Psoriasis in difficult-to-treat sites is a term that has been used to denote psoriasis affecting the nails, scalp, palms of the hands, and soles of the feet. Psoriasis affecting these sites is often associated with considerable physical, emotional, and functional impact, and most topical treatments are inconvenient, uncomfortable, and ineffective in these locations.58–60 There are very few controlled clinical trials comparing the safety and efficacy of systemic treatments, phototherapy, and biologic therapy in this setting.

In the case of nail psoriasis, the authors of a systematic Cochrane review, which included 18 randomized controlled clinical trials published between 1946 and 1982 involving 1266 participants, noted that the heterogeneity of the studies prevented them from drawing conclusive results.61 While systemic treatments have been shown to be beneficial, their use is limited by potentially serious adverse effects. Consequently, these drugs do not appear to be a realistic option in the treatment of nail psoriasis unless they are specifically indicated because of concomitant skin psoriasis or psoriatic arthritis or in the case of severe nail psoriasis refractory to other treatments or a condition that is having a major impact on the patient's quality of life. Evidence supporting the use of topical therapies is inconclusive and of poor quality.61 A post hoc analysis of the BELIEVE clinical trial included a sub-analysis of the effects of treatment with adalimumab in 733 patients with psoriasis of the nails and/or scalp. In all of the variables studied (PASI 75, a visual analog scale, and DLQI), the positive effect of adalimumab was greater in scalp psoriasis than in nail psoriasis.62 The US National Psoriasis Foundation recently published recommendations for the treatment of nail psoriasis based on a review of the relevant literature in the PubMed database, which was searched from 1947 to 2014 without language restrictions.63 The resulting recommendations indicated that all patients should be evaluated for fungal infection of the nails, which may complicate treatment. For disease confined to the nails, they recommended high-potency topical corticosteroids with or without vitamin D analogs as the first-line treatment, followed by biologic therapy (adalimumab, etanercept, or ustekinumab) or conventional systemic treatment (methotrexate, acitretin) when topical treatment is not effective. In the case of nail psoriasis associated with skin and/or joint involvement, they recommended treatment with adalimumab, etanercept, ustekinumab, acitretin, or infliximab, with the choice depending on the characteristics of the disease in each case and the criteria of the physician.63 No significant differences were observed between the treatment groups in a retrospective study that compared the efficacy of infliximab, adalimumab, etanercept, and ustekinumab in nail psoriasis, as measured by improvement in the Nail Psoriasis Severity Index (NAPSI) score at 12, 24, and 36 weeks.64

In the case of scalp psoriasis, a systematic review of the topical treatments used in 26 randomized controlled trials involving 8020 patients showed that potent topical corticosteroids were more effective than vitamin D analogs in this setting, although there is no data on the safety of long-term treatment.65 The findings of a network meta-analysis also supported the use of potent topical corticosteroids with or without vitamin D analogs (calcipotriol or betamethasone).66,67 Recommendations based on expert consensus suggest that phototherapy and biologic therapy should be reserved for patients with severe and recalcitrant disease68 and for cases in which scalp involvement is accompanied by generalized skin psoriasis.69

Although there is evidence supporting the efficacy of infliximab, adalimumab, and etanercept in difficult locations—including the palms and soles—no comparative, prospective studies have been published that justify the preferential use of any particular biologic drug. In a study of 15 patients with pustular palmoplantar psoriasis randomized to treatment with etanercept 50 mg or placebo twice weekly for 3 months (after the first 3 months all the patients were treated with etanercept for 3 additional months), the decline in median Palmoplantar Pustulosis Area and Severity Index score from baseline to 24 weeks was statistically significant (P = 0.038) for the etanercept group but not for the controls.70Patients with chronic palmoplantar psoriasis who took part in the REACH study were randomized to receive adalimumab or placebo for the first 16 weeks.71 In a post-hoc analysis of REACH, the authors found that the adalimumab-treated patients who achieved the primary endpoint (a reduction of at least 50% in NAPSI score) also improved in terms of clearing of disease as measured by the Physician's Global Assessment of hands and/or feet. The efficacy of adalimumab was not affected by age, sex, weight, PASI score, duration of disease, history of psoriatic arthritis, prior systemic treatment, smoking history, or nail disease.71

According to the evidence-based guidelines of the Spanish Psoriasis Working Group,72 treatment of psoriasis affecting difficult-to-treat sites with biologic agents is indicated when any of the following conditions are fulfilled: a) disease uncontrolled with topical or conventional systemic treatment; b) extensive lesions (NAPSI>10); c) rapid worsening of disease; d) subjective perception of severity (DLQI > 10); or e) concomitant psoriatic arthritis. Overall, only about 1 in 3 patients treated achieved complete or almost complete remission (for example, PGA 0/1) in the studies of biologic therapy in such sites. The methods used to assess results in those studies are extremely heterogeneous.

