Psoriasis- dysfunctional immune system and fat metabolism. Effects of vitamin D, psoriasis-specific treatments and bariatric surgery

Introduction

Psoriasis is a chronic, systemic, inflammatory and immune-mediated disease where both genetic and lifestyle factors play an important role in the disease pathogenesis. Psoriasis is a generalized inflammatory disease that can affect the joints, and is associated with metabolic complications such as diabetes, cardiovascular diseases and obesity. Psoriasis can be improved or worsened by a wide range of external and internal factors and therefore these factors can be used to investigate pathogenesis, prevention and treatment potentials in psoriasis.

We investigate how inflammation and the accompanying symptoms are affected by psoriasis-specific treatments and bariatric surgery. Our research program includes both registry-based studies and clinical interventional studies. By using biochemical and molecular biological methods as well as new advanced imaging techniques, we can study the skin and its metabolic and immunological processes.

Background

Psoriasis affects 2-3% of the Swedish population. Psoriasis is not limited to the skin but is associated with significant comorbidities such as psoriatic arthritis and metabolic syndrome. Obesity and metabolic syndrome (hypertension, hyperlipidemia, obesity and diabetes) are common in patients with psoriasis. High blood fats and disturbed metabolism of cholesterol and triglycerides are often found in these patients. Obesity can lead to more severe psoriasis and make patients less able to respond to their treatments. (1,2) On the other hand, obesity is a growing health problem with growing need for prevention and treatment options.

There are different types of psoriasis, however plaque psoriasis is the most common form (about 90%). To assess the severity of psoriasis, various assessment instruments are used in specialist care, such as PASI (Psoriasis Area and Severity Index), BSA (Body Surface Area), PGA (Physician`s Global Assessment) and DLQI (Dermatology Life Quality Index). PASI is the most commonly used tool based on an assessment of the extent and severity of the lesions (scale 0-72). With the help of these instruments, mild, moderate and severe psoriasis are defined.

• Mild psoriasis PASI <3, PGA <2, BSA <3, DLQI ≤ 5
• Moderate psoriasis PASI 4-10, PGA = 3, BSA 3-10, DLQI 6-10
• Severe psoriasis PASI> 10, PGA = 4, BSA> 10, DLQI> 10

The treatment for psoriasis consists of topical therapy including cortisone creams, calcipotriol cream (vitamin D preparations), phototherapy with ultra violet light B (UVB) and systemic treatments with oral immunomodulators (for example methotrexate (MTX)) or subcutaneous biological drugs (for example etanercept which is a tumor necrosis factor-αlpha inhibitor (TNF-α inhibitor). Decisions regarding psoriasis treatment are based on an assessment of the severity of the disease, the presence of comorbidities and, where possible, the identification and elimination of factors that aggravate the disease. Through changes in lifestyle (healthy diet, physical activity, smoking cessation and abstinence from alcohol) we can act preventively against psoriasis and its comorbidities but also improve the effect of medical treatments.

Inflammation vid psoriasis

The cause of psoriasis is considered to be a combination of genetic factors and external factors. The disease is presented by the red, sometimes thick, and scaly plaques in the skin. However, psoriasis is a generalized inflammatory disease with an increased risk of joint inflammation (psoriatic arthritis) and metabolic complications such as obesity, diabetes and cardiovascular diseases.

The inflammation is dominated by T helper cells type 1 (Th1) and Th17 cells and neutrophilic granulocytes.

Factors affecting inflammation in psoriasis

Vitamin D och ultraviolet light

Vitamin D is a cholesterol-derived hormone, produced in the skin by ultraviolet light B (UVB) of wavelength 280-315 nm. Vitamin D inhibits the proliferation of keratinocytes and stimulates their differentiation. UVB has an immunomodulatory effect that is considered partially mediated via vitamin D.

The immunomodulatory effect of vitamin D is exerted via binding of its active form (1,25(OH)2D3) to the vitamin D receptor (VDR). VDR is found in immune cells, T cells and in the keratinocytes.

