Multistage diagnostic dilemmas in de novo generalized pustular psoriasis- A case report and review of literature

Epidemiology

GPP can affect any age group from infancy to old age; the median age of presentation is around 50 years. There is usually a female preponderance in adults, while the male-to-female ratio in children is 3:2. As per studies from the Western world, prevalence ranges from 1.76 cases to 180 cases per million in France and Italy, respectively, while Japan reported it to be 7.46 per million population.²

Pathophysiology

The exact etiology of GPP is still an enigma; various factors are supposed to trigger the precipitation of pustular psoriasis in a genetically predisposed individual. These triggers, including infections, withdrawal of topical or systemic agents, drugs, topical irritants, hypocalcemia, pregnancy, and stress, are elaborated in Table 1.²

In our case, urinary tract infection or drugs (probably hydroxychloroquine /corticosteroids) are supposed to be the triggers. Recent studies demonstrate the role of IL-36, an innate immune response pathway in GPP. IL-36 belongs to the IL-1 family of cytokines, which includes IL-36 alpha, beta, and gamma subtypes, having intense pro-inflammatory effects on keratinocytes and immune cells.³ IL-36 receptor antagonist regulates the effect of IL-36 cytokines. A mutation in the IL-36RN gene leading to deficiency of IL-36 receptor antagonist (IL-36RA) causes unchecked overexpression of IL-36 cytokines, leading to chemotaxis of abundant neutrophils and hence macroscopically visible pustules. Deficiency of IL-36RA (DITRA) is usually seen in one-third of GPP patients and is commoner in early-onset GPP, which is considered a distinct auto-inflammatory disease mediated by innate immune response.⁴ In addition to IL-36RN mutations, CARD-14, AP1S3, and MPO gene mutations are also implicated in pustular psoriasis.⁵ CARD14 p. Asp176His gain-of-function mutations are present in GPP associated with plaque psoriasis and not with GPP alone.⁶

Relation to psoriasis

Pustulation in GPP may occur over preexisting psoriasis or as de novo disease without previous personal or family history of psoriasis. Plaque psoriasis is caused by hyperactivation of the adaptive immune response of TNF- α /IL-17/IL-22/IL-23 cytokine pathways, while recent studies demonstrated IL-1 and IL-36 innate immune pathways to be primarily involved in pustular psoriasis, leading to activation of chemokines CXCL1, CXCL2, and CXCL8, which are responsible for neutrophilic infiltration.⁷ Expression of IL-36 cytokines and related chemokines is increased by keratinocytes in response to increased levels of IL-1, TNF- α and IL-17A. An abundance of these cytokines, and hence their binding to IL-36RN receptors, leads to autocrine cell signaling and further amplifies IL-36 expression.⁸ This interrelated orchestra of cytokines explains the association of GPP to psoriasis vulgaris; however, the axial role in de novo GPP and early onset GPP is played primarily by sporadic or familial loss-of-function mutation of the IL-36RN gene. Studies have shown that recessive mutations lead to GPP over pre-existing plaque psoriasis, while homozygous or compound heterozygous mutations of the above-mentioned genes lead to de novo GPP. Late onset of disease is explained by multiple hits precipitated by various triggers.⁵

Clinical features

Von Zumbusch type of pustular psoriasis can develop de novo or over preexisting plaque psoriasis. Denovo GPP presents as a sudden onset (within 1 week or less) of burning pain or erythema over the skin before the development of pustules. Pustules initially are discrete, primarily affecting flexures, but later coalesce to form lakes of pus and progressively involve unaffected skin to spread to almost the whole body, leading to erythroderma. In addition to lakes of pus at some places, there may be a circinate pattern or a collarette of scales along with exfoliation at other places. Systemic involvement is associated with GPP in around 24-96% cases in the form of high-grade fever, generalized malaise, loss of appetite, and fatigue. There is an association with HLA-B27 in GPP patients presenting with polyarthritis. Von Zumbusch pustular psoriasis is the most severe form, and even life-threatening complications may occur, including electrolyte imbalance, acute tubular necrosis of the kidney, and sepsis, as seen in our patient. Hypocalcemia may precipitate GPP or may occur in the course of GPP due to associated hypoalbuminemia. Hypoalbuminemia occurs due to leakage of plasma proteins into the interstitial tissues as well as GI malabsorption.⁹ Keratinocytes' hyperproliferation leads to hyperlactatemia.¹⁰ With respect to the present patient with features of sepsis and hyperlactatemia, there was diagnostic confusion with septic shock; however, the mean arterial pressure was maintained without the need for inotropes. Other complications, including cardiovascular shock, fluid retention, aseptic or septic pneumonitis leading to shortness of breath and acute respiratory distress syndrome, can also occur. Mortality in Acute GPP is around 5%, predominantly due to sepsis, multiorgan damage, and disseminated intravascular coagulation.⁵

Mucosal involvement in GPP presents as geographic tongue or fissured tongue. Nail can be involved in the form of pitting, subungual hyperkeratosis, yellowish discoloration, subungual pustules, thickening of the nail plate, onycholysis, onychomadesis, and nail dystrophy.⁵

Clinical course of GPP may vary with relapses & remissions to chronic disease. Prognosis is usually better when associated with a trigger, as seen in GPP of pregnancy or drug-induced.

