**4.2.3 Coal tar**

Coal tar is an effective and cheap treatment modality for scalp Psoriasis but staining and an acrid smell associated with its use may have an important impact on patients QOL. Topical tar solution (liquor picis carbonis-LPC, or liquor carbonis detergens-LCD) is widely available and commonly used for scalp Psoriasis. Newer preparations specifically meant for scalp include coconut oil compound ointment (coal tar solution with precipitated sulfur, salicylic acid, coconut oil, yellow soft paraffin and emulsifying wax) and tar pomades (contain LCD, Tween 20 and salicylic acid in a hydrophilic ointment). Compound ointment should be applied once at night and washed off the next morning with a coal tar shampoo. Coal tar shampoos contain 1-20% coal tar extract. They are used twice a week. A tar blend 1% shampoo Polytar (Steifel, Johannesburg, South Africa) is made of coal tar, juniper tar (cade oil) and pine tar. In a comparative 4-week study of tar blend 1% shampoo (Polytar)

Head and Neck Psoriasis 91

properties. Calcipotriol/betamethasone dipropionate showed low systemic absorption and displayed local anti-inflammatory and immunoregulatory properties. It reduced hyperproliferation of keratinocytes and helped normalize keratinocyte differentiation. In large, well designed clinical trials, calcipotriol/betamethasone dipropionate, either as the ointment or the gel formulation, applied once a day for 4-8 weeks, was more effective than placebo, calcipotriol and tacalcitol, as well as betamethasone dipropionate in most instances, for the topical, symptomatic treatment of Psoriasis vulgaris of the trunk/limbs. Likewise, calcipotriol/betamethasone dipropionate gel applied once daily for 8 weeks was more effective than placebo or either component alone in the topical, symptomatic treatment of Psoriasis vulgaris of the scalp. Long-term, once a day, when required therapy with calcipotriol/betamethasone dipropionate for 52 weeks was more effective than calcipotriol alone for the treatment of scalp Psoriasis and was at least as effective as switching to calcipotriol for 48 weeks after 4 weeks of calcipotriol/betamethasone dipropionate or alternating between calcipotriol/betamethasone dipropionate and calcipotriol every 4 weeks for 52 weeks in the treatment of Psoriasis vulgaris of the trunk/limbs.

Calcipotriol/betamethasone dipropionate also improved health-related QOL.

(see Fig. 1).

Calcipotriol/betamethasone dipropionate was generally well tolerated, with most adverse drug reactions being lesional or perilesional effects of mild or moderate severity

Calcipotriol/betamethasone dipropionate was often associated with fewer lesional/ perilesional adverse reactions than calcipotriol or tacalcitol and did not appear to be

Fig. 1. Scalp Psoriasis after treatment with calcipotriol/betamethasone dipropionate gel

formulation , applied once daily for 4 weeks.

and CP 0.05% shampoo (Clobex, Galderma, Ft. Worth, USA), the corticosteroid shampoo was significantly more effective and showed a better patient's compliance too.

Coal tar has been a very popular traditional treatment for various types of Psoriasis for over a century and still it's the first-line treatment for scalp, hand, and foot Psoriasis. However, application of coal tar on hair invariably causes staining, which results in a high degree of patient non-compliance, especially in patients with non-black hair. Thus, treatment of scalp Psoriasis with a topical coal tar formulation requires that special concern to be paid to product esthetics. A novel lecithinized coal tar (LCT) formulation seems to be less likely to stain hair and thus has excellent potential to be exploited in treatment of scalp Psoriasis (Bhatia & al. 2011).

#### **4.2.4 Tazarotene**

There are no controlled studies on the use of tazarotene in scalp Psoriasis. Response to tazarotene (0.1%) compared to topical calcipotriol or steroids is less effective but relapse rates are reported to be minor as well. Dryness and irritation are common side effects.