Drug survival is defined as the period during which a given drug continues to be an adequate treatment for a specific patient. It is difficult to measure the survival of biologic drugs in psoriasis because of the heterogeneity of the studies undertaken and limitations in study design. Drug survival is a parameter that reflects the safety, efficacy, and convenience of the therapy. Safety data indicate that, at least during the initial months of treatment, biologic agents have a good safety profile, even better than conventional systemic treatments. In a meta-analysis of 24 randomized controlled trials involving 9384 patients, in which the primary endpoint was the proportion of patients who achieved a PASI-75 response, infliximab was the most effective drug (risk difference [RD], 77%) followed by adalimumab (RD, 44%), and etanercept (RD, 30%).73In a recent observational study that investigated the clinical efficacy and survival of drugs after 12 months of treatment, the survival rate was 96.7% for ustekinumab, 79.7% for adalimumab, and 73.3% for infliximab.74 A study that determined differences in biologic drug survival in a group of patients with psoriasis registered in the database of a medical center in Amsterdam reported similar drug survival in treatment-naïve patients at 1 and 4 years (etanercept, 85% and 64%, respectively; adalimumab, 77% and 77%; infliximab, 75% and 75%); survival was somewhat lower in non-naïve patients (etanercept, 86% and 42%, respectively; adalimumab, 84% and 56%; infliximab 68% and 43%; ustekinumab 84% and 57%).75 In the DERMBIO prospective registry, which includes all the patients with psoriasis treated with biologic agents in teaching hospitals in Denmark (1867 treatments in 1277 patients over 10 years), mean survival was 47 months and 67% of withdrawals were attributed to a lack of efficacy and 9.7% to adverse effects.76 In that registry, estimated mean survival was 59 months for adalimumab, 44 for infliximab, and 30 for etanercept; survival was better in men and patients not previously treated with biologic agents.

Another study analyzed data from the BioCAPTURE prospective registry of biologic treatments started after January 2010 (when all the biologic agents were available).77 A course of treatment was deemed continuous if the withdrawal period did not exceed 90 days (because treatment is often interrupted for surgeries, vacations, infections, etc.). The authors of this 1-year study reported drug survival and the percentage of “happy” drug survival, that is, continued treatment in conjunction with a DLQI of 5 or less. Ustekinumab showed better survival than etanercept and a trend towards better survival than adalimumab. The percentage of patients assessed as happy increased during the course of the study: 27%, 64%, 69%, 72%, and 79% at baseline and 3, 6, 9, and 12 months, respectively. Lack of response and adverse events, or both, were the main reasons for withdrawal of treatment. On the first round of voting, the panelists reached consensus (level of agreement, 92%) on the role of inefficacy (loss of response) as the main cause of withdrawal of treatment.

A 3-year study of the long-term safety and efficacy of etanercept and adalimumab in 85 patients aged 65 years or older with psoriasis and psoriatic arthritis found better drug survival rates for etanercept (74.5%) than adalimumab (60.7%) and reported that the majority of withdrawals were due to inefficacy.78 The OSCAR I study reported the following biologic drug survival rates in treatment-naive patients with psoriasis in routine clinical practice after follow-up of up to 6 years: etanercept 80.7%, infliximab 61.9%, and adalimumab 59.8%.79 In most cases, withdrawal of treatment was due to a lack of efficacy (etanercept 14.4%, infliximab 27.9%, adalimumab 27.2%) and in a few it was due to adverse events (etanercept 2.8%, infliximab 8.8%, adalimumab 4.4%).79 The Phase 4 OSCAR II study analyzed long-term treatment survival in patients with psoriasis on etanercept in routine clinical practice.80 Of the 367 patients studied, 152 had plaque psoriasis. These patients were treated with etanercept on either an intermittent (110 patients, 72.4%) or continuous (42 patients, 27.6%) regimen. Mean duration of treatment was 1706 days in the group of patients on the intermittent regimen and 1249 in the group on continuous treatment.80

It is importance to stress that lack of adherence to therapy is one of the main factors that increases the cost of treatment. Loss of response to biologic therapy often leads to the decision to switch the patient to another agent, involving another induction phase, which is more costly than a maintenance regime.81 Besides the inherent properties of each drug, authors of different studies have cited the following predictors of biologic drug survival: dose increase, frequency of administration, the use of combination regimens, antidrug antibody production, a higher catabolic rate, and the clinical factors that give rise to the decision to switch from one drug to another.

