**9.3.2 Laser treatment**

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 group (Treewittayapoom et al, in press).

#### **9.3.3 Ionising radiation**

**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-

Nail Psoriasis 173

**Cyclosporine** is a powerful immunosuppressive agent used successfully in wide-spread psoriasis. Nail lesions usually also respond favorably. In a median dose of 2.5 mg/kg bodyweight daily, cyclosporine effectively reduces skin and nail psoriasis. In a comparative trial, cyclosporine versus etretinate were given to 210 patients two thirds of whom had nail involvement. At the end of 10 weeks, both groups showed slight improvement of their nails which continued in the group that continued with tapered cyclosporine (Mahrle et al, 1995). Another patient was treated for her severe nail psoriasis with cyclosporine 3mg/kg/d, and the dose was increased twice by one mg after 4 weeks each. After 16 weeks, both skin and nails had improved with the nail improvement having been considerably faster. "Proximal nail clearing" was observed to be 45 to 60%. The patient stopped cyclosporine on her own because of drug-induced hypertrichosis (Arnold et al, 1993). In a retrospective evaluation, cyclosporine was found to improve the NAPSI score after 12, 24 and 48 weeks by 40%, 72%,

Cyclosporine adverse effects, such as gastrointestinal symptoms, fatigue, leg cramps, diastolic blood pressure increase, and peripheral oedema were more common than in the etretinate group that suffered more skin symptoms like dry skin, cheilitis, and dry mouth

Even though there are many reports on treatment of moderate to severe skin psoriasis with methotrexate, tacrolimus, mycophenolate mofetil, hydroxyurea, 6-thioguanine, sulfasalazine, fumaric esters, azathioprine, carbamazepine, calcitriol, and propylthiouracil, controlled studies concerning nail lesions in these patient cohorts are lacking. However, one may assume that they might also improve nail lesions when they

**Methotrexate** is still often administered for wide-spread skin psoriasis although lung, liver and kidney fibrosis are well documented adverse effects of long-term treatment. There is only one report specificially relating to MTX low dose therapy for 20-nail psoriasis (Lee, 2009). In an evaluation of patients with nail psoriasis treated systemically, MTX produced NAPSI score improvements of 7%, 31%, and 35%, respectively, after 12, 24 and 48 weeks (Sánchez-Regaña et al, 2011). MTX as a classical cytostatic drug not only inhibits the inflammatory and hyperproliferative processes of psoriasis but may also slow down nail growth speed making it difficult to observe a positive effect in a reasonable

Retinoids are vitamin A derivatives that are used for disorders of keratinisation. Their use in skin psoriasis is well documented with a number of studies. However, their potentials in nail psoriasis have not independently and systematically be studied (Tosti et al, 2009). In a comparative evaluation, acitretin was found to reduce the NAPSI score after 12, 24 and 48 weeks by 19%, 41%, and 52%, respectively during the treatment of moderate to severe skin psoriasis (Sánchez-Regaña et al, 2011). Acitretin is a first-line drug in pustular psoriasis, reduces subungual hyperkeratosis and improves symptoms in severe nail psoriasis (Duhard-Brohan, 1999, Piraccini et al, 2001, Tosti et al, 2009). Apart from the many potential side effects of retinoids, they may be onychodestructive in high doses as is

and 89%, respectively (Sánchez-Regaña et al, 2011).

(Mahrle et al, 1995).

time period.

**9.4.2 Retinoids** 

high-dose vitamin A (Baran 1986).

are able to improve the skin.

month treatment interval the nails regrew normally in the following 8 to 14 months, and one patient had disease-free nails even 20 years after cessation of the irradiation (Finnerty, 1979). Another ten patients were treated in a randomized prospective double-blind study with twice fractioned doses of 150 cGy superficial radiotherapy each a week apart. One hand was treated and the other left for comparison. After 10 and 15 weeks posttreatment, the irradiated hand was significantly better concerning pitting, subungual hyperkeratosis, onycholysis, total nail destruction and nail thickness, but afte 20 weeks no difference was seen anymore between the treated and untreated hands (Yu and King, 1992).

