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DOI: 10.1111/jdv.12981
ORIGINAL ARTICLE
Adalimumab in the treatment of moderate-to-severe chronic plaque psoriasis in patients switching from other biologics P. Sator,1 L. Richter,2 W. Saxinger,3 M. Vasiljevic,4 G. Stingl5,* €gel, Vienna, Austria Department of Dermatology, Hospital Hietzing with Neurologic Centre Rosenhu Hospital Rudolfstiftung including site Semmelweis Clinic of Gynaecology, Vienna, Austria 3 Department of Dermatology, Hospital Wels-Grieskirchen, Wels-Grieskirchen, Austria 4 AbbVie, Vienna, Austria 5 Division of Immunology Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Vienna, Austria *Correspondence: G. Stingl. E-mail: [email protected] 1 2
Abstract Background Ample evidence shows that switching from one biological agent to another may prove effective when response to the first one is inadequate. Nevertheless, there are little data so far showing the efficacy and safety of adalimumab in patients with plaque psoriasis who previously received another biologic agent. Objective We evaluated the 1-year effectiveness, safety and quality-of-life outcomes patients with psoriasis who had switched to adalimumab from other biologic therapies. Methods Forty-two patients who participated in this Austrian multicenter study were treated with adalimumab over a 1-year period, after switching from efalizumab, infliximab or etanercept. Effectiveness was assessed using standardized tools for measurement of disease severity [Psoriasis Area and Severity Index (PASI) and Nail Psoriasis Severity Index (NAPSI)] and quality of life [Dermatology Life Quality Index (DLQI)]. The study endpoints were evaluated using the all-treated population. Results The mean percentage of improvement at the end of the study was 74.3% for PASI, 81.6% for DLQI and 83.6% for NAPSI, demonstrating a considerable benefit of treatment with adalimumab. The safety profile observed was consistent with previous clinical trials for adalimumab, and no new safety signals were observed. Conclusion Adalimumab therapy in patients with plaque psoriasis previously treated with other biologic agents demonstrates effectiveness, safety and improvement in quality of life. Received: 14 July 2014; Accepted: 21 December 2014
Conflicts of interest In the last years, the participating authors received consultant and speaker fees from AbbVie Ltd. MV is an employee of AbbVie Ltd. AbbVie Ltd. contributed to the study design, research and interpretation of data, writing, reviewing and approving the publication
Funding sources The study was supported by AbbVie GmbH, Vienna Austria.
Previous presentations of parts of the study 1. Sator P-G et al. “A post-marketing observational study of the quality of life in adalimumab-treated psoriasis patients failing other biologic therapies over a period of 1 year: results of an Austrian non-interventional study”. Poster presented at the 21st Congress of the European Association of Dermatology and Venereology, Prague 28–30. September 2012, P941 (Original) €t bei mit Adalimumab €ber den Zeitraum eines Jahres zur Lebensqualita 2. Sator G-P. et al. “Anwendungsbeobachtung u behandelten Psoriasis-Patienten, die mit anderen Biologika ein Behandlungsversagen aufwiesen: Ergebnisse einer € nicht-interventionellen Studie in Osterreich”. Annual Meeting of the Austrian Society of Dermatology and Venereology, Vienna, 22–24. November 2013, P27 (Encore)
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Introduction In most of the patients affected, psoriasis (Ps) is a chronic immunologic disease characterized by marked skin inflammation and thickening of the epidermis. It affects 1–3% of the general population, with North America and Europe having the highest disease prevalence.1,2 Among patients with psoriasis, 75–80% are affected by plaque psoriasis.3 Depending on the severity of the disease, patients with psoriasis are treated either with only topical therapies, or in more severe cases, with systemic treatment or phototherapy. Systemic therapies include a series of chemical compounds also referred to as ‘classical therapies’ (e.g. methotrexate, cycloclosporine or fumaric acid ester), and new generation biologics (e.g. adalimumab, etanercept, infliximab and ustekinumab). In the past decade, biologics have revolutionized the treatment of moderate and severe forms of this condition. However, a certain number of patients will not initially respond to the prescribed biologic (primary non-responder), or they may lose the response over time (secondary non-responder). According to the European S3-Guidelines on the systemic treatment of plaque psoriasis,4 the current therapy should be reconsidered and optimized if the patient has an unsatisfactory response or has significantly impaired quality of life.5 In addition, patients may need to interrupt their current biologic treatment due to intolerability, side-effects, medical interventions or other reasons. In case of a primary or secondary failure to respond to a biologic monotherapy, or after a therapy interruption due to the aforementioned reasons, one of the treatment possibilities is a transition to another biologic agent.6 Adalimumab, a fully human monoclonal antibody directed against tumour necrosis factor alpha (TNF-a), is indicated for the treatment of moderate-to-severe plaque psoriasis. Little is known about the efficacy and safety of treatment with adalimumab after another biological drug had been discontinued. The purpose of this study was to assess the 1-year effectiveness and safety of adalimumab in patients who had been previously treated with efalizumab, infliximab or etanercept.
Methods Patients
After a previous study approval by the Ethics Committee, we obtained written informed consent from all patients prior to entry into the study. We recruited eligible patients (aged ≥18 years) with moderate-to-severe plaque psoriasis at eight hospitals in Austria (Klinikum Wels-Grieskirchen; State Hospital Feldkirch; Medical University of Graz; Wilhelminenspital Vienna; Medical University of Vienna; Hospital Hietzing, Vienna; Hospital Rudolfstiftung, Vienna; State Hospital Linz). The participating patients had an unsatisfactory response to prior biologic agents (efalizumab, infliximab or etanercept)
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or had initially achieved a satisfactory response, but lost it over time, or discontinued treatment due to intolerance/side effect(s) or other reasons (e.g. restart after regular stop of etanercept). A negative chest X-ray and a negative purified protein derivative (PPD) test for tuberculosis was required according to the Austrian Treatment Recommendation for use of biologics in psoriasis. Exclusion criteria included contraindications for the use of the adalimumab pen as outlined in the latest version of Summary of Product Characteristics (SPC), as well as for the use of biologics according to the Austrian Treatment Recommendations. Patients were excluded if they were simultaneously participating in another study or clinical trial. Intervention and study design
This was a post-marketing observational study conducted in a prospective, single-country, multicenter format. The study is registered in the U.S. National Institutes of Health database, ClinicalTrials.gov identifier NCT01084668. The patients received adalimumab as prescribed by the treating physician in accordance with the terms of the local marketing authorization with regard to dose, population and indication. Washout periods prior to the first adalimumab dose following previous biologic therapy were calculated according to the half-life of the respective biologic (etanercept >21 days, infliximab >56 days, efalizumab >42 days).6,16,17 Data collection took place during treatment visits that were part of the normal course of care and did not require any patient intervention beyond usual care. After therapy initiation, six visits were recorded over a period of 12 month, at approximately week 4, 12, 24, 36 and 52. Outcome measures
To obtain reliable data on disease severity in patients with moderate to severe chronic plaque psoriasis, we used validated scoring systems [Psoriasis Area and Severity Index (PASI); Nail Psoriasis Severity Index (NAPSI)] and quality-of-life (QoL) questionnaires [Dermatology Life Quality Index (DLQI)]. The primary objective of this study was to evaluate the 1-year effectiveness of adalimumab by using the PASI in patients who were pre-treated with efalizumab, infliximab, or etanercept and who either never achieved satisfactory response; achieved satisfactory response initially, but lost it over time; discontinued treatment due to intolerance/side effect(s); or had other reasons; for example, restart after the regular stop of etanercept or withdrawal of efalizumab from the market in 2009. Our secondary objectives were the evaluation of QoL using the DLQI score and the evaluation of improvement in NAPSI score. Finally, the safety of adalimumab and local tolerability when administered as a pen were evaluated by recording the incidence of adverse events (AEs) and local reactions.
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Statistical analysis
All parameters were analyzed descriptively. No confirmatory statistical testing was applied. An observed case approach was applied for all variables and missing data were not replaced. Statistical analysis was performed using the all-treated (AT) analysis population, comprising all patients with at least one application of adalimumab. Data were summarized with respect to demographic and baseline characteristics; disease history, including previous therapies; effectiveness and safety observations. The summary statistics included the number (%) of patients for categorical variables and mean, standard deviation (SD), median and minimum and maximum for continuous variables. For primary and secondary outcome measures, data of the prospective observation period (active phase) were used. All AEs were documented and analyzed descriptively and the incidence of AEs was summarized. The time to first PASI50/75/90/100 response from baseline was calculated using the Kaplan–Meier method.
