**9. Treatment of nail psoriasis**

Psoriasis of the nails is an often neglected or overlooked disease as is evidenced by the most recent 100-page strong guidelines on psoriasis treatment (Nast et al, 2011), and it has a serious impact on the individual's daily life.

The therapy of nail psoriasis is difficult, particularly that of isolated nail psoriasis as one usually hesitates to treat it systemically. In general, systemic treatment regimens that are effective in cutaneous psoriasis also improve nail lesions. There is a general lack of welldocumented studies and they are often not or difficult to compare (Jiaravuthisan et al, 2007) and few evidence-based treatments exist (Cassell and Kavanaugh, 2006). A standardized therapeutic approach does therefore not exist and preferred treatment regimens also differ between various countries. The treatment also depends on the nail structure involved, how severe the nail dystrophy is, whether there are extraungual lesions, the time needed for applying a specific therapy, and not the least also on its cost.

### **9.1 Topical therapy**

Topical treatments are generally held not to be very effective. This has several simple reasons: Pits come from the depth of the nail pocket where the lesions are protected by the overlying proximal nail fold from being treated; lesions in the intermediate matrix are both hidden by the proximal nail fold and the nail plate; nail bed lesions are under the nail plate, which is a considerable obstacle to penetration of drugs. Ointments applied on finger nails may interfere with paper work. There are very few controlled studies on topical therapies.

**Urea (**carbamide) is known for its keratolytic property. A paste containing 40% urea (Onyster®) softens fungus infected nails to a degree that it can be atraumatically removed; this may be a starting point for topical teatment. A 10% urea nail varnish was shown to improve the biophysical properties of the nail (Krüger et al, 2006). A 15% stable urea nail lacquer (Onypso®) is advertised as "the only specific topical treatment for nail psoriasis" as it is claimed to reduce subungual hyperkeratosis. No controlled studies are available.

Nail Psoriasis 169

be considerable. Topical corticosteroid application has even been linked to tapering of the

A study on 10 nail psoriasis patients with 8% clobetasol nail lacquer resulted in reduced pitting, onycholysis and salmon spots after only 3 months of treatment. The treatment was

Betamethasone diproprionate – salicylic acid ointment over 3 to 9 months reduced the nail bed hyperkeratosis by about one half (Tosti et al, 1996), which was virtually identical to the effect of **calcipotriol**. The authors' conclusion was that calcipotriol is a safe alternative to

A combination treatment with calcipotriol cream and clobetasol cream was shown to reduce subungual keratosis by 72% after 6 months and 81% after 12 months in finger nails whereas the improvement was 70 and 72.5% in toe nails, respectively (Rigopoulos et al, 2002). For the first 6 months, calcipotriol cream was applied on weekday evenings and clobetasol cream on weekend evenings, the next 6 months only clobetasol cream was used. Side effects of calcipotriol in the treatment of nail psoriasis are rare and mild, they mainly consist of irritation, burning, erythema and diffuse urticaria (Tosti et al, 1996, Rigopoulos et al, 2002). **Cyclosporine** is an immunosuppressive calcineurin inhibitor ultimately decreasing T cell growth and migration (Baker et al, 1987). A 10% formulation in maize oil was used in three fingers of a patient (Tosti et al, 1990) with marked improvement after 2 months and almost complete clearing after 3 months. No adverse effects were observed. Cyclosporine is a hydrophobic, large molecule of 1.5 kD and difficult to incorporate into a topical preparation, but the newer calcineurin inhibitors tacrolimus and pimecrolimus are available as ointment or cream, respectively. Curiously, no controlled study with any of these two potent drugs has been conducted in nail psoriasis. Tacrolimus was found to be ineffective in plaque psoriasis, most probably due to insufficient penetration because of its large molecular weight of 802 Da, and this might have discouraged investigators to try it in nail psoriasis. **Tazarotene** is a third-generation topical retinoid for the treatment of acne and psoriasis. It binds to the nuclear retin acid receptors RAR- and RAR- exerting an effect on epidermal proliferation and differentiation. Its action in psoriasis is mainly normalization of abnormal keratinocyte proliferation and control of inflammation (Kang et al, 1996). In addition to some case reports on tazarotene use in periungual psoriasis, a double-blind controlled study was performed with the vehicle as the control. Both tazarotene 0.1% under occlusion as well as without occlusion yielded a statistically significant better reduction in onycholysis and pitting (Scher et al, 2001). Erythema, peeling of the paronychia, irritation of the finger skin and paronychia were the side effects seen in the tazarotene group whereas the vehicle was

