CARD14-Mediated Psoriasis and Pityriasis Rubra Piliaris (PRP)
CARD14 is an important cutaneous scaffold protein. Gain of function mutations in CARD14 lead to enhanced or sustained NF-kB activation, and up-regulation of its target genes which include pro-inflammatory cytokines. The consequence of these and downstream transcriptional alterations are seen clinically as psoriasis or pityriasis rubra pilaris (PRP).
Introduction and Background
Discovery of Disease-Causing CARD14 Mutations
Psoriasis susceptibility locus 2 (PSORS2) was mapped in 1994 to human chromosomal region 17q25-qter in a single large European family (PS1) (Tomfohrde et al. 1994). Affected members had plaque psoriasis and 30% also developed psoriatic arthritis. A second genome-wide linkage scan in a five-generation Taiwanese family further implicated PSORS2 as the site of a genetic locus that could explain some psoriasis inheritance.
In 2012, mutations in the gene caspase recruitment domain family, member 14 (CARD14), were identified as being responsible for the PSORS2 locus (Jordan et al. 2012a, b). Targeted and exome capture followed by NextGen sequencing of DNA from members of family PS1 identified a mutation in CARD14 that segregated with psoriasis (c.349G > A; p.Gly117Ser). A second CARD14 mutation at the same splice donor site was discovered in the Taiwanese family (c.349 + 5G > A). These rare pathogenic variants, explained the highly penetrant autosomal dominant inheritance of psoriasis vulgaris in these families. A de novo mutation in CARD14 was discovered in a Haitian child with sporadic, severe, generalized pustular psoriasis (c.413A > C; p.Glu138Ala). CARD14 mutations were subsequently discovered as responsible for causing pityriasis rubra pilaris (PRP), another inflammatory skin disease, in four unrelated families (Fuchs-Telem et al. 2012). Although most clinicians consider PRP and psoriasis distinct diseases, mutations in the same gene in both conditions point to shared pathogenesis.
There have now been numerous studies of these rare CARD14 mutations in patients with psoriasis (sometimes termed CARD14 mediated psoriasis, CAMPS), psoriatic arthritis, and, pityriasis rubra pilaris (Fuchs-Telem et al. 2012; Jordan et al. 2012a, b; Van Nuffel et al. 2017). In a large cohort of 6000 psoriasis patients and 4000 controls, 15 additional rare missense variants within CARD14 were identified. Each of these variants, and the familial p.G117S mutation, is rare and found in less than one in 1000 psoriasis cases. However, a common single nucleotide polymorphism in CARD14 (R820W) originally identified by Jordan et al. exceeded genome-wide significance for association with psoriasis in a large meta-genome wide association study. In this instance, the W allele confers psoriasis risk and is seen in approximately 0.56 cases versus 0.52 controls. In the case of PRP patients, with CARD14 mutations are usually familial or de-novo and include early onset, prominent facial involvement, and favorable responses to ustekinumab therapy.
Functions of CARD14 in Healthy Tissues
CARD proteins form intracellular scaffolds that are important in cellular activation (Van Nuffel et al. 2017). The primary function of CARD14fl and CARD14sh is to activate the transcription factor nuclear factor-kappa B (NF-kB) (Fig. 1). After an appropriate stimulus, wild-type CARD14 assembles with adapter protein B-cell lymphoma 10 (BCL10) and recruits paracaspase MALT1 to form a CARD11/BCL10/MALT1 (CBM) signaling complex (Fig. 1). This CBM complex can activate NF-kB leading to expression of proinflammatory cytokines and chemokines. CARD14 isoforms may also play a role in epidermal differentiation where CARD14cardless might function as a dominant-negative regulator of CARD14 signaling.
Effects of CARD14 Variants in Inflammatory Skin Disease
In vitro studies utilizing the mutated CARD14 variants indicated that one consequence of the c.349G > A mutation found in the northern European PS1 psoriasis family, and c.349 + 5G > A mutation from the Taiwanese family with psoriasis, is an in-frame insertion of 22 amino acids between exon 3 and 4 of the CARD14 protein (Jordan et al. 2012a, b). Most other CARD14 mutations lead to single amino acid substitutions.
CARD14 mutations found in psoriasis and pityriasis rubra pilaris are gain-of-function mutations, leading to amplified NF-kB responses and cutaneous inflammation (Howes et al. 2016). Cultured keratinocytes from affected individuals with psoriasis containing CARD14 mutations, as well as keratinocyte cell lines transfected with mutant CARD14, show increased psoriasis-associated cytokine transcription compared to wild-type keratinocytes, such as CXCL8 (IL-8), CCL20, and IL36γ (Jordan et al. 2012b). Van Nuffel and colleagues have listed all published CARD14 variants identified in patients with psoriasis and pityriasis rubra pilaris, located by exon and CARD domain, as well as their effect on NF-kB activation (Van Nuffel et al. 2017).