#### **4.3 Combination therapies**

Combining different treatment allows enhanced efficacy and minimizes toxicity. Corticosteroids, when combined with vitamin D analogs, require a minor total amount of dose and induce less skin irritation. In treatment of moderate to severe plaque Psoriasis of the scalp, the fixed-combination suspension containing betamethasone 0.05% and calcipotriene 0.005% is used once a day. In a randomized double-blind controlled trial over 8 weeks, 71.2% patients achieved "absent" or "very mild" disease with the twocompound scalp formulation, compared to 64% treated with betamethasone dipropionate, 36.8% with calcipotriene and only 22.8% with the vehicle alone. Pruritus was the only adverse event reported.

Topical steroids with Puvasol gave better results: 37.3% clearance versus 13.3% with Puvasol alone. LPC 10% along with 2% salicylic acid in a cream base along with Puvasol for 8 weeks gave a much better clearance rate than Puvasol alone. Tazarotene has also been found to be efficacious in combination with topical steroids and calcipotriol.

In a prospective non-interventional trial in German dermatological practices, 721 patients with scalp Psoriasis received Xamiol(®) gel (calcipotriol 50 μg/g, betamethasone 0,5 mg/g) topically for 4 weeks. Severity was assessed by physician's global assessment (PGA) and QOL was assessed by using a scalp-specific questionnaire at the beginning of the study and after 4 weeks treatment. The mean disease severity of scalp Psoriasis (PGA) improved from 4.26 to 2.49 (-41.8 %, p < 0.0001) during 4 weeks treatment and QOL improved from 10.57 to 3.22 (-69.5 %, p < 0.0001). Among patients with pre-treatment 89.5% of patients and 87.9% of dermatologists judged treatment response to Xamiol(®) gel as better/much better compared to previous therapy. Tolerability of Xamiol(®) gel was rated good/very good by 98 % of dermatologists and patients, respectively. The use of Xamiol(®) gel was found easy/very easy by 90.4 % of the patients (Mrowietz, 2011).

McCormack (2001) reviewed the efficacy and tolerability of calcipotriol/betamethasone dipropionate in patients with Psoriasis vulgaris summarizing its pharmacological

and CP 0.05% shampoo (Clobex, Galderma, Ft. Worth, USA), the corticosteroid shampoo

Coal tar has been a very popular traditional treatment for various types of Psoriasis for over a century and still it's the first-line treatment for scalp, hand, and foot Psoriasis. However, application of coal tar on hair invariably causes staining, which results in a high degree of patient non-compliance, especially in patients with non-black hair. Thus, treatment of scalp Psoriasis with a topical coal tar formulation requires that special concern to be paid to product esthetics. A novel lecithinized coal tar (LCT) formulation seems to be less likely to stain hair and thus has excellent potential to be exploited in treatment of scalp Psoriasis

There are no controlled studies on the use of tazarotene in scalp Psoriasis. Response to tazarotene (0.1%) compared to topical calcipotriol or steroids is less effective but relapse rates are reported to be minor as well. Dryness and irritation are common side effects.

Combining different treatment allows enhanced efficacy and minimizes toxicity. Corticosteroids, when combined with vitamin D analogs, require a minor total amount of dose and induce less skin irritation. In treatment of moderate to severe plaque Psoriasis of the scalp, the fixed-combination suspension containing betamethasone 0.05% and calcipotriene 0.005% is used once a day. In a randomized double-blind controlled trial over 8 weeks, 71.2% patients achieved "absent" or "very mild" disease with the twocompound scalp formulation, compared to 64% treated with betamethasone dipropionate, 36.8% with calcipotriene and only 22.8% with the vehicle alone. Pruritus was the only

Topical steroids with Puvasol gave better results: 37.3% clearance versus 13.3% with Puvasol alone. LPC 10% along with 2% salicylic acid in a cream base along with Puvasol for 8 weeks gave a much better clearance rate than Puvasol alone. Tazarotene has also been found to be

