Generalized Pustular Psoriasis (GPP)

WEDNESDAY, May 1, 2024 -- International consensus has been achieved for the definition and diagnostic criteria for generalized pustular psoriasis (GPP). The consensus statement, issued by the International Psoriasis Council, was published online May 1 in JAMA Dermatology.Siew Eng Choon, M.B.B.S., from Monash University in Johor Bahru, Malaysia, and colleagues developed an international consensus definition and diagnostic criteria for GPP. Based on expert reviews of 64 challenging GPP cases, 43 statements that comprehensively addressed the fundamental aspects of the definitions and diagnostic criteria for GPP were formulated. These statements were presented to a panel of 33 global GPP experts.Consensus was achieved for 53 percent of the statements in the initial Delphi round, leading to the approval of 23 statements, which were then used to develop the proposed definitions and diagnostic criteria for GPP. The final definition was established in the second Delphi round and defined GPP as a "systemic inflammatory disease characterized by cutaneous erythema and macroscopically visible sterile pustules." GPP can occur with or without systemic symptoms, other types of psoriasis, and laboratory abnormalities. Manifestation can be as an acute form with widespread pustules or as a subacute form with an annular phenotype. The essential criterion identified was "macroscopically visible sterile pustules on erythematous base and not restricted to the acral region or within psoriatic plaques.""The resulting definition and diagnostic criteria for GPP are intended to provide a clear and standardized framework for diagnosis, ultimately leading to improved patient care, enhanced epidemiological research, and a better understanding of the disease's impact on affected individuals," the authors write.Several authors disclosed ties to the biopharmaceutical industry.

Final definition is 'systemic inflammatory disease characterized by cutaneous erythema and macroscopically visible sterile pustules'

