Psoriasis is a non contagious pathological condition of the skin which involves an inflammatory response (Ryan, Sheila, 2010). This disease has a greater impact on the social relationship of the patient, since there is the involvement of the skin. Skin is the largest organ in the human body, which covers almost 1.6-1.9 m2 and having thickness of less than 0.05 -0.03cm. Protection from UV radiation and microorganisms, temperature regulation, production of hormones and chemicals (e.g. Vit-D) and elimination of salts and water being its important functions (Torotora and Grabowski, 2003). Apart from the above mentioned functions skin play a crucial role in the exfoliation process. To know about psoriasis it is essential to know the anatomy of the skin and the process of cell cycle. Skin consists of two layers epidermis and dermis which meet at dermal- epidermal junction. Having a thickness on 1-3mm epidermis consists of stratified squamous epithelium with five different layers. They are,
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Stratum corneum : It is the outer most layer consists of dead squamous cells which is being shed and replaced continually.
Stratum lucidam : cells are closely packed and clear without nuclei, contain gel like material called elciden which get transformed into keratin.
Stratum granulosum : keratinisation begins from this layer with the help of keratohyalin.
Stratum spinosum : it consists of 8-10 layers cells are of irregularly shaped, equipped with RNA for protein synthesis.
Stratum basale : have single layer of columnar cells. Mitosis of epithelial cells commences here. Stratum spinosum together with stratum basale called stratum germinativum.
New cells are produced from Stratum basale and move towards Stratum corneum, takes place about 28-35 days to reach and this is known as regeneration time or turn over time. But in psoriatic skin, the actively dividing keratinocytes migrate from Stratum basale to Stratum cornium within a short span which takes place almost 4-7 days (Torotora and Grabowski, 2003). As a result of this immature keratinocytes reaches the surface of the skin which lacks nuclei and there is the accumulation of keratin on stratum corneum. This keratin is not desquamated resulting in the formation of scales of psoriasis (Ryan, Sheila, 2010). As a result of this there is an increased supply of blood to the dermis layer this ultimately cause erythamatous plaques and inflammatory response. There is no age limit for the disease to occur but studies suggest an increase incidence in late adolescence (Emanuel Rubin and Howard M. Reisner, 2009)
Aetiology and causes:
The precise reason behind the occurrence of the disease is unknown. However, scientists have discovered some factors that cause the condition. One among the factor is genetics or familial history of the patient. It was found that in close relatives the occurrence is more; the twin studies also support the fact. The incidence is more in monozygotic twins than the dizygotic. Studies also suggest the involvement of different genes (Ryan, Sheila, 2010).
Environment the very next factor plays a crucial role in the development of the disease. They are known as triggering factors. Some of them are as follows,
1. Trauma: There is an increase tendency for psoriasis to occur on trauma sites also known as Koebner phenomenon.
2. Alcohol: Enhances the condition, particularly in males.
3. Smoking: Increases the severity of the disease.
4. Drugs: Condition worsens with certain drugs like β-blockers, anti-malarial, lithium etc.
5. Stress: Emotional stress has a synergistic effect on psoriasis.
6. Infections: β-haemolytic streptococcal pharingitis, HIV enhances the disease state.
Skin appears flaky with more silvery scales at skin surface predominantly occur on elbows, knees and scalp. (Principles of Anatomy and Physiology 10th edition Gerard J. Torotora, Sandra Reynolds Grabowski-2003). There are different clinical manifestations of psoriasis. They are,
Plaque psoriasis: It's the frequently occurred form of psoriasis. It can be found in any part of the body with erythematous plaque and silvery scale.
Guttate psoriasis: It looks like a pink (rain) drops on the body and hence the name guttate psoriasis. It has a clinical manifestation of red papules. Streptococcal infection is a triggering factor for this infection.
Scalp Psoriasis: It can be present alone or along with other psoriasis. The scales are silvery in colour and are powdery in nature. Chances of hair loss are also there.
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Flexural psoriasis: The plaques are smooth and shiny. Usually present on groin regions, axillae, navel region, armpits, etc.