In a prospective non-interventional trial in German dermatological practices, 721 patients with scalp Psoriasis received Xamiol(®) gel (calcipotriol 50 μg/g, betamethasone 0,5 mg/g) topically for 4 weeks. Severity was assessed by physician's global assessment (PGA) and QOL was assessed by using a scalp-specific questionnaire at the beginning of the study and after 4 weeks treatment. The mean disease severity of scalp Psoriasis (PGA) improved from 4.26 to 2.49 (-41.8 %, p < 0.0001) during 4 weeks treatment and QOL improved from 10.57 to 3.22 (-69.5 %, p < 0.0001). Among patients with pre-treatment 89.5% of patients and 87.9% of dermatologists judged treatment response to Xamiol(®) gel as better/much better compared to previous therapy. Tolerability of Xamiol(®) gel was rated good/very good by 98 % of dermatologists and patients, respectively. The use of Xamiol(®) gel was found easy/very

McCormack (2001) reviewed the efficacy and tolerability of calcipotriol/betamethasone dipropionate in patients with Psoriasis vulgaris summarizing its pharmacological

efficacious in combination with topical steroids and calcipotriol.

easy by 90.4 % of the patients (Mrowietz, 2011).

was significantly more effective and showed a better patient's compliance too.

(Bhatia & al. 2011).

**4.2.4 Tazarotene** 

**4.3 Combination therapies** 

adverse event reported.

properties. Calcipotriol/betamethasone dipropionate showed low systemic absorption and displayed local anti-inflammatory and immunoregulatory properties. It reduced hyperproliferation of keratinocytes and helped normalize keratinocyte differentiation. In large, well designed clinical trials, calcipotriol/betamethasone dipropionate, either as the ointment or the gel formulation, applied once a day for 4-8 weeks, was more effective than placebo, calcipotriol and tacalcitol, as well as betamethasone dipropionate in most instances, for the topical, symptomatic treatment of Psoriasis vulgaris of the trunk/limbs. Likewise, calcipotriol/betamethasone dipropionate gel applied once daily for 8 weeks was more effective than placebo or either component alone in the topical, symptomatic treatment of Psoriasis vulgaris of the scalp. Long-term, once a day, when required therapy with calcipotriol/betamethasone dipropionate for 52 weeks was more effective than calcipotriol alone for the treatment of scalp Psoriasis and was at least as effective as switching to calcipotriol for 48 weeks after 4 weeks of calcipotriol/betamethasone dipropionate or alternating between calcipotriol/betamethasone dipropionate and calcipotriol every 4 weeks for 52 weeks in the treatment of Psoriasis vulgaris of the trunk/limbs. Calcipotriol/betamethasone dipropionate also improved health-related QOL.

Calcipotriol/betamethasone dipropionate was generally well tolerated, with most adverse drug reactions being lesional or perilesional effects of mild or moderate severity (see Fig. 1).

Calcipotriol/betamethasone dipropionate was often associated with fewer lesional/ perilesional adverse reactions than calcipotriol or tacalcitol and did not appear to be

Fig. 1. Scalp Psoriasis after treatment with calcipotriol/betamethasone dipropionate gel formulation , applied once daily for 4 weeks.

(n = 425).

Valladares & al., 2011).

produced lactamase.

**4.5 Miscellaneous agents** 

their Psoriasis. No adverse events were reported.