Results Patients
This study was initiated in November 2008 and the last patient completed the last visit in April 2011. Eight sites enrolled 46 patients in the study. Forty-two patients who had no prior exposure to adalimumab received more than one treatment dose and were analyzed. The most common reasons for switching to adalimumab from etanercept, infliximab or
Table 1 Baseline demographic and disease characteristics (n = total number of patients per visit) AT- all treated AT analysis population (N = 42) Male sex, n (%)
27 (64.3)
Age (years), Mean SD
47.1 11.5
Median (min–max)
46.0 (28–77)
Duration of plaque Ps (years), Mean SD
23.7 13.3
Median (min–max)
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efalizumab were unsatisfactory response to prior therapy (n = 6), the loss of response over time (n = 10), restart after regular stop of etanercept (n = 6), and adverse events (n = 5). Fifteen patients were switched to adalimumab for other reasons. A total of 33 patients (78.6%) completed all six visits of the study. Patients in the study were predominantly male (64.3%), the mean age of patients was 47 years, and patients had plaque psoriasis for an average of 23.7 years (Table 1). Nineteen patients (45.2%) had psoriatic nail manifestations. All patients had a normal chest X-ray at baseline. Thirty-eight of 39 patients who were tested had a negative purified protein derivative (PPD) skin test. The PPD skin test was not performed in three patients out of 42 treated patients. All patients had taken prior biologic medication (etanercept, infliximab or efalizumab), six patients had additionally received a classic systemic therapy (methotrexate), and another two patients had received phototherapy. The mean duration of prior therapy with etanercept, infliximab and efalizumab was 643.9, 431.0, and 914.4 days, respectively. The mean PASI score at baseline was 15.5 and the mean DLQI score was 13.8. The mean NAPSI score at baseline was 15.4 and the mean NAPSI score in the subgroup of patients with nail psoriasis was 29.0. Nine patients terminated the study prematurely because of a lack of effectiveness (n = 5) and other reasons (noncompliance, n = 1; patient decision, n = 1; dissatisfaction/pain on injection, n = 1; and pregnancy, n = 1). Among 42 patients, eight patients (19%) used a concomitant anti-psoriatic medication, 6 (14.3%) received corticosteroids and topical preparations, and 6 (14.3%) emollients and protectives alone or in combination. Four patients (9.5%) were on concomitant systemic antihistaminic, 3 (7.1%) on anti-inflammatory and 3 (7.1%) on immunosuppressive therapy. Unspecified herbals were applied by two patients (4.8%) and one patient used some other dermatological preparation (2.4%). Nine patients received concomitant medication for other concomitant diseases like hypertension or cardiac disease.
24.5 (1–65) n = 41
Effectiveness
Mean SD
15.5 11.4
Median (min–max)
13.8 (0–53.9)
Psoriasis Area and Severity Index scores can range from 0.0 to 72.0, with the highest score representing complete erythroderma of the severest possible degree. Figure 1 shows that PASI scores decreased from baseline at each subsequent study visit. At the end-of-study visit (week 52), a mean reduction of 12.5, corresponding to mean percentage reduction of 74.3%, was observed, demonstrating an improvement in disease severity throughout the study. Approximately half of all treated patients achieved a PASI50 response by week 4, a PASI75 response at week 12, and a PASI90 response at week 24 (Fig. 2). Disregarding the patients who dropped out, the proportion of patients who achieved at least 75% improvement in PASI score increased from 16.7% at week
PASI score at baseline
DLQI score at baseline Mean SD Median (min–max) NAPSI score at baseline Mean SD Median (min–max) Primary non-responders, n (%)
n = 36 13.8 8.3 13.5 (0–29) n = 34 15.4 24.0 3.0 (0–80) 6 (14.3)
Secondary non-responders, n (%)
10 (23.8)
Pre-treatment with Etanercept, n (%)
22 (52.4)
Pre-treatment with Infliximab, n (%) Pre-treatment with Efalizumab, n (%)
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5 (11.9) 15 (35.7)
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PASI score
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PASI score by visit
25 20 15 10 5 0 Week 0 (N = 41)
Week 4 (N = 36)
Week 12 (N = 31)
Week 24 (N = 31)
Mean PASI score
Week 36 (N = 28)
Week 52 (N = 27)
Early terminaƟon (N = 6)
Median PASI score
Figure 1 Psoriasis area and severity index score by visit (N values are the total number of patients per visit).
ProporƟon of paƟents with PASI50/PASI75/PASI90/PASI100 response 100 90 80
PaƟents, %
70 60 50 40 30 20
Proportion of subjects with already a PASI 75 response
Week 52 (N = 26)
Week 36 (N = 28)
Week 12 (N = 31)
Week 24 (N = 31)
Week 4 (N = 36)
Week 52 (N = 26)
Week 24 (N = 31)
Week 36 (N = 28)
Week 4 (N = 36)
Week 12 (N = 31)
Week 52 (N = 26)
Week 36 (N = 28)
Week 12 (N = 31)
Week 24 (N = 31)
Week 4 (N = 36)
Week 52 (N = 26)
Week 36 (N = 28)
Week 24 (N = 31)
Week 12 (N = 31)
0
Week 4 (N = 36)
10
Figure 2 Proportion of patients with improvement in psoriasis area and severity index of ≥50%, ≥75%, ≥90%, or 100% from baseline to weeks 4, 12, 24, 36, and 52, respectively.
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 0
50
100
150 I
200 250 300 Time [days]
350
400
Censored observations
4 to 88.5% at week 52 (Fig. 2). At week 4, a total of 5.6% of patients had a PASI90 response versus 69.2% of patients at week 52. At the end-of-study visit, 42.3% of all patients achieved a PASI100 response.
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500
Figure 3 Time to first PASI75 response – Kaplan–Meier curve (AT analysis population).
According to Kaplan–Meier, the analysis indicated that the first patient achieved a PASI75 response after 29 days of treatment and approximately 50% of patients achieved a PASI75 response by 168 days (Fig. 3). The median times to PASI50/90/
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DQLI score
100 responses were estimated to be 84, 249, and 382 days, respectively. Kaplan–Meier curves refer to the individual patient time, considering the common temporal deviations from the visit time schedule according to the protocol. Among 22 patients who were switched from etanercept to adalimumab, three were primary, eight were secondary nonresponders to etanercept .The remaining 11 etanercept patients were switched for some other reason. All primary etanercept non-responders completed the 52-weeks observation period and had a median improvement in PASI score of 98.2%. Four of the secondary etanercept non-responders completed the study and had a median PASI score improvement of 100% in week 52. Two patients of this group terminated study prematurely, as their disease failed to improve. Additional two patients were not evaluated at week 52 and for the remaining one patient a false PASI score was entered by the physician. In the infliximabswitch group, one patient was designated as a primary nonresponder and had a PASI improvement of 91.6% in week 52 and one as a secondary non-responder, who terminated the study earlier due to treatment failure. Three infliximab patients were switched to adalimumab for some other reason. Two efalizumab switch patients were primary and one was a secondary non-responder; the remaining 12 patients were switched to adalimumab for other reasons, the most common one being withdrawal of efalizumab from the market by the head authority. Two primary efalizumab non-responders did not respond to adalimumab therapy either; in contrast they experienced worsening of their psoriasis. The secondary non-responder achieved PASI improvement of 91.1% at week 52. In general, non-responders to TNF-a blockers had a more pronounced improvement in PASI score at week 52 (94.6% on average for the whole group) than efalizumab non-responders (median PASI improvement at week 52:91.1). DLQI scores can range from 0 to 30, with decreased scores indicating improvements in disease-related QoL. In this study, patients treated with adalimumab achieved a mean reduction of 11.1, which corresponds to a mean percentage reduction of 81.6% at week 52 (Fig. 4).
Figure 4 Dermatology life quality index score by visit (N values are the total number of patients per visit).