International Consensus Achieved for Generalized Pustular Psoriasis

<div class="raw-html-embed"><mux-player playback-id="arKVPkl2iEJjuZtsjm00nNwHHs12RIBZCLwyPf9HrrpA" env-key="ENV_KEY" metadata-video-title="LAUNCH ALERT: SPEVIGO approved for expanded indications in China and the US =" "=""></mux-player> </div>James Del Rosso, DO, gives an overview of GPP and discusses the expanded indication for Spevigo, including the use of subcutaneous injections between flares. &nbsp;LAUNCH ALERT: SPEVIGO expanded indications now available in the US&nbsp;The US FDA’s expanded approval makes SPEVIGO the first targeted therapy that addresses the need for acute and chronic treatment for patients with&nbsp;<ul><li>GPP Generalized pustular psoriasis (GPP) is a rare, chronic, heterogenous neutrophilic inflammatory disease associated with skin and systemic symptoms, such as fever, pain, and fatiguei-4&nbsp;</li><li>In China, SPEVIGO’s expanded approval adds the reduction of occurrences of GPP in pediatric patients aged 12 and above weighing ≥40 kg, and adultsii&nbsp;</li><li>The US FDA’s approval expands the use of SPEVIGO to include the treatment of GPP in adults and pediatric patients aged 12 and above weighing ≥40 kg, making it the first targeted therapy that addresses the need for acute and chronic treatment for GPP patientsiii&nbsp;</li><li>SPEVIGO is currently approved in 48 countriesiv&nbsp;</li></ul>The US Food and Drug Administration (FDA) has recently approved SPEVIGO® (spesolimab-sbzo) injection for the treatment of generalized pustular psoriasis (GPP) in adults and pediatric patients aged 12 and above weighing ≥40 kg.5 This approval follows the Chinese National Medical Products Administration’s (NMPA) recent approval of SPEVIGO for the reduction of occurrence of generalized pustular psoriasis (GPP) in adolescents from 12 years of age with a body weight ≥40 kg and adults. SPEVIGO is a novel, humanized selective IgG1 antibody that binds to interleukin-36 receptor (IL-36R), a key part of a signaling pathway within the immune system shown to be involved in the cause of GPP.8-12&nbsp;The regulatory authorities’ decisions are majorly based on the positive results of the Effisayil® 2 clinical trial, a 48-week clinical trial that showed that SPEVIGO significantly reduced the risk of GPP flares by 84%, compared with placebo. In the trial with 123 patients, no flares were observed after week 4 of SPEVIGO subcutaneous treatment in the high-dose group (n=30).13-16 the Effisayil 2 trial, SPEVIGO was associated with an increased incidence (≥9 cases per 100 patient-years) of injection site reaction, urinary tract infection, arthralgia, and pruritus compared to placebo.&nbsp;“Until now, people living with GPP have not had any approved options to treat their disease,” said Bruce Strober, MD, PhD, Clinical Professor, Dermatology, Yale University and Central Connecticut Dermatology. “SPEVIGO has the potential to redefine the treatment options for the patients we serve.”&nbsp;Distinct from plaque psoriasis, GPP is a rare, chronic, heterogenous, inflammatory neutrophilic disease associated with painful skin manifestations and systemic symptoms, such as fever, pain, and fatigue.1–4 GPP varies widely between individuals living with the condition, with symptoms presenting on a continuum, which means that it can present in either a persistent or a relapsing course.2–4 GPP often requires emergency care and can lead to life-threatening complications, such as multi-organ failure and sepsis.v GPP’s unpredictable nature can potentially have significant long-term impacts on quality of life for people living with it, and may cause fear and anxiety over the disease course.3,vi&nbsp;“SPEVIGO’s new approvals constitute a fundamental change for people living with GPP, addressing their huge need for acute and chronic treatment,” said Carinne Brouillon, Member of the Board of Managing Directors and Head of Human Pharma at Boehringer Ingelheim. “Experiencing GPP can be mentally and physically devastating, leaving those affected with uncertainty and fear of the next episode. Therefore, expanding the treatment of GPP is a critical step towards addressing patients’ needs.”&nbsp;With the expanded indication, SPEVIGO is supplied in 150 mg/mL prefilled syringes for subcutaneous use, now available in the US market.&nbsp;About SPEVIGO&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; SPEVIGO is a novel, humanized, selective antibody that specifically blocks the activation of the IL-36R, a signaling pathway within the immune system shown to be involved in the pathogenesis of several autoinflammatory diseases, including GPP.7–11 It is the first targeted therapy for the treatment of GPP and has been evaluated in the largest clinical program specifically for the treatment of patients with GPP.10,vii&nbsp;&nbsp;&nbsp; What is SPEVIGO?&nbsp;&nbsp;&nbsp; SPEVIGO is a prescription medicine used to treat generalized pustular psoriasis (GPP) in adults and children 12 years of age and older who weigh at least 88 pounds (40 kg). It is not known if SPEVIGO is safe and effective in children under 12 years of age or who weigh less than 88 pounds (40 kg).&nbsp;&nbsp;&nbsp; Important Safety Information&nbsp;Do not receive SPEVIGO if you or your child have had a severe or life-threatening allergic reaction to spesolimab-sbzo or any of the ingredients in SPEVIGO.&nbsp;&nbsp; What is the most important information I should know about SPEVIGO? SPEVIGO may cause serious side effects, including:&nbsp;&nbsp;<ul><li>Infections. SPEVIGO may lower the ability of your or your child’s immune system to fight infections and may increase your or your child’s risk of infections. Your healthcare provider should check you or your child for infections and tuberculosis (TB) before starting treatment with SPEVIGO and may treat you or your child for TB before you begin treatment with SPEVIGO if you have a history of TB or have active TB. Your healthcare provider should watch you or your child closely for signs and symptoms of TB during or after treatment with SPEVIGO. Tell your healthcare provider right away if you or your child have an infection or have symptoms of an infection during or after treatment with SPEVIGO, including:&nbsp;<ul><li>fevers, chills, or sweats&nbsp;</li><li>muscle aches&nbsp;</li><li>cough&nbsp;</li><li>shortness of breath&nbsp;</li><li>blood in your phlegm (mucus)&nbsp;</li><li>burning when you urinate&nbsp;</li><li>urinating more often than normal&nbsp;</li></ul></li><li>Allergic reactions and infusion-related reactions. Serious allergic reactions may happen during or after your or your child’s SPEVIGO injection. If you or your child have a serious allergic reaction, your healthcare provider will stop treatment with SPEVIGO. If you or your child are given SPEVIGO in a vein (intravenously) and have an infusion- related reaction, your healthcare provider will stop your or your child’s SPEVIGO infusion and treat your or your child’s symptoms and may restart SPEVIGO at a slower infusion rate. Tell your healthcare provider or get emergency medical help right away if you or your child get any of the following symptoms during or after your or your child’s SPEVIGO injection:&nbsp;<ul><li>feeling faint, dizzy, or lightheaded&nbsp;</li><li>swelling of your face, eyelids, lips, mouth, tongue, or throat&nbsp;</li><li>trouble breathing or throat tightness&nbsp;</li><li>fever&nbsp;</li><li>mouth sores&nbsp;</li><li>chest tightness&nbsp;</li><li>hives or skin rash that is different than the rash from generalized pustular psoriasis (GPP)&nbsp;</li><li>itching swollen lymph nodes&nbsp;</li></ul></li></ul>Before you or your child receive SPEVIGO, tell your healthcare provider about all of your medical conditions, including if you or your child:&nbsp;<ul><li>have an infection that does not go away or that keeps coming back.&nbsp;</li><li>have TB or have been in close contact with someone with TB.&nbsp;</li><li>have recently received or are scheduled to receive an immunization (vaccine). You or your child should not receive live vaccines during and for at least 16 weeks after treatment with SPEVIGO. You or your child should be brought up to date with all vaccines before starting SPEVIGO.&nbsp;</li><li>are pregnant or plan to become pregnant. It is not known if SPEVIGO can harm your or your child’s unborn baby.&nbsp;</li><li>are breastfeeding or plan to breastfeed. It is not known if SPEVIGO passes into your breast milk. Talk to your healthcare provider about the best way to feed your or your child’s baby during treatment with SPEVIGO.&nbsp;</li></ul>Tell your healthcare provider about all the medicines you or your child take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; What are the possible side effects of SPEVIGO?&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; The most common side effects of SPEVIGO given in a vein (intravenously) for GPP flare treatment include:&nbsp;<ul><li>feeling tired or weak&nbsp;</li><li>nausea and vomiting&nbsp;</li><li>headache&nbsp;</li><li>itching or itchy bumps&nbsp;</li><li>a collection of blood under the skin at the infusion site or bruising&nbsp;</li><li>urinary tract infection&nbsp;</li></ul>The most common side effects of SPEVIGO when given under the skin (subcutaneously) for treatment of GPP when not experiencing a flare include:&nbsp;<ul><li>redness, pain, swelling, hardening, hives, or warmth at the injection site&nbsp;</li><li>joint pain&nbsp;</li><li>urinary tract infection&nbsp;</li><li>itching&nbsp;</li></ul>These are not all of the possible side effects of SPEVIGO. Call your doctor for medical advice about side effects.&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1‐800‐FDA‐1088.&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Please see full <a target="_blank" rel="noopener noreferrer" href="http://chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https:/content.boehringer-ingelheim.com/DAM/18918a08-b1a0-44f0-8f01-af1e01236719/spevigo-us-pi.pdf">Prescribing Information</a>, <a target="_blank" rel="noopener noreferrer" href="http://chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https:/content.boehringer-ingelheim.com/DAM/6834ee9f-e3bc-4740-8a53-af1e012372f6/spevigo-us-mg.pdf">Medication Guide</a>, and <a target="_blank" rel="noopener noreferrer" href="http://chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https:/content.boehringer-ingelheim.com/DAM/9672fe0e-5d19-4bd6-b12e-b1300120a3ae/spevigo-us-ifu.pdf">Instructions for Use</a>.&nbsp;CL-SPG-100004 03.18.2024&nbsp;About the EFFISAYIL clinical trial program&nbsp;&nbsp;&nbsp;&nbsp; The EFFISAYIL clinical trial program evaluated the largest and broadest population of GPP patients in trials of a therapy specifically targeting the IL-36 pathway for GPP10,18:&nbsp;<ul><li>EFFISAYIL 1: A Phase II study that demonstrated treatment with a single intravenous dose of spesolimab significantly improved signs and symptoms of GPP in patients experiencing a flare, including rapid pustular and skin clearance. These results supported the approval of spesolimab as the first specific treatment for GPP flares in adults in major markets10,viii&nbsp;</li><li>EFFISAYIL 2: A Phase IIb study that showed spesolimab significantly reduced the risk of GPP flares by 84% over 48 weeks compared to placebo. In the trial with 123 patients, no flares were observed after week 4 of spesolimab SC treatment in the high-dose group (n=30)12–15</li><li>EFFISAYIL ON: An open-label extension study to evaluate the long-term safety and efficacy of spesolimab in patients with GPP who have completed previous spesolimab trialsix&nbsp;</li></ul>About generalized pustular psoriasis (GPP)&nbsp;&nbsp;&nbsp;&nbsp; GPP is a chronic, heterogenous, neutrophilic inflammatory disease associated with skin and systemic symptoms that is distinct from plaque psoriasis. GPP is recognized as a separate clinical entity from other forms of psoriasis, with the IL-36 pathway being a key driver of GPP and triggering response to treatment.1 Prevalence of GPP is low and varies considerably across geographical regions, ranging from 1.76 to 124 patients per million persons in reports from key countries, including France, Japan, Sweden, and South Korea.2 GPP can become life-threatening (mortality rates ranging from 2% to 16%) due to severe complications, such as multisystem organ failure and sepsis requiring urgent hospital care; many GPP patients also suffer from various comorbidities, which contribute to the ongoing burden for the patient and healthcare systems.2,16,17 GPP symptoms appear unpredictable and present on a continuum, which greatly impacts a patient’s quality of life, and may cause fear and anxiety over the disease course, as well as long-term impacts on quality of life related to work/school, emotional health, social activities, and finances.2-4

