Psoriasis is a chronic recurrent skin disease that affects 2.3% of the Spanish population1 and between 2% and 3% of the population worldwide.2 Approximately one-third of these patients have moderate to severe psoriasis, defined as disease requiring long-term systemic therapy, which is often associated with cumulative toxicity, intolerance and, in some cases, a poor response.3

The drugs best adapted to continuous treatment are the biologic agents. In most patients treated in routine practice, a reasonable therapeutic objective with the biologic agents currently available would be an improvement of more than 75% over the baseline Psoriasis Area Severity Index (PASI 75) during induction therapy, a phase that can last up to 24 weeks. The efficacy of all the biologic agents tends to reach a plateau by the end of this phase.4

Several authors have indicated that, in patients with psoriasis in remission, continuing the standard regimen of a biologic drug could result in overtreatment, and have suggested that it may be reasonable to tailor the regimen on a case-by-case basis.5,6 A number of authors have analyzed the application of dose modification strategies to biologic therapy in patients with rheumatoid arthritis in a state of remission; the results show, in the case of tumor necrosis factor (TNF) inhibitors, that efficacy is preserved in most patients.7 Modification of the dose of a biologic drug in carefully selected patients in remission could reduce both the drug-exposure risk and the economic burden on the health care system.8 This strategy has already been proposed in other chronic diseases, such as rheumatoid arthritis, as a way to tailor treatment and identify the minimum effective dosage in each case.9–12

It is particularly useful to analyze the risks and benefits associated with the use of non-standard regimens of the different biologic agents used in the treatment of psoriasis. It is also important to identify the clinical characteristics associated with the success or failure of such off-label regimens, including the risk of relapse and the likelihood that the patient will develop specific antibodies.13 The decision to use an off-label regimen should be based on the careful selection of appropriate candidates, bearing in mind that the potential risks and benefits will depend on disease severity, the patient's quality of life, and the presence of comorbidities.13

In the literature, there are very few articles and no guidelines on the modification of biologic regimens in the treatment of psoriasis.13-15 The studies that have been done provide valuable data because they include patients with recurring disease and varying comorbidities, who would probably have been excluded from clinical trials.14 In a systematic review, Brezinski et al.13 summarized the findings of 23 trials that studied non-standard dosing regimens with etanercept, adalimumab, infliximab, ustekinumab, and alefacept in moderate to severe psoriasis. In the case of treatment with TNF and IL12/23 inhibitors, they reported that continuous regimens had been shown to be more effective than intermittent therapy in maintaining control of disease and that, for most of the biologic agents, the initial response rates were not achieved with retreatment. Other authors have observed—with etanercept, adalimumab, and ustekinumab—that escalation of the dosing regimen in nonresponders generally achieved greater efficacy.16-20

In a study by Fotiadou et al.,14 the interval between adalimumab injections was increased from 2 to 3 weeks in 14 patients with moderate to severe psoriasis who achieved and sustained a PASI 100 response after the first year of treatment. None of those patients experienced a relapse and 71% of them were followed up for 2.5 years. In a study of patients with psoriatic arthritis by Cantini et al.,8 47 (88.6%) of the 53 patients who received a reduced dose of adalimumab (40 mg every 4 weeks) maintained clinical remission after a mean (SD) follow-up of 28.9 (8.4) months.

In light of these findings, the objective of the present study was to analyze the patterns of dose modification in biologic therapy in a cohort of patients with moderate to severe psoriasis in clinical practice and the repercussions of such regimens on disease control and the cost of treatment.

This was an observational, descriptive, cross-sectional study that included all patients with moderate to severe psoriasis who had been treated with biologic agents for at least 6 months and were in the maintenance phase in January 2014. Cases in which the patient had not achieved at least a PASI 50 response by the end of the induction phase were classified as primary treatment failures and were excluded from the study. The patients were followed up by a single investigator in a specialized hospital psoriasis unit.

Figure 1 shows the treatment algorithm used in this study. The treatment objective was to achieve and maintain a PASI 75 response during the course of biologic treatment. All of the patients started treatment with the dosage regimen specified in the Summary of Product Characteristics (the standard regimen). In the patients who achieved remission (at least a PASI 90 response) for at least 6 months, the dose of the biologic agent was reduced by either decreasing the dose or increasing the interval between doses (reduced-dose regimen) according to a protocol agreed 2 years earlier between the hospital's dermatology department and pharmacy. When, by contrast, the standard regimen failed to produce a PASI 75 response, the regimen was escalated by reducing the interval between doses or by combining biologic therapy with a classic systemic drug. The dose reduction strategy was maintained as long as the patient continued in remission. If the patient lost the PASI 90-100 response, the standard regimen was reinstated. The escalated regimen was maintained until the therapeutic objective (at least a PASI 75 response) was achieved.

Figure 1.

Treatment algorithm used in the study.

(0.17MB).

Data was collected on demographic characteristics (age, sex, weight) as well as on variables relating to the history of psoriasis (disease duration, baseline PASI, presence of psoriatic arthritis, prior systemic and/or biologic treatment) and to current biologic treatment (duration of treatment, PASI at the time of treatment modification, duration of modified regimen, and PASI at final follow-up visit).

To identify the characteristics or profiles that may make patients better candidates for biologic therapy at reduced doses, the results were analyzed to compare the patients in whom the dose was not reduced (those who received standard and escalated regimens) with those who followed a dose-reduced regimen. This analysis was performed for both continuous and categorical variables.

