Advancements in understanding and treating psoriasis: a comprehensive review of pathophysiology, diagnosis, and therapeutic approaches

Search/survey strategy

Until April 2022, most databases were searched to find the most recent reported information on the definition, prevalence, causes, pathogenesis, clinical features, diagnosis, treatment options, and psychosocial impact of psoriasis. These databases included PubMed, Elsevier, Scopus, Google Scholar, and Web of Science. Psoriasis, prevalence, aetiology, pathogenesis, clinical features, diagnosis, treatment options, biologic drugs, cytokines, disease severity, response to treatment, microbiome, epigenetics, biomarkers, technology, genomics, epidemiology, and disease burden were among the keywords used in the search criteria (Pradeep et al., 2025). Every article received was examined and filtered to gather information about psoriasis that occurs naturally; unpublished findings and products from other sources were not included in this investigation.

Prevalence and incidence

Psoriasis prevalence and incidence can differ by geographic location, age, and other variables. A total of 2.3% of the world’s population had psoriasis, with Europe and North America having the highest prevalence rates. The study also discovered that the prevalence of psoriasis rose with aging, peaking in people 60 years and older. Additionally, it was discovered that men are more likely than women to have psoriasis (Armstrong & Read, 2020), The ratio of incidence rates between men and women is 85.5:73.2 per 100,000 person-years (Pradeep et al., 2022b).

According to a population-based study in 2015, the incidence of psoriasis in the United States is 98 per 100,000 person-years (Rapp et al., 1999).

Psoriasis incidence and prevalence vary significantly across regions, with only a few reliable studies on its incidence due to non-mandatory case registration. Incidence rates range from 0.60 per 1,000 person-years in Minnesota (1980–1983) to 10.36–15.04 per 1,000 in North African countries (2012). More studies have focused on prevalence, but comparing results is challenging due to differing methodologies (definitions, population ages, and diagnostic techniques).

Globally, prevalence tends to be higher in Northern European populations, such as Norway (up to 11.4%) and lower in Eastern Asia, with Taiwan recording a prevalence as low as 0.05%. Psoriasis affects adults more than children, with the highest prevalence seen in Western Europe, North America, and Australasia. Australia, Norway, and Israel have some of the highest lifetime physician-diagnosed prevalence rates. In 2017, it was estimated that 29.5 million people globally had psoriasis, representing a lifetime prevalence of 0.59% of the adult population (World Health Organization, 2016).

The WHO’s global report on psoriasis also highlights the disparity in prevalence between high-income and low-income regions, with greater incidence reported in regions such as Europe and Australasia compared to East Asia. The prevalence in children is generally lower than in adults (Sandoval, Pierce & Feldman, 2014).

Causes and risk factors

The exact cause of psoriasis is not fully understood, but research recommends that it is likely a combination of environmental and genetic factors. Genetic variations have been identified that are related to an increased risk of developing psoriasis, particularly genes involved in the skin cell growth and immune system, according to the National Psoriasis Foundation. These genetic factors contribute to the underlying immune system dysfunction and abnormal skin cell proliferation observed in psoriasis (Ritchlin, Colbert & Gladman, 2017).

Alongside genetic factors, several environmental triggers have been identified that can contribute to the growth or worsening of psoriasis. Infections, particularly streptococcal infections, have been known to trigger psoriasis symptoms in some individuals. Certain medications, such as lithium (used for psychiatric conditions), antimalarial drugs, and beta-blockers (used for cardiovascular conditions), have also been associated with triggering or worsening psoriasis (Pradeep et al., 2022b).

Physical trauma to the skin, such as burns, cuts, or infections, can also act as triggers for psoriasis in susceptible individuals. Stress is another known trigger, with many people reporting that their symptoms worsen during periods of high stress. Lifestyle factors such as obesity and smoking have been related to an increased risk of expression of psoriasis as well (Strober et al., 2016).

It is important to note that while these triggers can contribute to the development or worsening of psoriasis, they do not affect every individual with the condition in the same way. Psoriasis is a multifactorial disease influenced by various factors, and the specific triggers and their impact can vary from one individual to another (Takeshita et al., 2017).

