International Consensus Definition and Diagnostic Criteria for Generalized Pustular Psoriasis From the International Psoriasis Council.

Importance: Generalized pustular psoriasis (GPP) lacks internationally accepted definitions and diagnostic criteria, impeding timely diagnosis and treatment and hindering cross-regional clinical and epidemiological study comparisons. Objective: To develop an international consensus definition and diagnostic criteria for GPP using the modified Delphi method. Evidence Review: The rarity of GPP presents a challenge in acquiring comprehensive published clinical data necessary for developing standardized definition and criteria. Instead of relying on a literature search, 43 statements that comprehensively addressed the fundamental aspects of the definitions and diagnostic criteria for GPP were formulated based on expert reviews of 64 challenging GPP cases. These statements were presented to a panel of 33 global GPP experts for voting, discussion, and refinements in 2 virtual consensus meetings. Consensus during voting was defined as at least 80% agreement; the definition and diagnostic criteria were accepted by all panelists after voting and in-depth discussion. Findings: In the first and second modified Delphi round, 30 (91%) and 25 (76%) experts participated. In the initial Delphi round, consensus was achieved for 53% of the statements, leading to the approval of 23 statements that were utilized to develop the proposed definitions and diagnostic criteria for GPP. During the second Delphi round, the final definition established was, "Generalized Pustular Psoriasis is a systemic inflammatory disease characterized by cutaneous erythema and macroscopically visible sterile pustules." It can occur with or without systemic symptoms, other psoriasis types, and laboratory abnormalities. GPP may manifest as an acute form with widespread pustules or a subacute variant with an annular phenotype. The identified essential criterion was, "Macroscopically visible sterile pustules on erythematous base and not restricted to the acral region or within psoriatic plaques." Conclusions and Relevance: The achievement of international consensus on the definition and diagnostic criteria for GPP underscores the importance of collaboration, innovative methodology, and expert engagement to address rare diseases. Although further validation is needed, these criteria can serve as a reference point for clinicians, researchers, and patients, which may contribute to more accurate diagnosis and improved management of GPP.

Regional differences in the prevalence of generalized pustular psoriasis in Japan.

Generalized pustular psoriasis (GPP), a rare form of psoriasis, is characterized by neutrophil-rich, sterile pustules. In Japan, GPP has intractable and rare disease designation, which allows patients to access support from national and local governments for medical expenses. Previously, similar numbers of patients in Tokyo and Hokkaido have been shown to have GPP designation, despite different population sizes. Here, we determine whether there are regional differences in the proportion of patients receiving GPP designation status in Japan and aim to identify causal factors. In this descriptive, retrospective cohort study, publicly available data were collected on the number of patients with intractable and rare disease designation for GPP in each prefecture and age classification (April 2018-March 2021). Three other designated intractable and rare disease cohorts were included: pemphigus, rare skin diseases, and all diseases. The primary outcome was the standardized morbidity ratio (SMR) of patients at prefecture level (observed numbers divided by expected). Regional differences were compared with the statistical expectation for the total population and age distribution of each prefecture. Regional differences were observed in all cohorts. Overall, 1910 patients had GPP as a designated intractable and rare disease in 2020. Regional differences in SMRs for GPP were observed with high SMRs (≥1.5) in Hokkaido, Tottori, Kagawa, and Miyazaki, and low SMRs (<0.6) in Gunma and Kanagawa. Regional differences in SMRs for GPP did not correlate with the number of medical doctors or dermatologists or internal migration. The number of medical doctors or dermatologists correlated with SMRs in the rare skin diseases and total cohorts. Regional differences in Japan exist in the number of patients with GPP who have an intractable and rare disease designation. Managing rare diseases is an important public health issue, and further research is required to elucidate the factors contributing to these differences.

Factors associated with generalized pustular psoriasis progression among patients with psoriasis vulgaris in Japan: Results from a claims database study.

Of those patients diagnosed with generalized pustular psoriasis (GPP) in Japan, approximately 30% have a prior psoriasis vulgaris (PsV) diagnosis. Therefore, understanding factors associated with a GPP diagnosis is essential for early diagnosis of GPP in patients with PsV. This retrospective cohort study was conducted to identify associated factors for GPP diagnosis in patients with PsV. Eligible patients with two confirmed diagnoses of PsV with/without a confirmed GPP diagnosis (International Classification of Disease 10th revision codes L40.0 and L40.1, respectively) were identified from the Japanese Medical Data Center database (JMDC) (July 1, 2005-January 31, 2019). Weighted logistic regression was used to identify associated factors (based on recorded comorbidities) between the PsV only and PsV with GPP cohorts. Odds ratios (ORs) of ≥1.5, associated with a high probability of a GPP diagnosis, were reported for factors with ≥5 patients/cohort. The time from event to GPP diagnosis was evaluated. The highest associated factor for GPP diagnosis was psoriatic arthritis (OR 20.2, 95% confidence interval [CI] 17.06-23.92, P < 0.0001), which also had the shortest time from event to GPP diagnosis (median 119 days). Other comorbidities associated with GPP diagnosis were other psoriasis, tonsillitis, and sinusitis. Treatments associated with GPP diagnosis included systemic corticosteroids (OR 2.19, 95% CI 1.98-2.43, P < 0.0001; median time from treatment initiation to GPP diagnosis 180 days). Other associated treatments (other immunosuppressants, interleukin [IL]-17 or IL-23 inhibitors, and phototherapy) had a delay of ≥1 year from treatment initiation to GPP diagnosis. Back pain, headache, and fever were also identified as associated with a GPP diagnosis. Patients with PsV requiring systemic therapies are more likely to receive a GPP diagnosis than those not requiring systemic treatment. These data will help identify patients with PsV at high risk of developing GPP and potentially support early GPP diagnosis.

