FormalPara Key Summary Points

The objective of this study was to assess the association of degree of skin clearance (measured by PASI) with the risk of treatment failure in the 15 months following initiation of a systemic biologic therapy among real-world patients from the CorEvitas Psoriasis Registry

To our knowledge, the relationships between achievement of complete and near-complete skin clearance and treatment failure have not been studied previously; we hypothesize that the patients least likely to experience treatment failure are those achieving the greatest PASI response

Following adjustment for confounders, the risk of treatment failure was two to three times higher in the PASI90 – < 100 and PASI75 – < 90 groups, and more than 20 times higher in the < PASI75 group, versus the PASI100 group

Given that PASI90 – 100 is an increasingly achievable outcome as more effective biologic therapies become available, this study builds on existing clinical trial evidence indicating that dermatologists and patients should consider near-complete to complete skin clearance an ideal treatment target

Introduction

Psoriasis is a chronic, immune-mediated dermatologic disease, characterized by inflammatory skin lesions and resulting in symptoms such as pain, itching, and scaling [1]. Psoriasis affects an estimated 7.5 million adults in the US [2] and is associated with significant negative impacts on patient quality of life (QoL), including impairments in activities of daily living, increased risk of mental illness, and productivity losses such as absenteeism [3,4,5].

Mild cases of psoriasis are often managed topically, but moderate-to-severe cases generally require systemic biologic therapy [6]. Biologic therapies that inhibit specific inflammatory cytokines implicated in disease manifestation, including tumor necrosis factor (TNF), interleukin (IL)-12/23, IL-17A, and IL-23, are increasingly prescribed as treatments for moderate-to-severe psoriasis [7,8,9,10,11]. Among patients receiving biologics for moderate-to-severe psoriasis, many switch between therapies because of treatment failure over the course of their disease journey [12, 13]. Treatment failure may be understood as discontinuation of a specific biologic due to either a lack of initial response to treatment or a loss of effectiveness over time [12].

The Psoriasis Area and Severity Index (PASI) is the most commonly used quantitative measure of disease severity for patients with psoriasis in clinical research [3]. PASI incorporates the body surface area involvement of lesions with the intensity of erythema (redness), induration (thickness), and desquamation (scaling) over four body regions (head, arms, trunk, and legs) [14]. Improvement of ≥ 75% in PASI from initiation (PASI75) is often used in clinical trials as a reasonable therapeutic target for biologic treatment of psoriasis, and patients who achieve this threshold are considered responders by many regulatory agencies [15]. However, with the emergence of IL-17A and IL-23 inhibitors in the treatment of psoriasis, near-complete skin clearance (≥ 90% improvement in PASI from initiation; PASI90) and complete skin clearance (100% improvement in PASI from initiation; PASI100) have become feasible treatment outcomes [15,16,17,18].

Despite patients indicating that treatment effectiveness is the main determinant of treatment satisfaction for psoriasis [19], there is limited real-world evidence to corroborate that achieving PASI100 has an impact on treatment patterns among patients receiving biologics, including treatment failure compared to lesser degrees of skin clearance [20]. A better understanding of the relationship between complete skin clearance and treatment failure may help dermatologists determine whether maximizing skin clearance should be the primary goal for treatment with biologic therapies.

To address this gap, the objective of this study was to assess the association of skin clearance with the risk of treatment failure in the 15 months following initiation of a systemic biologic therapy among real-world patients from the CorEvitas Psoriasis Registry. We hypothesized that the patients least likely to experience treatment failure are those achieving PASI100.

Methods

CorEvitas Psoriasis Registry Patient Population

This study utilized data from the CorEvitas Psoriasis Registry, an independent, prospective, multicenter, observational registry based in the US and Canada that was launched in April 2015 in collaboration with the National Psoriasis Foundation [21, 22]. Adult patients (≥ 18 years of age) are enrolled in the registry if they have psoriasis diagnosed by a dermatologist, are willing to provide written informed consent for participation in the registry, and have initiated an eligible medication at enrollment or within the previous 12 months (Supplementary Material Table S1). Patients participating in or planning to participate in an interventional clinical trial with a non-marketed or marketed investigational drug for psoriasis are ineligible.

At each registry visit, providers update medication usage and document disease severity. Any change or planned change in therapy status occurring on the day of a registry visit is recorded at that registry visit with the reason for the change. Changes in biologic or non-biologic therapies that occur between registry visits are recorded along with the reason for the change at subsequent registry visits. Registry data are collected by participating dermatologists and enrolled patients via questionnaires during registry visits occurring at approximately 6-month intervals [23].