Symptoms and diagnosis

Psoriasis can present with various symptoms depending on the type of psoriasis a person has. The most common symptoms include red, scaly patches of skin that are raised and have a silvery-white appearance in typical locations. These patches can be itchy or painful, and the skin affected by psoriasis may also be dry and cracked. Psoriasis can also affect the nails, causing them to thicken, develop pits, or develop ridges. Some individuals with psoriasis may also experience joint pain, stiffness, and swelling, which can be indicative of psoriatic arthritis, a condition that commonly accompanies psoriasis (Menter et al., 2009). It is important for the person experiencing these symptoms to look for medical attention for an accurate diagnosis and appropriate treatment.

Diagnosis of psoriasis is usually based on a physical examination of the skin and nails, as well as a review of a person’s medical history and symptoms. In some cases, a skin biopsy may be done to confirm the diagnosis (Bjerre et al., 2017).

Clinical features

Psoriasis is a persistent autoimmune condition that usually affects the skin, though it can also affect the joints and nails. Psoriasis patients experience varying rates of disease development; mild cases might persist for years in certain individuals, while moderate cases can escalate rapidly to moderate-to-severe cases. The progression of psoriasis is unpredictable, ranging from sporadic flare-ups to a persistently active condition. It may result in comorbidities such as metabolic syndrome, psoriatic arthritis, and an elevated risk of heart disease. Depression and anxiety are prevalent mental health conditions among individuals with psoriasis. To further complicate its effects on general health, psoriasis frequently coexists with autoimmune conditions including rheumatoid arthritis and Crohn’s disease. Depending on the type of psoriasis and the severity of the ailment, the symptoms and clinical characteristics of the condition can change (Table 1). Psoriatic arthritis is a form of arthritis that occasionally results from psoriasis, which can also affect the joints, we have knowledge of distinct types of psoriatic arthritis which react very differently to treatment (Parisi et al., 2015).

Types of psoriasis

Psoriasis comes in a variety of forms, each with unique features (Fig. 1). Plaque psoriasis is the most prevalent and is distinguished by elevated, inflammatory skin lesions covered in thick, silvery scales. Small, drop-like lesions dispersed across the body are the first signs of guttate psoriasis. Skin folds, such as those in the groin and armpits, are impacted by inverse psoriasis (Kim, Jerome & Yeung, 2017). The appearance of pus-filled blisters distinguishes pustular psoriasis from erythrodermic psoriasis, which is characterized by widespread inflammation and scale shedding. Pitting, discoloration, and detachment from the nail bed are just a few of the changes that nail psoriasis can make to the texture and look of the nails, for those who suffer from this ailment, knowing the various forms of psoriasis aids in precise diagnosis and effective treatment planning (Gelfand et al., 2005).

Differential diagnosis

Clinical signs including red, scaly skin patches and other related symptoms are used to diagnose psoriasis. Consider alternative differential diagnosis, though, as several other skin disorders might mirror psoriasis (Weber et al., 2021). Lesions from discoid lupus might also resemble psoriasis. They often don’t hurt or itch, though. Hair loss may result from scalp discoid lesions. These spots may remain on the skin for years without treatment. Individuals with darker skin tones could see the remnants of a discolored area that is either lighter or darker than the surrounding skin when discoid lupus resolves. Here are some of the common differential diagnoses of psoriasis (Table 2).

Diagnostic tests

Psoriasis is typically determined based on clinical features, such as the appearance of the skin lesions and a history of the condition. However, in some cases, diagnostic tests may be needed to certify the diagnosis and exclude other conditions (Parisi et al., 2015).

• Skin biopsy: A skin biopsy involves removing a small piece of skin tissue for inspection under a microscope. A skin biopsy can help authenticate the diagnosis of psoriasis and exclude other skin conditions that may mimic psoriasis (Lebwohl et al., 2016).

• Blood tests: This may be used to exclude other conditions, such as rheumatoid arthritis or lupus, that may be associated with psoriasis (Puig, 2017).

• X-rays and joint imaging: In some cases of psoriasis, imaging tests such as magnetic resonance imaging (MRI) or X-rays may be used to diagnose psoriatic arthritis, a type of arthritis associated with psoriasis (Sandoval, Pierce & Feldman, 2014).

High-resolution ultrasound (HRUS) has emerged as a superior tool for detecting early signs of inflammation in the joints and cartilage. HRUS allows for real-time visualization of soft tissues and can detect subtle inflammatory changes that may not yet be visible on X-rays. This makes HRUS a valuable diagnostic tool for catching psoriatic arthritis early, enabling prompt treatment to prevent long-term joint damage (Sampogna et al., 2006).