The US FDA’s expanded approval makes SPEVIGO the first targeted therapy that addresses the need for acute and chronic treatment for patients with GPP.

LAUNCH ALERT: SPEVIGO expanded indications now available in the US 

Patients with generalized pustular psoriasis (GPP) have increased comorbidity compared with the general population and with patients with psoriasis vulgaris (PV), according to a study published online Oct. 11 in the
 
 Journal of the American Academy of Dermatology
 
 .




 Sofia Löfvendahl, Ph.D., from the Swedish Institute for Health Economics in Lund, Sweden, and colleagues examined the comorbidity profile of GPP compared to the general population and patients with PV using the Swedish National Patient Register. A total of 1,093 GPP cases were identified during 2004 to 2015 and were matched in a 1:3 ratio with PV controls without GPP and in a 1:5 ratio with general population controls. Fifty-three percent of the GPP cases also had PV. A subgroup analysis was conducted including 514 GPP cases without PV and 1,518 corresponding PV controls.




 The researchers found that 70 percent of the GPP cases had any of the selected comorbidities compared with 46 and 63 percent of general population controls and PV controls, respectively. Hypertension, psoriatic arthritis, type 2 diabetes, and hyperlipidemia were the most prevalent conditions in GPP. Compared with both the general population controls and PV controls, GPP cases had significantly higher odds ratios for any of the selected comorbidities. The largest significant differences between GPP cases and general population controls were for allergic contact dermatitis, Crohn disease, non-alcoholic fatty liver disease, nephritic nonhypertensive disease, and obesity. Comparing GPP cases with PV controls, the largest significant differences were seen for hypertensive disease, Crohn disease, chronic renal failure, type 1 and 2 diabetes, peptic ulcer disease, and psoriasis arthritis.




 "The study indicates a higher comorbidity burden in GPP in Sweden compared to both the general population and PV," the authors write.




 The research was funded by AbbVie, Boehringer Ingelheim, Eli Lilly, Janssen Cilag, Leo Pharma, and Novartis.




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Most prevalent conditions in GPP were hypertension, psoriatic arthritis, type 2 diabetes, hyperlipidemia

Comorbidity Burden Higher in Generalized Pustular Psoriasis

The U.S. Food and Drug Administration has approved SPEVIGO (spesolimab-sbzo) as the first treatment option for generalized pustular psoriasis (GPP) flares in adults.




 SPEVIGO is a novel, selective antibody infusion that blocks the activation of the interleukin-36 receptor, which is part of an immune system signaling pathway thought to be involved in the cause of GPP. The approval was based on a 12-week trial in which 53 patients with a GPP flare were treated with SPEVIGO or placebo. After one week, more patients treated with SPEVIGO showed no visible pustules than those treated with placebo (54 versus 6 percent).




 The most common adverse reactions (≥5 percent) reported in patients taking SPEVIGO were asthenia and fatigue, nausea and vomiting, headache, pruritus and prurigo, infusion site hematoma and bruising, and urinary tract infection.




