Indian expert Delphi consensus on the diagnosis and management of flares of generalised pustular psoriasis

Study design

The objective of this Delphi panel study was to achieve consensus on six key domains of GPP: burden of GPP; diagnosis; severity assessment; investigations; treatment initiation, monitoring and escalation; and special populations.

Methodology

Twelve experts in the field of psoriasis agreed to participate in this consensus-building exercise. These experts are from various locations in India, and together provide a representation of all four zones – north, east, west and south – of India. Each of the experts (a) has an experience in the field of dermatology of more than 20 years, (b) has managed multiple patients of GPP, (c) works in a hospital-based (±office-based) setting with a facility to admit patients with GPP and (d) has an interest around psoriasis, as reflected by his/her publications. Based on discussions with each expert, Arun Dahiya & Tomson Toms identified problem areas related to the diagnosis and management of GPP, for which current evidence is absent or limited, and finalised topics/statements, removing duplicates and merging similar topics. This led to a total of 19 statements, which were then reconfirmed with the experts and classified under six domains. Consensus on these topics was assessed using the modified Delphi method, a well-established consensus technique for diseases in which clinical evidence might be insufficient. In round one, each expert was asked to opine on every statement by expressing his/her agreement/disagreement on a Google form (i.e., an asynchronous approach to consensus development). Experts were able to provide additional comments as freetext. Consensus was said to be reached when ≥80% of experts agreed to a statement. After round one, feedback (anonymised responses) was shared with all experts. Statements that reached consensus (i.e. ≥80% agreement) were not revised. Where consensus was not reached, statements were revised and the process of round one was repeated. In case stability in responses was reached (i.e. no change in response in two consecutive rounds), the Delphi iterations were closed.

Domain 1: Burden of GPP

GPP was first described by Leopold von Zumbusch in 1910 as a severe form of psoriasis.² However, it is now recognised as clinically, pathophysiologically and genetically distinct from plaque psoriasis.²

Traditionally, psoriasis comprised of both erythrosquamous and pustular lesions. These are distinct both clinically and histologically. More than 50% of patients with GPP can have concurrent or a previous history of plaque psoriasis.⁴ This may lead to an assumption that primary pustular conditions (e.g. GPP) are part of the psoriasis spectrum. However, primary pustules do not form part of the psoriasis spectrum except when pustules arise within or at the edge of plaques, and this should not be considered pustular psoriasis. In contrast,pustules are the primary lesions in GPP.¹⁵

GPP is an autoinflammatory pustular neutrophilic disease with a predominant involvement of innate immunity characterised by sterile inflammation without pathogenic autoantibodies or autoreactive T lymphocytes, whereas plaque psoriasis shows involvement of both innate and adaptive immunity and is an autoimmune disease.¹⁶ GPP is primarily driven by the IL-36 pathway while plaque psoriasis is driven by the TNF-α/IL-23/IL-17/IL-22 axis.^17,18

GPP is rare and studies show a wide degree of regional variability in prevalence: 0.02 per 10,000 in France, 0.07–0.09 per 10,000 in Brazil, 0.15 per 10,000 in Sweden, 0.2 per 10,000 in Japan, 0.9 per 10,000 in the USA, 1.1 per 10,000 in South Korea and 1.4 per 10,000 in Germany.^12,14,19 In India, however, there is limited published data on the prevalence of GPP.²⁰

Domain 2: Diagnosis

GPP should be suspected in any patient with acute onset erythema and pustulosis.^15,21 Diagnosis of GPP presents a clinical challenge due to the rarity of the disease and the absence of consistent diagnostic criteria.^3,22

GPP is most common in the fourth decade of life and has a female preponderance.²² The clinical presentation is heterogeneous. Many patients experience GPP in three phases over several years – an initial pre-pustular phase, first widespread flare and a post-flare chronic phase.⁵ The initial pre-pustular phase may last for several years, in which many patients may experience psoriatic lesions. The next phase is marked by acute onset, widespread sterile pustules and inflamed skin. In the post-flare/chronic phase, it is common to have persisting skin symptoms. Relapse of flares is observed in most patients.¹⁰

Readers can refer to the European Rare and Severe Psoriasis Expert Network (ERASPEN) and the Japanese Dermatological Association (JDA) criteria for diagnosis of GPP.^15,23 The most important diagnosis to exclude is acute generalised exanthematous pustulosis (AGEP), a severe and acute pustular condition most often triggered by medications. Typically, acute generalised exanthematous pustulosis has a rapid onset, shorter course of illness, no recurrence pattern and no personal or family history of plaque psoriasis. Resolution of acute generalised exanthematous pustulosis is often spontaneous and usually seen within 15 days of withdrawal of the causative agent.^21,24,25 Other differential diagnoses include annular pustular psoriasis, localised forms of pustular psoriasis (e.g. palmoplantar pustulosis, acrodermatitis continua of Hallopeau), pemphigus foliaceus, immunoglobulin A(IgA) pemphigus and subcorneal pustular dermatosis.²²

Statements

• 3.

  GPP can be diagnosed clinically in a patient presenting with acute, primary, generalised and macroscopically visible pustules on non-acral skin.

  Agreement level: 9/12 (75%)

  Additional comments: Pustules on an erythematous base, lakes of pus and peripheral scaling (which appears after a few days as a result of healing of pustules) are other characteristics. Bedside gram stain of smears from pustules helps in ruling out bacterial infection.

  Disagreement: 3/12 experts mentioned that a confident diagnosis of GPP cannot be made solely on clinical examination.

• 4.