The role of keratinocytes in psoriasis pathogenesis

Both the initial stages of psoriasis and its ongoing maintenance depend heavily on keratinocytes. Keratinocytes have a variety of stimuli they might react to as part of the innate immune system. The actions of keratinocytes are modulated, and psoriasis is influenced by a variety of variables including genetics, cytokines and receptors, metabolism, cell signaling, transcription factors, non-coding RNAs, antimicrobial peptides, etc. Self-nucleotides and antimicrobial peptides are released by stressed keratinocytes, which aid in pDC activation. Then, IFN-α, IFN-γ, TNF-α, and IL-1β are produced by the activated and matured mDCs (Wang et al., 2020).

In addition to taking part in the initiation phase, keratinocytes also contribute to the maintenance phase by amplifying psoriatic inflammation. Once activated by proinflammatory cytokines synergistically, keratinocytes are highly proliferative. They can produce copious chemokines (e.g., CXCL1/2/3, CXCL8, CXCL9/10/11, CCL2, and CCL20) to recruit leukocytes (such as neutrophils, Th17 cells, dendritic cells, and macrophages), antimicrobial peptides (e.g., S100A7/8/9/12, hBD2, and LL37) to induce innate immunity, and other inflammatory mediators to amplify inflammation. Additionally, keratinocytes, fibroblasts, and endothelial cells cause tissue reorganization by promoting the growth and activation of endothelial cells as well as the deposition of extracellular matrix. Keratinocyte hyperproliferation and aberrant differentiation, dilated and hyperplastic blood vessels, and infiltration of inflammatory cells such as leukocytes are all consequences of the interaction between keratinocytes and immune cells, particularly Th17 cells, which leads to the production and maintenance of psoriasis (Pradeep et al., 2022a). This process is explained below in Fig. 3.

The role of cytokines and their receptors in the pathogenesis of psoriasis

The development of psoriasis depends on cytokines and their receptors, which allow immune cells and keratinocytes to communicate. TNF-α, IFN-γ, IL-23/IL-17A, and IL-22 are immune-derived chemicals that stimulate keratinocytes, which set off several signaling pathways. Antimicrobial proteins, cytokines, chemokines, and growth factors are released due to aberrant keratinocyte development. To treat psoriasis, therapies targeting TNF-α, IL-17A, and IL-23 specifically work very well (Zhou et al., 2022). Researchers’ focus has recently increased on cytokines produced by keratinocytes or receptors expressed in those cells (Micali et al., 2019).

Psoriasis is thought to be primarily caused by the IL-23/IL-17 cytokine axis. Immune cells are thought to need to produce IL-23 to maintain and grow immune cells capable of generating IL-17. However, keratinocytes can also generate IL-23, however it is unknown if this IL-23 plays a part in psoriasis. Scientists recently showed, using a transgenic mouse model, that keratinocyte-derived IL-23 was sufficient to activate IL-17-producing immune cells, induce them to release IL-17, and result in a persistent skin inflammatory response. Further research revealed that IL-23 expression in keratinocytes was controlled by epigenetic regulation through H3K9 dimethylation, which may contribute to psoriasis (Kimball et al., 2008).

Another important cytokine generated mostly by CD4+ T cells and group 3 innate lymphoid cells (ILC3) after IL-23 is IL-22. Non-hematopoietic cells including keratinocytes, epithelial cells, and hepatocytes express its receptor, known as IL-22R. By preventing keratinocytes from differentiating to their final state, IL-22 promotes the development of psoriasis and promotes the production of proinflammatory chemokines and antimicrobial peptides. IL-22 binding protein (IL-22BP) is a naturally occurring IL-22 inhibitor that binds specifically to IL-22, preventing it from performing its biological role. elevated levels of epidermal thickening and elevated production of inflammatory cytokines and IL-22-inducible antimicrobial peptides were seen in IMQ-induced psoriasis-like skin condition, which was aggravated by both hereditary IL-22BP deficiency and anti-IL-22BP neutralizing antibody (Gisondi et al., 2021).