Erythroderma: Majority of the body appear red in colour due to red patches. There will be more thickening and peeling of the skin.
Localized pustular psoriasis: Occur on palms and soles of feet. As the name indicates there will be pustules which gradually become dry and form brown patches.
Generalised pustular psoriasis: groups of pustules are present with inflammation. This condition is associated with fever and pain. Systemic and topical steroids enhance the condition (Ryan, Sheila, 2010).
According to onset of age psoriasis can be classified into Type I and Type II.
Type I: Manifest at early age before 40 years of age and is associated with genetic factors.
Type II: Above 40 years and is sporadic in nature (Mallon et al, 19980).
The occurrence of the disease show geographical variation. Studies have been done by individual agencies and group of researcher workers to identify the prevalence and distribution of the disease. Various criteria's have been adopted for the study like age group of the patients, sex, type of psoriasis, onset of disease, also the environmental factors that trigger the condition etc. Studies suggest that the onset of action for childhood psoriasis is 35% in people before 20 years of age and is more common in females than male (Kumar, Bhushan et al, 2004). A study done in Middleast and Denmark agrees with the above statement. Considering the studies done with 5600 patients, 36% has a familial background.
Clinical study about severity, morbidity, and frequency of psoriasis by different dermatologists among patients in with an age group ranging from 1-74 found that, in USA 5.8% of total population were affected by psoriasis and in Australia 2.3%, UK moderately high rate- 15.8+ -8.9%. In Sweden it was found to be 0.3%. (Plunkett and Marks, 1998). Psoriasis thought to be one of the main causes of morbidity in Western countries. Cardiac disease, hypertension, and diabetes cause co-morbidity in psoriatic patients(Christophers, 2000
Physological depression is common in psoriatic patients. Symptoms like itching are higher in psoriatic women. The other symptoms commonly involved are irritation , stinging or burning sensation, less sensitivity, pain and bleeding. Symptoms vary with clinical condition. One of the commonly found symptoms in psoriasis is pruritis with a range of 67-92%(Sampogna et al, 2004).
Psoriasis is an auto immune disease initiated by activated T cell immune system. Hyper proliferation of keratinocytes in epidermis and lymphocytic activation in dermis are considered as the reason for psoriasis. (Kormeili and Yamauchi, 2004). Even though the pathogenesis is not clear, diagnosis of T- lymphocytes in the early stage of disease and response to immune system targeting therapies recommends that activation of these cells is the motivating factor responsible for disease. (Wojas Pelc and Janusz, 2007)
Antigen Presenting Cells present in both epidermis and dermis gain control over the antigen when skin exposed to various endogenous and exogenous antigens. Activation of antigen presenting cells and there by maturation indicate provoked expression of counter receptors on cell surface which stimulate T cells. Activated Antigen Presenting Cells move to lymph nodes, actuate CD4 or CD8 T cells and differentiate to Th1 and Tc1 phenotypes respectively by the influence of IFN-gamma and interleukin 12, generate Type I cytokines such as IL2, TNF -α , associated with higher level of cell mediated immunity. (Lee and Cooper, 2006) CD8+ T-lymphocytes are cytotoxic type, migrate and localized in epidermis but the CD4+ are localized in dermis. (Kormeili and Yamauchi, 2004)
Increased number of T cells and dendritic cells are found in psoriatic lesions. In psoriasis these immune mechanism together with keratinocytes develop inflammation through the exaggeration of cytokines. Psoriatic keratinocytes regularly produce wide range of cytokines like IL1, TNF-α, IL6, IL7, IL8, IL18, IL23, IL20 having different biological function. TNF-α thought to be main pro-inflammatory cytokines stimulate keratinocytes and produce other mediators like Reactive Oxygen Species and NO, involved in inflammation. Th1 cytokines are over riding in psoriasis. IL-19, IL-20, IL-22 impart keratinocytes hyperplasia (Wojas Pelc and Janusz, 2007).