**Indigo naturalis** is a dark-blue powder from the leaves of indigo-bearing plants. It inhibits proliferation, promotes differentiation of epidermal keratinocytes, inhibits neutrophil proinflammatory responses and suppresses TNF- induced vascular cell adhesion molecule 1 expression in endothelial cells thereby exerting an antipsoriatic effect (Lin et al, 2009). Six patients with psoriasis who had been treated for 4 years with indigo naturalis ointment or systemic Chinese herbs and whose skin lesions had responded well whereas the nails remained unchanged were treated twice daily with 1 to 2 drops of indigo naturalis oil extract onto the nail plate, fold and hyponychium. After three months, the mean reduction

found to be safe, effective and cosmetically acceptable (Sanchéz Regaña et al, 2005).

digits and to phalangeal bone resorption (Wolf et al, 1990).

topical steroids in nail bed psoriasis.

tolerated without adverse effects.

**Anthralin** (dithranol, cignoline) suppresses cell proliferation, inhibits neutrophils and monocytes, neutrophile migration and lymphocyte proliferation. It exerts a strong antiproliferative action on keratinocytes (Schröder et al, 1985). It is an old, extremely safe and very effective psoriasis remedy. Anthraline 0.4 to 2% in petrolatum was used in a study of 20 patients over a period of approximately 5 months (Yamamoto et al, 1998). There was no response in 8 and little to fair response on onycholysis, subungual hyperkeratosis and pitting in 12 individuals. Anthraline is not popular because it stains skin and clothes. Therefore the patients washed the anthraline ointment off after 30 minutes and applied 10% triethanol amine. However, nail staining cannot be completely avoided making the lesions even more obvious and embarrassing.

There are no studies on anthralin in combination with ultraviolet (Ingram regimen) or coal tar without or with UV (Goeckerman regimen) in nail psoriasis.

**5-Fluorouracil** (5-FU) is a cytostatic agent inhibiting nucleic acid synthesis and thus reducing cellular renewal. It was mainly used for the treatment of actinic keratoses and superficial basal carcinomas, but the application under occlusion or twice daily until an erosive reaction was achieved did not make it popular amongst the patients. A prospective study on 20 patients with very long-standing psoriatic pitting, hyperkeratosis or onycholysis was conducted with 1% 5-FU solution twice daily. This had to be massaged into the skin immediately adjacent to the nail for 6 months. Seventeen of the 20 subjects experienced marked improvement in pitting and subungual hyperkeratosis (Fredriksson, 1974). One patient with onycholysis lost all affected nails that finally regrew but with the same onycholysis as before.

In a double blind controlled study, 5-FU in a penetration enhancer consisting of urea and propylene glycol was compared to the penetration enhancer solution alone. The preparation was applied once daily over a period of 12 weeks. There was a statistically significant improvement of the total nail area severity (NAS) score comprised of the number of pits, degree of pitting, subungual hyperkeratosis, onycholysis and salmon spots, for both preparations with no superior results seen in the 5-FU group (de Jong et al, 1999). Six subjects in the 5-FU group experienced side effects such as pain, swelling, inflammation, discoloration, onycholysis, and nail perforations. 5-FU is not widely used anymore.

**Topical steroids** have been and continue to be the most commonly used therapeutic agents for local treatment of nail psoriasis. They exert an anti-inflammatory and immunosuppressive action, inhibit leukocyte migration into the skin, decrease vascular permeability, reduce the effect of pro-inflammatory cytokines, and have an antiproliferative action. All these effects taken together make them a good treatment of nail psoriasis provided they can reach the psoriatic lesion of the nail. However, no standard therapeutic regimes exist for topical steroid therapy of nail psoriasis (Jiaravuthisan et al, 2007) as there are very few controlled studies with their use in nail psoriasis. Generally, high-potency topical steroids are prescribed that are applied once or even twice daily to the nail folds and nail bed either as a cream, ointment or solution. Once an effect has been achieved the frequency of application is reduced until about twice weekly. A proactive treatment approach may be superior although there are no controlled studies in nail psoriasis. Side effects of long-term potent topical steroid use are hypopigmentation and skin atrophy with development of telangiectasiae. It may be wise to have the patient apply antiseptics once daily during this treatment as the risk of microbial growth, particularly of *Candida spp*, may

