Psoriasis

Psoriasis is a common chronic inflammatory disorder of the skin, which affects more than 2% of people with European ancestry (1). Its clinical signs and severity vary among individuals and over time. 
Four distinct pathological alterations characterise this disorder:
 

•		Inflammation.
•		Hyperproliferation of the epidermis
•		Altered maturation of the epidermis (resulting in scaling)
•		Vascular alterations (which add to redness).

Histology of psoriasis

1. Marked hyperkeratosis with parakeratosis (abnormal maturation) 

2. Loss of granular layer

3. Epidermal acathosis and elongation of rete ridges (reflecting hyperproliferative state)

4. Vascular dilatation (these vessels are abnormal as well). Generalised inflammation can also be seen, with T-lymphocytes in the dermis and epidermis. 

CLINICAL FEATURES OF PSORIASIS
Typically psoriasis presents as well-demarcated erythematous scaling plaques most often symmetrically involving the elbows, knees, lower back, and buttocks. The severity of psoriasis runs from relatively minor disease consisting of 1 or 2 small plaques to life-threatening erythrodermic psoriasis covering the entire cutaneous surface. In addition, approximate 5% of people with psoriasis eventualy develop psoriatic arthritis. This is frequently mild but can be severe and mutilating. Furthermore, pustular variants exist and some can be life threatening. 
The scalp, nails, intertriginous areas, and genitalia are often involved. When only small areas are involved, lesions are usually asymptomatic, slightly itchy, or sore. Extensive body coverage with very thick, or more inflamed lesions is more likely to itch, be tender, or bleed. These symptoms are often more striking when ambient humidity is lower (ie, in winter). Scalp plaques may be discrete and thick or may be diffuse, thick, pink, and scaly. Facial and intertriginous psoriasis usually presents as less distinct, thin, pink, scaling plaques. On the face, the scalp margin and central face are most often affected. These red scaly patches are usually found on the elbows, knees, lower back and scalp although not infrequently patches appear elsewhere including the nails. When psoriasis involves the groin, armpits, genital area and beneath the breasts, it tends to be less scaly and have a glazed appearance. Psoriasis does not cause scarring or hair loss and infrequently affects the face. 

Triger factors
The rash often seems to start after some sort of trigger factor. This may be emotional stress, skin injury (cuts and scratches for example), a streptococcal sore throat, hormones (it often first occurs at puberty), or rarely, certain medications. These factors should be avoided whenever possible by people with psoriasis. Moderate alcohol intake doesn't affect it, although it may interfere with certain treatments. Excessive alcohol aggravates psoriasis. Psoriasis is not an allergy, nor is it infectious to others. 
Psoriasis may improve or get worse during pregnancy. It does not have any harmful effect on either mother or child. 

Although the predisposition to psoriasis may pass on to the affected person's children, this does not necessarily mean they will develop the rash. If the father has psoriasis, there is about a one-in-three chance of a child developing it as well; if the mother has it the chance is about one-in-five. 
The extent of psoriasis varies, and fluctuates even without treatment. It may even disappear completely. However, the predisposition to develop psoriasis remains, so the rash may recur at a later date even when it has been absent for years. 

Differential diagnosis
Seborrhoeic dermatitis is the most common condition that is difficult to distinguish from psoriasis. When only thin, diffuse, scaly, plaques are present, seborrhoeic dermatitis of the scalp, face, or intertriginous areas and mild psoriasis may be indistinguishable. 

Chronic eczematous dermatitis may present as thick, well-demarcated plaques, which are usually more pruritic than psoriasis-related plaques. 

Other less common conditions sometimes mistaken for psoriasis includes, early cutaneous T-cell lymphoma, superficial fungal infections, and subacute cutaneous lupus erythematosus. Fortunately initial therapy for psoriasis, seborrhoeic dermatitis, eczema, and early cutaneous T-cell lymphoma, are similar. 