  Added to the clinical diagnosis, the presence of markers of systemic inflammation, such as fever, fatigue, myalgia, elevated C-Reactive Protein (CRP) levels and leucocytosis increases diagnostic certainty.

  Agreement level: 12/12 (100%)

• 5.

  Added to the clinical diagnosis, biopsy (showing presence of neutrophilic subcorneal pustules and other characteristic features of GPP) increases diagnostic certainty.

  Agreement level: 12/12 (100%)

• 6.

  Added to the clinical diagnosis, history of repeated episodes of flare-ups of disease increases diagnostic certainty.

  Agreement level: 12/12 (100%)

Domain 3: Assessment of severity

Physician Global Assessment (PGA) and Psoriasis Area and Severity Index (PASI) are clinical outcome measures widely used in plaque psoriasis to assess disease severity and response to treatment objectively.¹⁸ To improve the validity of these measures in GPP, the induration component in the above outcome measures was replaced with a pustular component, to develop the Generalised Pustular Psoriasis Physician Global Assessment (GPPGA) and the Generalised Pustular Psoriasis Area and Severity Index (GPPASI) respectively , which were externally validated.^{26, 27}

GPP interferes in activities of daily living such as exercise, attending important life events and socialising, thus severely impacting the quality of life(QoL).^5,28,29 A study among 102 patients with acute GPP reported a mean Dermatology Life Quality Index (DLQI) score of 12.4 during a follow-up visit (i.e. non-flare period), indicating severe impairment even in the post-flare chronic phase.¹⁰ Hence, assessment of clinical severity alone is inadequate to evaluate the burden of GPP, and patient-reported outcome measures can be used to assess the impact on QoL.²⁷

Domain 4: Investigations

Investigations are done to confirm diagnosis, assess severity/inflammation, assess involvement of other organs or to assess if certain medicines can be administered to a particular patient. Usual investigations include complete blood counts (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), liver function tests (LFT), renal function tests (RFT), urinalysis, blood chemistry, blood culture, gram staining of smear from pustules and skin biopsy.^22,23,30

Among patients with the first flare of GPP, a skin biopsy may be done to confirm the diagnosis. Kogoj’s spongiform pustules in histopathology are a distinct finding. Other features include parakeratosis, hyperkeratosis, and elongated rete ridges.^21,22

Screening for tuberculosis, hepatitis B, hepatitis C and human immunodeficiency virus (HIV) may be needed before initiating certain therapies.³¹

Loss of function mutations in the IL-36 receptor antagonist gene (IL36RN) associated with GPP were first identified in 2011. The frequency of this mutation in GPP patients ranges from 23% to 37%.^4,5 Other mutations associated with GPP occur in CARD14, AP1S3, TNIP1, SERPINA3, and MPO genes.³² It is noted that patients with these mutations have increased disease severity, an earlier age of onset, and an increased risk of systemic inflammation.¹⁷ Importantly, these mutations are distinct to GPP and are not reported in patients with plaque psoriasis.³³

Whether such mutations influence therapeutic responses hasn’t been wellstudied. Successful treatment with ustekinumab, IL-17A antagonists and spesolimab has been reported in patient subgroups with and without IL36RN mutations.³⁴

Domain 5: Treatment initiation, monitoring and escalation

Rapid control of skin symptoms, control of systemic inflammation and preventing complications are the immediate therapeutic goals during an acute flare.³⁵

Treatment algorithm

Systemic therapy should be initiated in patients with moderate/severe disease and in mild cases where topical therapy is ineffective.⁴ Various medicines that may be tried include retinoids, cyclosporine, TNF inhibitors, and biologics used for plaque psoriasis. Spesolimab has been recently approved for the management of flares of GPP in adult patients, and adds to the treatment armamentarium. Systemic corticosteroids should only be used in severe/life-threatening cases and only for a few days, considering the risks associated with steroids, including triggering a flare upon withdrawal.⁴ Standard protocol for tapering corticosteroids should be followed.

Supportive measures include maintenance of fluid and electrolyte balance, thermoregulation, monitoring for infections and other complications and treatment of symptoms such as pain/fever.²³

Based on the consensus, we have suggested an algorithm for the management of flares of GPP [see Figure 1].

Close

Figure 1:

Suggested algorithm to manage patients with a flare of GPP.

GPP: Generalised Pustular Psoriasis; GPPGA: GPP Physician Global Assessment; BSA: Body Surface Area; DLQI: Dermatology Life Quality Index

#Skin biopsy is recommended in all suspected GPP patients (unless an earlier biopsy had confirmed the diagnosis of GPP, and current clinical picture is suggestive of GPP flare). Routine laboratory investigations recommended in most cases include CBC (complete blood count), ESR (erythrocyte eedimentation rate), CRP (C-reactive protein), LFT (liver function tests), RFT (renal function tests) and urine analysis. Optional/additional investigations in select cases are: (a) Screening for infections such as tuberculosis, hepatitis B, hepatitis C, HIV and (b) Genetic testing to identify potential causative mutations in suspected patients.

^Skin biopsy, presence of markers of systemic inflammation and history of repeated episode of flare-up of disease help increase the diagnostic certainty in patients with suspected GPP flare (presenting with acute, primary, generalized and macroscopically visible pustules on non-acral skin).

*If systemic steroids are considered necessary, they should be used only for a few days and standard protocol for tapering steroids should be followed.

@Cost of medicine and patient preference may also affect the choice of treatment.

$No consensus was achieved on how to decide if the response to therapy is adequate (“minimal improvement” criteria). The decision about treatment escalation can be based on discussion between patient and doctor based on the clinical picture after one to two weeks on a particular treatment.

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Domain 6: Special populations