Approach to managing patients with nail psoriasis

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1 DOI: /j x JEADV Blackwell Publishing Ltd REVIEW ARTICLE Approach to managing patients with nail psoriasis K Reich* Dermatologikum Hamburg, Hamburg, Germany *Correspondence: K Reich. kreich@dermatologikum.de Abstract Psoriasis is a chronic inflammatory skin condition that affects approximately 2% of the population. Up to 50% of patients with psoriasis have concurrent nail psoriasis, with a lifetime incidence of 80% to 90%. Up to 30% of patients with skin psoriasis also have psoriatic arthritis (PsA) and of these, approximately 80% have nail disease. However, nail involvement is often overlooked by physicians, despite the significant burden it places on patients as a result of functional impairment of manual dexterity, pain and psychological stress. Affected nail plates often thicken and crumble, and because they are very visible, patients are usually concerned about the appearance of their nails, often causing them to avoid normal day-to-day activities (including work). In the longer-term, nail involvement may be a signal of a more severe form of psoriasis or a precursor of PsA. Conventional treatment of nail psoriasis is generally considered inconvenient by patients, and it is limited by adverse effects and often a reduction in efficacy over time. There is also a lack of controlled clinical trials data and no consistent treatment approach has been advocated. Recently, the effects of biologic agents targeted against tumour necrosis factor alpha (TNFα) on nail psoriasis have been investigated. The multicentre, double-blind EXPRESS [European Infliximab for Psoriasis (Remicade) Efficacy and Safety Study] trial revealed that infliximab 5 mg/kg at weeks 0, 2, 6, and then every 8 weeks significantly improved nail psoriasis, evaluated using the Nail Psoriasis Severity Index (NAPSI) in 378 patients with moderate to severe psoriasis. Significant improvement was reported as early as week 10, and at week 50 full nail clearance was evident in 45% of patients receiving infliximab. There is also evidence from small studies that infliximab significantly improves nail lesions and quality of life in patients with nail psoriasis. There is a need for improving the awareness of nail psoriasis and its impact on patients quality of life. Moreover, the potential role for nail involvement as a link between psoriasis and PsA underlines its importance and the need for effective management. Infliximab has been shown to improve psoriatic nail lesions and quality of life, and it should be considered as one of the most appropriate available treatment options for the many patients with this distressing condition. Received: 30 April 2009; Accepted: 28 May 2009 Keywords biologic therapy, infliximab, nail psoriasis, quality of life, treatment Conflicts of interest None declared. Introduction Psoriasis is a chronic inflammatory skin condition that affects approximately 2% of the population. 1,2 It is an incurable disease that interferes with many daily activities, and has been reported to cause greater physical and mental distress than other chronic conditions including arthritis, lung disease, heart failure and diabetes. 3 Psoriasis therefore has a profound emotional, social and physical impact on quality of life. 4 The severity of psoriasis ranges from mild localized plaques to severe erythrodermic forms. Plaque-type psoriasis is the most common form, accounting for over 80% of cases, and is characterized by sharply demarcated, erythematous-scaling plaques, typically affecting the elbows, knees, scalp, and intergluteal cleft. 5 Guttate psoriasis occurs in approximately 10% of cases, and erythrodermic and pustular forms each occur in less than 3% of patients. 5 Up to one-third of patients with skin psoriasis develop psoriatic arthritis (PsA), a chronic inflammatory arthropathy that is recognized as a distinct disease entity. 6 8 Defining features of PsA include involvement of the distal interphalangeal (DIP) joints, dactylitis, enthesitis, osteolysis and periarticular new bone formation. Nail involvement has long been recognized as a common manifestation of psoriasis, occurring in up to 50% of patients, 2,9 with an estimated lifetime incidence of 80 90%. Nail psoriasis

2 16 Reich Figure 1 Anatomy of the nail unit. [Reprinted with permission of Elsevier B.V.]. 2 occurs more frequently in patients with severe disease such as those with PsA, with a prevalence of 70 80% in this latter group. 8,10,11 Furthermore, it is associated with DIP joint involvement which is indicative of more severe PsA. 10,12,13 There is a positive association between nail psoriasis and duration of skin lesions, 14 and between its severity and the severity of skin and joint involvement. 9,10 However, nail psoriasis also occurs in 40% of patients with mild psoriasis [Psoriasis Area and Severity Index (PASI) score 10]. 9 Between 1% and 5% of patients have affected nails without skin lesions. 