Biologic Therapy for Moderate to Severe Psoriasis. Real-World Follow-up of Patients Who Initiated Biologic Therapy at Least 10 Years Ago

The efficacy and safety profiles of biologic therapies in psoriasis have been studied in numerous clinical trials. However, it should be noted that in most of these trials, efficacy was assessed based on the percentage of patients who achieved PASI 75. Also, clinical experience in the treatment of psoriasis with biologic therapies has shown relevant variations between the results of clinical trials and those obtained in daily practice.

The first biologic therapy authorized for moderate-to-severe plaque-type psoriasis in Europe was efalizumab, in October 2004. In February 2009, the European Medicines Agency suspended the marketing authorization for efalizumab after three confirmed cases of progressive multifocal leukoencephalopathy were reported [1].

Maintaining response to treatment is important in chronic conditions that require long-term treatment, such as psoriasis. It is known that drug survival decreases over time for all biologic therapies, mainly due to lack/loss of efficacy, eventual remission and side effects, depending on the study. Drug survival of biologics, defined as the time from initiation to discontinuation of a particular treatment, is well documented in several registries and cohort studies [2‐4].

Only a limited number of studies have considered long-term maintenance of the response as an indicator of treatment efficacy [5, 6]. Psoriasis response data to biologic therapy in clinical practice are scarce, such as studies evaluating long-term efficacy [7].

In the study reported here we have evaluated the response to biologic therapies, based on sequential PASI scores, as well as drug survival in patients with moderate to severe plaque-type psoriasis who initiated biologic therapy at least 10 years ago, in a real-world setting.

This is an observational retrospective follow-up study in patients with moderate to severe plaque type psoriasis who initiated biologic therapy between October 2006 and December 2009. Eligible patients could have started treatment with efalizumab (withdrawn in February 2009), etanercept, adalimumab, infliximab or ustekinumab, which were the biological treatments available at that time. The choice of biologic was made according to the availability of the drug at the time of prescribing and the characteristics of the patients. During patient recruitment, the biologics available for treatment were efalizumab, infliximab, etanercept and adalimumab. Efalizumab was authorized for moderate to severe plaque psoriasis in Spain in October 2004, infliximab in November 2005, etanercept in April 2007, adalimumab in May 2008 and ustekinumab in February 2009. Efalizumab was the drug of first choice until it was withdrawn from the drug market. Once etanercept became available, it was the biologic of second choice after treatment failure with efalizumab. When the marketing of efalizumab was discontinued, those patients treated with this drug were switched to etanercept, which became the first-choice biologic medicine for naïve patients. Treatment with infliximab requires intravenous infusion and, consequently, infliximab was reserved for severe patients who had associated comorbidities for whom efalizumab or etanercept were not suitable. Adalimumab and ustekinumab were marketed later than the others, and were therefore used in patients who had failed first-line treatment.

All patients enrolled in the study were followed up at the Department of Dermatology of the University Hospital of La Coruña (Spain) from October 2006 to December 2019. All patients received the standard doses established in the technical data sheet of the drugs. PASI and Body Surface Area (BSA) responses were evaluated at the first month and then every 3 months during the first year of treatment, and then every 12 months until the end of the follow-up or until the withdrawal of biologic therapy due to poor tolerance, lack of efficacy or adverse events.

The response to biologic therapy during the study period was evaluated in comparison with the baseline Psoriasis Area and Severity Index (PASI) score before initiation of a biologic therapy (course baseline). In addition, efficacy was expressed as the percentage of patients achieving a 50, 75 and 90% reduction from baseline in the PASI score (PASI 50, PASI 75, PASI 90, respectively) [5, 6].

Failure on biologic therapies was categorized into primary failure, secondary failure and side effects. Primary failure was defined as an insufficient response (patients not achieving PASI 50) at week 12–16, according to the medication. Secondary failure was defined as the loss of response (PASI > 50% of initial value) in a patient who had previously achieved PASI 50 response at week 12–16 [8].

This observational retrospective follow-up study, based on 56 patients, describes a real-world use of biologic therapy in patients with moderate to severe plaque-type psoriasis who initiated biologic therapy at least 10 years ago. This report provides valuable insight into the efficacy and safety of biologic therapy in clinical practice for up to 10 years of continued use.

Most patients continued biologic therapy at the end of the study period with good response, a duration of treatment of > 10 years and a median of two treatment lines (range 1–8). The efficacy and safety of biologic therapy have been demonstrated in several clinical trials in a short period of time. However, studies evaluating the continued use of biologic therapy for > 10 years in the real-world setting are scarce [3, 9].