For this longitudinal cohort study, instances of patients with PASI > 5 initiating a biologic (TNF, IL-12/23, IL-17A, or IL-23 inhibitors) were included (patient initiations) if they initiated a biologic ≤ 42 days after a registry visit (baseline) and had at least one follow-up visit within 15 months of a baseline visit (April 2015–August 2021). The 42-day window after a registry visit for initiation of a biologic was an allowance for the misalignment between treatment initiation and standard of care visits observed in the real world. Gaps between treatment decisions and first therapy may have occurred for a number of reasons, such as insurance approvals, and were incorporated to allow the results to apply to a more generalizable patient population.

This study was performed following the guidelines for Good Pharmacoepidemiology Practice [24] and in accordance with the current version of the applicable regulatory and International Council for Harmonisation Good Clinical Practice requirements [25], the ethical principles that have their origin in the principles of the Declaration of Helsinki, and the local laws of the countries involved. All participating investigators were required to obtain full board approval for conducting non-interventional research involving human subjects with a limited dataset. Sponsor (CorEvitas, LLC) approval and continuing review was obtained through a central institutional review board (IRB; IntegReview, protocol number is Corrona-PSO-500). For academic investigative sites that did not receive a waiver to use the central IRB, full board approval was obtained from the respective governing IRBs, and documentation of approval was submitted to CorEvitas, LLC, prior to the initiation of any study procedures.

Study Design

The outcome (treatment failure) and primary exposure (degree of skin clearance as measured by PASI) were assessed at all registry visits following initiation. Patients were able to contribute multiple patient initiations (and subsequent follow-ups) if each met the inclusion criteria. Baseline characteristics were recorded separately for each initiation. Patient initiations were followed from baseline until the occurrence of discontinuation of the biologic therapy, addition of a new non-biologic therapy, or the last registry visit over the 15-month study follow-up period, whichever occurred first (Supplementary Material Fig. S1). Biologic discontinuation or non-biologic additions that did not occur within 42 days of a registry visit were omitted from the analysis (Supplementary Material Fig. S2).

Study Measures

Outcome Measure

Treatment failure was defined as a discontinuation in biologic therapy due to lack of effectiveness (poor response or adverse event) or addition of a new non-biologic therapy. Discontinuations for reasons other than effectiveness (non-failure discontinuations) or no discontinuation of the biologic (persistence) were not considered treatment failures (Supplementary Material Table S2). The time from initiation until treatment failure, non-failure, or persistent visit was calculated for a time-to-event measure.

Exposure Measure

PASI was collected at each registry visit; scores ranged from 0 (no disease) to 72 (maximal disease severity) [3]. At each follow-up visit, the percent improvement in PASI response from baseline for patients was calculated, and patients were categorized by level of response: < 75% (< PASI75), 75% – < 90% (PASI75 – < PASI90), 90% – < 100% (PASI90 – < PASI100; near-complete skin clearance), or 100% (PASI100; complete skin clearance).

Covariates

All covariates were assessed at baseline. Demographics and baseline characteristics included age (years), gender (male, female), race (White, Black, Asian, other/unknown), ethnicity (Hispanic, yes/no), body mass index (kg/m2), and number of comorbidities. The number of comorbidities was defined as the sum of the following: myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, chronic obstructive pulmonary disease, peptic ulcer disease, diabetes mellitus, lymphoma, and solid tumor cancer (excluding non-melanoma of the skin). Disease and treatment characteristics included psoriasis duration (years), PASI score, PASI > 10 (yes/no), biologic naivety (no prior systemic biologic therapy use; yes/no), non-biologic naivety (no prior systemic non-biologic therapy use; yes/no), current use of systemic non-biologic therapy (yes/no), current use of phototherapy (yes/no), and current use of topical therapy (yes/no).

Statistical Analysis

Mean (standard deviation [SD]), median (first quartile, third quartile [Q1, Q3]), frequency, and percentage were reported for characteristics measured at baseline. Frequency of treatment failures and non-failure discontinuations that occurred during follow-up were reported for each PASI response level. Treatment failures and non-failure discontinuations were further categorized into reasons for discontinuation.

Proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) estimating the strength of association between PASI response level and treatment failure over the 15-month follow-up period. Patient initiations with a non-failure discontinuation or with persistence at their last registry visit were censored. A frailty term was used to consider multiple registry visits for the same patient initiation. PASI response level was considered a time-varying covariate. Models that produced adjusted HRs included the following a priori selected baseline covariates: age, gender, race, ethnicity, biologic-naivety, PASI > 10, systemic non-biologic use, topical use, and number of comorbidities.