Diversity in the clinical presentation of generalized pustular psoriasis (GPP): A series of case vignettes from around the world.

A key principle of clinical studies and case reports is that they should reflect the demographics and epidemiology of the patient population concerned. Here, we have compiled a diverse group of clinical cases of generalized pustular psoriasis (GPP) to showcase the differences in GPP presentation in patients worldwide. We attempt to capture the broad spectrum of clinical presentations of GPP and showcase the diversity of the patient population. The patients included in this series are diverse in age, genetic background, skin phototype and medical history. Moreover, they present with a variety of clinical courses of GPP and different degrees of systemic involvement, and experience flares triggered by different inciting factors. The key learnings from this case series may support physicians in identifying and managing patients with this rare and multifaceted disease that can affect patients both physically and psychologically.

Multi-institutional feasibility study of intensity-modulated radiotherapy with chemotherapy for locally advanced non-small cell lung cancer.

BACKGROUND: This multi-institutional clinical trial evaluated the feasibility of intensity-modulated radiotherapy (IMRT) for patients with locally advanced non-small cell lung cancer (NSCLC). METHODS: The major inclusion criteria were clinical stage III NSCLC, age 20-74 years, and Eastern Cooperative Oncology Group performance status 0-1. Patients were treated with either cisplatin + S-1 (CS; four cycles every 4 weeks) or carboplatin + paclitaxel (CP; administered weekly with thoracic radiotherapy [RT], plus two consolidation cycles) concurrently with IMRT (60 Gy in 30 fractions). The primary endpoint was a treatment completion rate, defined as at least two cycles of CS or five cycles of CP during IMRT and completing 60 Gy IMRT within 56 days after the start of treatment, assumed its 90% confidence interval exceeds 60%. RT quality assurance was mandatory for all the patients. RESULTS: Twenty-two patients were registered. One patient withdrew due to pulmonary infection before starting treatment. RT plans were reviewed and none was judged as a protocol violation. Grade 2 and 3 pneumonitis occurred in four (19%) and one (5%) patients, respectively. Seventeen patients met the primary endpoint, with a treatment completion rate of 77.3% (90% confidence interval [CI] 58.0%-90.6%). Four patients failed to complete chemotherapy due to chemotherapy-related adverse events, but 20 patients completed IMRT. There were no treatment-related deaths. The 2-year progression-free and overall survival rates were 31.8% (95% CI 17.3%-58.7%) and 77.3% (95% CI 61.6%-96.9%), respectively. CONCLUSION: The treatment completion rate did not meet the primary endpoint, but 20 of 22 patients completed IMRT.

Diagnosis of Generalized Pustular Psoriasis.

Generalized pustular psoriasis (GPP) is a severe rare skin disease characterized by widespread eruption of sterile superficial macroscopic pustules with or without systemic inflammation. Generalized pustular psoriasis flares may lead to life-threatening multiorgan complications, which highlights the need for rapid and accurate diagnosis. However, the rarity of the disease and its heterogeneous cutaneous and extracutaneous symptoms, and the resemblance of symptoms to other skin conditions, pose considerable challenges to the timely diagnosis and treatment of patients with GPP. Current laboratory tests used for GPP diagnosis are generally not GPP specific, and are mainly focused on the assessment of inflammatory markers and clinical and histopathologic features of GPP, and emerging genetic screening approaches. A differential diagnosis to distinguish GPP from other similar conditions requires careful assessment of the patient's skin symptoms, potential disease triggers, medical history, histopathologic features, laboratory tests, and clinical disease course. The comprehensive interpretation of these assessments can be challenging owing to the lack of standardized global guidelines. While there is currently a lack of standardized international guidelines for the diagnosis of GPP, recent advances in our understanding of the genetics and pathogenesis of the disease have provided new opportunities to enhance diagnosis. In the future, defining specific GPP subtypes using genetic and histopathologic strategies will guide therapeutic decisions, allowing patients to achieve their treatment goals without delay. In this article, we provide an overview of the current diagnostic methods, differential diagnostic strategies, and future advances in the diagnosis of GPP, as well as features of GPP variants.