T-cell activation and there by cytokine production involves various pathways. CD4+ T-cell activated by Antigen Presenting Cell lead to CD40 ligand up-regulation on T-lymphocytes. CD40 ligand of T- lymphocytes ligate with antigen presenting cell CD40, generate CD80 and CD86 on T-lymphocytes. Moreover, CD2 of T- lymphocytes bind with LFA-3 which is present on Antigen Presenting Cell enhance the cytotoxic function of T -lymphocytes. Various cytokines are induced intern regulate further activation of T cell, production of cytokines and proliferation.Th1 cells brings cell mediated immunity by the release of Interleukin-2 and Interferon gamma. But the Th2 cells contribute to human response by the production of Interleukins IL-4, IL-5 and IL-10. Th1 is pro-inflammatory and Th2 is anti-inflammatory. INF-gamma may increment the Bcl-x levels and inhibits keratinocyte apoptosis. INF gamma stimulates macrophages and produce increased level of Tumor necrosis factor [TNF-α]. These cytokines are present at increased level in synovial fluid plaques of psoriatic patients (Kormeili and Yamauchi, 2004). Polymorphism of TNF alpha in promoter region mainly when adenine is replaced with guanine in position 308 and 238 leads to increased TNF alpha production (Ferreira et al, 2010).
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A normal healthy skin is equipped with anti-oxidants like glutathione peroxide, keratinocyte catalase, ascorbic acid and superoxide dismutase to defence the skin against Reactive Oxygen Species when skin is overt to various endogenous and exogenous pro-oxidant agents. A decrease level of anti-oxidants fails to defense against and there is an elevated level of H2O2 with response to pro-oxidant agents like sunlight, UVA radiation, and free iron. Excess production of reactive oxygen species in psoriasis by keratinocytes as well as activated inflammatory cells especially neutrophils, substandard functioning of anti-oxidant system leads to the production of oxygen frees radicals that damage lipids, DNA and proteins. As the reactive oxygen species detoxifying enzyme, heame oxygenase enzymes are expressed form normal keratinocytes and are responsible for protection against oxidative stress. Haeme oxygenase produce biliverdin, bilirubin and carbon monoxide are known for its anti-oxidant, anti-inflammatory, cytoprotective properties. However over expression of heame oxygenase enzymes HO-1 and HO-2 have been demonstrated in psoriasis. But an insufficient production of ferritin synthesis to deactivate free iron enhances the production of reactive oxygen species results in inflammation (Wojas Pelc and Janusz 2007).
Role of genitic factor in psoriasis is under debate. Predispositions of psoriasis in families were initially reported in 1801. Various twin studies explain the accordance rate is higher with identical twins than fraternal twins support hereditary nature in psoriasis.(Glaser et al;2001).Human leukocyte antigen-HLA- have been postulated genetic factors in association with multiple class 1 and 2 MHC- Major Histocompatibility Complex- antigen. In Type 1 psoriasis Cw 0602 allele present significantly in increased rate.(Mallon et al;1998) Early onset type psoriasis usually develop at 16-22 years thought have genetic cogency and hereditary association. Human leukocyte antigen class 1 and 2 such as HLA-B13, HLA-B17, HLA-B57, HLA-B39, HLA-Cw6, HLA-DR7 are positively associated in psoriasis. HLA-Cw6 is implicated as major risk factor. Chromosomal studies indicate the role of several genes like 17q, 4q, 6p21, 8q and 20p in polygenic predisposition. Other susceptible gene IL12B and IL23R also have been identified (Kormeili and Yamauchi; 2004).
As we know it's an auto immune disease and manifested by dermal inflammation as well excessive epidermal proliferations and plaque formations. Normally the drugs administered are not results in the eradication of the disease. But the drugs may diminish the lesions. The therapy should be continued and the doses as well the combinations should be administered according to the severity and mode of the disease, it may vary from person to person as well the severity of the disease.
The present pharmacological approach to cure this disease is done in the various profiles like combinational therapy of topical agents, emollients, antifungal, keratolytics, etc. even though the corticosteroids are the primary drugs, they gives better cure in mild to moderate patients also gives action in the chronic stage too. The therapy can be done by the administration of a potent steroid and gradually it can be replaced by milder ones.
