Exploring the Connection Between IBD and Psoriasis

Inflammatory bowel disease (IBD) and psoriasis are chronic inflammatory conditions with a lifelong relapsing-remitting course. The prevalence of psoriasis among IBD patients increases compared to the general population and, similarly, psoriasis patients are at increased risk of developing IBD, with a particular association with psoriatic arthritis (PsA).

IBD and psoriasis require treatment, often with immunosuppressive medications with substantial overlap in effective drugs between the two conditions. The development of powerful targeted therapies is changing the landscape of these chronic inflammatory diseases.

In this clinical era, partnership between different specialists becomes more important and collaborative decision making has become more common. Due to this need, many centers have promoted cooperative forums. This article sought to bring together knowledge on the pathogenesis and treatment of psoriasis and IBD to allow effective assistance between physicians from different areas.

Psoriasis is characterized by inflammatory hyperproliferation of keratinocytes, impairment of skin barrier function, and infiltration of activated immune cells. IBD is also characterized by damage to the intestinal barrier function and infiltration of both innate and adaptive immune cells leading to inflammation of the intestinal mucosa with ulceration and fibrosis.

The onset of both conditions is usually at an early age with a maximum around 15 to 30 years of age. Both IBD and psoriasis tend to be more aggressive in those with pediatric onset.

In psoriasis, the predominant phenotypes are the following: plaque psoriasis (75-80%) with red, scaly, well-defined skin lesions that develop in typical locations such as the scalp and extensor surfaces and guttate psoriasis (15 to 18 %) with sudden onset of smaller, generalized scaly lesions that usually follow a throat infection. Rare and severe phenotypes are erythrodermic and pustular psoriasis.

The IBD phenotype is traditionally divided into ulcerative colitis (UC), which causes inflammation of the colonic mucosa continuously and proximally from the anus, and Crohn’s disease (CD), which generates discontinuous inflammation and affects any part of the gastrointestinal tract. Furthermore, CD may be associated with stricturing or penetrating behavior with the formation of abdominal and perianal fistulas and abscesses. There is increasing evidence, including both genetic and microbiological methods, that the traditional division between CD and UC may not reflect the true underlying pathogenesis and that the different phenotypes are likely to overlap across a spectrum of diseases.

> Associated inflammatory conditions

Both psoriasis and IBD are associated with a range of other inflammatory comorbidities (a clinical phenotype that can be termed multifocal inflammation) but with different profiles. Arthropathy occurs in both conditions and PsA develops in 30% of psoriasis patients. Unlike IBD, psoriasis is also highly associated with vascular inflammation and lipometabolic diseases, such as obesity, hypertension, diabetes, and cardiovascular diseases.

Up to 50% of IBD patients develop extraintestinal inflammation, the most common being spondyloarthropathies, primary sclerosing cholangitis, ocular inflammation such as anterior uveitis, and skin inflammation including erythema nodosum, pyoderma gangrenosum, and psoriasis. The prevalence of arthritis in patients with IBD is somewhat lower than in patients with psoriasis.

The current paradigm of IBD pathogenesis describes an aberrant immune response against the gut microbiota in a genetically susceptible host following (often as yet unidentified) environmental triggers. Similarly, in psoriasis, genetic predisposition combined with environmental factors leads to abnormal immune activation in the skin.

> Epidemiology

Psoriasis appears to affect men and women generally equally. Similarly, the overall incidence of IBD is comparable between sexes, although the relative frequency of diagnosis of CD and UC may vary at different ages. This is in contrast to many other autoimmune diseases that show a female preponderance.

For both IBD and psoriasis, there is geographic variation with higher incidence of the disease in Europe and North America and lower incidence rates in Asia and the Middle East.

> Genetics

Despite evidence of the role of environmental factors, it is clear that genotype underlies the risk of IBD and psoriasis.

One of the greatest risk factors for developing IBD is having an affected first-degree relative, with the risk of developing IBD in siblings of patients with CD being around 5%. Similarly, the risk of suffering from psoriasis throughout life increases with the number of related family members, being 25% with an affected sibling or parent and up to 50% with 2 close relatives.

New psoriasis susceptibility genes have recently been identified with functions including antigen presentation, specific cytokines and their cytokine receptors, downstream inflammatory signaling pathways, and epithelial functions. Similarly, many novel IBD pathways have been discovered including innate immunity, T cell activation and differentiation, T and B cell regulation, epithelial barrier function and repair, and NF-jB and IL-23 pathways.

