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Last updated: 7/11/2024
Years published: 2024
NORD gratefully acknowledges Mark Lebwohl, MD, Dean for Clinical Therapeutics at the Icahn School of Medicine at Mount Sinai and Professor and Chairman Emeritus of the Kimberly and Eric J. Waldman Department of Dermatology at Mount Sinai, for assistance in the preparation of this report.
SUMMARY
Generalized pustular psoriasis (GPP) is a rare type of psoriasis that appears as red patches covered by tiny pustules all over the body. GPP can appear suddenly with severe, more widespread symptoms like fever and malaise, or it can occur more gradually, with less severe symptoms that are mostly limited to the skin. In its worst presentations, GPP can cause body-wide inflammation that can lead to kidney, heart, or respiratory failure. Some cases of GPP occur in patients who already have the more common plaque psoriasis or a certain gene variant, but these factors are not associated with all GPP cases. Although GPP can affect anyone at any age, it is more common in middle age and is slightly more common in females than males.
There are several types and triggers of GPP. Often GPP will arise as a result of the withdrawal of systemic corticosteroids. Other drug triggers of GPP include antimalarials and lithium. In some patients pregnancy is a trigger, and this has been called impetigo herpetiformis. Other patients are genetically predisposed to GPP. Deficiency of the IL-36 receptor antagonist (DITRA) is the most common genetic form of GPP.
Medication that modifies the immune system is often needed in the long-term to control GPP. Most recently, antibodies to the IL-36 receptor have been used successfully to rapidly reverse GPP.
INTRODUCTION
GPP was first described by Leopold von Zumbusch in 1910 after he described a patient with plaque psoriasis who had episodes of pustular eruption over the body in a 20-year period.
Signs and symptoms of GPP vary, but general symptoms include the widespread appearance of pustules and skin redness (erythema). Pustules are white, pus-filled bumps on the skin that are painful. The pustules of GPP are sterile (i.e., not infected with bacteria or viruses and not contagious).
Von Zumbusch (acute GPP): Life-threatening and the most common form; characterized by sudden, painful red patches or plaques and tiny pustules spreading all over the skin within a week, with fever and fatigue
Annular GPP: Common in children; milder than von Zumbusch but can include fever and skin pain; characterized by ring-like lesions with pustules and scales on the edges; spread takes 1 week to 3 months, spreading from the center outward
Other skin signs and symptoms associated with GPP include the formation of scales and dry skin, swelling, redness, pain, itching and sensations of burning.
In acute GPP, Severe forms of GPP can also lead to sepsis, a life-threatening, body-wide (systemic) inflammatory response that can cause kidney, respiratory, or heart failure.
GPP is thought to be linked to a variety of triggers, but some cases of GPP are not associated with any trigger. Some triggers include emotional stress, infections, injuries, certain medications, vaccines, low calcium levels, sunlight, smoking, menstruation and pregnancy.
Infections reported to be associated with the development of GPP are cytomegalovirus, varicella zoster virus (chickenpox and shingles), streptococci infection (strep throat), Epstein-Barr virus (mononucleosis) and SARS-CoV-2 (COVID-19).
Multiple medications have also been linked to the onset of GPP. Discontinuing some drugs that suppress the immune system (taken for reasons other than GPP), like corticosteroids, cyclosporine, ustekinumab and rituximab, can result in the onset of GPP. GPP can also develop or worsen after starting treatment with tumor necrosis factor-ฮฑ (TNF-ฮฑ) and interleukin-17 (IL-17) inhibitors, which are drugs used to treat inflammatory conditions like plaque psoriasis, rheumatoid arthritis and Crohnโs disease. Other medications linked to GPP development include amoxicillin, ceftriaxone and oxacillin (antibiotics), codeine (pain medication) and terbinafine (antifungal medication).