In general the course of psoriasis is unpredictable. It can be controlled with aggressive therapy but cannot be cured completely. Exacerbations and remission are common. As we know it's an auto immune processed disease with the interference of the T-cells, the medical management is orientated to suppress or control the count of those cells in epidermis of the patient, as well controlling the cell turnover of epidermis. (K. D. Thripathi., 2008)
As mentioned above the disease has different forms and modes, so the pharmacological approach for the treatment also has a different mode which differs in every modules of the disease. Pharmacological Management as well the treatment and clinical approach of Psoriasis is enlisted below,
Generally the medicines used are
Calcipotriol-It's a moderate potency topical steroid given along with substitution of a steroid is found to be more effective. It binds with intracellular Vit D3 receptor and suppresses the proliferation-DAIVONEX 0.005%- it's an ointment applied on the skin of the psoriatic lesions twice daily.(K. D. Thripathy,2008)
Dithranol- is a potent drug used in the psoriasis especially for scalp psoriasis. It acts mainly by free radicals but its actual target is not identified yet. It is a mild irritant drug so the therapy is stated with little quantity. The cream is applied daily and gradually the quantity is increased from 0.1 to 3% until mild irritation or feeling of warmth is achieved. The course of medication is preferred with less contact time and the cream can be washed off after 30 to 45 minutes.(Carine et al.,2001)
Coal tar- it's a crude preparation which contains many phenolic groups which results in a phototoxic effect when exposed to the sunlight. It's a classic method and use has declined due to the incompatibility of the preparation like strong smell, irritation, as well allergy. Usually it is given in combination with salicylic acid in an alcoholic preparation or in the form of ointment. (carine et al., 2001)
Photo chemotherapy: PUVA-Psoralen ultra violet A- it's a method of treatment done by using UV rays in combination with photo activated psoralen. The activation is done by oxygen dependent and independent mechanisms. This therapy has its own demerits because the therapy is carried out with the help of UV rays which may cause skin cancer and other manifestations like immunological responses etc.
Tazarotene- is a topical retinoid, 0.05% and 0.1% tazarotene applied in gel form b.i.d. works by modifying abnormal epidermal differentiation. It binds to the retinoic acid receptor and modifies the gene function and stops the proliferation. It can be effective but it may produce irritation and it can be minimized by applying once in a day.
Acitretin- it's a retinoid analogue, or synthetic retinoid used i the treatment of psoriasis in combination with the other psoriatic drugs. It acts by binding on retinoic acid receptor and controls the epidermal cell maturation as well proliferation.
Demelanizing agents like-
Hydroquinone- as the name indicates it's a demelanizing agent which helps to prevent the formation of melanin in our body. In other way it inhibits the enzyme which helps in the formation of melanin, like tyrosinase, and other melanin forming enzymes. It is applied as a 2-6% creamy form for a month. Since it's a weak Demelanizing agent, there is a chance of pigmentation once the treatment is stopped or exposure to sunlight.
Monobenzone- is a derivative of hydroquinone, and gives better action. It destroys the melano cyte and produces a permanent depigmentation. The medication should be continued a period of six months and the patient should be aware of sunlight exposure.
Sunscreens- PABA and its esters- these are the agents which protect the skin from sunlight especially from those rays which are harmful to the skin tissues. They scatter those kinds of rays and protect the skin. Their ability to protect the skin can be justified by using a factor called SPF factor, most of the commercial preparation has SPF 15, (K. D. Thripathi, 2008).
Even though these above medication are available at the same time the aggressive therapy on each form of the disease gives better result than the general application of the above drugs.
Basic understanding about the pathogenesis of a disease condition is crucial for emerging new approaches to control inflammatory progression. An interventional remedy has been adopted based on the various cataract of events which lead to inflammation. They include,
- Inhibition of activated T -cell migration from epidermis to dermis.
- Disruption of Antigen Presenting cell pathway in T- cell activation.
- Inhibit cytokine production and antagonize their action.
- Annoy Th1 cytokine responses.
- Amplify Th2 cytokine reactions.