> Epigenetics

Epigenetic mechanisms alter gene expression without changing the underlying DNA sequence; some examples include DNA methylation, histone modifications, and non-coding RNA-mediated gene regulation. Fundamentally, these epigenetic factors represent a substrate for the interaction between genetic and environmental risk factors.

The extent to which epigenetic links may underlie the clinical relationship between IBD and psoriasis and potentially inform future treatments has not yet been fully explored.

> Environment

Several environmental factors have been identified as important for the development of IBD, including birth order, smoking, breastfeeding, and exposure to antibiotics in childhood or in utero.

For psoriasis, the relative contribution of the environment is smaller and the relevant factors are less defined. Stress, infections and some drugs have long been known to trigger psoriasis, while obesity and smoking increase the risk of developing psoriasis, but little is known about the mechanisms through which these factors act.

> Microbiota

The central role of the intestinal microbiota in the pathogenesis of IBD is clear. Diversion of fecal flow results in resolution of intestinal inflammation. A skin-joint axis has been proposed to explain the relationship between changes in gut microbiota, increased permeability, and disruption of immune homeostasis that may contribute to skin and joint inflammation; however, more evidence is needed to confirm and explore these associations.

The role of the microbiota is less clear in psoriasis. The composition of the skin microbiota changes in psoriasis compared to healthy skin; However, it is still unclear whether these changes are of pathogenic significance or simply a consequence of chronic skin inflammation.

> Diet

Diet is a key modulator of the gut microbiota. This observation, along with patients’ desire to manage the disease nutritionally, has led to a variety of studies on dietary management.

For example, adherence to a traditional Mediterranean diet (including legumes, fruits, vegetables, nuts, fermented dairy products) has been associated with a lower risk of developing CD. IBD patients with strictures are recommended to follow a low-fibre diet and, in pediatric IBD, there is good evidence of the effect of exclusive enteral nutrition (EEN) in the treatment of acute flares of the disease.

The impact of diet on psoriasis is controversial. Interestingly, there is an association between psoriasis and celiac disease, and in patients positive for antigliadin and with high transglutaminase titers, an improvement in skin lesions can occur with a gluten-free diet.

> Smoking

Smoking is associated with a higher risk of developing psoriasis and is also associated with more severe psoriasis and a worse response to treatment.

There is also a paradoxical association between smoking and IBD: smoking is positively associated with CD but negatively associated with UC. Smoking is also associated with lack of response to anti-TNF in patients with CD.

Smoking is also associated with an increased risk of some of the known comorbidities of psoriasis, primarily cardiovascular disease. Additionally, smoking appears to increase the risk of inflammatory skin disease and joint disease in IBD patients. Therefore, smoking cessation programs are a key feature for the treatment of psoriasis, PsA, and CD.

The identification of disease-associated cytokines has provided a basis for the development of antibody-based biological drugs. However, demonstration of the role of specific molecules in pathogenesis does not always translate into therapeutic efficacy.

TNF-α is a cytokine with broad proinflammatory effects and is a central target for inhibition in multiple immune-mediated diseases such as IBD, psoriasis, PsA, and spondyloarthritis.

IL-23 is produced by dendritic cells and promotes the proliferation and activation of Th17/Th22 cells, which in turn produce IL-17 and IL-22; This is a central pathway in the pathogenesis of psoriasis, as demonstrated by the effectiveness of biological treatments targeting this pathway in UC, CD, and psoriasis.

Additionally, many anti-inflammatory cytokines are critical for immune homeostasis and healing. In the intestine, IL-10 and TGF- β from regulatory T cells and IL-22 produced by Th17 cells and innate lymphoid cells are important in promoting mucosal restitution.

There are several common mechanisms proposed in the pathogenesis of IBD and psoriasis. Lifestyle factors such as obesity and smoking are important in both diseases. Genetic overlap has been identified and this link is evidenced by the higher rate of psoriasis in relatives of IBD patients and vice versa.

Evidence is accumulating to support the pathogenic role of a variety of specific dietary factors in IBD, as described above, while the psoriasis literature implicates dietary caloric content and obesity. This may reflect a difference in the importance of diet in pathogenesis, although it may also reflect the fact that diet is often a focus for patients with gastrointestinal symptoms.