Laboratory findings

Complete hemogram shows leukocytosis with neutrophilia in 30-70 % cases.⁸ Acute phase reactants like CRP and ESR are usually elevated. Electrolyte imbalance, hypocalcemia, hypoalbuminemia, and hyperlactatemia may be seen. There may be liver and kidney function derangements.

Histopathology

There is intense edema of the epidermis and papillary dermis. Infiltration of neutrophils leads to the formation of spongiform pustules of Kogoj in the stratum spinosum, and micro-Munro abscesses in the stratum corneum, later followed by macroscopic pustule formation. There is acanthosis of the stratum spinosum due to hyperproliferation of keratinocytes. Parakeratosis of the stratum corneum is seen as exfoliation of dried pustules starts.^{5 ,9,10}

Diagnostic criteria and scoring system

Diagnostic criteria proposed by Umezawa et al¹¹ in for GPP are

• (a) Constitutional symptoms–fever, generalized malaise,

• (b) Generalized appearance of aseptic pustules

• (c) Characteristic histopathology with spongiform pustules of Kogoj,

• (d) Leukocytosis, raised ESR, CRP, ASO titers, or hypocalcemia, and

• (e) Recurrences.

Severity assessment of GPP is done with GPPASI, similar to PASI scoring, but replacing induration with postulation. The total GPPASI score is calculated by averaging the scores for erythema, scaling, and pustulation for each body region.¹¹

Differential diagnosis

Due to heterogeneity of presentation, there can be diagnostic difficulty in early cases of GPP where postulation is not clinically evident. The most common differential diagnoses with respect to our case were drug reaction with Eosinophilia and systemic symptoms and /or acute generalized exanthemata’s pustulosis. The patient was on hydroxychloroquine, prednisolone, methotrexate, and on and off NSAIDS for 1 month. There are reports of DRESS/ AGEP secondary to hydroxychloroquine, while NSAIDS are notorious for causing any sort of drug reactions.^12,13 Facial swelling, fever, maculopapular rash initially, and leukocytosis also favored drug reaction. However, Koebner’s phenomenon, triggered by infection or probably drugs (hydroxychloroquine, corticosteroids, or NSAIDS), presence of lakes of pus, nonresponse to corticosteroids, as well as response to acitretin, confirmed GPP. Histopathologically, subcorneal pustules are more spongiform in AGEP as compared to GPP, and eosinophils and necrotic keratinocytes are characteristic features of AGEP. IgA pemphigus is more of a histopathological differential, as clinically it presents as slowly developing, gravitationally demarcated vesiculopustular. Differences between GPP, AGEP, and IgA pemphigus are elaborated in Table 2. Cutaneous candidiasis may also pose diagnostic difficulty clinically in immunocompromised patients, and it can be ruled out by microscopic KOH examination.

Our patient was taking corticosteroids, hydroxychloroquine, and NSAIDs, so GPP, DRESS, and AGEP were still confusing differentials to rule out. There are reports of GPP precipitated by withdrawal of corticosteroids,¹⁴ hydroxychloquine,¹⁵ and NSAIDs.¹⁶ Hydroxytoluene and NSAIDs are also notorious for causing DRESS or AGEP.

Treatment

Hydration and infection control are pivotal in the management of generalized pustular psoriasis. Normal saline compresses and soaks are applied to the skin to maintain hydration, followed by bland emollients after exfoliation starts.⁵ Electrolyte imbalance should be corrected with special emphasis on hypocalcemia and hypoproteinemia. Intake/ output monitoring should be done, promoting oral intake. Repeated pus, urine, and blood cultures need to be sent to rule out secondary infection and should be treated accordingly with parenteral antibiotics. Fungal and viral infections should also be ruled out. Abrupt withdrawal of topical/ systemic corticosteroids and ciclosporins should be avoided.

As per 2018 guidelines published in Japan, oral retinoids are considered the first-line treatment of choice unless contraindicated, as in females of reproductive age.¹⁷

Acetretin is given in a dose of 1mg/kg/day in acute von Zum Busch type of GPP, while 0.5-0.75 mg/kg/day may be given in milder disease or for maintenance purposes. Methotrexate has a slower onset of action; nevertheless, it is successfully used in children or in cases that are nonresponsive to retinoids. Cyclosporin is used for rapid control of the disease with strict monitoring of renal function, electrolytes, and other adverse effects. Ciclosporin is a suitable option for women of reproductive age or during pregnancy. Oral or parenteral corticosteroids are better avoided in acute GPP except in some metabolic complications; however, it remains the treatment of choice in GPP of pregnancy. Primulas are not effective in acute GPP, but there are reports of response in chronic cases.^5,17

Biologics like TNF-α inhibitors and IL-17 inhibitors can be used as second-line therapy. Infliximab is reported to have a rapid onset of action in various case series. Other biologics such as etanercept, adalimumab, certolizumab, Ustekinumab, secukinumab, ixekizumab, and IL-23 inhibitors are also used with favorable results in acute GPP.¹⁸

Spesolimab, a monoclonal antibody against IL-36R, is efficacious in control trials in acute GPP.¹⁶ Another antibody against IL-36 receptor is Imsidolimab in a phase 2 clinical trial for acute GPP.^5,16