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20 18 16 14 12 10 8 6 4 2 0
Nail Psoriasis Severity Index scores can range from 0 to 80, with higher scores representing higher psoriasis nail involvement. Mean reduction in NAPSI score for all patients was 11.4 corresponding to mean percent reduction of 83.6%. Regarding the patients with nail Ps whose NAPSI score was greater than 0 at more than one visit (n = 18; Fig. 5), the mean reduction in NAPSI score at week 52 was 20.2 and the mean percent reduction was 83.6%. At the end of the study, the investigator evaluated the global effectiveness of adalimumab based on the results of PASI, DLQI, and NAPSI assessments. The effectiveness of adalimumab for regular study completers and early terminations (N = 42) was considered ‘excellent’ or ‘sufficient’ for 78.6% of patients (n = 33), ‘moderate’ for 7.1% of patients (n = 3), and ‘unsatisfactory’ for 14.3% of patients (n = 6). Safety
On average, 24.7 injections of adalimumab per patient were administered over a mean period of 331.0 days. The mean cumulative adalimumab dosage per patient throughout the study was 1021.0 mg. During the study, 66.9% of patients took more than one concomitant medication (CM). The most frequently reported CMs, according to Anatomic Therapeutic Chemical (ATC) level 2, were agents acting on the renin-angiotensin system, anti-psoriatic agents, and acid-related disorder drugs in 21.4%, 19.0%, and 16.7% of patients, respectively. Overall, 17 adverse events (AEs) were reported by the investigators in nine patients (21.4%). All AEs were rated as mild or moderate in severity. The most common AEs were acute tonsillitis and nasopharyngitis, each reported by two patients. Six patients (14.3%) reported seven AEs that were considered to be related to adalimumab; almost all events (n = 5) were local reactions related to the injection site or skin and subcutaneous tissue disorders. The remaining events, which occurred in five patients (11.9%), were considered to be unrelated to therapy with adalimumab. The majority of the events (n = 12; 70.6%) were resolved by the end of the study. Only three serious AEs that
DLQI score by visit
Week 0 (N = 36)
Week 4 (N = 34)
Week 12 (N = 28)
Week 24 (N = 30)
Mean DLQI score
Week 36 (N = 26)
Median DLQI score
Week 52 (N = 27)
Early terminaon (N = 6)
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NAPSI score by visit (subgroup of paƟents with nail PS and a NAPSI score >0 at >= 1 visit) 35
NAPSI score
30 25 20 15 10 5 0 Week 0 (N = 18)
Week 4 (N = 16)
Week 12 (N = 15)
Week 24 (N = 15)
Mean NAPSI score
Week 36 (N = 12)
Median NAPSI score
were unrelated to adalimumab occurred in one patient: ‘ligament rupture’ (twice) and ‘arthroscopic surgery.’ According to the investigator’s evaluation at the end of the study, the safety of adalimumab was rated as ‘excellent’ or ‘sufficient’ in 97.6% of the patients (n = 41) and ‘moderate’ in one patient. Twenty-nine patients (87.9%) completed the study according to protocol and continued therapy with adalimumab after the end of the study. Reasons for discontinuing therapy included treatment failure (n = 2), adverse event (n = 1), and intended pregnancy (n = 1).
Discussion This study shows that chronic plaque psoriasis patients treated over a period of 1 year with adalimumab after they had interrupted their previous biological treatment with either TNF-a blockers like etanercept or infliximab, or with anti-CD11a antibody efalizumab, had a distinct reduction in the mean scores of effectiveness (PASI, DLQI and NAPSI), demonstrating an improvement in disease severity and QoL with treatment. Adalimumab was well tolerated and no new or unexpected safety concerns were identified during the observation period. All data were analyzed ‘as observed’. Even though it presents a weakness of the study, this is a common practice in non-interventional studies. The study population was predominantly male, which is in line with other published psoriasis trials with biologics. According to the study protocol, patients were allowed to receive a concomitant treatment with both topical and systemic anti-psoriatic treatment. Twelve patients out of 42 (28.6%) used concomitant corticosteroids, emollients, vitamin D topical treatment either alone or in combination. Most of them were prescribed by a physician to be used as necessary. In addition, 3 (7.1%) patients took oral antihistamines against pruritus and one patient received methotrexate due to psoriatic arthritis. The parallel use of topical treatments with adalimumab was studied in the randomized double-blind controlled BELIEVE trial7, where it was shown that the use of concomitant calcipotriole and betamethasone can be beneficial in the initial treatment phase. However,
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Week 52 (N = 13)
Early terminaƟon (N = 2)
Figure 5 Numbers presented are from a subgroup of patients with nail psoriasis and a nail psoriasis severity index score of >0 at ≥1 visit (N values are the total number of patients per visit).
this effect can no longer be observed after 8 weeks of treatment. In accordance to these findings, most of the patients from our study (10/14) stopped using the topical therapy before the end of the observational period. A subanalysis of the BELIEVE study7 described a rapid and sustainable response to adalimumab therapy after switching from other TNF- a blockers: at week 16, 61.7% of the TNF-aexperienced patients in this study achieved a PASI 75 response. The response to adalimumab in this patient population was clinically meaningful regardless of which previous TNF-a blockers had been used, the number of prior anti-TNF-a therapies, or reasons for discontinuation of prior anti-TNF-a therapies. In addition, there are several open-label uncontrolled studies that focused on the effectiveness and safety of biologic therapy in patients with plaque psoriasis who had previously failed therapy with one or more biologic agents. A multicenter study by Bissonnette et al.8 in 85 patients with plaque psoriasis who had failed to achieve or lost a response to etanercept noted a PASI75 improvement of clinical symptoms in approximately 52% of patients 24 weeks after switching to adalimumab. In a recent study by Strober et al.,9 patients with chronic plaque psoriasis with a suboptimal response to etanercept discontinued therapy 11–17 days before receiving adalimumab. After 16 weeks, 49% of patients achieved a Physician Global Assessment (PGA) score of clear or almost clear. Although all of these studies show a beneficial effect of transitioning therapy from etanercept to adalimumab, response rates appear to be lower in comparison to our study. This may be due to differences in baseline characteristics of the patient populations or in the pre-treatments and statistical analysis applied. A recent study by Fonseca et al.10 addressed the influence of previous etanercept failure on the effectiveness and safety of adalimumab in psoriasis patients in a real-world setting. Authors concluded that previous etanercept failure does not seem to jeopardize the success and safety of subsequent adalimumab treatment. In line with these findings our study shows that adalimumab therapy was successful in both primary and secondary non-responders who had been previously treated with any of the two anti-TNF-a agents. In contrast,
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patients who had never achieved a satisfactory response to efalizumab did not benefit from switch to adalimumab therapy. In general, the non-responder population of patients switching from the TNF-a inhibitors as group responded a bit better to adalimumab treatment (median PASI improvement at week 52: 98.2%) than patients who were switched from efalizumab due to lack of clinical response (median PASI improvement at week 52: 91.1%). However, the study population was not large enough to allow for precise conclusions on this topic. In patients with other disease states, such as rheumatoid arthritis, it has been noted that adalimumab restores effectiveness after a loss of response to other TNF-a blockers, including infliximab.11 Other forms of therapy transitioning in patients with plaque psoriasis with primary or secondary failure to a biologic treatment have also been studied. A majority of patients (54.5%) given infliximab after losing response to etanercept achieved a PASI75 response after 26 weeks.12 A switch from infliximab to etanercept can also be beneficial, although the study that noted these results was a small open-label study with a short follow-up period.13 The Vender study (2011)14 noted a successful treatment transition to etanercept upon loss of response to adalimumab in 10 patients. Therapy transitioning possibilities are described in detail and discussed in a consensus report by Mrowietz et al.5 These studies indicate that switching from one TNF-a blocker to another may still elicit a response, even though these therapeutic agents share the same molecular target. This may be because the differences between biologics lie not only in their target molecules, but also in their inherent properties (i.e. structure, absorption, distribution, and clearance mechanisms and rates) or in the dosage and administration regimens (i.e. dose amount, administration frequency, and route of administration).15 Despite the fact that all TNF-a blockers have the same target molecule, these agents are structurally different from one another. Infliximab and adalimumab are both monoclonal antibodies, but whereas infliximab is a murine-human chimeric antibody that combines the variable regions of a murine antibody with the constant region of human IgG1, adalimumab is an antibody with a fully human sequence.16,17 In contrast, etanercept is a fusion protein that combines the human TNF p75 receptor with the Fc domain of human IgG1.18 Since even small differences at the Fab binding region of antibodies can affect the specificity, affinity and epitope of the target molecule,19 the structural diversity of TNF-a blockers can significantly influence their pharmacologic properties. This is reflected in the different binding affinities of these molecules to the TNF-a. Even though all three TNF-a blockers bind to both the soluble (sTNF-a) and transmembrane form (tmTNF-a) of the TNF-a, it seems that etanercept binds to the tmTNF-a with a lower affinity.20 However, this does not seem to be the major factor that contributes to the variations in clinical effectiveness.21