In some people, GPP has been linked to a change (variant) in the IL36RN gene. Normally, this gene blocks inflammatory signals through the production of a certain immune cell known as an IL-36 receptor antagonist; thus, a disease-causing variant in this gene promotes inflammation that can lead to GPP and other skin conditions. GPP patients with a disease-causing IL36RN variant are more likely to develop GPP earlier, including in childhood. Some cases of childhood GPP are associated with autosomal recessive variants in the IL36RN gene known as DITRA syndrome, an inflammatory condition that is also associated with immune deficiency.
Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Patients with GPP who do not have a history of plaque psoriasis and who have symptoms of GPP that affect the mouth are thought to be more likely to have an IL36RN variant. Variants in the CARD14 gene have also been linked to some cases of GPP in children and adults.
The estimated incidence of GPP worldwide is 2 to 7 per million people. GPP can affect anyone at any age, but it is more likely to occur in people aged 40 to 60 years old. Females are slightly more likely to be affected than males.
About 50% of people with GPP also have plaque psoriasis, and about 3% of people with psoriasis develop pustular psoriasis. GPP, however, is only one of two types of pustular psoriasis (the other is localized pustular psoriasis), so the prevalence of GPP in patients with psoriasis is lower than 3%. In people with both plaque psoriasis and GPP, years often pass between the development of plaque psoriasis and then GPP.
GPP flares associated with pregnancy usually occur in the third trimester and clear up after delivery. Most people who develop GPP during pregnancy do not have a history of plaque psoriasis.
A diagnosis of GPP is based on the history of how the rash started, signs and symptoms, and skin biopsy results. The presence of widespread pustules on red skin should increase suspicion for GPP, along with any other signs and symptoms consistent with GPP including skin scales and dryness, swelling, pain, itching, burning sensations, and in cases of acute GPP, systemic symptoms such as fever, fatigue, headaches and body aches.
Findings in the patientโs history that can point to GPP include the rapid appearance of pustules or having recurrent episodes, a history of plaque psoriasis and a history of having taken drugs that are associated with GPP, such as corticosteroids, cyclosporine, ustekinumab, rituximab, TNF-ฮฑ inhibitors, IL-17 inhibitors, codeine, terbinafine and some antibiotics.
Laboratory tests alone do not confirm GPP, but they are useful in supporting the diagnosis and in identifying complications of GPP.
Blood exams in patients with acute GPP may show:
โข Elevated erythrocyte sedimentation rate
โข Increased levels of white blood cells (leukocytosis)
โข Low levels of the white blood cells known as lymphocytes (lymphopenia)
โข Elevated liver enzymes
โข Low levels of the protein albumin (hypoalbuminemia)
โข Elevated antistreptolysin antibodies (made against the bacteria group A Streptococcus which causes strep throat)
โข Low calcium levels (hypocalcemia) and other electrolyte disturbances (Electrolyte abnormalities are thought to be due to disruptions to the skin barrier that occur when the skin starts to peel after pustules have formed.)
Tests on the skin or blood may be used when infections are suspected.
Skin biopsies in patients with GPP are associated with specific findings that help distinguish GPP from other similar skin conditions that cause pustules. The skin changes in patients with GPP that can be seen under the microscope include:
โข Psoriasiform changes in immature keratinocytes (type of skin cell) in the epidermis (uppermost layer of the skin)
โข Presence of neutrophils and spongiform pustules of Kogoj
โข Layers of lymphocytes near blood vessels in the upper dermis (skin layer beneath the epidermis)
It should be noted that skin biopsy is not essential to make a diagnosis of GPP.
Genetic testing for IL36RN gene variants can be performed for GPP patients but is not readily available or commonly done.
At diagnosis, GPP can be classified into one of the four forms based on the presence of systemic symptoms, lesion shape, and whether symptoms come, go, and repeat or are persistent.
Treatment
The treatment of GPP depends on whether the disease is severe or relatively mild. For patients with the severe form of GPP, treatment also varies by whether treatment is for a flare or to maintain long-term remission. For many patients, ongoing treatment is needed to maintain remission and reduce the chance of flares.
