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group_3_presentation_3_-_plaque_psoriasis [2017/04/07 21:04]
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group_3_presentation_3_-_plaque_psoriasis [2018/01/25 15:18] (current)
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 ====== Presentation 3: Plaque Psoriasis Powerpoint File ====== ====== Presentation 3: Plaque Psoriasis Powerpoint File ======
  
-<​HTML>​ +{{:​psoriasis_slides.pdf|}}
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 ====== Introduction ====== ====== Introduction ======
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 Psoriasis is a chronic, autoimmune disease of the skin and joints (Langley et al., 2005). Robert Willan, the father of modern dermatology,​ is credited with the first detailed clinical description of psoriasis, and hence, it is also termed as Willan'​slepra (Dogra & Mahajan, 2016). Although there are five main types of of psoriasis, plaque psoriasis is the most common type, accounting for 90% of all cases (Mak et al., 2010). ​ Psoriasis is a chronic, autoimmune disease of the skin and joints (Langley et al., 2005). Robert Willan, the father of modern dermatology,​ is credited with the first detailed clinical description of psoriasis, and hence, it is also termed as Willan'​slepra (Dogra & Mahajan, 2016). Although there are five main types of of psoriasis, plaque psoriasis is the most common type, accounting for 90% of all cases (Mak et al., 2010). ​
  
-Plaque psoriasis is predominantly characterized by abnormal red, silver and scaly skin patches covering the body (Dogra & Mahajan, 2016). While the pathogenesis is unclear, plaque psoriasis is attributed to a T-cell mediated hyper proliferation of keratinocyte (Gudjonsson et al., 2004). The skin patches typically appear on the scalp, back, and the extensor surfaces like knees and elbows. Distribution and severity of plaques on the body is random, and vary greatly from patient to patient from large coverage of the body in lesions to localized plaques no larger than a dime. The stigmatizing visible markings of this condition can have a significant negative impact on the physical, emotional, and, psychosocial wellbeing of affected patients (Langley et al., 2005). ​+Plaque psoriasis is predominantly characterized by abnormal red, silver and scaly skin patches covering the body (Dogra & Mahajan, 2016). While the pathogenesis is unclear, plaque psoriasis is attributed to a T-cell mediated hyper proliferation of keratinocyte (Gudjonsson et al., 2004). The skin patches typically appear on the scalp, back, trunk, elbows, knees, and genital areas but can also affect any other areas of the body. Distribution and severity of plaques on the body is random, and vary greatly from patient to patient from large coverage of the body in lesions to localized plaques no larger than a dime. The stigmatizing visible markings of this condition can have a significant negative impact on the physical, emotional, and, psychosocial wellbeing of affected patients (Langley et al., 2005). ​
  
 {{:​pi1.png|}} {{:​pi1.png|}}
-   ​Figure:​ Plaque psoriasis +   ​Figure ​1: Plaque psoriasis 
-Image from: http://nopsoriasis.net+Image from: http://jamanetwork.com/​journals/​jama/​fullarticle/​1104805
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 {{:​screen_shot_2017-04-06_at_1.18.11_pm.png|}} {{:​screen_shot_2017-04-06_at_1.18.11_pm.png|}}
  
-   ​Figure:​ A typical psoriatic plaque+   ​Figure ​2: A typical psoriatic plaque
 Image from: http://​www.wikipedia.com Image from: http://​www.wikipedia.com
  
 {{:​screen_shot_2017-04-06_at_1.23.58_pm.png|}} {{:​screen_shot_2017-04-06_at_1.23.58_pm.png|}}
-   ​Figure:​ A red and scaly scalp lesion+   ​Figure ​3: A red and scaly scalp lesion
 Image from: http://​nopsoriasis.net Image from: http://​nopsoriasis.net
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 {{:​screen_shot_2017-04-06_at_1.16.39_pm.png|}} {{:​screen_shot_2017-04-06_at_1.16.39_pm.png|}}
  
-   ​Figure:​ Ranking the severity of psoriasis, via PASI+   ​Figure ​4: Ranking the severity of psoriasis, via PASI
 Image from: http://​www.healthline.com Image from: http://​www.healthline.com
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  ​{{:​psor_eti_.png|}}  ​{{:​psor_eti_.png|}}
-   ​Figure:​ The genetic linkage of plaque psoriasis ​+   ​Figure ​5: The genetic linkage of plaque psoriasis ​
 Image from: https://​www.slideshare.net/​Gurpgork/​psoriasis-35245580 Image from: https://​www.slideshare.net/​Gurpgork/​psoriasis-35245580
  
