Sites interested in participating please contact the Trial Manager
APRICOT Site Feasibility Questionnaire [38kb doc]
Sites & Key Dates
Stage 2: January 2018 – September 2019 **now recruiting**
Guy’s Hospital, London
Salford Royal Infirmary, Salford
Royal Victoria Infirmary, Newcastle upon Tyne
Univeristy Hospital of Wales, Cardiff
Ninewells Hospital, Dundee
St Luke’s Hopsital, Bradford
Broadgreen Hospital, Liverpool
Royal Royal Infirmary, Lancaster
Russells Hall Hospital, Dudley
Bristol Royal Infirmary, Bristol
Addenbrooke’s Hospital, Cambridge
Princess Alexandra Hospital, Harlow
Norfolk and Norwich University Hospital
Derby Royal Hospital
APRICOT SAE reporting is via the King’s Health Partners Clinical Trial Office. SAE forms should be downloaded from the website: www.khpcto.co.uk/SOP/SAE_Reporting
Fax number: 020 7188 8330
PLUM: Pustular psoriasis: eLucidating Underlying Mechanisms
We are running parallel mechanistic studies to further explore the genetic and immunological aspects of PPP, some of which will be performed in a project called PLUM (Pustular psoriasis, elucidating unnderlying mechanisms). PLUM Protocol_V1.1 [492kb pdf]
PLUM aims to validate the role of a signalling protein (IL-1) associated with pustular forms of psoriasis by combining genetic and other experimental data. Participants will be recruited to 3 cohorts (patients with pustular psoriasis, healthy controls, and disease controls) and will be invited to donate blood samples and to provide comparator skin and hair pluck samples.
PLUM is now open. If you would like to express an interest in this observational study complete and return the PLUM Site Feasibility Questionnaire [38kb doc]
The analysis of PLUM samples is being led by Dr Francesca Capon, Division of Medical and Molecular Genetics, King’s College London. Information on her research group can be found on her King’s College London webpage: Capon Lab KCL
PLUM Chief Investigator: Prof Catherine Smith
Pustular psoriasis constitutes less than 10% of all people with psoriasis, as opposed to the more common plaque types of the disease, but it consistently ranks the highest of all psoriasis variants in terms of symptoms (pain, itch), and functional impairment (limited mobility, interference with tasks of daily living and work). The consequent impact on patient health is therefore great and equivalent to major medical and psychiatric illness.
Management of the more common plaque-type disease has been revolutionised in the last 10 years with the advent of biological therapies and major investment in new therapies, driven in great part by the scientific discovery of underlying disease pathways. In contrast, treatment options for pustular psoriasis are profoundly limited, and, with the exception of one small, underpowered randomised controlled trial no relevant trials have been performed since 2001.
A recent Cochrane review evaluating interventions for pustular psoriasis identified 23 trials involving 724 people: there was evidence to support only the use of systemic retinoids (improvement rate difference 44%); oral PUVA (improvement rate difference 44%); and ciclosporin, although this was only to be ‘considered’. Tumour necrosis factor antagonists, such as adalimumab, typically used to great benefit in plaque type psoriasis, are largely ineffective in pustular disease and may instead precipitate or aggravate the disease. There is thus a significant unmet need for new and more effective treatment options in this patient group.
The poor response in pustular psoriasis to therapies used to great effect in plaque type disease may be explained by very recent evidence (2011 onwards) indicating that molecular pathways underlying pustular psoriasis are distinct and involve interleukin (IL)-36/IL-1 axis.
Several groups, including our own, have identified functionally relevant genetic markers in all forms of pustular disease that strongly indicate the over production of a protein, a cytokine call interleukin-1 (IL-1) in pustular disease. Disease mutations in the IL36RN gene, for example, disrupt the inhibitory function of IL-36 receptor antagonist causing enhanced production of inflammatory molecules including IL-1. IL-1 is known to sustain the inflammatory response initiated by skin keratinocytes in forms of psoriasis. We have also been able to uncover disease associated mutations in AP1S3, a gene that contributes to the regulation of innate immune homeostasis – i.e. the regulation of immune responses. Additionally, we have demonstrated that IL36RN alleles do not confer susceptibility to plaque type disease.
Our genetic studies therefore suggest that PPP may be caused by pathogenic mechanisms distinct from plaque type disease, involving abnormal activation of innate immune cells and enhanced IL-1 production. This is also consistent with the poor response to treatment with therapeutics that target other immunological pathways, for example the IL-12/IL-23 targeted drug ustekinumab.
Given the proven therapeutic effect of IL-1 antagonists in the treatment of other IL-1 mediated diseases, such as rheumatoid arthritis, we hypothesise that IL-1 blockade will also deliver benefit in pustular forms of psoriasis. Early studies support this hypothesis: anakinra, a highly effective IL-1 antagonist produced complete and rapid resolution of pustules within days in patients with pustular psoriasis. In two patients with disease relapse on stopping anakinra, pustules cleared on restarting therapy. In contrast, efficacy of anakinra in plaque type disease is limited.
APRICOT therefore aims to investigate the clinical efficacy of IL-1 blockade in PPP, using the model IL-1 antagonist, anakinra, in a double blind, randomised, placebo-controlled trial.
1) S Hussein et al 2015: IL36RN mutations define a severe autoinflammatory phenotype of generalized pustular psoriasis
2) A Onoufriadis et al 2011: Mutations in IL36RN/IL1F5 Are Associated with the Severe Episodic Inflammatory Skin Disease Known as Generalized Pustular Psoriasis
3) F Capon 2013: IL36RN Mutations in Generalized Pustular Psoriasis: Just the Tip of the Iceberg?