In a systematic review of drug survival in biologic treatments in psoriasis, No et al. [3] selected 36 studies in which the inclusion criteria of patients previously treated with biologics varied widely and included patients naïve to biologics, patients who had failed biologic treatment and patients whose exposure to biologics was unknown. The majority of biologic treatments were with etanercept (43.1%), followed by adalimumab (25.6%), ustekinumab (22.6%) and infliximab (8.7%). In our study, the most prescribed biologic was also etanercept: 39.3% of treatments in 98.2% of patients; efalizumab was the second most commonly prescribed biologic (in 17.1% of treatments), followed by adalimumab (16.4%), ustekinumab (13.6%) and infliximab (6.4%). Thus, the use of biologics in terms of most prescribed drugs in our study is in agreement with the order in the study of No et al. [3], with the exception of efalizumab. In our study, efalizumab was only prescribed as first-line biologic therapy due to its withdrawal from the drug market in 2009. The 24 patients who were being treated with efalizumab as first-line treatment at that time were switched to etanercept.

The median number of treatment lines in our study was two (range 1–8). We cannot compare these data with data from other studies since the latter only distinguish between naive and non-naive patients [3, 9].

Roche et al. [7] describe drug survival in a 12-year, long-term real-life experience with biologics in psoriasis patients. In their study, patients received a mean (± SD) of 2.1 ± 0.9 different biologics, which is similar to the number of biologics seen in our study. However, Roche et al. included all patients treated with biologics during the 12-year study period, did not define a minimum treatment time and excluded patients treated with efalizumab; in comparison, in our study, we only included patients that initiated biologic therapy at least 10 years ago.

In our study, lack of efficacy of a specific biologic was the most common reason to discontinue that specific biologic therapy, which is in agreement with published studies [2, 3, 7, 9]. The precise mechanism that causes the clinical decline is not entirely understood, but may be associated with immune-mediated mechanisms by which antidrug antibodies are developed via a T-cell-dependent humoral response. These anti-drug antibodies likely form immune complexes that interrupt drug–end target interaction or increase drug clearance, thereby altering the efficacy and bioavailability of biologic drugs [3]. These data arenot available in our study because this strategy was not used in our hospital until 2013, 7 years after the start of the study inclusion period.

The percentage of discontinuation of an individual drug in our study was 62.1%, which is very similar to the 65.4% found by Roche et al. [7]. However, these authors reported a loss efficacy percentage of 44.9% and serious adverse events in 17.4% of patients; these values were 24.3% and 3.6% in our study, respectively.

Only five of our patients discontinued a biologic due to adverse events, all were treated with an anti-TNF drug. The adverse effects resolved upon discontinuation of the specific biologic or switch to an anti-TNF drug. No patients treated with anti-interleukins had to discontinue their treatment due to side effects. This result supports the long-term safety of biologic therapy.

We found that ustekinumab had the best drug survival in psoriatic patients who initiated biologic therapy at least 10 years ago. This result is consistent with those of previous studies on drug survival [2‐4, 7, 9‐11].

In addition, we found that patients being treated with efalizumab and infliximab showed a trend towards a significantly higher HR of switching than those receiving ustekinumab, but this trend was not observed with the other biologics. The reason for the higher probability of switching among patients receiving efalizumab could be related to the suspension of the marketing authorization for efalizumab in February 2009, which resulted in patients having to change treatment at that time [1]. Regarding infliximab, the higher probability of switching seen among patients receiving this biologic may be due to its intravenous administration route. Currently, there are several biologic treatment options administered subcutaneously that patients are more comfortable with. However, we did not have adequate data on the drug survival of biologics that are newly available on the market, such as secukinumab, ixekizumab or guselkumab, similar to the Lin et al. study [9].

Puig et al. [2] describe the drug survival of conventional and biologic therapies in patients with moderate to severe psoriasis in a real-world setting. Nevertheless, their study is a 2-year observational prospective study that only evaluates the first-line treatments. Drug survival decreases over time for all conventional and biologic therapies, mainly due to lack/loss of efficacy, eventual remission and side effects, depending on the study [2].

The limitations of our study are its single-center retrospective design, the limited number of patients included and its analysis of the real-world environment in which the data may be influenced by different times at which biologics are introduced onto the market.

This real world-setting study shows maintenance of long-term efficacy and safety of biologic therapy in patients with moderate to severe plaque psoriasis who initiated biologic therapy at least 10 years ago. Long-term clinical practice studies of biological psoriasis treatments are essential to understand the behavior of these drugs in real life, outside the context of clinical trials.