Scalp psoriasis


Classic well-demarcated scaling plaque


Palmar psoriasis


Genital Psoriasis


Nail Psoriasis


Intertriginous psoriasis


Psoriatic widespread erythema with superficial pustulation
(Typically seen after systemic-steroid withdrawal)


Guttate Psoriasis

Clinical subtypes:

Guttate psoriasis
More than 90% of patients who present with psoriasis have symmetrical discrete plaques, but clinical manifestations can vary greatly. The acute generalized onset of numerous small erythematous raindrop-like papules which are initially pink and become scaly characterize guttate psoriasis, the most common psoriasis variant. Pharyngeal streptococcal infection often triggers this eruption, perhaps as a result of superantigen stimulation of the immune system (2,3). 

Presumptive antistreptococcal antibiotic therapy is usually indicated. Although widespread and usually explosive in onset, guttate psoriasis often rapidly responds to sunlight or ultraviolet light therapy (4).

Pustular psoriasis:
Withdrawal of systemic steroid therapy is a frequent precipitating factor in erythrodermic and pustular flares of psoriasis (5). Pustular psoriasis may be localised or generalised. In the generalised form, fever, malaise, and widespread erythema with superficial pustulation occur. Affected individuals require expert care. Fever, fluid and electrolyte imbalances, and fear of infection may necessitate admission to hospital. Pustular soriasis may be difficult to distinguish from acute generalised exanthematous pustulosis, which is usually drug induced (6) Localised pustular psoriasis often involves the palms and soles. Inflammation and erosions from denuded pustules can be disabling. 

Nail psoriasis:
Psoriatic nail changes are frequent. They may occur alone and are associated with a higher frequency of psoriatic arthritis. Nail changes can vary from small superficial pits to severe nail dystrophy and subungual debris. Given the popularity of new treatments of onychomycosis, it is especially important to find out whether a nail dystrophy is due to psoriasis or onychomycosis. Only systemic therapies are likely to help nail psoriasis. 

Intertriginous and genital psoriasis:
Especially of the glans penis, are frequent, difficult to treat, and disturbing to patients. The characteristic genital lesion is a well-demarcated pink plaque of the glans penis. 
Psoriasis is a treatable and often overlooked cause of vulvar discomfort. Other mucosal sites are rarely affected. 
Inverse psoriasis (axilla) Well-demarcated slightly moist red plaques, with little scale, typical of inverse psoriasis seen in axilla, groin, inframammary areas, and body folds. 

Scalp psoriais:
Scalp involvement is frequent, ranging from diffuse erythema and scaling, to thick, discrete, red scaling of plaques. Whether psoriasis causes alopecia (aside from that due to traction alopecia) is not established. 

The Pathological Changes in Psoriasis Skin Lesion
 

•		In lesioned skin, polymorphonuclear leukocytes migrate from dermal vessels into the epidermis where they may form spongiform pustules.
•		Lesional psoriasis is also rich in activated CD4+ and CD8+ T-cells.
•		T- lymphocytes release proinflammatory cytokines and lymphokines that stimulate keratinocyte proliferation and induce abnormal epidermal maturation (7)
•		The superficial dermal capillary plexuses in lesioned skin become lengthened and dilatated (8) . These vascular abnormalities may persist even after treatment and clinical normalisation of the epidermis. Persistence of vascular abnormalities is associated with a more rapid recurrence of the disease.

The pathogenesis of psoriasis
The pathogenesis of psoriasis has been obscure until only recently. The dramatic increase in epidermal proliferation that occurs in psoriasis has led many investigators to focus on potential abnormalities in the keratinocytes. Recently, several lines of evidence have suggested involvement of the immune system. Many agents effective in the therapy of psoriasis are immunosuppressive. Methotrexate, ultraviolet-B radiation, psoralen photochemotherapy, corticosteroids, cyclosporine and anthralin all inhibit aspects of an immune response. The finding of two categories of lymphocytes that are concerned with cellular immunity, CD4+ and CD8+ lymphocytes at sites of psoriasis has led many authors to hypothesize that psoriasis is a T lymphocyte-mediated (9,10,11).

[1] Psoriasis is a T cell deriven disease
Recently, clinical studies provided fairly direct evidence for an involvement of T cells in the pathogenesis of psoriasis (12). T- lymphocytes release proinflammatory cytokines and lymphokines that stimulate keratinocyte proliferation and induce abnormal epidermal maturation.

The important cytokines that controle the extent of psoriatic lesion are:

• Increased production of type 1 cytokines has been demonstrated in psoriasis and is believed to be of pathophysiological importance.