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Furthermore, structurally distinct TNF-a blockers are capable of eliciting different immune responses. Owing to the presence of the CH1 domain of IgG1, which is crucial for complement activation, monoclonal antibodies can trigger complementdependent cytotoxicity (CDC), whereas etanercept lacks this sequence, and therefore does not induce CDC. Interestingly, although all three TNF-a blocker contain CH2 and CH3 domains, which are necessary for binding of the IgG Fc fragment to the respective receptor on natural killer cells, it seems that the monoclonal antibodies possess a stronger affinity to trigger antibody-dependent cell-mediated cytotoxicity.22 Yet another difference regarding the action of anti-TNF-a biologics on tmTNF-a is derived from the ability of the monoclonal antibodies to cross-link 2 tmTNF-a trimers and bring about apoptosis in the target cell via reverse signalling.23 Conversely, a study by Brunner et al.24 shows that an intravenous application of infliximab does not lead to increased cell death of TNF-aproducing cells in lesional psoriatic skin. Further investigations are necessary to determine the role of cell death in the mode of action of TNF-a blockers. Structural variations among TNF-a blockers also affect their specificity: while infliximab and adalimumab bind only TNF-a, etanercept can also target and bind lymphotoxin-a, also known as TNF-b. The clinical relevance of this binding remains unclear.20 Additionally, differences in drug administration can also contribute to the distinct pharmacokinetic profiles of the TNF-a blockers. Whereas infliximab is administered intravenously, adalimumab and etanercept are administered subcutaneously.16–18 Thus, high peaks, low minimums and high peak-to-trough ratios can be observed after the administration of infliximab. This is in contrast to the smooth and uniform concentration–time profiles seen at steady state with etanercept and adalimumab.15 Finally, differences in drug clearance (e.g. due to the presence of anti-drug antibodies to the specific biologic) may offer another explanation for treatment response after switching between two therapeutic molecules that share the same molecular target.25 In conclusion, our study demonstrates the effectiveness and safety of adalimumab for up to 1 year in patients with moderate to severe chronic plaque psoriasis who switched from another biologic agent. Treatment with adalimumab resulted in high rates of patient acceptance, leading to therapy continuation after the end of the study in the majority of the patients. In the absence of large randomized blinded trials, this study offers additional evidence that supports a possible therapeutic benefit in the transitioning from one biologic drug to another in a selected population of patients who were non-responders to initial treatment with a biologic agent.
Acknowledgements Mrs. Birgit Winninger from the ‘Dr. Robert Heinz and Partner’ company is gratefully acknowledged for medical writing services.
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References 1 Greaves MW, Weinstein GD. Treatment of psoriasis. New Engl J Med 1995; 332: 581–588. 2 Kim N, Thrash B, Menter A. Comorbidities in psoriasis patients. Semin Cutan Med Surg 2010; 29: 10–15. 3 Camp RDR. Psoriasis. In Champion RH, Burton JL, Burns DA, Breathnach SM, eds. Textbook of Dermatology, 6th edn. Blackwell Science Ltd, Oxford, 1998: 1589–1649. 4 Nast A, Boehncke WH, Mrowietz U et al. S3 – Guidelines on the treatment of psoriasis vulgaris (English version). Update. J Dtsch Dermatol Ges 2012; 10(suppl 2): S1–S95. 5 Mrowietz U, de Jong EM, Kragballe K, Langley R, Nast A, Puig L, Reich K, Schmitt J, Warren RB. A consensus report on appropriate treatment optimization and transitioning in the management of moderate-to-severe plaque psoriasis. J Eur Acad Dermatol Venereol 2014; 28: 438–53. 6 Raptiva (efalizumab). EPAR product information. [WWW document] 2009. URL http://www.ema.europa.eu/docs/en_GB/document_library/ EPAR_-_Product_Information/human/000542/WC500057853.pdf (last assessed: 30 November 2014). 7 Ortonne JP1, Chimenti S, Reich K. et al. Efficacy and safety of adalimumab in patients with psoriasis previously treated with anti-tumour necrosis factor agents: subanalysis of BELIEVE. J Eur Acad Dermatol Venereol 2011; 25: 1012–1020. 8 Bissonnette R, Bolduc C, Poulin Y, Guenther L, Lynde CW, Maari C. Efficacy and safety of adalimumab in patients with plaque psoriasis who have shown an unsatisfactory response to etanercept. J Am Acad Dermatol 2010; 63: 228–234. 9 Strober BE, Poulin Y, Kerdel FA et al. Switching to adalimumab for psoriasis patients with a suboptimal response to etanercept, methotrexate, or phototherapy: efficacy and safety results from an open-label study. J Am Acad Dermatol 2011; 64: 671–681. 10 Fonseca E, Iglesias R, Paradela S et al. Efficacy and safety of adalimumab in psoriatic patients previously treated with etanercept in a real-world setting. J Dermatolog Treatment 2014 Jul; 1: 1–6. 11 Ernestam S, Lindblad S, Bratt J, Klareskog L, van Vollenhoven RF. Adalimumab (Humira) restores clinical response in patients with secondary loss of efficacy from infliximab (Remicade) or etanercept (Enbrel): results from the STURE registry at Karolinska University Hospital. Scand J Rheumatol 2005; 34: 353–358. 12 Gottlieb AB, Kalb RE, Blauvelt A et al. The efficacy and safety of infliximab in patients with plaque psoriasis who had an inadequate response to etanercept: results of a prospective, multicenter, open-label study. J Am Acad Dermatol 2012; 67: 642–650. 13 Pitarch G, Sanchez-Carazo JL, Mahiques L, Oliver V. Efficacy of etanercept in psoriatic patients previously treated with infliximab. Dermatology 2008; 216: 312–316.
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14 Vender R. An open-label, prospective cohort pilot study to evaluate the efficacy and safety of etanercept in the treatment of moderate to severe plaque psoriasis in patients who have not had an adequate response to adalimumab. J Drugs Dermatol 2011; 10: 396–402. 15 Nestorov I. Clinical pharmacokinetics of TNF antagonists: how do they differ? Semin Arthritis Rheum 2005; 34(suppl 1): 12–18. 16 Humira (adalimumab). EPAR product information. [WWW document] 2014. URL http://www.ema.europa.eu/docs/en_GB/document_library/ EPAR_-_Product_Information/human/000481/WC500050870.pdf (last assessed: 30 November 2014). 17 Remicade (infliximab). EPAR product information. [WWW document] 2009. URL http://www.ema.europa.eu/docs/en_GB/document_library/ EPAR_-_Product_Information/human/000240/WC500050888.pdf (last assessed: 30 November 2014). 18 Enbrel (etanercept). EPAR product information. [WWW document] 2009. URL http://www.ema.europa.eu/docs/en_GB/document_library/ EPAR_-_Product_Information/human/000262/WC500027361.pdf (last assessed: 30 November 2014). 19 Tomoyuki I, Hiroyuki T, Taichi K, Zenjiro S, Shinya I, Kunihiro H. Engineering the variable region of therapeutic IgG antibodies. MAbs 2011; 3: 243–252. 20 Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 2008; 117: 244–279. 21 Kaymakcalan Z, Sakorafas P, Bose S et al. Comparisons of affinities, avidities, and complement activation of adalimumab, infliximab, and etanercept in binding to soluble and membrane tumor necrosis factor. Clin Immunol 2009; 131: 308–316. 22 Sterry W, van de Kerkhof P. Is ‘class effect’ relevant when assessing the benefit/risk profile of a biologic agent? J Eur Acad Dermatol Venereol 2012; 26(suppl 5): 9–16. 23 Horiuchi T, Mitoma H, Harashima S, Tsukamoto H, Shimoda T. Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents. Rheumatology (Oxford) 2010; 49: 1215–1228. 24 Brunner PM, Koszik F, Reininger B, Kalb ML, Bauer W, Stingl G. Infliximab induces downregulation of the IL-12/IL-23 axis in 6-sulfo-LacNac (slan)(+) dendritic cells and macrophages. J Allergy Clin Immunol 2013; 132: 1184–1193. e8. 25 Vincent FB, Morand EF, Murphy K, Mackay F, Mariette X, Marcelli C. Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective. Ann Rheum Dis 2013; 72: 165–178.