 "GPP flares can greatly impact a patient's life and lead to serious, life-threatening complications," Mark Lebwohl, M.D., lead investigator for the trial, said in a statement. "The approval of SPEVIGO is a turning point for dermatologists and clinicians."




 Approval of SPEVIGO was granted to Boehringer Ingelheim.




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The monoclonal antibody infusion is approved for use in adults

FDA Approves SPEVIGO for Generalized Pustular Psoriasis Flares

There is unmet need for the treatment of generalized pustular psoriasis (GPP) flares, according to a study published online Aug. 10 in
 
 JAMA Dermatology
 
 .




 Carla L. Zema, Ph.D., from Boehringer Ingelheim Pharmaceuticals in Ridgefield, Connecticut, and colleagues used electronic health records from 1,535 patients with GPP to assess flares and treatment.




 The researchers found that compared with patients without flares, patients with flares had a 34 percent higher mean Charlson Comorbidity Index score, were almost three times more likely to have inpatient visits, were more than twice as likely to have emergency department visits, and had higher use of almost all treatment classes. Flares were observed across treatment settings (outpatient, 53 percent; inpatient, 36 percent; emergency department, 9 percent). Topical corticosteroids (35 percent), opioids (21 percent), other oral treatments (e.g., methotrexate, cyclosporine, tacrolimus; 13 percent), and oral corticosteroids (11 percent) were the most common treatments for flares. For almost one-quarter of flare episodes (24 percent), patients had no dermatologic treatment 30 days before, during, or 30 days after the episode.




 "This cohort study suggests that there is significant unmet need for the treatment of GPP and its flares, as evidenced by patients seeking treatment in inpatient and emergency department settings, as well as the lack of advanced treatments," the authors write.




 Several authors disclosed financial ties to the pharmaceutical industry.




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Patients with flares more likely to have inpatient, emergency department visits

Treatment Needs Often Unmet for Generalized Pustular Psoriasis

Closing the Gap in GPP Treatment: Clinical Perspectives on Spesolimab 

In this episode of Topical Conversations, Brad P. Glick, DO, MPH, and Aaron Farberg, MD, explore the advancements in treating generalized pustular psoriasis (GPP) with the introduction of subcutaneous spesolimab. They discuss the chronic nature of GPP, the trial data that led to the drug’s approval, and its significant impact on the treatment landscape and patient experience.&nbsp;A targeted agent for a challenging condition&nbsp;The conversation begins with an overview of spesolimab IV, highlighting its significance as the first FDA-approved systemic therapeutic agent for acute GPP flares. They discuss the challenges in managing this chronic, heterogeneous condition, which previously lacked specific therapeutic options, noting that spesolimab now provides a targeted treatment for the quiescent yet active phases of the disease.&nbsp;Addressing the educational gap and increased GPP awarenessDr Farberg notes that he anticipates an increase in GPP diagnosis and treatment as awareness and education improve. He stresses the importance of having an effective, approved medication for GPP, noting the substantial impact compared to older, less targeted treatments. He also discusses the recent approval of subcutaneous spesolimab, which offers a new dosing option for sustained disease management between flares.&nbsp;Clinical insights on GPP management&nbsp;Dr Glick shares his clinical experiences managing GPP, particularly in acute settings such as hospitals and emergency rooms. He underscores the IL-36 pathway’s pivotal role in GPP pathogenesis and how spesolimab effectively targets this pathway. He highlights the transition from IV dosing in acute flares to subcutaneous dosing for ongoing disease control, enhancing long-term patient outcomes.&nbsp;Effisayil-2 data: chronic GPP treatment insights&nbsp;The conversation then addresses the Effisayil-2 trial data, a randomised, placebo-controlled, dose-finding phase 2b trial that assessed the efficacy and safety of spesolimab for GPP flare prevention. The study identified a higher dose every 4 weeks as most effective in preventing flares and maintaining disease control. This dosing regimen, which kept about 90% of subjects clear at 48 weeks, offers a promising long-term management strategy for this often unpredictable disease.&nbsp;Comparing IV and subcutaneous dosing&nbsp;Addressing a common clinical question, Drs Glick and Farberg discuss the differing roles of IV and subcutaneous spesolimab and whether subcutaneous dosing can be used in place of intravenous. The subcutaneous dose is 150 mg, while the IV dose is 900 mg; achieving the same bioavailability with subcutaneous dosing would require a high number of injections, highlighting the distinct roles of each. Dr Farberg recommends the IV version for acute flares due to its higher dosage and rapid effect. Dr Glick concurs, noting that patients with acute GPP require aggressive treatment, whereas subcutaneous dosing is ideal for maintaining stability between flares.&nbsp;The necessity of ongoing GPP management and flare prevention&nbsp;Dr Farberg emphasizes the importance of treating the chronic aspects of GPP to prevent flares, which significantly impact patients’ quality of life. The Effisayil-2 trial supports proactive management to mitigate these severe episodes and improve long-term outcomes.&nbsp;Safety and efficacy of subcutaneous spesolimab&nbsp;The doctors review safety and efficacy data from the Effisayil-1 and Effisayil-2 trials. While some patients experienced fatigue, infections, flu-like symptoms, and injection site reactions with the IV drug, the subcutaneous dosing showed fewer side effects, with some urinary tract infections being the most notable.&nbsp;Quality of life improvements&nbsp;The stable dosing regimen of subcutaneous spesolimab greatly enhances the quality of life for patients, their families, and caregivers. It simplifies the treatment process, making disease management more feasible and maintaining almost clear or clear conditions. This underscores the importance of having both IV and subcutaneous options, providing flexibility and comprehensive care for patients with GPP.&nbsp;Drs Glick and Farberg conclude that the availability of both IV and subcutaneous spesolimab marks a significant advancement in GPP management. These therapies not only improve patient outcomes but also enhance the overall treatment experience, offering improved quality of life for those affected by this challenging condition.

