Generalized pustular psoriasis (GPP) is a rare and severe variant of psoriasis characterized by widespread sterile pustules on the skin.1 Despite its distinctive clinical presentation, diagnosis of GPP poses significant challenges for both patients and physicians. The complexities lie in its atypical features, symptoms that overlap with those of other pustular dermatoses, and potentially life-threatening consequences associated with delayed or incorrect diagnosis.
Diagnosing GPP involves meticulously analyzing a patient’s laboratory tests, clinical and histopathologic features, and medical history to effectively differentiate it from other inflammatory skin conditions. Unfortunately, there are no existing international consensus guidelines for the diagnosis of GPP. Many patients embark on lengthy diagnostic odysseys before receiving a correct diagnosis.
Here we aim to explore the challenges in diagnosing GPP and propose strategies to overcome them, with a focus on enhancing clinical acumen and reducing the time to diagnosis.
The Problem With Disease Heterogeneity
One of the primary difficulties in diagnosing GPP stems from its clinical heterogeneity. The varied presentation of pustular eruptions may lead to confusion and misdiagnosis, particularly when distinguishing GPP from conditions such as acute generalized exanthematous pustulosis or drug-induced eruptions.2 The subtle differences in clinical manifestations, combined with the rarity of GPP, necessitate heightened vigilance and expertise among physicians.
GPP shares overlapping features with various systemic diseases, including infections, autoimmune conditions, and other forms of psoriasis. Its diagnosis is also complicated by the absence of pathognomonic signs and symptoms solely indicative of GPP.
Read more on the differential diagnosis of GPP
The rarity of GPP and lack of experience with it among healthcare providers (HCPs) also contribute to the diagnostic delay. In a recent global workshop, 13 dermatologists from 10 countries convened to share their perspectives on the diagnosis and treatment of GPP. It was identified that lack of experience among HCPs is a significant shortcoming globally. Nonspecialists often possess limited knowledge regarding the presentation and pathogenesis of GPP, resulting in frequent misdiagnosis and subsequent delays in referral and treatment.3
In certain countries, where patients typically seek assistance from general practitioners or in emergency departments, GPP is commonly mistaken for an infectious condition. While some dermatologists can proficiently diagnose GPP, their limited understanding of treatment options often necessitates referral to a colleague with greater expertise in GPP management.3
At the organizational level, the identified necessities include the education of emergency department HCPs in recognizing GPP as an autoimmune inflammatory disease, as well as enhancements in communication, collaboration, and clarification of roles within multidisciplinary teams dedicated to supporting patients with GPP.3
At the regulatory level, the prioritized objectives encompass the acquisition of robust clinical trial data, the establishment of clear and consistent treatment guidelines, and the approval of therapeutic interventions for GPP.3
The Long Journey to a Diagnosis
A survey of patients in the US living with GPP was presented at the 2021 European Academy of Dermatology and Venereology (EADV) congress.4 The responses revealed eye-opening experiences that patients encountered and brought to light the journey that many faced to receive a proper diagnosis.5
It was reported that 36% of patients lived with symptoms for months and almost 40% were symptomatic for years before receiving a GPP diagnosis. Unfortunately, approximately 60% of patients were misdiagnosed with another condition (usually an infection) and more than half of patients reported consulting multiple HCPs or specialists before receiving a correct diagnosis.5
Read more on the diagnosis of GPP
Flares during this time (and even after a diagnosis) have repercussions on both physical and mental well-being that permeate various facets of life, encompassing routine activities, education, occupational engagements, and social interactions. The deleterious effects of flares should not be underestimated. As attested by a substantial majority (86%) of surveyed patients, multiple flares occurred within the preceding year, with over three-quarters reporting a moderate to high impact on various aspects of daily functioning. These flares can persist for extended durations, spanning weeks or even months, rendering simple activities such as bathing or venturing outdoors arduous.5
The recent survey also revealed that a majority of participants (71%) have an underlying fear of experiencing flares, while two-thirds of patients expressed anxiety concerning their condition. Notably, emotional stress emerged as a prominent trigger for flares, identified by 83% of respondents surveyed.5
Working Toward a Unified Stance
Consensus among experts on diagnostic criteria for GPP remains elusive. The current discourse surrounding this subject prompted the undertaking of a global Delphi panel study, incorporating the perspectives of 21 distinguished practitioners from diverse continents, with the aim of attaining a unified stance on various disease domains pertaining to GPP. The publication of this study earlier this year was encouraging.6
Despite the panel’s inability to achieve consensus—defined as obtaining an 80% agreement threshold—on several statements, including the recommended diagnostic steps for GPP, the majority of their deliberations resulted in agreement. This noteworthy endeavor constitutes a significant stride toward the formulation of official consensus guidelines for the diagnosis of GPP.
As alluded to earlier, remaining updated on these advancements allows physicians to enhance their diagnostic acumen and shorten the diagnostic journey of many patients with undiagnosed GPP. Prior to the formal release of official guidelines, we can obtain invaluable insights from the perspectives of experts, and integrate this knowledge into our clinical decision-making process.