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 {{:​patho_psor.png|}} {{:​patho_psor.png|}}
-   ​Figure:​ Cytokine networks in psoriasis ​+   ​Figure ​6: Cytokine networks in psoriasis ​
 Image from: http://​www.nature.com/​nature/​journal/​v445/​n7130/​abs/​nature05663.html Image from: http://​www.nature.com/​nature/​journal/​v445/​n7130/​abs/​nature05663.html
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 ====== Prognosis ====== ====== Prognosis ======
  
-<style justify>TEXT</​style>​+<style justify> 
 + 
 +Psoriasis is, unfortunately,​ an incurable disease. Treatment and management options mainly exist to enhance the patient’s sense of well-being and independence (Menter et al., 2008). Although most sufferers of psoriasis do not experience any more than mild skin lesions, which are easily treatable with the use of topical therapies, some patients have a more severe form of the disease which can have a significantly negative impact on their quality of life (Menter et al., 2008). Depending on the location and severity of outbreaks, caring for, and performing basic functions, like sleeping and self-care, can become highly difficult. Plaques on certain locations, like the face and scalp, can also be particularly embarrassing for the patient and may cause individuals to isolate themselves from social activities (Menter et al., 2008). Individuals with this disease may also feel particularly self-conscious about their appearance, which could lead to a lower self-esteem and may cause depression. Some of the younger patients may also experience bullying, as a result of their condition; these factors lead to a high rate of suicide contemplation (Menter et al., 2008). However, these concerns can be mitigated if the patients seek help earlier on. Various traditional and alternative therapeutic practices exist to reduce the appearance or onset of plaques on the skin, that may allow the patient to develop a healthy self-image (Menter et al., 2008). Most of these treatment and management strategies exist only to make the patient more comfortable,​ physically and psychologically.  
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 ====== Treatment and Management ====== ====== Treatment and Management ======
  