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DOI: 10.1111/jdv.12981
ORIGINAL ARTICLE
Adalimumab in the treatment of moderate-to-severe chronic plaque psoriasis in patients switching from other biologics P. Sator,1 L. Richter,2 W. Saxinger,3 M. Vasiljevic,4 G. Stingl5,* €gel, Vienna, Austria Department of Dermatology, Hospital Hietzing with Neurologic Centre Rosenhu Hospital Rudolfstiftung including site Semmelweis Clinic of Gynaecology, Vienna, Austria 3 Department of Dermatology, Hospital Wels-Grieskirchen, Wels-Grieskirchen, Austria 4 AbbVie, Vienna, Austria 5 Division of Immunology Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Vienna, Austria *Correspondence: G. Stingl. E-mail: [email protected] 1 2
Abstract Background Ample evidence shows that switching from one biological agent to another may prove effective when response to the first one is inadequate. Nevertheless, there are little data so far showing the efficacy and safety of adalimumab in patients with plaque psoriasis who previously received another biologic agent. Objective We evaluated the 1-year effectiveness, safety and quality-of-life outcomes patients with psoriasis who had switched to adalimumab from other biologic therapies. Methods Forty-two patients who participated in this Austrian multicenter study were treated with adalimumab over a 1-year period, after switching from efalizumab, infliximab or etanercept. Effectiveness was assessed using standardized tools for measurement of disease severity [Psoriasis Area and Severity Index (PASI) and Nail Psoriasis Severity Index (NAPSI)] and quality of life [Dermatology Life Quality Index (DLQI)]. The study endpoints were evaluated using the all-treated population. Results The mean percentage of improvement at the end of the study was 74.3% for PASI, 81.6% for DLQI and 83.6% for NAPSI, demonstrating a considerable benefit of treatment with adalimumab. The safety profile observed was consistent with previous clinical trials for adalimumab, and no new safety signals were observed. Conclusion Adalimumab therapy in patients with plaque psoriasis previously treated with other biologic agents demonstrates effectiveness, safety and improvement in quality of life. Received: 14 July 2014; Accepted: 21 December 2014
Conflicts of interest In the last years, the participating authors received consultant and speaker fees from AbbVie Ltd. MV is an employee of AbbVie Ltd. AbbVie Ltd. contributed to the study design, research and interpretation of data, writing, reviewing and approving the publication
Funding sources The study was supported by AbbVie GmbH, Vienna Austria.
Previous presentations of parts of the study 1. Sator P-G et al. “A post-marketing observational study of the quality of life in adalimumab-treated psoriasis patients failing other biologic therapies over a period of 1 year: results of an Austrian non-interventional study”. Poster presented at the 21st Congress of the European Association of Dermatology and Venereology, Prague 28–30. September 2012, P941 (Original) €t bei mit Adalimumab €ber den Zeitraum eines Jahres zur Lebensqualita 2. Sator G-P. et al. “Anwendungsbeobachtung u behandelten Psoriasis-Patienten, die mit anderen Biologika ein Behandlungsversagen aufwiesen: Ergebnisse einer € nicht-interventionellen Studie in Osterreich”. Annual Meeting of the Austrian Society of Dermatology and Venereology, Vienna, 22–24. November 2013, P27 (Encore)
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Introduction In most of the patients affected, psoriasis (Ps) is a chronic immunologic disease characterized by marked skin inflammation and thickening of the epidermis. It affects 1–3% of the general population, with North America and Europe having the highest disease prevalence.1,2 Among patients with psoriasis, 75–80% are affected by plaque psoriasis.3 Depending on the severity of the disease, patients with psoriasis are treated either with only topical therapies, or in more severe cases, with systemic treatment or phototherapy. Systemic therapies include a series of chemical compounds also referred to as ‘classical therapies’ (e.g. methotrexate, cycloclosporine or fumaric acid ester), and new generation biologics (e.g. adalimumab, etanercept, infliximab and ustekinumab). In the past decade, biologics have revolutionized the treatment of moderate and severe forms of this condition. However, a certain number of patients will not initially respond to the prescribed biologic (primary non-responder), or they may lose the response over time (secondary non-responder). According to the European S3-Guidelines on the systemic treatment of plaque psoriasis,4 the current therapy should be reconsidered and optimized if the patient has an unsatisfactory response or has significantly impaired quality of life.5 In addition, patients may need to interrupt their current biologic treatment due to intolerability, side-effects, medical interventions or other reasons. In case of a primary or secondary failure to respond to a biologic monotherapy, or after a therapy interruption due to the aforementioned reasons, one of the treatment possibilities is a transition to another biologic agent.6 Adalimumab, a fully human monoclonal antibody directed against tumour necrosis factor alpha (TNF-a), is indicated for the treatment of moderate-to-severe plaque psoriasis. Little is known about the efficacy and safety of treatment with adalimumab after another biological drug had been discontinued. The purpose of this study was to assess the 1-year effectiveness and safety of adalimumab in patients who had been previously treated with efalizumab, infliximab or etanercept.
Methods Patients
After a previous study approval by the Ethics Committee, we obtained written informed consent from all patients prior to entry into the study. We recruited eligible patients (aged ≥18 years) with moderate-to-severe plaque psoriasis at eight hospitals in Austria (Klinikum Wels-Grieskirchen; State Hospital Feldkirch; Medical University of Graz; Wilhelminenspital Vienna; Medical University of Vienna; Hospital Hietzing, Vienna; Hospital Rudolfstiftung, Vienna; State Hospital Linz). The participating patients had an unsatisfactory response to prior biologic agents (efalizumab, infliximab or etanercept)
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or had initially achieved a satisfactory response, but lost it over time, or discontinued treatment due to intolerance/side effect(s) or other reasons (e.g. restart after regular stop of etanercept). A negative chest X-ray and a negative purified protein derivative (PPD) test for tuberculosis was required according to the Austrian Treatment Recommendation for use of biologics in psoriasis. Exclusion criteria included contraindications for the use of the adalimumab pen as outlined in the latest version of Summary of Product Characteristics (SPC), as well as for the use of biologics according to the Austrian Treatment Recommendations. Patients were excluded if they were simultaneously participating in another study or clinical trial. Intervention and study design
This was a post-marketing observational study conducted in a prospective, single-country, multicenter format. The study is registered in the U.S. National Institutes of Health database, ClinicalTrials.gov identifier NCT01084668. The patients received adalimumab as prescribed by the treating physician in accordance with the terms of the local marketing authorization with regard to dose, population and indication. Washout periods prior to the first adalimumab dose following previous biologic therapy were calculated according to the half-life of the respective biologic (etanercept >21 days, infliximab >56 days, efalizumab >42 days).6,16,17 Data collection took place during treatment visits that were part of the normal course of care and did not require any patient intervention beyond usual care. After therapy initiation, six visits were recorded over a period of 12 month, at approximately week 4, 12, 24, 36 and 52. Outcome measures
To obtain reliable data on disease severity in patients with moderate to severe chronic plaque psoriasis, we used validated scoring systems [Psoriasis Area and Severity Index (PASI); Nail Psoriasis Severity Index (NAPSI)] and quality-of-life (QoL) questionnaires [Dermatology Life Quality Index (DLQI)]. The primary objective of this study was to evaluate the 1-year effectiveness of adalimumab by using the PASI in patients who were pre-treated with efalizumab, infliximab, or etanercept and who either never achieved satisfactory response; achieved satisfactory response initially, but lost it over time; discontinued treatment due to intolerance/side effect(s); or had other reasons; for example, restart after the regular stop of etanercept or withdrawal of efalizumab from the market in 2009. Our secondary objectives were the evaluation of QoL using the DLQI score and the evaluation of improvement in NAPSI score. Finally, the safety of adalimumab and local tolerability when administered as a pen were evaluated by recording the incidence of adverse events (AEs) and local reactions.
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Statistical analysis
All parameters were analyzed descriptively. No confirmatory statistical testing was applied. An observed case approach was applied for all variables and missing data were not replaced. Statistical analysis was performed using the all-treated (AT) analysis population, comprising all patients with at least one application of adalimumab. Data were summarized with respect to demographic and baseline characteristics; disease history, including previous therapies; effectiveness and safety observations. The summary statistics included the number (%) of patients for categorical variables and mean, standard deviation (SD), median and minimum and maximum for continuous variables. For primary and secondary outcome measures, data of the prospective observation period (active phase) were used. All AEs were documented and analyzed descriptively and the incidence of AEs was summarized. The time to first PASI50/75/90/100 response from baseline was calculated using the Kaplan–Meier method.
