Antivascular Endothelial Growth Factor-A Therapy: A Novel Personalized Treatment Approach for Psoriasis

Andrea Luengas-Martinez; Ralf Paus; Helen S. Young


The British Journal of Dermatology. 2022;186(5):782-791. 

In This Article

Abstract and Introduction


Chronic plaque psoriasis is an inflammatory skin disease in which genetic predisposition along with environmental factors lead to the development of the disease, which affects 2% of the UK's population and is associated with extracutaneous morbidities and a reduced quality of life. A complex crosstalk between innate and adaptive immunity, the epithelia and the vasculature maintain the inflammatory milieu in psoriasis. Despite the development of promising treatment strategies, mostly targeting the immune system, treatments fail to fulfil every patient's goals. Vascular endothelial growth factor-A (VEGF-A) mediates angiogenesis and is upregulated in the plaques and plasma of patients with psoriasis. Transgenic expression of VEGF-A in experimental models led to the development of skin lesions that share many psoriasis features. Targeting VEGF-A in in vivo models of psoriasis-like inflammation resulted in disease clearance. Anti-angiogenesis treatments are widely used for cancer and eye disease and there are clinical reports of patients treated with VEGF-A inhibitors who have experienced Psoriasis Area and Severity Index improvement. Existing psoriasis treatments downregulate VEGF-A and angiogenesis as part of their therapeutic effect. Pharmacogenetics studies suggest the existence of different genetic signatures within patients with psoriasis that correspond with different treatment responsiveness and disease severity. There is a subset of patients with psoriasis with an increased predisposition to produce high levels of VEGF-A, who may be most likely to benefit from anti-VEGF-A therapy, offering an opportunity to personalize treatment in psoriasis. Anti-VEGF-A therapies may offer an alternative to existing anticytokine strategies or be complementary to standard treatments for the management of psoriasis.


Chronic plaque psoriasis, an immune-mediated disease affecting approximately 125 million people worldwide,[1,2] is associated with multiple comorbidities including psoriatic arthritis (PsA),[3] metabolic syndrome[4] and cardiovascular disease.[5,6] As a polygenic disease with more than 80 susceptibility loci identified,[7,8] psoriasis is characterized by interpatient variability and heterogeneous response to treatment.[9]

The pathogenesis of psoriasis is driven by an exacerbated immune response, inflammatory angiogenesis in combination with abnormal keratinocyte differentiation and proliferation.[10,11] Blood and lymphatic vessels play a central role in the development of psoriasis,[12,13] mediated by members of the vascular endothelial growth factor (VEGF) superfamily, including VEGF-A.[14] Expression of VEGF-A, which binds to VEGF-A receptor-1 (VEGFR-1) and VEGFR-2,[15] is increased within plaques of psoriasis compared with nonlesional skin (Figure 1).[16–19] Patients with psoriasis also have increased plasma levels of VEGF-A, which correlate with disease severity.[16,20–22]

Figure 1.

(a) Haematoxylin and eosin immunohistochemistry staining of a plaque of psoriasis, presenting key psoriasis histological features such as epidermal hyperplasia, immune-cell infiltration and elongated blood vessels in the papillary dermis. (b) Plaque of psoriasis cryosection stained with a double immunofluorescence staining for endothelial cells (CD31 in red) and for lymphatic vessel hyaluronan receptor-1 (Lyve-1 in green). The blood vessels (CD31+/Lyve-1) appear enlarged, tortuous and extend up to the rete ridges in the papillary dermis. Very few lymphatic vessels are detected (CD31+/Lyve-1+).45, 46 The red arrows point to blood vessels that reach the skin surface through a thinned epithelium and the green arrows point to the lymphatic vessels. (c) vascular endothelial growth factor-A messenger RNA (mRNA) strains detected with fluorescent in situ hybridization in epidermal keratinocytes of psoriasis plaque skin. Each dot represents one mRNA strain. Scale bars = 100 μm.

The emergence of biologic therapy over the last two decades[23] has shifted psoriasis management from treatment with conventional systemic treatments (methotrexate, oral retinoids and ciclosporin) to those which target key cytokines in the inflammatory pathways involved in psoriasis [e.g. tumour necrosis factor (TNF)-α, interleukin (IL)-23 or IL-17A].[24] However, despite these therapeutic advances, patients with psoriasis continue to have heterogeneous responses to treatment, resulting in suboptimal control of the disease that fails to meet the shared treatment goals of patient and prescriber. As a result, patients may try and fail multiple lines of therapy before they are established on treatment that is well tolerated and provides long-term efficacy.[25–27] Failure of treatment can be defined as: (i) primary failure: there is never a response to treatment; or (ii) secondary failure: there is loss of efficacy after an initial satisfactory response. A retrospective study of 250 patients over the course of 9 years reported that biologic therapies fail more often due to secondary failure (24% of failure rate), whereas adverse effects (16% of failure rate) were the main cause of failure for systemic therapies.[28] Unfortunately, even the most efficacious therapies do not achieve skin clearance in all individuals, and this continues to drive the need for the development of new treatments and treatment paradigms.[1] In addition, psoriasis management would also benefit from a personalized management approach where care and treatment are tailored according to the healthcare needs and phenotype of each patient. Matching patients with the right treatments for them could avoid the toxicities associated with treatments, reduce the risk of developing comorbid disease and lead to significant healthcare savings.[27]

Inhibition of angiogenesis has been studied extensively since it was suggested in the 1970s that the growth of new blood vessels was required for tumour growth.[29] Therapeutic strategies for VEGF-A blockade have been developed including: (i) VEGF-A direct neutralization using monoclonal antibodies (mAbs) such as bevacizumab,[30,31] ranibizumab[32] and ramucirumab;[33] (ii) VEGF-A receptor inhibition using VEGF-A receptor tyrosine kinase inhibitors such as sorafenib,[34] regorafenib,[35] sunitinib[36] and vandetanib;[37] and (iii) prevention of VEGF-A binding to its receptors using a decoy receptor fusion protein that binds to free VEGF-A, such as VEGF Trap (aflibercept).[38] Pharmacological approaches to target the VEGF-A/VEGFR system are now widely used, particularly in the fields of oncology and ophthalmology.[38,39] However, despite the importance of the vasculature in the pathogenesis of psoriasis, no anti-VEGF-A therapies have been licensed for psoriasis.

In this review, we discuss the potential of targeting the VEGF-A/VEGFR signalling pathway as a promising therapeutic strategy for the management of psoriasis. The scientific data available suggest that anti-VEGF-A therapy is particularly amenable to personalized treatment.[40–42]