We have previously published a new application for mass spectrometry, Time of Flight Secondary Ion Mass Spectrometry (TOF-SIMS), to analyze the distribution of cholesterol, vitamin D and its metabolites in adipose tissue. (3)

Vitamin D circulates in the blood as 25(OH)D bound to both DBP (vitamin D-binding protein) and albumin, and as free vitamin D. It is technically complicated to measure free vitamin D and this is not routinely done in the clinic. As an alternative, free vitamin D can be calculated using validated mathematical models. (4) Recently, a new method for measuring free vitamin D has been established at Department of Clinical chemistry at Sahlgrenska University Hospital.

The free hormone hypothesis has been proposed and free vitamin D is the best biomarker for clinical effect because the positive health effects attributed to vitamin D correlate better with the level of free vitamin D in serum than with the level of protein-bound vitamin. This could explain why previous studies examining the link between vitamin D and the severity of psoriasis have shown conflicting results. (5)

Tumor necrosis factor αlpha inhibitor (TNF-α inhibitor)

Patients with severe psoriasis are treated with biologics where TNF-α inhibitors are most common. (6) Vitamin D inhibits TNF-α production in vitro. However, the opposite theory that TNF-α inhibition induces increased levels of vitamin D, has not been fully examined. Moreover, the knowledge about how vitamin D deficiency and UVB induced increase in vitamin D affect inflammation in psoriasis is stil limited.

Our preliminary results show that circulating immune cells in patients who have received UVB treatment release less TNF-α. It supports our hypothesis that external treatment with UVB can reduce inflammation in the skin through its effect on vitamin D. It underlines the importance of treating inflammation in the skin and by that reduce the risk of associated diseases.

Adipose tissue

The metabolic syndrome, obesity and lipid disturbances are common in patients with psoriasis. Obesity causes more severe psoriasis and can also worsen the response to a given treatment. Several studies have shown that adipose tissue is involved in the development of psoriasis. (1,2) This effect has previously been linked to abdominal fat, but recent findings show that subcutaneous fat can also have a direct effect on overlying skin.

With advanced microscopy (non-linear microscopy (NLM) and mass spectrometry imaging (MSI)) technology, we have recently shown that the lipid content in psoriasis plaques is higher than in unaffected skin and normalizes during UVB-therapy.(7)

Time-Of-Flight Secondary ion mass spectrometry (TOF-SIMS) is an imaging technique that can identify elements and organic molecules. In our pilot studies, we have demonstrated a new unique application of the method that makes it possible to study the distribution and quantification of lipids, vitamin D and its metabolites in the skin. (7,8) TOF-SIMS therefore becomes a valuable tool in our sub-projects.

Bariatric surgery - effects on psoriasis

The clinical link between obesity and psoriasis is strengthened by studies presenting that bariatric surgery leads to the improvement, and in some cases complete remission, of psoriasis. It has also been shown that bariatric surgery has a positive effect on comorbidity in psoriasis. The link between bariatric surgery and improvement in psoriasis thus seems clear, but the conclusions are so far based on a few smaller studies and long-term follow-up evidence is lacking (9).

Obesity surgery today is performed using mainly two different methods, Roux-en-Y gastric bypass (RYGP) and Sleeve gastrectomy (SG), with different endocrine effects. One theory behind the known positive effect of the RYGP method on diabetes is to increase the secretion of Glucagon-like peptide 1 (GLP-1) which stimulates glucose metabolism. It has also been shown that GLP-1 may have positive effects on psoriasis (10). Therefore it is important  to compare the impact of different surgical methods on the psoriasis disease.

Scientific question / purpose

We investigate how inflammation in psoriasis is affected by obesity and psoriasis-specific treatments. We are looking for knowledge that aims to improve the prevention and treatment of chronic systemic inflammation related to psoriasis.

Therefore, we want to investigate:

How are the skin, subcutaneous fat, vitamin D and lipid metabolism affected by the treatment of psoriasis?