**Anthralin** (dithranol, cignoline) suppresses cell proliferation, inhibits neutrophils and monocytes, neutrophile migration and lymphocyte proliferation. It exerts a strong antiproliferative action on keratinocytes (Schröder et al, 1985). It is an old, extremely safe and very effective psoriasis remedy. Anthraline 0.4 to 2% in petrolatum was used in a study of 20 patients over a period of approximately 5 months (Yamamoto et al, 1998). There was no response in 8 and little to fair response on onycholysis, subungual hyperkeratosis and pitting in 12 individuals. Anthraline is not popular because it stains skin and clothes. Therefore the patients washed the anthraline ointment off after 30 minutes and applied 10% triethanol amine. However, nail staining cannot be completely avoided making the lesions

There are no studies on anthralin in combination with ultraviolet (Ingram regimen) or coal

**5-Fluorouracil** (5-FU) is a cytostatic agent inhibiting nucleic acid synthesis and thus reducing cellular renewal. It was mainly used for the treatment of actinic keratoses and superficial basal carcinomas, but the application under occlusion or twice daily until an erosive reaction was achieved did not make it popular amongst the patients. A prospective study on 20 patients with very long-standing psoriatic pitting, hyperkeratosis or onycholysis was conducted with 1% 5-FU solution twice daily. This had to be massaged into the skin immediately adjacent to the nail for 6 months. Seventeen of the 20 subjects experienced marked improvement in pitting and subungual hyperkeratosis (Fredriksson, 1974). One patient with onycholysis lost all affected nails that finally regrew but with the same

In a double blind controlled study, 5-FU in a penetration enhancer consisting of urea and propylene glycol was compared to the penetration enhancer solution alone. The preparation was applied once daily over a period of 12 weeks. There was a statistically significant improvement of the total nail area severity (NAS) score comprised of the number of pits, degree of pitting, subungual hyperkeratosis, onycholysis and salmon spots, for both preparations with no superior results seen in the 5-FU group (de Jong et al, 1999). Six subjects in the 5-FU group experienced side effects such as pain, swelling, inflammation,

**Topical steroids** have been and continue to be the most commonly used therapeutic agents for local treatment of nail psoriasis. They exert an anti-inflammatory and immunosuppressive action, inhibit leukocyte migration into the skin, decrease vascular permeability, reduce the effect of pro-inflammatory cytokines, and have an antiproliferative action. All these effects taken together make them a good treatment of nail psoriasis provided they can reach the psoriatic lesion of the nail. However, no standard therapeutic regimes exist for topical steroid therapy of nail psoriasis (Jiaravuthisan et al, 2007) as there are very few controlled studies with their use in nail psoriasis. Generally, high-potency topical steroids are prescribed that are applied once or even twice daily to the nail folds and nail bed either as a cream, ointment or solution. Once an effect has been achieved the frequency of application is reduced until about twice weekly. A proactive treatment approach may be superior although there are no controlled studies in nail psoriasis. Side effects of long-term potent topical steroid use are hypopigmentation and skin atrophy with development of telangiectasiae. It may be wise to have the patient apply antiseptics once daily during this treatment as the risk of microbial growth, particularly of *Candida spp*, may

discoloration, onycholysis, and nail perforations. 5-FU is not widely used anymore.

even more obvious and embarrassing.

onycholysis as before.

tar without or with UV (Goeckerman regimen) in nail psoriasis.

be considerable. Topical corticosteroid application has even been linked to tapering of the digits and to phalangeal bone resorption (Wolf et al, 1990).

A study on 10 nail psoriasis patients with 8% clobetasol nail lacquer resulted in reduced pitting, onycholysis and salmon spots after only 3 months of treatment. The treatment was found to be safe, effective and cosmetically acceptable (Sanchéz Regaña et al, 2005).

Betamethasone diproprionate – salicylic acid ointment over 3 to 9 months reduced the nail bed hyperkeratosis by about one half (Tosti et al, 1996), which was virtually identical to the effect of **calcipotriol**. The authors' conclusion was that calcipotriol is a safe alternative to topical steroids in nail bed psoriasis.