• Deficiency of type 2 cytokine IL 10 wich has major impact on immunoregulation, since it inhibits type 1 proinflammatory cytokine formation. It has been found that there is a relative deficiency in cutaneous IL-10 mRNA expression in psoriasis compared with other inflammatory dermatoses. Interestingly, patients during established antipsoriatic therapy showed higher IL-10 mRNA expression of peripheral blood mononuclear cells than patients before therapy. This suggested that IL-10 might have antipsoriatic capacity.

Clinical trial was performed with subcutaneous IL-10 administration , Clinical efficiency measured by objective and subjective parameters was found. A shift toward type 2 cytokine pattern (increasing proportion of IL-4, IL-5, and IL-10 producing T cells, was observed. This clinical study demonstrated the major importance of IL-10 in psoriasis and show that IL-10 administration represents a new therapeutic approach (13). 

[2] Psoriasis may be due in part to over expresion of alpha 5 integrin fibronectin receptor 
In addition to being T lymphocyte-driven, psoriasis may be due in part to abnormal integrin expression. The alpha5 integrin fibronectin receptor is overexpressed in the in vivo nonlesional psoriatic epidermis. Thus, the fibronectin receptor appears to be one of the components required for the development of the hyperresponsiveness of psoriatic keratinocytes to signals for proliferation provided by lymphokines produced by intralesional T lymphocytes in psoriasis (14). 

Treatment
To give optimum treatment, the clinician must find out:
 

• Which aspects and to what extent the disease worries the patient and what type of improvement would substantially reduce this worry. In addition to cost and risk of treatment.

• Time required for treatment and the patient's attitude towards risk should be considered. 

• The chronic nature of the disease and the lack of treatments that induce very long-term remissions mean that treatment decisions should be viewed in the context of a lifelong disease that varies in severity when not treated. 

Pharmacological treatment
 

1. Topical corticosteroids have anti-inflammatory and antiproliferative actions. Usually they substantially flatten plaques and decrease inflammation, but complete normalisation of skin or lasting remission is the exception (15). There are dozens of topical corticosteroids available in many formulations.
   When an agent is being chosen, anatomic site, season, and type of psoriasis should be considered. With prolonged use, high potency steroids may produce striae, atrophy, and telangiectasia. Facial and intertriginous areas are particularly susceptible. Occlusive dressings enhance steroid delivery but also enhance absorption and local side effects. Withdrawal of high potency steroids can produce flares (16). Except for very high potency agents, topical steroids used on limited body areas without occlusion are unlikely to produce clinically important systemic adverse effects. Cost of chronic treatment can be substantial.

2. Topical calcipotriol: a vitamin-D analogue, binds to receptors on keratinocytes. It induces terminal epidermal differentiation and inhibits epidermal proliferation without having cytotoxic effects. It also has immunomodulatory effects. Topical calcipotriol is about as effective as moderate-to-high potency topical steroids (17). Which agent is superior varies between patients. Absorption of calcipotriol is only a problem if large quantities (>100g/week) are applied. Topical calcipotriol is more likely to irritate the facial and intertriginous areas. As with topical steroids, most patients see improvement but not complete clearing. 

3. Dithranol, a hydroxyanthrone, has been a mainstay of psoriasis treatment in Europe but is less popular in North America. It inhibits mitotic activity and a variety of enzymes crucial to reducing epidermal proliferation. It also reduces binding of growth factors to epidermal cells. Even with short-contact therapy (ie, applying for 10-60 min) irritation and staining of skin limit its acceptance (18). Although probably about as effective, dithranols are less convenient and less accepted by patients than are topical calcipotriol and steroid preparations. 

4. Topical tars: were once very popular. Their mechanism of action is not well understood. They have modest efficacy(19). Because of their smell and messiness, many patients find their use unacceptable. Although traditionally used as part of ultraviolet-B (UVB) therapy, their limited added effect and potential toxicity stand against them. Topical tar is a component of many over-the-counter preparations. 

5. Topical retinoids may be helpful, but relative efficacy or safety compared to other treatments is well quantified. 

Oral medications
At present oral medication is reserved for those with very extensive psoriasis (when 40% or more of the body surface is affected) or when it significantly interferes with function, eg. psoriasis on the palms preventing work, or on the feet preventing walking. All have potential side effects and risks which need to be carefully explained.