Possible additional pathogenic signaling pathways of the CARD14 variants include direct stimulation of MALT1 paracaspase activity and activation of ERK1/2 and p38α MAP kinases (Howes et al. 2016; Van Nuffel et al. 2017). The molecular mechanism leading to CARD14 activation is similar to that identified for mutations in CARD11 that lead to diffuse large B cell lymphoma. The CARD14 linker region between the CC and PDZ domains exerts an auto-inhibitory effect due to its conformation and this is abolished in the presence of psoriasis-associated CARD14 mutations. This leads to enhanced, sustained, or constitutive levels of NF-kB activation following IkB proteosomal degradation to release NF-kB for nuclear translocation (Howes et al. 2016).
In skin biopsies from patients with familial psoriasis (PS1) and CARD14 mutations, the histological appearance is of typical psoriasis, with acanthosis (thickened epidermis), parakeratosis, dilated blood vessels, and abundant mixed inflammatory cell infiltrate. Similarly, histology of skin biopsies from patients with pityriasis rubra pilaris and CARD14 mutations is that of typical pityriasis rubra pilaris, with alternating orthokeratosis and parakeratosis, acanthosis with broadening of rete ridges, follicular plugging, and dermal lymphocytic infiltrate (Fuchs-Telem et al. 2012). However, in both psoriasis and pityriasis rubra pilaris associated with CARD14 mutations, there is less CARD14 expression in basal keratinocytes, with abundant CARD14 expression throughout the upper epidermis (Fuchs-Telem et al. 2012; Jordan et al. 2012b). CARD14 is also found in psoriatic lesional and nonlesional dermal CD31+ endothelial cells and LYVE-1+ lymphatics (Harden et al. 2014). Phosphorylated NF-kB colocalizes in CARD14+ dermal endothelial cells, indicating that this pathway is active in these cells (Harden et al. 2014). Aortic endothelial cells also express CARD14 protein (Harden et al. 2014), suggesting a possible contribution of CARD14 in the cardiovascular comorbidity associated with psoriasis.
In summary, CARD14 mutations appear to augment immune responses to drive persistent cutaneous inflammation through NF-kB activation. It is not yet clear how the CARD14 mutations result in distinct clinical phenotypes such as psoriasis versus pityriasis rubra pilaris.
Clinical Presentation (History/PE)
CARD14 mutations have been described in patients with psoriasis vulgaris (the most typical presentation of psoriasis), generalized pustular psoriasis, psoriatic arthritis, palmoplantar pustulosis, and pityriasis rubra pilaris. Patients with CARD14 mutations cannot yet be easily distinguished clinically or histologically from those without CARD14 mutations.
The most common clinical presentation of psoriasis associated with CARD14 mutations is psoriasis vulgaris, which is classical large plaque psoriasis. Presentation involves well-demarcated erythematous scaly plaques usually on the extensor surfaces such as elbows and knees. Generalized pustular psoriasis can also be the presentation of CARD14 mutations, with small pustules on a widespread erythematous background. Joint symptoms associated with CARD14 mutations (seen in 30% of PS1 family members) are usually that of typical psoriatic arthritis.
Pityriasis rubra pilaris is described as follicular papules and salmon-pink erythematous plaques, with characteristic normal skin adjacent to these plaques called “islands of sparing,” and often present on palms and soles as keratoderma. Type V pityriasis rubra pilaris, which is “atypical juvenile type,” appears to be most commonly associated with CARD14 mutations. This type of pityriasis rubra pilaris has onset in infancy or early childhood with a chronic course.
Laboratory Findings/Diagnostic Testing
At the current time, clinicians are not able to routinely test patients with psoriasis or pityriasis rubra pilaris for CARD14 mutations.
Specific recommendations for treatment options or prognosis are not yet available for patients with CARD14 mutations. The therapeutic approach includes traditional medications prescribed for moderate-to-severe psoriasis or pityriasis rubra pilaris. This can be effective in the case of psoriasis due to some CARD14 alterations, such as the p.G117S change. However, there is an impression that some patients with severe psoriasis due to CARD14 mutations, such as the p.E138A change, are more refractory to treatment and may require biologics such as anti-IL-12/23 and anti-IL-17 monoclonal antibodies. There have also been reports of anti-IL-12/23 and anti-TNF agents to treat familial pityriasis rubra pilaris (Fuchs-Telem et al. 2012; Eytan et al. 2014). Prospective studies are required to understand the clinical significance and potential therapeutic options for patients who harbor CARD14 mutations.