15 Nail psoriasis is approximately 10% more common in males than in females, and it is positively associated with higher bodyweight. Importance of the nail in psoriasis Despite its frequent occurrence, nail psoriasis is often overlooked and not treated effectively. 9 This has important implications for the management of patients with psoriasis, since nail involvement has a serious negative impact on functioning and quality of life. Furthermore, it may be a predictor of future inflammatory joint damage, a precursor to PsA, and a visible indicator of disease activity. 16 Clinical signs The nail consists of the nail plate, and four epithelial structures: the proximal nail fold, matrix, nail bed and hyponychium (Fig. 1). Nail psoriasis results in different types of lesion depending on which part of the nail unit is affected. Pitting is the most common clinical sign of nail psoriasis (in nearly 70% of patients), followed by nail bed discoloration, onycholysis, subungal hyperkeratosis and splinter haemorrhages, although some studies have found that nail bed discoloration occurs less frequently than the other lesions. 2,17 Nail matrix psoriasis usually presents as pitting, leukonychia (whitening), erythema of the lunula and dystrophy (crumbling), whereas psoriasis of the nail bed presents as oil drop discoloration, splinter haemorrahages, subungual hyperkeratosis and onycholysis (Fig. 2). Pits in the nails are superficial depressions in the nail plate that indicate abnormalities in the proximal matrix. In nail psoriasis, Figure 2 Common clinical signs of nail psoriasis. keratinization is disrupted by parakeratotic cells in the stratum corneum from lesions in the matrix. These cells are exposed as the nail grows, and are sloughed off to form pits (Fig. 3). Deeper pits indicate involvement of the intermediate and ventral as well as the dorsal nail matrix, while leukonychia is believed to reflect involvement of the intermediate and ventral matrix only. 2 Psoriatic lesions in the nail bed present as oil drop or salmon patch discoloration that can be seen through the nail plate. Onycholysis is likely to result if lesions involve the hyponychium. Separation of the nail plate from the bed leaves a space that increases the risk of secondary infection. In subungual hyperkeratosis, the nail plate is raised off the bed as a result of deposition of cells that have not undergone desquamation. 2 Impact on function and quality of life The clinical signs of nail psoriasis are highly visible and have a significant impact on quality of life. In a survey to evaluate the subjective complaints associated with nail involvement, questionnaires

3 Management of nail psoriasis 17 Figure 3 Pit formation in the nail plate arising from the nail matrix. [Reprinted with permission of Elsevier B.V.]. 2 Table 1 Assessment tools and nail involvement Assessment tool Psoriasis Area and Severity Index (PASI) Baran s nail psoriasis severity index 18 Cannavò s scoring system 19 Nail Psoriasis Severity Index (NAPSI) 20 Dermatology Life Quality Index (DLQI) 21 Involvement of nails Does not take the severity of nail involvement into account Yes, but does not focus on function, pain or quality of life Yes, but relatively little focus on function, pain or quality of life (3 items, no validation) Yes, but does not focus on function, pain or quality of life Does not focus on nails, only mentions skin were sent to 7000 patients with psoriasis. 14 One thousand seven hundred twenty-eight patients of mean age 47 years and mean disease duration of 12 years provided evaluable responses. Nail psoriasis was present in 1369 (79.2%), with both fingers and toes affected in 62.6% of patients, just fingers in 26.8% and only toes in 8.6%. There was a positive association between duration of skin lesions and nail psoriasis. Pitting was reported by 75.3% of patients, upward lifting of the nail by 49.3%, onycholysis by 46.2% and discoloration by 29.2%. Pain caused by nail changes occurred in 51.8% of patients, and more then 90% were concerned about the cosmetic appearance of their nails. Normal daily activities were negatively impacted in 58.9% of patients and a similar number (56.1%) reported that nail psoriasis inhibited their usual housekeeping activities. Importantly, 47.9% of respondents noted that their nail condition restricted their professional activities. Another study in 69 patients with PsA found that severe nail disease was associated with functional impairment related to arthritis and with higher depression (r = 0.39, P < 0.001) and anxiety (r = 0.34, P = 0.004) scores on the Stanford hospital anxiety and depression scale (HADS). 10 Assessment and management of nail disease Although nail disease is important, it is often overlooked in the clinical management of patients with psoriasis, and in many clinical trials in patients with PsA. Skin plaques are usually the primary motivation for the decision to treat psoriasis, and patients are also sometimes referred to a rheumatologist for assessment of joint involvement. Several possibilities have been proposed for the lack of attention to nail psoriasis. It has been suggested that rheumatologists are poor at detecting nail disease, but this was shown not to be the case, and rheumatologic assessment was found to be highly sensitive in detecting nail involvement, and correlated well with dermatologic assessment. 