Methotrexate
Methotrexate tablets are taken once a week and usually result in dramatic improvement. Methotrexate inhibits dyhydrofolate reductase affecting proliferation of rapidly growing cells more than normal cells. In addition to its antimetabolic effects, methotrexate has immunological effects, such that cytokine production and lymphocyte activity are inhibited. At relatively low doses, it can induce leukopenia, hepatitis, and pneumonitis, especially in the elderly and those with impaired renal function. Even with normal liver-function tests, long-term therapy can produce liver fibrosis, necessitating periodic liver biopsy samples being taken (20). Pregnancy and breastfeeding as well as wishing to father a child are contraindications to methotrexate therapy. Only clinicians expert in its use should prescribe methotrexate. 

Acetretin
This vitamin A-like compound results in slow improvement in most cases. Unfortunately it has some side effects including dry lips, peeling palms and soles, thinning hair, tiredness and muscle pains. The side effects are dose-related but blood tests are usually necessary. It can also cause liver damage. Pregnancy must be strictly avoided whilst on acetretin and for at least 3 years afterwards.
Oral aromatic retinoids (etretinate and acitretin) modulate epidermal differentiation and immunological function. Oral retinoids are especially useful for erythrodermic and pustular psoriasis (21). 

Cyclosporin
This is an immune suppressive agent reserved for the most severe cases of psoriasis. It is very effective but may result in raised blood pressure and kidney damage, so must be carefully monitored. The observation that cyclosporin improves psoriasis made apparent the importance of immune alterations in the pathogenesis of psoriasis (22). Unfortunately, the toxicity of immunosuppressive therapies and the short duration of the remissions these agents induce limit their usefulness. 

Sunburn spectrum, narrowband, UVB 
Sunburn spectrum and narrowband,UVB inhibits DNA synthesis, and depletes intraepidermal T-cells found in psoriatic but not normal epidermis (23). The technology to rapidly deliver sufficient doses of narrowband UVB is now available. Pretreatment removal of scale is essential. Pretreatment phototesting to assess a patient's erythema response should be done to guide dosing. 

The risks of ultraviolet radiation and sunlight are similar (sunburn, photoaging, skin cancer). The long-term risks of both broadband and narrow band UVB radiation have not been well quantified, but are probably greatest for children and adolescents, and for the genitals and face in all ages. If areas of greatest susceptibility are protected, the long-term risk of ultraviolet therapy relative to the benefit for patients with moderate and severe psoriasis is usually favourable. 

Oral psoralen and UVA (PUVA) radiation has potent antiproliferative and immunomodulatory effects. PUVA also inhibits cytokine release and depletes both epidermal and dermal T-cells. Usually, PUVA rapidly clears even severe psoriasis. Remissions are longer than with UVB. Disadvantages of PUVA include cost, acute side effects (itching, nausea, headache), and its potent carcinogenic effects. The risk of squamous-cell carcinoma of the skin is strikingly increased in patients with high-dose exposure (>250 treatments) (24). The risk of melanoma is increased in patients with long-term high-dose exposure to PUVA (25). Therefore, PUVA should be reserved for whom topical therapy and UVB therapy are impractical or ineffective. 

NEW PROMISING TREATMENT OF PSORIASIS
Current pharmacological treatments are either modestly effective or have substantial risk. Psoriasis is a dynamic disease and treatment risks usually increase with cumulative doses of a specific therapy. Optimum treatment requires periodic re-evaluation often leading to changes in treatment. Because of its chronic nature, psoriasis is a great burden to many patients and a constant challenge to the clinician.

Fortunately, at most times, most patients have limited areas of affected skin, which are amenable to topical treatment. Topical medications are generally safe but vary greatly in cost and convenience. 

PhytoMe introduced PhytoCort Psoriasis cream, a completely natural product that effectively clears psoriasis without side effects. The emulsifier used in the preparation of the cream has been modified to allow the achievement of maximal effect of the active ingredient on dermal application. It is applied locally to the site of psoriatic lesion to inhibit all the pathological factors that are included in the pathogenesis of psoriasis.

