. 19.3%, P = 0.044), liver (6.7% vs. 19.3%, P <0.001) and renal diseases (15.9% vs. 25.9%, P = 0.015), EP (10.3% vs. 18.1%, P = 0.03), and PsA (8.2% vs. 20.6%, P <0.001). Among those undergoing joint ultrasound, differences were observed in synovitis (10.8% vs. 22.2%, P = 0.002) and tenosynovitis (3.1% vs. 8.6%, P = 0.027) [Supplementary Table 4, https://links.lww.com/CM9/C521]. PGPP had a higher proportion of GPP-only (76.3% vs. 32.8%) and ≥2 flares (88.1% vs. 61.9%) (P <0.001). Allergy history was more prevalent in PGPP (19.5% vs. 10.0%, P = 0.013), who also exhibited lower body mass index (BMI) (38.1% vs. 8.1%, P <0.001), higher temperature (39.00 [37.77, 39.82]°C vs. 38.35 [36.60, 39.40]°C, P = 0.003) and increased platelet counts (378.37 ± 119.98 × 109vs. 311.76 ± 137.52 × 109/L, P = 0.001). AGPP was more likely to develop PP lesions from the limbs (6.8% vs. 31.2%, P <0.001) and had longer hospitalization days (13.50 [10.00, 18.25] vs. 15.00 [11.00, 21.00], P = 0.026). AGPP also showed greater associations with PsA (5.9% vs. 18.4%, P = 0.002), post-GPP EP (8.5% vs. 16.9%, P = 0.04), and nail involvement (28.0% vs. 42.8%, P = 0.007). Multiple comorbidities, including overweight, hypertension, diabetes, fatty liver, autoimmune disorders, liver and kidney involvement, respiratory diseases, and mortality, were more frequent in AGPP. Joint ultrasound revealed higher rates of synovitis, enthesitis, and tenosynovitis. As for nail involvement, nail plate thickening (14.4% vs. 31.6%, P <0.001) and discoloration (16.1% vs. 29.1%, P = 0.008) were more common in AGPP [Supplementary Table 5, https://links.lww.com/CM9/C521]. This retrospective study delineated GPP heterogeneity in China according to flare frequency, IL36RN mutations, PsV history, and onset age, while also providing novel insights into nail and joint involvement via ultrasound. We identified distinct phenotypic differences based on flare frequency. IL36RN was positive in 59.3% of cases, including single-flare patients. Bi-allelic IL36RN variants (41.8%, 38/91) aligned with reported rates (19%–41%), suggesting minimal selection bias.[4,5] Study limitations include a single-center, retrospective design, which may lead to missing data and recall bias. In conclusion, our study broadens the GPP phenotypic spectrum based on flare frequency, genetic background, PsV history, and onset age, offering insights into PsA and nail deformities to aid disease recognition and personalized management. Funding This work was supported by grants from “Whole genome sequencing of 100,000 cases with rare diseases (No. GSRD-100KWCH),” the 135 Project for Disciplines of Excellence, West China Hospital, Sichuan University (No. ZYJC20002); National Natural Science Foundation of China (No. 82304062); the 135 Project for Clinical Research Fund, West China Hospital, Sichuan University (No. 2023HXFH030); Achievement Transformation Demonstration Project of the Key Research and Development (R&D) Program of Science & Technology Department of Chengdu (No. 2023-YF09-00003-SN). Conflicts of interest None.