10 Another explanation is that therapy for nail psoriasis is perceived to be ineffective, and there is no standard treatment guideline or method for evaluating outcomes. Selecting an appropriate therapy is hampered by a lack of good quality clinical trial evidence using widely accepted objective tools to measure outcomes. Several tools have been used, and these are outlined in Table The Psoriasis Area and Severity Index (PASI) is commonly used in clinical studies, but only measures skin involvement. The Physician s Global Assessment is more widely used in clinical practice, but again it does not assess nail involvement. These two tools do not evaluate quality of life in patients with psoriasis. This can be assessed using the Dermatology Life Quality Index (DLQI), but again nail psoriasis is omitted. The Nail Psoriasis Severity Index (NAPSI) has been developed as an objective and reproducible tool for estimating nail involvement, and which can therefore be used to determine the efficacy of therapeutic interventions. 20 Each nail is divided into four quadrants, which are evaluated for the presence of any manifestations of psoriasis in the nail matrix (pitting, leukonychia, nail plate crumbling) and nail bed (oil drop discoloration, onycholysis, hyperkeratosis, splinter haemorrhages). If any sign is present in all four quadrants, the nail is given a score of 4 through to a score of 0 if there are no signs in any quadrant. Each nail is assigned a nail matrix and a nail bed score of 0 4, which are combined to yield a total score of 0 8 for each nail. All nails may be evaluated, with the total NAPSI score being the sum of the scores, up to 80 if only

4 18 Reich fingers (10 nails) are considered or up to 160 if toes are also included (20 nails). Often, specific nails are targeted to assess to the effects of drug therapy. The NAPSI is reproducible and simple to perform, and whilst it represents an improvement on more generic measures of treatment efficacy in nail psoriasis, it must be used in conjunction with a tool that also assesses quality of life. Current treatment options for nail psoriasis Treatment of nail psoriasis should be viewed in the context of treating psoriasis in general, with the aim of producing rapid and sustainable control of psoriatic nail lesions. Ideally, the goal should be to achieve a NAPSI score of 0, whilst at the same time improving the patient s quality of life. However, the usefulness of existing treatments is hindered by difficulty in drug delivery to the site of inflammation and limited efficacy. 11 Nail psoriasis is often refractory to treatment and slow to heal, and therefore, patients must be motivated to adhere to treatment for prolonged periods and this counts against the long-term use of topical medications. Topical treatment As well as being used to treat skin lesions in psoriasis, topical glucocorticosteroids and vitamin D 3 analogues, such as calcipotriol, have been shown to be effective in improving the signs and symptoms of nail psoriasis. For psoriasis affecting the nail matrix, treatment can be applied to the nail folds, but for nail bed psoriasis, onycholytic nails need to be trimmed back to the hyponychium before applying treatment as close as possible to the nail bed. 2 Twice-daily application of calcipotriol ointment was as effective as twice-daily betamethasone diproprionate in reducing subungual hyperkeratosis after 3 to 9 months in 58 patients with nail bed psoriasis. 22 A combination of calcipotriol cream once daily for 5 days each week and clobetasol propionate once daily for the other 2 days each week for 6 months reduced subungual hyperkeratosis by 72% in 142 affected fingers and by 70% in 109 affected toes in a study involving 62 patients with nail psoriasis. 23 Treatment with clobetasol was continued for a further 6 months at which time reductions of 81% and 72.5%, respectively, were documented. Long-term use of topical glucocorticosteroids is associated with adverse effects including skin atrophy, tapering of the digit, striae, telangiectasias and tachypylaxis. Skin irritation can occur with calcipotriol. Furthermore, topical therapy is both tedious and inconvenient for the patient, and results in poor compliance during long-term management. Other topical agents that have demonstrated some efficacy in small numbers of patients include 5-fluorouracil, 24 cyclosporine 19 and the retinoid tazorotene. 25 Anthralin has also been studied, with modest results after 5 months in 20 patients. 26 Intralesional injections Despite a relative paucity of controlled studies, intralesional injections with corticosteroids are considered by many physicians to be a standard treatment for nail psoriasis. 