Head and Neck Psoriasis 93

Recent findings suggest that Efalizumab may be effective for treatment of head and neck Psoriasis (Krell & al., 2008). Katsambas (2009) recorded a PSSI score for 1150 patients at baseline and by week 12; there had been a median improvement in PSSI score of 73.3% (IQR 33.3–94.3) compared with baseline. At week 12, PSSI 50 and PSSI 75 responses were achieved by 62.4% (718/1150) and 44.7% (514/1150) of patients, respectively. In many cases, a response to Efalizumab was apparent early in treatment, with over half of the patients classified as PSSI 50 responders at week 12 having already achieved this response by week 4

However, Efalizumab has now been recommended for withdrawal in European market due to adverse effects. European Medicines Agency evaluated all safety data in light of postmarketing surveillance of patients with Psoriasis receiving Efalizumab continuously for more than 3 years that showed opportunistic infections and, in particular, cases of JC virus infection (polyomavirus) resulting in progressive multifocal leucoencephalopathy (PML). It was concluded that the benefits of Efalizumab treatment no longer outweighed the risks associated with the drug and was recommended suspension of marketing authorization on 19 February 2009. The drug has also been voluntarily withdrawn from the US market.

Adalimumab, a monoclonal humanized tumor necrosis factor alpha inhibitor proved to be

Accumulating evidence supports efficacy and safety of ustekinumab for treatment of moderate to severe Psoriasis. There is some suggestion from head-to-head comparisons that ustekinumab may offer some advantage over TNF-α inhibitors. However, there is a need for larger and longer-term studies to assess the safety profile, cost-effectiveness and advantages of anti-interleukin 12 and 23 activity in the modern era of biological therapy (Garcia-

Salicylic acid 5-10% is combined with other topical therapies as a keratolytic. Many topical treatments do not work well until thick scales that reduce drug penetration are removed. Urea 10% and lactic acid 10% have been used as scalp moisturizers. In resistant cases topical imidazole derivatives are used to control the overgrowth of Pityrosporum in scalp Psoriasis. Kircik (2011) stated that Salicylic acid 6% emollient foam provides a useful option that is highly effective, well tolerated and acceptable to patients. Efficacy, tolerability and patient acceptability of salicylic acid 6% emollient foam were assessed in an open-label pilot study of 10 subjects with scalp Psoriasis. All Psoriasis severity parameters were reduced with a significant decrease in PSSI score from 15.3 to 3.0 after four weeks of monotherapy (P<0.001). Sixty percent of subjects were either "completely cleared" or "almost cleared" from

Psoriasis skin lesions can be secondarily infected with bacteria according with Brook (Brook & al., 1999). In this report the predominant aerobic and facultative bacteria were S. aureus, group D Enterococcus and Escherichia coli while the predominant anaerobes were Peptostreptococcus spp. and Bacteroides spp., Propionibacterium acnes and pigmented Prevotella spp. in two each. Nineteen of the micro-organisms isolated from 78% patients

successful in treatment of severe facial Psoriasis (Noiles & Vender, 2008).

associated with a higher incidence of corticosteroid-related adverse events during long-term therapy. Pharmaco-economic analyses predicted calcipotriol/betamethasone dipropionate to be more cost effective than other topical therapies.

Puig & al. (2010) reported the recommendations developed by an expert panel using the Delphi process to reach a consensus and then ratified by the members of the Psoriasis Group of the Spanish Academy of Dermatology and Venereology. The recommended induction therapy for scalp Psoriasis is either a topical corticosteroid or a topical treatment combining calcipotriol and betamethasone. The choice of an appropriate vehicle is crucial in improving effectiveness and patient adherence to treatment. The only formulations that have been studied in long-term treatment of scalp Psoriasis are a combination of calcipotriol and betamethasone in gel and calcipotriol alone in solution.

#### **4.4 Second line treatments for recalcitrant disease**

These are used when all topical treatments fail. No controlled studies exist regarding their use and include phototherapy and systemic drugs like methotrexate, retinoids, cyclosporine and biologics. They are used based on physician experience, choice and risk versus benefit ratio.

#### **4.4.1 Phototherapy**

Hair blocks adequate penetration of ultraviolet light. Better results are achieved with conventional UV units, if hair is parted in many rows or if the patient has thin hair or if the head is shaved. Hand-held devices (UV combs) deliver a higher intensity of UV light. There are reports of the use of targeted phototherapy with excimer laser which provides narrowband ultraviolet B (NB-UVB) (308 nm) phototherapy with a very high irradiance, allowing for a shorter treatment time.