**Grenz rays** are very soft X-rays not penetrating the skin. In a randomized, double-blind study of 22 patients, 5 Gy of Grenz rays were applied in ten weekly courses to one hand only. Only 1 patient showed complete clearance, 7 mild improvement and 14 remained unchanged. Only non-hyperkeratotic lesions responded, which might have to be expected as Grenz rays do not penetrate the skin and hyperkeratosis. Six months after the irradiation, 2 patients were improved, two had worsened, and 18 remained unchanged. Slight nail fold pigmentation was the only adverse effect (Lindelöf, 1989).

**Electron beam therapy** was chosen by another group as the electrons are able to penetrate the nail bed (Kwang et al, 1995). Twelve patients were treated on one hand with a weekly dose of 750 cGy for a period of 8 weeks. Assessment at 3, 6 and 12 months showed improvement in 3 patients, slight improvement in 6 subjects, and a complete failure in 3 individuals after 3 months. At 6 and 12 months, only one patient continued to improve, 9 regressed to pretreatment conditions. A temporary deep brown-black discoloration of the treated nails was observed in some subjects.

All ionizing treatments have to be used with utmost care as long-term side effects may occur, often so late that the patient does not remember to have been treated with this modality.

#### **9.3.4 Climatotherapy**

Climatotherapy, in particular balneotherapy in sunny regions, is very popular in countries with little sunshine. It often has a positive effect on the skin and the emotional aspect of the patients. Although some patients claim that also their nails improve there are no systematic evaluations of the treatment modality on psoriatic nails.

#### **9.4 Systemic therapies**

Systemic treatments are indicated when there is wide-spread skin involvement. Isolated nail psoriasis is rarely seen as an indication for systemic therapy. All systemic treatments known to reduce skin lesions will also have a beneficial effect on nail lesions. Controlled studies are as a whole rather rare.

#### **9.4.1 Immunosupressive treatments**

**Corticosteroids** have for a long time given to psoriatics although their disadvantages such as general steroid adverse effects, tachyphylaxis and rebound phenomenon have been known for decades. There are no controlled trials of systemic steroids in nail psoriasis.

month treatment interval the nails regrew normally in the following 8 to 14 months, and one patient had disease-free nails even 20 years after cessation of the irradiation (Finnerty, 1979). Another ten patients were treated in a randomized prospective double-blind study with twice fractioned doses of 150 cGy superficial radiotherapy each a week apart. One hand was treated and the other left for comparison. After 10 and 15 weeks posttreatment, the irradiated hand was significantly better concerning pitting, subungual hyperkeratosis, onycholysis, total nail destruction and nail thickness, but afte 20 weeks no difference was

**Grenz rays** are very soft X-rays not penetrating the skin. In a randomized, double-blind study of 22 patients, 5 Gy of Grenz rays were applied in ten weekly courses to one hand only. Only 1 patient showed complete clearance, 7 mild improvement and 14 remained unchanged. Only non-hyperkeratotic lesions responded, which might have to be expected as Grenz rays do not penetrate the skin and hyperkeratosis. Six months after the irradiation, 2 patients were improved, two had worsened, and 18 remained unchanged. Slight nail fold

**Electron beam therapy** was chosen by another group as the electrons are able to penetrate the nail bed (Kwang et al, 1995). Twelve patients were treated on one hand with a weekly dose of 750 cGy for a period of 8 weeks. Assessment at 3, 6 and 12 months showed improvement in 3 patients, slight improvement in 6 subjects, and a complete failure in 3 individuals after 3 months. At 6 and 12 months, only one patient continued to improve, 9 regressed to pretreatment conditions. A temporary deep brown-black discoloration of the

All ionizing treatments have to be used with utmost care as long-term side effects may occur, often so late that the patient does not remember to have been treated with this