Results Patients
This study was initiated in November 2008 and the last patient completed the last visit in April 2011. Eight sites enrolled 46 patients in the study. Forty-two patients who had no prior exposure to adalimumab received more than one treatment dose and were analyzed. The most common reasons for switching to adalimumab from etanercept, infliximab or
Table 1 Baseline demographic and disease characteristics (n = total number of patients per visit) AT- all treated AT analysis population (N = 42) Male sex, n (%)
27 (64.3)
Age (years), Mean SD
47.1 11.5
Median (min–max)
46.0 (28–77)
Duration of plaque Ps (years), Mean SD
23.7 13.3
Median (min–max)
3
efalizumab were unsatisfactory response to prior therapy (n = 6), the loss of response over time (n = 10), restart after regular stop of etanercept (n = 6), and adverse events (n = 5). Fifteen patients were switched to adalimumab for other reasons. A total of 33 patients (78.6%) completed all six visits of the study. Patients in the study were predominantly male (64.3%), the mean age of patients was 47 years, and patients had plaque psoriasis for an average of 23.7 years (Table 1). Nineteen patients (45.2%) had psoriatic nail manifestations. All patients had a normal chest X-ray at baseline. Thirty-eight of 39 patients who were tested had a negative purified protein derivative (PPD) skin test. The PPD skin test was not performed in three patients out of 42 treated patients. All patients had taken prior biologic medication (etanercept, infliximab or efalizumab), six patients had additionally received a classic systemic therapy (methotrexate), and another two patients had received phototherapy. The mean duration of prior therapy with etanercept, infliximab and efalizumab was 643.9, 431.0, and 914.4 days, respectively. The mean PASI score at baseline was 15.5 and the mean DLQI score was 13.8. The mean NAPSI score at baseline was 15.4 and the mean NAPSI score in the subgroup of patients with nail psoriasis was 29.0. Nine patients terminated the study prematurely because of a lack of effectiveness (n = 5) and other reasons (noncompliance, n = 1; patient decision, n = 1; dissatisfaction/pain on injection, n = 1; and pregnancy, n = 1). Among 42 patients, eight patients (19%) used a concomitant anti-psoriatic medication, 6 (14.3%) received corticosteroids and topical preparations, and 6 (14.3%) emollients and protectives alone or in combination. Four patients (9.5%) were on concomitant systemic antihistaminic, 3 (7.1%) on anti-inflammatory and 3 (7.1%) on immunosuppressive therapy. Unspecified herbals were applied by two patients (4.8%) and one patient used some other dermatological preparation (2.4%). Nine patients received concomitant medication for other concomitant diseases like hypertension or cardiac disease.
24.5 (1–65) n = 41
Effectiveness
Mean SD
15.5 11.4
Median (min–max)
13.8 (0–53.9)
Psoriasis Area and Severity Index scores can range from 0.0 to 72.0, with the highest score representing complete erythroderma of the severest possible degree. Figure 1 shows that PASI scores decreased from baseline at each subsequent study visit. At the end-of-study visit (week 52), a mean reduction of 12.5, corresponding to mean percentage reduction of 74.3%, was observed, demonstrating an improvement in disease severity throughout the study. Approximately half of all treated patients achieved a PASI50 response by week 4, a PASI75 response at week 12, and a PASI90 response at week 24 (Fig. 2). Disregarding the patients who dropped out, the proportion of patients who achieved at least 75% improvement in PASI score increased from 16.7% at week
PASI score at baseline
DLQI score at baseline Mean SD Median (min–max) NAPSI score at baseline Mean SD Median (min–max) Primary non-responders, n (%)
n = 36 13.8 8.3 13.5 (0–29) n = 34 15.4 24.0 3.0 (0–80) 6 (14.3)
Secondary non-responders, n (%)
10 (23.8)
Pre-treatment with Etanercept, n (%)
22 (52.4)
Pre-treatment with Infliximab, n (%) Pre-treatment with Efalizumab, n (%)
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5 (11.9) 15 (35.7)
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PASI score
4
PASI score by visit
25 20 15 10 5 0 Week 0 (N = 41)
Week 4 (N = 36)
Week 12 (N = 31)
Week 24 (N = 31)
Mean PASI score
Week 36 (N = 28)
Week 52 (N = 27)
Early terminaƟon (N = 6)
Median PASI score
Figure 1 Psoriasis area and severity index score by visit (N values are the total number of patients per visit).
ProporƟon of paƟents with PASI50/PASI75/PASI90/PASI100 response 100 90 80
PaƟents, %
70 60 50 40 30 20
Proportion of subjects with already a PASI 75 response
Week 52 (N = 26)
Week 36 (N = 28)
Week 12 (N = 31)
Week 24 (N = 31)
Week 4 (N = 36)
Week 52 (N = 26)
Week 24 (N = 31)
Week 36 (N = 28)
Week 4 (N = 36)
Week 12 (N = 31)
Week 52 (N = 26)
Week 36 (N = 28)
Week 12 (N = 31)
Week 24 (N = 31)
Week 4 (N = 36)
Week 52 (N = 26)
Week 36 (N = 28)
Week 24 (N = 31)
Week 12 (N = 31)
0
Week 4 (N = 36)
10
Figure 2 Proportion of patients with improvement in psoriasis area and severity index of ≥50%, ≥75%, ≥90%, or 100% from baseline to weeks 4, 12, 24, 36, and 52, respectively.
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 0
50
100
150 I
200 250 300 Time [days]
350
400
Censored observations
4 to 88.5% at week 52 (Fig. 2). At week 4, a total of 5.6% of patients had a PASI90 response versus 69.2% of patients at week 52. At the end-of-study visit, 42.3% of all patients achieved a PASI100 response.
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450
500
Figure 3 Time to first PASI75 response – Kaplan–Meier curve (AT analysis population).
According to Kaplan–Meier, the analysis indicated that the first patient achieved a PASI75 response after 29 days of treatment and approximately 50% of patients achieved a PASI75 response by 168 days (Fig. 3). The median times to PASI50/90/
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DQLI score
100 responses were estimated to be 84, 249, and 382 days, respectively. Kaplan–Meier curves refer to the individual patient time, considering the common temporal deviations from the visit time schedule according to the protocol. Among 22 patients who were switched from etanercept to adalimumab, three were primary, eight were secondary nonresponders to etanercept .The remaining 11 etanercept patients were switched for some other reason. All primary etanercept non-responders completed the 52-weeks observation period and had a median improvement in PASI score of 98.2%. Four of the secondary etanercept non-responders completed the study and had a median PASI score improvement of 100% in week 52. Two patients of this group terminated study prematurely, as their disease failed to improve. Additional two patients were not evaluated at week 52 and for the remaining one patient a false PASI score was entered by the physician. In the infliximabswitch group, one patient was designated as a primary nonresponder and had a PASI improvement of 91.6% in week 52 and one as a secondary non-responder, who terminated the study earlier due to treatment failure. Three infliximab patients were switched to adalimumab for some other reason. Two efalizumab switch patients were primary and one was a secondary non-responder; the remaining 12 patients were switched to adalimumab for other reasons, the most common one being withdrawal of efalizumab from the market by the head authority. Two primary efalizumab non-responders did not respond to adalimumab therapy either; in contrast they experienced worsening of their psoriasis. The secondary non-responder achieved PASI improvement of 91.1% at week 52. In general, non-responders to TNF-a blockers had a more pronounced improvement in PASI score at week 52 (94.6% on average for the whole group) than efalizumab non-responders (median PASI improvement at week 52:91.1). DLQI scores can range from 0 to 30, with decreased scores indicating improvements in disease-related QoL. In this study, patients treated with adalimumab achieved a mean reduction of 11.1, which corresponds to a mean percentage reduction of 81.6% at week 52 (Fig. 4).
Figure 4 Dermatology life quality index score by visit (N values are the total number of patients per visit).