#### **4.4.2 Biologics**

The emergence of biologic therapies as an effective modality for treatment of plaque Psoriasis may provide another option for patients. The biological agents employed in therapy of Psoriasis are classified into three groups (see Tab. 2).


Table 2. Biological agents employed in scalp Psoriasis.

associated with a higher incidence of corticosteroid-related adverse events during long-term therapy. Pharmaco-economic analyses predicted calcipotriol/betamethasone dipropionate

Puig & al. (2010) reported the recommendations developed by an expert panel using the Delphi process to reach a consensus and then ratified by the members of the Psoriasis Group of the Spanish Academy of Dermatology and Venereology. The recommended induction therapy for scalp Psoriasis is either a topical corticosteroid or a topical treatment combining calcipotriol and betamethasone. The choice of an appropriate vehicle is crucial in improving effectiveness and patient adherence to treatment. The only formulations that have been studied in long-term treatment of scalp Psoriasis are a combination of calcipotriol and

These are used when all topical treatments fail. No controlled studies exist regarding their use and include phototherapy and systemic drugs like methotrexate, retinoids, cyclosporine and biologics. They are used based on physician experience, choice and risk versus benefit ratio.

Hair blocks adequate penetration of ultraviolet light. Better results are achieved with conventional UV units, if hair is parted in many rows or if the patient has thin hair or if the head is shaved. Hand-held devices (UV combs) deliver a higher intensity of UV light. There are reports of the use of targeted phototherapy with excimer laser which provides narrowband ultraviolet B (NB-UVB) (308 nm) phototherapy with a very high irradiance,

The emergence of biologic therapies as an effective modality for treatment of plaque Psoriasis may provide another option for patients. The biological agents employed in

**Inhibitors of tumor necrosis factor-α**

**Inhibitors of Interleukin-12 and Interleukin-23** 

**T-cell modulating agents** 

to be more cost effective than other topical therapies.

betamethasone in gel and calcipotriol alone in solution.

**4.4 Second line treatments for recalcitrant disease** 

therapy of Psoriasis are classified into three groups (see Tab. 2).

Table 2. Biological agents employed in scalp Psoriasis.

**4.4.1 Phototherapy** 

**4.4.2 Biologics** 

allowing for a shorter treatment time.

Adalimumab Certolizumab Etanercept Golimumab Infliximab

Ustekinumab Briakinumab

Alefacept Efalizumab Recent findings suggest that Efalizumab may be effective for treatment of head and neck Psoriasis (Krell & al., 2008). Katsambas (2009) recorded a PSSI score for 1150 patients at baseline and by week 12; there had been a median improvement in PSSI score of 73.3% (IQR 33.3–94.3) compared with baseline. At week 12, PSSI 50 and PSSI 75 responses were achieved by 62.4% (718/1150) and 44.7% (514/1150) of patients, respectively. In many cases, a response to Efalizumab was apparent early in treatment, with over half of the patients classified as PSSI 50 responders at week 12 having already achieved this response by week 4 (n = 425).

However, Efalizumab has now been recommended for withdrawal in European market due to adverse effects. European Medicines Agency evaluated all safety data in light of postmarketing surveillance of patients with Psoriasis receiving Efalizumab continuously for more than 3 years that showed opportunistic infections and, in particular, cases of JC virus infection (polyomavirus) resulting in progressive multifocal leucoencephalopathy (PML). It was concluded that the benefits of Efalizumab treatment no longer outweighed the risks associated with the drug and was recommended suspension of marketing authorization on 19 February 2009. The drug has also been voluntarily withdrawn from the US market.

Adalimumab, a monoclonal humanized tumor necrosis factor alpha inhibitor proved to be successful in treatment of severe facial Psoriasis (Noiles & Vender, 2008).