Results

There were 3299 biologic patient initiations that met study inclusion criteria, with 4530 total registry visits over follow-up (Fig. 1). A total of 645 follow-up visits were omitted because they ended in a treatment failure that did not occur within 42 days of a registry visit; 598 patient initiations were excluded because of no follow-up visits in the 15 months following initiation. The final analytic cohort included 2701 patient initiations from 2516 unique patients with 3846 total visits over follow-up.

Fig. 1
figure 1

Patient selection criteria and attrition for study analysis. N unique initiation, n unique follow-up visit, PASI Psoriasis Area and Severity Index

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Patient Demographics and Disease Characteristics

Among 2701 patient initiations, mean age (SD) was 49.9 (14.6) years, 42.4% occurred in females, and 76.6% occurred in White patients. At baseline, 2168 (80.3%) patient initiations occurred in overweight or obese patients, and 708 (26.2%) patient initiations occurred in patients with at least one comorbidity (Table 1).

Table 1 Demographics and baseline characteristics for all eligible patient initiations of biologic therapy in the CorEvitas Psoriasis Registry
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The median (Q1, Q3) psoriasis disease duration was 12.0 (5.0, 24.0) years. At initiation, over half of the patient initiations were in those with PASI > 10 (n = 1412; 52.3%), under half included patients who were biologic-naïve (n = 1157; 42.8%), and 1279 (47.4%) included patients that were non-biologic-naïve. Only 198 (7.3%) patient initiations included concomitant non-biologic therapy use at baseline, with 1301 (48.2%) including concomitant topical therapy use and 106 (3.9%) including concomitant phototherapy use at baseline (Table 1).

Skin Clearance and Treatment Failure

Discontinuation of a systemic biologic therapy occurred in 315 patient initiations. The majority (n = 236; 74.9%) of these discontinuations were attributed to lack of effectiveness or adverse events, and an additional 48 patient initiations included a non-biologic therapy added as a combination therapy, resulting in 284 total treatment-failures. Lack of effectiveness of the initiated biologic therapy (failure to maintain initial response or inadequate initial response) was the most common reason for treatment failure (Table 2).

Table 2 Frequencies of biologic treatment failures and non-failure discontinuations, and recorded reasons, by PASI response level, observed over 15 months of follow-up among eligible patient initiations in the CorEvitas Psoriasis Registry
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The risk of treatment failure was higher for visits at which < PASI100 was achieved compared to visits at which PASI100 was achieved. Treatment failure occurred in 1.3% (17/1349) of visits at which PASI100 was achieved, while those achieving PASI90 – < 100 and PASI75 – < 90 at registry visits had treatment failure rates of 3.4% (22/646) and 3.5% (26/749), respectively. Among those visits at which < PASI75 was achieved, treatment failure was 19.9% (219/1102). In unadjusted models, the risk of treatment failure was approximately three times higher in the PASI90 – < 100 (HR = 2.78; CI 1.47, 5.23; p = 0.002) and PASI75 – < 90 (HR = 3.01; CI 1.63, 5.55; p < 0.001) groups compared to the PASI100 group. In the < PASI75 group, the risk of treatment failure was approximately 18 times higher (HR = 17.58; CI 10.73, 28.81; p < 0.001). Findings were similar after adjustment for potential confounders among the PASI90 – < 100 (HR = 2.61; CI 1.35, 5.02; p = 0.004), PASI75 – < 90 (HR = 2.97; CI 1.58, 5.58; p = 0.001), and < PASI75 (HR = 22.26; CI 13.32, 37.21; p < 0.001) groups (Table 3).

Table 3 Hazard ratios for the association between PASI response level and treatment failure over 15 months following biologic initiation among patients in the CorEvitas Psoriasis Registry
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Discussion

In the real-world sample of patients with psoriasis who initiated a biologic therapy in the CorEvitas Psoriasis Registry, achievement of less than complete skin clearance was associated with a greater risk of treatment failure. The proportion of treatment failures for patients who achieved a response of ≥ PASI75 was low; among patients who achieved either PASI90 – < 100 or PASI75 – < 90 at registry visits, 3.4% and 3.5%, respectively, either discontinued a biologic used at initiation because of lack of effectiveness or added a non-biologic therapy. Nevertheless, compared to the PASI100 group, treatment failure was three times more likely for the group that achieved ≥ PASI75 – < PASI100, while for those achieving < PASI75, risk of treatment failure was 20 times higher than in the PASI100 group after adjustment for potential confounders. These large relative effect measures (HRs) should be interpreted in the context of the small number of failures across the different PASI response groups and considered alongside the absolute differences. To the best of our knowledge, this study is among the first real-world evidence studies demonstrating an incremental benefit of PASI100 over PASI90 – < 100 for reduced treatment failure.