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 + 
 +**__TREATMENT__** 
 + 
 +Treatment options are chosen that are appropriate to the severity of the condition. Mild, localized psoriasis is treated with topical therapy while more extensive, severe disease will require systemic, expensive, and potentially hazardous treatment.  
 + 
 +**Topical agents**  
 + 
 +There are several topical treatment agents available for short-term relief of this disease. The most common ones are available both over-the-counter (OTC) and by prescription,​ depending on the degree of severity (Mason et al., 2009). The first line of effective treatments includes topical steroid cream and dithranol. Alternatively,​ coal tars and keratolytic treatments, such as salicylic acid, can be employed by patients (Mason et al., 2009). These are available OTC and can be found in a variety of forms such as, shampoos (best for scalp psoriasis), creams, lotions, and ointments (Mason et al., 2009). In some cases, physicians prescribe vitamin D analogs, which act on vitamin D receptors on the skin to reduce the appearance of plaques (Wolters, 2005). Although coal tars, keratolytics,​ and vitamin D analogues are sometimes effective, some research suggests that they may be no better than placebos in the treatment of localized lesions (Mason et al., 2009).  
 + 
 +//Topical Corticosteroids//​ 
 + 
 +As mentioned in pathophysiology,​ psoriasis is an autoinflammatory disease, actively involving keratinocytes and leukocytes in the immunopathology of the disease (Uva et al., 2012). Topical corticosteroids mainly interact with the glucocorticoid receptor and initiate a series of signal transduction pathways both intracellularly and extracellularly (Uva et al., 2012). Glucocorticoids possess numerous functions such as anti-inflammatory,​ antimitotic,​ apoptotic, vasoconstrictive and immunomodulatory functions (Uva et al., 2012). These properties are closely associated with their efficacy in the skin disease treatment. The main function in the treatment of psoriasis is to reduce inflammation and modulate the activity of immune responders. This is mainly done by altering transcription of respective genes involved in anti-inflammatory,​ inflammatory,​ and immunomodulatory activity (Uva et al., 2012).  
 + 
 +//​Dithranol//​ 
 + 
 +Corticosteroids are effective when they are employed for short-term flares, but with worsening, chronic flares, dithranol is deemed more effective. Dithranol works to slow the growth of abnormal skin cells, which is why it is better for chronic and prolonged relief (Kemeny et al., 1990). The drug inhibits keratinocyte hyperproliferation,​ granulocyte function, and, in addition, may exert an immunosuppressive effect (Kemeny et al., 1990). 
 + 
 +This is supported by the results of a systemic analysis conducted by Lowe et al., which compared psoriasis improvement rates in patients treated with either dithranol or a corticosteroid. The researchers concluded that corticosteroids are most effective when used for short-term flares, and dithralin was best used for chronic treatment of the disease (Lowe et al., 1984).  
 + 
 +**Systemic Agents** 
 + 
 +Systemic agents are prescription drugs that affect the entire body. Most patients prescribed these agents will have moderate to severe psoriasis and/or psoriatic arthritis. Systemic medications are also used by those who are not responsive to or are unable to use topical medications or ultraviolet (UV) light treatment (Feldman, 2013).  
 +  
 +These drugs are taken by mouth in liquid or pill form or given by injection into the skin or muscle or through intravenous (IV) infusion (Feldman, 2013).  
 + 
 +//​Methotrexate//​  
 + 
 +This drug is in a class of medications known as antimetabolites and is typically only used in moderate to severe cases of psoriasis (Feldman, 2013). Its mechanism of action involves immunosuppression,​ in which T-cells are deactivated in order to decrease the autoimmune response to epidermal cells (Felman, 2013). It is usually taken orally, either in pill or liquid form, but can be taken via IV (Mayo Clinic, 2015). There are risks surrounding long-term use of methotrexate,​ including severe liver damage or the decreased production of white and red blood cells or blood platelets (Mayo Clinic, 2015).  
 + 
 +//​Cyclosporine//​  
 + 
 +This drug is used for adults with severe psoriasis and otherwise normal immune systems. It suppresses the activity of T-cells within the immune system, which slows the growth of skin cells (Feldman, 2013). Cyclosporine is typically taken orally in 3 to 5 mg/kg per day with symptom relief within 4 weeks (Feldman, 2013). Since this drug is suppressing your immune system, this increases the patient’s chances of infection or related health problems. There are risks with taking the medication in high doses or for long-term use and these include, high blood pressure or kidney ailments (Mayo Clinic, 2015).  
 + 
 +//Soriatane (acitretin)//​  
 + 
 +This drug is an oral retinoid, which is a synthetic form of vitamin A and usually prescribed to those with severe cases of psoriasis (Feldman, 2013). Retinoids help control the multiplication of cells, including the speed with which skin cells grow and shed, which increases in psoriasis (Mayo Clinic, 2015). The dose ranges of acitretin can be anywhere from 25 mg every other day to 50 mg daily (Feldman, 2013). Acitretin can also be prescribed in combination with UVA or PUVA therapy; shown to increase response rates (Feldman, 2013). The use of this medication may put one at risk of lip inflammation or hair loss. Those who are or may become pregnant should also be wary of this medication as it has been shown to elicit birth defects in pregnant women (Mayo Clinic, 2015).  
 + 
 +**__MANAGEMENT__** 
 + 
 +**Moisturizers and emollients** 
 + 