Accumulating evidence supports efficacy and safety of ustekinumab for treatment of moderate to severe Psoriasis. There is some suggestion from head-to-head comparisons that ustekinumab may offer some advantage over TNF-α inhibitors. However, there is a need for larger and longer-term studies to assess the safety profile, cost-effectiveness and advantages of anti-interleukin 12 and 23 activity in the modern era of biological therapy (Garcia-Valladares & al., 2011).

#### **4.5 Miscellaneous agents**

Salicylic acid 5-10% is combined with other topical therapies as a keratolytic. Many topical treatments do not work well until thick scales that reduce drug penetration are removed. Urea 10% and lactic acid 10% have been used as scalp moisturizers. In resistant cases topical imidazole derivatives are used to control the overgrowth of Pityrosporum in scalp Psoriasis.

Kircik (2011) stated that Salicylic acid 6% emollient foam provides a useful option that is highly effective, well tolerated and acceptable to patients. Efficacy, tolerability and patient acceptability of salicylic acid 6% emollient foam were assessed in an open-label pilot study of 10 subjects with scalp Psoriasis. All Psoriasis severity parameters were reduced with a significant decrease in PSSI score from 15.3 to 3.0 after four weeks of monotherapy (P<0.001). Sixty percent of subjects were either "completely cleared" or "almost cleared" from their Psoriasis. No adverse events were reported.

Psoriasis skin lesions can be secondarily infected with bacteria according with Brook (Brook & al., 1999). In this report the predominant aerobic and facultative bacteria were S. aureus, group D Enterococcus and Escherichia coli while the predominant anaerobes were Peptostreptococcus spp. and Bacteroides spp., Propionibacterium acnes and pigmented Prevotella spp. in two each. Nineteen of the micro-organisms isolated from 78% patients produced lactamase.

Head and Neck Psoriasis 95

The occurrence of true psoriatic lesions on mucous membranes is disputed. For many years it has been claimed that this disease does not affect oral mucosa. Today it is thought that involvement of the oral cavity is rare but does exist. Oppenheim (1903) was the first to describe oral Psoriasis in a biopsy after histological examination. In a review of Englishlanguage and European non-English literature Younai and Phelan (1997) identified only 57 cases of oral Psoriasis. Since then, few new cases have been reported bringing the total to less than 100 cases described. The reports described a number of oral sites affected, such as lips, buccal mucosa, gums, palate, tongue and floor of the mouth. In the cases reviewed by Younai and Phelan, clinical presentation was a white intraoral lesion in 44% of patients, erythematous in 24% and red and white mixed in 13%. The remaining lesions appeared ulcerative, vesicular, pustular, or indurated. The histopathological findings in oral mucous membranes are assumed to be similar to those found in skin lesions. Epithelial parakeratosis, elongated rete ridges and the presence of an inflammatory infiltrate of the upper dermis were described in most cases. Differential diagnosis from other oral diseases such as benign migratory glossitis, fissured tongue, oral candidosis and the oral lesions of Reiter's syndrome may be subtle. The diagnosis is easily made when the clinical features of oral lesions parallels that of skin lesions and it is supported by histological investigation

**6. The rare mucous occurrence and the PPP-tonsil-related disease** 

(Weathers et al., 1974; Younai and Phelan, 1997; Bruce and Rogers, 2003).