When patients with acute GPP (the severe form) are experiencing symptoms for the first time or are having a flare, they may need to be hospitalized if they have abnormal vital signs (i.e., heart rate, blood pressure, breathing rate, temperature), have abnormal fluid and electrolyte levels, or are thought to have a serious infection or organ dysfunction (sepsis).
In cases of GPP caused by a medication, stopping the drug, when possible, is part of treatment.
Specific medications that target the immune system are prescribed for patients with GPP. For patients with acute GPP, intravenous administration of antibodies to the IL-36 receptor has resulted in dramatic and rapid reversal of GPP. The first antibody to the IL-36 receptor approved by the U.S. Food and Drug Administration (FDA) to treat GPP is spesolimab (Spevigo). Spesolimab has been found to be effective even in GPP patients without an IL36RN gene variant that affects inflammatory signals to the IL-36 receptor associated with GPP. Monthly subcutaneous spesolimab has been FDA approved to prevent recurrences of GPP. Intravenous spesolimab is administered for acute flares of GPP on day 1 and again if needed on day 8.
Prior to the development of spesolimab, the initial drugs prescribed to control more severe symptoms included cyclosporine, infliximab, acitretin and anti-IL-17 and anti-IL-23 antibodies. Subcutaneous spesolimab is safer and more effective and is likely to replace these drugs as a treatment for GPP.
Cyclosporine is associated with significant side effects long-term. If patients are given this drug to initially control symptoms, they will have to be switched to another medication for long-term treatment. If taken long-term, cyclosporine can cause high blood pressure, damage the kidneys and can increase the chance for infections or cancer. Acitretin can be rapidly effective for some patients with GPP, but side effects include hair loss, hyperlipidemia and numerous mucocutaneous side effects including chronic inflammation of the lips (cheilitis).
Infliximab, a TNF-ฮฑ inhibitor, has been given as an IV infusion for severe GPP and continued for long-term maintenance once severe symptoms subside. Although safer to be on long-term than cyclosporine, reported potential side effects of infliximab include an increased risk of shingles, cancer, heart failure and diseases that affect the nervous system (demyelinating diseases). Other drugs in the same class as infliximab that have reportedly been successful in treating some cases of GPP are adalimumab, certolizumab and etanercept.
Anti-IL-17, and IL-23 medications (i.e., IL-17and IL-23 inhibitors) are a type of medication known as monoclonal antibodies. They target the IL-17 and IL-23 cytokines, respectively, which can reduce the inflammatory response involved in diseases like GPP. These medications are administered as injections under the skin. IL-17 inhibitors that have been used to treat GPP include secukinumab, ixekizumab, brodalumab and bimekizumab. IL-23 inhibitors for GPP include ustekinumab, tildrakizumab, risankizumab and guselkumab.
For patients with less severe forms of GPP or for patients with severe GPP who need to transition to safer long-term therapy after initial symptoms are under control, the drugs acitretin or methotrexate have been typically prescribed. Acitretin, however, must be cautiously used in people who can get pregnant. Females who take acitretin should not become pregnant for three years after taking acitretin because this medication can cause birth defects. Patients on methotrexate treatment must have their kidney and liver function monitored because this medication can harm these organs. Methotrexate cannot be taken during pregnancy because it can also cause birth defects.
When GPP occurs during pregnancy, treatment options include systemic corticosteroids, cyclosporine, antibiotics and a type of light therapy known as narrow-band ultraviolet B light therapy. Spesolimab has not been tested in pregnancy.
For smaller areas of skin that do not fully respond to the typical medications, topical medications that are placed directly on the affected area can be useful. Topical medications for GPP include topical corticosteroids, topical vitamin D analogs and topical tacrolimus. Other general skin care recommendations for patients with GPP include the use of moisturizing creams, oatmeal baths and wet wraps. Wet wraps involve placing a wet dressing over irritated skin to increase moisture.