The challenge in the management of psoriasis is not only to achieve long-term remission of the signs and symptoms of the disease, but also to improve the patients’ quality of life. Given the considerable impact of the disease on multiple dimensions of these patients’ lives, validated questionnaires are an essential tool in the evaluation of quality of life in this setting. In actual practice, however, the systematic use of such tools is not well established.

In an expert consensus study based on evidence from 154 articles selected from among 10 642 studies published between 1980 and 2009, 44 dermatologists formulated 10 recommendations for clinical practice, including the use of the DLQI, the SF-36, and Skindex-29 before starting systemic treatment and during follow-up.82 That study also highlighted the fact that these questionnaires are incomplete and do not effectively assess certain factors, such as mood, stress, impact on sleep or the family environment, level of fatigue, and the patient's acceptance of and satisfaction with their current treatment regimen. The findings of a recent study showed that the Lifetime DLQI (LT DLQI), which measures chronic quality of life, is a better predictor of quality of life than the DLQI scales relating to the previous week or year.83

All the biologic drugs (etanercept, infliximab, adalimumab, and ustekinumab) have been shown to be effective in improving quality of life in patients with psoriasis as measured by several different quality-of-life scales.

Itching is an important symptom in psoriasis and one that has a major impact on quality of life. The PRISTINE randomized controlled trial assessed 2 etanercept treatment regimens84: 50 mg subcutaneously once weekly versus 50mg subcutaneously twice weekly. In that study, quality-of-life scores correlated with severity of pruritus: the more severe the pruritus, the greater the negative impact on the patients’ quality of life. After 24 weeks of treatment, itching levels decreased in both treatment groups, with concurrent improvement in all of the quality of life scores. Further evidence on the influence of different regimens on quality of life comes from the 54-week CRYSTEL trial, in which patients were randomized to either a continuous or an intermittent etanercept regimen.85 The group on the continuous regimen received etanercept 25 mg subcutaneously twice weekly for 54 weeks. The group on the intermittent regimen received etanercept 50 mg subcutaneously twice weekly for no more than 12 weeks (until a PGA of 2 or less was reached); upon relapse, etanercept was resumed at a dose of 25 mg twice weekly. The continuous regimen was evaluated in 352 patients and the intermittent regimen in 359. At 54 weeks, both groups showed significant improvement on the DLQI, the EuroQOL 5-dimension questionnaire (EQ-5D), the Hospital Anxiety and Depression, and the SF-36-Vitality scales. The continuous group showed significantly greater improvement in the DLQI and EQ-5D, but the different was small.

The authors of a meta-analysis on the comparative effects of biological therapies on quality of life in patients with plaque psoriasis concluded that all the biologic agents improved quality of life (DLQI) more than placebo.86 A recent systematic review demonstrated that the discomfort and dissatisfaction caused by psoriasis (measured using the EQ-5D) were comparable to that produced by other chronic diseases (cardiovascular disease, diabetes, end-stage renal diseases, liver diseases, cancer, and visual disorders).87 A survey of 5604 patients with psoriasis or psoriatic arthritis carried out by the US National Psoriasis Foundation between 2003 and 2011 showed that 92% of the unemployed respondents cited their disease as the cause of their unemployment. Among the working respondents, 49% reported regularly missing work because of psoriasis. After adjusting for age and sex, the patients with severe psoriasis were 1.8 more likely to be unemployed than those with mild psoriasis.88

Finally, other factors that affect the quality of life of patients with psoriasis include the extent of the skin lesions, consultation of numerous physicians, younger age, the perception on the part of the patient of not being supported by medical professionals, a feeling that the care they are being offered is deficient because the medical facilities are inadequate or information on side effects and alternative treatment options is not provided. Finally, while the decision to prescribe biologic therapy is influenced by both the results of DLQI and the PASI score, in clinical practice the PASI score appears to have a greater influence on this decision.89