A combination treatment with calcipotriol cream and clobetasol cream was shown to reduce subungual keratosis by 72% after 6 months and 81% after 12 months in finger nails whereas the improvement was 70 and 72.5% in toe nails, respectively (Rigopoulos et al, 2002). For the first 6 months, calcipotriol cream was applied on weekday evenings and clobetasol cream on weekend evenings, the next 6 months only clobetasol cream was used. Side effects of calcipotriol in the treatment of nail psoriasis are rare and mild, they mainly consist of irritation, burning, erythema and diffuse urticaria (Tosti et al, 1996, Rigopoulos et al, 2002).

**Cyclosporine** is an immunosuppressive calcineurin inhibitor ultimately decreasing T cell growth and migration (Baker et al, 1987). A 10% formulation in maize oil was used in three fingers of a patient (Tosti et al, 1990) with marked improvement after 2 months and almost complete clearing after 3 months. No adverse effects were observed. Cyclosporine is a hydrophobic, large molecule of 1.5 kD and difficult to incorporate into a topical preparation, but the newer calcineurin inhibitors tacrolimus and pimecrolimus are available as ointment or cream, respectively. Curiously, no controlled study with any of these two potent drugs has been conducted in nail psoriasis. Tacrolimus was found to be ineffective in plaque psoriasis, most probably due to insufficient penetration because of its large molecular weight of 802 Da, and this might have discouraged investigators to try it in nail psoriasis.

**Tazarotene** is a third-generation topical retinoid for the treatment of acne and psoriasis. It binds to the nuclear retin acid receptors RAR- and RAR- exerting an effect on epidermal proliferation and differentiation. Its action in psoriasis is mainly normalization of abnormal keratinocyte proliferation and control of inflammation (Kang et al, 1996). In addition to some case reports on tazarotene use in periungual psoriasis, a double-blind controlled study was performed with the vehicle as the control. Both tazarotene 0.1% under occlusion as well as without occlusion yielded a statistically significant better reduction in onycholysis and pitting (Scher et al, 2001). Erythema, peeling of the paronychia, irritation of the finger skin and paronychia were the side effects seen in the tazarotene group whereas the vehicle was tolerated without adverse effects.

**Indigo naturalis** is a dark-blue powder from the leaves of indigo-bearing plants. It inhibits proliferation, promotes differentiation of epidermal keratinocytes, inhibits neutrophil proinflammatory responses and suppresses TNF- induced vascular cell adhesion molecule 1 expression in endothelial cells thereby exerting an antipsoriatic effect (Lin et al, 2009). Six patients with psoriasis who had been treated for 4 years with indigo naturalis ointment or systemic Chinese herbs and whose skin lesions had responded well whereas the nails remained unchanged were treated twice daily with 1 to 2 drops of indigo naturalis oil extract onto the nail plate, fold and hyponychium. After three months, the mean reduction

Nail Psoriasis 171

Although **intralesional cyclosporine** has shown good effects in cutaneous psoriasis there

Phototherapy has been used for psoriasis for more than 100 years. Ultraviolet (UV) is known to exert an immunosuppressive effect through an effect on local and circulating immune cells, particularly on dendritic cells. Narrow band UV B of 311 nm has been shown to be most effective. Photochemotherapy combines the use of UV, usually UV A, with the topical or systemic administration of a photosensitizing agent, most commonly a psoralen. In contrast to skin psoriasis, nail psoriasis barely responds. In a study with oral PUVA on 10 patients, the skin of the proximal nail fold improved, but pitting did not improve. Nail plate crumbling cleared in three out of 4 individuals whereas onycholysis and oil drops improved slightly by approximately 50% (Marx and Scher, 1980). In contrast, in a retrospective study on the effect of different systemic treatments, PUVA improved the NAPSI score after 12, 24 and 48 weeks by 21%, 51% and 69%, Re-PUVA (combination of a retinoid with PUVA) by 27%, 65%, and 85%, ReNUVB (retinoid plus narrow-band UV B) by 21%, 48% and 64%, respectively, whereas narrow-band UV B alone had no beneficial effect (Regana et al, 2011). Topical PUVA resulted in clearing of 2 subjects with pitting and 2 with onycholysis improved substantially (Handfield-Jones et al, 1987). Even these results are surprising as the