Recent and evolving immune modulatory treatments include;
Alefacept - a recombinant protein fusion consist of LFA-3 terminal part and Fe part of Human immunoglobulin. LFA-3 interaction with Antigen Presenting cell and CD2 are blocked by Alefacept by competitive inhibition. LFA-3 content of Alefacept binds with CD2 and inhibit the Antigen Presenting cell pathway, thus T- cells are not activated in addition immunosuppressant effect is produced. This is manufactured by Biogan, USA, approved by FDA in 2003, administered intra muscularly in moderate to severe plaque psoriasis.
Efalizumab- A humanized IgG1 monoclonal antibody inhibits binding of LFA-1 with ICAM-1, direct to the prevention of signal transduction and thus leading to leucocyte function loss. Manufactured by Genentech/ Xoma, USA, approved by FDA in 2003. Subcutanious injection is preferred once a week.
Etanercept - Recombinant molecular fusion of human TNF-α -p-75 receptor with Fc portion of huma IgG1. Inhibit TNF- α by binding and prevent the interaction with receptors on cell surface by inactivating TNF-α used to treat psoriatic arthritis. Manufactured by Amgen Thousand Oaks, USA. 50mg/kg/week is adult dose and for children [4-17years]0.8mg/kg/week, can be self administred subcutaneously.
Infliximab -A human mouse monoclonal antibody prevent action of TNF- alpha. It is administered intra venously 5mg/kg or 10mg/kg/week. Without any serious side effect Infliximab is well tolerated. Combination with methotrexate or alone can be used in the treatment of recalcitrant psoriasis.
Adalimumab - Human IgG1 - monoclonal antibody prevents TNF-α interact with p55 and p75 receptors on cell surface. Manufactured by Abbott Laboratories, USA and approved by FDA on 2002. 40mg/week administered sub-cutaneously.
Pimercrolimus(SDS-ASM-981) - A derivative of Macrolactum ascomycin recently being inspected to treat inflammatory disorder and known for its T- cell activation inhibition and there by proliferation. Durg for topical application is marketed by Novartis Pharmaceuticals, Switzerland.
Rosiglitazone Maleate - A well known oral thiazolidinedione manufactured by GSK, UK. Even though is used in Type 2 Diabetis treatment, it is under supervision for the psoriatic management. It is a selective agonist for Peroxime Proliferator- Activated Receptor- gamma [PPAR-gamma] exist in hepatic tissue and muscles. PPAR-gamma prevent production of cytokine and stimulate cell differentiation.PPAR- gamma is highly articulated in keratinocytes, Rosiglitazone shows decreased proliferation and differentiation of keratinocytes in the lesions of psoriasis since it is PPAR- gamma agonist.
Tazarotene - Is a retinoid orally adninistered for the management of plaque psoriasis.Tazarotenic acid an active metabolite is formed from Tazarotene is known for its action.Manufactured by Allergan, USA.(Lee and Cooper;2006)
The advancement in molecular genetics has led to the identification of genes responsible for psoriasis. Explicating the role of immune system can escort to develop improved clinical therapy. With the advancement in pharmacogenetic field the therapeutic strategies for psoriasis can be re- designed. Thus the side effect of anti-mitotic drugs is predominantly reduced; treatement is improved with maximum efficacy.
T- Cell targetting therapy: - therapies target on T- cell immune system provides better treatment in psoriasis. An effective and safe therapycan be atributed with IgG-LFA-3 fusion protein that blocks the binding of T- cell with LFA-3 via CD2.antibody targetting CD11a which is a sub unit of LFA-1 and CTLA4IG fusion protein that inhibits CD28-B7 binding are emerging therapies in psoriasis. By using these therapies, helps the patients to think ahead and lead life with conviction.
Cytokine Modulating therapies: - Treatment strategies involving monoclonal antibodies against INF-alpha have directed to a well tolerated and effective therapy for psoriatic arthrities and psoriasis. Intradermal administration of Mycobacterium vaccae has shown improvement in psoriasis by shifting Th1 cytokine to Th2. Combinational therapies like low dose of Rapamycin with low dose of cyclosporin shows significant improvement in chronic plaque psoriasis.(Kirby and Griffiths;2001).