Climatotherapy, in particular balneotherapy in sunny regions, is very popular in countries with little sunshine. It often has a positive effect on the skin and the emotional aspect of the patients. Although some patients claim that also their nails improve there are no systematic

Systemic treatments are indicated when there is wide-spread skin involvement. Isolated nail psoriasis is rarely seen as an indication for systemic therapy. All systemic treatments known to reduce skin lesions will also have a beneficial effect on nail lesions. Controlled studies are

**Corticosteroids** have for a long time given to psoriatics although their disadvantages such as general steroid adverse effects, tachyphylaxis and rebound phenomenon have been known for decades. There are no controlled trials of systemic steroids in nail psoriasis.

seen anymore between the treated and untreated hands (Yu and King, 1992).

pigmentation was the only adverse effect (Lindelöf, 1989).

evaluations of the treatment modality on psoriatic nails.

treated nails was observed in some subjects.

modality.

**9.3.4 Climatotherapy** 

**9.4 Systemic therapies** 

as a whole rather rare.

**9.4.1 Immunosupressive treatments** 

**Cyclosporine** is a powerful immunosuppressive agent used successfully in wide-spread psoriasis. Nail lesions usually also respond favorably. In a median dose of 2.5 mg/kg bodyweight daily, cyclosporine effectively reduces skin and nail psoriasis. In a comparative trial, cyclosporine versus etretinate were given to 210 patients two thirds of whom had nail involvement. At the end of 10 weeks, both groups showed slight improvement of their nails which continued in the group that continued with tapered cyclosporine (Mahrle et al, 1995). Another patient was treated for her severe nail psoriasis with cyclosporine 3mg/kg/d, and the dose was increased twice by one mg after 4 weeks each. After 16 weeks, both skin and nails had improved with the nail improvement having been considerably faster. "Proximal nail clearing" was observed to be 45 to 60%. The patient stopped cyclosporine on her own because of drug-induced hypertrichosis (Arnold et al, 1993). In a retrospective evaluation, cyclosporine was found to improve the NAPSI score after 12, 24 and 48 weeks by 40%, 72%, and 89%, respectively (Sánchez-Regaña et al, 2011).

Cyclosporine adverse effects, such as gastrointestinal symptoms, fatigue, leg cramps, diastolic blood pressure increase, and peripheral oedema were more common than in the etretinate group that suffered more skin symptoms like dry skin, cheilitis, and dry mouth (Mahrle et al, 1995).

Even though there are many reports on treatment of moderate to severe skin psoriasis with methotrexate, tacrolimus, mycophenolate mofetil, hydroxyurea, 6-thioguanine, sulfasalazine, fumaric esters, azathioprine, carbamazepine, calcitriol, and propylthiouracil, controlled studies concerning nail lesions in these patient cohorts are lacking. However, one may assume that they might also improve nail lesions when they are able to improve the skin.

**Methotrexate** is still often administered for wide-spread skin psoriasis although lung, liver and kidney fibrosis are well documented adverse effects of long-term treatment. There is only one report specificially relating to MTX low dose therapy for 20-nail psoriasis (Lee, 2009). In an evaluation of patients with nail psoriasis treated systemically, MTX produced NAPSI score improvements of 7%, 31%, and 35%, respectively, after 12, 24 and 48 weeks (Sánchez-Regaña et al, 2011). MTX as a classical cytostatic drug not only inhibits the inflammatory and hyperproliferative processes of psoriasis but may also slow down nail growth speed making it difficult to observe a positive effect in a reasonable time period.

#### **9.4.2 Retinoids**

Retinoids are vitamin A derivatives that are used for disorders of keratinisation. Their use in skin psoriasis is well documented with a number of studies. However, their potentials in nail psoriasis have not independently and systematically be studied (Tosti et al, 2009). In a comparative evaluation, acitretin was found to reduce the NAPSI score after 12, 24 and 48 weeks by 19%, 41%, and 52%, respectively during the treatment of moderate to severe skin psoriasis (Sánchez-Regaña et al, 2011). Acitretin is a first-line drug in pustular psoriasis, reduces subungual hyperkeratosis and improves symptoms in severe nail psoriasis (Duhard-Brohan, 1999, Piraccini et al, 2001, Tosti et al, 2009). Apart from the many potential side effects of retinoids, they may be onychodestructive in high doses as is high-dose vitamin A (Baran 1986).