ACTIVE INGREDIENTS

FUMARIA OFFICINALIS
Fumaria Officinalis extract containing fumaric acid esters has been found effective by empirical means. For severe forms of psoriasis vulgaris, the antipsoriatic fumaric acid esters (FAE) therapy has recently gained increasing acceptance and importance. Recently, clinical studies have confirmed the antipsoriatic activity of mixture of different fumaric acid esters in the treatment of large number of patients with severe psoriasis vulgaris. From 101 patients included in the study 70 completed the treatment period of 4 months. Evaluation of overall efficacy showed a decrease in psoriasis area and severity index of 80% after 4 months of therapy. None of the patients showed changes in renal function parameters throughout the study. No severe adverse events occurred. Fumaric acid derivatives are indicated in cases of severe therapy-resistant psoriasis to and can be used even for long-term application (26,27) 

It has immunomodulatory effect, which is followed after some delay by a reduction in acanthosis and hyperkeratosis. The reduction in infiltrating T-lymphocytes corresponds to that seen after systemic or intralesional therapy with cyclosporin. However, the normalization of the psoriatic plaques takes longer under the influence of fumaric acid esters than under cyclosporin (28) Within the T cell fraction a strong suppression of CD4+ and CD8+ lymphocytes was observed (29). 

This immunomodulation and the suppression of cytokines from the psoriatic cytokine network could be responsible for the beneficial effect of fumaria in the treatment of a hyperproliferative, cytokine-mediated skin disease (30). 

Studies showed regression of acanthosis and rate of proliferation, during the process of healing of the psoriatic lesions by fumaric acid esters (31 

Fumaria extract showed significant (P < 0.01) antihepatotoxic activity (32), an advantage over most of pharmacologic therapies that are hepatotoxic. In addition it controls cell functions and thus stimulates the anti-inflammatory mediator profile in human leucocytes and inhibits the proliferation of keratinocytes (33). 

ALOE VERA
Aloe vera appears to have significant antiinflammatory effect (34). Double-blind, placebo-controlled study has been done to evaluate the clinical efficacy and tolerability of topical Aloe vera extract 0.5% in a hydrophilic cream to cure patients with psoriasis vulgaris. Sixty patients with slight to moderate chronic plaque-type psoriasis were enrolled. The mean duration of the disease prior to enrollment was 8.5 years (range 1-21). Applying the cream topically without occlusion 3 times daily for 5 consecutive days per week (maximum 4 weeks active treatment with 12 months of follow-up on a monthly basis. The treatment was well tolerated by all the patients, with no adverse drug-related symptoms. By the end of the study, the cure rate of Aloe vera extract cream was 83.3% compared to the placebo cure rate of 6.6% resulting in significant clearing of the psoriatic lesion. Therefore it has been considered a safe and alternative treatment for the cure of patients suffering from psoriasis (35). 

ROSA CANINA
Rosa canina (Rosaceae) is considered a rich source of major carotenoids (natural Vitamin A source) (36). 
Studies showed that Rosa canina roots has, inhibitory effect on some of the cytokines of type 1 that contribute to the pathogenesis of Psoriasis (37), that play important role in the pathogenesis of psoriatic lesion.

ECHINACEA
Significant pharmacological effects have been found in vitro and in vivo for echinacea extract. The activity is mainly directed towards the nonspecific cellular immune system (38). 

Echinacea extract has been evaluated for its ability to stimulate the production of cytokines by normal human peripheral blood macrophages in vitro. Macrophages cultured in low concentration of Echinacea produced significantly higher levels of IL-10 (39). , which has been proved to have a protctive effect against the flaring up of psoriasis.

CALENDULA OFFICINALIS
Extract of Calendula flowers, containing triterpenoids, has been proved to be an important topical anti-inflammatory agent (40 Using emulsifier that has been modified to allow proper viscosity of the cream leads to optimaization of its antiinflammatory effect.

The healing properties of Calendula officinalis are well known, mainly in sun burn (41). 
Thus dermal application of PhytoCort cream containing the calendula extract, before sun exposure, protects the skin from the sun burning effect and allow maximum benefit of sun exposure which is considered an important line of clearing psoriasis.