Various studies have shown efficacy of laser treatments on cutaneous psoriasis. As angiogenesis was found to be one of the driving factors in psoriasis pathogenesis (Heidenreich et al, 2009) most studies were performed with the pulsed dye laser, which specifically targets blood vessels (Taibjee et al, 2005, Bovenschen et al, 2006). Two recent studies used the pulsed dye laser for nail psoriasis, one in comparison with photodynamic treatment (Fernández-Guarino et al, 2009), the other evaluated the effect of PDL on nail psoriasis (Oram et al, 2010). A third study not yet published (Treewittayapoom et al, in press) used two different pulse widths. All studies used a 595-nm pulsed dye laser with a spot size of 7 mm. The pulse duration in the Spanish study was 6 ms, in the Turkish one 1.5, and the Thai one compared the efficacy of 6 ms with 0.45 ms pulse width, fluences were 9, 8 – 10, and 9 and 6 J/cm², respectively. Both the PDT and the PDL group showed a decrease in the NAPSI score with no difference between the two groups (Fernández-Guarino et al, 2009). The Turkish study showed an improvement mainly of the nail bed NAPSI (Oram et al, 2010). The Thai study did not demonstrate a difference in treatment outcome between the long 6 ms pulse with 9 J/cm² group and the short 0.45 ms pulse duration with 6 J/cm² group; however, the pain was statistically significantly more intense in the longer pulse

**Superficial radiotherapy** delivers the radiation energy mainly to the skin surface. Three patients were treated with 400 to 600 cGy. Although no changes were noted during the 4-

are no reports on intralesional cyclosporine in nail psoriasis.

**9.3 Physical treatment modalities** 

**9.3.1 Phototherapy and photochemotherapy** 

nail is a very efficient UV shield (Stern et al, 2011).

group (Treewittayapoom et al, in press).

**9.3.3 Ionising radiation** 

**9.3.2 Laser treatment** 

in PASI was 51%, and two patients had even PASI reductions of 89 and 82%, respectively. No adverse side effects were noted (Lin, 2011).

#### **9.2 Intralesional treatments**

Intralesional injections of **corticosteroids** are widely used, either with an injection needle or by a high-pressure injector (Dermojet®, Port-O-Jet®). In most cases, crystal suspensions of triamcinolone acetonide are used with variable concentrations of 1 mg/mL (Zaias,1990) to 10 mg/mL (Scher and Daniels, 2003, de Berker and Lawrence 1998). Injections ranged from a single one (Gerstein, 1962) to once every 3 to 4 weeks for 4 to 6 months (Abell and Samman, 1973, Zaias, 1990) or monthly for the first 6 months and then 4 injections over the next 6 months followed by once every two months for the next 6 to 12 months (Norton, 1982). It appears that the number of affected nails may be a limiting factor as many patients complain of discomfort and pain. In our experience, even though most patients prefer the needle-less high pressure air gun they admitted that injection with a 30-gauge needle is less painful (unpubl. observation). The sort of high pressure injector appears to be important as there are good results with some devices and disappointing ones with others. Side effects of high pressure devices are subungual haematomas, shortterm paraesthesias, atrophy at the injection site, epidermoid inclusion cysts (de Berker, 2000), tattooing with minute rubber particles and blood splash back on the instrument and the physician.

Most intralesional injections are given into the proximal nail fold, best one each into each side of it with sparing the central area where the extensor tendon inserts in order to avoid steroid-induced tendolysis. These injection sites are good for lesions originating from the matrix, i.e. pits, ridges and severe nail plate dystrophy whereas nail bed-derived lesions such as subungual hyperkeratosis and salmon spots profit from sub-nailbed injections. These are, however, even more painful and usually require an anaesthesia to be applied.

The concentration of triamcinolon per mL does not appear to be critical as there are variations from 1mg/mL to 10 mg/mL in the literature. Higher concentrations allow smaller volumes to be injected, which then is less painful. It is still a matter of debate whether lidocaine or another local anaesthetic should be used to dilute the triamcinolone solution. In our opinion, it is both the needle prick and the pressure from the injection that are felt as uncomfortable to painful and no local anaesthetic can prevent this. Topical anaesthesia may be used, for instance with lidocaine-prilocain mixture (EMLA®), to alleviate the needle prick.