2 Triamcinolone is most often used, and the few published studies have employed a range of dosages from 2.5 to 10 mg/ml. Triamcinolone 10 mg/ml given as four 0.1 ml injections, two into the proximal nail fold to target the nail matrix and two in the lateral nail fold to reach the nail bed, cleared subungual hyperkeratosis in 19 patients with 46 affected nails. 27 Ridging improved in 93% of nails, thickening in 83%, onycholysis in 50% and pitting in 45%. Patients required a mean of 1.2 treatments, separated by an interval of 2 months. This regimen involving higher doses administered less frequently was considered to be as effective as lower doses given more often. Intralesional injection causes pain at the injection site, which may necessitate local anaesthetic. It also requires repeat injections, as the benefit does not appear to be sustained beyond 2 to 9 months, depending on the dosage used. Phototherapy While phototherapy is a mainstay of the treatment of psoriasis skin lesions, the evidence for its use in nail psoriasis is very limited. Small numbers of patients have benefited from psoralen plus UVA (PUVA), with improvements in nail bed lesions. 28,29 Systemic therapy Systemic treatment may be used in patients with nail psoriasis when topical, intralesional or phototherapy has failed. The effect of systemic therapy with cyclosporine or etretinate on nails has been investigated in 210 patients with psoriasis, of whom two-thirds had nail involvement. 30 Cyclosporine and etretinate improved nail signs after 10 weeks, but the improvement was not statistically significant. However, a subgroup of patients with a > 60% reduction in baseline PASI score after 10 weeks, who went on to receive a tapering dosage regimen of cyclosporine for a further 12 weeks experienced a significant improvement in nail involvement. Patients treated with cyclosporine did, however, experience more adverse effects than etretinate recipients. Acitretin is now used clinically instead of etretinate. When given in combination with topical calcipotriol cream (50 μg/kg twice daily), oral treatment with cyclosporine ( mg/kg/day) resulted in improvement in nail psoriasis in 26 of 33 patients (79%) compared with 10 of 21 patients (48%) receiving cyclosporine alone. 31 Combination treatment using drugs with different mechanisms of action therefore appears to hold promise for the treatment of nail psoriasis, although this requires confirmation from prospective controlled clinical trials. Biologic therapy Overall, conventional treatment of nail psoriasis has proven to be inconvenient for the patient, and it is often limited by the fact that while it reduces psoriatic nail lesions, complete clearance is infrequent and efficacy decreases with time. Furthermore, unwanted adverse effects are a concern with long-term topical therapy, and intralesional injections are extremely painful. More recently, systemic therapy with biologic agents targeted against tumour necrosis factor

5 Management of nail psoriasis 19 Figure 4 Mean percentage improvement in NAPSI score with infliximab in the EXPRESS study. [Reprinted with permission of Elsevier B.V.]. 38 alpha (TNFα) has found a place in the management of psoriasis and PsA, 7,32 and their effects on nail psoriasis have been investigated. Many of the trials with biologics need to be considered as preliminary because of the lack of controls to reduce bias (open-label, unblinded design) and variation (lack of a control group). For example, etanercept 25 mg twice weekly produced a mean reduction in NAPSI score of 57.5% after 54 weeks in an unblinded non-comparative study in 708 patients with psoriasis, 80% of whom had nail involvement. 33 After 1 year, nails were cleared of lesions in 32.1% of cases. Similarly, adalimumab 40 mg every other week reduced the mean NAPSI score by 65% after 20 weeks in 161 evaluable patients with PsA. 34 A third biologic agent, efalizumab, given at a dosage of 1 mg/kg to 189 patients (60% with nail psoriasis), resulted in at least a 75% improvement in NAPSI scores in 17% of patients and a 50% improvement in 31%, after 24 weeks. 35 In other studies, alefacept has also been shown to be effective. 36,37 Infliximab in nail psoriasis Possibly the most robust scientific best evidence for the efficacy of a TNFα antagonist in nail psoriasis comes from the well-controlled EXPRESS trial [European Infliximab for Psoriasis (Remicade) Efficacy and Safety Study]. This was a phase III, multicentre, doubleblind, placebo-controlled trial designed to evaluate the long-term efficacy and safety of infliximab in patients with moderate-tosevere plaque psoriasis. 