In both psoriasis and IBD, a combination of genetic/epigenetic and environmental factors leads to immune activation in the affected tissue. In both conditions, TNF-α and IL-23 appear to play an important role in promoting inflammation, while the roles of other inflammatory mediators such as IL-17 and IL-22 differ in psoriasis and IBD, which also is reflected in the response to targeted treatments.

> Treatments - IBD

Conventional treatment: IBD cannot currently be cured, but many patients can achieve a prolonged remission with long-term medications. Glucocorticosteroids are a mainstay for IBD flare and can be administered locally, orally, and/or intravenously.

The second pillar of treatment for acute IBD are 5-aminosalicylate (5-ASA) drugs, which can be used locally or orally in high doses for the induction of remission and in lower doses for maintenance.

Antimetabolites: Thiopurines (azathioprine and 6-mercaptopurine) interfere with cell replication through their metabolite 6-thioguanine, which replaces guanine in DNA replication.

Another anticancer drug, methotrexate, inhibits folic acid metabolism, reducing the conversion of homocysteine ​​to methionine and suppressing lymphoproliferation. The use of antimetabolites is limited to maintenance treatment due to delayed therapeutic effect.

Monoclonal antibodies: have revolutionized the treatment of systemic inflammation and are used to suppress acute inflammation and maintenance therapy. Infliximab, adalimumab and golimumab were the first to show convincing clinical efficacy in IBD, targeting TNF-α and its precursor.

Ustekinumab, a second-generation monoclonal antibody against the p40 subunit common to the cytokines IL-12 and IL-23, is an established therapy for psoriasis and by blocking these cytokines it promotes Th1 and Th17 responses. This antibody has also been shown to be effective for both CD and UC.

JAK inhibitors: The intracellular tyrosine kinases, Janus kinase (JAK)1, JAK2 and JAK3, and tyrosine kinase 2 (TYK2), regulate a wide range of different cellular functions such as activation, proliferation, differentiation and migration.

> Treatments - Psoriasis

Psoriasis is very heterogeneous and most patients have mild disease. For these, topical agents remain the mainstay of treatment, including topical corticosteroids and vitamin D analogues, often in combination with natural sunlight or ultraviolet (UV) therapy. For the 20-30% of people with more severe psoriasis, treatment options have changed and improved dramatically in recent decades.

Traditional systems: Methotrexate has been used for the treatment of psoriasis and PsA for decades and is still widely used. For patients with moderate disease activity, it may be sufficient to control symptoms. Potential dangers include liver and bone marrow toxicity, and the medication requires close monitoring.

Acitretin was introduced in the 1970s. Its role is diminished in favor of newer and less teratogenic drugs, but it may be indicated, for example, in pustular psoriasis. Cyclosporine is highly effective and is currently used primarily as short-term rescue, as long-term use is associated with nephrotoxicity.

Biological: The introduction of monoclonal antibodies targeting cytokines with a central role in the pathogenesis of psoriasis has completely changed the perspectives of patients. Starting with medications that block TNF-a and later moving to more specific targets such as IL-17 and IL-23

The main obstacles currently are rare phenotypes, such as pustular psoriasis, and multifocal disease, such as concomitant arthritis or IBD, where therapies may not work equally well in both conditions.

Despite impressive progress in our understanding and treatment of immune-mediated inflammatory diseases, significant challenges remain. In this sense, we not only see many similarities but also differences between IBD and psoriasis.

> Prognostic indicators

In IBD and psoriasis, current clinical phenotypes harbor a collection of biological variations with differences in severity, prognosis, and therapeutic response. However, robust diagnostic biomarkers are still lacking; This is an area that deserves more research and where we can expect real progress.

An important aspect of the treatment of both IBD and psoriasis is the early identification of patients who will have an aggressive course of the disease, offering the possibility of timely and targeted interventions. This can prevent suffering and organ damage and protect patients from unnecessary exposure to medication side effects.

> Biomarkers

So far there is very limited data. In IBD, frequently relapsing disease has been predicted using CD8+ T cells. Prognostic value has also been found for fecal markers such as calprotectin and lactoferrin and serological markers directed at autoantigens.

> Top-down versus bottom-up strategies

In both psoriasis and IBD, the traditional treatment paradigm has been a stepwise procedure that begins with the least potent therapies, which are also typically the safest, and progresses up the therapeutic ladder to more potent therapies with greater associated risks (the "intensive" approach).

> Secondary response loss

Secondary loss of response to biologic drugs occurs when a patient with a good initial response to a drug subsequently develops symptoms attributable to the initial inflammatory diagnosis while still taking the drug.

