Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.
Generalized pustular psoriasis (GPP) is a chronic, rare skin condition that can be fatal if left untreated. The disease is characterized by sudden flare-ups that cause painful, pus-filled blisters covering significant portions of the body. Skin manifestations are often accompanied by constitutional symptoms, including fever, headache, excessive fatigue, and burning skin sensations.1
Generalized pustular psoriasis is a complex disease that occurs due to a combination of genetic and environmental risk factors. Several genetic mutations have been found to be associated with disease development. In addition, there are many other factors that may exacerbate or trigger GPP, including infections, certain medications, psychological stress, and hypocalcemia.2
Genetic Risk Factors
Several genetic mutations have been linked to pustular forms of psoriasis, though these mutations only account for a small proportion of GPP cases.3
The IL36RN gene encodes the anti-inflammatory interleukin 36 receptor antagonist (IL-36RA). Loss-of-function mutations in IL36RN result in the impairment of IL-36RA and cause hyperactivity of the proinflammatory responses mediated by IL-36. Both homozygous and heterozygous IL36RN mutations have been identified in sporadic and familial cases of GPP. In retrospective studies, IL36RN mutations have been found in 23% to 37% of individuals with GPP. Patients without coexisting plaque psoriasis are considered to have a higher prevalence of these mutations, which have been linked to severe disease and early disease onset.3
A gain-of-function mutation in the CARD14 gene results in overactivation of the proinflammatory nuclear factor κB pathway. CARD14 mutations have been associated with cases of GPP with concurrent psoriasis vulgaris. This may indicate that there are different etiologies for de novo GPP vs GPP in people with a history of psoriasis.3
AP1S3 mutations have also been detected in patients with GPP.2 A loss-of-function mutation in the AP1S3 gene leads to abnormalities in endosomal trafficking and autophagy with enhanced expression of IL-36α.3
Mutations in the MPO gene, which encodes myeloperoxidase, have also been detected as a genetic risk factor for GPP.2
Read more about GPP genetics
Risk Factors Related to Infections
Other common factors that may trigger or worsen GPP include viral and bacterial infections, including those of the upper respiratory tract.2.4 Pustular dermatoses, including GPP and acute generalized exanthematous pustulosis (AGEP), have been linked to viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19) infection. There has been evidence of a connection between COVID-19 infection and a later diagnosis or worsening of GPP, with an average interval of 19 days between infection and the development of pustular eruptions.2.5
Read more about GPP diagnosis
Risk Factors Related to Drug Exposures
The development of GPP secondary to medications is also common, including after lithium administration and withdrawal from steroids.2 There is strong evidence that stopping systemic corticosteroid therapy can trigger GPP. Other systemic medications such as cyclosporine (sold as Gengraf®, Neoral®, and Sandimmune®), Lamisil® (terbinafine), Inderal® (propranolol), Wellbutrin® (bupropion), lithium, phenylbutazone, salicylates, and potassium iodide have also been linked to GPP. When the disease is unstable, improper application of coal tar and dithranol may result in pustulation.4
Read more about GPP therapies
Risk Factors Related to Psychological Stress
Worsening of disease has been noted when patients with GPP are experiencing psychological stress.4
Risk Factors Related to Hypocalcemia
Generalized pustular psoriasis can lead to hypocalcemia, and it has also been observed that hypocalcemia brought on by hypoparathyroidism can activate the disease.4
Read more about GPP complications
Risk Factors Related to Pregnancy
Pregnancy has been implicated as a risk factor for GPP.4,6 Pregnancy-related GPP is also referred to as impetigo herpetiformis. Due to the morbidity it causes for both the mother and the fetus, it has been termed the most serious dermatologic disorder during pregnancy.
It typically presents during the third trimester and resolves after delivery. However, it may recur during the first menstrual period after delivery. As a result of placental insufficiency, there are risks of stillbirth, intrauterine fetal death, and neonatal death.7
Read more about GPP types
Other Risk Factors
According to a recent study, patients who have a history of smoking, obesity, or anxiety disorders appear to be more likely to develop GPP. Given the rarity of GPP, risk increases are minimal in absolute terms.8
- GPP. Boehringer Ingelheim. Accessed May 22, 2023.
- Kuhns L. Generalized pustular psoriasis: clinical updates. Consultant360. May 15, 2023. Accessed May 22, 2023.
- Reynolds KA, Pithadia DJ, Lee EB, Clarey D, Liao W, Wu JJ. Generalized pustular psoriasis: a review of the pathophysiology, clinical manifestations, diagnosis, and treatment. Cutis. 2022;110(2S):19-25. doi:10.12788/cutis.0579
- Mirza HA, Badri T, Kwan E. Generalized pustular psoriasis. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2023. Updated September 12, 2022. Accessed May 22, 2023.
- Goyal PK, Mohammed TO, Mahmoud A, Zaidi AJ, Nguyen CV. COVID-19 infection leading to acute pustular dermatoses. Arch Dermatol Res. 2023;315(4):685-697. doi:10.1007/s00403-022-02450-z
- Choon SE, Lai NM, Mohammad NA, Nanu NM, Tey KE, Chew SF. Clinical profile, morbidity, and outcome of adult-onset generalized pustular psoriasis: analysis of 102 cases seen in a tertiary hospital in Johor, Malaysia. Int J Dermatol. 2014;53(6):676-684. doi:10.1111/ijd.12070
- Hoegler KM, John AM, Handler MZ, Schwartz RA. Generalized pustular psoriasis: a review and update on treatment. J Eur Acad Dermatol Venereol. 2018;32(10):1645-1651. doi:10.1111/jdv.14949
- Mastacouris N, Feda A, Strunk A, Garg A. Risk factors for generalized pustular psoriasis: a case-control study. J Am Acad Dermatol. Published online June 16, 2023. doi:10.1016/j.jaad.2023.06.018
Reviewed by Hasan Avcu, MD, on 5/25/2023.