MARINE YEAST SUPEROXIDE DISMUTASE
Cu, Zn-superoxide-dismutase (Cu,Zn-SOD) is an antioxidant enzyme that can be obtained from different sources with different anti-inflammatory activities. The anti-inflammatory capacity of the marine yeast was studied and compared to SOD of other sources. Studies showed that for therapy purposes alone, it appears to be a better ant-inflammatory agent than that of other sourcs (42). 

Superoxide dismutase, as antioxidant, is a free radical scavenger (43). it reduces tissue injury (44). Applying PhytoCor Cream ,containing superoxide Dismutase, locally to the skin before sun exposure protects the skin from its burning effect (45). Thus SOD is expected to have good efect in keeping the vitality of the skin and protects its layers from the aging process that could happen during the healing of the psoriathic lesion. The SOD is so effective in protecting the skin that it has been used in improving the survival of skin flap in graft transplantation (46). 

LEPTOSPERMUM
The essential oils of Leptospermum scoparium(manuka) have antimicrobial activity which is due its triketone content(47). Thus the antimicrobial activity of Leptospermum essential oil protect the skin which is affected by the psoriatic lesion from secondary infection. Also it plays important role in prophylaxis agains bacterial infection which constitue a major trigger factor for the flare up of psoriatic lesions.

VITAMIN E
Evidence from animal and human studies indicates that vitamin E plays an important role in the maintenance of the immune system. Even a marginal vitamin E deficiency impairs the immune response, while supplementation with higher than recommended dietary levels of vitamin E enhances humoral and cell-mediated immunity (48Vitamin E is considered a major antioxidant which could suppresses the inflammatory response. It inhibits the secretion of inflammatory mediators such as cytokines, vasoactive substances, free radicals and chemokines which leads to aggrevation of the inflammatory response and leads sometimes to sepsis (49). 

VITAMIN A
Experimental studies showed that Vitamin A reduces the nomber of CD4 + T-cells (50). Thus it supress CD4 cells which are involved in the pathogenesis of psoriatic lesions. Studies showed that daily vitamin is effective in preventing Squamous Cell Carcinoma (51). 

VITAMIN D3
It is vitamin-D analogue, that binds to receptors on keratinocytes. If it is applied locally it induces terminal epidermal differentiation and inhibits epidermal proliferation without having cytotoxic effects. It also has immunomodulatory effects. It is about as effective as moderate-to-high potency topical steroids (17).

METHOD OF APPLICATION:
Applied locally to the site of lesion (3-5 times daily)and massaged gently until it is absorbed by the skin. The times of application can be reduced during remission to 2-3 times daily.

GENERAL MEASURES:
Sunshine: Sun exposure is often beneficial. In order to optimize benefits and minimize risks of natural sunlight exposure for psoriasis, the following steps should be followed:
 

• Before sun exposure, patients should remove the scales using baths or emollients and apply a thin coating of HerbaCort Psoriasis Cream just before the exposure. 

• Unaffected areas and genitals should be shielded.

• Patients should regulate the duration of their exposure to achieve minimal pinkness but avoid severe sunburns, which may exacerbate psoriasis.

Baths: Soaking in warm water with a bath oil solution can soften the psoriasis and lift the scale. Bland soaps or soap substitutes are useful; detergents and antiseptics are not necessary and may irritate. 
Emollients: the psoriatic lesions should be kept soft with the moisturizing effect of HerbaCort cream to prevent it from cracking and becoming sore. 

Occlusive dressings: Patches of psoriasis that are limited in extent may improve with occlusive dressing i.e. waterproof adhesive dressings after the HerbaCort Psoriasis Cream application. 

Scalp Care: The daily use of special medicated shampoos, like dermamed therapeutic shampoo, before applying HerbaCort Psoriasis cream, is very important in scalp psoriasis. The shampoo works best if rubbed well into the scalp, and left in for 5 or 10 minutes and then washed. HerbaCort Psoriasis Cream has to be applied 3-5 times daily to keep the scalp clear. 

PRECAUTIONS:
Before starting the medication, apply the cream to small area on the front area of the forearm. Watch the area of application for immediate (15-30 minutes) or delayed (up to 24 hours) reaction in the form of redness, itchiness or burning. This test is important to exclude rare cases of hypersensitivity.

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