It may be due to subtherapeutic drug levels secondary to the development of anti-drug antibodies (ADA). To prevent ADAs, many patients treated with infliximab also receive concomitant thiopurines, which appear to inhibit ADA formation and result in higher concentrations of the biologic drug. However, combined therapy implies a greater infectious and neoplastic risk.

> Treatment of patients with comorbidities

Patients with psoriasis are at increased risk of developing not only IBD but also PsA, cardiovascular disease, obesity, diabetes, depression, and other comorbidities such as other immune-mediated diseases and depression. Along with genetic and lifestyle factors, it has been proposed that the association of psoriasis with these diseases may be explained by low-grade systemic inflammation.

> Special shapes and locations that are difficult to treat

In both psoriasis and IBD, the severity of the disease and the response to treatment are heterogeneous. However, in both patient groups there are also specific phenotypes that are particularly difficult to manage. While most patients with plaque psoriasis respond well to biological treatment, other forms of psoriasis (such as pustular psoriasis) represent a challenge for treatment.

In certain forms of IBD, such as perianal CD and fistulizing disease, remission may be difficult to achieve. Management of perianal disease requires carefully planned coordination between surgical intervention and immunosuppression.

Despite the many similarities in the pathogenesis and treatment of IBD and psoriasis, there are clinical challenges that are specific to each condition.

> Therapeutic alternatives

In the treatment of IBD, there are 6 biological drugs available covering 3 different molecular targets (TNF, IL-23/IL-12 and anti-integrin therapies). For psoriasis there are around 12 biological drugs available that cover 4 therapeutic targets (TNF, IL-23/IL-12(p40), IL-23 (p19) and IL-17).

> Lack of primary response to medications

A specific challenge in the management of IBD is the phenomenon of primary nonresponse to first-line biologic medications.

This is thought to be due to the molecular target of the therapy being irrelevant or redundant in the inflammatory cascade in the specific individual (mechanical failure), but may also be related to inadequate serum concentrations of the drug (pharmacokinetic failure). The reason for the higher rate of primary nonresponse in IBD compared with other chronic inflammatory diseases is unknown, but may be due to greater molecular heterogeneity.

> Dose optimization: therapeutic drug monitoring

There may be specific characteristics of IBD that negatively affect the maintenance of constant drug levels; For example, loss of biologic drugs through the intestine is important in IBD, while serum drug concentrations may be more stable in psoriasis. With this in mind, there is increasing evidence of the benefits of proactive therapeutic drug monitoring.

> Treatment goals

Treatment goals are defined with the goal of improving outcomes and reducing the risk of end-organ damage, which for IBD includes progression to stricture, fistula, or functional impairment of the intestine. Recently, mucosal healing defined endoscopically (but increasingly also histologically and in the future perhaps even molecularly) has become the gold standard for establishing treatment success in IBD and has also been linked to improved outcomes.

In psoriasis, the development of more effective treatments has meant that treatment goals have become more ambitious. A 75% improvement in disease severity, the previous gold standard, is no longer considered a sufficient response to treatment, but >90% improvement, resulting in clear or nearly clear skin, is often a goal. realistic treatment.

The use of biologic drugs is associated in some patients with the induction of inflammatory disease at a second site (e.g., a patient with CD may develop psoriasis during treatment with infliximab). Although patients with inflammatory disease are intrinsically at increased risk of developing multifocal inflammation, it would appear that new manifestations of inflammation may be drug dependent. When a new inflammatory condition occurs during treatment with a drug that is generally considered a treatment for that condition (such as infliximab), it is called paradoxical.

Paradoxical inflammation poses a diagnostic and therapeutic challenge. Specific inquiry into the presence of skin lesions in patients newly diagnosed with IBD will define those in whom psoriasis is present before starting biologics.

The reverse scenario (development of IBD during anti-TNF treatment for psoriasis) is less common. Paradoxical IBD (most commonly CD) has been reported in rheumatologic patients receiving anti-TNF or etanercept.

Psoriasis and IBD represent classic immune-mediated inflammatory diseases that were once considered on a course destined with little hope for effective or curative treatment.

Today the perspective has changed drastically. A deeper understanding of pathogenic mechanisms coupled with successful drug development is now providing hope to patients, and there is even talk of changing the course of the disease.

Greater understanding of the clinical and molecular links between different chronic inflammatory conditions has developed closer collaboration between specialties in hospitals around the world with great potential for the exchange of skills and knowledge.