 +Emollients, moisturizers,​ and keratolytic agents are types of topical agents for the treatment of psoriasis. These can be used instead of, or in conjunction with classic pharmaceutical treatments to help reduce the appearance of plaques. Moisturizers are highly beneficial in normalizing the hyperproliferation,​ differentiation,​ and apoptosis of pathological keratinocytes (Fluhr et al., 2008). They also exert anti-inflammatory effects through lipids found in the moisturizer itself. Hydration of the dry surface layer of these plaques allows for repair of the barrier and improved barrier function, along with making the epidermis more resistant to external stressors (Fluhr et al., 2008). Keratolytic agents, such as salicylic acid, are beneficial when used in the initial phase of plaque formation, because it allows loosening and shedding of dead skin layers (Fluhr et al., 2008). Moisturizers and emollients, which are lipid-rich, are best used in the intermediate and chronic phase of the disease, since they allow hydration of dry skin layers and increase the water binding ability of the skin (Fluhr et al., 2008). These can also be combined with the use of bath oils, which is also another strategy patients can employ (Fluhr et al., 2008).  
 + 
 +**Balneotherapy** 
 + 
 +This type of therapy is used to treat disease by bathing in mineral springs or mineralized,​ treated, warm water. Some spas offer this type of treatment and it has shown to be particularly beneficial in the treatment of psoriasis. The emergence of this type of treatment dates back to the 1800s and was initially scoffed at by the scientific community but recent scientific evidence is emerging to support this type of treatment (Peroni et al., 2008). Although balneotherapy is practiced with a variety of mineral springs and muds, that are considerably different in hydrogeological origin, temperature,​ and chemical composition,​ the most common type used for the treatment of psoriasis is employed by bathing in the Dead Sea (Peroni et al., 2008). Since this is not readily available anywhere outside of Jordan, Israel, and Palestine, many spas utilize treatment methods that closely mimic the composition of the Dead Sea waters. A more effective, albeit costly, form of this type of therapy combines phototherapy and balneotherapy (photobalneotherapy) (Peroni et al., 2008). In a study conducted by Peroni et al., researchers evaluated the safety and efficacy of balneotherapy compared with photobalneotherapy in the treatment of chronic plaque psoriasis. The results demonstrate that even 1 week of balneotherapy and photobalneotherapy was sufficient to obtain statistically significant improvements in the PASI score (Peroni et al., 2008). Two weeks of this type of therapy induced an even greater effect in the reduction of psoriatic plaques, but in this case, photobalneotherapy was marginally more effective than balneotherapy alone (Peroni et al., 2008). Although these treatments provide a safe and effective way to reduce the appearance of plaques, they demonstrate only short-term effects (Peroni et al., 2008). When researchers followed up with these participants a few weeks after the cessation of treatment, they found that the plaques were slowly forming again, however, the treatment seemed to reduce the severity and size of plaque formation (Peroni et al., 2008). In this case, photobalneotherapy provided a more protective effect than balneotherapy alone (Peroni et al., 2008). Therefore, balneotherapy appears to be an interesting adjuvant or alternative therapy for patients with chronic plaque psoriasis, and can thus be offered to patients willing to discontinue momentarily pharmacologic therapy (Peroni et al., 2008). 
 + 
 +//​Mechanism://​  
 +Balneotherapy with sulphurous medicinal waters is known as an effective treatment in psoriasis, but there is no exact explanation for its mode of action (Boros et al., 2013). However, studies speculate that it may be linked to an increase in serum levels of anti-inflammatory neuropeptides (Boros et al., 2013).  
 + 
 +**Phototherapy** 
 + 
 +Dermatological practices of phototherapy subject patients to ultraviolet radiation in order to treat certain skin diseases. In Ancient Egyptian and Indian times, sunlight, and a plant-based extract known as psoralens, were used to treat some of the more common skin conditions, like vitiligo (Matz, 2010). Now, this type of combination is known as Psoralens and UVA therapy (PUVA) (Matz, 2010). In the past 30 years, phototherapy has cracked its way into modern medicine. Although there were some skepticisms from physicians and researchers,​ this type of therapy is best used in conjunction with other pharmacological or complementary and alternative treatments (Matz, 2010).  
 + 
 +Ultraviolet light has three categories: UVA, UVB, and UVC. Although phototherapy is most often used to treat psoriasis vulgaris, some forms of phototherapy,​ such as PUVA and UVB therapy, are effective in almost all forms of the disease (Matz, 2010). UVB therapy, which provides high doses of UVB rays, is more widely accepted because it does not require oral medication and can be used in more severe cases, or cases of pregnancy and lactation (Matz, 2010). Patients that are younger or have comorbidities with other skin diseases should avoid subjection to UV radiation, to avoid risk of malignant skin cancers (Matz, 2010).  
 + 
 +**Diet** 
 + 
 +Diet has been suggested to play a role in the aetiology and pathogenesis of psoriasis. Fasting periods, low energy diets and vegetarian diets improved psoriasis symptoms in some studies (Wolters, 2005). Most commonly, diets rich in n-3 polyunsaturated fatty acids from fish oil showed beneficial effects. All these diets modify the polyunsaturated fatty acid metabolism so that inflammatory processes are suppressed (Wolters, 2005).  
 + 
 + 
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 +<​HTML>​ 
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 +</​HTML>​ 
 + 
 +====== Future Studies ====== 
 + 
 +<style justify>​ 
 + 
 +Some studies demonstrate that patients who suffer from chronic psoriasis also have more insulin resistant profiles than healthy adults (Ucak et al., 2006). They are also more likely to develop insulin resistance (Ucak et al., 2006). The mechanism of this particular phenomenon is mostly unknown, however, future studies are being conducted to test the underlying mechanisms of action.  
 + 
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 ====== References ====== ====== References ======
 +Boros, M., Kemény, Á., Sebők, B., Bagoly, T., Perkecz, A., Petőházi, Z., ... & Helyes, Z. (2013). Sulphurous medicinal waters increase somatostatin release: it is a possible mechanism of anti-inflammatory effect of balneotherapy in psoriasis. European Journal of Integrative Medicine, 5(2), 109-118.
 +
 +Burke, A. (2017). Plaque Psoriasis. Retrieved from http://​jamanetwork.com/​journals/​jama/​fullarticle/​1104805
  