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20 18 16 14 12 10 8 6 4 2 0
Nail Psoriasis Severity Index scores can range from 0 to 80, with higher scores representing higher psoriasis nail involvement. Mean reduction in NAPSI score for all patients was 11.4 corresponding to mean percent reduction of 83.6%. Regarding the patients with nail Ps whose NAPSI score was greater than 0 at more than one visit (n = 18; Fig. 5), the mean reduction in NAPSI score at week 52 was 20.2 and the mean percent reduction was 83.6%. At the end of the study, the investigator evaluated the global effectiveness of adalimumab based on the results of PASI, DLQI, and NAPSI assessments. The effectiveness of adalimumab for regular study completers and early terminations (N = 42) was considered ‘excellent’ or ‘sufficient’ for 78.6% of patients (n = 33), ‘moderate’ for 7.1% of patients (n = 3), and ‘unsatisfactory’ for 14.3% of patients (n = 6). Safety
On average, 24.7 injections of adalimumab per patient were administered over a mean period of 331.0 days. The mean cumulative adalimumab dosage per patient throughout the study was 1021.0 mg. During the study, 66.9% of patients took more than one concomitant medication (CM). The most frequently reported CMs, according to Anatomic Therapeutic Chemical (ATC) level 2, were agents acting on the renin-angiotensin system, anti-psoriatic agents, and acid-related disorder drugs in 21.4%, 19.0%, and 16.7% of patients, respectively. Overall, 17 adverse events (AEs) were reported by the investigators in nine patients (21.4%). All AEs were rated as mild or moderate in severity. The most common AEs were acute tonsillitis and nasopharyngitis, each reported by two patients. Six patients (14.3%) reported seven AEs that were considered to be related to adalimumab; almost all events (n = 5) were local reactions related to the injection site or skin and subcutaneous tissue disorders. The remaining events, which occurred in five patients (11.9%), were considered to be unrelated to therapy with adalimumab. The majority of the events (n = 12; 70.6%) were resolved by the end of the study. Only three serious AEs that
DLQI score by visit
Week 0 (N = 36)
Week 4 (N = 34)
Week 12 (N = 28)
Week 24 (N = 30)
Mean DLQI score
Week 36 (N = 26)
Median DLQI score
Week 52 (N = 27)
Early terminaon (N = 6)
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NAPSI score by visit (subgroup of paƟents with nail PS and a NAPSI score >0 at >= 1 visit) 35
NAPSI score
30 25 20 15 10 5 0 Week 0 (N = 18)
Week 4 (N = 16)
Week 12 (N = 15)
Week 24 (N = 15)
Mean NAPSI score
Week 36 (N = 12)
Median NAPSI score
were unrelated to adalimumab occurred in one patient: ‘ligament rupture’ (twice) and ‘arthroscopic surgery.’ According to the investigator’s evaluation at the end of the study, the safety of adalimumab was rated as ‘excellent’ or ‘sufficient’ in 97.6% of the patients (n = 41) and ‘moderate’ in one patient. Twenty-nine patients (87.9%) completed the study according to protocol and continued therapy with adalimumab after the end of the study. Reasons for discontinuing therapy included treatment failure (n = 2), adverse event (n = 1), and intended pregnancy (n = 1).
Discussion This study shows that chronic plaque psoriasis patients treated over a period of 1 year with adalimumab after they had interrupted their previous biological treatment with either TNF-a blockers like etanercept or infliximab, or with anti-CD11a antibody efalizumab, had a distinct reduction in the mean scores of effectiveness (PASI, DLQI and NAPSI), demonstrating an improvement in disease severity and QoL with treatment. Adalimumab was well tolerated and no new or unexpected safety concerns were identified during the observation period. All data were analyzed ‘as observed’. Even though it presents a weakness of the study, this is a common practice in non-interventional studies. The study population was predominantly male, which is in line with other published psoriasis trials with biologics. According to the study protocol, patients were allowed to receive a concomitant treatment with both topical and systemic anti-psoriatic treatment. Twelve patients out of 42 (28.6%) used concomitant corticosteroids, emollients, vitamin D topical treatment either alone or in combination. Most of them were prescribed by a physician to be used as necessary. In addition, 3 (7.1%) patients took oral antihistamines against pruritus and one patient received methotrexate due to psoriatic arthritis. The parallel use of topical treatments with adalimumab was studied in the randomized double-blind controlled BELIEVE trial7, where it was shown that the use of concomitant calcipotriole and betamethasone can be beneficial in the initial treatment phase. However,
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Week 52 (N = 13)
Early terminaƟon (N = 2)
Figure 5 Numbers presented are from a subgroup of patients with nail psoriasis and a nail psoriasis severity index score of >0 at ≥1 visit (N values are the total number of patients per visit).
this effect can no longer be observed after 8 weeks of treatment. In accordance to these findings, most of the patients from our study (10/14) stopped using the topical therapy before the end of the observational period. A subanalysis of the BELIEVE study7 described a rapid and sustainable response to adalimumab therapy after switching from other TNF- a blockers: at week 16, 61.7% of the TNF-aexperienced patients in this study achieved a PASI 75 response. The response to adalimumab in this patient population was clinically meaningful regardless of which previous TNF-a blockers had been used, the number of prior anti-TNF-a therapies, or reasons for discontinuation of prior anti-TNF-a therapies. In addition, there are several open-label uncontrolled studies that focused on the effectiveness and safety of biologic therapy in patients with plaque psoriasis who had previously failed therapy with one or more biologic agents. A multicenter study by Bissonnette et al.8 in 85 patients with plaque psoriasis who had failed to achieve or lost a response to etanercept noted a PASI75 improvement of clinical symptoms in approximately 52% of patients 24 weeks after switching to adalimumab. In a recent study by Strober et al.,9 patients with chronic plaque psoriasis with a suboptimal response to etanercept discontinued therapy 11–17 days before receiving adalimumab. After 16 weeks, 49% of patients achieved a Physician Global Assessment (PGA) score of clear or almost clear. Although all of these studies show a beneficial effect of transitioning therapy from etanercept to adalimumab, response rates appear to be lower in comparison to our study. This may be due to differences in baseline characteristics of the patient populations or in the pre-treatments and statistical analysis applied. A recent study by Fonseca et al.10 addressed the influence of previous etanercept failure on the effectiveness and safety of adalimumab in psoriasis patients in a real-world setting. Authors concluded that previous etanercept failure does not seem to jeopardize the success and safety of subsequent adalimumab treatment. In line with these findings our study shows that adalimumab therapy was successful in both primary and secondary non-responders who had been previously treated with any of the two anti-TNF-a agents. In contrast,
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Adalimumab treatment of plaque psoriasis
patients who had never achieved a satisfactory response to efalizumab did not benefit from switch to adalimumab therapy. In general, the non-responder population of patients switching from the TNF-a inhibitors as group responded a bit better to adalimumab treatment (median PASI improvement at week 52: 98.2%) than patients who were switched from efalizumab due to lack of clinical response (median PASI improvement at week 52: 91.1%). However, the study population was not large enough to allow for precise conclusions on this topic. In patients with other disease states, such as rheumatoid arthritis, it has been noted that adalimumab restores effectiveness after a loss of response to other TNF-a blockers, including infliximab.11 Other forms of therapy transitioning in patients with plaque psoriasis with primary or secondary failure to a biologic treatment have also been studied. A majority of patients (54.5%) given infliximab after losing response to etanercept achieved a PASI75 response after 26 weeks.12 A switch from infliximab to etanercept can also be beneficial, although the study that noted these results was a small open-label study with a short follow-up period.13 The Vender study (2011)14 noted a successful treatment transition to etanercept upon loss of response to adalimumab in 10 patients. Therapy transitioning possibilities are described in detail and discussed in a consensus report by Mrowietz et al.5 These studies indicate that switching from one TNF-a blocker to another may still elicit a response, even though these therapeutic agents share the same molecular target. This may be because the differences between biologics lie not only in their target molecules, but also in their inherent properties (i.e. structure, absorption, distribution, and clearance mechanisms and rates) or in the dosage and administration regimens (i.e. dose amount, administration frequency, and route of administration).15 Despite the fact that all TNF-a blockers have the same target molecule, these agents are structurally different from one another. Infliximab and adalimumab are both monoclonal antibodies, but whereas infliximab is a murine-human chimeric antibody that combines the variable regions of a murine antibody with the constant region of human IgG1, adalimumab is an antibody with a fully human sequence.16,17 In contrast, etanercept is a fusion protein that combines the human TNF p75 receptor with the Fc domain of human IgG1.18 Since even small differences at the Fab binding region of antibodies can affect the specificity, affinity and epitope of the target molecule,19 the structural diversity of TNF-a blockers can significantly influence their pharmacologic properties. This is reflected in the different binding affinities of these molecules to the TNF-a. Even though all three TNF-a blockers bind to both the soluble (sTNF-a) and transmembrane form (tmTNF-a) of the TNF-a, it seems that etanercept binds to the tmTNF-a with a lower affinity.20 However, this does not seem to be the major factor that contributes to the variations in clinical effectiveness.21