**6.2 Recurrent streptococcal infection theory in pathogenesis of psoriasis** 

Recent immunological studies have shown that hyperactivation of tonsillar T cells is caused by a hyperimmune response to α-streptococci; recruitment of the T cells to lesions may be involved in the pathogenesis of PPP. ß1 integrin, expressed on T cells, not only provides a co-stimulatory signal for T-cell activation but also facilitates the accumulation of T cells in inflammatory skin lesions. In this study was found that expression of ß1 integrin on both tonsillar and peripheral blood CD4-positive T cells was higher in PPP patients than in non-PPP patients. It was demonstrated that ß1 integrin may play a key role in the pathogenesis

Psoriasis is a T-cell-mediated disease that can be triggered by group A beta-haemolytic

The results of many experimental studies provide evidence that Psoriasis is largely a T-cell mediated disorder. It may result from antigen-specific activation of T cells in the skin of genetically predisposed individuals. These T cells apparently have a particular functional differentiation and promote the psoriatic skin changes by secreting a certain set of cytokines. Based on the fact that streptococcal throat infections are a trigger of guttate Psoriasis, the putative psoriatic antigens are assumed to be in keratinocyte proteins that share structural homologies with streptococcal proteins and thus induce cross-reactive responses of antibacterial T cells against skin components. Together with the particular phenotype of psoriatic skin lesions these findings can suggest that Psoriasis represents a sterile antibacterial tissue reaction, which is mediated by streptococci-specific T cells that cross-

**6.1 Mucous membrane localization** 

of PPP (Ueda & al., 2010).

react against epidermal autoantigens.

streptococci infection.

The U.S. Food and Drug Administration (FDA) has approved two drugs, Protopic and Elidel, for treatment of eczema which many dermatologists have found to work well in treating Psoriasis of the face or of other sensitive areas.

#### **5. The aberrant epidermal-mesenchymal interactions theory**

The normal adult epidermis is a self-renewing tissue consisting of 10 to 20 layers in which cell proliferation is primarily restricted to the basal layer. Orthokeratinized epithelium similar to that in skin is seen in the hard palate, whereas other regions are either parakeratinized (gingiva) or nonkeratinized (buccal mucosa) (Squier & al., 1976). Injury to the epidermis activates a homeostatic response resulting in inflammation, reepithelialization, followed by tissue remodelling (Martin, 1997). Several studies have suggested release of interleukin-1 from keratinocytes at the wound site as the initial trigger for the inflammatory reaction. This serves as an autocrine signal to surrounding keratinocytes and paracrine signal to other cells, such as fibroblasts, endothelial cells, and lymphocytes resulting in a pleiotropic effect on them (Freedberg & al., 2001). The changes in gene expression that accompany re-epithelialization are similar to those seen in other disorders associated with hyperproliferation such as Psoriasis, contact dermatitis, and squamous cell carcinoma (SCC) suggesting considerable overlap in the signaling cascades. The development of a normal scar is dependent on the reversal of expression of these genes at the wound site. However, in some cases the inflammatory and proliferative signals persist even after wound closure resulting in pathological scars, such as hypertrophic (HTS) and keloid scars. Although most previous studies have considered these scars as dermal phenomena (Akagi & al., 1999), others have identified abnormalities associated with epidermal keratinocytes in HTS perhaps as a result of aberrant epidermal-mesenchymal interaction (Niessen & al., 2001). One of the most sensitive biochemical markers of terminal differentiation in keratinocytes is the keratin protein family that constitutes the major cytoskeletal architecture of all epithelia. In humans, the family consists of 30 polypeptides (including trichocytic keratins of hair and nail) that are divided into two types; type I is acidic and includes K9 to K20; type II is basic/neutral and includes K1 to K8. The normal expression of K2e in the upper spinous and granular layers of interfollicular epidermis is increased in keloid scars but showed distinct down-regulation in Psoriasis and hypertrophic scars where keratinocytes are known to undergo activation. Unlike normal and psoriatic skin, K2e expression in hypertrophic and keloid scars began in the deepest suprabasal layer. In cutaneous basal and squamous cell carcinomas, K2e was absent in most tumor islands but the overlying epidermis showed strong expression. In mild-to-moderate oral dysplasia with orthokeratinization, K2e was highly expressed compared with parakeratinized areas but in severe dysplasia as well as in oral squamous cell carcinoma, K2e expression was undetectable. Taken together, the data suggest that K2e expression in skin is sensitive to keratinocyte activation but its up-regulation in oral lesions is a reflection of the degree of orthokeratinization (Bloor & al., 2003). K 15 protein and mRNA are primarily located in the basal keratinocytes of stratified tissues (Waseem al., 1999) and the k 15 gene is upregulated in human subjects where both alleles for k 14 have beeen inactivated. In hyperproliferating epidermis, such as in Psoriasis, K 15 expression, both protein and mRNA, is downregulated, suggesting that K 15 expression may not be compatible with the activated phenotype.

