Severe atypical juvenile pityriasis rubra pilaris diagnosed in adulthood with a dramatic improvement with ustekinumab

Abstract Pityriasis rubra pilaris (PRP) is a rare skin disease which manifests as a psoriasiform dermatosis and palmoplantar keratoderma and has significant clinical‐histopathological overlap with psoriasis. Recently, several case reports have demonstrated successful treatment of PRP with anti‐IL7A and anti‐IL12/anti‐IL23 monoclonal antibodies. We report a case of atypical juvenile PRP definitively diagnosed during adulthood with presence of CARD14 mutation. This case demonstrates a dramatic improvement with ustekinumab and highlights the role of genetic testing in chronic disease of diagnostic uncertainty.


| INTRODUCTION
Pityriasis rubra pilaris (PRP) is a rare skin disease which manifests as a psoriasiform dermatosis and palmoplantar keratoderma, with significant clinicalhistopathological overlap with psoriasis.There are six PRP subtypes classified by age at onset, disease extent, prognosis, and other features. 1We present a case of atypical juvenile onset (type V) PRP with a dramatic improvement with ustekinumab.We obtained written informed consent for the use of the patient's anonymised clinical information and images.
The patient is a 32-year-old female, known to dermatology departments since birth.From aged six weeks and throughout childhood she had scaly erythroderma, sparing the flexural surfaces and parts of the back, and yellowish hyperkeratotic palms and soles.She was initially thought to have congenital ichthyosiform erythroderma and was subsequently diagnosed with progressive symmetrical erythrokeratoderma.She was a non-smoker with no other health conditions or medications.Her paternal grandmother had ichthyosis during childhood.
Her skin was very well controlled on acitretin 20 mg daily for many years.Aged 29 years she was referred to the dermatology genetics clinic to explore alternative treatment as the patient was considering trying to conceive in the future.She was switched to isotretinoin 40 mg daily.Blood sampling for genetic testing was performed.One year later, her skin was notably worse with extensive, erythematous, scaly plaques, more confluent on the abdomen and thighs (Figure 1a-c).The working diagnosis was changed to PRP.She commenced ciclosporin 100 mg twice daily (BD), later increased to 150 mg BD.After one year of treatment without adequate control, the multidisciplinary team agreed to commence biologic therapy.
She commenced 12-weekly subcutaneous ustekinumab 45 mg.Within one month of introduction, there was a significant improvement in skin appearance and her dermatology life quality index (DLQI) score improved from 19 to 5 (Figure 1d-f).This control was maintained after interval dose adjustment to 10-weekly administration of ustekinumab 45 mg.Her dosing regimen mirrors the literature. 2 Next generation sequencing (Panel R165, ICHTHY_v1.3_R165_Green)3identified a heterozygous CARD14 mutation (c.356 T > C p. [Met119Thr]) classified as 'likely pathogenic' by the genetics laboratory.Given that this patient's parents are not affected, but have not had genetic testing, it is suspected that this is a de novo mutation.
PRP is a rare, papulosquamous, inflammatory dermatosis.Historically it was divided into five subtypes based upon disease extent, age of onset and expected prognosis, however a sixth HIV-related PRP has since been recognised. 1,4The most common form is type I (classical adult), which carries the best prognosis.Other forms are types II (atypical adult), III (classic juvenile), IV (circumscribed juvenile) and VI (HIV-associated). 1 Atypical juvenile (type V) PRP represents 5% of cases and is most associated with familial forms of PRP and presence of CARD14 mutations. 5It is characterised by early onset, protracted disease, with follicular hyperkeratosis, ichthyosiform features and sclerodermatous changes of the hands and feet. 1,4,5ur patient has atypical juvenile PRP with diagnosis delayed into adulthood.Earlier genetic sequencing and diagnosis may have enabled a personalised approach to treatment, including exploring other opportunities for family planning.
The term CARD14 Associated Papulosquamous Eruption (CAPE), first proposed in 2018, describes the spectrum of conditions associated with features of psoriasis, PRP, or both, and CARD14 mutations. 6CARD14 is highly expressed in the skin and mutant forms are independently associated with psoriasis and PRP. 5 CARD14 mutations result in inappropriate NF-kB and mitogen-activated protein kinase pathway activations thought to cause CCL20 overexpression, and IL13 and IL17A activation. 5,7stekinumab is a monoclonal antibody against the IL12 and IL23 p40 subunit and has downstream effects on the NF-kB pathway, hence is a pathogenesis-based treatment for PRP. 8 Good response to ustekinumab has been described in several PRP cases. 2,8,9esponse to ustekinumab in the literature varies, however is largely successful, with five out of six patients in one case series of patients with CAPE experiencing near complete response to ustekinumab. 6Anti-IL17 agents including ixekizumab 10,11 and secukinumab 12 have also been used successfully for the treatment of CAPE.
Due to the rare nature of CAPE, treatment options for PRP are primarily based upon case reports.This patient experienced a dramatic improvement with ustekinumab combined with ciclosporin for PRP associated with a CARD14 c356 T > C variant.This case augments the literature supporting the use of ustekinumab for atypical juvenile PRP, or CAPE.It highlights the role of genetic testing in dermatological conditions where there is diagnostic uncertainty to enable personalised treatment and improved patient outcomes.