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Professor of Dermatology
Department of Dermatology
Tufts University School of Medicine
Alice Gottlieb, MD, PhD: consultant/advisor: AnaptsysBio, Amgen, Avotres Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb Co, Dermavant, Eli Lilly, Janssen, Novartis, Pfizer, Sanofi, Sun Pharmaceutical Industries, UCB; stock options: Xbiotech (for a rheumatoid arthritis program); research (paid to institution): AnapytsysBio, Bristol-Myers Squibb, Janssen, Novartis, Ortho, Sun Pharmaceutical, UCB
Pustular psoriasis (PP) is a rare form of psoriasis that can be classified into 2 types, generalized (GPP) or localized. GPP can be life-threatening and includes acute GPP, impetigo herpetiformis, and infantile juvenile pustular psoriasis. The localized forms—which are not life-threatening—are palmoplantar pustulosis and acrodermatitis continua of Hallopeau (ACH). Both types of PP present with sterile neutrophil-filled pustules on an erythematous or red base and are distinguishable from plaque-type psoriasis clinically, histologically, and genetically. Patients with GPP have a worse quality of life than patients with plaque-type psoriasis due to the severity of their condition and the painful flares.
Differential diagnosis of GPP requires the exclusion of acute generalized exanthematous pustulosis (AGEP) as the clinical course of these conditions differs. AGEP is often triggered by medications and shares a similar histopathology with GPP. Other generalized pustular drug eruptions that must also be excluded are palmoplantar pustulosis, atopic dermatitis with secondary infection, miliaria, contact dermatitis, and bullous tinea.
Sterile pustules that may merge on erythematous skin and neutrophilic subcorneal pustules are characteristic of GPP. In the acute phase, patients can be very sick with systemic symptoms including fever, fatigue, and unstable vital signs (ie, cardiopulmonary or high output cardiac failure) that can be life-threatening. Determining if the clinical and histologic features are recurrent and if they were preceded by psoriasis vulgaris is also helpful to distinguish GPP from other conditions. GPP may be accompanied by psoriasis, arthritis, and ocular symptoms such as uveitis, keratoconjunctivitis, and iritis. If GPP continues long enough without appropriate treatment, secondary amyloidosis can develop.
Distinguishing From AGEP
Since AGEP is usually a drug reaction, obtaining a history of recent drug use (ie, antibiotics including beta-lactams or macrolides; calcium channel blockers; antimalarials) can be very helpful. In AGEP, the onset of pustules is temporarily related to the onset of starting the drugs and is usually 4 days or less. The sterile pustules of AGEP often begin on the face and can spread elsewhere. AGEP can be accompanied by petechiae purpura, erythema multiforme-like lesions with vesicles. However, the histopathology of AGEP differs from GPP with edema of the superficial dermis and eosinophilia of the skin. Vasculitis and necrosis of keratinocytes may also be present.
Laboratory Tests in the Evaluation of GPP
Currently used laboratory tests are not specific for GPP but are helpful for confirmation of the diagnosis: 1) a complete blood count to detect anemia, leukocytosis and lymphopenia; 2) an erythrocyte sedimentation rate, which is elevated; 3) a C-reactive protein (CRP), which is elevated; and 4) blood chemistries to assess liver function and damage, and detect decreased calcium and zinc, which are lost through the skin. Both immunoglobulin (Ig)G and IgA plasma globulins are also elevated. If the kidneys start to fail or the patient is very dehydrated, the blood urea nitrogen and creatinine will be elevated. Urinalysis positive for albumin indicates kidney damage.
To distinguish between atopic dermatitis with bacterial infection, superinfection, and other diagnoses, a smear of the pustule is taken for culture. If sepsis is a concern, blood cultures should be done as well as culturing samples from any suspicious orifices or organs. Serum procalcitonin level and CRP can be helpful as an elevation indicates systemic bacterial infection, but I do not think that it has to be done.
Patients with GPP have an increased prevalence of comorbidities including obesity, hyperlipidemia, diabetes, infections, psoriasis vulgaris, psoriatic arthritis, rheumatoid arthritis, and hypertension. Therefore, it is important to monitor for several conditions including metabolic conditions, thyroid disorders, other autoimmune conditions, malignancies, liver disease, infection, cardiovascular disease, heart attacks, renal insufficiency, acute renal failure, electrolyte disorders, and depression and anxiety. Some comorbidities are directly related to the disease, but I think that some of them are more related to the treatment or to having psoriasis.
The Importance of an Early and Accurate Diagnosis
I think an early and accurate diagnosis is more important in patients with GPP as they tend to come to the ED because they are very sick. They can barely drive, they have trouble standing up, and they are not going to work. They have high fever, pustules all over, their skin hurts, and they are in a lot of pain. They may have unstable vital signs that can lead to high-output cardiac failure. Therefore, early diagnosis and treatment is critical because they can die.
In early September 2022, the US Food and Drug Administration approved spesolimab, a monoclonal antibody directed against the interleukin (IL)-36 receptor, for the treatment of flares in adult patients with GPP. The IL-36 signaling pathway is involved in the pathogenesis of GPP and will be directly targeted with spesolimab. Spesolimab is given intravenously over 90 minutes as a single 900 mg dose. Access is often the problem for many patients with GPP, as they tend to come to the emergency room where the currently used biologic therapies are not readily available. Therefore, in that scenario, I use acitretin and cyclosporine most often. Biologics such as IL-17 and infliximab, a TNF inhibitor, work quickly and quite well, and until very recently were the best treatments that we had available. Patients can do topical management to make them more comfortable, but these patients generally require systemic treatment. Systemic corticosteroids should be avoided because abrupt cessation can trigger GPP.
In general, I am very optimistic about the new IL-36 receptor antagonists and look forward to more education about these new treatments, not only for patients and dermatologists but also for ED physicians, primary care physicians, NPs, PAs, and patients.