 Dogra, S., & Mahajan, R. (2016). Psoriasis: Epidemiology,​ clinical features, co-morbidities,​ and clinical scoring. Indian Dermatology Online Journal, 7(6), 471. Dogra, S., & Mahajan, R. (2016). Psoriasis: Epidemiology,​ clinical features, co-morbidities,​ and clinical scoring. Indian Dermatology Online Journal, 7(6), 471.
 +
 +Feldman, S. R., Pearce, D. J., Dellavalle, R. P., & Duffin, K. C. (2013). Treatment of psoriasis. UpToDate. http://​www.uptodate.com (accessed April, 2017).
 +
 +Fluhr, J. W., Cavallotti, C., & Berardesca, E. (2008). Emollients, moisturizers,​ and keratolytic agents in psoriasis. Clinics in dermatology,​ 26(4), 380-386.
  
 Gudjonsson, J. E., Johnston, A., Sigmundsdottir,​ H., & Valdimarsson,​ H. (2004). Immunopathogenic mechanisms in psoriasis. Clinical & Experimental Immunology, 135(1), 1-8. Gudjonsson, J. E., Johnston, A., Sigmundsdottir,​ H., & Valdimarsson,​ H. (2004). Immunopathogenic mechanisms in psoriasis. Clinical & Experimental Immunology, 135(1), 1-8.
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 Jain, S. (2012). Dermatology:​ illustrated study guide and comprehensive board review. Springer Science & Business Media. Jain, S. (2012). Dermatology:​ illustrated study guide and comprehensive board review. Springer Science & Business Media.
 +
 +Kemeny, L., Ruzicka, T., & Braun-Falco,​ O. (1990). Dithranol: a review of the mechanism of action in the treatment of psoriasis vulgaris. Skin Pharmacology and Physiology,​ 3(1),​ 1-20.
  
 Langley, R. G., Krueger, G. G., & Griffiths, C. E. M. (2005). Psoriasis: epidemiology,​ clinical features, and quality of life. Annals of the rheumatic diseases, 64(suppl 2), ii18-ii23. Langley, R. G., Krueger, G. G., & Griffiths, C. E. M. (2005). Psoriasis: epidemiology,​ clinical features, and quality of life. Annals of the rheumatic diseases, 64(suppl 2), ii18-ii23.
  
 Lew, W., Bowcock, A. M., & Krueger, J. G. (2004). Psoriasis vulgaris: cutaneous lymphoid tissue supports T-cell activation and ‘Type 1’inflammatory gene expression. Trends in immunology,​ 25(6),​ 295-305. Lew, W., Bowcock, A. M., & Krueger, J. G. (2004). Psoriasis vulgaris: cutaneous lymphoid tissue supports T-cell activation and ‘Type 1’inflammatory gene expression. Trends in immunology,​ 25(6),​ 295-305.
 +
 +Lowe, N. J., Ashton, R. E., Koudsi, H., Verschoore, M., & Schaefer, H. (1984). Anthralin for psoriasis: Short-contact anthralin therapy compared with topical steroid and conventional anthralin. Journal of the American Academy of Dermatology,​ 10(1), 69-72.
  