Personalized Care in GPP: From Flares to Maintenance  

In this episode of Topical Conversations, Jason Hawkes, MD, MS, and Saakshi Khattri, MD, discuss the complexities of generalized pustular psoriasis (GPP) and how the treatment landscape has changed with the approval of a novel targeted therapy that treats acute flares through intravenous administration and ongoing symptoms via maintenance therapy with subcutaneous injections, effectively managing the chronic manifestations of the condition.&nbsp;Clinical presentation of a challenging condition&nbsp;The conversation begins with an overview of GPP, highlighting its clinical presentation with sterile pustules on an erythematous background and its sudden onset. Historically, GPP has been rare and often difficult to diagnose, sometimes being mistaken for other conditions. Dr Khattri adds to this by discussing the inflammatory nature of GPP, its symptoms including pain, itching, and systemic involvement, and its distinction from plaque psoriasis.&nbsp;A distinct mechanism of disease&nbsp;The conversation then addresses the immunological differences between GPP and plaque psoriasis. Dr Hawkes explains that while plaque psoriasis is primarily driven by cytokines IL-23 and IL-17, GPP is driven by IL-36, leading to keratinocyte proliferation and recruitment of neutrophils. This distinction is crucial as it affects treatment approaches, with traditional psoriasis treatments often ineffective for GPP.&nbsp;Emergence of a novel therapy&nbsp;They discuss the challenges in managing GPP before the approval of the targeted therapy spesolimab, an IL-36 receptor antibody. Historically, treatment options were limited, and management relied on adapting treatments for plaque psoriasis.&nbsp;Dr Hawkes highlights the complexity of GPP management, noting the overlap with plaque psoriasis and the need for personalized care. He emphasizes the significance of having targeted treatments like spesolimab, which can effectively address the underlying immune pathways driving GPP.&nbsp;The patient experience and counseling tips&nbsp;Dr Khattri shares her experience using spesolimab in practice, sharing the case of a patient who she transitioned from intravenous spesolimab to subcutaneous injections to manage the patient’s ongoing symptoms beyond flares.&nbsp;She also shares how she manages patient expectations on the treatment and course of GPP, comparing it to hypertension in that it requires maintenance therapy to keep symptoms under control. She emphasizes that while flares are a significant aspect of the disease, they are just one part of the overall picture.&nbsp;Full-spectrum management of GPP&nbsp;Finally, they discuss practical tips for managing GPP, with Dr Khattri emphasizing the importance of recognizing it as a treatable condition now with the availability of an approved medication. She advises colleagues to consider spesolimab for both acute flares and maintenance therapy, reflecting on the positive impact of having both intravenous and subcutaneous treatment options for patients with GPP.

Transformative Therapy for GPP: From Flares to Maintenance  

In this installment of Topical Conversations, Mark Lebwohl, MD, and Boni Elewski, MD, discuss spesolimab, the first FDA-approved treatment for generalized pustular psoriasis (GPP). Dr Elewski <a target="_blank" rel="noopener noreferrer" href="https://dermsquared.com/case-studies/rash-decisions-life-saving-treatment-rapid-eruption-pustules">recounts the case</a> of a patient who experienced a severe GPP flare after receiving systemic steroids and experienced rapid improvement after a single intravenous infusion of spesolimab 900 mg along with triamcinolone 0.1% ointment and hydrocortisone 1% cream. Spesolimab, an IL-36 receptor antagonist, initially approved for the treatment of GPP flares, has now also received<a target="_blank" rel="noopener noreferrer" href="https://dermsquared.com/news-research/launch-alert-spevigo-exp-indications"> an expanded subcutaneous indication</a> for maintenance therapy, recognizing that <a target="_blank" rel="noopener noreferrer" href="https://dermsquared.com/videos/topical-conversations/understanding-chronic-nature-gpp">the chronic nature of GPP</a> requires continuous management beyond just reactive treatment for flares. This expansion was majorly based on results from the Effisayil 2 clinical trial, a 48-week clinical trial that showed that spesolimab significantly reduced the risk of GPP flares by 84%, compared with placebo. In the trial with 123 patients, no flares were observed after week 4 of spesolimab subcutaneous treatment in the high-dose group (n=30).

Beyond the Flare: Understanding the Chronic Nature of GPP

In this episode of Topical Conversations, Raj Chovatiya, MD, PhD, and Laura Ferris, MD, PhD, explore the complexities of generalized pustular psoriasis (GPP), highlighting its chronic nature and the challenges it poses for both patients and providers. They stress the importance of recognizing and treating GPP not just during acute flares but throughout its chronic course.&nbsp;Longitudinal disease activity and the patient-provider disconnect&nbsp;Dr Chovatiya emphasizes that while some patients with GPP may present for the first time in the hospital with severe flares requiring intensive care, many others experience longitudinal activity with symptoms that persist over time. These patients may have less severe manifestations, such as scaly or pustular lesions covering only a small percentage of their body surface area. There exists a disconnect between patients and HCPs, with patients often downplaying their chronic symptoms and HCPs underestimating the severity of the disease unless it presents in its most extreme form.&nbsp;Continuous management and between-flare challenges&nbsp;Dr Ferris echoes the sentiment that GPP is a chronic condition that requires continuous management. She emphasizes 2 key aspects of care: preventing flares and addressing the symptoms that persist between flares. Despite not reaching the severity seen during hospitalization, patients still endure discomfort and impairment in their day-to-day lives. However, historically there has been a lack of effective treatment options for managing these in-between symptoms.&nbsp;A comprehensive approach to GPP management&nbsp;Dr Chovatiya advocates for a comprehensive approach to managing GPP, consisting of 3 steps: treating acute flares, preventing future flares, and providing ongoing control to minimize disease activity over time. By adopting this strategy, the goal is to achieve long-term disease remission or low disease activity. He also suggests that GPP may be more prevalent than commonly thought, emphasizing the need for improved diagnostic accuracy and targeted therapies.&nbsp;Future directions&nbsp;Both physicians acknowledge the current limitations in accurately diagnosing and effectively treating GPP, particularly during periods of low disease activity. They advocate for the development of more targeted therapies that address the underlying mechanisms of the disease to better manage patients' symptoms and improve their quality of life. Ultimately, their discussion underscores the importance of recognizing GPP as a chronic condition that requires continuous monitoring and intervention to minimize its impact on patients.