Nail Psoriasis 175

24 and 48 weeks was 50%, 81%, and 92%, respectively (Sánchez-Regaña et al 2011). There appears to be general agreement that infliximab is the most potent antipsoriatic biologic

**Adalimumab** (Humira®) is a human antibody. In an open study, significant NAPSI reductions were obtained for finger and toe nails both in patients with cutaneous psoriasis as well as with psoriatic arthritis (Rigopoulos et al, 2010). In a large cohort of 442 patients with psoriatic arthritis, the mean NAPSI was reduced by 44% (Van den Bosch et al, 2010). Nail psoriasis response may be rapid (Irla and Yawalkar, 2009) although some authors found skin lesions to respond less than articular inflammation (Otten et al, 2011). In a group of ankylosing spondylitis and psoriatic arthritis patients, the NAPSI score was demonstrated to be reduced by 6 points (Rudwaleit et al, 2010). Adalimumab-induced improvement in nail psoriasis correlated with a good response in palmar plantar psoriasis (Langley et al, 2011). In the Spanish study, NAPSI improvement after 12, 24 and 48 weeks was 37%, 73%, 84%, respectively. Adalimumab was also beneficial for nail psoriasis after etanercept

**Etanercept**, a fully human TNF-α receptor fusion protein, binds TNF-α with greater affinity than natural receptors. The bound TNF-α is biologically inactive and many of the proinflammatory pathways responsible for initiation, maintenance, and recurrence of skin lesions in psoriasis are inhibited (Weinberg, 2003). The starting dose is twice weekly 50 mg subcutaneously, which may be reduced to once weekly 50 mg or twice weekly 25 mg. In a comparison of systemic nail psoriasis treatments, NAPSI improvement after 12, 24 and 48 weeks was 24%, 68%, and 87%, respectively (Sánchez-Regaña et al, 2011). The commonest adverse effect is an irritation reaction at the injection site. Infections and reactivations may occur as in infliximab treatment though probably less commonly. It should not be combined with systemic corticosteroids (Sanchez et al, 2006, Scheinfeld, 2004). There are some otherwise rare skin diseases that have been observed during etanercept treatment, such as lupus erythematosus, vasculitis, eosinophilic cellulitis like inflammation and interstitial granulomatous dermatitis (Scheinfeld, 2004, Winfield et al,

**Golimumab** (Simponi®) is a new human monoclonal antibody against TNF- binding with high affinity and specificity to soluble and transmembrane TNF-. It was studied once in psoriasis and nail psoriasis and showed an improvement in the NAPSI score of 25% and 43% after 14 weeks and 33% and 54% after 24 weeks in a dose of 50mg or 100 mg

All TNF- inhibitors were reported to have induced psoriasis or psoriasiform skin and nail lesions (Sfikakis et al, 2005, Wollina et al, 2010). The spectrum of conditions induced by TNF- is very wide and it apparently does not depend on the specific disease treated nor on the anti-TNF- agent used (Pine et al, 2010, Conrad et al, 2011; Lee et al 2011). In more than half of the cases, the TNF- induced skin lesions were successfully suppressed despite continuation of the drug. It is speculated that as TNF- blockade is one of the strongest inducers of interferon- production an unabated IFN- production by plasmocytoid dendritic cells might result in these paradoxical psoriasis flares under anti-TNF- treatment

subcutaneously, respectively, at weeks 0, 4, 8, 12, 16, and 20 (Kavanaugh et al, 2009). **Certulizumab** (Cimzia®) has not been used in nail psoriasis (Gartlehner et al, 2009).

(Noiles and Vender, 2009).

treatment (Puig et al, 2010).

2006, Deng et al, 2006).

(Conrad et al, 2011).