Where They Agree
Consensus was reached on the definition of GPP as “primary, macroscopically visible pustules of variable size on inflamed skin classically affecting non-acral areas associated with systemic symptoms.” All agreed that “GPP is historically considered a variant of psoriasis but is indeed phenotypically, genetically, immunologically and histopathologically distinct from psoriasis vulgaris/plaque psoriasis.”6
All experts agreed that the Japanese Dermatological Association (JDA) diagnostic criteria can be used to define GPP and that GPP should be suspected in patients with acute onset erythema and pustulosis. Furthermore, a complete and thorough medication history should be conducted and the patient’s medical history (such as a personal history or family history of psoriasis vulgaris or pustular psoriasis) is useful to confirm the diagnosis.6
Lab tests are useful for diagnostic and therapeutic purposes and consensus was reached that leukocytosis with left shift with/without eosinophilia and neutrophilia, elevated erythrocyte sedimentation rate (ESR), elevated C-reactive protein (CRP), decreased albumin, decreased calcium and zinc, high blood urea nitrogen and creatinine (if the patient is oligemic), and elevated liver function enzymes are compatible with a GPP diagnosis.6
Where They Disagree
No consensus was reached on the relevance of certain laboratory tests for the diagnosis of GPP, genetic screening in GPP diagnosis, and certain histopathologic features of the disease.
Read more on GPP testing
The threshold was not reached on the relevance of hypo/hyperkalemia, hyponatremia, and elevated plasma globulins regarding testing blood chemistries in the diagnosis of GPP. Regarding the role of genetic testing in diagnosing GPP, 76% agreed that it should be reserved for research and not for routine clinical practice. Likewise, only 67% of the experts agreed that parakeratosis, acanthosis, hyperkeratosis, elongation of rete ridges, diminished stratum granulosum, and capillary dilation of the papillary dermis are hallmark histopathologic features of GPP.6
What Can We Do in the Meantime?
The experts appear to be on the right track toward achieving consensus diagnostic guidelines; however, the debate is ongoing. The question then becomes, “What can we as physicians do in the meantime?”
While certainly cliché, the best we can do is to improve our familiarity with the distinct clinical characteristics of GPP through regular educational updates. Without established guidelines, we can stay up to date on the evolving landscape surrounding GPP and current expert opinions.
Additionally, paying attention to the patient’s perspective of living with a rare disease allows physicians to develop a deeper understanding of the challenges these patients face. This understanding can lead to more compassionate care, improved patient satisfaction, and better treatment outcomes. Acknowledge the physical, emotional, and social impact of the disease on the patient’s life, and strive to provide comprehensive support tailored to their individual needs. By taking a patient-centered approach, you can make a significant difference in the lives of those living with rare diseases.
We also need to recognize the importance of collaboration with specialists who have extensive experience in treating rare diseases. Seek consultations from experts in the relevant field, as they can offer valuable insights and guidance tailored to the disease in question. Multidisciplinary approaches often yield the best outcomes for patients with rare diseases.
Finally, understand that each patient with a rare disease is unique, and a personalized approach is essential. Tailor treatment plans to address the patient’s specific needs, taking into account factors such as disease severity, comorbidities, and the patient’s preferences and goals. Always consider the impact of the disease on their quality of life and well-being.
References
1. Rivera-Díaz R, Daudén E, Carrascosa JM, Cueva P de la, Puig L. Generalized pustular psoriasis: a review on clinical characteristics, diagnosis, and treatment. Dermatol Ther (Heidelb). 2023;13(3):673-688. doi:10.1007/s13555-022-00881-0
2. Crowley JJ, Pariser DM, Yamauchi PS. A brief guide to pustular psoriasis for primary care providers. Postgrad Med. 2021;133(3):330-344. doi:10.1080/00325481.2020.1831315
3. Strober B, Leman J, Mockenhaupt M, et al. Unmet educational needs and clinical practice gaps in the management of generalized pustular psoriasis: global perspectives from the front line. Dermatol Ther (Heidelb). 2021;12(2):381-393. doi:10.1007/s13555-021-00661-2
4. Bridging the gap in generalized pustular psoriasis. Boehringer Ingelheim. Published September 16, 2021. Accessed June 23, 2023.
5. Reisner DV, Johnsson FD, Kotowsky N, Brunette S, Valdecantos W, Eyerich K. Impact of generalized pustular psoriasis from the perspective of people living with the condition: results of an online survey. Am J Clin Dermatol. 2022;23(Suppl 1):65-71. doi:10.1007/s40257-021-00663-y
6. Puig L, Choon SE, Gottlieb AB, et al. Generalized pustular psoriasis: a global Delphi consensus on clinical course, diagnosis, treatment goals and disease management. J Eur Acad Dermatol Venereol. 2023;37(4):737-752. doi:10.1111/jdv.18851