In this study of routine clinical practice, we analyzed various dose modification strategies for biologic therapy in a cohort of 112 patients with moderate to severe psoriasis and the outcomes achieved in terms of disease control and cost of treatment.

Of the total of 112 patients, 52 (46.4%) received adalimumab, 28 (25%) ustekinumab, 24 (21.4%) etanercept, and 8 (7.1%) infliximab (Table 1). As this was a cross-sectional study, the uneven distribution in the cohort of the biologic agents studied may have been affected by the length of time each one of these drugs had been available on the market.

Therapeutic response was closely monitored in all the patients throughout the study and the dose modification strategy was applied according to a treatment algorithm (Figure 1). Use of this dose modification algorithm led to the following mean annual dose reductions per patient: 21% for adalimumab, 13.8% for etanercept, 0.9% for ustekinumab, and 0.55% for infliximab.

While dose modification is a common practice in dermatology departments, there are few studies in the literature providing evidence to support such strategies.13,21–23 Given that the optimization of economic resources should always be accompanied by the achievement of therapeutic objectives, more information is needed about the outcomes achieved with reduced-dose regimens, which are more common in settings where the control of expenditure is stricter.

There is currently only limited data on the safety of off-label biologic regimens. The use of such regimens should therefore be tailored to each patient, taking into account the severity of psoriasis, the patient's quality of life, and the presence of comorbidities.13 Measurement of drug levels could also facilitate the clinical decision by identifying the patients in remission who have excessively high concentrations, but most dermatology departments do not routinely monitor drug levels. Although it has been postulated that increasing the interval between doses with adalimumab may increase the risk of anti-adalimumab antibody formation,15 there is currently no evidence to confirm this hypothesis.22 With infliximab, also a TNF inhibitor, the use of lower doses or longer intervals between doses has been correlated with a higher risk of developing anti-infliximab antibodies, with a subsequent loss of treatment response.24

In our study, the comparative analysis between the reduced-dose subgroup and the rest of the patients revealed 2 significant differences: the patients on a reduced regimen had longer disease duration (P=.049) and had been on biologic therapy for longer (P=.009) (Table 3). These differences could be attributed to the fact that patients who had been in treatment for a longer period and were in remission, having achieved good disease control, might present a higher threshold for relapse so that their psoriasis could be controlled with lower doses. The differences between the groups in the PASI score were an artifact of the algorithm used, which called for a reduction of the dose when the patient was in remission. By contrast, among the patients who were not candidates for dose reduction, there was a higher proportion of patients with psoriatic arthritis (P<.05) (Table 3). It can therefore be concluded that the presence of psoriatic arthritis, a condition that influences the severity of psoriasis, could be a factor that limits a patient's suitability for a dose reduction strategy.

There are very few publications on the factors that might influence the efficacy of modified biologic regimens in patients with psoriasis and such factors could serve as predictors of suitability for off-label dosing strategies in these patients. In a study of clinical practice involving 119 Spanish patients with moderate to severe psoriasis treated with adalimumab,21 multivariant analysis established that the only independent variables predicting retention of biologic treatment were a PASI 75 response at 1 year and the ability to increase the interval between injections in the patients with the best response. In that study, the likelihood of treatment retention appeared to be greater in patients who had not previously received biologic therapy and who had the best responses at various time points, an outcome that made them good candidates for an increased interval between doses.21 In our cohort, the percentage of biologic-naive patients receiving each biologic drug was variable: 77% for etanercept, 36.3% for adalimumab, 25% for infliximab, and 17.85% for ustekinumab. These variations may have had some influence on the likelihood that the dosing regimen could be modified in each one of the biologic agents.

The present study has a series of limitations that should be mentioned. In the first place, since it was an observational study of clinical practice without any predefined protocol, the decision to reduce the dose and the timing of any such decision was based on the researcher's criteria in each case. The reduced-dose regimen was empirical and applied progressively; however, the therapeutic objective was always taken into account and the standard dose was always reinstated in the case of relapse. Furthermore, given the retrospective nature of the study, not all the patients were treated for the same period of time. In addition, only patients who achieved the therapeutic objective were included, making it impossible to obtain any information concerning clinical efficacy.

In summary, we present a cohort of 112 patients treated in routine clinical practice, 50% of whom received a reduced dose after achieving a sustained response greater than PASI 90. The patients most likely to be candidates for dose reduction were those who had a longer disease duration and had been receiving biologic therapy for a longer period. Among the patients who were not candidates for dose reduction there was a higher proportion of patients with psoriatic arthritis. The application in clinical practice of a dose modification algorithm in this population yielded an overall saving of 13% in pharmaceutical expenditure. The saving varied for each one of the biologic drugs: 21.5% for adalimumab, 13.8% for etanercept, 0.9% for ustekinumab, and 0.55% for infliximab.

Prospective controlled studies are needed to further define the profile of patients best suited for dose reduction strategies. More data is also needed on the percentage of patients who have to return to the standard regimen because of a loss of response and whether in such cases the strategy is associated with a loss of long-term treatment efficacy.

Ofelia Baniandrés declares that she has received remuneration from Abbvie, Pfizer, Janssen, and MSD in respect of participation in clinical trials, speakers fees, and consultancy fees. The other authors declare that they have no conflicts of interest.