**Intralesional methotrexate** (MTX) has recently been used in a single patient (Sarcaoglu et al, 2011). MTX is a folic acid analogue irreversibly binding to dehydrofolate reductase thus blocking deoxyribonucleic acid synthesis. In addition, it was shown to exhibit an antiinflammatory effect by inhibiting the polyamine pathway in autoimmune diseases. Intralesional MTX has been shown to be effective and safe in a variety of conditions (Agostini et al, 2007). This was the rationale to use it in a psoriatic patient with pitting and subungual hyperkeratosis of only one nail. MTX 2.5 mg was injected into each side of the proximal nail fold once weekly for 6 weeks. Pain was tolerable. During the 4-month followup, the psoriatic nail alterations improved and no clinical or laboratory side effects were noted. No recurrence of the nail lesions was observed in the following two years.

in PASI was 51%, and two patients had even PASI reductions of 89 and 82%, respectively.

Intralesional injections of **corticosteroids** are widely used, either with an injection needle or by a high-pressure injector (Dermojet®, Port-O-Jet®). In most cases, crystal suspensions of triamcinolone acetonide are used with variable concentrations of 1 mg/mL (Zaias,1990) to 10 mg/mL (Scher and Daniels, 2003, de Berker and Lawrence 1998). Injections ranged from a single one (Gerstein, 1962) to once every 3 to 4 weeks for 4 to 6 months (Abell and Samman, 1973, Zaias, 1990) or monthly for the first 6 months and then 4 injections over the next 6 months followed by once every two months for the next 6 to 12 months (Norton, 1982). It appears that the number of affected nails may be a limiting factor as many patients complain of discomfort and pain. In our experience, even though most patients prefer the needle-less high pressure air gun they admitted that injection with a 30-gauge needle is less painful (unpubl. observation). The sort of high pressure injector appears to be important as there are good results with some devices and disappointing ones with others. Side effects of high pressure devices are subungual haematomas, shortterm paraesthesias, atrophy at the injection site, epidermoid inclusion cysts (de Berker, 2000), tattooing with minute rubber particles and blood splash back on the instrument

Most intralesional injections are given into the proximal nail fold, best one each into each side of it with sparing the central area where the extensor tendon inserts in order to avoid steroid-induced tendolysis. These injection sites are good for lesions originating from the matrix, i.e. pits, ridges and severe nail plate dystrophy whereas nail bed-derived lesions such as subungual hyperkeratosis and salmon spots profit from sub-nailbed injections. These are, however, even more painful and usually require an anaesthesia to be applied.

The concentration of triamcinolon per mL does not appear to be critical as there are variations from 1mg/mL to 10 mg/mL in the literature. Higher concentrations allow smaller volumes to be injected, which then is less painful. It is still a matter of debate whether lidocaine or another local anaesthetic should be used to dilute the triamcinolone solution. In our opinion, it is both the needle prick and the pressure from the injection that are felt as uncomfortable to painful and no local anaesthetic can prevent this. Topical anaesthesia may be used, for instance with lidocaine-prilocain mixture (EMLA®), to

**Intralesional methotrexate** (MTX) has recently been used in a single patient (Sarcaoglu et al, 2011). MTX is a folic acid analogue irreversibly binding to dehydrofolate reductase thus blocking deoxyribonucleic acid synthesis. In addition, it was shown to exhibit an antiinflammatory effect by inhibiting the polyamine pathway in autoimmune diseases. Intralesional MTX has been shown to be effective and safe in a variety of conditions (Agostini et al, 2007). This was the rationale to use it in a psoriatic patient with pitting and subungual hyperkeratosis of only one nail. MTX 2.5 mg was injected into each side of the proximal nail fold once weekly for 6 weeks. Pain was tolerable. During the 4-month followup, the psoriatic nail alterations improved and no clinical or laboratory side effects were

noted. No recurrence of the nail lesions was observed in the following two years.

No adverse side effects were noted (Lin, 2011).

**9.2 Intralesional treatments** 

and the physician.

alleviate the needle prick.

Although **intralesional cyclosporine** has shown good effects in cutaneous psoriasis there are no reports on intralesional cyclosporine in nail psoriasis.