As biologics continue to demonstrate achievement of significant, rapid, and sustained improvements in skin outcomes, complete and near-complete skin clearance have become reasonable parameters to measure the effectiveness of these therapies [18, 26]. As a result, near-complete skin clearance (PASI 90, PASI ≤ 2) has been identified as a relevant endpoint for treat-to-target approaches in psoriasis [27]. Furthermore, in randomized-controlled trials, complete skin clearance (PASI100) has been shown to be an achievable treatment outcome [28] and, compared with minimal residual disease (≥ PASI90), has also been shown to substantially reduce the physical burden of psoriasis and reduce the impact of psoriasis on QoL [29,30,31,32].

For example, patient-reported outcomes for health-related QoL (HRQoL) and self-reported signs and symptoms have shown incremental improvements with greater PASI response or other measures of skin clearance, including Physician’s Global Assessment (PGA) [30, 31, 33, 34]. Additionally, a study of pooled data from three phase 3 trials showed that complete skin clearance resulted in incremental improvements for both HRQoL (18% for a Dermatology Life Quality Index [DLQI] score of 0) and self-reported signs and symptoms (28% for a Psoriasis Symptom Inventory score of 0) over near-complete skin clearance (PASI90 – < 100) [29]. Likewise, in a pooled analysis of two phase 3 trials, there were significantly more PASI90 – 100 responders who achieved a DLQI score of 0/1 than among PASI75 – < 90 responders [35]. Meanwhile, in this study, treatment failure among patients who achieved PASI90 – < 100 versus those that achieved PASI75 – < 90 was similar (3.4% versus 3.5%).

Previous studies have evaluated the effect of switching biologics on outcome measures such as PASI or PGA in both real-world evidence studies and clinical trials [16, 30, 31, 33, 34, 36]. However, to our knowledge, the achievement of complete skin clearance and near-complete skin clearance and their relationship with biologic treatment failure have not been studied previously. We hypothesized that the patients least likely to experience treatment failure are those achieving the greatest PASI response. This is supported by the findings in this study as patients achieving ≥ PASI75 had low rates of treatment failure (< 4%), with even fewer treatment failures experienced by those patients achieving complete skin clearance (1.3%). Furthermore, this study supports that effectiveness is the main determinant of treatment satisfaction as the most frequent reason for treatment failure among patients that achieved complete skin clearance was due to side effects (n = 7; 41.2%).

Strengths and Limitations

A major strength of the CorEvitas Psoriasis Registry is the documentation of reasons for changes in biologic therapy, which allowed for differentiation between treatment failures and non-failure discontinuations in the analysis. However, the specific reasons for non-failure discontinuations marked “other” are unknown and therefore may have been misclassified. Since the CorEvitas Psoriasis Registry collects data from academic and private practice dermatologists across the US and Canada, these patients are more likely to reflect the typical real-world patient population than those participating in controlled clinical trials. However, the generalizability of the findings presented may be limited since patient initiations were only eligible for this analysis if the patient had not experienced an interruption in treatment for > 180 days within the 15 months after initiation. Moreover, the CorEvitas Psoriasis Registry is based in the US and Canada, limiting extrapolation to other geographical settings. Furthermore, recruitment of both dermatologists and participating patients is voluntary; therefore, the CorEvitas Psoriasis Registry may not be representative of all patients with psoriasis initiating a biologic.

There is also a potential bias in excluding treatment failures or non-failure discontinuations that occurred outside the 42-day window surrounding registry visits if the relationship between treatment failure and PASI response in the excluded patients was different from that among those included in the study. However, we would not expect therapy changes occurring outside registry visit windows to be systematically different; thus, any impact of this potential bias would be nominal.

Finally, the study was designed to evaluate the association between skin clearance and treatment failure among users of all biologic therapies; thus, conclusions regarding potential differential impact of different biologic therapies cannot be drawn. Furthermore, given that the presence of comorbidities may influence the choice of and adherence to therapy, future studies may evaluate the association between skin clearance and treatment failure in the presence of additional comorbidities.

Conclusion

In this real-world study of patients with psoriasis who initiated a biologic therapy, findings demonstrate that those who achieved less than complete skin clearance (< PASI100) were at greater risk of treatment failure compared to patients who achieved complete skin clearance (PASI100). The results suggest that patients are more likely to remain on a biologic if they achieve near-complete or complete skin clearance. Given that PASI100 is an increasingly achievable outcome as more effective biologic therapies become available, this study builds on existing clinical trial evidence indicating that dermatologists should consider complete skin clearance as the ideal treatment target for patients with psoriasis.