An additional therapy for patients once their symptoms have become more stable is psoralen plus ultraviolet (PUVA) photochemotherapy. This type of therapy involves exposing the skin to ultraviolet A light after the patient has taken psoralen either orally or topically. Psoralen is a chemical from plants that makes the skin more sensitive to ultraviolet light. PUVA photochemotherapy reduces activity of immune cells in the skin and reduces the rate of skin cell growth to help clear lesions. This type of treatment involves frequent visits to a clinic per week. Because of its association with the development of skin cancers, and limited data on effectiveness for GPP, PUVA is seldom used.
Other monoclonal antibodies that target the IL-36 receptor, similar to spesolimab, are under investigation for GPP. One of these drugs is imsidolimab, and results are pending.
Other studies are underway to compare the effectiveness of secukinumab and ustekinumab in the treatment of GPP. These studies are also looking at how the presence of gene variants associated with GPP may affect treatment response to these medications.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/
All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Armstrong AW, Elston CA, Elewski BE, et al. Generalized pustular psoriasis: A consensus statement from the National Psoriasis Foundation. J Am Acad Dermatol. 2024;90(4):727-730. doi:10.1016/j.jaad.2023.09.080
Bernardo D, Thaรงi D, Torres T. Spesolimab for the treatment of generalized pustular psoriasis. Drugs. 2024;84(1):45-58. doi:10.1007/s40265-023-01988-0
Morita A, Strober B, Burden AD, et al. Efficacy and safety of subcutaneous spesolimab for the prevention of generalised pustular psoriasis flares (Effisayil 2): an international, multicentre, randomised, placebo-controlled trial. Lancet. 2023;402(10412):1541-1551. doi:10.1016/S0140-6736(23)01378-8
Rivera-Dรญaz R, Daudรฉn E, Carrascosa JM, Cueva P, 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
Choon SE, Navarini AA, Pinter A. Clinical course and characteristics of generalized pustular psoriasis. Am J Clin Dermatol. 2022;23(Suppl 1):21-29. doi:10.1007/s40257-021-00654-z
Bachelez H, Choon SE, Marrakchi S, et al. Trial of spesolimab for generalized pustular psoriasis. N Engl J Med. 2021;385(26):2431-2440. doi:10.1056/NEJMoa2111563
Trivedi MK, Vaughn AR, Murase JE. Pustular psoriasis of pregnancy: current perspectives. Int J Womens Health. 2018;10:109-115. Published 2018 Feb 26. doi:10.2147/IJWH.S125784
INTERNET
Kalb RE. Pustular psoriasis: management. UpToDate. Available at: https://www.uptodate.com/contents/pustular-psoriasis-management?search=generalized+pustular+psoriasis&source=search_result&selectedTitle=1%7E15&usage_type=default&display_rank=1. Accessed June 28, 2024.
Kalb RE. Pustular psoriasis: pathogenesis, clinical manifestations, and diagnosis. UpToDate. Available at: https://www.uptodate.com/contents/pustular-psoriasis-pathogenesis-clinical-manifestations-and-diagnosis?search=generalized%20pustular%20psoriasis&source=search_result&selectedTitle=2%7E15&usage_type=default&display_rank=2. Accessed June 28, 2024.
Shields BE. Approach to the patient with pustular skin lesions. UpToDate. Available at: https://www.uptodate.com/contents/approach-to-the-patient-with-pustular-skin-lesions?search=generalized%20pustular%20psoriasis&source=search_result&selectedTitle=3%7E19&usage_type=default&display_rank=3#H3601742493. Accessed June 28, 2024.
Paller AS, Lund EB. Psoriasis in children: epidemiology, clinical manifestations, and diagnosis. UpToDate. Available at: https://www.uptodate.com/contents/psoriasis-in-children-epidemiology-clinical-manifestations-and-diagnosis?search=generalized%20pustular%20psoriasis&source=search_result&selectedTitle=4%7E19&usage_type=default&display_rank=4. Accessed June 28, 2024.
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