 Lowes, M. A., Bowcock, A. M., & Krueger, J. G. (2007). Pathogenesis and therapy of psoriasis. Nature,​ 445(7130),​ 866-873. Lowes, M. A., Bowcock, A. M., & Krueger, J. G. (2007). Pathogenesis and therapy of psoriasis. Nature,​ 445(7130),​ 866-873.
  
 Mak, R. K. H., Hundhausen, C., & Nestle, F. O. (2009). Progress in understanding the immunopathogenesis of psoriasis. Actas dermo-sifiliograficas,​ 100, 2-13. Mak, R. K. H., Hundhausen, C., & Nestle, F. O. (2009). Progress in understanding the immunopathogenesis of psoriasis. Actas dermo-sifiliograficas,​ 100, 2-13.
 +
 +Mason, A. R., Mason, J., Cork, M., Dooley, G., & Edwards, G. (2009). Topical treatments for chronic plaque psoriasis. The Cochrane Library.
 +
 +Matz, H. (2010). Phototherapy for psoriasis: what to choose and how to use: facts and controversies. Clinics in dermatology,​ 28(1), 73-80.
 +
 +Menter, A., Gottlieb, A., Feldman, S. R., Van Voorhees, A. S., Leonardi, C. L., Gordon, K. B., ... & Beutner, K. R. (2008). Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. Journal of the American Academy of Dermatology,​ 58(5), 826-850.
  
 Nestle, F., Kaplan, D., & Barker, J. (2009). Psoriasis. New England Journal Of Medicine,​ 361(5),​ 496-509. http://​dx.doi.org/​10.1056/​nejmra0804595 Nestle, F., Kaplan, D., & Barker, J. (2009). Psoriasis. New England Journal Of Medicine,​ 361(5),​ 496-509. http://​dx.doi.org/​10.1056/​nejmra0804595
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 Parrish, L. (2012). Psoriasis: symptoms, treatments and its impact on quality of life. British journal of community nursing,​ 17(11),​ 524-528. Parrish, L. (2012). Psoriasis: symptoms, treatments and its impact on quality of life. British journal of community nursing,​ 17(11),​ 524-528.
 +
 +Peroni, A., Gisondi, P., Zanoni, M., & Girolomoni, G. (2008). Balneotherapy for chronic plaque psoriasis at Comano spa in Trentino, Italy. Dermatologic therapy, 21(s1), S31-S38.
  
 “Plaque Psoriasis Pictures”. Healthline. Retrieved 2017-03-29. “Plaque Psoriasis Pictures”. Healthline. Retrieved 2017-03-29.
  
 “Psoriasis Symptoms and Triggers”. WebMD. Retrieved 2017-03-29. “Psoriasis Symptoms and Triggers”. WebMD. Retrieved 2017-03-29.
 +
 +Psoriasis: Treatment and Drugs. (2015). Mayo Clinic. http://​www.mayoclinic.org (accessed April, 2017).
  
 Raychaudhuri,​ S. K., Maverakis, E., & Raychaudhuri,​ S. P. (2014). Diagnosis and classification of psoriasis. Autoimmunity reviews, 13(4), 490-495. Raychaudhuri,​ S. K., Maverakis, E., & Raychaudhuri,​ S. P. (2014). Diagnosis and classification of psoriasis. Autoimmunity reviews, 13(4), 490-495.
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 Smith, C. H., & Barker, J. N. W. N. (2006). Psoriasis and its management. BMJ:​ British Medical Journal,​ 333(7564),​ 380. Smith, C. H., & Barker, J. N. W. N. (2006). Psoriasis and its management. BMJ:​ British Medical Journal,​ 333(7564),​ 380.
 +
 +Ucak, S., Ekmekci, T. R., Basat, O., Koslu, A., & Altuntas, Y. (2006). Comparison of various insulin sensivity indices in psoriatic patients and their relationship with type of psoriasis. Journal of the European Academy of Dermatology and Venereology,​ 20(5),​ 517-522.
 +
 +Uva, L., Miguel, D., Pinheiro, C., Antunes, J., Cruz, D., Ferreira, J., & Filipe, P. (2012). Mechanisms of action of topical corticosteroids in psoriasis. International journal of endocrinology,​ 2012.
 +
 +Wolters, M. (2005). Diet and psoriasis: experimental data and clinical evidence. British Journal of Dermatology,​ 153(4), 706-714.
 +
 +
  
  
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