TNF-like weak inducer of apoptosis (TWEAK), a crucial cytokine in psoriasis, has recently come to light. TWEAK deficiency reduced psoriatic dermatitis brought on by IMQ. Furthermore, animals lacking fibroblast growth factor-inducible 14 (Fn14, the TWEAK receptor) also had less severe illness. Scientists have most recently shown that keratinocytes play a crucial role in TWEAK’s function in psoriasis utilizing a mouse model with keratinocyte-specific deletion of Fn14. Mice were shielded against IMQ-induced inflammation and psoriasiform hyperplasia by Fn14 loss in keratinocytes. It is significant to note that inhibiting TWEAK had a comparable effect on reducing epidermal thickness, skin infiltrates, and inflammatory mediators as inhibiting TNF-α and IL-17A (Chauhan et al., 2020).

Role of microbiome in psoriasis pathogenesis

Research on the impact of the microbiome on psoriasis severity is emerging, providing insight into the complex interplay between the body’s microbial ecosystems and an inflammatory, chronic skin disorder. Dysbiosis, which is marked by changes in the variety and makeup of the microbiota and includes opportunistic pathogens such as human papillomavirus, Malassezia, and Candida albicans, as well as bacteria (Staphylococcus aureus and Streptococcus pyogenes). Psoriasis and dysbiosis are closely related conditions (Baliwag, Barnes & Johnston, 2015).

Cell signaling

The signaling pathway, which affects both keratinocytes and immune cells, is a key regulator of psoriasis and is implicated in a variety of biological factors. Nuclear factor-kappa B (NF-κB), Signal transducer and activator of transcription (STAT), MAPK, and other significant signalling pathways are changed in psoriasis (Megna et al., 2020).

NF-κB signaling pathway

NF-κB signaling affects immune cells and keratinocytes, which has been demonstrated to contribute to the development of psoriasis. In psoriatic patients’ lesional skin, NF-κB was intensely active. Various mice models have shown that aberrant NF-κB activation in keratinocytes and T cells is crucial for the emergence of inflammatory skin conditions like psoriasis. Skin symptoms resembling psoriasis appeared in mice with IκBα global deletion, although IκBα loss in keratinocytes only produced epidermal hyperplasia without epidermal inflammation. However, the loss of IκBα in keratinocytes and T cells produced a phenotype that was comparable to that of global deficit. Furthermore, the phenotype that emerged in global IκBα knockout animals was reversed by the targeted deletion of RelA from keratinocytes. Additionally, Imiquimod-induced psoriasis-like dermatitis was less severe in mice lacking in NF-κB. These findings suggest that NF-κB activation is necessary for psoriasis to develop in immune cells as well as keratinocytes (Pradeep et al., 2022a).

The phosphorylation, ubiquitination, and proteasomal degradation of the IκBs occur as a result of the stimulation of several cell membrane receptors, including the tumour necrosis factor receptor (TNF)R, IL-1 receptor, Toll-like receptor, T-cell receptor (TCR), and B-cell receptor (BCR). IκB kinases (IKKs), α and β which are complexed with the regulatory component NEMO (NF-κB essential modulator; IKKγ), catalyse the phosphorylation at two serines at the amino-terminus of IκB. The active IKK complex primarily uses IKKβ to phosphorylate IκB. This causes adjacent lysine residues to undergo lysine 48 (K48)-linked polyubiquitination, which is started by the ubiquitin E3 ligase complex Skp1/Cul1/F-box protei–TrCp. The NF-κB bound IκB is then degraded at the 26S proteasome because of this. Once in the nucleus, free NF-κB dimers link to NF-κB DNA sites and start the transcription of genes (Fig. 4) (Rosenbach et al., 2010).

STAT signaling pathways

It is well established that the JAK (Janus kinase)/STAT signaling is crucial for the development of psoriasis. Notably, STAT3 is the most hyperactive of the STATs and controls cell proliferation, differentiation, and death in both immune cells and keratinocytes. In response to several inflammatory cytokines in psoriasis, such as IL-6, IL-17, IL-21, IL-19, IL-22, etc., STAT3 plays a key function in keratinocytes. Inhibition of cell differentiation, increased cell proliferation, and generation of antimicrobial peptides were all effects of STAT3 activation in keratinocytes. The psoriasis-like lesions with cytokine profiles comparable to those of human psoriatic plaques spontaneously developed in the transgenic mouse model overexpressing STAT3 in keratinocytes. Additionally, selective ablation of STAT3 in keratinocytes as opposed to T cells decreased dermatitis like psoriasis. Therefore, STAT3 in keratinocytes plays a more significant role in the development of psoriasis (Shivalingaiah et al., 2022a) this is shown in Fig. 5.