Therapeutic Pearls

Hi. I am very pleased to be speaking today on therapeutic pearls, and we will be discussing a lot of off label uses of medications that we have. Some of them are new medications like spicolamab, which is approved for generalized pustural psoriasis and dramatically effective for that. It also happens to be dramatically effective for pyodem. We're now doing a trial of spicymab for pyodermagangrenosum, but many other medications, for example, jack inhibitors. We had a patient with coudisab linear morphea on the forehead in just weeks of a topical jack inhibitor, ruxolitinib cream that resolved, and many other off label uses of oral jack inhibitors for conditions other than ones for which they are improved. I'm also going to discuss the use of bixaratine for Darier's disease. Dramatically effective. And also going to look at the use of ducravacitinib, a new treatment, oral treatment that we have for psoriasis, again, quite effective for psoriasis, but we have used it in combination with other biologic treatments for psoriasis is for patients who don't respond to either and respond to the combination. So you'll be hearing about a lot of new things from me.

What is the mechanism of action of spesolimab?

You. And this is unique for us in dermatology and for those of us who treat generalized pusturiasis. So what we know is that it works by inhibiting the inflammatory signaling pathway of interleukin 36, which we know is often overexpressed and hyperaband and overactive in individuals with generalized pustural psoriasis. I would add that not only are we treating potentially an individual who is susceptible and has hyperabarant interleukin 36, but there are those with a loss of function mutation of the Il 36 Ra or the receptor antagonist, when they have that genetic mutation, that they, too, are susceptible to hyperabarant IL 36. And that is just another part of the mechanism and the need for this, this targeted therapy in spazolab.

What is the recommended dosing regimen for spesolimab?

You? Well, it's 900 milligrams by intravenous infusion over 90 minutes, and that's one time. Now, I will comment that if there is not a desired response, and I can tell you from my experience, having used this agent and from what I know from my colleagues around the country that are using it, the response is typically rapid, and we may talk about that in a couple of minutes. But I will say that if the desired response is not achieved in the first week, a second dose of 900 milligrams intravenously can be utilized. If symptoms and signs persist, I do want to mention that the drug has to be diluted. It does come in a 450 milligram per 7.5 millimeter solution. So it's going to be utilized in two doses to create eight the 900 milligrams. And then again, it's a slow infusion, as I mentioned, and we typically not going to instill this into a second infusion site the second time. And what I mean by that is no other drug should be used parallel with this therapy, and that's very important.

Can patients treated with spesolimab receive live vaccines? 

You. That's a little bit of a tricky question. The correct answer is no. And we know from the package insert, it specifically states to avoid the use of live vaccines in patients treated with spazolamov. There have not been specific studies for this agent in clinical trials where subjects have recently received live viral or live bacterial vaccines. Now, I do want to point out, and I'll make a caveat here, that this is Brad Glick speaking. It's me as an individual. It's not dermbits, it's not bi the company that makes the company that produces this product. But I want to say that in some cases, this condition can be really health threatening, life threatening with significant potential morbidity and mortality. And so I think in emerging circumstances, if one were to have known that a recent live vaccine was administered, then I don't personally think that Spizolamov should be withheld. And I just wanted to point that out. But the correct answer is no, we really don't know. And live vaccines should not be traditionally administered in the setting of using spizolumov for treating generalized pushular psoriasis.

What spesolimab-associated hypersensitivity reactions should patients be monitored for? 

You? Well, first and foremost, like any systemic therapy, and especially a biologic therapy, like an interleukin 36 inhibitor such as spazolamob, we worry about hypersensitivity reactions in general, allergic reactions, infusion related reactions, which can occur with any monoclonal antibody, including spizolamob. So hypersensitivity reactions in general may include mood, immediate hypersensitivity reactions, like an anaphylaxis, for which we have to be prepared, particularly since this is an infusion or delayed reactions, such as the drug reaction with eosinophilia, and systemic symptoms known as dress. So, in the clinical trials, there actually were two cases of dress which were reported in study FSAL, one in those subjects with GPP who were treated with this agent. Now, it's important to note that there is a regist or an regiscar dress validation scoring system. And what it means is it's either no, it wasn't caused by this agent. Possible, possibly unlikely, but possible, probable and also definite. And so those four categories are what were assessed in this particular clinical trial for these two cases. And it was found that in these two cases, they were reported that it's either no dress or not dress, but no. And also possible dress. And so I think that this gives us pretty good comfort that it may not be related directly to therapy. But I think the most important thing is that we keep an index of suspicion. If a patient develops the signs and symptoms of an anaphylactic or hypersensitivity reaction, we're going to discontinue spizolamob immediately and initiate the proper treatment that we would typically do for supportive care for these patients. But what I also wanted to point out is that sometimes patients will develop what we know is more of a mild or moderate infusion type reaction. And so what we do at that point is stop spizolamob, stop that infusion, consider the appropriate therapy, like hydration and systemic antihistamines, corticosteroids. And then upon resolution of the reaction, the infusion may be restarted, and probably best so at a slower infusion rate.