Can bariatric surgery lead to durable improvement of psoriasis in obese patients with severe disease? Is there any difference between bariatric surgery procedures?

Can imaging techniques such as non-linear microscopy (NLM) and mass spectrometric imaging (MSI) with high three-dimensional resolution map the distribution of different types of lipids and proteins in the skin of patients with psoriasis? Can morphological changes in adipose tissue under the psoriasis plaque correlate with the treatment response and disease prognosis?

Is there any link between vitamin D and the severity of psoriasis  and how can knowledge about this be translated into clinical practice?

Preliminary results and significance

Our use of MSI including TOF-SIMS to study lipids and vitamin D in skin and subcutaneous fat provides unique opportunities to visualize the distribution of these molecules in the skin tissue. This method has great potential to become an important tool in research of the local and systemic impact of adipose tissue in psoriasis. (7,8) We will investigate  this connection from several standpoints, not least through planned clinical registry-based and intervention studies that will examine how the treatment of obesity in the form of bariatric surgery affects psoriasis.

Vitamin D as a hot topic in medical research is well studied, but when serum levels of vitamin D are related to clinical outcomes, then it can cause inconsistent results.             Free vitamin D in serum can be a better biomarker and therefore our study of free vitamin D, vitamin D-binding protein (DBP) and relation to the severity of psoriasis is of particular value. Phototherapy of psoriatic skin may reduce the release of TNF-α. This effect is probably mediated via UVB induced production of vitamin D.

References

1. 1. Herron, M.D., et al., Impact of obesity and smoking on psoriasis presentation and management. Arch Dermatol, 2005. 141(12): p. 1527-34.

2.Fleming, P., et al., The Relationship of Obesity With the Severity of Psoriasis: A Systematic Review. J Cutan Med Surg, 2015. 19(5): p. 450-6.

3. Malmberg P, Karlsson T, Svensson H, Lönn M, Carlsson NG, Sandberg AS, Jennische E,Osmancevic A, Holmäng A. A novel approach to measuring vitamin D in adipose tissue using time-of-flight secondary ion mass spectrometry: A pilot study. Journal of Photochemistry and Photobiology B: Biology 138 (2014) 295–301

4. Karlsson T, Osmancevic A, Jansson N, Hulthen L, Holmäng A, Larsson I. Higher vitamin D binding protein and lower free 25(OH)D in obese Swedish women of reproductive age, Eur J Nutr. 2014 Feb;53(1):259-67,

5. Osmancevic A, Landin-Wilhelmsen K, Larko O, AL Krogstad. "Vitamin D status in psoriasis patients during different treatments with phototherapy" J Photochem Photobiol B. 2010 (2):117-23. PMID: 20579901

6.Salah L, Gillstedt M, Osmancevic A. A Retrospective Study on Patients with Psoriasis Treated with Biologics: Relation to BMI and Gender UP Acta Derm Venereol. 2016 Nov 2;96(7):974-975. 10.2340/00015555-2438.PMID:27120180,

7. Siekkeri Vandikas M, Hellström E, Malmberg P, Osmancevic A. Imaging of vitamin D in psoriatic skin using time-of-flight secondary ion mass spectrometry (ToF-SIMS): A pilot case study. J Steroid Biochem Mol Biol. 2019 Feb 28;189:154-160. Impact factor 4.095                                          
8. Agarwal NR, Dowlatshahi Pour M, Vandikas MS, Neittaanmäki N, Osmancevic A, Malmberg P Investigation of psoriasis skin tissue by label-free multi-modal imaging: a case study on a phototherapy-treated patient. Psoriasis, 2019 Jul 17;9:43-57. doi: 10.2147/PTT.S200366. eCollection 2019

9. (Sako, E.Y., S. Famenini, and J.J. Wu, Bariatric surgery and psoriasis. J Am Acad Dermatol, 2014. 70(4): p. 774-9.).

10. (Faurschou, A., et al., Gastric bypass surgery: improving psoriasis through a GLP-1-dependent mechanism? Med Hypotheses, 2011. 77(6): p. 1098-101).