Complications and prognosis

Psoriasis is a chronic inflammatory disorder that can affect multiple organ systems in the body and is associated with various complications. Here are some of the complications of psoriasis along with their respective research article references (Robinson et al., 2012).

Comorbidities

Psoriasis is largely caused by chronic inflammation, which also increases the risk of autoimmune diseases like multiple sclerosis and inflammatory bowel disease as well as endocrine abnormalities like thyroid dysfunction. Psoriasis has been connected to chronic kidney disease, most likely because of nephrotoxicity from medications and systemic inflammation (Fernández-Guarino et al., 2016). Patients with psoriasis are also more likely to experience sleep problems, such as obstructive sleep apnea, which may exacerbate fatigue and negatively impact general health. These comorbidities emphasize the necessity of treating psoriasis with a multidisciplinary approach, making sure that treatment plans consider both the skin ailment and its more extensive systemic repercussions (Boehncke & Schön, 2015).

Psychosocial impact

Psoriasis is accompanied by severe psychological comorbidity, which imposes a burden that goes far beyond the disease’s outward clinical manifestations. Suicidal thoughts, drug abuse, and psychosocial comorbidities including anxiety and depression are all closely linked to psoriasis. According to recent studies, even while up to 98% of patients believed that their skin condition had impacted their emotional or psychological health, just 18% sought assistance. This care gap is mostly a result of inadequate detection, diagnosis, and triage, as well as a lack of knowledge about the few services that are offered (Armstrong, Harskamp & Armstrong, 2013).

One study investigated the impact of psoriasis on the quality of life of patients. The study found that psoriasis patients reported a reduced quality of life compared to the general population. The patients reported experiencing emotional distress, social stigmatization, and lower self-esteem due to the disease. Furthermore, the study found that patients with more severe psoriasis reported more significant negative impacts on their quality of life than those with mild or moderate psoriasis (Koller et al., 2011).

The patients with extreme psoriasis were more likely to experience depression than those with milder forms of the disease. The study also found that depression was more common in patients who reported a higher degree of disability due to psoriasis. Several studies have also found that psoriasis can have a notable impact on a patient’s social and occupational life. Patients may experience social isolation, discrimination, and decreased work productivity due to the disease (Parisi et al., 2013).

These studies highlight the significant psychosocial impact of psoriasis on patients’ lives. Healthcare providers should consider the emotional and social aspects of the disease when managing psoriasis patients and provide appropriate psychological support when needed.

Impact on quality of life

Psoriasis significantly impairs the health-related quality of life (HRQoL) of its patients. According to a National Psoriasis Foundation survey, more than 75% of patients said their illness interfered with their everyday activities. At least 20% of patients have considered suicide, indicating that emotional suffering is also prevalent (Raho et al., 2012). Due to the physical and psychological effects of the illness, over 60% of patients report missing an average of 26 days of work annually, which has an impact on productivity. Due to missing employment and treatment expenses, this results in financial burdens (Strohal et al., 2015).

Patients frequently experience stigma, humiliation, and embarrassment, as well as poor body image and bad coping strategies. These elements lead to a lower quality of life, which is further worse by actions like concealing lesions or avoiding social situations. However, psoriasis’s non-contagious characteristic can improve the quality of life and ease some social discomfort (Aurangabadkar, 2013).

Coping strategies are essential for handling the mental and physical difficulties associated with psoriasis. The quality of life is enhanced by constructive coping mechanisms like seeking assistance, lowering stress, and keeping up excellent skincare practices. While open communication with loved ones lessens isolation, stress management practices like mindfulness and taking up a hobby can help manage symptoms (Table 4). Additionally, getting medical advice guarantees individualized care and emotional support (Armstrong et al., 2017).

HRQoL is also considerably improved by support groups. Patients who take part in these groups report feeling less depressed and anxious, knowing more about their illnesses, and following their treatment regimens more closely. These communities offer emotional support and a feeling of belonging, which enhances general well-being (Svanström, Lonne-Rahm & Nordlind, 2019).