Which patients are recommended for treatment with spesolimab, and are there any exclusions? 

You. If we look at the clinical trials for spizolamob, the inclusion criteria, first of all started with adult patients and those were 18 years of age, up to 75 years of age. And in terms of inclusions, they had to have new appearance or worsening of their pustules and they needed to have a generalized postulous psoriasis physicians global assess of greater than or equal to three pustules. They also were required to have a GPP, PGA or generalized pustulous psoriasis physicians global assessment postulation subscore of greater than or equal to two. They also were required to have a minimum of 5% body surface area covered with erythema and the presence of what we like to call those monomorphic pustules that we see with patients classically with GPP. Now, what were some of the exclusions? Well, anything that was a drug event triggering postules that look like GPP, such as the so called acute generalized execmatis postulosis, any immediate life threatening GPP, at least for the trials, that was a flare requiring an intensive care unit admission if they had dose escalation of a treatment that we were using previously, like cyclosporin retinoids, methotrexate within two weeks of initiation of the trial, prior to randomization, and in terms of systemic therapy that also includes biologic therapies.

What was the primary endpoint of the Effasayil trial? 

You? Well, the primary endpoint in FSAl one is a generalized pustular psoriasis physicians global assessment postulation subscore of zero. And that was at the end of that first week. And after one infusion in the second trial, there's actually another endpoint that is just simply the time to a GPP flare, just for important information, circumstances.

How quickly can patients see the onset of pustular clearance after a spesolimab infusion? 

You, the speed of this agent is actually pretty rapid and in the general sense, and even to some extent, what we saw in the clinical trials, that over 10% of the subjects in the first, just really 24 hours, had complete clearance of their pustules. And then, as we got between day two and up to about day ten, we had about 30% of the subjects in the clinical trials. And by the end of one week, 23 of over 50 subjects in the clinical trials, and then up to about over 65% of the subjects overall in that first week were actually able to achieve clearance of their posturals overall. So this drug works quite quickly. But I think that what we know, in the clinical sense, and what we've heard from our colleagues around the country, that we can see rapid responses with almost complete clearance in the first 24 hours, and a significant number of individuals in that 1st 48 hours.

The use, tapering, or stopping of which medications can be associated with GPP?

This is actually kind of a complex question, because we know in basic patients that end up with GPP often may have plaque psoriasis in the background, and they may be out in the community, they might receive some IM steroids or some prednisone. And when they withdraw from the prednisone, because they're being treated with steroids, which are really not appropriate for psoriasis patients in general, they may end up with this acute or sometimes a flare or recurrent flares of what we now know as postural psoriasis. So we know one of these agents up that upon withdrawal are certainly corticosteroids. There are other agents, like analgesics, where this has happened, nonsteroidal antiinflammatory drugs, morphine, some antihypertensids, withdrawed patients in rare cases, like remipopril or diltiazam, other antihypertensives. I will also add for the audience that hydroxychloroquine, which we know has been responsible for potentially causing cases of plaque psoriasis or the appearance of plaque psoriasis. We also have seen cases where either upon the initiation of hydroxychloroquine or its withdrawal, we have seen the development of generalized pustular psoriasis. There are also some other interesting scenarios where we see GPP. Now, we mentioned before that an exclusion from the trial was acute generalized ectemicus postulosis, and that is a very different entity. But we have seen circumstances where certain drugs like penicillins, pristinomycin, sulf, anamides, even tribinophene, have caused pushal reactions that make it very tricky. And they are very much GPP, like.

What are some of the biggest challenges in treating GPP?

You. For me, up till now, until we've actually had a therapy to treat generalized postular psoriasis, is, in fact, indeed just that. We've never really had a drug in the toolbox specifically studied in a landmark, double blind, placebo controlled trial where subjects were treated with generalized postular psoriasis. Of course, now we have an agent in spizolama. But the challenges are that, whether it's early on or even when there's severe disease, this condition falls into the category of exfoliative erythroderma, where the skin is red and there may be a whole host of pustules. It's not so easy all the time to separate this from other conditions, whether it be other causes of exfoliative erythroderma, other pustular diseases like acute generalized ecthematis, postulosis, which usually there is a drug that initiates the event. So I think the challenges in general is sometimes the delay in diagnosis, potentially a misdiagnosis, and then, at least until previous, we had a hodgepodge of therapies, retinoids. We've been playing with certain biologic therapies, including tnf inhibitors, il 17 inhibitors, even il 23 inhibitors, and, of course, in the past, agents like methotrexate and cyclosporin. So now we have quite a drug specific therapeutic intervention by interleuking 36 inhibition by using an agent like spizolamol.

What are some lesser-known risk factors of GPP?

You stress, anxiety, and of course, in the setting of pregnancy, we now know that there's a form of generalized posture psoriasis that is also known as impetigo herpetiformis. Really, those are the particular circumstances where we see initiating factors and risk, if you will, of developing postular psoriasis. And I would kind of end that, just kind of piggybacking off of what I said before. Sometimes infectious processes, patients with pneumonia, viral infections, retroviral infections, have developed GPP. Also, patients who have received certain vaccines, such as even the Covid-19 vaccine, have been known to develop generalized pustular psoriasis. And just in general, those individuals with genetic mutations, as I mentioned before, the il 36 receptor antagonists. But those with card 14 or ap 153 deficiencies or genetic mutations more than likely have great risk of developing a generalized postular psoriasis.

What is the clinical presentation of GPP?