38 The primary endpoint of the study was the proportion of patients achieving at least 75% improvement in PASI compared with baseline. The percentage improvement in NAPSI at weeks 10, 24 and 50 was also specifically investigated. Three hundred seventy-eight patients were randomly assigned in a 4 : 1 ratio to receive infliximab 5 mg/kg at weeks 0, 2, 6 and every 8 weeks through to week 46 (n = 301), or placebo at weeks 0, 2, 6, 14 and 22, then crossing over to infliximab at weeks 24, 26, 30, 38 and 46 (n = 77). Nail psoriasis was present in 240 of the infliximab group (81%) and in 65 (86%) of the placebo group, with corresponding mean NAPSI scores at baseline of 4.6 and 4.3 based on the most severely affected target nail. The mean number of affected nails was 7.4 and 7.5, respectively, and the right thumb was most often selected as the target nail. 17 The clinical signs of target nail psoriasis in each group are shown in Table 2. Significantly greater reductions in NAPSI scores occurred with infliximab compared with placebo by week 10, with continued improvement by week 24 (Fig. 4). NAPSI scores also improved significantly at week 50 in patients crossed over to infliximab from placebo, and improvements in the infliximab group were maintained. Importantly, infliximab resulted in complete clearing of nail psoriasis in 6.9% of patients within 10 weeks, rising to 26.4% Table 2 Frequency (%) of clinical signs of nail psoriasis in target nails of patients in the EXPRESS study [Adapted from Riich et al. 2008] 17 Infliximab group (n = 240) Placebo group (n = 65) Nail matrix psoriasis Pitting Leukonychia Nail plate crumbling Red spots in lunula Nail bed psoriasis Onycholysis Oil drop discoloration Hyperkeratosis Splinter haemorrhage

6 20 Reich Figure 5 Clearance of nail psoriasis with infliximab in the EXPRESS study. [Reprinted with permission of Elsevier B.V.]. 17 after 24 weeks, and 44.7% after 50 weeks (Fig. 5). 17 Nail clearance was observed in 1.7% and 5.1% of patients at weeks 10 and 24 in placebo recipients, but this increased to 34.5% at week 38 and to 48.2% at week 50 after the patients had switched to infliximab. Compared with baseline, nail matrix NAPSI scores improved by a mean of 52.9% after 24 weeks in the infliximab group but worsened by 1.9% with placebo (P < 0.001). Nail bed NAPSI scores improved by 69.2% with infliximab vs. 18.4% with placebo (P < 0.001). Of the various lesions, lunula red spots were most responsive to infliximab, their incidence decreasing to 33.3% by week 10 and to just 4% by week 50. The incidence of pitting, which was the most common feature of nail psoriasis, decreased to 88.5% at week 10 and subsequently to 43.6% by the end of the study. The differences between infliximab and placebo were significant at week 24 for both pitting and leukonychia. Although nail plate crumbling also improved, it was less responsive than other nail matrix manifestations, and was still present in 33.3% of affected patients treated with infliximab at week 50. With nail bed lesions, the incidence of onycholysis, splinter haemorrhages, oil drop discoloration and hyperkeratosis was below 60% after 10 weeks in infliximab recipients. At week 50, the incidence of each was 26.8%, 12%, 18.8% and 21.3%, respectively. Improvements with infliximab in onycholysis and oil drop discoloration were significant vs. placebo after 24 weeks, and both discoloration and hyperkeratosis continued to improve between weeks 24 and 50. Switching patients from placebo to infliximab at week 24 improved NAPSI scores for all nail matrix and nail bed features by week 50. Response to infliximab was independent of PsA, although nail improvement correlated with skin improvement during the course of the study. A small open-label study of infliximab 5 mg/kg in 18 patients with psoriasis similarly reported a significant improvement in nail psoriasis, with a > 90% decrease in mean NAPSI score from 55.8 to 3.3 after six infusions and 38 weeks follow-up. 39 The notable feature of this study is that patient quality of life was also assessed, using a Greek translation of an international onychomycosisspecific questionnaire adapted for nail psoriasis. The mean score decreased from 66.3 to 19.1 after 38 weeks (P < 0.01), indicating a significant improvement in quality of life. Conclusions Nail involvement is highly prevalent in psoriasis and PsA, and may be predictive of a more severe disease, representing a link between skin disease and joint involvement. It is associated with a significant negative impact on the patient s quality of life and ability to perform daily activities. Yet, its significance is not fully recognized, and consequently, it is poorly managed with no established severity scores, no specific evaluation of disease burden, and no established treatment goals and guidelines. Current topical, intralesional, systemic and phototherapies are relatively ineffective, often tedious to administer and they are associated with troublesome adverse effects which limits their long-term usefulness. TNFα antagonists have recently been introduced for psoriasis and PsA, and these agents are also effective for nail disease. Infliximab has been shown in a double-blind, randomized clinical trial to significantly improve nail lesions, with complete clearance in almost half of treated patients. Improvement is rapid and sustained in most patients for up to a year. There is also some evidence that infliximab improves quality of life to a significant degree, which is a key consideration when selecting treatment for

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