The U.S. Food and Drug Administration (FDA) has approved two drugs, Protopic and Elidel, for treatment of eczema which many dermatologists have found to work well in

The normal adult epidermis is a self-renewing tissue consisting of 10 to 20 layers in which cell proliferation is primarily restricted to the basal layer. Orthokeratinized epithelium similar to that in skin is seen in the hard palate, whereas other regions are either parakeratinized (gingiva) or nonkeratinized (buccal mucosa) (Squier & al., 1976). Injury to the epidermis activates a homeostatic response resulting in inflammation, reepithelialization, followed by tissue remodelling (Martin, 1997). Several studies have suggested release of interleukin-1 from keratinocytes at the wound site as the initial trigger for the inflammatory reaction. This serves as an autocrine signal to surrounding keratinocytes and paracrine signal to other cells, such as fibroblasts, endothelial cells, and lymphocytes resulting in a pleiotropic effect on them (Freedberg & al., 2001). The changes in gene expression that accompany re-epithelialization are similar to those seen in other disorders associated with hyperproliferation such as Psoriasis, contact dermatitis, and squamous cell carcinoma (SCC) suggesting considerable overlap in the signaling cascades. The development of a normal scar is dependent on the reversal of expression of these genes at the wound site. However, in some cases the inflammatory and proliferative signals persist even after wound closure resulting in pathological scars, such as hypertrophic (HTS) and keloid scars. Although most previous studies have considered these scars as dermal phenomena (Akagi & al., 1999), others have identified abnormalities associated with epidermal keratinocytes in HTS perhaps as a result of aberrant epidermal-mesenchymal interaction (Niessen & al., 2001). One of the most sensitive biochemical markers of terminal differentiation in keratinocytes is the keratin protein family that constitutes the major cytoskeletal architecture of all epithelia. In humans, the family consists of 30 polypeptides (including trichocytic keratins of hair and nail) that are divided into two types; type I is acidic and includes K9 to K20; type II is basic/neutral and includes K1 to K8. The normal expression of K2e in the upper spinous and granular layers of interfollicular epidermis is increased in keloid scars but showed distinct down-regulation in Psoriasis and hypertrophic scars where keratinocytes are known to undergo activation. Unlike normal and psoriatic skin, K2e expression in hypertrophic and keloid scars began in the deepest suprabasal layer. In cutaneous basal and squamous cell carcinomas, K2e was absent in most tumor islands but the overlying epidermis showed strong expression. In mild-to-moderate oral dysplasia with orthokeratinization, K2e was highly expressed compared with parakeratinized areas but in severe dysplasia as well as in oral squamous cell carcinoma, K2e expression was undetectable. Taken together, the data suggest that K2e expression in skin is sensitive to keratinocyte activation but its up-regulation in oral lesions is a reflection of the degree of orthokeratinization (Bloor & al., 2003). K 15 protein and mRNA are primarily located in the basal keratinocytes of stratified tissues (Waseem al., 1999) and the k 15 gene is upregulated in human subjects where both alleles for k 14 have beeen inactivated. In hyperproliferating epidermis, such as in Psoriasis, K 15 expression, both protein and mRNA, is downregulated, suggesting that K 15 expression

treating Psoriasis of the face or of other sensitive areas.

may not be compatible with the activated phenotype.

**5. The aberrant epidermal-mesenchymal interactions theory** 