The clinical presentation of GPP can be varied. There's two main presentations, one of which is plaque stage psoriasis, and then superimposed on these plaques are multiple monomorphous pustules. Additionally, other patients with GPP can have these pustules on a background of erythroderma, resulting in confluent lakes of us. And these patients oftentimes are very, very sick and require immediate attention and.

What is Generalized Pustular Psoriasis (GPP)?

Generalized pustulous psoriasis, or GPP, is a chronic and often relapsing disease. It's a subvariant of psoriasis vulgaris, and it consists of widespread generalized pustulosis, sometimes superimposed on plaques. Sometimes it can occur on a background of erythroderma. These patients can very sick and require hospitalization, and others often will go and have a chronic relapsing, outpatient sort of presentation.

What are some of the systemic associations of acute GPP?

Now, acute GPP can present with systemic manifestations. It can also be actually without systemic manifestations. But when we see GPP and systemic manifestations, we need to think very carefully, and watch for biochemical hepatitiso there's liver involvement. We could have renal involvement. Patients with generalized GPP can also have fatigue, anorexia, chills, rigors, often looking like an infection. So, we have to be suspicious when we see a patient with these systemic symptoms because those are the patients that do require immediate intervention.<o:p></o:p>

Who is at risk for GPP?

Patients who are at risk for GPP can be really any patient, with or without psoriasis. So, interestingly, some patients will have a new onset of GPP. Classically, however, we see that it tends to be more common in women, and women of ages between 40, 50, 60. It is also more common in patients who have had plaque stage psoriasis in the past. The prevalence runs around 1 in 10,000 individuals.<o:p></o:p>

What are some known triggers of GPP?

The triggers that are associated with GPP are varied. Some of them can be just stress, anxiety, or some that will really provoke a nuanced set of GPP. Other stressors are ones that we really want to be aware of and that's the acute or abrupt withdrawal of systemic steroids. And this can happen very commonly. Other triggers may include infections. They can also include drug reactions, so you want to think about all of those potential entities when we're looking at a patient who has suspected GPP.<o:p></o:p>

What is the pathophysiology of GPP?  

The pathophysiology of GPP is very interesting. It does vary from plaque stage psoriasis. Now all of us are familiar now with the drivers of plaque stage psoriasis. We've learned IL-17, IL-23 can drive psoriasis. But it's a bit different in GPP. In GPP, what we see is extremely high levels of IL-36. IL-36 is an inflammatory cytokine which actually upregulates one of the innate immune response pathways, which then subsequently goes on to generate more IL-17 and IL-23. So, the target cytokine here is IL-36.<o:p></o:p>

How does the pathophysiology in GPP differ from plaque type psoriasis?  

Now since GPP has, as its driver, IL-36, that's a little bit different than our classic plaque psoriasis. When IL-36 is overexpressed it then will bind to the IL-36 receptor, which is on the cell surface of all of our cells and as a consequence of that, they go in and activate this innate pathway which runs through NF Kappa. B. We see elevated levels of IL-36, so you think well, “So what?”, IL-36 drives neutrophil recruitment. Neutrophils come massively and infiltrate into the dermis and the epidermis resulting in pustules. And actually those pustules then go on to become confluent lakes of puss.&nbsp;<o:p></o:p>

When evaluating a patient with suspected GPP, what other entities does one need to exclude?

When you're evaluating a patient with GPP, you have to think about other entities besides GPP. We have to think about infections, that's a common cause of pustulosis. We have to think of pustular drug eruption such as ajab. Those are also very common. Occasionally when you have this common sort of confined GPP, that is, pustules on plaques, we have to think of even folliculitis. So those are common things that should be running through your head when you see a patient who has suspected GPP. Oftentimes a biopsy is the best way to exclude these other entities. As well as a careful history. History can often direct you to the diagnosis of GPP.<o:p></o:p>

What are some of the common laboratory abnormalities associated with GPP?

When you have a patient with GPP, especially those with systemic symptoms and those who are very systemically ill, those with fever, chills, erythroderma, we have to think of other things that can occur and make this disease worse. Comorbidities such as renal insufficiency, liver abnormalities are all associated with the GPP. Additionally, electrolytes can be very much out of whack with GPP, so we do see hypocalcemia very commonly in GPP. We also see, as sort of pathognomonic, a neutrophilia in the blood component. So when you get a CBC with the dip, you'll see an absolute neutrophilia or lymphocytosis and those are little characteristic abnormalities that should direct you more towards GPP than other potential differential diagnosis.<o:p></o:p>

What are treatment options for GPP?

Now the treatment options for GPP have been woefully inadequate until this very past year. In the past, we've used systemic agents such as retinoids, we use cyclosporine, methotrexate. Even we've used in the recent past biologics. These do not adequately capture response with GPP. Currently we have a new agent called spesolimab or brand name Spevigo which has been very useful in treating GPP. In fact, it is fabulous in terms of its rapid response. GPP is run by IL-36. Well spesolimab targets IL-36 receptor gene antagonists and blocks the production of IL-36 which then decreases your neutrophils in the dermis, so we see a rapid clearing with this drug and this is fast going to become the treatment of choice for generalized pustulosis.&nbsp;<o:p></o:p>

What is the safety profile for spesolimab?

The safety profile for spesolimab is actually quite excellent. There are very few things that we have to worry about. There's nothing to monitor pre-treatment other than your monitoring that you're doing for the baseline work-up. When we give spesolimab, we don't have to pretreat with Tylenol, Benadryl or anything like that. It is a very easy treatment - IV over 90 minutes. We can do it as an outpatient or an inpatient. Mainly people may complain a little bit of fatigue, nausea, sometimes a little bit of burning and stinging, but it's really a very, very safe drug and patient patients tolerate it quite well.<o:p></o:p>

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