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Furthermore, structurally distinct TNF-a blockers are capable of eliciting different immune responses. Owing to the presence of the CH1 domain of IgG1, which is crucial for complement activation, monoclonal antibodies can trigger complementdependent cytotoxicity (CDC), whereas etanercept lacks this sequence, and therefore does not induce CDC. Interestingly, although all three TNF-a blocker contain CH2 and CH3 domains, which are necessary for binding of the IgG Fc fragment to the respective receptor on natural killer cells, it seems that the monoclonal antibodies possess a stronger affinity to trigger antibody-dependent cell-mediated cytotoxicity.22 Yet another difference regarding the action of anti-TNF-a biologics on tmTNF-a is derived from the ability of the monoclonal antibodies to cross-link 2 tmTNF-a trimers and bring about apoptosis in the target cell via reverse signalling.23 Conversely, a study by Brunner et al.24 shows that an intravenous application of infliximab does not lead to increased cell death of TNF-aproducing cells in lesional psoriatic skin. Further investigations are necessary to determine the role of cell death in the mode of action of TNF-a blockers. Structural variations among TNF-a blockers also affect their specificity: while infliximab and adalimumab bind only TNF-a, etanercept can also target and bind lymphotoxin-a, also known as TNF-b. The clinical relevance of this binding remains unclear.20 Additionally, differences in drug administration can also contribute to the distinct pharmacokinetic profiles of the TNF-a blockers. Whereas infliximab is administered intravenously, adalimumab and etanercept are administered subcutaneously.16–18 Thus, high peaks, low minimums and high peak-to-trough ratios can be observed after the administration of infliximab. This is in contrast to the smooth and uniform concentration–time profiles seen at steady state with etanercept and adalimumab.15 Finally, differences in drug clearance (e.g. due to the presence of anti-drug antibodies to the specific biologic) may offer another explanation for treatment response after switching between two therapeutic molecules that share the same molecular target.25 In conclusion, our study demonstrates the effectiveness and safety of adalimumab for up to 1 year in patients with moderate to severe chronic plaque psoriasis who switched from another biologic agent. Treatment with adalimumab resulted in high rates of patient acceptance, leading to therapy continuation after the end of the study in the majority of the patients. In the absence of large randomized blinded trials, this study offers additional evidence that supports a possible therapeutic benefit in the transitioning from one biologic drug to another in a selected population of patients who were non-responders to initial treatment with a biologic agent.
Acknowledgements Mrs. Birgit Winninger from the ‘Dr. Robert Heinz and Partner’ company is gratefully acknowledged for medical writing services.
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References 1 Greaves MW, Weinstein GD. Treatment of psoriasis. New Engl J Med 1995; 332: 581–588. 2 Kim N, Thrash B, Menter A. Comorbidities in psoriasis patients. Semin Cutan Med Surg 2010; 29: 10–15. 3 Camp RDR. Psoriasis. In Champion RH, Burton JL, Burns DA, Breathnach SM, eds. Textbook of Dermatology, 6th edn. Blackwell Science Ltd, Oxford, 1998: 1589–1649. 4 Nast A, Boehncke WH, Mrowietz U et al. S3 – Guidelines on the treatment of psoriasis vulgaris (English version). Update. J Dtsch Dermatol Ges 2012; 10(suppl 2): S1–S95. 5 Mrowietz U, de Jong EM, Kragballe K, Langley R, Nast A, Puig L, Reich K, Schmitt J, Warren RB. A consensus report on appropriate treatment optimization and transitioning in the management of moderate-to-severe plaque psoriasis. J Eur Acad Dermatol Venereol 2014; 28: 438–53. 6 Raptiva (efalizumab). EPAR product information. [WWW document] 2009. URL http://www.ema.europa.eu/docs/en_GB/document_library/ EPAR_-_Product_Information/human/000542/WC500057853.pdf (last assessed: 30 November 2014). 7 Ortonne JP1, Chimenti S, Reich K. et al. Efficacy and safety of adalimumab in patients with psoriasis previously treated with anti-tumour necrosis factor agents: subanalysis of BELIEVE. J Eur Acad Dermatol Venereol 2011; 25: 1012–1020. 8 Bissonnette R, Bolduc C, Poulin Y, Guenther L, Lynde CW, Maari C. Efficacy and safety of adalimumab in patients with plaque psoriasis who have shown an unsatisfactory response to etanercept. J Am Acad Dermatol 2010; 63: 228–234. 9 Strober BE, Poulin Y, Kerdel FA et al. Switching to adalimumab for psoriasis patients with a suboptimal response to etanercept, methotrexate, or phototherapy: efficacy and safety results from an open-label study. J Am Acad Dermatol 2011; 64: 671–681. 10 Fonseca E, Iglesias R, Paradela S et al. Efficacy and safety of adalimumab in psoriatic patients previously treated with etanercept in a real-world setting. J Dermatolog Treatment 2014 Jul; 1: 1–6. 11 Ernestam S, Lindblad S, Bratt J, Klareskog L, van Vollenhoven RF. Adalimumab (Humira) restores clinical response in patients with secondary loss of efficacy from infliximab (Remicade) or etanercept (Enbrel): results from the STURE registry at Karolinska University Hospital. Scand J Rheumatol 2005; 34: 353–358. 12 Gottlieb AB, Kalb RE, Blauvelt A et al. The efficacy and safety of infliximab in patients with plaque psoriasis who had an inadequate response to etanercept: results of a prospective, multicenter, open-label study. J Am Acad Dermatol 2012; 67: 642–650. 13 Pitarch G, Sanchez-Carazo JL, Mahiques L, Oliver V. Efficacy of etanercept in psoriatic patients previously treated with infliximab. Dermatology 2008; 216: 312–316.
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14 Vender R. An open-label, prospective cohort pilot study to evaluate the efficacy and safety of etanercept in the treatment of moderate to severe plaque psoriasis in patients who have not had an adequate response to adalimumab. J Drugs Dermatol 2011; 10: 396–402. 15 Nestorov I. Clinical pharmacokinetics of TNF antagonists: how do they differ? Semin Arthritis Rheum 2005; 34(suppl 1): 12–18. 16 Humira (adalimumab). EPAR product information. [WWW document] 2014. URL http://www.ema.europa.eu/docs/en_GB/document_library/ EPAR_-_Product_Information/human/000481/WC500050870.pdf (last assessed: 30 November 2014). 17 Remicade (infliximab). EPAR product information. [WWW document] 2009. URL http://www.ema.europa.eu/docs/en_GB/document_library/ EPAR_-_Product_Information/human/000240/WC500050888.pdf (last assessed: 30 November 2014). 18 Enbrel (etanercept). EPAR product information. [WWW document] 2009. URL http://www.ema.europa.eu/docs/en_GB/document_library/ EPAR_-_Product_Information/human/000262/WC500027361.pdf (last assessed: 30 November 2014). 19 Tomoyuki I, Hiroyuki T, Taichi K, Zenjiro S, Shinya I, Kunihiro H. Engineering the variable region of therapeutic IgG antibodies. MAbs 2011; 3: 243–252. 20 Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 2008; 117: 244–279. 21 Kaymakcalan Z, Sakorafas P, Bose S et al. Comparisons of affinities, avidities, and complement activation of adalimumab, infliximab, and etanercept in binding to soluble and membrane tumor necrosis factor. Clin Immunol 2009; 131: 308–316. 22 Sterry W, van de Kerkhof P. Is ‘class effect’ relevant when assessing the benefit/risk profile of a biologic agent? J Eur Acad Dermatol Venereol 2012; 26(suppl 5): 9–16. 23 Horiuchi T, Mitoma H, Harashima S, Tsukamoto H, Shimoda T. Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents. Rheumatology (Oxford) 2010; 49: 1215–1228. 24 Brunner PM, Koszik F, Reininger B, Kalb ML, Bauer W, Stingl G. Infliximab induces downregulation of the IL-12/IL-23 axis in 6-sulfo-LacNac (slan)(+) dendritic cells and macrophages. J Allergy Clin Immunol 2013; 132: 1184–1193. e8. 25 Vincent FB, Morand EF, Murphy K, Mackay F, Mariette X, Marcelli C. Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective. Ann Rheum Dis 2013; 72: 165–178.
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